WorldWideScience

Sample records for biopharmaceutics

  1. The state of biopharmaceutical manufacturing.

    Science.gov (United States)

    Molowa, David T; Mazanet, Rosemary

    2003-01-01

    The manufacturing of protein-based biopharmaceuticals is done in bacterial or mammalian cell cultures. While bacterial cultures are inexpensive, dependable, and approved by regulatory authorities, many complex proteins cannot be manufactured this way. Complex proteins must be manufactured in mammalian cell cultures to produce active products. Mammalian cell culture capacity is limited and has slowed the delivery of necessary biopharmaceutical products to patients. The nature of the production capacity problem and future outlook are critically examined.

  2. Biopharmaceuticals as Challenges to the Regulatory System

    NARCIS (Netherlands)

    Ebbers, H.C.

    2012-01-01

    Biopharmaceuticals differ from small molecules in terms of structure and pharmacology. Furthermore, they are also prescribed for different patient populations. The protein nature of biopharmaceuticals makes them especially prone for immunological reactions and their safety profile may be affected by

  3. Risk Management in Biopharmaceutical Supply Chains

    OpenAIRE

    Ma, Yao

    2011-01-01

    Biopharmaceutical supply chains present considerable complexity issue for the formulation of optimal plans due to significant uncertainty in the supply chain. The primary goal of biopharmaceutical supply chain planning is to provide reliable supply to patients while coping with various supply chain risks. In chapter 1 first I discuss the key elements and basic characteristics of the biopharmaceutical supply chain . Then I present the major challenges in biopharmaceutical supply chain planning...

  4. Next Generation Biopharmaceuticals: Product Development.

    Science.gov (United States)

    Mathaes, Roman; Mahler, Hanns-Christian

    2018-04-11

    Therapeutic proteins show a rapid market growth. The relatively young biotech industry already represents 20 % of the total global pharma market. The biotech industry environment has traditionally been fast-pasted and intellectually stimulated. Nowadays the top ten best selling drugs are dominated by monoclonal antibodies (mABs).Despite mABs being the biggest medical breakthrough in the last 25 years, technical innovation does not stand still.The goal remains to preserve the benefits of a conventional mAB (serum half-life and specificity) whilst further improving efficacy and safety and to open new and better avenues for treating patients, e.g., improving the potency of molecules, target binding, tissue penetration, tailored pharmacokinetics, and reduced adverse effects or immunogenicity.The next generation of biopharmaceuticals can pose specific chemistry, manufacturing, and control (CMC) challenges. In contrast to conventional proteins, next-generation biopharmaceuticals often require lyophilization of the final drug product to ensure storage stability over shelf-life time. In addition, next-generation biopharmaceuticals require analytical methods that cover different ways of possible degradation patterns and pathways, and product development is a long way from being straight forward. The element of "prior knowledge" does not exist equally for most novel formats compared to antibodies, and thus the assessment of critical quality attributes (CQAs) and the definition of CQA assessment criteria and specifications is difficult, especially in early-stage development.

  5. Bioethical issues in the development of biopharmaceuticals

    Directory of Open Access Journals (Sweden)

    Todorović Zoran

    2012-01-01

    Full Text Available Development of biopharmaceuticals is a challenging issue in bioethics. Unlike conventional, small molecular weight drugs, biopharmaceuticals are proteins derived from DNA technology and hybrid techniques with complex three dimensional structures. Immunogenicity of biopharmaceuticals should always be tested in clinical settings due to low predictive value of preclinical animal models. However, non-human primates (NHP and transgenic mice could be used to address certain aspects of immunogenicity. Substantial efforts have been made to reduce NHP use in biopharmaceutical drug development, e.g. study design improvements and changes in regulatory policy. In addition, several expert groups are active in this field (e.g. NC3Rs, BioSafe, and Biopharmaceutical Technical Group. Despite that, there is an increasing trend of use of NHP in preclinical safety testing of biopharmaceuticals, especially regarding monoclonal antibodies. Other potential bioethical issues related biopharmaceutical drug development are their cost/effectiveness ratio, clinical safety assessment, production of biosimilars, and comparison of their efficacy with placebo in countries without intention to market. Identification of the human genome has opened many new bioethical issues. Development of biopharmaceuticals is an important bioethical issue for several reasons. It connects all aspects of contemporary bioethics: bio­medicine (e.g. clinical trials in vulnerable subjects, animal welfare and the most recent ad­vances in biotechnology. In particular, biopharmaceutical drug development is a challenging issue regarding treatment of rare diseases.

  6. Biosurfactants in cosmetics and biopharmaceuticals.

    Science.gov (United States)

    Varvaresou, A; Iakovou, K

    2015-09-01

    Biosurfactants are surface-active biomolecules that are produced by various micro-organisms. They show unique properties i.e. lower toxicity, higher biodegradability and environmental compatibility compared to their chemical counterparts. Glycolipids and lipopeptides have prompted application in biotechnology and cosmetics due to their multi-functional profile i.e. detergency, emulsifying, foaming and skin hydrating properties. Additionally, some of them can be served as antimicrobials. In this study the current status of research and development on rhamnolipids, sophorolipids, mannosyloerythritol lipids, trehalipids, xylolipids and lipopeptides particularly their commercial application in cosmetics and biopharmaceuticals, is described. © 2015 The Society for Applied Microbiology.

  7. Small and Medium Enterprises and Biopharmaceutical Innovations ...

    African Journals Online (AJOL)

    Small and Medium Enterprises and Biopharmaceutical Innovations in Africa: ... through biotechnological processes with links to biological sources especially those of live ... There are more than 500 biopharmaceutical products that have been ... By Country · List All Titles · Free To Read Titles This Journal is Open Access.

  8. Continuous downstream processing of biopharmaceuticals.

    Science.gov (United States)

    Jungbauer, Alois

    2013-08-01

    Continuous manufacturing has been applied in many different industries but has been pursued reluctantly in biotechnology where the batchwise process is still the standard. A shift to continuous operation can improve productivity of a process and substantially reduce the footprint. Continuous operation also allows robust purification of labile biomolecules. A full set of unit operations is available to design continuous downstream processing of biopharmaceuticals. Chromatography, the central unit operation, is most advanced in respect to continuous operation. Here, the problem of 'batch' definition has been solved. This has also paved the way for implementation of continuous downstream processing from a regulatory viewpoint. Economic pressure, flexibility, and parametric release considerations will be the driving force to implement continuous manufacturing strategies in future. Copyright © 2013 Elsevier Ltd. All rights reserved.

  9. Small and Medium Enterprises and Biopharmaceutical Innovations ...

    African Journals Online (AJOL)

    Erah

    Benin City, 300001 Nigeria. All rights ... are challenges facing African Small and Medium Enterprises (SMEs) in biopharmaceutical industry, the ... Network for Drug and Diagnostics recognizes .... functionality is in place, integration into the.

  10. Process analytical technology (PAT) for biopharmaceuticals

    DEFF Research Database (Denmark)

    Glassey, Jarka; Gernaey, Krist; Clemens, Christoph

    2011-01-01

    Process analytical technology (PAT), the regulatory initiative for building in quality to pharmaceutical manufacturing, has a great potential for improving biopharmaceutical production. The recommended analytical tools for building in quality, multivariate data analysis, mechanistic modeling, novel...

  11. Bioanalytical LC-MS/MS of protein-based biopharmaceuticals

    NARCIS (Netherlands)

    Broek, I. van den; Niessen, W.M.A.; Dongen, W.D. van

    2013-01-01

    Biotechnology increasingly delivers highly promising protein-based biopharmaceutical candidates to the drug development funnel. For successful biopharmaceutical drug development, reliable bioanalytical methods enabling quantification of drugs in biological fluids (plasma, urine, tissue, etc.) are

  12. Cell Engineering and Molecular Pharming for Biopharmaceuticals

    Science.gov (United States)

    Abdullah, M.A; Rahmah, Anisa ur; Sinskey, A.J; Rha, C.K

    2008-01-01

    Biopharmaceuticals are often produced by recombinant E. coli or mammalian cell lines. This is usually achieved by the introduction of a gene or cDNA coding for the protein of interest into a well-characterized strain of producer cells. Naturally, each recombinant production system has its own unique advantages and disadvantages. This paper examines the current practices, developments, and future trends in the production of biopharmaceuticals. Platform technologies for rapid screening and analyses of biosystems are reviewed. Strategies to improve productivity via metabolic and integrated engineering are also highlighted. PMID:19662143

  13. Mammalian cell culture capacity for biopharmaceutical manufacturing.

    Science.gov (United States)

    Ecker, Dawn M; Ransohoff, Thomas C

    2014-01-01

    : With worldwide sales of biopharmaceuticals increasing each year and continuing growth on the horizon, the manufacture of mammalian biopharmaceuticals has become a major global enterprise. We describe the current and future industry wide supply of manufacturing capacity with regard to capacity type, distribution, and geographic location. Bioreactor capacity and the use of single-use products for biomanufacturing are also profiled. An analysis of the use of this capacity is performed, including a discussion of current trends that will influence capacity growth, availability, and utilization in the coming years.

  14. Traceability of biopharmaceuticals in spontaneous reporting systems

    DEFF Research Database (Denmark)

    Vermeer, Niels S; Straus, Sabine M J M; Mantel-Teeuwisse, Aukje K

    2013-01-01

    the period 2004-2010, including ADR reports from two major SRSs: the FDA Adverse Event Reporting System (FAERS) in the US and EudraVigilance (EV) in the EU. MAIN OUTCOME MEASURES: The availability of batch numbers was determined for biopharmaceuticals, and compared with small molecule drugs...

  15. High-Throughput Process Development for Biopharmaceuticals.

    Science.gov (United States)

    Shukla, Abhinav A; Rameez, Shahid; Wolfe, Leslie S; Oien, Nathan

    2017-11-14

    The ability to conduct multiple experiments in parallel significantly reduces the time that it takes to develop a manufacturing process for a biopharmaceutical. This is particularly significant before clinical entry, because process development and manufacturing are on the "critical path" for a drug candidate to enter clinical development. High-throughput process development (HTPD) methodologies can be similarly impactful during late-stage development, both for developing the final commercial process as well as for process characterization and scale-down validation activities that form a key component of the licensure filing package. This review examines the current state of the art for HTPD methodologies as they apply to cell culture, downstream purification, and analytical techniques. In addition, we provide a vision of how HTPD activities across all of these spaces can integrate to create a rapid process development engine that can accelerate biopharmaceutical drug development. Graphical Abstract.

  16. Plant-made vaccine antigens and biopharmaceuticals.

    Science.gov (United States)

    Daniell, Henry; Singh, Nameirakpam D; Mason, Hugh; Streatfield, Stephen J

    2009-12-01

    Plant cells are ideal bioreactors for the production and oral delivery of vaccines and biopharmaceuticals, eliminating the need for expensive fermentation, purification, cold storage, transportation and sterile delivery. Plant-made vaccines have been developed for two decades but none has advanced beyond Phase I. However, two plant-made biopharmaceuticals are now advancing through Phase II and Phase III human clinical trials. In this review, we evaluate the advantages and disadvantages of different plant expression systems (stable nuclear and chloroplast or transient viral) and their current limitations or challenges. We provide suggestions for advancing this valuable concept for clinical applications and conclude that greater research emphasis is needed on large-scale production, purification, functional characterization, oral delivery and preclinical evaluation.

  17. Health economics of market access for biopharmaceuticals and biosimilars.

    Science.gov (United States)

    Simoens, Steven

    2009-09-01

    This article discusses health economic challenges of research and development, registration, pricing and reimbursement of biopharmaceuticals and biosimilars. A literature search was carried out of PubMed, Centre for Reviews and Dissemination databases, Cochrane Database of Systematic Reviews and EconLit up to March 2009. The development process of biopharmaceuticals is risky, lengthy, complex and expensive. Registration is complicated by the inherent variation between biopharmaceuticals. Also, as biopharmaceuticals are likely to be efficacious in a subgroup of the patient population, there is a need to select the most responsive target population and to identify biomarkers. To inform pricing and reimbursement decisions, the development process needs to collect comparative data to calculate the incremental cost effectiveness and budget impact of biopharmaceuticals. There is a role for innovative mechanisms such as risk-sharing arrangements to reimburse biopharmaceuticals. Given that biosimilars are similar, but not identical to the reference biopharmaceutical, the development process needs to generate clinical trial data in order to gain marketing authorisation. From a health economic perspective, the question arises whether inherent differences between biopharmaceuticals and biosimilars produce differences in safety, effectiveness and costs: to date, this question is unresolved. The early inclusion of health economics in the process of developing biopharmaceuticals and biosimilars is imperative with a view to demonstrating their relative (cost) effectiveness and informing registration, pricing and reimbursement decisions.

  18. The market of biopharmaceutical medicines: A snapshot of a diverse industrial landscape

    NARCIS (Netherlands)

    Moorkens, E. (Evelien); Meuwissen, N. (Nicolas); Huys, I. (Isabelle); P.J. Declerck (Paul); A.G. Vulto (Arnold); S. Simoens (Steven)

    2017-01-01

    textabstractBackground: Biopharmaceutical medicines represent a growing share of the global pharmaceutical market, and with many of these biopharmaceutical products facing loss of exclusivity rights, also biosimilars may now enter the biopharmaceutical market. Objectives: This study aims to identify

  19. Investigating investment in biopharmaceutical R&D

    Science.gov (United States)

    Carter, Percy H.; Berndt, Ernst R.; DiMasi, Joseph A.; Trusheim, Mark

    2016-01-01

    Recent studies have highlighted a reduction in projected financial returns associated with biopharmaceutical R&D, owing to decreased productivity, increases in costs and flattening revenue per new drug, prompting calls for dramatic revisions to R&D models. On the basis of previous financial modelling, the simplest hypothesis would be that new investment in such R&D should be minimal and focused on biologics in preference to small molecules, as the internal rate of return on investment for biologics projects has been reported to be higher. PMID:27616295

  20. Exploring the potential of Saccharomyces cerevisiae for biopharmaceutical protein production

    DEFF Research Database (Denmark)

    Wang, Guokun; Huang, Mingtao; Nielsen, Jens

    2017-01-01

    Production of recombinant proteins by yeast plays a vital role in the biopharmaceutical industry. It is therefore desirable to develop yeast platform strains for over-production of various biopharmaceutical proteins, but this requires fundamental knowledge of the cellular machinery, especially th...

  1. Delivery and Immunogenicity of Biopharmaceuticals for Vaccination or Therapy

    NARCIS (Netherlands)

    de Groot, A.M.

    2017-01-01

    Biopharmaceuticals (or biologicals) are a new class of drugs produced by the biotechnology field and offer many advantages compared to classical small molecule synthetic drugs. Biopharmaceuticals (BP) are from biological origin and may consist of proteins or peptides, nucleic acids such as RNA and

  2. Glycan characterization of biopharmaceuticals: Updates and perspectives

    Energy Technology Data Exchange (ETDEWEB)

    Planinc, Ana [Analytical Platform of the Faculty of Pharmacy and Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, Universite Libre de Bruxelles (ULB), Brussels (Belgium); Bones, Jonathan [Characterisation and Comparability Laboratory, NIBRT – The National Institute for Bioprocessing Research and Training, Foster Avenue, Mount Merrion, Blackrock, Co. Dublin (Ireland); Dejaegher, Bieke [Laboratory of Instrumental Analysis and Bioelectrochemistry, Faculty of Pharmacy, Université Libre de Bruxelles (ULB), Boulevard du Triomphe, B-1050 Brussels (Belgium); Department of Analytical Chemistry and Pharmaceutical Technology (FABI), Center for Pharmaceutical Research (CePhaR), Faculty of Medicines and Pharmacy, Vrije Universiteit Brussel - VUB, Laarbeeklaan 103, B-1090 Brussels (Belgium); Van Antwerpen, Pierre [Analytical Platform of the Faculty of Pharmacy and Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, Universite Libre de Bruxelles (ULB), Brussels (Belgium); Delporte, Cédric, E-mail: cedric.delporte@ulb.ac.be [Analytical Platform of the Faculty of Pharmacy and Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, Universite Libre de Bruxelles (ULB), Brussels (Belgium)

    2016-05-19

    Therapeutic proteins are rapidly becoming the most promising class of pharmaceuticals on the market due to their successful treatment of a vast array of serious diseases, such as cancers and immune disorders. Therapeutic proteins are produced using recombinant DNA technology. More than 60% of therapeutic proteins are posttranslationally modified following biosynthesis by the addition of N- or O-linked glycans. Glycosylation is the most common posttranslational modifications of proteins. However, it is also the most demanding and complex posttranslational modification from the analytical point of view. Moreover, research has shown that glycosylation significantly impacts stability, half-life, mechanism of action and safety of a therapeutic protein. Considering the exponential growth of biotherapeutics, this present review of the literature (2009–2015) focuses on the characterization of protein glycosylation, which has witnessed an improvement in methodology. Furthermore, it discusses current issues in the fields of production and characterization of therapeutic proteins. This review also highlights the problem of non-standard requirements for the approval of biosimilars with regard to their glycosylation and discusses recent developments and perspectives for improved glycan characterization. - Highlights: • Biopharmaceuticals have emerged as the new class of blockbuster drugs in the pharmaceutical industry. • More than 60% of the approved biopharmaceuticals are glycosylated. • Glycosylation has an effect on the efficacy and the safety of therapeutic glycoproteins. • N-glycosylation characterization of therapeutic glycoproteins is a regulatory requirement. • Biosimilar releases are increasing and demonstration of comparability poses challenges for N-glycosylation characterization.

  3. Glycan characterization of biopharmaceuticals: Updates and perspectives

    International Nuclear Information System (INIS)

    Planinc, Ana; Bones, Jonathan; Dejaegher, Bieke; Van Antwerpen, Pierre; Delporte, Cédric

    2016-01-01

    Therapeutic proteins are rapidly becoming the most promising class of pharmaceuticals on the market due to their successful treatment of a vast array of serious diseases, such as cancers and immune disorders. Therapeutic proteins are produced using recombinant DNA technology. More than 60% of therapeutic proteins are posttranslationally modified following biosynthesis by the addition of N- or O-linked glycans. Glycosylation is the most common posttranslational modifications of proteins. However, it is also the most demanding and complex posttranslational modification from the analytical point of view. Moreover, research has shown that glycosylation significantly impacts stability, half-life, mechanism of action and safety of a therapeutic protein. Considering the exponential growth of biotherapeutics, this present review of the literature (2009–2015) focuses on the characterization of protein glycosylation, which has witnessed an improvement in methodology. Furthermore, it discusses current issues in the fields of production and characterization of therapeutic proteins. This review also highlights the problem of non-standard requirements for the approval of biosimilars with regard to their glycosylation and discusses recent developments and perspectives for improved glycan characterization. - Highlights: • Biopharmaceuticals have emerged as the new class of blockbuster drugs in the pharmaceutical industry. • More than 60% of the approved biopharmaceuticals are glycosylated. • Glycosylation has an effect on the efficacy and the safety of therapeutic glycoproteins. • N-glycosylation characterization of therapeutic glycoproteins is a regulatory requirement. • Biosimilar releases are increasing and demonstration of comparability poses challenges for N-glycosylation characterization.

  4. Interplay of biopharmaceutics, biopharmaceutics drug disposition and salivary excretion classification systems

    Science.gov (United States)

    Idkaidek, Nasir M.

    2013-01-01

    The aim of this commentary is to investigate the interplay of Biopharmaceutics Classification System (BCS), Biopharmaceutics Drug Disposition Classification System (BDDCS) and Salivary Excretion Classification System (SECS). BCS first classified drugs based on permeability and solubility for the purpose of predicting oral drug absorption. Then BDDCS linked permeability with hepatic metabolism and classified drugs based on metabolism and solubility for the purpose of predicting oral drug disposition. On the other hand, SECS classified drugs based on permeability and protein binding for the purpose of predicting the salivary excretion of drugs. The role of metabolism, rather than permeability, on salivary excretion is investigated and the results are not in agreement with BDDCS. Conclusion The proposed Salivary Excretion Classification System (SECS) can be used as a guide for drug salivary excretion based on permeability (not metabolism) and protein binding. PMID:24493977

  5. Second International Conference on Accelerating Biopharmaceutical Development

    Science.gov (United States)

    2009-01-01

    The Second International Conference on Accelerating Biopharmaceutical Development was held in Coronado, California. The meeting was organized by the Society for Biological Engineering (SBE) and the American Institute of Chemical Engineers (AIChE); SBE is a technological community of the AIChE. Bob Adamson (Wyeth) and Chuck Goochee (Centocor) were co-chairs of the event, which had the theme “Delivering cost-effective, robust processes and methods quickly and efficiently.” The first day focused on emerging disruptive technologies and cutting-edge analytical techniques. Day two featured presentations on accelerated cell culture process development, critical quality attributes, specifications and comparability, and high throughput protein formulation development. The final day was dedicated to discussion of technology options and new analysis methods provided by emerging disruptive technologies; functional interaction, integration and synergy in platform development; and rapid and economic purification process development. PMID:20065637

  6. Separation science is the key to successful biopharmaceuticals.

    Science.gov (United States)

    Guiochon, Georges; Beaver, Lois Ann

    2011-12-09

    The impact of economic change, advances in science, therapy and production processes resulted in considerable growth in the area of biopharmaceuticals. Progress in selection of microorganisms and improvements in cell culture and bioreactors is evidenced by increased yields of the desired products in the complex fermentation mixture. At this stage the downstream process of extraction and purification of the desired biopharmaceutical requires considerable attention in the design and operation of the units used for preparative chromatography. Understanding of the process, optimization of column design and experimental conditions have become critical to the biopharmaceutical industry in order to minimize production costs while satisfying new regulatory requirements. Optimization of the purification of biopharmaceuticals by preparative liquid chromatography including an examination of column preparation and bed properties is the focus of this manuscript. Copyright © 2011 Elsevier B.V. All rights reserved.

  7. Capillary electrophoresis in the N-glycosylation analysis of biopharmaceuticals

    Czech Academy of Sciences Publication Activity Database

    Guttman, András

    2013-01-01

    Roč. 48, JUL-AUG (2013), s. 132-143 ISSN 0165-9936 Institutional support: RVO:68081715 Keywords : automated workflow * biopharmaceuticals * capillary electrophoresis Subject RIV: CB - Analytical Chemistry, Separation Impact factor: 6.612, year: 2013

  8. Follow-on biologics: competition in the biopharmaceutical marketplace.

    Science.gov (United States)

    Devine, Joshua W; Cline, Richard R; Farley, Joel F

    2006-01-01

    To describe the implications of a follow-on biologic approval process with focus on current stakeholders, implications of the status quo, and recommendations for future policy. A search using Medline, International Pharmaceutical Abstracts, Med Ad News, F-D-C Reports/Pink Sheets, and Google index directories was conducted with terms such as biologic, biopharmaceutical, generic, and follow-on. Articles pertaining to the follow-on biologic debate. By the authors. Over the past decade, the biopharmaceutical market has experienced substantial growth in the number of product approvals and sales. In contrast with prescription medications, biologic agents currently lack an abbreviated regulatory approval process. Evidence from the Drug Price Competition and Patent Term Restoration Act of 1984 suggests that reducing barriers to generic competition in the pharmaceutical market successfully increases generic market penetration and reduces overall prices to consumers. Although scientific and regulatory dissimilarities between biopharmaceuticals and other medications exist, a follow-on biologic approval process has the potential to play an important role in containing growth in pharmaceutical spending. In addition to biopharmaceutical and generic biopharmaceutical manufacturers, stakeholders with a vested interest in this debate include individual consumers who continue to bear the burden of spending increases in the pharmaceutical market. The debate over a follow-on process likely will be difficult as parties seek a balance between incentives for biopharmaceutical innovation, consumer safety, and affordability of existing biologic products.

  9. Biopharmaceutical potentials of Prosopis spp. (Mimosaceae, Leguminosa

    Directory of Open Access Journals (Sweden)

    Santhaseelan Henciya

    2017-01-01

    Full Text Available Prosopis is a commercially important plant genus, which has been used since ancient times, particularly for medicinal purposes. Traditionally, Paste, gum, and smoke from leaves and pods are applied for anticancer, antidiabetic, anti-inflammatory, and antimicrobial purposes. Components of Prosopis such as flavonoids, tannins, alkaloids, quinones, or phenolic compounds demonstrate potentials in various biofunctions, such as analgesic, anthelmintic, antibiotic, antiemetic, microbial antioxidant, antimalarial, antiprotozoal, antipustule, and antiulcer activities; enhancement of H+, K+, ATPases; oral disinfection; and probiotic and nutritional effects; as well as in other biopharmaceutical applications, such as binding abilities for tablet production. The compound juliflorine provides a cure in Alzheimer disease by inhibiting acetylcholine esterase at cholinergic brain synapses. Some indirect medicinal applications of Prosopis spp. are indicated, including antimosquito larvicidal activity, chemical synthesis by associated fungal or bacterial symbionts, cyanobacterial degradation products, “mesquite” honey and pollens with high antioxidant activity, etc. This review will reveal the origins, distribution, folk uses, chemical components, biological functions, and applications of different representatives of Prosopis.

  10. Production of biopharmaceutical proteins by yeast: Advances through metabolic engineering

    DEFF Research Database (Denmark)

    Nielsen, Jens

    2013-01-01

    Production of recombinant proteins for use as pharmaceuticals, so-called biopharmaceuticals, is a multi-billion dollar industry. Many different cell factories are used for the production of biopharmaceuticals, but the yeast Saccharomyces cerevisiae is an important cell factory as it is used for p...... production. The involvement of directed metabolic engineering through the integration of tools from genetic engineering, systems biology and mathematical modeling, is also discussed....... by yeast are human serum albumin, hepatitis vaccines and virus like particles used for vaccination against human papillomavirus. Here is given a brief overview of biopharmaceutical production by yeast and it is discussed how the secretory pathway can be engineered to ensure more efficient protein...

  11. Animal models for evaluation of oral delivery of biopharmaceuticals

    DEFF Research Database (Denmark)

    Harloff-Helleberg, Stine; Nielsen, Line Hagner; Nielsen, Hanne Mørck

    2017-01-01

    of systems for oral delivery of biopharmaceuticals may result in new treatment modalities to increase the patient compliance and reduce product cost. In the preclinical development phase, use of experimental animal models is essential for evaluation of new formulation designs. In general, the limited oral...... bioavailability of biopharmaceuticals, of just a few percent, is expected, and therefore, the animal models and the experimental settings must be chosen with utmost care. More knowledge and focus on this topic is highly needed, despite experience from the numerous studies evaluating animal models for oral drug...... delivery of small molecule drugs. This review highlights and discusses pros and cons of the most currently used animal models and settings. Additionally, it also looks into the influence of anesthetics and sampling methods for evaluation of drug delivery systems for oral delivery of biopharmaceuticals...

  12. Biopharmaceutical production: Applications of surface plasmon resonance biosensors.

    Science.gov (United States)

    Thillaivinayagalingam, Pranavan; Gommeaux, Julien; McLoughlin, Michael; Collins, David; Newcombe, Anthony R

    2010-01-15

    Surface plasmon resonance (SPR) permits the quantitative analysis of therapeutic antibody concentrations and impurities including bacteria, Protein A, Protein G and small molecule ligands leached from chromatography media. The use of surface plasmon resonance has gained popularity within the biopharmaceutical industry due to the automated, label free, real time interaction that may be exploited when using this method. The application areas to assess protein interactions and develop analytical methods for biopharmaceutical downstream process development, quality control, and in-process monitoring are reviewed. 2009 Elsevier B.V. All rights reserved.

  13. Multivariate PAT solutions for biopharmaceutical cultivation: current progress and limitations

    NARCIS (Netherlands)

    Mercier, S.M.; Diepenbroek, B.; Wijffels, R.H.; Streefland, M.

    2014-01-01

    Increasingly elaborate and voluminous datasets are generated by the (bio)pharmaceutical industry and are a major challenge for application of PAT and QbD principles. Multivariate data analysis (MVDA) is required to delineate relevant process information from large multi-factorial and multi-collinear

  14. An Intercompany Perspective on Biopharmaceutical Drug Product Robustness Studies.

    Science.gov (United States)

    Morar-Mitrica, Sorina; Adams, Monica L; Crotts, George; Wurth, Christine; Ihnat, Peter M; Tabish, Tanvir; Antochshuk, Valentyn; DiLuzio, Willow; Dix, Daniel B; Fernandez, Jason E; Gupta, Kapil; Fleming, Michael S; He, Bing; Kranz, James K; Liu, Dingjiang; Narasimhan, Chakravarthy; Routhier, Eric; Taylor, Katherine D; Truong, Nobel; Stokes, Elaine S E

    2018-02-01

    The Biophorum Development Group (BPDG) is an industry-wide consortium enabling networking and sharing of best practices for the development of biopharmaceuticals. To gain a better understanding of current industry approaches for establishing biopharmaceutical drug product (DP) robustness, the BPDG-Formulation Point Share group conducted an intercompany collaboration exercise, which included a bench-marking survey and extensive group discussions around the scope, design, and execution of robustness studies. The results of this industry collaboration revealed several key common themes: (1) overall DP robustness is defined by both the formulation and the manufacturing process robustness; (2) robustness integrates the principles of quality by design (QbD); (3) DP robustness is an important factor in setting critical quality attribute control strategies and commercial specifications; (4) most companies employ robustness studies, along with prior knowledge, risk assessments, and statistics, to develop the DP design space; (5) studies are tailored to commercial development needs and the practices of each company. Three case studies further illustrate how a robustness study design for a biopharmaceutical DP balances experimental complexity, statistical power, scientific understanding, and risk assessment to provide the desired product and process knowledge. The BPDG-Formulation Point Share discusses identified industry challenges with regard to biopharmaceutical DP robustness and presents some recommendations for best practices. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  15. The successes and challenges of open-source biopharmaceutical innovation.

    Science.gov (United States)

    Allarakhia, Minna

    2014-05-01

    Increasingly, open-source-based alliances seek to provide broad access to data, research-based tools, preclinical samples and downstream compounds. The challenge is how to create value from open-source biopharmaceutical innovation. This value creation may occur via transparency and usage of data across the biopharmaceutical value chain as stakeholders move dynamically between open source and open innovation. In this article, several examples are used to trace the evolution of biopharmaceutical open-source initiatives. The article specifically discusses the technological challenges associated with the integration and standardization of big data; the human capacity development challenges associated with skill development around big data usage; and the data-material access challenge associated with data and material access and usage rights, particularly as the boundary between open source and open innovation becomes more fluid. It is the author's opinion that the assessment of when and how value creation will occur, through open-source biopharmaceutical innovation, is paramount. The key is to determine the metrics of value creation and the necessary technological, educational and legal frameworks to support the downstream outcomes of now big data-based open-source initiatives. The continued focus on the early-stage value creation is not advisable. Instead, it would be more advisable to adopt an approach where stakeholders transform open-source initiatives into open-source discovery, crowdsourcing and open product development partnerships on the same platform.

  16. Biopharmaceutical insights of particulate emulsified systems - a prospective overview.

    Science.gov (United States)

    Katamreddy, Jyothshna Devi; Yalavarthi, Prasanna Raju; D, Subba Rao; Battu, Sowjanya; Peesa, Jaya Preethi

    2018-05-10

    During the twenty-first century, drug discovery is expanding rapidly and a large number of chemical moieties are recognized. Many of them are poorly soluble and hence related biopharmaceutical constraints are to be addressed systematically. Among novel approaches to resolving biopharmaceutical issues, micro- and nano-emulsified systems serve as the best strategy for delivering both hydrophobic and hydrophilic drugs owing to their greater solubilization and transportation capabilities. Of late, the unique physical and biopharmaceutical properties of these liquid isotropic homogenous systems have gained substantive research importance. In addition nano/micro lipid systems share structural and functional similarity with that of the physiological lipids which offer better tolerance ability in the body. In this context, this article provides information on the historical emergence of particulate emulsified systems, importance and rationale of selection of carriers. It also encompasses the physicochemical principles that are responsible for the elevation of therapeutic outcomes of delivery systems. Detailed and schematic absorption of these drug delivery systems is explained here. Gastro-intestinal biochemistry necessary in the understanding of digestion process, lipolytic products formed, micellar structures, enzymes, transporters, mechanism of cell uptake involved after subsequent oral absorption are also emphasized. In addition, this article also explains disposition and pharmacokinetic properties of emulsified systems with real-time therapeutic research outcomes. The influence of biochemical compositions and biopharmaceutical principles on absorption and disposition patterns of ME/NEs was described in the article for the interest of readers and young researchers.

  17. Biopharmaceutic Risk Assessment of Brand and Generic Lamotrigine Tablets.

    Science.gov (United States)

    Vaithianathan, Soundarya; Raman, Siddarth; Jiang, Wenlei; Ting, Tricia Y; Kane, Maureen A; Polli, James E

    2015-07-06

    The therapeutic equivalence of generic and brand name antiepileptic drugs has been questioned by neurologists and the epilepsy community. A potential contributor to such concerns is pharmaceutical quality. The objective was to assess the biopharmaceutic risk of brand name Lamictal 100 mg tablets and generic lamotrigine 100 mg tablets from several manufacturers. Lamotrigine was characterized in terms of the Biopharmaceutics Classification System (BCS), including aqueous solubility and Caco-2 permeability. A panel of pharmaceutical quality tests was also performed on three batches of Lamictal, three batches of Teva generic, and one batch of each of four other generics: appearance, identity, assay, impurity, uniformity of dosage units, disintegration, dissolution, friability, and loss on drying. These market surveillance results indicate that all brand name and generic lamotrigine 100 mg tablets passed all tests and showed acceptable pharmaceutical quality and low biopharmaceutic risk. Lamotrigine was classified as a BCS class IIb drug, exhibiting pH-dependent aqueous solubility and dissolution. At pH 1.2 and 4.5, lamotrigine exhibited high solubility, whereas lamotrigine exhibited low solubility at pH 6.8, including non-sink dissolution. Lamotrigine showed high Caco-2 permeability. The apparent permeability (Papp) of lamotrigine was (73.7 ± 8.7) × 10(-6) cm/s in the apical-to-basolateral (AP-BL) direction and (41.4 ± 1.6) × 10(-6) cm/s in the BL-AP direction, which were higher than metoprolol's AP-BL Papp of (21.2 ± 0.9) × 10(-6) cm/s and BL-AP Papp of (34.6 ± 4.6) × 10(-6) cm/s. Overall, lamotrigine's favorable biopharmaceutics from a drug substance perspective and favorable quality characteristics from a tablet formulation perspective suggest that multisource lamotrigine tablets exhibit a low biopharmaceutic risk.

  18. Modeling in biopharmaceutics, pharmacokinetics and pharmacodynamics homogeneous and heterogeneous approaches

    CERN Document Server

    Macheras, Panos

    2016-01-01

    The state of the art in Biopharmaceutics, Pharmacokinetics, and Pharmacodynamics Modeling is presented in this new second edition book. It shows how advanced physical and mathematical methods can expand classical models in order to cover heterogeneous drug-biological processes and therapeutic effects in the body. The book is divided into four parts; the first deals with the fundamental principles of fractals, diffusion and nonlinear dynamics; the second with drug dissolution, release, and absorption; the third with epirical, compartmental, and stochastic pharmacokinetic models, with two new chapters, one on fractional pharmacokinetics and one on bioequivalence; and the fourth mainly with classical and nonclassical aspects of pharmacodynamics. The classical models that have relevance and application to these sciences are also considered throughout. This second edition has new information on reaction limited models of dissolution, non binary biopharmaceutic classification system, time varying models, and interf...

  19. Biopharmaceutical industry-sponsored global clinical trials in emerging countries.

    Science.gov (United States)

    Alvarenga, Lenio Souza; Martins, Elisabeth Nogueira

    2010-01-01

    To evaluate biopharmaceutical industry-sponsored clinical trials placed in countries previously described as emerging regions for clinical research, and potential differences for those placed in Brazil. Data regarding recruitment of subjects for clinical trials were retrieved from www.clinicaltrials.gov on February 2nd 2009. Proportions of sites in each country were compared among emerging countries. Multiple logistic regressions were performed to evaluate whether trial placement in Brazil could be predicted by trial location in other countries and/or by trial features. A total of 8,501 trials were then active and 1,170 (13.8%) included sites in emerging countries (i.e., Argentina, Brazil, China, Czech Republic, Hungary, India, Mexico, Poland, Russia, South Korea, and South Africa). South Korea and China presented a significantly higher proportion of sites when compared to other countries (pattractiveness for biopharmaceutical industry-sponsored clinical trials.

  20. Safe handling of cytotoxic compounds in a biopharmaceutical environment.

    Science.gov (United States)

    Hensgen, Miriam I; Stump, Bernhard

    2013-01-01

    Handling cytotoxic drugs such as antibody-drug conjugates (ADCs) in a biopharmaceutical environment represents a challenge based on the potency of the compounds. These derivatives are dangerous to humans if they accidentally get in contact with the skin, are inhaled, or are ingested, either as pure compounds in their solid state or as a solution dissolved in a co-solvent. Any contamination of people involved in the manufacturing process has to be avoided. On the other hand, biopharmaceuticals need to be protected simultaneously against any contamination from the manufacturing personnel. Therefore, a tailor-made work environment is mandatory in order to manufacture ADCs. This asks for appropriate technical equipment to keep potential hazardous substances contained. In addition, clearly defined working procedures based on risk assessments as well as proper training for all personnel involved in the manufacturing process are needed to safely handle these highly potent pharmaceuticals.

  1. [Construction of biopharmaceutics classification system of Chinese materia medica].

    Science.gov (United States)

    Liu, Yang; Wei, Li; Dong, Ling; Zhu, Mei-Ling; Tang, Ming-Min; Zhang, Lei

    2014-12-01

    Based on the characteristics of multicomponent of traditional Chinese medicine and drawing lessons from the concepts, methods and techniques of biopharmaceutics classification system (BCS) in chemical field, this study comes up with the science framework of biopharmaceutics classification system of Chinese materia medica (CMMBCS). Using the different comparison method of multicomponent level and the CMMBCS method of overall traditional Chinese medicine, the study constructs the method process while setting forth academic thoughts and analyzing theory. The basic role of this system is clear to reveal the interaction and the related absorption mechanism of multicomponent in traditional Chinese medicine. It also provides new ideas and methods for improving the quality of Chinese materia medica and the development of new drug research.

  2. THE BIOPHARMACEUTICAL CLASSIFICATION SYSTEM (BCS): PRESENT STATUS AND FUTURE PROSPECTIVES

    OpenAIRE

    Budhwaar Vikaas; Nanda Arun

    2012-01-01

    The Biopharmaceutical classification system (BCS) was introduced By Amidon et al., (1995) as a method for classifying drug substances based on their dose/solubility ratio and intestinal permeability. It allows predicting the in vivo pharmacokinetic performance of drug products. The drug can be categorized into four classes of BCS, namely, High solubility high permeability, low solubility high permeability, High solubility low permeability and low solubility low permeability. An objective of B...

  3. BIOPHARMACEUTICS CLASSIFICATION SYSTEM: A STRATEGIC TOOL FOR CLASSIFYING DRUG SUBSTANCES

    OpenAIRE

    Rohilla Seema; Rohilla Ankur; Marwaha RK; Nanda Arun

    2011-01-01

    The biopharmaceutical classification system (BCS) is a scientific approach for classifying drug substances based on their dose/solubility ratio and intestinal permeability. The BCS has been developed to allow prediction of in vivo pharmacokinetic performance of drug products from measurements of permeability and solubility. Moreover, the drugs can be categorized into four classes of BCS on the basis of permeability and solubility namely; high permeability high solubility, high permeability lo...

  4. Just how good an investment is the biopharmaceutical sector?

    Science.gov (United States)

    Thakor, Richard T; Anaya, Nicholas; Zhang, Yuwei; Vilanilam, Christian; Siah, Kien Wei; Wong, Chi Heem; Lo, Andrew W

    2017-12-01

    Uncertainty surrounding the risk and reward of investments in biopharmaceutical companies poses a challenge to those interested in funding such enterprises. Using data on publicly traded stocks, we track the performance of 1,066 biopharmaceutical companies from 1930 to 2015-the most comprehensive financial analysis of this sector to date. Our systematic exploration of methods for distinguishing biotech and pharmaceutical companies yields a dynamic, more accurate classification method. We find that the performance of the biotech sector is highly sensitive to the presence of a few outlier companies, and confirm that nearly all biotech companies are loss-making enterprises, exhibiting high stock volatility. In contrast, since 2000, pharmaceutical companies have become increasingly profitable, with risk-adjusted returns consistently outperforming the market. The performance of all biopharmaceutical companies is subject not only to factors arising from their drug pipelines (idiosyncratic risk), but also from general economic conditions (systematic risk). The risk associated with returns has profound implications both for patterns of investment and for funding innovation in biomedical R&D.

  5. Delivery Systems for Biopharmaceuticals. Part I: Nanoparticles and Microparticles.

    Science.gov (United States)

    Silva, Ana C; Lopes, Carla M; Lobo, José M S; Amaral, Maria H

    2015-01-01

    Pharmaceutical biotechnology has been showing therapeutic success never achieved with conventional drug molecules. Therefore, biopharmaceutical products are currently well-established in clinic and the development of new ones is expected. These products comprise mainly therapeutic proteins, although nucleic acids and cells are also included. However, according to their sensitive molecular structures, the efficient delivery of biopharmaceuticals is challenging. Several delivery systems (e.g. microparticles and nanoparticles) composed of different materials (e.g. polymers and lipids) have been explored and demonstrated excellent outcomes, such as: high cellular transfection efficiency for nucleic acids, cell targeting, increased proteins and peptides bioavailability, improved immune response in vaccination, and viability maintenance of microencapsulated cells. Nonetheless, important issues need to be addressed before they reach clinics. For example, more in vivo studies in animals, accessing the toxicity potential and predicting in vivo failure of these delivery systems are required. This is the Part I of two review articles, which presents the state of the art of delivery systems for biopharmaceuticals. Part I deals with microparticles and polymeric and lipid nanoparticles.

  6. A new large-scale manufacturing platform for complex biopharmaceuticals.

    Science.gov (United States)

    Vogel, Jens H; Nguyen, Huong; Giovannini, Roberto; Ignowski, Jolene; Garger, Steve; Salgotra, Anil; Tom, Jennifer

    2012-12-01

    Complex biopharmaceuticals, such as recombinant blood coagulation factors, are addressing critical medical needs and represent a growing multibillion-dollar market. For commercial manufacturing of such, sometimes inherently unstable, molecules it is important to minimize product residence time in non-ideal milieu in order to obtain acceptable yields and consistently high product quality. Continuous perfusion cell culture allows minimization of residence time in the bioreactor, but also brings unique challenges in product recovery, which requires innovative solutions. In order to maximize yield, process efficiency, facility and equipment utilization, we have developed, scaled-up and successfully implemented a new integrated manufacturing platform in commercial scale. This platform consists of a (semi-)continuous cell separation process based on a disposable flow path and integrated with the upstream perfusion operation, followed by membrane chromatography on large-scale adsorber capsules in rapid cycling mode. Implementation of the platform at commercial scale for a new product candidate led to a yield improvement of 40% compared to the conventional process technology, while product quality has been shown to be more consistently high. Over 1,000,000 L of cell culture harvest have been processed with 100% success rate to date, demonstrating the robustness of the new platform process in GMP manufacturing. While membrane chromatography is well established for polishing in flow-through mode, this is its first commercial-scale application for bind/elute chromatography in the biopharmaceutical industry and demonstrates its potential in particular for manufacturing of potent, low-dose biopharmaceuticals. Copyright © 2012 Wiley Periodicals, Inc.

  7. Glyco-engineering for biopharmaceutical production in moss bioreactors

    Directory of Open Access Journals (Sweden)

    Eva L. Decker

    2014-07-01

    Full Text Available The production of recombinant biopharmaceuticals (pharmaceutical proteins is a strongly growing area in the pharmaceutical industry. While most products to date are produced in mammalian cell cultures, namely CHO cells, plant-based production systems gained increasing acceptance over the last years. Different plant systems have been established which are suitable for standardization and precise control of cultivation conditions, thus meeting the criteria for pharmaceutical production.The majority of biopharmaceuticals comprise glycoproteins. Therefore, differences in protein glycosylation between humans and plants have to be taken into account and plant-specific glycosylation has to be eliminated to avoid adverse effects on quality, safety and efficacy of the products.The basal land plant Physcomitrella patens (moss has been employed for the recombinant production of high-value therapeutic target proteins (e.g., Vascular Endothelial Growth Factor, Complement Factor H, monoclonal antibodies, Erythropoietin. Being genetically excellently characterized and exceptionally amenable for precise gene targeting via homologous recombination, essential steps for the optimization of moss as a bioreactor for the production of recombinant proteins have been undertaken.Here, we discuss the glyco-engineering approaches to avoid non-human N- and O-glycosylation on target proteins produced in moss bioreactors.

  8. The Market of Biopharmaceutical Medicines: A Snapshot of a Diverse Industrial Landscape

    Directory of Open Access Journals (Sweden)

    Evelien Moorkens

    2017-06-01

    Full Text Available Background: Biopharmaceutical medicines represent a growing share of the global pharmaceutical market, and with many of these biopharmaceutical products facing loss of exclusivity rights, also biosimilars may now enter the biopharmaceutical market.Objectives: This study aims to identify and document which investment and development strategies are adopted by industrial players in the global biopharmaceutical market.Methods: A descriptive analysis was undertaken of the investment and development strategies of the top 25 pharmaceutical companies according to 2015 worldwide prescription drug sales. Strategies were documented by collecting data on manufacturing plans, development programs, acquisition and collaboration agreements, the portfolio and pipeline of biosimilar, originator and next-generation biopharmaceutical products. Data were extracted from publicly available sources.Results: Various investment and development strategies can be identified in the global biopharmaceutical market: (a development of originator biopharmaceuticals, (b investment in biotechnology, (c development of next-generation biopharmaceuticals, (d development of biosimilars, (e investment in emerging countries, and (f collaboration between companies. In the top 25 pharmaceutical companies almost every company invests in originator biopharmaceuticals and in biotechnology in general, but only half of them develops next-generation biopharmaceuticals. Furthermore, only half of them invest in development of biosimilars. The companies' biosimilar pipeline is mainly focused on development of biosimilar monoclonal antibodies and to some extent on biosimilar insulins. A common strategy is collaboration between companies and investment in emerging countries.Conclusions: A snapshot of investment and development strategies used by industrial players in the global biopharmaceutical market shows that all top 25 pharmaceutical companies are engaged in the biopharmaceutical market and

  9. CROHN'S DISEASE: GENERAL CHARACTERISTICS AND TREATMENT WITH ADALIMUMABE BIOPHARMACEUTICAL

    Directory of Open Access Journals (Sweden)

    S. A. Marques

    2018-02-01

    Full Text Available Crohn's Disease (CD is a chronic inflammatory disease that affects the gastrointestinal system. The etiology is not fully understood, however, genetic, immunological, microbiological and environmental factors are related to its genesis. The most common manifestations of this disease are diarrhea, abdominal pain, ulcers and fistulas. In the absence of adequate treatment it can evolve into extra intestinal complications and is also an important risk factor for colon and rectal cancer. The treatment of the disease is palliative and there is no cure for the disease, being considered only the period of remission of symptoms, as a good prognosis. The biopharmaceutical, Adalimumabe, produced by recombinant DNA technology has demonstrated efficacy in the treatment of this disease, as it prevents the action of TNF-α, a cytokine involved in inflammation and is abundant in individuals with CD. Although Adalimumabe has good results, its use leads to side effects that can be mild or fatal, such as the activation of tuberculosis.

  10. Single-use disposable technologies for biopharmaceutical manufacturing.

    Science.gov (United States)

    Shukla, Abhinav A; Gottschalk, Uwe

    2013-03-01

    The manufacture of protein biopharmaceuticals is conducted under current good manufacturing practice (cGMP) and involves multiple unit operations for upstream production and downstream purification. Until recently, production facilities relied on the use of relatively inflexible, hard-piped equipment including large stainless steel bioreactors and tanks to hold product intermediates and buffers. However, there is an increasing trend towards the adoption of single-use technologies across the manufacturing process. Technical advances have now made an end-to-end single-use manufacturing facility possible, but several aspects of single-use technology require further improvement and are continually evolving. This article provides a perspective on the current state-of-the-art in single-use technologies and highlights trends that will improve performance and increase the market penetration of disposable manufacturing in the future. Copyright © 2012 Elsevier Ltd. All rights reserved.

  11. Carrot cells: a pioneering platform for biopharmaceuticals production.

    Science.gov (United States)

    Rosales-Mendoza, Sergio; Tello-Olea, Marlene Anahí

    2015-03-01

    Carrot (Daucus carota L.) is of importance in the molecular farming field as it constitutes the first plant species approved to produce biopharmaceuticals for human use. In this review, features that make carrot an advantageous species in the molecular farming field are analyzed and a description of the developments achieved with this crop thus far is presented. A guide for genetic transformation procedures is also included. The state of the art comprises ten vaccine prototypes against Measles virus, Hepatitis B virus, Human immunodeficiency virus, Yersinia pestis, Chlamydia trachomatis, Mycobacterium tuberculosis, enterotoxigenic Escherichia coli, Corynebacterium diphtheria/Clostridium tetani/Bordetella pertussis, and Helicobacter pylori; as well as the case of the glucocerebrosidase, an enzyme used for replacement therapy, and other therapeutics. Perspectives for these developments are envisioned and innovations are proposed such as the use of transplastomic technologies-, hairy roots-, and viral expression-based systems to improve yields and develop new products derived from this advantageous plant species.

  12. Modeling in biopharmaceutics, pharmacokinetics, and pharmacodynamics homogeneous and heterogeneous approaches

    CERN Document Server

    Macheras, Panos

    2006-01-01

    The state of the art in Biopharmaceutics, Pharmacokinetics, and Pharmacodynamics Modeling is presented in this book. It shows how advanced physical and mathematical methods can expand classical models in order to cover heterogeneous drug-biological processes and therapeutic effects in the body. The book is divided into four parts; the first deals with the fundamental principles of fractals, diffusion and nonlinear dynamics; the second with drug dissolution, release, and absorption; the third with empirical, compartmental, and stochastic pharmacokinetic models, and the fourth mainly with nonclassical aspects of pharmacodynamics. The classical models that have relevance and application to these sciences are also considered throughout. Many examples are used to illustrate the intrinsic complexity of drug administration related phenomena in the human, justifying the use of advanced modeling methods. This timely and useful book will appeal to graduate students and researchers in pharmacology, pharmaceutical scienc...

  13. Capillary electrophoresis – mass spectrometry using noncovalently coated capillaries for the analysis of biopharmaceuticals

    NARCIS (Netherlands)

    Haselberg, R.

    2010-01-01

    With efficient methodologies available in biotechnology today, increasing numbers of recombinantly manufactured pharmaceutical peptides and proteins are being commercialized. The assessment of biopharmaceutical quality in terms of identity, content and purity is an important issue during

  14. The development of Bio-pharmaceutical industry in China: problems and solutions.

    Science.gov (United States)

    Yan, Gujun

    2014-07-01

    Known as the "sunrise industry" of the 21st century, bio-pharmaceutical industry has been a fast-growing global industry, and many countries have been developing this industry as the focus of their national economies. In China, there exists a huge market demand for the development of bio-pharmaceutical industry, but at the present stage the industry is faced with some problems, such as low level of R & D for innovative drugs, and inappropriate capital investment in the industrialization. In order to accelerate the development of China's bio-pharmaceutical industry, it is necessary to take strategic initiatives of improving the technology transfer system, developing the bio-pharmaceutical outsourcing, and building a diversified industrial financing system.

  15. Capacity Planning for Batch and Perfusion Bioprocesses Across Multiple Biopharmaceutical Facilities

    OpenAIRE

    Siganporia, Cyrus C; Ghosh, Soumitra; Daszkowski, Thomas; Papageorgiou, Lazaros G; Farid, Suzanne S

    2014-01-01

    Production planning for biopharmaceutical portfolios becomes more complex when products switch between fed-batch and continuous perfusion culture processes. This article describes the development of a discrete-time mixed integer linear programming (MILP) model to optimize capacity plans for multiple biopharmaceutical products, with either batch or perfusion bioprocesses, across multiple facilities to meet quarterly demands. The model comprised specific features to account for products with fe...

  16. Biopharmaceutics classification system: importance and inclusion in biowaiver guidance

    Directory of Open Access Journals (Sweden)

    Lorena Barbosa Arrunátegui

    2015-03-01

    Full Text Available Pharmacological therapy is essential in many diseases treatment and it is important that the medicine policy is intended to offering safe and effective treatment with affordable price to the population. One way to achieve this is through biowaiver, defined as the replacement of in vivo bioequivalence studies by in vitro studies. For biowaiver of new immediate release solid oral dosage forms, data such as intestinal permeability and solubility of the drug are required, as well as the product dissolution. The Biopharmaceutics Classification System (BCS is a scientific scheme that divides drugs according to their solubility and permeability and has been used by various guides as a criterion for biowaiver. This paper evaluates biowaiver application, addressing the general concepts and parameters used by BCS, making a historical account of its use, the requirements pertaining to the current legislation, the benefits and risks associated with this decision. The results revealed that the use of BCS as a biowaiver criterion greatly expands the therapeutics options, contributing to greater therapy access of the general population with drug efficacy and safety guaranteed associated to low cost.

  17. Ion-exchange chromatography for the characterization of biopharmaceuticals.

    Science.gov (United States)

    Fekete, Szabolcs; Beck, Alain; Veuthey, Jean-Luc; Guillarme, Davy

    2015-09-10

    Ion-exchange chromatography (IEX) is a historical technique widely used for the detailed characterization of therapeutic proteins and can be considered as a reference and powerful technique for the qualitative and quantitative evaluation of charge heterogeneity. The goal of this review is to provide an overview of theoretical and practical aspects of modern IEX applied for the characterization of therapeutic proteins including monoclonal antibodies (Mabs) and antibody drug conjugates (ADCs). The section on method development describes how to select a suitable stationary phase chemistry and dimensions, the mobile phase conditions (pH, nature and concentration of salt), as well as the temperature and flow rate, considering proteins isoelectric point (pI). In addition, both salt-gradient and pH-gradient approaches were critically reviewed and benefits as well as limitations of these two strategies were provided. Finally, several applications, mostly from pharmaceutical industries, illustrate the potential of IEX for the characterization of charge variants of various types of biopharmaceutical products. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. The Research on International Development Path of China’s Marine Biopharmaceutical Industry

    Directory of Open Access Journals (Sweden)

    Xiu-Mei Fu

    2018-02-01

    Full Text Available Under the backdrop of the Maritime Silk Road Initiative, the study on the international development of China’s marine biopharmaceutical industry based on factor allocation is of great practical significance for industrial sustainability and building the industry into a leading international player in the global market. In this paper, we first identify the leading factors that influence the development of the marine biopharmaceutical industry, namely, resources, technologies, talents, investments and policies. Furthermore, the hierarchical structure model of these factors was established and analyzed using the analytic hierarchy process (AHP. The importance ranking of these constraints was identified, as follows: technologies > talents > resources > policies > investments. Then, based on the theory of comparative advantage and game theory, we analyzed the necessity of China’s marine biopharmaceutical industry going global, that is, international cooperation may lay a solid foundation for the win-win outcome of this industry in countries along the Maritime Silk Road. According to the status quo of China’s marine biopharmaceutical industry, based on these findings, an international factor–allocation cooperation path was designed, and the path chart of the international development of the marine biopharmaceutical industry was drawn. Finally, methods for the development of China’s marine biopharmaceutical industry were proposed, which covers efforts to protect marine resources, promote R&D for core technologies, establish a strong talent pool, encourage more investments, provide policy support and promote worldwide cooperation. It is the first report to investigate the path of the sustainable exploitation of the marine biopharmaceutical industry from the perspective of factor allocation amidst the backdrop of the Maritime Silk Road Initiative.

  19. Role of Knowledge Management in Development and Lifecycle Management of Biopharmaceuticals.

    Science.gov (United States)

    Rathore, Anurag S; Garcia-Aponte, Oscar Fabián; Golabgir, Aydin; Vallejo-Diaz, Bibiana Margarita; Herwig, Christoph

    2017-02-01

    Knowledge Management (KM) is a key enabler for achieving quality in a lifecycle approach for production of biopharmaceuticals. Due to the important role that it plays towards successful implementation of Quality by Design (QbD), an analysis of KM solutions is needed. This work provides a comprehensive review of the interface between KM and QbD-driven biopharmaceutical production systems as perceived by academic as well as industrial viewpoints. A comprehensive set of 356 publications addressing the applications of KM tools to QbD-related tasks were screened and a query to gather industrial inputs from 17 major biopharmaceutical organizations was performed. Three KM tool classes were identified as having high relevance for biopharmaceutical production systems and have been further explored: knowledge indicators, ontologies, and process modeling. A proposed categorization of 16 distinct KM tool classes allowed for the identification of holistic technologies supporting QbD. In addition, the classification allowed for addressing the disparity between industrial and academic expectations regarding the application of KM methodologies. This is a first of a kind attempt and thus we think that this paper would be of considerable interest to those in academia and industry that are engaged in accelerating development and commercialization of biopharmaceuticals.

  20. Impact of Postapproval Evidence Generation on the Biopharmaceutical Industry.

    Science.gov (United States)

    Milne, Christopher-Paul; Cohen, Joshua P; Felix, Abigail; Chakravarthy, Ranjana

    2015-08-01

    Meeting marketplace demands for proving the value of new products requires more data than the industry has routinely produced. These data include evidence from comparative effectiveness research (CER), including randomized, controlled trials; pragmatic clinical trials; observational studies; and meta-analyses. We designed and conducted a survey to examine the industry's perceptions on new data requirements regarding CER evidence, the acceptability of postapproval study types, payer-specific issues related to CER, communication of data being generated postapproval, and methods used for facilitating postapproval evidence generation. CER is being used by payers for most types of postapproval decisions. Randomized, controlled trials were indicated as the most acceptable form of evidence. At the same time, there was support for the utility of other types of studies, such as pragmatic clinical trials and observational studies. Respondents indicated the use of multiple formats for communicating postapproval data with many different stakeholders including regulators, payers, providers, and patients. Risk-sharing agreements with payers were unanimously supported by respondents with regard to certain products with unclear clinical and economic outcomes at launch. In these instances, conditional reimbursement through coverage with evidence development was considered a constructive option. The Food and Drug Administration's initiative called Regulatory Science was considered by the respondents as having the most impact on streamlining the generation of postapproval research-related evidence. The biopharmaceutical industry is faced with a broad and complex set of challenges related to evidence generation for postapproval decisions by a variety of health care system stakeholders. Uncertainty remains as to how the industry and payers use postapproval studies to guide decision making with regard to pricing and reimbursement status. Correspondingly, there is uncertainty regarding

  1. Hybrid and Disposable Facilities for Manufacturing of Biopharmaceuticals: Pros and Cons

    Science.gov (United States)

    Ravisé, Aline; Cameau, Emmanuelle; de Abreu, Georges; Pralong, Alain

    Modern biotechnology has grown over the last 35 years to a maturing industry producing and delivering high-value biopharmaceuticals that yield important medical and economical benefits. The constantly increasing need for biopharmaceuticals and significant costs related to time-consuming R&D work makes this industry risky and highly competitive. This trend is confirmed by the important number of biopharmaceuticals that are actually under development at all stages by all major pharmaceutical industry companies. A consequence of this evolution is an increasing need for development and manufacturing capacity. The build up of traditional - stainless steel - technology is complicated, time consuming and very expensive. The decision for such a major investment needs to be taken early in the development cycle of a promising drug to cope with future demands for clinical trials and product launch. Possibilities for the reduction of R&D and manufacturing costs are therefore of significant interest in order to be competitive.

  2. Examining the sources of variability in cell culture media used for biopharmaceutical production.

    Science.gov (United States)

    McGillicuddy, Nicola; Floris, Patrick; Albrecht, Simone; Bones, Jonathan

    2018-01-01

    Raw materials, in particular cell culture media, represent a significant source of variability to biopharmaceutical manufacturing processes that can detrimentally affect cellular growth, viability and specific productivity or alter the quality profile of the expressed therapeutic protein. The continual expansion of the biopharmaceutical industry is creating an increasing demand on the production and supply chain consistency for cell culture media, especially as companies embrace intensive continuous processing. Here, we provide a historical perspective regarding the transition from serum containing to serum-free media, the development of chemically-defined cell culture media for biopharmaceutical production using industrial scale bioprocesses and review production mechanisms for liquid and powder culture media. An overview and critique of analytical approaches used for the characterisation of cell culture media and the identification of root causes of variability are also provided, including in-depth liquid phase separations, mass spectrometry and spectroscopic methods.

  3. Capillary electrophoresis – mass spectrometry using noncovalently coated capillaries for the analysis of biopharmaceuticals

    OpenAIRE

    Haselberg, R.

    2010-01-01

    With efficient methodologies available in biotechnology today, increasing numbers of recombinantly manufactured pharmaceutical peptides and proteins are being commercialized. The assessment of biopharmaceutical quality in terms of identity, content and purity is an important issue during manufacturing. The biotechnological production process may show variability, which can introduce product diversity, isoforms and closely-related degradation products. Clearly, there is an increasing demand fo...

  4. Biopharmaceutical innovation and industrial developments in South Korea, Singapore and Taiwan.

    Science.gov (United States)

    Hsieh, Chee-Ruey; Löfgren, Hans

    2009-05-01

    South Korea, Singapore and Taiwan are well known as export-oriented developmental states which for decades employed industrial policy to target particular industries for government support. In the past fifteen years, these three countries all identified the biopharmaceutical industry as a strategic sector. This article explores, through economic analysis, the rationale for this decision and the strategies chosen for linking into the global bio-economy with the objective of catching up in biopharmaceuticals. The paper identifies three comparative advantages enjoyed by these countries in the biopharma sector: (1) public investments in basic research; (2) private investments in phase 1 clinical trials; and (3) a potentially significant contract research industry managing latter-stage clinical trials. Governments employ a range of industrial policies, consistent with these comparative advantages, to promote the biopharmaceutical industry, including public investment in biomedical hubs, research funding and research and development (R&D) tax credits. We argue that the most important feature of the biopharmaceutical industry in these countries is the dominant role of the public sector. That these countries have made progress in innovative capabilities is illustrated by input measures such as R&D expenditure as share of gross domestic product, number of patents granted and clinical trials, and volume of foreign direct investment. In contrast, output indicators such as approval of new chemical entities suggest that the process of catching up has only just commenced. Pharmaceutical innovation is at the stage of mainly generating inputs to integrated processes controlled by the globally incumbent firms.

  5. Emergence of biopharmaceutical innovators in China, India, Brazil, and South Africa as global competitors and collaborators

    Directory of Open Access Journals (Sweden)

    Rezaie Rahim

    2012-06-01

    Full Text Available Abstract Biopharmaceutical innovation has had a profound health and economic impact globally. Developed countries have traditionally been the source of most innovations as well as the destination for the resulting economic and health benefits. As a result, most prior research on this sector has focused on developed countries. This paper seeks to fill the gap in research on emerging markets by analyzing factors that influence innovative activity in the indigenous biopharmaceutical sectors of China, India, Brazil, and South Africa. Using qualitative research methodologies, this paper a shows how biopharmaceutical innovation is taking place within the entrepreneurial sectors of these emerging markets, b identifies common challenges that indigenous entrepreneurs face, c highlights the key role played by the state, and d reveals that the transition to innovation by companies in the emerging markets is characterized by increased global integration. It suggests that biopharmaceutical innovators in emerging markets are capitalizing on opportunities to participate in the drug development value chain and thus developing capabilities and relationships for competing globally both with and against established companies headquartered in developed countries.

  6. Emergence of biopharmaceutical innovators in China, India, Brazil, and South Africa as global competitors and collaborators.

    Science.gov (United States)

    Rezaie, Rahim; McGahan, Anita M; Frew, Sarah E; Daar, Abdallah S; Singer, Peter A

    2012-06-06

    Biopharmaceutical innovation has had a profound health and economic impact globally. Developed countries have traditionally been the source of most innovations as well as the destination for the resulting economic and health benefits. As a result, most prior research on this sector has focused on developed countries. This paper seeks to fill the gap in research on emerging markets by analyzing factors that influence innovative activity in the indigenous biopharmaceutical sectors of China, India, Brazil, and South Africa. Using qualitative research methodologies, this paper a) shows how biopharmaceutical innovation is taking place within the entrepreneurial sectors of these emerging markets, b) identifies common challenges that indigenous entrepreneurs face, c) highlights the key role played by the state, and d) reveals that the transition to innovation by companies in the emerging markets is characterized by increased global integration. It suggests that biopharmaceutical innovators in emerging markets are capitalizing on opportunities to participate in the drug development value chain and thus developing capabilities and relationships for competing globally both with and against established companies headquartered in developed countries.

  7. Biotechnological production of pharmaceuticals and biopharmaceuticals in plant cell and organ cultures.

    Science.gov (United States)

    Hidalgo, Diego; Sanchez, Raul; Lalaleo, Liliana; Bonfill, Mercedes; Corchete, Purificacion; Palazon, Javier

    2018-03-09

    Plant biofactories are biotechnological platforms based on plant cell and organ cultures used for the production of pharmaceuticals and biopharmaceuticals, although to date only a few of these systems have successfully been implemented at an industrial level. Metabolic engineering is possibly the most straightforward strategy to boost pharmaceutical production in plant biofactories, but social opposition to the use of GMOs means empirical approaches are still being used. Plant secondary metabolism involves thousands of different enzymes, some of which catalyze specific reactions, giving one product from a particular substrate, whereas others can yield multiple products from the same substrate. This trait opens plant cell biofactories to new applications, in which the natural metabolic machinery of plants can be harnessed for the bioconversion of phytochemicals or even the production of new bioactive compounds. Synthetic biological pipelines involving the bioconversion of natural substrates into products with a high market value may be established by the heterologous expression of target metabolic genes in model plants. To summarize the state of the art of plant biofactories and their applications for the pipeline production of cosme-, pharma- and biopharmaceuticals. In order to demonstrate the great potential of plant biofactories for multiple applications in the biotechnological production of pharmaceuticals and biopharmaceuticals, this review broadly covers the following: plant biofactories based on cell and hairy root cultures; secondary metabolite production; biotransformation reactions; metabolic engineering tools applied in plant biofactories; and biopharmaceutical production. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  8. Guidance to Achieve Accurate Aggregate Quantitation in Biopharmaceuticals by SV-AUC.

    Science.gov (United States)

    Arthur, Kelly K; Kendrick, Brent S; Gabrielson, John P

    2015-01-01

    The levels and types of aggregates present in protein biopharmaceuticals must be assessed during all stages of product development, manufacturing, and storage of the finished product. Routine monitoring of aggregate levels in biopharmaceuticals is typically achieved by size exclusion chromatography (SEC) due to its high precision, speed, robustness, and simplicity to operate. However, SEC is error prone and requires careful method development to ensure accuracy of reported aggregate levels. Sedimentation velocity analytical ultracentrifugation (SV-AUC) is an orthogonal technique that can be used to measure protein aggregation without many of the potential inaccuracies of SEC. In this chapter, we discuss applications of SV-AUC during biopharmaceutical development and how characteristics of the technique make it better suited for some applications than others. We then discuss the elements of a comprehensive analytical control strategy for SV-AUC. Successful implementation of these analytical control elements ensures that SV-AUC provides continued value over the long time frames necessary to bring biopharmaceuticals to market. © 2015 Elsevier Inc. All rights reserved.

  9. Formulation Strategies and Particle Engineering Technologies for Pulmonary Delivery of Biopharmaceuticals

    DEFF Research Database (Denmark)

    Cun, Dongmei; Wan, Feng; Yang, Mingshi

    2015-01-01

    . In this review we discussed the formulation strategies and particle engineering technologies to improve the efficiency of pulmonary delivery of biopharmaceutical, with a focus on systemic therapy of pharmaceutical proteins/peptides and local delivery of siRNA via the lung administration....

  10. Innovator Organizations in New Drug Development: Assessing the Sustainability of the Biopharmaceutical Industry.

    Science.gov (United States)

    Kinch, Michael S; Moore, Ryan

    2016-06-23

    The way new medicines are discovered and brought to market has fundamentally changed over the last 30 years. Our previous analysis showed that biotechnology companies had contributed significantly to the US Food and Drug Administration approval of new molecular entities up to the mid-1980s, when the trends started to decline. Although intriguing, the focus on biotechnology necessarily precluded the wider question of how the biopharmaceutical industry has been delivering on its goals to develop new drugs. Here, we present a comprehensive analysis of all biopharmaceutical innovators and uncover unexpected findings. The present biopharmaceutical industry grew steadily from 1800 to 1950 and then stagnated for two decades, before a burst of growth attributable to the biotechnology revolution took place; but consolidation has reduced the number of active and independent innovators to a level not experienced since 1945. The trajectories and trends we observe raise fundamental questions about biopharmaceutical innovators and the sustainability of the drug-development enterprise. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Immunogenicity of biopharmaceuticals and biosimilars in relation to storage, handling and stability

    International Nuclear Information System (INIS)

    Hincal, F.

    2009-01-01

    Therapeutic proteins or biopharmaceuticals provide effective treatment for many diseases and medical conditions, and vaccines, immunoglobulins and monoclonal antibodies are critical biodefense biopharmaceuticals which constitute an indispensable part of biodefense stockpiles. The manufacturing process for biopharmaceuticals and their generic forms which are called biosimilars is far more complex than for low molecular weight drugs and generics. Any minor change made at any stage may have a critical effect on the clinical efficacy and safety. Potential immunogenicity is the key issue for biopharmaceuticals and biosimilars and may have serious clinical consequences ranging from allergy and anaphylaxis, as well as loss of efficacy of the product. Immunogenicity may be influenced by factors related to manufacturing process, formulation, aggregate formation, contaminants and impurities, and also by the factors related to the storage and handling. Stability is particularly important with larger protein molecules, because their in vivo effects often depend on their three-dimensional structure. Proteins usually aggregate from partially unfolded molecules and aggregates can enhance immunogenicity. Although product formulations are developed to maximize and maintain the fraction of the protein molecules present in the native state, significant amounts of aggregates can form, especially over pharmaceutically relevant time scales and under stress conditions. Exposure to air-liquid and solid-liquid interfaces, light, temperature fluctuations or minor impurities can induce aggregation. Such exposure can occur during processing steps, as well as in the final product container during storage, shipment and handling. Biopharmaceuticals are particularly sensitive to temperature changes and/or shaking. Strict storage and handling conditions and timely and effective stability/shelf-life testing are therefore essential for maintaining product integrity and stability, and hence efficacy

  12. Summary of the NICHD-BPCA Pediatric Formulation Initiatives Workshop-Pediatric Biopharmaceutics Classification System (PBCS) Working Group

    OpenAIRE

    Abdel-Rahman, Susan; Amidon, Gordon L.; Kaul, Ajay; Lukacova, Viera; Vinks, Alexander A.; Knipp, Gregory

    2012-01-01

    The Biopharmaceutics Classification System (BCS) allows compounds to be classified based on their in vitro solubility and intestinal permeability. The BCS has found widespread use in the pharmaceutical community as an enabling guide for the rational selection of compounds, formulation for clinical advancement and generic biowaivers. The Pediatric Biopharmaceutics Classification System (PBCS) working group was convened to consider the possibility of developing an analogous pediatric based clas...

  13. Manufacturing, regulatory and commercial challenges of biopharmaceuticals production: a Finnish perspective.

    Science.gov (United States)

    Närhi, Marko; Nordström, Katrina

    2005-04-01

    Biopharmaceuticals product development is a broad and multidisciplinary field. Science and technology are combined with new manufacturing, regulatory and commercial challenges. However, although there is ample literature on the molecular biology and biochemistry of products, the implementation of processes from test tube to commercial scale has not received similar attention. Consequently, the present study aims to highlight, from practical point of view, some of the key issues involved with manufacturing technologies of biopharmaceuticals at a commercial scale. Regulatory requirements and investments are also addressed based on the practical experiences of start-up and small companies. Finland is used as a case-example of such companies as this is a EU-member state with strong technological growth and rapidly increasing number of biotech companies.

  14. Antibodies Against Complement Components: Relevance for the Antiphospholipid Syndrome-Biomarkers of the Disease and Biopharmaceuticals.

    Science.gov (United States)

    Bećarević, Mirjana

    2017-07-01

    Laboratory criterion for the diagnosis of antiphospholipid syndrome (APS) is the presence of antiphospholipid antibodies (aPL Abs). Complement system has a role in mediating aPL Abs-induced thrombosis in animal models. The importance of antibodies against complement components (potential biomarkers of APS) and the importance of antibodies with beneficial anti-complement effects in APS (as biopharmaceuticals) are reviewed. Antibodies against complement components described in APS patients, so far, are anti-C1q and anti-factor H Abs, although anti-factor B Abs and anti-C5a Abs were described in animal models of APS. Clinical studies in APS patients are limited to a small number of case reports. Studies that would confirm potential role of Abs against complement components (as potential biomarkers of APS) are lacking. Lack of randomized clinical trials (that would provide complete data for confirmation of beneficial effects of biopharmaceuticals in complement inhibition) in APS is alarming.

  15. Cellular targets for improved manufacturing of virus-based biopharmaceuticals in animal cells.

    Science.gov (United States)

    Rodrigues, Ana F; Carrondo, Manuel J T; Alves, Paula M; Coroadinha, Ana S

    2014-12-01

    The past decade witnessed the entry into the market of new virus-based biopharmaceuticals produced in animal cells such as oncolytic vectors, virus-like particle vaccines, and gene transfer vectors. Therefore, increased attention and investment to optimize cell culture processes towards enhanced manufacturing of these bioproducts is anticipated. Herein, we review key findings on virus-host interactions that have been explored in cell culture optimization. Approaches supporting improved productivity or quality of vector preparations are discussed, mainly focusing on medium design and genetic manipulation. This review provides an integrated outline for current and future efforts in exploring cellular targets for the optimization of cell culture manufacturing of virus-based biopharmaceuticals. Copyright © 2014 Elsevier Ltd. All rights reserved.

  16. [Study on biopharmaceutics classification system for Chinese materia medica of extract of Huanglian].

    Science.gov (United States)

    Liu, Yang; Yin, Xiu-Wen; Wang, Zi-Yu; Li, Xue-Lian; Pan, Meng; Li, Yan-Ping; Dong, Ling

    2017-11-01

    One of the advantages of biopharmaceutics classification system of Chinese materia medica (CMMBCS) is expanding the classification research level from single ingredient to multi-components of Chinese herb, and from multi-components research to holistic research of the Chinese materia medica. In present paper, the alkaloids of extract of huanglian were chosen as the main research object to explore their change rules in solubility and intestinal permeability of single-component and multi-components, and to determine the biopharmaceutical classification of extract of Huanglian from holistic level. The typical shake-flask method and HPLC were used to detect the solubility of single ingredient of alkaloids from extract of huanglian. The quantitative research of alkaloids in intestinal absorption was measured in single-pass intestinal perfusion experiment while permeability coefficient of extract of huanglian was calculated by self-defined weight coefficient method. Copyright© by the Chinese Pharmaceutical Association.

  17. Managing Risk to the Patient: Recoding Quality Risk Management for the Pharmaceutical and Biopharmaceutical Industries

    OpenAIRE

    Waldron, Kelly

    2017-01-01

    This thesis explores the application of quality risk management (QRM) in pharmaceutical and biopharmaceutical companies and its effectiveness at managing risk to the patient. The objective of the research described in this thesis was to characterize a maturity state of QRM implementation in which the patient is adequately protected from the risks associated with medicinal products of inadequate quality. The research was conducted over three phases: first, to determine whether patients are bet...

  18. Hybrid and disposable facilities for manufacturing of biopharmaceuticals: pros and cons.

    Science.gov (United States)

    Ravisé, Aline; Cameau, Emmanuelle; De Abreu, Georges; Pralong, Alain

    2009-01-01

    Modern biotechnology has grown over the last 35 years to a maturing industry producing and delivering high-value biopharmaceuticals that yield important medical and economical benefits. The constantly increasing need for biopharmaceuticals and significant costs related to time-consuming R&D work makes this industry risky and highly competitive. This trend is confirmed by the important number of biopharmaceuticals that are actually under development at all stages by all major pharmaceutical industry companies. A consequence of this evolution is an increasing need for development and manufacturing capacity. The build up of traditional - stainless steel - technology is complicated, time consuming and very expensive. The decision for such a major investment needs to be taken early in the development cycle of a promising drug to cope with future demands for clinical trials and product launch. Possibilities for the reduction of R&D and manufacturing costs are therefore of significant interest in order to be competitive.In this chapter, four case studies are presented which outline ways to reduce significantly R&D and manufacturing costs by using disposable technology in the frame of a the transfer of an antibody manufacturing process, the preparation of media and buffers in commercial manufacturing and a direct comparison of a traditional and a fully disposable pilot plant.

  19. Chemometrics-based process analytical technology (PAT) tools: applications and adaptation in pharmaceutical and biopharmaceutical industries.

    Science.gov (United States)

    Challa, Shruthi; Potumarthi, Ravichandra

    2013-01-01

    Process analytical technology (PAT) is used to monitor and control critical process parameters in raw materials and in-process products to maintain the critical quality attributes and build quality into the product. Process analytical technology can be successfully implemented in pharmaceutical and biopharmaceutical industries not only to impart quality into the products but also to prevent out-of-specifications and improve the productivity. PAT implementation eliminates the drawbacks of traditional methods which involves excessive sampling and facilitates rapid testing through direct sampling without any destruction of sample. However, to successfully adapt PAT tools into pharmaceutical and biopharmaceutical environment, thorough understanding of the process is needed along with mathematical and statistical tools to analyze large multidimensional spectral data generated by PAT tools. Chemometrics is a chemical discipline which incorporates both statistical and mathematical methods to obtain and analyze relevant information from PAT spectral tools. Applications of commonly used PAT tools in combination with appropriate chemometric method along with their advantages and working principle are discussed. Finally, systematic application of PAT tools in biopharmaceutical environment to control critical process parameters for achieving product quality is diagrammatically represented.

  20. Delivery systems for biopharmaceuticals. Part II: Liposomes, Micelles, Microemulsions and Dendrimers.

    Science.gov (United States)

    Silva, Ana C; Lopes, Carla M; Lobo, José M S; Amaral, Maria H

    2015-01-01

    Biopharmaceuticals are a generation of drugs that include peptides, proteins, nucleic acids and cell products. According to their particular molecular characteristics (e.g. high molecular size, susceptibility to enzymatic activity), these products present some limitations for administration and usually parenteral routes are the only option. To avoid these limitations, different colloidal carriers (e.g. liposomes, micelles, microemulsions and dendrimers) have been proposed to improve biopharmaceuticals delivery. Liposomes are promising drug delivery systems, despite some limitations have been reported (e.g. in vivo failure, poor long-term stability and low transfection efficiency), and only a limited number of formulations have reached the market. Micelles and microemulsions require more studies to exclude some of the observed drawbacks and guarantee their potential for use in clinic. According to their peculiar structures, dendrimers have been showing good results for nucleic acids delivery and a great development of these systems during next years is expected. This is the Part II of two review articles, which provides the state of the art of biopharmaceuticals delivery systems. Part II deals with liposomes, micelles, microemulsions and dendrimers.

  1. Proposal on How To Conduct a Biopharmaceutical Process Failure Mode and Effect Analysis (FMEA) as a Risk Assessment Tool.

    Science.gov (United States)

    Zimmermann, Hartmut F; Hentschel, Norbert

    2011-01-01

    With the publication of the quality guideline ICH Q9 "Quality Risk Management" by the International Conference on Harmonization, risk management has already become a standard requirement during the life cycle of a pharmaceutical product. Failure mode and effect analysis (FMEA) is a powerful risk analysis tool that has been used for decades in mechanical and electrical industries. However, the adaptation of the FMEA methodology to biopharmaceutical processes brings about some difficulties. The proposal presented here is intended to serve as a brief but nevertheless comprehensive and detailed guideline on how to conduct a biopharmaceutical process FMEA. It includes a detailed 1-to-10-scale FMEA rating table for occurrence, severity, and detectability of failures that has been especially designed for typical biopharmaceutical processes. The application for such a biopharmaceutical process FMEA is widespread. It can be useful whenever a biopharmaceutical manufacturing process is developed or scaled-up, or when it is transferred to a different manufacturing site. It may also be conducted during substantial optimization of an existing process or the development of a second-generation process. According to their resulting risk ratings, process parameters can be ranked for importance and important variables for process development, characterization, or validation can be identified. Health authorities around the world ask pharmaceutical companies to manage risk during development and manufacturing of pharmaceuticals. The so-called failure mode and effect analysis (FMEA) is an established risk analysis tool that has been used for decades in mechanical and electrical industries. However, the adaptation of the FMEA methodology to pharmaceutical processes that use modern biotechnology (biopharmaceutical processes) brings about some difficulties, because those biopharmaceutical processes differ from processes in mechanical and electrical industries. The proposal presented here

  2. Protein N-glycosylation in eukaryotic microalgae and its impact on the production of nuclear expressed biopharmaceuticals

    Directory of Open Access Journals (Sweden)

    Elodie eMathieu-Rivet

    2014-07-01

    Full Text Available Microalgae are currently used for the production of food compounds. Recently, few microalgae species have been investigated as potential biofactories for the production of biopharmaceuticals. Indeed in this context, microalgae are cheap, classified as Generally Recognized As Safe (GRAS organisms and can be grown easily. However, problems remain to be solved before any industrial production of microalgae-made biopharmaceuticals. Among them, post-translational modifications of the proteins need to be considered. Especially, N-glycosylation acquired by the secreted recombinant proteins is of major concern since most of the biopharmaceuticals are N-glycosylated and it is well recognized that glycosylation represent one of their critical quality attribute. Therefore, the evaluation of microalgae as alternative cell factory for biopharmaceutical productions thus requires to investigate their N-glycosylation capability in order to determine to what extend it differs from their human counterpart and to determine appropriate strategies for remodelling the microalgae glycosylation into human-compatible oligosaccharides. Here, we review the secreted recombinant proteins which have been successfully produced in microalgae. We also report on recent bioinformatics and biochemical data concerning the structure of glycans N-linked to proteins from various microalgae phyla and comment the consequences on the glycan engineering strategies that may be necessary to render those microalgae-made biopharmaceuticals compatible with human therapy.

  3. Manufacturing Amorphous Solid Dispersions with a Tailored Amount of Crystallized API for Biopharmaceutical Testing.

    Science.gov (United States)

    Theil, Frank; Milsmann, Johanna; Anantharaman, Sankaran; van Lishaut, Holger

    2018-05-07

    The preparation of an amorphous solid dispersion (ASD) by dissolving a poorly water-soluble active pharmaceutical ingredient (API) in a polymer matrix can improve the bioavailability by orders of magnitude. Crystallization of the API in the ASD, though, is an inherent threat for bioavailability. Commonly, the impact of crystalline API on the drug release of the dosage form is studied with samples containing spiked crystallinity. These spiked samples possess implicit differences compared to native crystalline samples, regarding size and spatial distribution of the crystals as well as their molecular environment. In this study, we demonstrate that it is possible to grow defined amounts of crystalline API in solid dosage forms, which enables us to study the biopharmaceutical impact of actual crystallization. For this purpose, we studied the crystal growth in fenofibrate tablets over time under an elevated moisture using transmission Raman spectroscopy (TRS). As a nondestructive method to assess API crystallinity in ASD formulations, TRS enables the monitoring of crystal growth in individual dosage forms. Once the kinetic trace of the crystal growth for a certain environmental condition is determined, this method can be used to produce samples with defined amounts of crystallized API. To investigate the biopharmaceutical impact of crystallized API, non-QC dissolution methods were used, designed to identify differences between the various amounts of crystalline materials present. The drug release in the samples manufactured in this fashion was compared to that of samples with spiked crystallinity. In this study, we present for the first time a method for targeted crystallization of amorphous tablets to simulate crystallized ASDs. This methodology is a valuable tool to generate model systems for biopharmaceutical studies on the impact of crystallinity on the bioavailability.

  4. Study on Biopharmaceutics Classification and Oral Bioavailability of a Novel Multikinase Inhibitor NCE for Cancer Therapy

    Directory of Open Access Journals (Sweden)

    Yang Yang

    2014-04-01

    Full Text Available Specific biopharmaceutics classification investigation and study on phamacokinetic profile of a novel drug candidate (2-methylcarbamoyl-4-{4-[3- (trifluoromethyl benzamido] phenoxy} pyridinium 4-methylbenzenesulfonate monohydrate, NCE were carried out. Equilibrium solubility and intrinsic dissolution rate (IDR of NCE were estimated in different phosphate buffers. Effective intestinal permeability (Peff of NCE was determined using single-pass intestinal perfusion technique in rat duodenum, jejunum and ileum at three concentrations. Theophylline (high permeability and ranitidine (low permeability were also applied to access the permeability of NCE as reference compounds. The bioavailability after intragastrical and intravenous administration was measured in beagle dogs. The solubility of NCE in tested phosphate buffers was quite low with the maximum solubility of 81.73 μg/mL at pH 1.0. The intrinsic dissolution ratio of NCE was 1 × 10−4 mg·min−1·cm−2. The Peff value of NCE in all intestinal segments was more proximate to the high-permeability reference theophylline. Therefore, NCE was classified as class II drug according to Biopharmaceutics Classification System due to its low solubility and high intestinal permeability. In addition, concentration-dependent permeability was not observed in all the segments, indicating that there might be passive transportation for NCE. The absolute oral bioavailability of NCE in beagle dogs was 26.75%. Therefore, dissolution promotion will be crucial for oral formulation development and intravenous administration route will also be suggested for further NCE formulation development. All the data would provide a reference for biopharmaceutics classification research of other novel drug candidates.

  5. Study on biopharmaceutics classification and oral bioavailability of a novel multikinase inhibitor NCE for cancer therapy.

    Science.gov (United States)

    Yang, Yang; Fan, Chun-Mei; He, Xuan; Ren, Ke; Zhang, Jin-Kun; He, Ying-Ju; Yu, Luo-Ting; Zhao, Ying-Lan; Gong, Chang-Yang; Zheng, Yu; Song, Xiang-Rong; Zeng, Jun

    2014-04-25

    Specific biopharmaceutics classification investigation and study on phamacokinetic profile of a novel drug candidate (2-methylcarbamoyl-4-{4-[3- (trifluoromethyl) benzamido] phenoxy} pyridinium 4-methylbenzenesulfonate monohydrate, NCE) were carried out. Equilibrium solubility and intrinsic dissolution rate (IDR) of NCE were estimated in different phosphate buffers. Effective intestinal permeability (P(eff)) of NCE was determined using single-pass intestinal perfusion technique in rat duodenum, jejunum and ileum at three concentrations. Theophylline (high permeability) and ranitidine (low permeability) were also applied to access the permeability of NCE as reference compounds. The bioavailability after intragastrical and intravenous administration was measured in beagle dogs. The solubility of NCE in tested phosphate buffers was quite low with the maximum solubility of 81.73 μg/mL at pH 1.0. The intrinsic dissolution ratio of NCE was 1 × 10⁻⁴ mg·min⁻¹·cm⁻². The P(eff) value of NCE in all intestinal segments was more proximate to the high-permeability reference theophylline. Therefore, NCE was classified as class II drug according to Biopharmaceutics Classification System due to its low solubility and high intestinal permeability. In addition, concentration-dependent permeability was not observed in all the segments, indicating that there might be passive transportation for NCE. The absolute oral bioavailability of NCE in beagle dogs was 26.75%. Therefore, dissolution promotion will be crucial for oral formulation development and intravenous administration route will also be suggested for further NCE formulation development. All the data would provide a reference for biopharmaceutics classification research of other novel drug candidates.

  6. Assessing the Inventiveness of Bio-Pharmaceuticals under European and US Patent Law

    DEFF Research Database (Denmark)

    Minssen, Timo

    , is utterly wrong, since any DNA and the information it contains is the embodiment of the code of life and should be regarded part of the common heritage of mankind. Some patent opponents go even further and argue for a prohibition of patents on proteins. Others, and in particular the life science industry...... specifically, it investigates how the European and US patent systems interpret and apply the so called "inventive step" (Europe) or "non-obviousness" requirement (U.S.) vis-à-vis bio-pharmaceutical technology with a special emphasis on DNA-and protein related inventions. In addition to evaluating the de lata...

  7. Hydrogen deuterium exchange mass spectrometry in biopharmaceutical discovery and development – A review

    Energy Technology Data Exchange (ETDEWEB)

    Deng, Bin, E-mail: dengbin@yorku.ca [Chemistry Department, York University, 4700 Keele Street, Toronto, ON, M3J 1P3 (Canada); The Centre for Research in Mass Spectrometry, York University, Toronto, ON, M3J1P3 (Canada); Lento, Cristina, E-mail: clento@yorku.ca [Chemistry Department, York University, 4700 Keele Street, Toronto, ON, M3J 1P3 (Canada); The Centre for Research in Mass Spectrometry, York University, Toronto, ON, M3J1P3 (Canada); Wilson, Derek J., E-mail: dkwilson@yorku.ca [Chemistry Department, York University, 4700 Keele Street, Toronto, ON, M3J 1P3 (Canada); The Centre for Research in Mass Spectrometry, York University, Toronto, ON, M3J1P3 (Canada)

    2016-10-12

    Protein therapeutics have emerged as a major class of biopharmaceuticals over the past several decades, a trend that has motivated the advancement of bioanalytical technologies for protein therapeutic characterization. Hydrogen deuterium exchange mass spectrometry (HDX-MS) is a powerful and sensitive technique that can probe the higher order structure of proteins and has been used in the assessment and development of monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs) and biosimilar antibodies. It has also been used to quantify protein-ligand, protein-receptor and other protein-protein interactions involved in signaling pathways. In manufacturing and development, HDX-MS can validate storage formulations and manufacturing processes for various biotherapeutics. Currently, HDX-MS is being refined to provide additional coverage, sensitivity and structural specificity and implemented on the millisecond timescale to reveal residual structure and dynamics in disordered domains and intrinsically disordered proteins. - Highlights: • The pharmaceuticals industry is increasingly shifting to protein therapeutics. • Hydrogen deuterium exchange mass spectrometry is uniquely well suited to support biopharmaceutical development. • Applications for hydrogen deuterium exchange span drug discovery, development and manufacturing. • Future developments will allow improved sensitivity, structural resolution and a broader range of dynamics to be monitored.

  8. Advances in industrial biopharmaceutical batch process monitoring: Machine-learning methods for small data problems.

    Science.gov (United States)

    Tulsyan, Aditya; Garvin, Christopher; Ündey, Cenk

    2018-04-06

    Biopharmaceutical manufacturing comprises of multiple distinct processing steps that require effective and efficient monitoring of many variables simultaneously in real-time. The state-of-the-art real-time multivariate statistical batch process monitoring (BPM) platforms have been in use in recent years to ensure comprehensive monitoring is in place as a complementary tool for continued process verification to detect weak signals. This article addresses a longstanding, industry-wide problem in BPM, referred to as the "Low-N" problem, wherein a product has a limited production history. The current best industrial practice to address the Low-N problem is to switch from a multivariate to a univariate BPM, until sufficient product history is available to build and deploy a multivariate BPM platform. Every batch run without a robust multivariate BPM platform poses risk of not detecting potential weak signals developing in the process that might have an impact on process and product performance. In this article, we propose an approach to solve the Low-N problem by generating an arbitrarily large number of in silico batches through a combination of hardware exploitation and machine-learning methods. To the best of authors' knowledge, this is the first article to provide a solution to the Low-N problem in biopharmaceutical manufacturing using machine-learning methods. Several industrial case studies from bulk drug substance manufacturing are presented to demonstrate the efficacy of the proposed approach for BPM under various Low-N scenarios. © 2018 Wiley Periodicals, Inc.

  9. Opportunities and challenges of real-time release testing in biopharmaceutical manufacturing.

    Science.gov (United States)

    Jiang, Mo; Severson, Kristen A; Love, John Christopher; Madden, Helena; Swann, Patrick; Zang, Li; Braatz, Richard D

    2017-11-01

    Real-time release testing (RTRT) is defined as "the ability to evaluate and ensure the quality of in-process and/or final drug product based on process data, which typically includes a valid combination of measured material attributes and process controls" (ICH Q8[R2]). This article discusses sensors (process analytical technology, PAT) and control strategies that enable RTRT for the spectrum of critical quality attributes (CQAs) in biopharmaceutical manufacturing. Case studies from the small-molecule and biologic pharmaceutical industry are described to demonstrate how RTRT can be facilitated by integrated manufacturing and multivariable control strategies to ensure the quality of products. RTRT can enable increased assurance of product safety, efficacy, and quality-with improved productivity including faster release and potentially decreased costs-all of which improve the value to patients. To implement a complete RTRT solution, biologic drug manufacturers need to consider the special attributes of their industry, particularly sterility and the measurement of viral and microbial contamination. Continued advances in on-line and in-line sensor technologies are key for the biopharmaceutical manufacturing industry to achieve the potential of RTRT. Related article: http://onlinelibrary.wiley.com/doi/10.1002/bit.26378/full. © 2017 Wiley Periodicals, Inc.

  10. Hydrogen deuterium exchange mass spectrometry in biopharmaceutical discovery and development – A review

    International Nuclear Information System (INIS)

    Deng, Bin; Lento, Cristina; Wilson, Derek J.

    2016-01-01

    Protein therapeutics have emerged as a major class of biopharmaceuticals over the past several decades, a trend that has motivated the advancement of bioanalytical technologies for protein therapeutic characterization. Hydrogen deuterium exchange mass spectrometry (HDX-MS) is a powerful and sensitive technique that can probe the higher order structure of proteins and has been used in the assessment and development of monoclonal antibodies (mAbs), antibody-drug conjugates (ADCs) and biosimilar antibodies. It has also been used to quantify protein-ligand, protein-receptor and other protein-protein interactions involved in signaling pathways. In manufacturing and development, HDX-MS can validate storage formulations and manufacturing processes for various biotherapeutics. Currently, HDX-MS is being refined to provide additional coverage, sensitivity and structural specificity and implemented on the millisecond timescale to reveal residual structure and dynamics in disordered domains and intrinsically disordered proteins. - Highlights: • The pharmaceuticals industry is increasingly shifting to protein therapeutics. • Hydrogen deuterium exchange mass spectrometry is uniquely well suited to support biopharmaceutical development. • Applications for hydrogen deuterium exchange span drug discovery, development and manufacturing. • Future developments will allow improved sensitivity, structural resolution and a broader range of dynamics to be monitored.

  11. Novel approaches to vaginal delivery and safety of microbicides: biopharmaceuticals, nanoparticles, and vaccines.

    Science.gov (United States)

    Whaley, Kevin J; Hanes, Justin; Shattock, Robin; Cone, Richard A; Friend, David R

    2010-12-01

    The HIV-1 epidemic remains unchecked despite existing technology; vaccines and microbicides in development may help reverse the epidemic. Reverse transcriptase inhibitors (RTIs) formulated in gels tenofovir (TFV) and IVRs (dapivirine) are under clinical development. While TFV or similar products may prove successful for HIV-1, alternatives to RTIs may provide additional benefits, e.g., broader STI prevention. Biopharmaceutical agents under development as microbicides include cyanovirin, RANTES analogues, commensals, and Mabs. Cost of manufacturing biopharmaceuticals has been reduced and they can be formulated into tablets, films, and IVRs for vaginal delivery. Nanotechnology offers a novel approach to formulate microbicides potentially leading to uniform epithelial delivery. Delivery through vaginal mucus may be possible by controlling nanoparticle size and surface characteristics. Combining prevention modalities may be the most effective means of preventing STI transmission, importantly, codelivery of microbicides and vaccines has demonstrated. Finally, the safety of microbicide preparations and excipients commonly used can be assessed using a mouse/HSV-2 susceptibility model. Screening of new microbicide candidates and formulation excipients may avoid past issues of enhancing HIV-1 transmission. This article forms part of a special supplement covering several presentations on novel microbicide formulations from the symposium on "Recent Trends in Microbicide Formulations" held on 25 and 26 January 2010, Arlington, VA. Copyright © 2010 Elsevier B.V. All rights reserved.

  12. Characterization of systems with amino-acids and oligosaccharides as modifiers of biopharmaceutical properties of furosemide.

    Science.gov (United States)

    Miranda, Julieta Abraham; Garnero, Claudia; Zoppi, Ariana; Sterren, Vanesa; Ayala, Alejandro P; Longhi, Marcela R

    2018-02-05

    Furosemide is the most commonly prescribed diuretic drug in spite of its suboptimal biopharmaceutical properties. In this work, the addition of different amino-acids was studied with the aim of selecting an enhancer of the furosemide solubility. The best results were obtained with arginine. Also, binary (furosemide:arginine) and ternary (furosemide:arginine:β-cyclodextrin and furosemide:arginine:maltodextrin) systems were prepared by the kneading method and they were compared with their corresponding physical mixtures. These new systems were characterized by Fourier transform infrared and Raman spectroscopy, X-ray powder diffractometry, scanning electron microscopy, thermogravimetric analysis, and differential scanning calorimetry. In addition, dissolution studies were performed in simulated gastric fluid. The best results in relation to improving biopharmaceutical properties were obtained with a binary combination of furosemide and arginine, demonstrating that this system could result in a suitable candidate for the development of a promising pharmaceutical formulation of the drug. Copyright © 2017 Elsevier B.V. All rights reserved.

  13. Impact of Magnetic Stirring on Stainless Steel Integrity: Effect on Biopharmaceutical Processing.

    Science.gov (United States)

    Thompson, Christopher; Wilson, Kelly; Kim, Yoen Joo; Xie, Min; Wang, William K; Wendeler, Michaela

    2017-11-01

    Stainless steel containers are widely used in the pharmaceutical and biopharmaceutical industry for the storage of buffers, process intermediates, and purified drug substance. They are generally held to be corrosion resistant, biocompatible, and nonreactive, although it is well established that trace amounts of metal ions can leach from stainless steel equipment into biopharmaceutical products. We report here that the use of stainless steel containers in conjunction with magnetic stirring bars leads to significantly aggravated metal contamination, consisting of both metal particles and significantly elevated metal ions in solution, the degree of which is several orders of magnitude higher than described for static conditions. Metal particles are analyzed by scanning electron microscopy with electron-dispersive X-ray spectroscopy, and metal content in solution is quantitated at different time points by inductively coupled plasma-mass spectrometry. The concentration of iron, chromium, nickel, and manganese increases with increasing stirring time and speed. We describe the impact of buffer components on the extent of metal particles and ions in solution and illustrate the effect on model proteins. Copyright © 2017 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  14. Characterization of Protein-Excipient Microheterogeneity in Biopharmaceutical Solid-State Formulations by Confocal Fluorescence Microscopy.

    Science.gov (United States)

    Koshari, Stijn H S; Ross, Jean L; Nayak, Purnendu K; Zarraga, Isidro E; Rajagopal, Karthikan; Wagner, Norman J; Lenhoff, Abraham M

    2017-02-06

    Protein-stabilizer microheterogeneity is believed to influence long-term protein stability in solid-state biopharmaceutical formulations and its characterization is therefore essential for the rational design of stable formulations. However, the spatial distribution of the protein and the stabilizer in a solid-state formulation is, in general, difficult to characterize because of the lack of a functional, simple, and reliable characterization technique. We demonstrate the use of confocal fluorescence microscopy with fluorescently labeled monoclonal antibodies (mAbs) and antibody fragments (Fabs) to directly visualize three-dimensional particle morphologies and protein distributions in dried biopharmaceutical formulations, without restrictions on processing conditions or the need for extensive data analysis. While industrially relevant lyophilization procedures of a model IgG1 mAb generally lead to uniform protein-excipient distribution, the method shows that specific spray-drying conditions lead to distinct protein-excipient segregation. Therefore, this method can enable more definitive optimization of formulation conditions than has previously been possible.

  15. Considerations for a Pediatric Biopharmaceutics Classification System (BCS): application to five drugs.

    Science.gov (United States)

    Gandhi, Shivani V; Rodriguez, William; Khan, Mansoor; Polli, James E

    2014-06-01

    It has been advocated that biopharmaceutic risk assessment should be conducted early in pediatric product development and synchronized with the adult product development program. However, we are unaware of efforts to classify drugs into a Biopharmaceutics Classification System (BCS) framework for pediatric patients. The objective was to classify five drugs into a potential BCS. These five drugs were selected since both oral and intravenous pharmacokinetic data were available for each drug, and covered the four BCS classes in adults. Literature searches for each drug were conducted using Medline and applied to classify drugs with respect to solubility and permeability in pediatric subpopulations. Four pediatric subpopulations were considered: neonates, infants, children, and adolescents. Regarding solubility, dose numbers were calculated using a volume for each subpopulation based on body surface area (BSA) relative to 250 ml for a 1.73 m(2) adult. Dose numbers spanned a range of values, depending upon the pediatric dose formula and subpopulation. Regarding permeability, pharmacokinetic literature data required assumptions and decisions about data collection. Using a devised pediatric BCS framework, there was agreement in adult and pediatric BCS class for two drugs, azithromycin (class 3) and ciprofloxacin (class 4). There was discordance for the three drugs that have high adult permeability since all pediatric permeabilities were low: dolasetron (class 3 in pediatric), ketoprofen (class 4 in pediatric), and voriconazole (class 4 in pediatric). A main contribution of this work is the identification of critical factors required for a pediatric BCS.

  16. A new roadmap for biopharmaceutical drug product development: Integrating development, validation, and quality by design.

    Science.gov (United States)

    Martin-Moe, Sheryl; Lim, Fredric J; Wong, Rita L; Sreedhara, Alavattam; Sundaram, Jagannathan; Sane, Samir U

    2011-08-01

    Quality by design (QbD) is a science- and risk-based approach to drug product development. Although pharmaceutical companies have historically used many of the same principles during development, this knowledge was not always formally captured or proactively submitted to regulators. In recent years, the US Food and Drug Administration has also recognized the need for more controls in the drug manufacturing processes, especially for biological therapeutics, and it has recently launched an initiative for Pharmaceutical Quality for the 21st Century to modernize pharmaceutical manufacturing and improve product quality. In the biopharmaceutical world, the QbD efforts have been mainly focused on active pharmaceutical ingredient processes with little emphasis on drug product development. We present a systematic approach to biopharmaceutical drug product development using a monoclonal antibody as an example. The approach presented herein leverages scientific understanding of products and processes, risk assessments, and rational experimental design to deliver processes that are consistent with QbD philosophy without excessive incremental effort. Data generated using these approaches will not only strengthen data packages to support specifications and manufacturing ranges but hopefully simplify implementation of postapproval changes. We anticipate that this approach will positively impact cost for companies, regulatory agencies, and patients, alike. Copyright © 2011 Wiley-Liss, Inc.

  17. Accumulation of organic compounds leached from plastic materials used in biopharmaceutical process containers.

    Science.gov (United States)

    Jenke, Dennis R; Zietlow, David; Garber, Mary Jo; Sadain, Salma; Reiber, Duane; Terbush, William

    2007-01-01

    Plastic materials are widely used in medical items, such as solution containers, transfusion sets, transfer tubing, and devices. An emerging trend in the biotechnology industry is the utilization of plastic containers to prepare, transport, and store an assortment of solutions including buffers, media, and in-process and finished product. The direct contact of such containers with the product at one or more points in its lifetime raises the possibility that container leachables may accumulate in the finished product. The interaction between several commercially available container materials and numerous model test solutions (representative of buffers and media used in biopharmaceutical applications) was investigated. This paper summarizes the identification of leachables associated with the container materials and documents the levels to which targeted leachables accumulate in the test solutions under defined storage conditions.

  18. RFID sensors as the common sensing platform for single-use biopharmaceutical manufacturing

    International Nuclear Information System (INIS)

    Potyrailo, Radislav A; Surman, Cheryl; Monk, David; Morris, William G; Wortley, Timothy; Vincent, Mark; Diana, Rafael; Pizzi, Vincent; Carter, Jeffrey; Gach, Gerard; Klensmeden, Staffan; Ehring, Hanno

    2011-01-01

    The lack of reliable single-use sensors prevents the biopharmaceutical industry from fully embracing single-use biomanufacturing processes. Sensors based on the same detection platform for all critical parameters in single-use bioprocess components would be highly desirable to significantly simplify their installation, calibration and operation. We review here our approach for passive radio-frequency identification (RFID)-based sensing that does not rely on costly proprietary RFID memory chips with an analog input but rather implements ubiquitous passive 13.56 MHz RFID tags as inductively coupled sensors with at least 16 bit resolution provided by a sensor reader. The developed RFID sensors combine several measured parameters from the resonant sensor antenna with multivariate data analysis and deliver unique capability of multiparameter sensing and rejection of environmental interferences with a single sensor. This general sensing approach provides an elegant solution for both analytical measurement and identification and documentation of the measured location. (topical review)

  19. Approval of the first biosimilar antibodies in Europe: a major landmark for the biopharmaceutical industry.

    Science.gov (United States)

    Beck, Alain; Reichert, Janice M

    2013-01-01

    In a defining moment for the European Medicines Agency (EMA) and the biopharmaceutical industry, on June 27, 2013 EMA's Committee for Medicinal Products for Human Use adopted a positive opinion for two biosimilar infliximab products (Celltrion's Remsima® and Hospira's Inflectra®), and recommended that they be approved for marketing in the European Union (EU). The European Commission's decision on an application is typically issued 67 d after an opinion is provided; thus, decisions are expected in early September 2013. If approved, the products will comprise the first biosimilar antibody made available to patients in a highly regulated market, although launch may be delayed due to an extension of the reference product's (Remicade®) patent in the EU.

  20. Second International Conference on Accelerating Biopharmaceutical Development: March 9-12, 2009, Coronado, CA, USA.

    Science.gov (United States)

    Reichert, Janice M; Jacob, Nitya M; Amanullah, Ashraf

    2009-01-01

    The Second International Conference on Accelerating Biopharmaceutical Development was held in Coronado, California. The meeting was organized by the Society for Biological Engineering (SBE) and the American Institute of Chemical Engineers (AIChE); SBE is a technological community of the AIChE. Bob Adamson (Wyeth) and Chuck Goochee (Centocor) were co-chairs of the event, which had the theme "Delivering cost-effective, robust processes and methods quickly and efficiently." The first day focused on emerging disruptive technologies and cutting-edge analytical techniques. Day two featured presentations on accelerated cell culture process development, critical quality attributes, specifications and comparability, and high throughput protein formulation development. The final day was dedicated to discussion of technology options and new analysis methods provided by emerging disruptive technologies; functional interaction, integration and synergy in platform development; and rapid and economic purification process development.

  1. Microtools for single-cell analysis in biopharmaceutical development and manufacturing.

    Science.gov (United States)

    Love, Kerry Routenberg; Bagh, Sangram; Choi, Jonghoon; Love, J Christopher

    2013-05-01

    Biologic drugs are promoting growth in the biopharmaceutical industry. Despite the clinical benefits of these drugs, the time and costs required to bring new biologics to market still are substantial. Three key challenges, among others, persist in the development of biologic drugs: namely, establishing product similarity, product toxicity, and global accessibility. New classes of microtools that facilitate the isolation and interrogation of single cells have the potential to impact each of these challenges. This opinion considers recent examples of microtools with demonstrated or potential utility to address problems in these areas. Integrating these advanced technologies into the development of new biologics could greatly reduce time and costs required to bring alternative products to market, and thus expand their global availability. Copyright © 2013 Elsevier Ltd. All rights reserved.

  2. [Impacts of multicomponent environment on solubility of puerarin in biopharmaceutics classification system of Chinese materia medica].

    Science.gov (United States)

    Hou, Cheng-Bo; Wang, Guo-Peng; Zhang, Qiang; Yang, Wen-Ning; Lv, Bei-Ran; Wei, Li; Dong, Ling

    2014-12-01

    To illustrate the solubility involved in biopharmaceutics classification system of Chinese materia medica (CMMBCS) , the influences of artificial multicomponent environment on solubility were investigated in this study. Mathematical model was built to describe the variation trend of their influence on the solubility of puerarin. Carried out with progressive levels, single component environment: baicalin, berberine and glycyrrhizic acid; double-component environment: baicalin and glycyrrhizic acid, baicalin and berberine and glycyrrhizic acid and berberine; and treble-component environment: baicalin, berberin, glycyrrhizic acid were used to describe the variation tendency of their influences on the solubility of puerarin, respectively. And then, the mathematical regression equation model was established to characterize the solubility of puerarin under multicomponent environment.

  3. Pharmacokinetic and biopharmaceutic aspects of some psoralen derivatives used in dermatology

    International Nuclear Information System (INIS)

    Stolk, L.M.L.

    1982-01-01

    In the present thesis the pharmacokinetic and biopharmaceutic properties of some psoralen derivatives, that are used in photochemotherapy of dermatological diseases like vitiligo and psoriasis, are studied. Photochemotherapy is a combination of oral administration of one of the psoralen derivatives, 8-methoxypsoralen (8-MOP), 5-methoxypsoralen (5-MOP) or 4, 5', 8-trimethylpsoralen (TMP), and irradiation with long wave ultraviolet light, U.V.-A (320-400 nm), two hours later. This treatment is commonly called PUVA (Psoralen-UV-A). The purpose of the investigation was to develop an 8-MOP dosage form with a fast and reproducible absorption. Various dosage forms of 8-MOP were administered to volunteers and patients and 8-MOP concentrations in body fluids determined. Also the pharmacokinetic properties of 5-MOP and TMP were investigated in a pilot study. (Auth.)

  4. Cell-Penetrating Peptides as Carriers for Oral Delivery of Biopharmaceuticals

    DEFF Research Database (Denmark)

    Kristensen, Mie; Nielsen, Hanne Mørck

    2016-01-01

    Oral delivery of biopharmaceuticals, for example peptides and proteins, constitutes a great challenge in drug delivery due to their low chemical stability and poor permeation across the intestinal mucosa, to a large extent limiting the mode of administration to injections, which is not favouring...... patient compliance. Nevertheless, cell-penetrating peptides (CPPs) have shown promising potential as carriers to overcome the epithelium, and this minireview highlights recent knowledge gained within the field of CPP-mediated transepithelial delivery of therapeutic peptides and proteins from the intestine...... is to be preferred depends on the physicochemical properties of both the specific CPP and the specific cargo. In addition to the physical epithelial barrier, a metabolic barrier must be overcome in order to obtain CPP-mediated delivery of a cargo drug from the intestine, and a number of strategies have been employed...

  5. Capacity Planning for Batch and Perfusion Bioprocesses Across Multiple Biopharmaceutical Facilities

    Science.gov (United States)

    Siganporia, Cyrus C; Ghosh, Soumitra; Daszkowski, Thomas; Papageorgiou, Lazaros G; Farid, Suzanne S

    2014-01-01

    Production planning for biopharmaceutical portfolios becomes more complex when products switch between fed-batch and continuous perfusion culture processes. This article describes the development of a discrete-time mixed integer linear programming (MILP) model to optimize capacity plans for multiple biopharmaceutical products, with either batch or perfusion bioprocesses, across multiple facilities to meet quarterly demands. The model comprised specific features to account for products with fed-batch or perfusion culture processes such as sequence-dependent changeover times, continuous culture constraints, and decoupled upstream and downstream operations that permit independent scheduling of each. Strategic inventory levels were accounted for by applying cost penalties when they were not met. A rolling time horizon methodology was utilized in conjunction with the MILP model and was shown to obtain solutions with greater optimality in less computational time than the full-scale model. The model was applied to an industrial case study to illustrate how the framework aids decisions regarding outsourcing capacity to third party manufacturers or building new facilities. The impact of variations on key parameters such as demand or titres on the optimal production plans and costs was captured. The analysis identified the critical ratio of in-house to contract manufacturing organization (CMO) manufacturing costs that led the optimization results to favor building a future facility over using a CMO. The tool predicted that if titres were higher than expected then the optimal solution would allocate more production to in-house facilities, where manufacturing costs were lower. Utilization graphs indicated when capacity expansion should be considered. © 2013 The Authors Biotechnology Progress published by Wiley Periodicals, Inc. on behalf of American Institute of Chemical Engineers Biotechnol. Prog., 30:594–606, 2014 PMID:24376262

  6. Aspects of research and development contract terms in the bio/pharmaceutical sector.

    Science.gov (United States)

    Banerjee, Tannista

    2012-01-01

    The cost of new drug development is increasing every year. Pharmaceutical companies use R&D joint ventures, mergers, and outsource different stages of pharmaceutical R&D activities for a faster and cost minimizing method of innovation. Pharmaceutical companies outsource R&D activities to independent small biotech or pharmaceutical companies that specialize in different stages of pharmaceutical R&D. This chapter examines the determinants of the payment structure of research contracts between large bio/pharmaceutical companies and specialized research firms. Determinants of R&D contracts are analyzed using detailed R&D contract data between bio/pharmaceutical companies and independent research firms for 10 years. A multinomial logit model is used in order to understand the determinants of three different types of contracts; royalty contracts, fixed payment contracts, and the mixed contracts. Under uncertainty, the likelihood of a royalty contract rises for the early stages of the research and with the patent stock of the research firm. It is more likely to observe both royalty and fixed payment if the pharmaceutical client has past contracts with the same research firm. The results also suggest that if Food and Drug Administration (FDA) is more stringent in any disease area in reviewing the new drug application, then the likelihood of signing pure royalty contract decreases. Understanding the nature of R&D contracts and the effects of FDA's behavior on the pharmaceutical R&D contract is important because these contracts not only affect the cost of new drug invention but also the quality and the rate of invention. VALUE: Results are useful for both the pharmaceutical companies and the economic/business researchers.

  7. Biopharmaceutical characterization of praziquantel cocrystals and cyclodextrin complexes prepared by grinding.

    Science.gov (United States)

    Cugovčan, Martina; Jablan, Jasna; Lovrić, Jasmina; Cinčić, Dominik; Galić, Nives; Jug, Mario

    2017-04-15

    Mechanochemical activation using several different co-grinding additives was applied as a green chemistry approach to improve physiochemical and biopharmaceutical properties of praziquantel (PZQ). Liquid assisted grinding with an equimolar amount of citric acid (CA), malic acid (MA), salicylic acid (SA) and tartaric acid (TA) gained in cocrystal formation, which all showed pH-dependent solubility and dissolution rate. However, the most soluble cocrystal of PZQ with MA was chemically unstable, as seen during the stability testing. Equimolar cyclodextrin complexes prepared by neat grinding with amorphous hydroxypropyl-β-cyclodextrin (HPβCD) and randomly methylated β-cyclodextrin (MEβCD) showed the highest improvement in drug solubility and the dissolution rate, but only PZQ/HPβCD product presented an acceptable chemical and photostability profile. A combined approach, by co-grinding the drug with both MA and HPβCD in equimolar ratio, also gave highly soluble amorphous product which again was chemical instable and therefore not suitable for the pharmaceutical use. Studies on Caco-2 monolayer confirmed the biocompatibility of PZQ/HPβCD complex and showed that complexation did not adversely affect the intrinsically high PZQ permeability (P app (PZQ)=(3.72±0.33)×10 -5 cms -1 and P app (PZQ/HPβCD)=(3.65±0.21)×10 -5 cms -1 ; p>0.05). All this confirmed that the co-grinding with the proper additive is as a promising strategy to improve biopharmaceutical properties of the drug. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Endotoxin inactivation via steam-heat treatment in dilute simethicone emulsions used in biopharmaceutical processes.

    Science.gov (United States)

    Britt, Keith A; Galvin, Jeffrey; Gammell, Patrick; Nti-Gyabaah, Joseph; Boras, George; Kolwyck, David; Ramirez, José G; Presente, Esther; Naugle, Gregory

    2014-01-01

    Simethicone emulsion is used to regulate foaming in cell culture operations in biopharmaceutical processes. It is also a potential source of endotoxin contamination. The inactivation of endotoxins in dilute simethicone emulsions was assessed as a function of time at different steam temperatures using a Limulus amebocyte lysate kinetic chromogenic technique. Endotoxin inactivation from steam-heat treatment was fit to a four-parameter double exponential decay model, which indicated that endotoxin inactivation was biphasic, consisting of fast and slow regimes. In the fast regime, temperature-related effects were dominant. Transitioning into the slow regime, the observed temperature dependence diminished, and concentration-related effects became increasingly significant. The change in the Gibbs free energy moving through the transition state indicated that a large energy barrier must be overcome for endotoxin inactivation to occur. The corresponding Arrhenius pre-exponential factor was >10(12) s(-1) suggesting that endotoxins in aqueous solution exist as aggregates. The disorder associated with the endotoxin inactivation reaction pathway was assessed via the change in entropy moving through the transition state. This quantity was positive indicating that endotoxin inactivation may result from hydrolysis of individual endotoxin molecules, which perturbs the conformation of endotoxin aggregates, thereby modulating the biological activity observed. Steam-heat treatment decreased endotoxin levels by 1-2 logarithm (log) reduction (LRV), which may be practically relevant depending on incoming raw material endotoxin levels. Antifoam efficiency and cell culture performance were negligibly impacted following steam-heat treatment. The results from this study show that steam-heat treatment is a viable endotoxin control strategy that can be implemented to support large-scale biopharmaceutical manufacturing. © 2014 American Institute of Chemical Engineers.

  9. Capacity planning for batch and perfusion bioprocesses across multiple biopharmaceutical facilities.

    Science.gov (United States)

    Siganporia, Cyrus C; Ghosh, Soumitra; Daszkowski, Thomas; Papageorgiou, Lazaros G; Farid, Suzanne S

    2014-01-01

    Production planning for biopharmaceutical portfolios becomes more complex when products switch between fed-batch and continuous perfusion culture processes. This article describes the development of a discrete-time mixed integer linear programming (MILP) model to optimize capacity plans for multiple biopharmaceutical products, with either batch or perfusion bioprocesses, across multiple facilities to meet quarterly demands. The model comprised specific features to account for products with fed-batch or perfusion culture processes such as sequence-dependent changeover times, continuous culture constraints, and decoupled upstream and downstream operations that permit independent scheduling of each. Strategic inventory levels were accounted for by applying cost penalties when they were not met. A rolling time horizon methodology was utilized in conjunction with the MILP model and was shown to obtain solutions with greater optimality in less computational time than the full-scale model. The model was applied to an industrial case study to illustrate how the framework aids decisions regarding outsourcing capacity to third party manufacturers or building new facilities. The impact of variations on key parameters such as demand or titres on the optimal production plans and costs was captured. The analysis identified the critical ratio of in-house to contract manufacturing organization (CMO) manufacturing costs that led the optimization results to favor building a future facility over using a CMO. The tool predicted that if titres were higher than expected then the optimal solution would allocate more production to in-house facilities, where manufacturing costs were lower. Utilization graphs indicated when capacity expansion should be considered. © 2014 The Authors Biotechnology Progress published by Wiley Periodicals, Inc. on behalf of American Institute of Chemical Engineers.

  10. Animal cell cultures: recent achievements and perspectives in the production of biopharmaceuticals.

    Science.gov (United States)

    Butler, Michael

    2005-08-01

    There has been a rapid increase in the number and demand for approved biopharmaceuticals produced from animal cell culture processes over the last few years. In part, this has been due to the efficacy of several humanized monoclonal antibodies that are required at large doses for therapeutic use. There have also been several identifiable advances in animal cell technology that has enabled efficient biomanufacture of these products. Gene vector systems allow high specific protein expression and some minimize the undesirable process of gene silencing that may occur in prolonged culture. Characterization of cellular metabolism and physiology has enabled the design of fed-batch and perfusion bioreactor processes that has allowed a significant improvement in product yield, some of which are now approaching 5 g/L. Many of these processes are now being designed in serum-free and animal-component-free media to ensure that products are not contaminated with the adventitious agents found in bovine serum. There are several areas that can be identified that could lead to further improvement in cell culture systems. This includes the down-regulation of apoptosis to enable prolonged cell survival under potentially adverse conditions. The characterization of the critical parameters of glycosylation should enable process control to reduce the heterogeneity of glycoforms so that production processes are consistent. Further improvement may also be made by the identification of glycoforms with enhanced biological activity to enhance clinical efficacy. The ability to produce the ever-increasing number of biopharmaceuticals by animal cell culture is dependent on sufficient bioreactor capacity in the industry. A recent shortfall in available worldwide culture capacity has encouraged commercial activity in contract manufacturing operations. However, some analysts indicate that this still may not be enough and that future manufacturing demand may exceed production capacity as the number

  11. Pediatric Biopharmaceutical Classification System: Using Age-Appropriate Initial Gastric Volume.

    Science.gov (United States)

    Shawahna, Ramzi

    2016-05-01

    Development of optimized pediatric formulations for oral administration can be challenging, time consuming, and financially intensive process. Since its inception, the biopharmaceutical classification system (BCS) has facilitated the development of oral drug formulations destined for adults. At least theoretically, the BCS principles are applied also to pediatrics. A comprehensive age-appropriate BCS has not been fully developed. The objective of this work was to provisionally classify oral drugs listed on the latest World Health Organization's Essential Medicines List for Children into an age-appropriate BCS. A total of 38 orally administered drugs were included in this classification. Dose numbers were calculated using age-appropriate initial gastric volume for neonates, 6-month-old infants, and children aging 1 year through adulthood. Using age-appropriate initial gastric volume and British National Formulary age-specific dosing recommendations in the calculation of dose numbers, the solubility classes shifted from low to high in pediatric subpopulations of 12 years and older for amoxicillin, 5 years, 12 years and older for cephalexin, 9 years and older for chloramphenicol, 3-4 years, 9-11 and 15 years and older for diazepam, 18 years and older (adult) for doxycycline and erythromycin, 8 years and older for phenobarbital, 10 years and older for prednisolone, and 15 years and older for trimethoprim. Pediatric biopharmaceutics are not fully understood where several knowledge gaps have been recently emphasized. The current biowaiver criteria are not suitable for safe application in all pediatric populations.

  12. Quantification of biopharmaceuticals and biomarkers in complex biological matrices: a comparison of liquid chromatography coupled to tandem mass spectrometry and ligand binding assays

    NARCIS (Netherlands)

    Bults, Peter; van de Merbel, Nico C; Bischoff, Rainer

    2015-01-01

    The quantification of proteins (biopharmaceuticals or biomarkers) in complex biological samples such as blood plasma requires exquisite sensitivity and selectivity, as all biological matrices contain myriads of proteins that are all made of the same 20 proteinogenic amino acids, notwithstanding

  13. Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: recommendations of the Innovative Medicines Initiative ABIRISK consortium

    NARCIS (Netherlands)

    Rup, B.; Pallardy, M.; Sikkema, D.; Albert, T.; Allez, M.; Broet, P.; Carini, C.; Creeke, P.; Davidson, J.; de Vries, N. [=Niek; Finco, D.; Fogdell-Hahn, A.; Havrdova, E.; Hincelin-Mery, A.; C Holland, M.; H Jensen, P. E.; Jury, E. C.; Kirby, H.; Kramer, D.; Lacroix-Desmazes, S.; Legrand, J.; Maggi, E.; Maillère, B.; Mariette, X.; Mauri, C.; Mikol, V.; Mulleman, D.; Oldenburg, J.; Paintaud, G.; R Pedersen, C.; Ruperto, N.; Seitz, R.; Spindeldreher, S.; Deisenhammer, F.

    2015-01-01

    Biopharmaceuticals (BPs) represent a rapidly growing class of approved and investigational drug therapies that is contributing significantly to advancing treatment in multiple disease areas, including inflammatory and autoimmune diseases, genetic deficiencies and cancer. Unfortunately, unwanted

  14. License Compliance Issues For Biopharmaceuticals: Special Challenges For Negotiations Between Companies And Non-Profit Research Institutions

    Science.gov (United States)

    Ponzio, Todd A.; Feindt, Hans; Ferguson, Steven

    2011-01-01

    Summary Biopharmaceuticals are therapeutic products based on biotechnology. They are manufactured by or from living organisms and are the most complex of all commercial medicines to develop, manufacture and qualify for regulatory approval. In recent years biopharmaceuticals have rapidly increased in number and importance with over 4001 already marketed in the U.S. and European markets alone. Many companies throughout the world are now ramping up investments in biopharmaceutical R&D and expanding their portfolios through licensing of early-stage biotechnologies from universities and other non-profit research institutions, and there is an increasing number of license agreements for biopharmaceutical product development relative to traditional small molecule drug compounds. This trend will only continue as large numbers of biosimilars and biogenerics enter the market. A primary goal of technology transfer offices associated with publicly-funded, non-profit research institutions is to establish patent protection for inventions deemed to have commercial potential and license them for product development. Such licenses help stimulate economic development and job creation, bring a stream of royalty revenue to the institution and, hopefully, advance the public good or public health by bringing new and useful products to market. In the course of applying for such licenses, a commercial development plan is usually put forth by the license applicant. This plan indicates the path the applicant expects to follow to bring the licensed invention to market. In the case of small molecule drug compounds, there exists a widely-recognized series of clinical development steps, dictated by regulatory requirements, that must be met to bring a new drug to market, such as completion of preclinical toxicology, Phase 1, 2 and 3 testing and product approvals. These steps often become the milestone/benchmark schedule incorporated into license agreements which technology transfer offices use to

  15. Microencapsulation for the Therapeutic Delivery of Drugs, Live Mammalian and Bacterial Cells, and Other Biopharmaceutics: Current Status and Future Directions

    Directory of Open Access Journals (Sweden)

    Catherine Tomaro-Duchesneau

    2013-01-01

    Full Text Available Microencapsulation is a technology that has shown significant promise in biotherapeutics, and other applications. It has been proven useful in the immobilization of drugs, live mammalian and bacterial cells and other cells, and other biopharmaceutics molecules, as it can provide material structuration, protection of the enclosed product, and controlled release of the encapsulated contents, all of which can ensure efficient and safe therapeutic effects. This paper is a comprehensive review of microencapsulation and its latest developments in the field. It provides a comprehensive overview of the technology and primary goals of microencapsulation and discusses various processes and techniques involved in microencapsulation including physical, chemical, physicochemical, and other methods involved. It also summarizes the state-of-the-art successes of microencapsulation, specifically with regard to the encapsulation of microorganisms, mammalian cells, drugs, and other biopharmaceutics in various diseases. The limitations and future directions of microencapsulation technologies are also discussed.

  16. License Compliance Issues For Biopharmaceuticals: Special Challenges For Negotiations Between Companies And Non-Profit Research Institutions.

    Science.gov (United States)

    Ponzio, Todd A; Feindt, Hans; Ferguson, Steven

    2011-09-01

    Biopharmaceuticals are therapeutic products based on biotechnology. They are manufactured by or from living organisms and are the most complex of all commercial medicines to develop, manufacture and qualify for regulatory approval. In recent years biopharmaceuticals have rapidly increased in number and importance with over 400() already marketed in the U.S. and European markets alone. Many companies throughout the world are now ramping up investments in biopharmaceutical R&D and expanding their portfolios through licensing of early-stage biotechnologies from universities and other non-profit research institutions, and there is an increasing number of license agreements for biopharmaceutical product development relative to traditional small molecule drug compounds. This trend will only continue as large numbers of biosimilars and biogenerics enter the market.A primary goal of technology transfer offices associated with publicly-funded, non-profit research institutions is to establish patent protection for inventions deemed to have commercial potential and license them for product development. Such licenses help stimulate economic development and job creation, bring a stream of royalty revenue to the institution and, hopefully, advance the public good or public health by bringing new and useful products to market. In the course of applying for such licenses, a commercial development plan is usually put forth by the license applicant. This plan indicates the path the applicant expects to follow to bring the licensed invention to market. In the case of small molecule drug compounds, there exists a widely-recognized series of clinical development steps, dictated by regulatory requirements, that must be met to bring a new drug to market, such as completion of preclinical toxicology, Phase 1, 2 and 3 testing and product approvals. These steps often become the milestone/benchmark schedule incorporated into license agreements which technology transfer offices use to monitor

  17. Microencapsulation for the Therapeutic Delivery of Drugs, Live Mammalian and Bacterial Cells, and Other Biopharmaceutics: Current Status and Future Directions

    Science.gov (United States)

    Saha, Shyamali; Malhotra, Meenakshi; Kahouli, Imen; Prakash, Satya

    2013-01-01

    Microencapsulation is a technology that has shown significant promise in biotherapeutics, and other applications. It has been proven useful in the immobilization of drugs, live mammalian and bacterial cells and other cells, and other biopharmaceutics molecules, as it can provide material structuration, protection of the enclosed product, and controlled release of the encapsulated contents, all of which can ensure efficient and safe therapeutic effects. This paper is a comprehensive review of microencapsulation and its latest developments in the field. It provides a comprehensive overview of the technology and primary goals of microencapsulation and discusses various processes and techniques involved in microencapsulation including physical, chemical, physicochemical, and other methods involved. It also summarizes the state-of-the-art successes of microencapsulation, specifically with regard to the encapsulation of microorganisms, mammalian cells, drugs, and other biopharmaceutics in various diseases. The limitations and future directions of microencapsulation technologies are also discussed. PMID:26555963

  18. Evaluation of the physicochemical and biopharmaceutical properties of fluoro-indomethacin.

    Science.gov (United States)

    Mori, Michela M; Airaksinen, Anu J; Hirvonen, Jouni T; Santos, Hélder A; Caramella, Carla M

    2013-01-01

    Drug nanocarriers have shown great potential in therapy and as diagnostic probes, e.g. in imaging of cancer and inflammation. Imaging can be applied to localize the carrier or the drug itself in the body and/or tissues. In this particular case it is important that drug molecules have the characteristics for possible detection, e.g. after modification with positron emission tomography compliant radioisotopes, without affecting their pharmacological behavior. In order to easily and efficiently follow the ADME profile of the drug after loaded into nanocarriers, the drug can be radiolabelled with, e.g. 18F-label, in order to assess its biodistribution after enteral and parenteral administration in rats. However, this is only possible if the derivative compound behaves similarly to the parent drug compound. In this study, indomethacin (a poorly water-soluble drug) was chosen as a model compound and aimed to evaluate the physicochemical and biopharmaceutical properties of an analog of indomethacin (IMC), fluoro-indomethacin (F-IMC). Although some of the physicochemical and biopharmaceutical properties of IMC are already known, in order to establish a feasible comparison between IMC and F-IMC, the behavior of the former was also investigated in the same conditions as for F-IMC. In this context, both IMC and F-IMC were thermally and morphologically studied. Furthermore, the following properties were also studied for both compounds: pKa and logP, solubility and dissolution profiles at physiological pH values, and toxicity at different concentrations in Caco-2 cells. Finally, the transport across Caco- 2 monolayers of the IMC and F-IMC at physiological pH range was also investigated. The results obtained showed similar values in pKalogP, solubility, dissolution, cytotoxicity, and permeability for both compounds. Thus, there might be strong evidence that both IMC and F-IMC should have a similar ADME behavior and profiles in vivo. The results provide fundamental tools and

  19. Improved Protease-Targeting and Biopharmaceutical Properties of Novel Prodrugs of Ganciclovir.

    Science.gov (United States)

    Sun, Kefeng; Xu, Hao; Hilfinger, John L; Lee, Kyung-Dall; Provoda, Chester J; Sabit, Hairat; Amidon, Gordon L

    2018-02-05

    The prodrug strategy has been frequently employed as a chemical approach for overcoming the disadvantages of existing parent drugs. In this report, we synthesized four monoester prodrugs of ganciclovir, an anticytomegalovirus drug, and demonstrated their potential advantages in protease-targeted activation and biopharmaceutical profiles over the parent compound. We demonstrated that these four prodrugs of ganciclovir, i.e., N-benzyloxycarbonyl-(L)-alanine-ganciclovir (CbzAlaGCV), N-benzyloxycarbonyl-(α,l)-aminobutyric acid-ganciclovir (CbzAbuGCV), N-acetyl-(l)-phenylalanine-(l)-alanine-ganciclovir (AcPheAlaGCV), and N-acetyl-(l)-phenylalanine-(α,l)-aminobutyric acid-ganciclovir (AcPheAbuGCV), are hydrolytically activated by the protease of human cytomegalovirus (hCMV), a serine protease that possesses intrinsic esterase activities. CbzAlaGCV and AcPheAlaGCV were found to be activated at a higher rate by the hCMV protease than CbzAbuGCV and AcPheAbuGCV. These ganciclovir prodrugs could potentially be targeted to selective activation by the hCMV protease which is only present at the viral infection sites, thereby achieving higher efficacy and lower systemic toxicity. The tissue stability, cellular uptake, and trans-epithelial transport of these ganciclovir prodrugs were also characterized. The N-acetylated dipeptide prodrugs of ganciclovir were found to be generally more stable than Cbz-amino acid prodrugs in various tissue matrices. Among the four prodrug candidates, AcPheAbuGCV was the most stable in human cell homogenates, plasma, and pooled liver microsomes. AcPheAbuGCV also possessed a superior cellular uptake profile and permeability across epithelial cell monolayers. Since the targeting and selective activation of a prodrug is determined by not only its rate of hydrolysis catalyzed by the hCMV protease target but also its biopharmaceutical properties, i.e., oral absorption and systemic availability, AcPheAbuGCV is considered the best overall candidate among

  20. Principles for interactions with biopharmaceutical companies: the development of guidelines for patient advocacy organizations in the field of rare diseases.

    Science.gov (United States)

    Stein, Susan; Bogard, Elizabeth; Boice, Nicole; Fernandez, Vivian; Field, Tessa; Gilstrap, Alan; Kahn, Susan R; Larkindale, Jane; Mathieson, Toni

    2018-01-22

    Rare diseases are a global public health concern, affecting an estimated 350 million individuals. Only 5% of approximately 7000 known rare diseases have a treatment, and only about half have a patient advocacy organization. Biopharmaceutical companies face complex challenges in developing treatments for rare diseases. Patient advocacy organizations may play a major role by positively influencing research and development, clinical trials, and regulations. Thus, collaboration among patient advocacy organizations and industry is essential to bring new therapeutics to patients. We identified an unmet need for guidelines on day-to-day decision-making by rare disease patient advocacy organizations when working with biopharmaceutical partners. We convened an Independent Expert Panel experienced in collaborations between patient advocacy organizations and biopharmaceutical companies (April 2017) to develop consensus guidelines for these relationships. The guidelines were based on an original version by the International Fibrodysplasia Ossificans Progressiva Association (IFOPA). The Expert Panel reviewed and broadened these to be applicable to all patient advocacy organizations. Comments on the draft Guidelines were provided first by Panel participants and subsequently by six independent experts from patient advocacy organizations and industry. The Panel comprised four experts from the rare disease community who lead patient advocacy organizations; three leaders who perform advocacy functions within biopharmaceutical companies; and two facilitators, both having leadership experience in rare diseases and industry. The finalized Guidelines consist of four main sections: Identification and Engagement With Companies, Patient Engagement and Patient Privacy, Financial Contributions, and Clinical Trial Communication and Support. The Guidelines address the daily considerations, choices, and consequences of patient advocacy organizations as they engage with biopharmaceutical

  1. Optimization‐based framework for resin selection strategies in biopharmaceutical purification process development

    Science.gov (United States)

    Liu, Songsong; Gerontas, Spyridon; Gruber, David; Turner, Richard; Titchener‐Hooker, Nigel J.

    2017-01-01

    This work addresses rapid resin selection for integrated chromatographic separations when conducted as part of a high‐throughput screening exercise during the early stages of purification process development. An optimization‐based decision support framework is proposed to process the data generated from microscale experiments to identify the best resins to maximize key performance metrics for a biopharmaceutical manufacturing process, such as yield and purity. A multiobjective mixed integer nonlinear programming model is developed and solved using the ε‐constraint method. Dinkelbach's algorithm is used to solve the resulting mixed integer linear fractional programming model. The proposed framework is successfully applied to an industrial case study of a process to purify recombinant Fc Fusion protein from low molecular weight and high molecular weight product related impurities, involving two chromatographic steps with eight and three candidate resins for each step, respectively. The computational results show the advantage of the proposed framework in terms of computational efficiency and flexibility. © 2017 The Authors Biotechnology Progress published by Wiley Periodicals, Inc. on behalf of American Institute of Chemical Engineers Biotechnol. Prog., 33:1116–1126, 2017 PMID:28393478

  2. Mechanical characterisation of agarose-based chromatography resins for biopharmaceutical manufacture.

    Science.gov (United States)

    Nweke, Mauryn C; McCartney, R Graham; Bracewell, Daniel G

    2017-12-29

    Mechanical characterisation of agarose-based resins is an important factor in ensuring robust chromatographic performance in the manufacture of biopharmaceuticals. Pressure-flow profiles are most commonly used to characterise these properties. There are a number of drawbacks with this method, including the potential need for several re-packs to achieve the desired packing quality, the impact of wall effects on experimental set up and the quantities of chromatography media and buffers required. To address these issues, we have developed a dynamic mechanical analysis (DMA) technique that characterises the mechanical properties of resins based on the viscoelasticity of a 1ml sample of slurry. This technique was conducted on seven resins with varying degrees of mechanical robustness and the results were compared to pressure-flow test results on the same resins. Results show a strong correlation between the two techniques. The most mechanically robust resin (Capto Q) had a critical velocity 3.3 times higher than the weakest (Sepharose CL-4B), whilst the DMA technique showed Capto Q to have a slurry deformation rate 8.3 times lower than Sepharose CL-4B. To ascertain whether polymer structure is indicative of mechanical strength, scanning electron microscopy images were also used to study the structural properties of each resin. Results indicate that DMA can be used as a small volume, complementary technique for the mechanical characterisation of chromatography media. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

  3. A non-binary biopharmaceutical classification of drugs: the ABΓ system.

    Science.gov (United States)

    Macheras, Panos; Karalis, Vangelis

    2014-04-10

    The purpose of the present work is to develop a non-binary biopharmaceutical classification system the so called ABΓ system. The original mathematical model used for the development of BCS, appropriately modified, was applied to estimate the limiting values of drug solubility and permeability when the fraction of dose absorbed, Fa, was 0.90 or 0.20. The ABΓ system is based on the fraction of dose absorbed and relies on permeability, solubility plane. The first category (A, alpha) includes drugs with Fa ≥ 0.90, whereas the B (beta) category consists of drugs with Fa ≤ 0.20. The area lying between the two boundaries of A and B defines the third category (gamma), Γ, (0.20

  4. Continuous counter-current chromatography for capture and polishing steps in biopharmaceutical production.

    Science.gov (United States)

    Steinebach, Fabian; Müller-Späth, Thomas; Morbidelli, Massimo

    2016-09-01

    The economic advantages of continuous processing of biopharmaceuticals, which include smaller equipment and faster, efficient processes, have increased interest in this technology over the past decade. Continuous processes can also improve quality assurance and enable greater controllability, consistent with the quality initiatives of the FDA. Here, we discuss different continuous multi-column chromatography processes. Differences in the capture and polishing steps result in two different types of continuous processes that employ counter-current column movement. Continuous-capture processes are associated with increased productivity per cycle and decreased buffer consumption, whereas the typical purity-yield trade-off of classical batch chromatography can be surmounted by continuous processes for polishing applications. In the context of continuous manufacturing, different but complementary chromatographic columns or devices are typically combined to improve overall process performance and avoid unnecessary product storage. In the following, these various processes, their performances compared with batch processing and resulting product quality are discussed based on a review of the literature. Based on various examples of applications, primarily monoclonal antibody production processes, conclusions are drawn about the future of these continuous-manufacturing technologies. Copyright © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Workflow for Criticality Assessment Applied in Biopharmaceutical Process Validation Stage 1

    Directory of Open Access Journals (Sweden)

    Thomas Zahel

    2017-10-01

    Full Text Available Identification of critical process parameters that impact product quality is a central task during regulatory requested process validation. Commonly, this is done via design of experiments and identification of parameters significantly impacting product quality (rejection of the null hypothesis that the effect equals 0. However, parameters which show a large uncertainty and might result in an undesirable product quality limit critical to the product, may be missed. This might occur during the evaluation of experiments since residual/un-modelled variance in the experiments is larger than expected a priori. Estimation of such a risk is the task of the presented novel retrospective power analysis permutation test. This is evaluated using a data set for two unit operations established during characterization of a biopharmaceutical process in industry. The results show that, for one unit operation, the observed variance in the experiments is much larger than expected a priori, resulting in low power levels for all non-significant parameters. Moreover, we present a workflow of how to mitigate the risk associated with overlooked parameter effects. This enables a statistically sound identification of critical process parameters. The developed workflow will substantially support industry in delivering constant product quality, reduce process variance and increase patient safety.

  6. Human Embryonic Kidney 293 Cells: A Vehicle for Biopharmaceutical Manufacturing, Structural Biology, and Electrophysiology.

    Science.gov (United States)

    Hu, Jianwen; Han, Jizhong; Li, Haoran; Zhang, Xian; Liu, Lan Lan; Chen, Fei; Zeng, Bin

    2018-01-01

    Mammalian cells, e.g., CHO, BHK, HEK293, HT-1080, and NS0 cells, represent important manufacturing platforms in bioengineering. They are widely used for the production of recombinant therapeutic proteins, vaccines, anticancer agents, and other clinically relevant drugs. HEK293 (human embryonic kidney 293) cells and their derived cell lines provide an attractive heterologous system for the development of recombinant proteins or adenovirus productions, not least due to their human-like posttranslational modification of protein molecules to provide the desired biological activity. Secondly, they also exhibit high transfection efficiency yielding high-quality recombinant proteins. They are easy to maintain and express with high fidelity membrane proteins, such as ion channels and transporters, and thus are attractive for structural biology and electrophysiology studies. In this article, we review the literature on HEK293 cells regarding their origins but also stress their advancements into the different cell lines engineered and discuss some significant aspects which make them versatile systems for biopharmaceutical manufacturing, drug screening, structural biology research, and electrophysiology applications. © 2018 S. Karger AG, Basel.

  7. Rational design and optimization of downstream processes of virus particles for biopharmaceutical applications: current advances.

    Science.gov (United States)

    Vicente, Tiago; Mota, José P B; Peixoto, Cristina; Alves, Paula M; Carrondo, Manuel J T

    2011-01-01

    The advent of advanced therapies in the pharmaceutical industry has moved the spotlight into virus-like particles and viral vectors produced in cell culture holding great promise in a myriad of clinical targets, including cancer prophylaxis and treatment. Even though a couple of cases have reached the clinic, these products have yet to overcome a number of biological and technological challenges before broad utilization. Concerning the manufacturing processes, there is significant research focusing on the optimization of current cell culture systems and, more recently, on developing scalable downstream processes to generate material for pre-clinical and clinical trials. We review the current options for downstream processing of these complex biopharmaceuticals and underline current advances on knowledge-based toolboxes proposed for rational optimization of their processing. Rational tools developed to increase the yet scarce knowledge on the purification processes of complex biologicals are discussed as alternative to empirical, "black-boxed" based strategies classically used for process development. Innovative methodologies based on surface plasmon resonance, dynamic light scattering, scale-down high-throughput screening and mathematical modeling for supporting ion-exchange chromatography show great potential for a more efficient and cost-effective process design, optimization and equipment prototyping. Copyright © 2011 Elsevier Inc. All rights reserved.

  8. Immune checkpoint blockade therapy: The 2014 Tang prize in biopharmaceutical science

    Directory of Open Access Journals (Sweden)

    Ya-Shan Chen

    2015-02-01

    Full Text Available The first Tang Prize for Biopharmaceutical Science has been awarded to Prof. James P. Allison and Prof. Tasuku Honjo for their contributions leading to an entirely new way to treat cancer by blocking the molecules cytotoxic T lymphocyte-associated antigen 4 (CTLA-4 and programmed cell death protein 1 (PD-1 that turn off immune response. The treatment, called "immune checkpoint blockade therapy," has opened a new therapeutic era. Here the discoveries of the immune checkpoints and how they contribute to the maintenance of self-tolerance, as well as how to protect tissues from the excess immune responses causing damage are reviewed. The efforts made by Prof. Allison and Prof. Honjo for developing the most promising approaches to activate therapeutic antitumor immunity are also summarized. Since these certain immune checkpoint pathways appear to be one of the major mechanisms resulting in immune escape of tumors, the presence of anti-CTLA-4 and/or anti-PD-1 should contribute to removal of the inhibition signals for T cell activation. Subsequently, it will enhance specific T cell activation and, therefore, strengthen antitumor immunity.

  9. Particle shedding from peristaltic pump tubing in biopharmaceutical drug product manufacturing.

    Science.gov (United States)

    Saller, Verena; Matilainen, Julia; Grauschopf, Ulla; Bechtold-Peters, Karoline; Mahler, Hanns-Christian; Friess, Wolfgang

    2015-04-01

    In a typical manufacturing setup for biopharmaceutical drug products, the fill and dosing pump is placed after the final sterile filtration unit in order to ensure adequate dispensing accuracy and avoid backpressure peaks. Given the sensitivity of protein molecules, peristaltic pumps are often preferred over piston pumps. However, particles may be shed from the silicone tubing employed. In this study, particle shedding and a potential turbidity increase during peristaltic pumping of water and buffer were investigated using three types of commercially available silicone tubing. In the recirculates, mainly particles of around 200 nm next to a very small fraction of particles in the lower micrometer range were found. Using 3D laser scanning microscopy, surface roughness of the inner tubing surface was found to be a determining factor for particle shedding from silicone tubing. As the propensity toward particle shedding varied between tubing types and also cannot be concluded from manufacturer's specifications, individual testing with the presented methods is recommended during tubing qualification. Choosing low abrasive tubing can help to further minimize the very low particle counts to be expected in pharmaceutical drug products. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association.

  10. Lipid Based Formulations of Biopharmaceutics Classification System (BCS Class II Drugs: Strategy, Formulations, Methods and Saturation

    Directory of Open Access Journals (Sweden)

    Šoltýsová I.

    2016-12-01

    Full Text Available Active ingredients in pharmaceuticals differ by their physico-chemical properties and their bioavailability therefore varies. The most frequently used and most convenient way of administration of medicines is oral, however many drugs are little soluble in water. Thus they are not sufficiently effective and suitable for such administration. For this reason a system of lipid based formulations (LBF was developed. Series of formulations were prepared and tested in water and biorelevant media. On the basis of selection criteria, there were selected formulations with the best emulsification potential, good dispersion in the environment and physical stability. Samples of structurally different drugs included in the Class II of the Biopharmaceutics classification system (BCS were obtained, namely Griseofulvin, Glibenclamide, Carbamazepine, Haloperidol, Itraconazol, Triclosan, Praziquantel and Rifaximin, for testing of maximal saturation in formulations prepared from commercially available excipients. Methods were developed for preparation of formulations, observation of emulsification and its description, determination of maximum solubility of drug samples in the respective formulation and subsequent analysis. Saturation of formulations with drugs showed that formulations 80 % XA and 20 % Xh, 35 % XF and 65 % Xh were best able to dissolve the drugs which supports the hypothesis that it is desirable to identify limited series of formulations which could be generally applied for this purpose.

  11. Aftermarket Performance of Health Care and Biopharmaceutical IPOs: Evidence From ASEAN Countries.

    Science.gov (United States)

    Komenkul, Kulabutr; Kiranand, Santi

    2017-01-01

    We examine the evidence from the long-run abnormal returns using data for 76 health care and biopharmaceutical initial public offerings (IPOs) listed in a 29-year period between 1986 and 2014 in the Association of Southeast Asian Nations (ASEAN) countries such as Indonesia, Malaysia, Singapore, Thailand, the Philippines, Vietnam, Myanmar, and Laos. Based on the event-time approach, the 3-year stock returns of the IPOs are investigated using cumulative abnormal return (CAR) and buy-and-hold abnormal return (BHAR). As a robustness check, the calendar-time approach, related to the market model as well as Fama-French and Carhart models, was applied for verifying long-run abnormal returns. We found evidence that the health care IPOs overperform in the long-run, irrespective of the alternative benchmarks and methods. In addition, when we divide our sample into 5 groups by listing countries, our results show that the health care stock prices of the Singaporean firms behaved differently from those of most of the other firms in ASEAN. The Singaporean IPOs are characterized by a worse post-offering performance, whereas the IPOs of Malaysian and Thai health care companies performed better in the long-run.

  12. Bioengineering of rFVIIa Biopharmaceutical and Structure Characterization for Biosimilarity Assessment

    Directory of Open Access Journals (Sweden)

    Othman Montacir

    2018-01-01

    Full Text Available Eptacog alfa (NovoSeven® is a vitamin K-dependent recombinant Factor VIIa produced by genetic engineering from baby hamster kidney (BHK cells as a single peptide chain of 406 residues. After activation, it consists of a light chain (LC of 152 amino and a heavy chain (HC of 254 amino acids. Recombinant FVIIa undergoes many post-translational modifications (PTMs. The first ten glutamic acids of the N-terminal moiety are γ-carboxylated, Asn145 and Asn322 are N-glycosylated, and Ser52 and Ser60 are O-glycosylated. A head-to-head biosimilarity study was conducted for the originator and the first biosimilar AryoSeven™ to evaluate comparable bioengineering. Physicochemical properties were analyzed based on mass spectrometry, including intact mass, PTMs and higher-order structure. Both biotherapeutics exhibit a batch-to-batch variability in their N-glycan profiles. N-Glycopeptide analysis with UHPLC-QTOF-MSE confirmed N-glycosylation sites as well as two different O-glycopeptide sites. Ser60 was found to be O-fucosylated and Ser52 had O-glucose or O-glucose-(xylose1,2 motifs as glycan variants. Ion mobility spectrometry (TWIMS and NMR spectroscopy data affirm close similarity of the higher-order structure of both biologicals. Potency of the biodrugs was analyzed by a coagulation assay demonstrating comparable bioactivity. Consequently, careful process optimization led to a stable production process of the biopharmaceuticals.

  13. Profiling biopharmaceutical deciding properties of absorption of lansoprazole enteric-coated tablets using gastrointestinal simulation technology.

    Science.gov (United States)

    Wu, Chunnuan; Sun, Le; Sun, Jin; Yang, Yajun; Ren, Congcong; Ai, Xiaoyu; Lian, He; He, Zhonggui

    2013-09-10

    The aim of the present study was to correlate in vitro properties of drug formulation to its in vivo performance, and to elucidate the deciding properties of oral absorption. Gastrointestinal simulation technology (GST) was used to simulate the in vivo plasma concentration-time curve and was implemented by GastroPlus™ software. Lansoprazole, a typical BCS class II drug, was chosen as a model drug. Firstly, physicochemical and pharmacokinetic parameters of lansoprazole were determined or collected from literature to construct the model. Validation of the developed model was performed by comparison of the predicted and the experimental plasma concentration data. We found that the predicted curve was in a good agreement with the experimental data. Then, parameter sensitivity analysis (PSA) was performed to find the key parameters of oral absorption. The absorption was particularly sensitive to dose, solubility and particle size for lansoprazole enteric-coated tablets. With a single dose of 30 mg and the solubility of 0.04 mg/ml, the absorption was complete. A good absorption could be achieved with lansoprazole particle radius down to about 25 μm. In summary, GST is a useful tool for profiling biopharmaceutical deciding properties of absorption of lansoprazole enteric-coated tablets and guiding the formulation optimization. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.

  14. Closed-loop optimization of chromatography column sizing strategies in biopharmaceutical manufacture.

    Science.gov (United States)

    Allmendinger, Richard; Simaria, Ana S; Turner, Richard; Farid, Suzanne S

    2014-10-01

    This paper considers a real-world optimization problem involving the identification of cost-effective equipment sizing strategies for the sequence of chromatography steps employed to purify biopharmaceuticals. Tackling this problem requires solving a combinatorial optimization problem subject to multiple constraints, uncertain parameters, and time-consuming fitness evaluations. An industrially-relevant case study is used to illustrate that evolutionary algorithms can identify chromatography sizing strategies with significant improvements in performance criteria related to process cost, time and product waste over the base case. The results demonstrate also that evolutionary algorithms perform best when infeasible solutions are repaired intelligently, the population size is set appropriately, and elitism is combined with a low number of Monte Carlo trials (needed to account for uncertainty). Adopting this setup turns out to be more important for scenarios where less time is available for the purification process. Finally, a data-visualization tool is employed to illustrate how user preferences can be accounted for when it comes to selecting a sizing strategy to be implemented in a real industrial setting. This work demonstrates that closed-loop evolutionary optimization, when tuned properly and combined with a detailed manufacturing cost model, acts as a powerful decisional tool for the identification of cost-effective purification strategies. © 2013 The Authors. Journal of Chemical Technology & Biotechnology published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

  15. Biopharmaceuticals and biosimilars in psoriasis: what the dermatologist needs to know.

    Science.gov (United States)

    Strober, Bruce E; Armour, Katherine; Romiti, Ricardo; Smith, Catherine; Tebbey, Paul W; Menter, Alan; Leonardi, Craig

    2012-02-01

    The entry of biosimilar forms of biopharmaceutical therapies for the treatment of psoriasis and other immune-mediated disorders has provoked considerable interest. Although dermatologists are accustomed to the use of a wide range of generic topical agents, recognition of key differences between original agent (ie, the name brand) and the generic or biosimilar agent is necessary to support optimal therapy management and patient care. In this review we have summarized the current state of the art related to the impending introduction of biosimilars into dermatology. Biosimilars represent important interventions that are less expensive and hence offer the potential to deliver benefit to large numbers of patients who may not currently be able to access these therapies. But the development of biosimilars is not equivalent to that of small molecule generic therapies because of differences in molecular structure and processes of manufacture. The planned regulatory guidelines and path to approval may not encompass all of these potentially important differences and this may have clinical relevance to the prescriber and patient. Consequently, we have identified a series of key issues that should be considered to support the full potential of biosimilars for the treatment of psoriasis; ie, that of increased access to appropriate therapy for the psoriasis population worldwide. Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  16. Computational fluid dynamics (CFD) insights into agitation stress methods in biopharmaceutical development.

    Science.gov (United States)

    Bai, Ge; Bee, Jared S; Biddlecombe, James G; Chen, Quanmin; Leach, W Thomas

    2012-02-28

    Agitation of small amounts of liquid is performed routinely in biopharmaceutical process, formulation, and packaging development. Protein degradation commonly results from agitation, but the specific stress responsible or degradation mechanism is usually not well understood. Characterization of the agitation stress methods is critical to identifying protein degradation mechanisms or specific sensitivities. In this study, computational fluid dynamics (CFD) was used to model agitation of 1 mL of fluid by four types of common laboratory agitation instruments, including a rotator, orbital shaker, magnetic stirrer and vortex mixer. Fluid stresses in the bulk liquid and near interfaces were identified, quantified and compared. The vortex mixer provides the most intense stresses overall, while the stir bar system presented locally intense shear proximal to the hydrophobic stir bar surface. The rotator provides gentler fluid stresses, but the air-water interfacial area and surface stresses are relatively high given its low rotational frequency. The orbital shaker provides intermediate-level stresses but with the advantage of a large stable platform for consistent vial-to-vial homogeneity. Selection of experimental agitation methods with targeted types and intensities of stresses can facilitate better understanding of protein degradation mechanisms and predictability for "real world" applications. Copyright © 2011 Elsevier B.V. All rights reserved.

  17. Isolation and characterization of bioactive fungi from shark Carcharodon carcharias' gill with biopharmaceutical prospects

    Science.gov (United States)

    Zhang, Yi; Han, Jinyuan; Feng, Yan; Mu, Jun; Bao, Haiyan; Kulik, Andreas; Grond, Stephanie

    2016-01-01

    Until recently, little was known about the fungi found in shark gills and their biomedicinal potential. In this article, we described the isolation, bioactivity, diversity, and secondary metabolites of bioactive fungi from the gill of a shark ( Carcharodon carcharias). A total of 115 isolates were obtained and grown in 12 culture media. Fifty-eight of these isolates demonstrated significant activity in four antimicrobial, pesticidal, and cytotoxic bioassay models. Four randomly selected bioactive isolates inhibited human cancer cell proliferation during re-screening. These active isolates were segregated into 6 genera using the internal transcribed spacer-large subunit (ITS-LSU) rDNA-sequence BLAST comparison. Four genera, Penicillium, Aspergillus, Mucor, and Chaetomium were the dominant taxa. A phylogenic tree illustrated their intergenera and intragenera genetic diversity. HPLC-DAD-HRMS analysis and subsequent database searching revealed that nine representative strains produced diverse bioactive compound profiles. These results detail the broad range of bioactive fungi found in a shark's gills, revealing their biopharmaceutical potential. To the best of our knowledge, this is the first study characterizing shark gill fungi and their bioactivity.

  18. Early Implementation of QbD in Biopharmaceutical Development: A Practical Example

    Directory of Open Access Journals (Sweden)

    Jesús Zurdo

    2015-01-01

    Full Text Available In drug development, the “onus” of the low R&D efficiency has been put traditionally onto the drug discovery process (i.e., finding the right target or “binding” functionality. Here, we show that manufacturing is not only a central component of product success, but also that, by integrating manufacturing and discovery activities in a “holistic” interpretation of QbD methodologies, we could expect to increase the efficiency of the drug discovery process as a whole. In this new context, early risk assessment, using developability methodologies and computational methods in particular, can assist in reducing risks during development in a cost-effective way. We define specific areas of risk and how they can impact product quality in a broad sense, including essential aspects such as product efficacy and patient safety. Emerging industry practices around developability are introduced, including some specific examples of applications to biotherapeutics. Furthermore, we suggest some potential workflows to illustrate how developability strategies can be introduced in practical terms during early drug development in order to mitigate risks, reduce drug attrition and ultimately increase the robustness of the biopharmaceutical supply chain. Finally, we also discuss how the implementation of such methodologies could accelerate the access of new therapeutic treatments to patients in the clinic.

  19. Mini review: Recombinant production of tailored bio-pharmaceuticals in different Bacillus strains and future perspectives.

    Science.gov (United States)

    Lakowitz, Antonia; Godard, Thibault; Biedendieck, Rebekka; Krull, Rainer

    2018-05-01

    Bio-pharmaceuticals like antibodies, hormones and growth factors represent about one-fifth of commercial pharmaceuticals. Host candidates of growing interest for recombinant production of these proteins are strains of the genus Bacillus, long being established for biotechnological production of homologous and heterologous proteins. Bacillus strains benefit from development of efficient expression systems in the last decades and emerge as major industrial workhorses for recombinant proteins due to easy cultivation, non-pathogenicity and their ability to secrete recombinant proteins directly into extracellular medium allowing cost-effective downstream processing. Their broad product portfolio of pharmaceutically relevant recombinant proteins described in research include antibody fragments, growth factors, interferons and interleukins, insulin, penicillin G acylase, streptavidin and different kinases produced in various cultivation systems like microtiter plates, shake flasks and bioreactor systems in batch, fed-batch and continuous mode. To further improve production and secretion performance of Bacillus, bottlenecks and limiting factors concerning proteases, chaperones, secretion machinery or feedback mechanisms can be identified on different cell levels from genomics and transcriptomics via proteomics to metabolomics and fluxomics. For systematical identification of recurring patterns characteristic of given regulatory systems and key genetic targets, systems biology and omics-technology provide suitable and promising approaches, pushing Bacillus further towards industrial application for recombinant pharmaceutical protein production. Copyright © 2017. Published by Elsevier B.V.

  20. Oral delivery of human biopharmaceuticals, autoantigens and vaccine antigens bioencapsulated in plant cells.

    Science.gov (United States)

    Kwon, Kwang-Chul; Verma, Dheeraj; Singh, Nameirakpam D; Herzog, Roland; Daniell, Henry

    2013-06-15

    Among 12billion injections administered annually, unsafe delivery leads to >20million infections and >100million reactions. In an emerging new concept, freeze-dried plant cells (lettuce) expressing vaccine antigens/biopharmaceuticals are protected in the stomach from acids/enzymes but are released to the immune or blood circulatory system when plant cell walls are digested by microbes that colonize the gut. Vaccine antigens bioencapsulated in plant cells upon oral delivery after priming, conferred both mucosal and systemic immunity and protection against bacterial, viral or protozoan pathogens or toxin challenge. Oral delivery of autoantigens was effective against complications of type 1 diabetes and hemophilia, by developing tolerance. Oral delivery of proinsulin or exendin-4 expressed in plant cells regulated blood glucose levels similar to injections. Therefore, this new platform offers a low cost alternative to deliver different therapeutic proteins to combat infectious or inherited diseases by eliminating inactivated pathogens, expensive purification, cold storage/transportation and sterile injections. Copyright © 2012 Elsevier B.V. All rights reserved.

  1. Optimization of capillary zone electrophoresis for charge heterogeneity testing of biopharmaceuticals using enhanced method development principles.

    Science.gov (United States)

    Moritz, Bernd; Locatelli, Valentina; Niess, Michele; Bathke, Andrea; Kiessig, Steffen; Entler, Barbara; Finkler, Christof; Wegele, Harald; Stracke, Jan

    2017-12-01

    CZE is a well-established technique for charge heterogeneity testing of biopharmaceuticals. It is based on the differences between the ratios of net charge and hydrodynamic radius. In an extensive intercompany study, it was recently shown that CZE is very robust and can be easily implemented in labs that did not perform it before. However, individual characteristics of some examined proteins resulted in suboptimal resolution. Therefore, enhanced method development principles were applied here to investigate possibilities for further method optimization. For this purpose, a high number of different method parameters was evaluated with the aim to improve CZE separation. For the relevant parameters, design of experiments (DoE) models were generated and optimized in several ways for different sets of responses like resolution, peak width and number of peaks. In spite of product specific DoE optimization it was found that the resulting combination of optimized parameters did result in significant improvement of separation for 13 out of 16 different antibodies and other molecule formats. These results clearly demonstrate generic applicability of the optimized CZE method. Adaptation to individual molecular properties may sometimes still be required in order to achieve optimal separation but the set screws discussed in this study [mainly pH, identity of the polymer additive (HPC versus HPMC) and the concentrations of additives like acetonitrile, butanolamine and TETA] are expected to significantly reduce the effort for specific optimization. 2017 The Authors. Electrophoresis published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

  2. Initial cytotoxicity assays of media for sulfate-reducing bacteria: An endodontic biopharmaceutical product under development.

    Science.gov (United States)

    Heggendorn, Fabiano Luiz; Silva, Gabriela Cristina de Carvalho; Cardoso, Elisama Azevedo; Castro, Helena Carla; Gonçalves, Lúcio Souza; Dias, Eliane Pedra; Lione, Viviane de Oliveira Freitas; Lutterbach, Márcia Teresa Soares

    2016-01-01

    This study assessed the cell viability of the inoculation vehicle of BACCOR (a combination of sulfate-reducing bacteria plus a culture media for bacteria), a biopharmaceutical product under development for dental use as aid in fractured endodontic file removal from the root canal. Different culture media for bacteria were evaluated: modified Postgate E (MCP-E mod), Modified Postgate E without Agar-agar (MCP-E w/Ag), Postgate C with Agar-agar (MCP-C Ag) and Postgate C without Agar-agar (MCP-C w/Ag). Cytotoxicity was quantified by the MTT test, exposing L929 and Vero cell lines to the vehicles over 24 h. The exposure of L929 cell line to MCP-E w/Ag resulted in biocompatibility (52% cell viability), while the exposure of the Vero kidney line revealed only MCP-E mod as cytotoxic. When diluted, all the vehicles showed biocompatibility with both cell lines. MCP-E w/Ag was the vehicle chosen for BACCOR, because of its biocompatibility with the cells used.

  3. Regulatory policy and the location of bio-pharmaceutical foreign direct investment in Europe.

    Science.gov (United States)

    Koenig, Pamina; Macgarvie, Megan

    2011-09-01

    This paper examines the relationship between cross-country differences in drug price regulation and the location of biopharmaceutical Foreign Direct Investment (FDI) in Europe. Simple theory predicts that price regulation in one country might affect total investment, but not the location of that investment, if sales are global. Nevertheless, some manufacturers threaten that the introduction of price regulation in a country will motivate them to move their investments to other countries. Are such threats cheap talk, or is there evidence that firms avoid price-controlling countries when making FDI location choices? We use data on 527 investments initiated in 27 European countries between 2002 and 2009 and find that investors are less likely to choose countries with price controls, after controlling for other determinants of investment. We also observe a relative decline in investment in countries that increased the stringency of regulatory regimes during our sample period. The effect is restricted to non-manufacturing investments and is most robust for those related to administrative functions. Copyright © 2011 Elsevier B.V. All rights reserved.

  4. [Biopharmaceutics classification and absorption mechanisms primary study on four kinds of flavonoids].

    Science.gov (United States)

    Li, Hui-Fang; Zhang, Dong; Qu, Wen-Jun; Wang, Hai-Lin; Liu, Yang; Borjigdai, Almaz; Cui, Jian; Dong, Zheng-Qi

    2016-04-01

    The solubility and permeability on four kinds of flavonoids (kaempferol, hesperidin, apigenin, genistein) were test according to the theory of biopharmaceutics classification system (BCS), and their absorption mechanism. The solubility was investigated by the method in determination of solubility of "Chinese Pharmacopoeia 2010". To detect appearance permeability of compounds mentioned above, the appropriate concentrations were selected by the MTT method in cell transfer experiments in Caco-2 cell model, which established by in vitro cell culture method. Therefore, these compounds were classified with BCS according to solubility and permeability. In addition, to explore absorption mechanisms, the experiments in three different concentrations of compounds in high, medium and low in bidirectional transformation methods in Caco-2 cell model contacted. The study indicated that all of kaempferol, hesperidin, apigenin, genistein have the characteristics in low solubility and high permeability, which belong to BCSⅡ, and the absorption mechanism of kaempferol was active transportation. Whereas, hesperidin, apigenin, genistein were passive transportation. In this study, it carried out initial explorations on establishment of determination for solubility and permeability in flavonoids, and provided theoretical reference for further research on BCS in traditional Chinese medicine. Copyright© by the Chinese Pharmaceutical Association.

  5. A Model of Risk Analysis in Analytical Methodology for Biopharmaceutical Quality Control.

    Science.gov (United States)

    Andrade, Cleyton Lage; Herrera, Miguel Angel De La O; Lemes, Elezer Monte Blanco

    2018-01-01

    One key quality control parameter for biopharmaceutical products is the analysis of residual cellular DNA. To determine small amounts of DNA (around 100 pg) that may be in a biologically derived drug substance, an analytical method should be sensitive, robust, reliable, and accurate. In principle, three techniques have the ability to measure residual cellular DNA: radioactive dot-blot, a type of hybridization; threshold analysis; and quantitative polymerase chain reaction. Quality risk management is a systematic process for evaluating, controlling, and reporting of risks that may affects method capabilities and supports a scientific and practical approach to decision making. This paper evaluates, by quality risk management, an alternative approach to assessing the performance risks associated with quality control methods used with biopharmaceuticals, using the tool hazard analysis and critical control points. This tool provides the possibility to find the steps in an analytical procedure with higher impact on method performance. By applying these principles to DNA analysis methods, we conclude that the radioactive dot-blot assay has the largest number of critical control points, followed by quantitative polymerase chain reaction, and threshold analysis. From the analysis of hazards (i.e., points of method failure) and the associated method procedure critical control points, we conclude that the analytical methodology with the lowest risk for performance failure for residual cellular DNA testing is quantitative polymerase chain reaction. LAY ABSTRACT: In order to mitigate the risk of adverse events by residual cellular DNA that is not completely cleared from downstream production processes, regulatory agencies have required the industry to guarantee a very low level of DNA in biologically derived pharmaceutical products. The technique historically used was radioactive blot hybridization. However, the technique is a challenging method to implement in a quality

  6. Perfusion seed cultures improve biopharmaceutical fed-batch production capacity and product quality.

    Science.gov (United States)

    Yang, William C; Lu, Jiuyi; Kwiatkowski, Chris; Yuan, Hang; Kshirsagar, Rashmi; Ryll, Thomas; Huang, Yao-Ming

    2014-01-01

    Volumetric productivity and product quality are two key performance indicators for any biopharmaceutical cell culture process. In this work, we showed proof-of-concept for improving both through the use of alternating tangential flow perfusion seed cultures coupled with high-seed fed-batch production cultures. First, we optimized the perfusion N-1 stage, the seed train bioreactor stage immediately prior to the production bioreactor stage, to minimize the consumption of perfusion media for one CHO cell line and then successfully applied the optimized perfusion process to a different CHO cell line. Exponential growth was observed throughout the N-1 duration, reaching >40 × 10(6) vc/mL at the end of the perfusion N-1 stage. The cultures were subsequently split into high-seed (10 × 10(6) vc/mL) fed-batch production cultures. This strategy significantly shortened the culture duration. The high-seed fed-batch production processes for cell lines A and B reached 5 g/L titer in 12 days, while their respective low-seed processes reached the same titer in 17 days. The shortened production culture duration potentially generates a 30% increase in manufacturing capacity while yielding comparable product quality. When perfusion N-1 and high-seed fed-batch production were applied to cell line C, higher levels of the active protein were obtained, compared to the low-seed process. This, combined with correspondingly lower levels of the inactive species, can enhance the overall process yield for the active species. Using three different CHO cell lines, we showed that perfusion seed cultures can optimize capacity utilization and improve process efficiency by increasing volumetric productivity while maintaining or improving product quality. © 2014 American Institute of Chemical Engineers.

  7. Strategic biopharmaceutical portfolio development: an analysis of constraint-induced implications.

    Science.gov (United States)

    George, Edmund D; Farid, Suzanne S

    2008-01-01

    Optimizing the structure and development pathway of biopharmaceutical drug portfolios are core concerns to the developer that come with several attached complexities. These include strategic decisions for the choice of drugs, the scheduling of critical activities, and the possible involvement of third parties for development and manufacturing at various stages for each drug. Additional complexities that must be considered include the impact of making such decisions in an uncertain environment. Presented here is the development of a stochastic multi-objective optimization framework designed to address these issues. The framework harnesses the ability of Bayesian networks to characterize the probabilistic structure of superior decisions via machine learning and evolve them to multi-objective optimality. Case studies that entailed three- and five-drug portfolios alongside a range of cash flow constraints were constructed to derive insight from the framework where results demonstrate that a variety of options exist for formulating nondominated strategies in the objective space considered, giving the manufacturer a range of pursuable options. In all cases limitations on cash flow reduce the potential for generating profits for a given probability of success. For the sizes of portfolio considered, results suggest that naïvely applying strategies optimal for a particular size of portfolio to a portfolio of another size is inappropriate. For the five-drug portfolio the most preferred means for development across the set of optimized strategies is to fully integrate development and commercial activities in-house. For the three-drug portfolio, the preferred means of development involves a mixture of in-house, outsourced, and partnered activities. Also, the size of the portfolio appears to have a larger impact on strategy and the quality of objectives than the magnitude of cash flow constraint.

  8. Molecular and biopharmaceutical investigation of alginate-inulin synbiotic coencapsulation of probiotic to target the colon.

    Science.gov (United States)

    Atia, Abdelbasset; Gomma, Ahmed I; Fliss, Ismail; Beyssac, Eric; Garrait, Ghislain; Subirade, Muriel

    2017-03-01

    Colon targeting, as a site-specific delivery for oral formulation, remains a major challenge, especially for sensitive bioactive components such as therapeutic forms of phages, live attenuated virus and prebiotics-probiotics association. Synbiotics could be used to protect encapsulated probiotics during the gastrointestinal tract and control their release in the colon. To achieve these goals, effective prebiotics, such as inulin, could be combined with alginate - the most exploited polymer used for probiotic encapsulation - in the form of beads. This work aimed to study the biopharmaceutical behaviour of alginate beads (A) and inulin-alginate beads of different inulin concentrations (5 or 20%) in 2% alginate (AI5, AI20). Beads were loaded with three probiotic strains (Pediococcus acidilactici Ul5, Lactobacillus reuteri and Lactobacillus salivarius). Dissolution of beads was studied by USP4 under conditions simulating the gastrointestinal condition. The survival rates of the bacterial strains were measured by a specific qPCR bacterial count. Mucoadhesiveness of beads was studied by an ex vivo method using intestinal mucosa. To understand the behaviour of each formulation, the ultrastructure of the polymeric network was studied using scanning electron microscopy (SEM). Molecular interactions between alginate and inulin were studied by Fourier transform infra-red spectroscopy (FTIR). Dissolution results suggested that the presence of inulin in beads provided more protection for the tested bacterial strains against the acidic pH. AI5 was the most effective formulation to deliver probiotics to the colon simulation conditions. FTIR and SEM investigations explained the differences in behaviour of each formula. The developed symbiotic form provided a promising matrix for the development of colonic controlled release systems.

  9. Biopharmaceutical Characterization and Bioavailability Study of a Tetrazole Analog of Clofibric Acid in Rat.

    Science.gov (United States)

    Vara-Gama, Nancy; Valladares-Méndez, Adriana; Navarrete-Vazquez, Gabriel; Estrada-Soto, Samuel; Orozco-Castellanos, Luis Manuel; Rivera-Leyva, Julio César

    2017-02-14

    In the current investigation, the physicochemical, biopharmaceutical and pharmacokinetic characterization of a new clofibric acid analog (Compound 1 ) was evaluated. Compound 1 showed affinity by lipophilic phase in 1 to 5 pH interval, indicating that this compound would be absorbed favorably in duodenum or jejunum. Also, Compound 1 possess two ionic species, first above of pH 4.43 and, the second one is present over pH 6.08. The apparent permeability in everted sac rat intestine model was 8.73 × 10 -6 cm/s in duodenum and 1.62 × 10 -5 cm/s in jejunum, suggesting that Compound 1 has low permeability. Elimination constant after an oral administration of 50 μg/kg in Wistar rat was 1.81 h -1 , absorption constant was 3.05 h -1 , C max was 3.57 μg/mL at 0.33 h, AUC 0-α was 956.54 μ/mL·h and distribution volume was 419.4 mL. To IV administration at the same dose, ke was 1.21 h -1 , Vd was 399.6 mL and AUC 0-α was 747.81 μ/mL·h. No significant differences were observed between pharmacokinetic parameters at every administration route. Bioavailability evaluated was 10.4%. Compound 1 is metabolized to Compound 2 probably by enzymatic hydrolysis, and it showed a half-life of 9.24 h. With these properties, Compound 1 would be considered as a prodrug of Compound 2 with potential as an antidiabetic and anti dyslipidemic agent.

  10. Biopharmaceutical Characterization and Bioavailability Study of a Tetrazole Analog of Clofibric Acid in Rat

    Directory of Open Access Journals (Sweden)

    Nancy Vara-Gama

    2017-02-01

    Full Text Available In the current investigation, the physicochemical, biopharmaceutical and pharmacokinetic characterization of a new clofibric acid analog (Compound 1 was evaluated. Compound 1 showed affinity by lipophilic phase in 1 to 5 pH interval, indicating that this compound would be absorbed favorably in duodenum or jejunum. Also, Compound 1 possess two ionic species, first above of pH 4.43 and, the second one is present over pH 6.08. The apparent permeability in everted sac rat intestine model was 8.73 × 10−6 cm/s in duodenum and 1.62 × 10−5 cm/s in jejunum, suggesting that Compound 1 has low permeability. Elimination constant after an oral administration of 50 μg/kg in Wistar rat was 1.81 h−1, absorption constant was 3.05 h−1, Cmax was 3.57 μg/mL at 0.33 h, AUC0–α was 956.54 μ/mL·h and distribution volume was 419.4 mL. To IV administration at the same dose, ke was 1.21 h−1, Vd was 399.6 mL and AUC0–α was 747.81 μ/mL·h. No significant differences were observed between pharmacokinetic parameters at every administration route. Bioavailability evaluated was 10.4%. Compound 1 is metabolized to Compound 2 probably by enzymatic hydrolysis, and it showed a half-life of 9.24 h. With these properties, Compound 1 would be considered as a prodrug of Compound 2 with potential as an antidiabetic and anti dyslipidemic agent.

  11. Provisional in-silico biopharmaceutics classification (BCS) to guide oral drug product development.

    Science.gov (United States)

    Wolk, Omri; Agbaria, Riad; Dahan, Arik

    2014-01-01

    The main objective of this work was to investigate in-silico predictions of physicochemical properties, in order to guide oral drug development by provisional biopharmaceutics classification system (BCS). Four in-silico methods were used to estimate LogP: group contribution (CLogP) using two different software programs, atom contribution (ALogP), and element contribution (KLogP). The correlations (r(2)) of CLogP, ALogP and KLogP versus measured LogP data were 0.97, 0.82, and 0.71, respectively. The classification of drugs with reported intestinal permeability in humans was correct for 64.3%-72.4% of the 29 drugs on the dataset, and for 81.82%-90.91% of the 22 drugs that are passively absorbed using the different in-silico algorithms. Similar permeability classification was obtained with the various in-silico methods. The in-silico calculations, along with experimental melting points, were then incorporated into a thermodynamic equation for solubility estimations that largely matched the reference solubility values. It was revealed that the effect of melting point on the solubility is minor compared to the partition coefficient, and an average melting point (162.7 °C) could replace the experimental values, with similar results. The in-silico methods classified 20.76% (± 3.07%) as Class 1, 41.51% (± 3.32%) as Class 2, 30.49% (± 4.47%) as Class 3, and 6.27% (± 4.39%) as Class 4. In conclusion, in-silico methods can be used for BCS classification of drugs in early development, from merely their molecular formula and without foreknowledge of their chemical structure, which will allow for the improved selection, engineering, and developability of candidates. These in-silico methods could enhance success rates, reduce costs, and accelerate oral drug products development.

  12. Solubility behavior and biopharmaceutical classification of novel high-solubility ciprofloxacin and norfloxacin pharmaceutical derivatives.

    Science.gov (United States)

    Breda, Susana A; Jimenez-Kairuz, Alvaro F; Manzo, Ruben H; Olivera, María E

    2009-04-17

    The hydrochlorides of the 1:3 aluminum:norfloxacin and aluminum:ciprofloxacin complexes were characterized according to the Biopharmaceutics Classification System (BCS) premises in comparison with their parent compounds. The pH-solubility profiles of the complexes were experimentally determined at 25 and 37 degrees C in the range of pH 1-8 and compared to that of uncomplexed norfloxacin and ciprofloxacin. Both complexes are clearly more soluble than the antibiotics themselves, even at the lowest solubility pHs. The increase in solubility was ascribed to the species controlling solubility, which were analyzed in the solid phases at equilibrium at selected pHs. Additionally, permeability was set as low, based on data reported in the scientific literature regarding oral bioavailability, intestinal and cell cultures permeabilities and also considering the influence of stoichiometric amounts of aluminum. The complexes fulfill the BCS criterion to be classified as class 3 compounds (high solubility/low permeability). Instead, the active pharmaceutical ingredients (APIs) currently used in solid dosage forms, norfloxacin and ciprofloxacin hydrochloride, proved to be BCS class 4 (low solubility/low permeability). The solubility improvement turns the complexes as potential biowaiver candidates from the scientific point of view and may be a good way for developing more dose-efficient formulations. An immediate release tablet showing very rapid dissolution was obtained. Its dissolution profile was compared to that of the commercial ciprofloxacin hydrochloride tablets allowing to dissolution of the complete dose at a critical pH such as 6.8.

  13. pH-Dependent solubility and permeability criteria for provisional biopharmaceutics classification (BCS and BDDCS) in early drug discovery.

    Science.gov (United States)

    Varma, Manthena V; Gardner, Iain; Steyn, Stefanus J; Nkansah, Paul; Rotter, Charles J; Whitney-Pickett, Carrie; Zhang, Hui; Di, Li; Cram, Michael; Fenner, Katherine S; El-Kattan, Ayman F

    2012-05-07

    The Biopharmaceutics Classification System (BCS) is a scientific framework that provides a basis for predicting the oral absorption of drugs. These concepts have been extended in the Biopharmaceutics Drug Disposition Classification System (BDDCS) to explain the potential mechanism of drug clearance and understand the effects of uptake and efflux transporters on absorption, distribution, metabolism, and elimination. The objective of present work is to establish criteria for provisional biopharmaceutics classification using pH-dependent passive permeability and aqueous solubility data generated from high throughput screening methodologies in drug discovery settings. The apparent permeability across monolayers of clonal cell line of Madin-Darby canine kidney cells, selected for low endogenous efflux transporter expression, was measured for a set of 105 drugs, with known BCS and BDDCS class. The permeability at apical pH 6.5 for acidic drugs and at pH 7.4 for nonacidic drugs showed a good correlation with the fraction absorbed in human (Fa). Receiver operating characteristic (ROC) curve analysis was utilized to define the permeability class boundary. At permeability ≥ 5 × 10(-6) cm/s, the accuracy of predicting Fa of ≥ 0.90 was 87%. Also, this cutoff showed more than 80% sensitivity and specificity in predicting the literature permeability classes (BCS), and the metabolism classes (BDDCS). The equilibrium solubility of a subset of 49 drugs was measured in pH 1.2 medium, pH 6.5 phosphate buffer, and in FaSSIF medium (pH 6.5). Although dose was not considered, good concordance of the measured solubility with BCS and BDDCS solubility class was achieved, when solubility at pH 1.2 was used for acidic compounds and FaSSIF solubility was used for basic, neutral, and zwitterionic compounds. Using a cutoff of 200 μg/mL, the data set suggested a 93% sensitivity and 86% specificity in predicting both the BCS and BDDCS solubility classes. In conclusion, this study identified

  14. The Biopharmaceutics Classification System: subclasses for in vivo predictive dissolution (IPD) methodology and IVIVC.

    Science.gov (United States)

    Tsume, Yasuhiro; Mudie, Deanna M; Langguth, Peter; Amidon, Greg E; Amidon, Gordon L

    2014-06-16

    The Biopharmaceutics Classification System (BCS) has found widespread utility in drug discovery, product development and drug product regulatory sciences. The classification scheme captures the two most significant factors influencing oral drug absorption; solubility and intestinal permeability and it has proven to be a very useful and a widely accepted starting point for drug product development and drug product regulation. The mechanistic base of the BCS approach has, no doubt, contributed to its wide spread acceptance and utility. Nevertheless, underneath the simplicity of BCS are many detailed complexities, both in vitro and in vivo which must be evaluated and investigated for any given drug and drug product. In this manuscript we propose a simple extension of the BCS classes to include sub-specification of acid (a), base (b) and neutral (c) for classes II and IV. Sub-classification for Classes I and III (high solubility drugs as currently defined) is generally not needed except perhaps in border line solubility cases. It is well known that the , pKa physical property of a drug (API) has a significant impact on the aqueous solubility dissolution of drug from the drug product both in vitro and in vivo for BCS Class II and IV acids and bases, and is the basis, we propose for a sub-classification extension of the original BCS classification. This BCS sub-classification is particularly important for in vivo predictive dissolution methodology development due to the complex and variable in vivo environment in the gastrointestinal tract, with its changing pH, buffer capacity, luminal volume, surfactant luminal conditions, permeability profile along the gastrointestinal tract and variable transit and fasted and fed states. We believe this sub-classification is a step toward developing a more science-based mechanistic in vivo predictive dissolution (IPD) methodology. Such a dissolution methodology can be used by development scientists to assess the likelihood of a

  15. [Effect of multicomponent environment on intestinal permeability of puerarin in biopharmaceutics classification system of Chinese materia medica].

    Science.gov (United States)

    Liu, Yang; Wang, Gang; Dong, Ling; Tang, Ming-Min; Zhu, Mei-Ling; Dong, Hong-Huant; Hou, Cheng-Bo

    2014-12-01

    The evaluation of permeability in biopharmaceutics classification system of Chinese materia medica (CMMBCS) requires multicomponent as a whole in order to conduct research, even in the study of a specific component, should also be put in the multicomponent environment. Based on this principle, the high content components in Gegen Qinlian decoction were used as multicomponent environmental impact factors in the experiment, and the relevant parameters of intestinal permeability about puerarin were measured with using in situ single-pass intestinal perfusion model, to investigate and evaluate the intestinal permeability of puerarin with other high content components. The experimental results showed that different proportions of baicalin, glycyrrhizic acid and berberine had certain influence on intestinal permeability of puerarin, and glycyrrhizic acid could significantly inhibit the intestinal absorption of puerarin, moreover, high concentration of berberine could promote the absorption of puerarin. The research results indicated that the important research ideas of permeability evaluation in biopharmaceutics classification system of Chinese materia medica with fully considering the effects of other ingredients in multicomponent environment.

  16. The biopharmaceutics of successful controlled release drug product: Segmental-dependent permeability of glipizide vs. metoprolol throughout the intestinal tract.

    Science.gov (United States)

    Zur, Moran; Cohen, Noa; Agbaria, Riad; Dahan, Arik

    2015-07-15

    The purpose of this work was to study the challenges and prospects of regional-dependent absorption in a controlled-release scenario, through the oral biopharmaceutics of the sulfonylurea antidiabetic drug glipizide. The BCS solubility class of glipizide was determined, and its physicochemical properties and intestinal permeability were thoroughly investigated, both in-vitro (PAMPA and Caco-2) and in-vivo in rats. Metoprolol was used as the low/high permeability class boundary marker. Glipizide was found to be a low-solubility compound. All intestinal permeability experimental methods revealed similar trend; a mirror image small intestinal permeability with opposite regional/pH-dependency was obtained, a downward trend for glipizide, and an upward trend for metoprolol. Yet the lowest permeability of glipizide (terminal Ileum) was comparable to the lowest permeability of metoprolol (proximal jejunum). At the colon, similar permeability was evident for glipizide and metoprolol, that was higher than metoprolol's jejunal permeability. We present an analysis that identifies metoprolol's jejunal permeability as the low/high permeability class benchmark anywhere throughout the intestinal tract; we show that the permeability of both glipizide and metoprolol matches/exceeds this threshold throughout the entire intestinal tract, accounting for their success as controlled-release dosage form. This represents a key biopharmaceutical characteristic for a successful controlled-release dosage form. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Summary of the NICHD-BPCA Pediatric Formulation Initiatives Workshop-Pediatric Biopharmaceutics Classification System (PBCS) Working Group

    Science.gov (United States)

    Abdel-Rahman, Susan; Amidon, Gordon L.; Kaul, Ajay; Lukacova, Viera; Vinks, Alexander A.; Knipp, Gregory

    2012-01-01

    The Biopharmaceutics Classification System (BCS) allows compounds to be classified based on their in vitro solubility and intestinal permeability. The BCS has found widespread use in the pharmaceutical community as an enabling guide for the rational selection of compounds, formulation for clinical advancement and generic biowaivers. The Pediatric Biopharmaceutics Classification System (PBCS) working group was convened to consider the possibility of developing an analogous pediatric based classification system. Since there are distinct developmental differences that can alter intestinal contents, volumes, permeability and potentially biorelevant solubilities at the different ages, the PBCS working group focused on identifying age specific issues that would need to be considered in establishing a flexible, yet rigorous PBCS. Objective To summarize the findings of the PBCS working group and provide insights into considerations required for the development of a pediatric based biopharmaceutics classification system. Methods Through several meetings conducted both at The Eunice Kennedy Shriver National Institute of Child Health, Human Development (NICHD)-US Pediatric Formulation Initiative (PFI) workshop (November 2011) and via teleconferences, the PBCS working group considered several high level questions that were raised to frame the classification system. In addition, the PBCS working group identified a number of knowledge gaps that would need to be addressed in order to develop a rigorous PBCS. Results It was determined that for a PBCS to be truly meaningful, it would need to be broken down into several different age groups that would account for developmental changes in intestinal permeability, luminal contents, and gastrointestinal transit. Several critical knowledge gaps where identified including: 1) a lack of fully understanding the ontogeny of drug metabolizing enzymes and transporters along the gastrointestinal (GI) tract, in the liver and in the kidney; 2

  18. Application of transglycosylated stevia and hesperidin as drug carriers to enhance biopharmaceutical properties of poorly-soluble artemisinin.

    Science.gov (United States)

    Letchmanan, Kumaran; Shen, Shou-Cang; Ng, Wai Kiong; Tan, Reginald B H

    2018-01-01

    Biopharmaceutical properties of poorly water-soluble antimalarial drug, Artemisinin (ART), were improved by formulating amorphous solid dispersions with transglycosylated food additives (Hsp-G and Stevia-G) via co-spray drying. Both the formulated ART/Hsp-G and ART/Stevia-G showed superior dissolution properties with a burst release of more than 95% of drug within 5 min, whereas untreated ART dissolved only 4% in 5min. The supersaturation solubility of the formulated ART was enhanced by 2-fold as compared with untreated counterpart. The storage stability tests indicated that these formulations chemically stable at room temperature and under low humidity (water-soluble ART. Copyright © 2017 Elsevier B.V. All rights reserved.

  19. Prediction of bioavailability of selected bisphosphonates using in silico methods towards categorization into a biopharmaceutical classification system.

    Science.gov (United States)

    Biernacka, Joanna; Betlejewska-Kielak, Katarzyna; Kłosińska-Szmurło, Ewa; Pluciński, Franciszek A; Mazurek, Aleksander P

    2013-01-01

    The physicochemical properties relevant to biological activity of selected bisphosphonates such as clodronate disodium salt, etidronate disodium salt, pamidronate disodium salt, alendronate sodium salt, ibandronate sodium salt, risedronate sodium salt and zoledronate disodium salt were determined using in silico methods. The main aim of our research was to investigate and propose molecular determinants thataffect bioavailability of above mentioned compounds. These determinants are: stabilization energy (deltaE), free energy of solvation (deltaG(solv)), electrostatic potential, dipole moment, as well as partition and distribution coefficients estimated by the log P and log D values. Presented values indicate that selected bisphosphonates a recharacterized by high solubility and low permeability. The calculated parameters describing both solubility and permeability through biological membranes seem to be a good bioavailability indicators of bisphosphonates examined and can be a useful tool to include into Biopharmaceutical Classification System (BCS) development.

  20. Optimizing solubility and permeability of a biopharmaceutics classification system (BCS) class 4 antibiotic drug using lipophilic fragments disturbing the crystal lattice.

    Science.gov (United States)

    Tehler, Ulrika; Fagerberg, Jonas H; Svensson, Richard; Larhed, Mats; Artursson, Per; Bergström, Christel A S

    2013-03-28

    Esterification was used to simultaneously increase solubility and permeability of ciprofloxacin, a biopharmaceutics classification system (BCS) class 4 drug (low solubility/low permeability) with solid-state limited solubility. Molecular flexibility was increased to disturb the crystal lattice, lower the melting point, and thereby improve the solubility, whereas lipophilicity was increased to enhance the intestinal permeability. These structural changes resulted in BCS class 1 analogues (high solubility/high permeability) emphasizing that simple medicinal chemistry may improve both these properties.

  1. Evaluation of the Membrane Permeability (PAMPA and Skin) of Benzimidazoles with Potential Cannabinoid Activity and their Relation with the Biopharmaceutics Classification System (BCS)

    OpenAIRE

    Alvarez-Figueroa, M. Javiera; Pessoa-Mahana, C. David; Palavecino-González, M. Elisa; Mella-Raipán, Jaime; Espinosa-Bustos, Cristián; Lagos-Muñoz, Manuel E.

    2011-01-01

    The permeability of five benzimidazole derivates with potential cannabinoid activity was determined in two models of membranes, parallel artificial membrane permeability assay (PAMPA) and skin, in order to study the relationship of the physicochemical properties of the molecules and characteristics of the membranes with the permeability defined by the Biopharmaceutics Classification System. It was established that the PAMPA intestinal absorption method is a good predictor for classifying thes...

  2. Calculating radiation exposures during use of (14)C-labeled nutrients, food components, and biopharmaceuticals to quantify metabolic behavior in humans.

    Science.gov (United States)

    Kim, Seung-Hyun; Kelly, Peter B; Clifford, Andrew J

    2010-04-28

    (14)C has long been used as a tracer for quantifying the in vivo human metabolism of food components, biopharmaceuticals, and nutrients. Minute amounts (food components, biopharmaceuticals, or nutrients to be organized into models suitable for quantitative hypothesis testing and determination of metabolic parameters. In vivo models are important for specification of intake levels for food components, biopharmaceuticals, and nutrients. Accurate estimation of the radiation exposure from ingested (14)C is an essential component of the experimental design. Therefore, this paper illustrates the calculation involved in determining the radiation exposure from a minute dose of orally administered (14)C-beta-carotene, (14)C-alpha-tocopherol, (14)C-lutein, and (14)C-folic acid from four prior experiments. The administered doses ranged from 36 to 100 nCi, and radiation exposure ranged from 0.12 to 5.2 microSv to whole body and from 0.2 to 3.4 microSv to liver with consideration of tissue weighting factor and fractional nutrient. In comparison, radiation exposure experienced during a 4 h airline flight across the United States at 37000 ft was 20 microSv.

  3. Stock market returns and clinical trial results of investigational compounds: an event study analysis of large biopharmaceutical companies.

    Science.gov (United States)

    Hwang, Thomas J

    2013-01-01

    For biopharmaceutical companies, investments in research and development are risky, and the results from clinical trials are key inflection points in the process. Few studies have explored how and to what extent the public equity market values clinical trial results. Our study dataset matched announcements of clinical trial results for investigational compounds from January 2011 to May 2013 with daily stock market returns of large United States-listed pharmaceutical and biotechnology companies. Event study methodology was used to examine the relationship between clinical research events and changes in stock returns. We identified public announcements for clinical trials of 24 investigational compounds, including 16 (67%) positive and 8 (33%) negative events. The majority of announcements were for Phase 3 clinical trials (N = 13, 54%), and for oncologic (N = 7, 29%) and neurologic (N = 6, 24%) indications. The median cumulative abnormal returns on the day of the announcement were 0.8% (95% confidence interval [CI]: -2.3, 13.4%; P = 0.02) for positive events and -2.0% (95% CI: -9.1, 0.7%; P = 0.04) for negative events, with statistically significant differences from zero. In the day immediately following the announcement, firms with positive events were associated with stock price corrections, with median cumulative abnormal returns falling to 0.4% (95% CI: -3.8, 12.3%; P = 0.33). For firms with negative announcements, the median cumulative abnormal returns were -1.7% (95% CI: -9.5, 1.0%; P = 0.03), and remained significantly negative over the two day event window. The magnitude of abnormal returns did not differ statistically by indication, by trial phase, or between biotechnology and pharmaceutical firms. The release of clinical trial results is an economically significant event and has meaningful effects on market value for large biopharmaceutical companies. Stock return underperformance due to negative events is greater in magnitude and persists longer than

  4. Do the recommended standards for in vitro biopharmaceutic classification of drug permeability meet the "passive transport" criterion for biowaivers?

    Science.gov (United States)

    Žakelj, Simon; Berginc, Katja; Roškar, Robert; Kraljič, Bor; Kristl, Albin

    2013-01-01

    BCS based biowaivers are recognized by major regulatory agencies. An application for a biowaiver can be supported by or even based on "in vitro" measurements of drug permeability. However, guidelines limit the application of biowaivers to drug substances that are transported only by passive mechanisms. Regarding published permeability data as well as measurements obtained in our institution, one can rarely observe drug substances that conform to this very strict criterion. Therefore, we measured the apparent permeability coefficients of 13 drugs recommended by FDA's Guidance to be used as standards for "in vitro" permeability classification. The asymmetry of permeability data determined for both directions (mucosal-to-serosal and serosalto- mucosal) through the rat small intestine revealed significant active transport for four out of the nine high-permeability standards and for all four low-permeability standard drugs. As could be expected, this asymmetry was abolished at 4°C on rat intestine. The permeability of all nine high-permeability, but none of the low permeability standards, was also much lower when measured with intestinal tissue, Caco-2 cell monolayers or artificial membranes at 4°C compared to standard conditions (37°C). Additionally, concurrent testing of several standard drugs revealed that membrane transport can be affected by the use of internal permeability standards. The implications of the results are discussed regarding the regulatory aspects of biopharmaceutical classification, good practice in drug permeability evaluation and regarding the general relevance of transport proteins with broad specificity in drug absorption.

  5. Quantifying Trace Amounts of Aggregates in Biopharmaceuticals Using Analytical Ultracentrifugation Sedimentation Velocity: Bayesian Analyses and F Statistics.

    Science.gov (United States)

    Wafer, Lucas; Kloczewiak, Marek; Luo, Yin

    2016-07-01

    Analytical ultracentrifugation-sedimentation velocity (AUC-SV) is often used to quantify high molar mass species (HMMS) present in biopharmaceuticals. Although these species are often present in trace quantities, they have received significant attention due to their potential immunogenicity. Commonly, AUC-SV data is analyzed as a diffusion-corrected, sedimentation coefficient distribution, or c(s), using SEDFIT to numerically solve Lamm-type equations. SEDFIT also utilizes maximum entropy or Tikhonov-Phillips regularization to further allow the user to determine relevant sample information, including the number of species present, their sedimentation coefficients, and their relative abundance. However, this methodology has several, often unstated, limitations, which may impact the final analysis of protein therapeutics. These include regularization-specific effects, artificial "ripple peaks," and spurious shifts in the sedimentation coefficients. In this investigation, we experimentally verified that an explicit Bayesian approach, as implemented in SEDFIT, can largely correct for these effects. Clear guidelines on how to implement this technique and interpret the resulting data, especially for samples containing micro-heterogeneity (e.g., differential glycosylation), are also provided. In addition, we demonstrated how the Bayesian approach can be combined with F statistics to draw more accurate conclusions and rigorously exclude artifactual peaks. Numerous examples with an antibody and an antibody-drug conjugate were used to illustrate the strengths and drawbacks of each technique.

  6. Transgenic mammalian species, generated by somatic cell cloning, in biomedicine, biopharmaceutical industry and human nutrition/dietetics--recent achievements.

    Science.gov (United States)

    Samiec, M; Skrzyszowska, M

    2011-01-01

    Somatic cell cloning technology in mammals promotes the multiplication of productively-valuable genetically engineered individuals, and consequently allows also for standardization of transgenic farm animal-derived products, which, in the context of market requirements, will have growing significance. Gene farming is one of the most promising areas in modern biotechnology. The use of live bioreactors for the expression of human genes in the lactating mammary gland of transgenic animals seems to be the most cost-effective method for the production/processing of valuable recombinant therapeutic proteins. Among the transgenic farm livestock species used so far, cattle, goats, sheep, pigs and rabbits are useful candidates for the expression of tens to hundreds of grams of genetically-engineered proteins or xenogeneic biopreparations in the milk. At the beginning of the new millennium, a revolution in the treatment of disease is taking shape due to the emergence of new therapies based on recombinant human proteins. The ever-growing demand for such pharmaceutical or nutriceutical proteins is an important driving force for the development of safe and large-scale production platforms. The aim of this paper is to present an overall survey of the state of the art in investigations which provide the current knowledge for deciphering the possibilities of practical application of the transgenic mammalian species generated by somatic cell cloning in biomedicine, the biopharmaceutical industry, human nutrition/dietetics and agriculture.

  7. Chloroplast-derived vaccine antigens and biopharmaceuticals: protocols for expression, purification, or oral delivery and functional evaluation.

    Science.gov (United States)

    Singh, N Dolendro; Ding, Yi; Daniell, Henry

    2009-01-01

    Many vaccine antigens and biopharmaceutical proteins have been expressed at high levels via the chloroplast genome and their functionality has been evaluated using in vitro assays in cell cultures (i.e., macrophage lysis assay, inhibition of vesicular stomatitis virus-induced cytopathicity in baby hamster kidney cells, or inhibition of human HIV infection in TZM-BL cells) as well as protection after challenge with bacterial or viral pathogens or antitumor assays or delay the onset of insulitis in suitable animal models. Production of therapeutic proteins in chloroplasts eliminates the expensive fermentation technology. Moreover, oral delivery of chloroplast-derived therapeutic proteins eliminates expensive purification steps, cold storage, cold transportation, and delivery via sterile needles, thereby further decreasing their cost. In this chapter, we describe detailed protocols for chloroplast transformation including the construction of chloroplast transformation vectors, delivery of DNA into plant cells using particle bombardment, selection and regeneration of transformants by tissue culture, confirmation of transgene integration into the chloroplast genome and homoplasmy, evaluation of foreign gene expression, purification of foreign protein, or oral delivery via bioencapsulation, functional evaluation using in vitro and in vivo assays, and evaluation of immunity after challenge with pathogens in suitable animal models.

  8. The study of base and surface-active substances influence on biopharmaceutical characteristics of suppository with praziquantel

    Directory of Open Access Journals (Sweden)

    D. M. Romanina

    2016-12-01

    Full Text Available Acne dermatoses (rosacea, perioral dermatitis, seborrheic dermatitis etc. are one of the most actual problems in dermatology. Praziquantel is an antiparasitic medication effective towards trematodes, cestodes. Investigations developed by domestic scientists revealed antidemodicosis activity of praziquantel. Use of semisolid dosage forms for rectal administration will allow to increase its efficacy and minimize the risks of adverse reactions. The aim of this work is the study of influence of excipients (bases and surfactants use in suppository manufacturing on the biopharmaceutical characteristics of praziquantel rectal dosage form. Methods and results. As excipients for praziquantel rectal dosage form we have investigated suppository bases and surfactants, which are widely used in manufacturing and compounding of semisolid dosage forms and are described in literature. Suppositories were made by the fusion method. Concentration of surfactants in all compositions was 2%, praziquantel – 0,6 g on one suppository. Investigation was carried out by the 2-factors dispersive analysis with repeated observations. Suppository compounding was carried out by the suspension type. After thorough pulverization of praziquantel, it was mixed with some part of the base and then obtained mixture was added to the all melted base. As optimization parameter the praziquantel releasing was chosen as the first step of bioavailability investigation. Praziquantel releasing from suppository was studied by the equilibrium dialysis by Kruvchinsky. Ethyl alcohol was chosen as a dialysis medium considering the solubility of praziquantel. Concentration of released praziquantel after 30 minutes of the dialysis was determined by spectrophotometric analysis. Conclusion. It has been established that the sort of the base and surfactant have significant influence on praziquantel releasing from rectal suppository. It has been revealed that sort of base has the greatest influence on

  9. Acceptability and characteristics of 124 human bioequivalence studies with active substances classified according to the Biopharmaceutic Classification System

    Science.gov (United States)

    Ramirez, Elena; Laosa, Olga; Guerra, Pedro; Duque, Blanca; Mosquera, Beatriz; Borobia, Alberto M; Lei, Suhua H; Carcas, Antonio J; Frias, Jesus

    2010-01-01

    AIM The aim of this study was to evaluate the acceptability of 124 bioequivalence (BE) studies with 80 active substances categorized according to the Biopharmaceutics Classification System (BCS) in order to establish if there were different probabilities of proving BE between the different BCS classes. METHODS We evaluated the differences between pharmaceutical products with active substances from different BCS classes in terms of acceptability, number of subjects in the study (n), the point estimates, and intra- and inter-subject coefficients of variation data from BE studies with generic products. RESULTS Out of 124 BE studies 89 (71.77%) were performed with pharmaceutical products containing active substances classified by the BCS. In all BCS classes there were non-bioequivalent pharmaceutical products: 4 out of 26 (15.38%) in class 1, 14 out of 28 (50%) in class 2, 3 out of 22 (13.63%) in class 3 and 1 out of 13 (7.69%) in class 4. When we removed those pharmaceutical products in which intra-subject variability was higher than predicted (2 in class 1 active substances, 9 in class 2 and 2 in class 3) there were still non-BE pharmaceutical products in classes 1, 2 and 3. CONCLUSIONS Comparisons between pharmaceutical products with active substances from the four BCS classes have not allowed us to define differential characteristics of each class in terms of n, inter and intra-subject variability for Cmax or AUC. Despite the usually employed test dissolution methodology proposed as quality control, pharmaceutical products with active substances from the four classes of BCS showed non-BE studies. PMID:21039763

  10. Therapeutic monoclonal antibodies: scFv patents as a marker of a new class of potential biopharmaceuticals

    Directory of Open Access Journals (Sweden)

    Manuela Berto Pucca

    2011-03-01

    Full Text Available Monoclonal antibodies represent the fastest growing class of biopharmaceutical products and have a host of applications in medical research, diagnosis, therapy, and basic science. The production of recombinant monoclonal antibodies has revolutionized the generation of immunoglobulins, and their use represents a strategic breakthrough, affecting the global pharmaceutical market for therapeutic proteins. In the present work, a review of scFv, and the number of related patents, has been carried out. The results show that several countries have scFv patents, most notably the United States, China and United Kingdom. The target of these scFv antibodies was also assessed and the results demonstrate that most are directed toward cancer therapy.Anticorpos monoclonais representam a classe de maior crescimento em produtos de biofármacos e possuem várias aplicações em pesquisa médica, diagnóstico, terapias e ciência básica. A produção de anticorpos monoclonais recombinantes revolucionou a geração de imunoglobulinas e sua utilização implica em avanço estratégico, afetando o mercado farmacêutico global de proteínas terapêuticas. No presente trabalho, uma revisão sobre scFv e a relação do seu número de patentes foi analisada. Os resultados mostram que vários países apresentam patentes de scFv com destaque para os Estados Unidos, China e Reino Unido. Os alvos desses anticorpos também foram avaliados e as análises revelaram que a maioria é destinado a terapias contra o câncer.

  11. Intestinal permeability study of minoxidil: assessment of minoxidil as a high permeability reference drug for biopharmaceutics classification.

    Science.gov (United States)

    Ozawa, Makoto; Tsume, Yasuhiro; Zur, Moran; Dahan, Arik; Amidon, Gordon L

    2015-01-05

    The purpose of this study was to evaluate minoxidil as a high permeability reference drug for Biopharmaceutics Classification System (BCS). The permeability of minoxidil was determined in in situ intestinal perfusion studies in rodents and permeability studies across Caco-2 cell monolayers. The permeability of minoxidil was compared with that of metoprolol, an FDA reference drug for BCS classification. In rat perfusion studies, the permeability of minoxidil was somewhat higher than that of metoprolol in the jejunum, while minoxidil showed lower permeability than metoprolol in the ileum. The permeability of minoxidil was independent of intestinal segment, while the permeability of metoprolol was region-dependent. Similarly, in mouse perfusion study, the jejunal permeability of minoxidil was 2.5-fold higher than that of metoprolol. Minoxidil and metoprolol showed similar permeability in Caco-2 study at apical pH of 6.5 and basolateral pH of 7.4. The permeability of minoxidil was independent of pH, while metoprolol showed pH-dependent transport in Caco-2 study. Minoxidil exhibited similar permeability in the absorptive direction (AP-BL) in comparison with secretory direction (BL-AP), while metoprolol had higher efflux ratio (ER > 2) at apical pH of 6.5 and basolateral pH of 7.4. No concentration-dependent transport was observed for either minoxidil or metoprolol transport in Caco-2 study. Verapamil did not alter the transport of either compounds across Caco-2 cell monolayers. The permeability of minoxidil was independent of both pH and intestinal segment in intestinal perfusion studies and Caco-2 studies. Caco-2 studies also showed no involvement of carrier mediated transport in the absorption process of minoxidil. These results suggest that minoxidil may be an acceptable reference drug for BCS high permeability classification. However, minoxidil exhibited higher jejunal permeability than metoprolol and thus to use minoxidil as a reference drug would raise the

  12. A reaction limited in vivo dissolution model for the study of drug absorption: Towards a new paradigm for the biopharmaceutic classification of drugs.

    Science.gov (United States)

    Macheras, Panos; Iliadis, Athanassios; Melagraki, Georgia

    2018-05-30

    The aim of this work is to develop a gastrointestinal (GI) drug absorption model based on a reaction limited model of dissolution and consider its impact on the biopharmaceutic classification of drugs. Estimates for the fraction of dose absorbed as a function of dose, solubility, reaction/dissolution rate constant and the stoichiometry of drug-GI fluids reaction/dissolution were derived by numerical solution of the model equations. The undissolved drug dose and the reaction/dissolution rate constant drive the dissolution rate and determine the extent of absorption when high-constant drug permeability throughout the gastrointestinal tract is assumed. Dose is an important element of drug-GI fluids reaction/dissolution while solubility exclusively acts as an upper limit for drug concentrations in the lumen. The 3D plots of fraction of dose absorbed as a function of dose and reaction/dissolution rate constant for highly soluble and low soluble drugs for different "stoichiometries" (0.7, 1.0, 2.0) of the drug-reaction/dissolution with the GI fluids revealed that high extent of absorption was found assuming high drug- reaction/dissolution rate constant and high drug solubility. The model equations were used to simulate in vivo supersaturation and precipitation phenomena. The model developed provides the theoretical basis for the interpretation of the extent of drug's absorption on the basis of the parameters associated with the drug-GI fluids reaction/dissolution. A new paradigm emerges for the biopharmaceutic classification of drugs, namely, a model independent biopharmaceutic classification scheme of four drug categories based on either the fulfillment or not of the current dissolution criteria and the high or low % drug metabolism. Copyright © 2018. Published by Elsevier B.V.

  13. Analysis, biomedicine, collaboration, and determinism challenges and guidance: wish list for biopharmaceuticals on the interface of computing and statistics.

    Science.gov (United States)

    Goodman, Arnold F

    2011-11-01

    I have personally witnessed processing advance from desk calculators and mainframes, through timesharing and PCs, to supercomputers and cloud computing. I have also witnessed resources grow from too little data into almost too much data, and from theory dominating data into data beginning to dominate theory while needing new theory. Finally, I have witnessed problems advance from simple in a lone discipline into becoming almost too complex in multiple disciplines, as well as approaches evolve from analysis driving solutions into solutions by data mining beginning to drive the analysis itself. How we do all of this has transitioned from competition overcoming collaboration into collaboration starting to overcome competition, as well as what is done being more important than how it is done has transitioned into how it is done becoming as important as what is done. In addition, what or how we do it being more important than what or how we should actually do it has shifted into what or how we should do it becoming just as important as what or how we do it, if not more so. Although we have come a long way in both our methodology and technology, are they sufficient for our current or future complex and multidisciplinary problems with their massive databases? Since the apparent answer is not a resounding yes, we are presented with tremendous challenges and opportunities. This personal perspective adapts my background and experience to be appropriate for biopharmaceuticals. In these times of exploding change, informed perspectives on what challenges should be explored with accompanying guidance may be even more valuable than the far more typical literature reviews in conferences and journals of what has already been accomplished without challenges or guidance. Would we believe that an architect who designs a skyscraper determines the skyscraper's exact exterior, interior and furnishings or only general characteristics? Why not increase dependability of conclusions in

  14. Multivariate statistical monitoring as applied to clean-in-place (CIP) and steam-in-place (SIP) operations in biopharmaceutical manufacturing.

    Science.gov (United States)

    Roy, Kevin; Undey, Cenk; Mistretta, Thomas; Naugle, Gregory; Sodhi, Manbir

    2014-01-01

    Multivariate statistical process monitoring (MSPM) is becoming increasingly utilized to further enhance process monitoring in the biopharmaceutical industry. MSPM can play a critical role when there are many measurements and these measurements are highly correlated, as is typical for many biopharmaceutical operations. Specifically, for processes such as cleaning-in-place (CIP) and steaming-in-place (SIP, also known as sterilization-in-place), control systems typically oversee the execution of the cycles, and verification of the outcome is based on offline assays. These offline assays add to delays and corrective actions may require additional setup times. Moreover, this conventional approach does not take interactive effects of process variables into account and cycle optimization opportunities as well as salient trends in the process may be missed. Therefore, more proactive and holistic online continued verification approaches are desirable. This article demonstrates the application of real-time MSPM to processes such as CIP and SIP with industrial examples. The proposed approach has significant potential for facilitating enhanced continuous verification, improved process understanding, abnormal situation detection, and predictive monitoring, as applied to CIP and SIP operations. © 2014 American Institute of Chemical Engineers.

  15. On-line coupling of size exclusion chromatography with mixed-mode liquid chromatography for comprehensive profiling of biopharmaceutical drug product.

    Science.gov (United States)

    He, Yan; Friese, Olga V; Schlittler, Michele R; Wang, Qian; Yang, Xun; Bass, Laura A; Jones, Michael T

    2012-11-02

    A methodology based on on-line coupling of size exclusion chromatography (SEC) with mixed-mode liquid chromatography (LC) has been developed. The method allows for simultaneous measurement of a wide range of components in biopharmaceutical drug products. These components include the active pharmaceutical ingredient (protein) and various kinds of excipients such as cations, anions, nonionic hydrophobic surfactant and hydrophilic sugars. Dual short SEC columns are used to separate small molecule excipients from large protein molecules. The separated protein is quantified using a UV detector at 280 nm. The isolated excipients are switched, online, to the Trinity P1 mixed-mode column for separation, and detected by an evaporative light scattering detector (ELSD). Using a stationary phase with 1.7 μm particles in SEC allows for the use of volatile buffers for both SEC and mix-mode separation. This facilitates the detection of different excipients by ELSD and provides potential for online characterization of the protein with mass spectrometry (MS). The method has been applied to quantitate protein and excipients in different biopharmaceutical drug products including monoclonal antibodies (mAb), antibody drug conjugates (ADC) and vaccines. Copyright © 2012 Elsevier B.V. All rights reserved.

  16. Evaluation of spectral libraries and sample preparation for DIA-LC-MS analysis of host cell proteins: A case study of a bacterially expressed recombinant biopharmaceutical protein.

    Science.gov (United States)

    Heissel, Søren; Bunkenborg, Jakob; Kristiansen, Max Per; Holmbjerg, Anne Fich; Grimstrup, Marie; Mørtz, Ejvind; Kofoed, Thomas; Højrup, Peter

    2018-07-01

    Recombinantly expressed biopharmaceutical proteins often undergo a series of purification steps with the aim of removing contaminating material. Depending on the application of the protein, there are various requirements for the degree of purity, but host cell proteins (HCPs) will in general remain in small amounts. LC-MS has emerged as an orthogonal technique, capable of providing detailed information regarding the individual proteins. The aim of this case study was to characterize the HCPs associated with a biopharmaceutical protein, provided by Statens Serum Institut (DK), which is used in the field of tuberculosis and has not previously been studied by LC-MS. The developed method and acquired experiences served to develop a generalized strategy for HCP-characterization in our laboratory. We evaluated the use of different spectral libraries, recorded in data-dependent mode for obtaining the highest HCP coverage, combined with SWATH-based absolute quantification. The accuracy of two label-free absolute quantification strategies was evaluated using stable isotope peptides. Two different sample preparation workflows were evaluated for optimal HCP yield. . The label-free strategy produced accurate quantification across several orders of magnitude, and the calculated purity was found to be in agreement with previously obtained ELISA data. Copyright © 2018 Elsevier Inc. All rights reserved.

  17. Preclinical tools in PET-tracer development : automatisation and biopharmaceutical evaluation with special emphasis on the adenosine A3 receptor

    International Nuclear Information System (INIS)

    Haeusler, D. I. B.

    2010-01-01

    Positron Emission Tomography (PET) is the first choice technology for the visualization and quantification of receptors and transporters, enabling examination of e.g. neurological, psychiatric and oncological diseases on a molecular level. Therefore, new and innovative PET-radiopharmaceuticals need to be developed to get further insights into the biochemical mechanisms involved in pathological changes. PET-tracer development starts with the idea or modelling of the chemical structure of a (new) molecule with (hopefully) good binding characteristics to the desired target site. As next steps, the compound needs to be synthesized and radiolabelled with a suitable PET-nuclide. Then it has to be evaluated regarding its parameters in various preclinical experimental settings. Hence, two major tools are crucial in the development-process of new PET-tracers: 1) a fast and reliable production method, most desirable and optimal in an automated set-up, and 2) proof of tracer suitability (high affinity, high selectivity and specificity, beside low unspecific binding) through preclinical evaluation in an animal model, prior to human application. Both aspects, the radiochemical preparation and automatisation, as well as the biopharmaceutical evaluation are presented in the thesis in 5 different manuscripts. In detail, the development and preclinical evaluation of 4 different PET-tracers ([11C]DASB, [18F]FE SUPPY, [18F]FE SUPPY:2, and [18F]FE CIT) for 3 targets, the serotonin transporter (SERT), the adenosine A3 receptor (A3R) and the dopamine transporter (DAT), respectively, are covered in the present thesis. The first manuscript presents a method for a fast, reliable and fully-automated radiosynthesis of [11C]DASB (a tracer for the imaging of the SERT in human brain in e.g. depression patients) will facilitate further clinical investigations (e.g. for the department of psychiatry and psychotherapy of the medical university of Vienna) with this tracer. [18F]FE SUPPY was

  18. The "high solubility" definition of the current FDA Guidance on Biopharmaceutical Classification System may be too strict for acidic drugs.

    Science.gov (United States)

    Yazdanian, Mehran; Briggs, Katherine; Jankovsky, Corinne; Hawi, Amale

    2004-02-01

    The purpose of this study was to assess if the definition of high solubility as proposed in the FDA Guidance on Biopharmaceutical Classification System (BCS) is too strict for highly permeable acidic drugs. The solubility and permeability values of 20 (18 acidic and 2 non-acidic) nonsteroidal anti-inflammatory drugs (NSAID) were determined. The NSAIDs were grouped into three different sets having acetic acid, propionic acid, or other acidic moieties such as fenamate, oxicam, and salicylate. Two nonacidic NSAIDs (celecoxib and rofecoxib) were also included for comparison purposes. Equilibrium solubility values were determined at pH 1.2, 5.0, 7.4, and in biorelevant media simulating fed intestinal fluid at pH 5.0. For a select number of acids, we also measured solubility values in media simulating gastric and fasted intestinal fluids. Permeability classification was established relative to that of reference drugs in the Caco-2 cell permeability model. Permeability coefficients for all drugs were measured at concentrations corresponding to the lowest and highest marketed dose strengths dissolved in 250 ml volume, and their potential interaction with cellular efflux pumps was investigated. All NSAIDs with different acidic functional groups were classified as highly permeable based on their Caco-2 cell permeability. Only ketorolac appeared to have a potential for interaction with cellular efflux pumps. Solubility classification was based on comparison of equilibrium solubility at pH 1.2, 5.0. and 7.4 relative to marketed dose strengths in 250 ml. The pKa values for the acidic NSAIDs studied were between 3.5 and 5.1. and, as expected, their solubility increased dramatically at pH 7.4 compared to pH 1.2. Only three NSAIDs, ketorolac, ketoprofen. and acetyl salicylic acid, meet the current criteria for high solubility over the entire pH range. However, with the exception of ibuprofen, oxaprozin, and mefenamic acid, the remaining compounds can be classified as Class I drugs

  19. Evaluation of the membrane permeability (PAMPA and skin) of benzimidazoles with potential cannabinoid activity and their relation with the Biopharmaceutics Classification System (BCS).

    Science.gov (United States)

    Alvarez-Figueroa, M Javiera; Pessoa-Mahana, C David; Palavecino-González, M Elisa; Mella-Raipán, Jaime; Espinosa-Bustos, Cristián; Lagos-Muñoz, Manuel E

    2011-06-01

    The permeability of five benzimidazole derivates with potential cannabinoid activity was determined in two models of membranes, parallel artificial membrane permeability assay (PAMPA) and skin, in order to study the relationship of the physicochemical properties of the molecules and characteristics of the membranes with the permeability defined by the Biopharmaceutics Classification System. It was established that the PAMPA intestinal absorption method is a good predictor for classifying these molecules as very permeable, independent of their thermodynamic solubility, if and only if these have a Log P(oct) value permeability is conditioned on the solubility of the molecule so that it can only serve as a model for classifying the permeability of molecules that possess high solubility (class I: high solubility, high permeability; class III: high solubility, low permeability).

  20. Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: recommendations of the Innovative Medicines Initiative ABIRISK consortium.

    Science.gov (United States)

    Rup, B; Pallardy, M; Sikkema, D; Albert, T; Allez, M; Broet, P; Carini, C; Creeke, P; Davidson, J; De Vries, N; Finco, D; Fogdell-Hahn, A; Havrdova, E; Hincelin-Mery, A; C Holland, M; H Jensen, P E; Jury, E C; Kirby, H; Kramer, D; Lacroix-Desmazes, S; Legrand, J; Maggi, E; Maillère, B; Mariette, X; Mauri, C; Mikol, V; Mulleman, D; Oldenburg, J; Paintaud, G; R Pedersen, C; Ruperto, N; Seitz, R; Spindeldreher, S; Deisenhammer, F

    2015-09-01

    Biopharmaceuticals (BPs) represent a rapidly growing class of approved and investigational drug therapies that is contributing significantly to advancing treatment in multiple disease areas, including inflammatory and autoimmune diseases, genetic deficiencies and cancer. Unfortunately, unwanted immunogenic responses to BPs, in particular those affecting clinical safety or efficacy, remain among the most common negative effects associated with this important class of drugs. To manage and reduce risk of unwanted immunogenicity, diverse communities of clinicians, pharmaceutical industry and academic scientists are involved in: interpretation and management of clinical and biological outcomes of BP immunogenicity, improvement of methods for describing, predicting and mitigating immunogenicity risk and elucidation of underlying causes. Collaboration and alignment of efforts across these communities is made difficult due to lack of agreement on concepts, practices and standardized terms and definitions related to immunogenicity. The Innovative Medicines Initiative (IMI; www.imi-europe.org), ABIRISK consortium [Anti-Biopharmaceutical (BP) Immunization Prediction and Clinical Relevance to Reduce the Risk; www.abirisk.eu] was formed by leading clinicians, academic scientists and EFPIA (European Federation of Pharmaceutical Industries and Associations) members to elucidate underlying causes, improve methods for immunogenicity prediction and mitigation and establish common definitions around terms and concepts related to immunogenicity. These efforts are expected to facilitate broader collaborations and lead to new guidelines for managing immunogenicity. To support alignment, an overview of concepts behind the set of key terms and definitions adopted to date by ABIRISK is provided herein along with a link to access and download the ABIRISK terms and definitions and provide comments (http://www.abirisk.eu/index_t_and_d.asp). © 2015 British Society for Immunology.

  1. Summary of the National Institute of Child Health and Human Development-best pharmaceuticals for Children Act Pediatric Formulation Initiatives Workshop-Pediatric Biopharmaceutics Classification System Working Group.

    Science.gov (United States)

    Abdel-Rahman, Susan M; Amidon, Gordon L; Kaul, Ajay; Lukacova, Viera; Vinks, Alexander A; Knipp, Gregory T

    2012-11-01

    The Biopharmaceutics Classification System (BCS) allows compounds to be classified based on their in vitro solubility and intestinal permeability. The BCS has found widespread use in the pharmaceutical community to be an enabling guide for the rational selection of compounds, formulation for clinical advancement, and generic biowaivers. The Pediatric Biopharmaceutics Classification System (PBCS) Working Group was convened to consider the possibility of developing an analogous pediatric-based classification system. Because there are distinct developmental differences that can alter intestinal contents, volumes, permeability, and potentially biorelevant solubilities at different ages, the PBCS Working Group focused on identifying age-specific issues that need to be considered in establishing a flexible, yet rigorous PBCS. We summarized the findings of the PBCS Working Group and provided insights into considerations required for the development of a PBCS. Through several meetings conducted both at The Eunice Kennedy Shriver National Institute of Child Health, Human Development-US Pediatric Formulation Initiative Workshop (November 2011) and via teleconferences, the PBCS Working Group considered several high-level questions that were raised to frame the classification system. In addition, the PBCS Working Group identified a number of knowledge gaps that need to be addressed to develop a rigorous PBCS. It was determined that for a PBCS to be truly meaningful, it needs to be broken down into several different age groups that account for developmental changes in intestinal permeability, luminal contents, and gastrointestinal (GI) transit. Several critical knowledge gaps were identified, including (1) a lack of fully understanding the ontogeny of drug metabolizing enzymes and transporters along the GI tract, in the liver, and in the kidney; (2) an incomplete understanding of age-based changes in the GI, liver, and kidney physiology; (3) a clear need to better understand

  2. Preparation, in-vitro and in-vivo evaluation of spray-dried ternary solid dispersion of biopharmaceutics classification system class II model drug.

    Science.gov (United States)

    Paidi, Sharan K; Jena, Sunil K; Ahuja, Bhupesh K; Devasari, Naresh; Suresh, Sarasija

    2015-05-01

    The objective of this study was to investigate the impact of a novel spray-dried ternary solid dispersion (TSD) on the dissolution rate and bioavailability of a biopharmaceutics classification system (BCS) class II model drug, atorvastatin calcium trihydrate (ATC), and evaluate its in-vitro and in-vivo performance. TSD of ATC was prepared by spray-drying method employing ethanol/water solvent systems. The TSD formulations, composed of hydroxypropyl methylcellulose (HPMC E5) and nicotinamide, were optimized by rotatable central composite design. Physicochemical characterization along with dissolution, stability and pharmacokinetic study of optimized TSD was evaluated. The optimized TSD was found to be amorphous with spherical shape morphology. It exhibited a fourfold increase in dissolution rate in comparison to ATC, with a considerable enhancement in oral bioavailability (relative bioavailability of 134.11%). Physicochemical characterization and dissolution study of optimized TSD at the end of stability studies clearly indicated that the stability of optimized TSD was due to hydrogen bonding between drug and HPMC E5 and nicotinamide. This bonding remained unaffected even under stressful conditions of high temperature and humidity. The TSD exhibits a significant increase in dissolution rate, and for this reason should be useful as an efficacious tool to enhance the bioavailability of BCS class II drug molecule, ATC. © 2015 Royal Pharmaceutical Society.

  3. Evaluation of the use of partition coefficients and molecular surface properties as predictors of drug absorption: a provisional biopharmaceutical classification of the list of national essential medi

    Directory of Open Access Journals (Sweden)

    NU Rahman

    2011-05-01

    Full Text Available Background and the purpose of the study: Partition coefficients (log D and log P and molecular surface area (PSA are potential predictors of the intestinal permeability of drugs. The aim of this investigation was to evaluate and compare these intestinal permeability indicators.   Methods: Aqueous solubility data were obtained from literature or calculated using ACD/Labs and ALOGPS. Permeability data were predicted based on log P, log D at pH 6.0 (log D6.0, and PSA.  Results: Metoprolol's log P, log D6.0 and a PSA of <65 Å correctly predicted 55.9%, 50.8% and 54.2% of permeability classes, respectively. Labetalol's log P, log D6.0, and PSA correctly predicted 54.2%, 64.4% and 61% of permeability classes, respectively. Log D6.0 correlated well (81% with Caco-2 permeability (Papp. Of the list of national essential medicines, 135 orally administered drugs were classified into biopharmaceutical classification system (BCS. Of these, 57 (42.2%, 28 (20.7%, 44 (32.6%, and 6 (4.4% were class I, II, III and IV respectively. Conclusion: Log D6.0 showed better prediction capability than log P. Metoprolol as permeability internal standard was more conservative than labetalol.

  4. BIOPHARMACEUTICAL RESEARCHES IN VITRO ON THE CHOICE OF OPTIMAL COMPOSITION OF PHARMACEUTICAL AID FOR OINTMENT PRODUCTION BASED ON СО2 EXTRACT OF SCHISANDRA CHINENSIS SEEDS

    Directory of Open Access Journals (Sweden)

    Y. A. Morozov

    2014-01-01

    Full Text Available Schisandra chinensis is valuable species of herbal medicines raw materials (fruits, seeds, caruncles, leaves, stem cortex, and roots with root systems which are used for medicines and biologically active supplements production in food and cosmetic industry. However nowadays medicines from Schisandra chinensis are only represented by tincture for internal use on domestic pharmaceutical market. There are data about positive implementation of medicines based on raw materials of Schisandra chinensis as external medicine forms in folk medicine and in literature. The purpose of this work is the development of soft external medicine form – ointment based on СО2 extract of Schisandra chinensis seeds. Biopharmaceutical researches in vitro on the choice of optimal ointment composition by the method of dialysis through semi permeable membrane were conducted for this purpose. Release rate was calculated in relation to base biologically active substances of Schisandra chinensis – lignans (schizandrin and γ-schizandrin which determine its basic pharmacological value. Based on the results of the research conducted it is possible to conclude that the best ointment bases are hydrophilous “classic” poly ethylene oxide and oleogel based on paraffinic oil and aerosil.

  5. First Steps to Develop and Validate a CFPD Model in Order to Support the Design of Nose-to-Brain Delivered Biopharmaceuticals.

    Science.gov (United States)

    Engelhardt, Lucas; Röhm, Martina; Mavoungou, Chrystelle; Schindowski, Katharina; Schafmeister, Annette; Simon, Ulrich

    2016-06-01

    Aerosol particle deposition in the human nasal cavity is of high interest in particular for intranasal central nervous system (CNS) drug delivery via the olfactory cleft. The objective of this study was the development and comparison of a numerical and experimental model to investigate various parameters for olfactory particle deposition within the complex anatomical nasal geometry. Based on a standardized nasal cavity, a computational fluid and particle dynamics (CFPD) model was developed that enables the variation and optimization of different parameters, which were validated by in vitro experiments using a constructed rapid-prototyped human nose model. For various flow rates (5 to 40 l/min) and particle sizes (1 to 10 μm), the airflow velocities, the calculated particle airflow patterns and the particle deposition correlated very well with the experiment. Particle deposition was investigated numerically by varying particle sizes at constant flow rate and vice versa assuming the particle size distribution of the used nebulizer. The developed CFPD model could be directly translated to the in vitro results. Hence, it can be applied for parameter screening and will contribute to the improvement of aerosol particle deposition at the olfactory cleft for CNS drug delivery in particular for biopharmaceuticals.

  6. [Factors affecting the adoption of ICT tools in experiments with bioinformatics in biopharmaceutical organizations: a case study in the Brazilian Cancer Institute].

    Science.gov (United States)

    Pitassi, Claudio; Gonçalves, Antonio Augusto; Moreno Júnior, Valter de Assis

    2014-01-01

    The scope of this article is to identify and analyze the factors that influence the adoption of ICT tools in experiments with bioinformatics at the Brazilian Cancer Institute (INCA). It involves a descriptive and exploratory qualitative field study. Evidence was collected mainly based on in-depth interviews with the management team at the Research Center and the IT Division. The answers were analyzed using the categorical content method. The categories were selected from the scientific literature and consolidated in the Technology-Organization-Environment (TOE) framework created for this study. The model proposed made it possible to demonstrate how the factors selected impacted INCA´s adoption of bioinformatics systems and tools, contributing to the investigation of two critical areas for the development of the health industry in Brazil, namely technological innovation and bioinformatics. Based on the evidence collected, a research question was posed: to what extent can the alignment of the factors related to the adoption of ICT tools in experiments with bioinformatics increase the innovation capacity of a Brazilian biopharmaceutical organization?

  7. Clinical Trial Data as Public Goods: Fair Trade and the Virtual Knowledge Bank as a Solution to the Free Rider Problem - A Framework for the Promotion of Innovation by Facilitation of Clinical Trial Data Sharing among Biopharmaceutical Companies in the Era of Omics and Big Data.

    Science.gov (United States)

    Evangelatos, Nikolaos; Reumann, Matthias; Lehrach, Hans; Brand, Angela

    2016-01-01

    Knowledge in the era of Omics and Big Data has been increasingly conceptualized as a public good. Sharing of de-identified patient data has been advocated as a means to increase confidence and public trust in the results of clinical trials. On the other hand, research has shown that the current research and development model of the biopharmaceutical industry has reached its innovation capacity. In response to that, the biopharmaceutical industry has adopted open innovation practices, with sharing of clinical trial data being among the most interesting ones. However, due to the free rider problem, clinical trial data sharing among biopharmaceutical companies could undermine their innovativeness. Based on the theory of public goods, we have developed a commons arrangement and devised a model, which enables secure and fair clinical trial data sharing over a Virtual Knowledge Bank based on a web platform. Our model uses data as a virtual currency and treats knowledge as a club good. Fair sharing of clinical trial data over the Virtual Knowledge Bank has positive effects on the innovation capacity of the biopharmaceutical industry without compromising the intellectual rights, proprietary interests and competitiveness of the latter. The Virtual Knowledge Bank is a sustainable and self-expanding model for secure and fair clinical trial data sharing that allows for sharing of clinical trial data, while at the same time it increases the innovation capacity of the biopharmaceutical industry. © 2016 S. Karger AG, Basel.

  8. Protein A affinity chromatography of Chinese hamster ovary (CHO) cell culture broths containing biopharmaceutical monoclonal antibody (mAb): Experiments and mechanistic transport, binding and equilibrium modeling.

    Science.gov (United States)

    Grom, Matic; Kozorog, Mirijam; Caserman, Simon; Pohar, Andrej; Likozar, Blaž

    2018-04-15

    Protein A-based affinity chromatography is a highly-efficient separation method to capture, purify and isolate biosimilar monoclonal antibodies (mAb) - an important medical product of biopharmaceutical industrial manufacturing. It is considered the most expensive step in purification downstream operations; therefore, its performance optimization offers a great cost saving in the overall production expenditure. The biochemical mixture-separating specific interaction experiments with Chinese hamster ovary (CHO) cell culture harvest, containing glycosylated extracellular immunoglobulins (Ig), were made using five different state-of-the-art commercial resins. Packing breakthrough curves were recorded at an array of prolonged residence times. A mathematical simulation model was developed, applied and validated in combination with non-linear regression algorithms on bed effluent concentrations to determine the previously-unknown binding properties of stationary phase materials. Apart from the columns' differential partitioning, the whole external system was also integrated. It was confirmed that internal pore diffusion is the global rate-limiting resistance of the compound retention process. Immobilizing substrate characteristics, obtained in this engineering study, are indispensable for the scale-up of the periodic counter-current control with mechanistic load, elution and wash reduction. Furthermore, unit's volumetric flow screening measurements revealed dynamic effect correlation to eluate quality parameters, like the presence of aggregates, the host cell-related impurities at supernatant's extended feeding, and titre. Numerical sensitivity outputs demonstrated the impacts of fluidics (e.g. axial dispersion coefficient), thermodynamics (Langmuir adsorption) and mass transfer fluxes. Copyright © 2018 Elsevier B.V. All rights reserved.

  9. Biopharmaceuticals: From peptide to drug

    Science.gov (United States)

    Hannappel, Margarete

    2017-08-01

    Biologics are therapeutic proteins or peptides that are produced by means of biological processes within living organisms and cells. They are highly specific molecules and play a crucial role as therapeutics for the treatment of severe and chronic diseases (e.g. cancer, rheumatoid arthritis, diabetes, autoimmune disorders). The development of new biologics and biologics-based drugs gains more and more importance in the fight against various diseases. A short overview on biotherapeutical drug development is given. Cone snails are a large group of poisonous, predatory sea snails with more than 700 species. They use a very powerful venom which rapidly inactivates and paralyzes their prey. Most bioactive venom components are small peptides (conotoxins, conopeptides) which are precisely directed towards a specific target (e.g. ion channel, receptors). Due to their small size, their precision and speed of action, naturally occurring cone snail venom peptides represent an attractive source for the identification and design of novel biological drug entities. The Jagna cone snail project is an encouraging initiative to map the ecological variety of cone snails around the island of Bohol (Philippines) and to conserve the biological information for potential future application.

  10. Emerging biopharmaceuticals from marine actinobacteria.

    Science.gov (United States)

    Hassan, Syed Shams Ul; Anjum, Komal; Abbas, Syed Qamar; Akhter, Najeeb; Shagufta, Bibi Ibtesam; Shah, Sayed Asmat Ali; Tasneem, Umber

    2017-01-01

    Actinobacteria are quotidian microorganisms in the marine world, playing a crucial ecological role in the recycling of refractory biomaterials and producing novel secondary metabolites with pharmaceutical applications. Actinobacteria have been isolated from the huge area of marine organisms including sponges, tunicates, corals, mollusks, crabs, mangroves and seaweeds. Natural products investigation of the marine actinobacteria revealed that they can synthesize numerous natural products including alkaloids, polyketides, peptides, isoprenoids, phenazines, sterols, and others. These natural products have a potential to provide future drugs against crucial diseases like cancer, HIV, microbial and protozoal infections and severe inflammations. Therefore, marine actinobacteria portray as a pivotal resource for marine drugs. It is an upcoming field of research to probe a novel and pharmaceutically important secondary metabolites from marine actinobacteria. In this review, we attempt to summarize the present knowledge on the diversity, chemistry and mechanism of action of marine actinobacteria-derived secondary metabolites from 2007 to 2016. Copyright © 2016 Elsevier B.V. All rights reserved.

  11. Use of near-infrared spectroscopy (NIRs) in the biopharmaceutical industry for real-time determination of critical process parameters and integration of advanced feedback control strategies using MIDUS control.

    Science.gov (United States)

    Vann, Lucas; Sheppard, John

    2017-12-01

    Control of biopharmaceutical processes is critical to achieve consistent product quality. The most challenging unit operation to control is cell growth in bioreactors due to the exquisitely sensitive and complex nature of the cells that are converting raw materials into new cells and products. Current monitoring capabilities are increasing, however, the main challenge is now becoming the ability to use the data generated in an effective manner. There are a number of contributors to this challenge including integration of different monitoring systems as well as the functionality to perform data analytics in real-time to generate process knowledge and understanding. In addition, there is a lack of ability to easily generate strategies and close the loop to feedback into the process for advanced process control (APC). The current research aims to demonstrate the use of advanced monitoring tools along with data analytics to generate process understanding in an Escherichia coli fermentation process. NIR spectroscopy was used to measure glucose and critical amino acids in real-time to help in determining the root cause of failures associated with different lots of yeast extract. First, scale-down of the process was required to execute a simple design of experiment, followed by scale-up to build NIR models as well as soft sensors for advanced process control. In addition, the research demonstrates the potential for a novel platform technology that enables manufacturers to consistently achieve "goldenbatch" performance through monitoring, integration, data analytics, understanding, strategy design and control (MIDUS control). MIDUS control was employed to increase batch-to-batch consistency in final product titers, decrease the coefficient of variability from 8.49 to 1.16%, predict possible exhaust filter failures and close the loop to prevent their occurrence and avoid lost batches.

  12. G.L. Amidon, H. Lennernas, V.P. Shah, and J.R. Crison. A theoretical basis for a biopharmaceutic drug classification: the correlation of in vitro drug product dissolution and in vivo bioavailability, Pharm Res 12, 413-420, 1995--backstory of BCS.

    Science.gov (United States)

    Shah, Vinod P; Amidon, Gordon L

    2014-09-01

    The Biopharmaceutics Classification System (BCS) has become widely accepted today in the academic, industrial, and regulatory world. While the initial application of the BCS was to regulatory science bioequivalence (BE) issues and related implications, it has come to be utilized widely by the pharmaceutical industry in drug discovery and development as well. This brief manuscript will relate the story of the BCS development. While much of the ground work for the BCS goes back to the pharmacokinetic and drug absorption research by Gordon Amidon (GLA) in the 1970s and 1980s, the realization of the need for a classification or categorization of drug and drug products for setting dissolution standards became apparent to GLA during his 1990-1991 sabbatical year at the FDA. Initiated at the invitation of the then CEDR director, Dr. Carl Peck, to become a visiting scientist at the FDA, the goal was to promote regulatory research at the FDA, in my case, in biopharmaceutics, and to develop a science-based system to simplify regulatory requirements.

  13. Comparative evaluation of the biopharmaceutical and chemical ...

    African Journals Online (AJOL)

    Erah

    disintegration test, dissolution rate, thin layer chromatography and non-aqueous ... system of many developing countries was aimed ... products. The need to select one product from among several generic drug products of the same active.

  14. Comparative evaluation of the biopharmaceutical and chemical ...

    African Journals Online (AJOL)

    ... of weight and friability test, while one of the brands failed the disintegration test. ... and chemically equivalent, while a particular brand is obviously a fake product. ... equipments that are not easily available in most developing countries.

  15. Biopharmaceutical aspects of oral drug delivery

    NARCIS (Netherlands)

    Faassen, Werenfriedus Adrianus

    2004-01-01

    Most drugs display their therapeutic activity on specific places in the human body and should reach the systemic circulation in order to be transported towards the site of action. Irrespective of the route of administration the same sequence of steps are of relevance for the exposure to a drug:

  16. Perspectives from a new entrant in Biopharmaceuticals

    CSIR Research Space (South Africa)

    Magwaza, Martin S

    2017-10-01

    Full Text Available middle class with more disposable income Challenges & Opportunities Challenges • Regulatory hurdles for Ready-to Market-products and technologies • MCC backlogs – Local • Lack of mutual recognition (EU , US , etc) – e.g. Medicinal status of CAMs... as an Innovative nation • SA Govt Tax incentives encourage early stage high risk investment • Convergence of technology platforms and capabilities reduce resource requirements for new entrants Priority Medicines for Europe and the World Update Report...

  17. Interference in Bacterial Quorum Sensing: A Biopharmaceutical Perspective

    Directory of Open Access Journals (Sweden)

    Benjamin Rémy

    2018-03-01

    Full Text Available Numerous bacteria utilize molecular communication systems referred to as quorum sensing (QS to synchronize the expression of certain genes regulating, among other aspects, the expression of virulence factors and the synthesis of biofilm. To achieve this process, bacteria use signaling molecules, known as autoinducers (AIs, as chemical messengers to share information. Naturally occurring strategies that interfere with bacterial signaling have been extensively studied in recent years, examining their potential to control bacteria. To interfere with QS, bacteria use quorum sensing inhibitors (QSIs to block the action of AIs and quorum quenching (QQ enzymes to degrade signaling molecules. Recent studies have shown that these strategies are promising routes to decrease bacterial pathogenicity and decrease biofilms, potentially enhancing bacterial susceptibility to antimicrobial agents including antibiotics and bacteriophages. The efficacy of QSIs and QQ enzymes has been demonstrated in various animal models and are now considered in the development of new medical devices against bacterial infections, including dressings, and catheters for enlarging the therapeutic arsenal against bacteria.

  18. Consumer cost sharing and use of biopharmaceuticals for rheumatoid arthritis.

    Science.gov (United States)

    Robinson, James C

    2013-06-01

    To evaluate the effect of consumer cost sharing on use of physician-administered and patient self-administered specialty drugs for rheumatoid arthritis. Multivariate statistical analysis of probability and use of physician-administered specialty drugs, patient self-injected specialty drugs, non-biologic disease-modifying anti-rheumatic drugs, and symptom relief drugs. Analyses were conducted for patients enrolling in preferred provider organization (PPO) plans and health maintenance organization (HMO) plans with different cost-sharing requirements, adjusted for patient demographics, health status, and geographical location. Professional, facility, and pharmaceutical claims for beneficiaries of CalPERS, the public employee insurance purchasing alliance in California, for 2008-2009. Consumer cost-sharing requirements were obtained for each type of drug and service for each type of insurance plan. PPO insurance enrollees face substantially higher cost sharing for physician-administered specialty drugs, compared with HMO enrollees in CalPERS. PPO patients with rheumatoid arthritis are only half as likely as HMO enrollees to choose a physician-administered specialty drug (4.2% vs 9.3%) (P ≤.05), and use 25% less of the drugs if they use any ($10,356 vs $13,678) (P ≤.05). They are 30% more likely to use a self-administered specialty drug than are HMO enrollees (29.3% vs 22.1%) (P ≤.05), and use 35% more of the drugs if any ($16,015 vs $12,378) (P ≤.05). Consumer cost sharing reduces the use of physician-administered specialty drugs for rheumatoid arthritis. The higher use of patient self-administered specialty drugs suggests that the disincentives for use of physician-administered drugs were offset by an increased incentive to use self-administered drugs.

  19. Drug-sensing hydrogels for the inducible release of biopharmaceuticals

    Science.gov (United States)

    Ehrbar, Martin; Schoenmakers, Ronald; Christen, Erik H.; Fussenegger, Martin; Weber, Wilfried

    2008-10-01

    Drug-dependent dissociation or association of cellular receptors represents a potent pharmacologic mode of action for regulating cell fate and function. Transferring the knowledge of pharmacologically triggered protein-protein interactions to materials science will enable novel design concepts for stimuli-sensing smart hydrogels. Here, we show the design and validation of an antibiotic-sensing hydrogel for the trigger-inducible release of human vascular endothelial growth factor. Genetically engineered bacterial gyrase subunit B (GyrB) (ref. 4) coupled to polyacrylamide was dimerized by the addition of the aminocoumarin antibiotic coumermycin, resulting in hydrogel formation. Addition of increasing concentrations of clinically validated novobiocin (Albamycin) dissociated the GyrB subunits, thereby resulting in dissociation of the hydrogel and dose- and time-dependent liberation of the entrapped protein pharmaceutical VEGF121 for triggering proliferation of human umbilical vein endothelial cells. Pharmacologically controlled hydrogels have the potential to fulfil the promises of stimuli-sensing materials as smart devices for spatiotemporally controlled delivery of drugs within the patient.

  20. Biopharmaceutical formulations for pre-filled delivery devices.

    Science.gov (United States)

    Jezek, Jan; Darton, Nicholas J; Derham, Barry K; Royle, Nikki; Simpson, Iain

    2013-06-01

    Pre-filled syringes are becoming an increasingly popular format for delivering biotherapeutics conveniently and cost effectively. The device design and stable liquid formulations required to enable this pre-filled syringe format are technically challenging. In choosing the materials and process conditions to fabricate the syringe unit, their compatibility with the biotherapeutic needs to be carefully assessed. The biothereaputic stability demanded for the production of syringe-compatible low-viscosity liquid solutions requires critical excipient choices to be made. The purpose of this review is to discuss key issues related to the stability aspects of biotherapeutics in pre-filled devices. This includes effects on both physical and chemical stability due to a number of stress conditions the product is subjected to, as well as interactions with the packaging system. Particular attention is paid to the control of stability by formulation. We anticipate that there will be a significant move towards polymer primary packaging for most drugs in the longer term. The timescales for this will depend on a number of factors and hence will be hard to predict. Formulation will play a critical role in developing successful products in the pre-filled syringe format, particularly with the trend towards concentrated biotherapeutics. Development of novel, smart formulation technologies will, therefore, be increasingly important.

  1. Modeling of biopharmaceutical processes. Part 2: Process chromatography unit operation

    DEFF Research Database (Denmark)

    Kaltenbrunner, Oliver; McCue, Justin; Engel, Philip

    2008-01-01

    Process modeling can be a useful tool to aid in process development, process optimization, and process scale-up. When modeling a chromatography process, one must first select the appropriate models that describe the mass transfer and adsorption that occurs within the porous adsorbent. The theoret......Process modeling can be a useful tool to aid in process development, process optimization, and process scale-up. When modeling a chromatography process, one must first select the appropriate models that describe the mass transfer and adsorption that occurs within the porous adsorbent...

  2. Enabling local production of biopharmaceuticals in South Africa

    CSIR Research Space (South Africa)

    Tsekoa, Tsepo L

    2017-10-01

    Full Text Available - based pharmaceuticals. 9 Case study 1: Rabivir, new-generation rabies post-exposure prophylaxis 10 Case study 2: Microbial production of biosimilar CRM197 carrier protein • Problem/Need: Accessible and cost-competitive paediatric vaccines... • Prohibitively expensive pricing of protein reagent (CRM197) used in manufacture of conjugate vaccines for children (e.g. multivalent pneumococcal vaccine) • Solution: Fermentation-based production in recombinant E. coli • Stage: Proof of concept complete...

  3. Biomass performance : monitoring and control in bio-pharmaceutical production

    NARCIS (Netherlands)

    Neeleman, R.

    2002-01-01

    The primary concern in the pharmaceutical industry is not the optimisation of product yield or the reduction of manufacturing cost, but the production of a product of consistently high quality. This has resulted in 'process monitoring' becoming an integral part of process operation. In this

  4. Mycobacterium bovis: realities and challenges for the veterinary biopharmaceutical industry

    Directory of Open Access Journals (Sweden)

    Aníbal Domínguez Odio

    2016-01-01

    Full Text Available Mycobacterium bovis is the main etiological agent of bovine tuberculosis, bacterial diseases of world distribution, chronicle, of easy transmission, debilitating, zoonotic and antropozoonotic that affects any organ and which can be presented without symptoms On this base, it was carried out a study with the objective of approaching the current state and the scientific-technological projections for the prevention and diagnosis of the bovine tuberculosis, caused by M. bovis. It was demonstrated that the 45.09% of the original articles on inmunoprophylaxis against bacteria, registered in the Scopus database and contextualised until principles of 2014, were focused toward M. bovis. In spite of the advances in molecular biology and the hopes deposited in the Ag85A, Rv0287, Rv0288, Rv0251c, MPB70, MPB83, ESAT-6 and CFP-10 molecules, jointly with their combinations, it will continue absent in the market an effective, safety and differentiating vaccine; as well as a robust DIVA diagnosis system. It can be concluded that in the next 5 years, an officially recognized vacinal formulation will continue absent and that the tuberculin test in spite of its weaknesses will continue being the main tool of surveillance.

  5. Biopharmaceutical Classification System in Invitro/ In-vivo Correlation

    African Journals Online (AJOL)

    Drug development is a very laborious and expensive process. One of the major reasons for failure during the clinical phases of drug development is inadequate pharmacokinetic data on the drug candidate. Therefore, it would be advantageous if the pharmacokinetic properties of drug candidates be predicted beforehand.

  6. Whole-cell Escherichia coli lactate biosensor for monitoring mammalian cell cultures during biopharmaceutical production.

    Science.gov (United States)

    Goers, Lisa; Ainsworth, Catherine; Goey, Cher Hui; Kontoravdi, Cleo; Freemont, Paul S; Polizzi, Karen M

    2017-06-01

    Many high-value added recombinant proteins, such as therapeutic glycoproteins, are produced using mammalian cell cultures. In order to optimize the productivity of these cultures it is important to monitor cellular metabolism, for example the utilization of nutrients and the accumulation of metabolic waste products. One metabolic waste product of interest is lactic acid (lactate), overaccumulation of which can decrease cellular growth and protein production. Current methods for the detection of lactate are limited in terms of cost, sensitivity, and robustness. Therefore, we developed a whole-cell Escherichia coli lactate biosensor based on the lldPRD operon and successfully used it to monitor lactate concentration in mammalian cell cultures. Using real samples and analytical validation we demonstrate that our biosensor can be used for absolute quantification of metabolites in complex samples with high accuracy, sensitivity, and robustness. Importantly, our whole-cell biosensor was able to detect lactate at concentrations more than two orders of magnitude lower than the industry standard method, making it useful for monitoring lactate concentrations in early phase culture. Given the importance of lactate in a variety of both industrial and clinical contexts we anticipate that our whole-cell biosensor can be used to address a range of interesting biological questions. It also serves as a blueprint for how to capitalize on the wealth of genetic operons for metabolite sensing available in nature for the development of other whole-cell biosensors. Biotechnol. Bioeng. 2017;114: 1290-1300. © 2017 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc. © 2017 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc.

  7. Formation, clearance, deposition, pathogenicity, and identification of biopharmaceutical-related immune complexes: review and case studies.

    Science.gov (United States)

    Rojko, Jennifer L; Evans, Mark G; Price, Shari A; Han, Bora; Waine, Gary; DeWitte, Mark; Haynes, Jill; Freimark, Bruce; Martin, Pauline; Raymond, James T; Evering, Winston; Rebelatto, Marlon C; Schenck, Emanuel; Horvath, Christopher

    2014-06-01

    Vascular inflammation, infusion reactions, glomerulopathies, and other potentially adverse effects may be observed in laboratory animals, including monkeys, on toxicity studies of therapeutic monoclonal antibodies and recombinant human protein drugs. Histopathologic and immunohistochemical (IHC) evaluation suggests these effects may be mediated by deposition of immune complexes (ICs) containing the drug, endogenous immunoglobulin, and/or complement components in the affected tissues. ICs may be observed in glomerulus, blood vessels, synovium, lung, liver, skin, eye, choroid plexus, or other tissues or bound to neutrophils, monocytes/macrophages, or platelets. IC deposition may activate complement, kinin, and/or coagulation/fibrinolytic pathways and result in a systemic proinflammatory response. IC clearance is biphasic in humans and monkeys (first from plasma to liver and/or spleen, second from liver or spleen). IC deposition/clearance is affected by IC composition, immunomodulation, and/or complement activation. Case studies are presented from toxicity study monkeys or rats and indicate IHC-IC deposition patterns similar to those predicted by experimental studies of IC-mediated reactions to heterologous protein administration to monkeys and other species. The IHC-staining patterns are consistent with findings associated with generalized and localized IC-associated pathology in humans. However, manifestations of immunogenicity in preclinical species are generally not considered predictive to humans. © 2014 by The Author(s).

  8. Preparation and the Biopharmaceutical Evaluation for the Metered Dose Transdermal Spray of Dexketoprofen

    Science.gov (United States)

    Luo, Huafei; Zhu, Zhuangzhi; Wu, Yubo; Luo, Jing; Wang, Hao

    2014-01-01

    The objective of the present work was to develop a metered dose transdermal spray (MDTS) formulation for transdermal delivery of dexketoprofen (DE). DE release from a series of formulations was assessed in vitro. Various qualitative and quantitative parameters like spray pattern, pump seal efficiency test, average weight per metered dose, and dose uniformity were evaluated. The optimized formulation with good skin permeation and an appropriate drug concentration and permeation enhancer (PE) content was developed incorporating 7% (w/w, %) DE, 7% (v/v, %) isopropyl myristate (IPM), and 93% (v/v, %) ethanol. In vivo pharmacokinetic study indicated that the optimized formulation showed a more sustainable plasma-concentration profile compared with the Fenli group. The antiinflammatory effect of DE MDTS was evaluated by experiments involving egg-albumin-induced paw edema in rats and xylene-induced ear swelling in mice. Acetic acid-induced abdominal constriction was used to evaluate the anti-nociceptive actions of DE MDTS. Pharmacodynamic studies indicated that the DE MDTS has good anti-inflammatory and anti-nociceptive activities. Besides, skin irritation studies were performed using rat as an animal model. The results obtained show that the MDTS can be a promising and innovative therapeutic system used in transdermal drug delivery for DE. PMID:24660066

  9. Process analytical technology (PAT) tools for the cultivation step in biopharmaceutical production

    NARCIS (Netherlands)

    Streefland, M.; Martens, D.E.; Beuvery, E.C.; Wijffels, R.H.

    2013-01-01

    The process analytical technology (PAT) initiative is now 10 years old. This has resulted in the development of many tools and software packages dedicated to PAT application on pharmaceutical processes. However, most applications are restricted to small molecule drugs, mainly for the relatively

  10. Chloroplast-Derived Vaccine Antigens and Biopharmaceuticals: Expression, Folding, Assembly and Functionality

    Science.gov (United States)

    Chebolu, S.; Daniell, H.

    2009-01-01

    Chloroplast genetic engineering offers several advantages, including high levels of transgene expression, transgene containment via maternal inheritance, and multi-gene expression in a single transformation event. Oral delivery is facilitated by hyperexpression of vaccine antigens against cholera, tetanus, anthrax, plague, or canine parvovirus (4%–31% of total soluble protein, TSP) in transgenic chloroplasts (leaves) or non-green plastids (carrots, tomato) as well as the availability of antibiotic free selectable markers or the ability to excise selectable marker genes. Hyperexpression of several therapeutic proteins, including human serum albumin (11.1% TSP), somatotropin (7% TSP), interferon-alpha (19% TSP), interferon-gamma (6% TSP), and antimicrobial peptide (21.5% TSP), facilitates efficient and economic purification. Also, the presence of chaperones and enzymes in chloroplasts facilitates assembly of complex multisubunit proteins and correct folding of human blood proteins with proper disulfide bonds. Functionality of chloroplast-derived vaccine antigens and therapeutic proteins has been demonstrated by several assays, including the macrophage lysis assay, GM1-ganglioside binding assay, protection of HeLA cells or human lung carcinoma cells against encephalomyocarditis virus, systemic immune response, protection against pathogen challenge, and growth or inhibition of cell cultures. Purification of human proinsulin has been achieved using novel purification strategies (inverse temperature transition property) that do not require expensive column chromatography techniques. Thus, transgenic chloroplasts are ideal bioreactors for production of functional human and animal therapeutic proteins in an environmentally friendly manner. PMID:19401820

  11. Integrated Teaching of Structure-Based Drug Design and Biopharmaceutics: A Computer-Based Approach

    Science.gov (United States)

    Sutch, Brian T.; Romero, Rebecca M.; Neamati, Nouri; Haworth, Ian S.

    2012-01-01

    Rational drug design requires expertise in structural biology, medicinal chemistry, physiology, and related fields. In teaching structure-based drug design, it is important to develop an understanding of the need for early recognition of molecules with "drug-like" properties as a key component. That is, it is not merely sufficient to teach…

  12. Determination of mangiferin solubility in solvents used in the biopharmaceutical industry

    Directory of Open Access Journals (Sweden)

    Jhoany Acosta

    2016-04-01

    Full Text Available Context: Pharmacological properties and studies of methods of extraction of mangiferin have been reported, but there are not studies related to the solubility of mangiferin in the solvents used in the pharmaceutical industry. Aims: Study the solubility of mangiferin in different solvents used in the pharmaceutical industry. Methods: The mangiferin used had a purity of 97.3% determined by High-Performance Liquid Chromatographic (HPLC, and solubility measurements were made in ethanol, methanol, water, acetone, diethyl ether, and hexane at 5, 15, 30, 40, 50 and 600C of temperature. The mangiferin concentrations were determined by ultraviolet spectrometry at 254 nm. The experimental solubility data were correlated with the Van´t Hoff equation and the dissolution heat determined. Results: The solubility of mangiferin in pure solvents decreases with increasing of temperature and in the following order: ethanol>methanol>water>diethyl ether>acetone>n hexane. Conclusions: This results indicated that mangiferin is slightly soluble in ethanol, sparingly soluble in methanol and water and practically insoluble in diethyl ether, acetone, and n-hexane.

  13. Biopharmaceutical evaluation of transnasal, sublingual, and buccal disk dosage forms of butorphanol.

    Science.gov (United States)

    Shyu, W C; Mayol, R F; Pfeffer, M; Pittman, K A; Gammans, R E; Barbhaiya, R H

    1993-07-01

    A series of three-way crossover randomized studies were conducted to evaluate the absolute bioavailability of butorphanol, a potent agonist-antagonist analgesic, from transnasal, sublingual, and buccal disk formulations in order to identify a practical alternative to oral administration. In each study, healthy male volunteers received 2 mg doses of butorphanol tartrate intravenously and either transnasally, sublingually or buccally. Serial blood samples were collected over 12 h and butorphanol plasma concentrations were determined by radioimmunoassay. The plasma concentration data were subjected to non-compartmental pharmacokinetic analysis. The elimination half-life of butorphanol was about 3-5 h and was independent of the route of administration. Absorption of butorphanol following transnasal administration was faster than that observed following sublingual or buccal administration. Mean absolute bioavailabilities of sublingual tablet and buccal disk formulation were only 19 per cent and 29 per cent, respectively, but for transnasal administration the value rose significantly, to 70 per cent. Based on the results of these studies, transnasal dosage form of butorphanol was selected for further clinical trials of treatment of moderate to severe pain.

  14. A comparative study of monosaccharide composition analysis as a carbohydrate test for biopharmaceuticals.

    Science.gov (United States)

    Harazono, Akira; Kobayashi, Tetsu; Kawasaki, Nana; Itoh, Satsuki; Tada, Minoru; Hashii, Noritaka; Ishii, Akiko; Arato, Teruyo; Yanagihara, Shigehiro; Yagi, Yuki; Koga, Akiko; Tsuda, Yuriko; Kimura, Mikiko; Sakita, Masashi; Kitamura, Satoshi; Yamaguchi, Hideto; Mimura, Hisashi; Murata, Yoshimi; Hamazume, Yasuki; Sato, Takayuki; Natsuka, Shunji; Kakehi, Kazuaki; Kinoshita, Mitsuhiro; Watanabe, Sakie; Yamaguchi, Teruhide

    2011-05-01

    The various monosaccharide composition analysis methods were evaluated as monosaccharide test for glycoprotein-based pharmaceuticals. Neutral and amino sugars were released by hydrolysis with 4-7N trifluoroacetic acid. The monosaccharides were N-acetylated if necessary, and analyzed by high-performance liquid chromatography (HPLC) with fluorometric or UV detection after derivatization with 2-aminopyridine, ethyl 4-aminobenzoate, 2-aminobenzoic acid or 1-phenyl-3-methyl-5-pyrazolone, or high pH anion exchange chromatography with pulsed amperometric detection (HPAEC-PAD). Sialic acids were released by mild acid hydrolysis or sialidase digestion, and analyzed by HPLC with fluorometric detection after derivatization with 1,2-diamino-4,5-methylenedioxybenzene, or HPAEC-PAD. These methods were verified for resolution, linearity, repeatability, and accuracy using a monosaccharide standard solution, a mixture of epoetin alfa and beta, and alteplase as models. It was confirmed that those methods were useful for ensuring the consistency of glycosylation. It is considered essential that the analytical conditions including desalting, selection of internal standards, release of monosaccharides, and gradient time course should be determined carefully to eliminate interference of sample matrix. Various HPLC-based monosaccharide analysis methods were evaluated as a carbohydrate test for glycoprotein pharmaceuticals by an inter-laboratory study. Copyright © 2011 The International Association for Biologicals. Published by Elsevier Ltd. All rights reserved.

  15. Predicting biopharmaceutical performance of oral drug candidates - Extending the volume to dissolve applied dose concept.

    Science.gov (United States)

    Muenster, Uwe; Mueck, Wolfgang; van der Mey, Dorina; Schlemmer, Karl-Heinz; Greschat-Schade, Susanne; Haerter, Michael; Pelzetter, Christian; Pruemper, Christian; Verlage, Joerg; Göller, Andreas H; Ohm, Andreas

    2016-05-01

    The purpose of the study was to experimentally deduce pH-dependent critical volumes to dissolve applied dose (VDAD) that determine whether a drug candidate can be developed as immediate release (IR) tablet containing crystalline API, or if solubilization technology is needed to allow for sufficient oral bioavailability. pH-dependent VDADs of 22 and 83 compounds were plotted vs. the relative oral bioavailability (AUC solid vs. AUC solution formulation, Frel) in humans and rats, respectively. Furthermore, in order to investigate to what extent Frel rat may predict issues with solubility limited absorption in human, Frel rat was plotted vs. Frel human. Additionally, the impact of bile salts and lecithin on in vitro dissolution of poorly soluble compounds was tested and data compared to Frel rat and human. Respective in vitro - in vivo and in vivo - in vivo correlations were generated and used to build developability criteria. As a result, based on pH-dependent VDAD, Frel rat and in vitro dissolution in simulated intestinal fluid the IR formulation strategy within Pharmaceutical Research and Development organizations can be already set at late stage of drug discovery. Copyright © 2016 Elsevier B.V. All rights reserved.

  16. Antibody Fragments as Potential Biopharmaceuticals for Cancer Therapy: Success and Limitations.

    Science.gov (United States)

    Kholodenko, Roman V; Kalinovsky, Daniel V; Doronin, Igor I; Ponomarev, Eugene D; Kholodenko, Irina V

    2017-08-17

    Monoclonal antibodies (mAbs) are an important class of therapeutic agents approved for the therapy of many types of malignancies. However, in certain cases applications of conventional mAbs have several limitations in anticancer immunotherapy. These limitations include insufficient efficacy and adverse effects. The antigen-binding fragments of antibodies have a considerable potential to overcome the disadvantages of conventional mAbs, such as poor penetration into solid tumors and Fc-mediated bystander activation of the immune system. Fragments of antibodies retain antigen specificity and part of functional properties of conventional mAbs and at the same time have much better penetration into the tumors and a greatly reduced level of adverse effects. Recent advantages in antibody engineering allowed to produce different types of antibody fragments with improved structure and properties for efficient elimination of tumor cells. These molecules opened up new perspectives for anticancer therapy. Here we will overview the structural features of the various types of antibody fragments and their applications for anticancer therapy as separate molecules and as part of complex conjugates or structures. Mechanisms of antitumor action of antibody fragments as well as their advantages and disadvantages for clinical application will be discussed in this review. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  17. Production of biopharmaceuticals and vaccines in plants via the chloroplast genome.

    Science.gov (United States)

    Daniell, Henry

    2006-10-01

    Transgenic plants offer many advantages, including low cost of production (by elimination of fermenters), storage and transportation; heat stability; and absence of human pathogens. When therapeutic proteins are orally delivered, plant cells protect antigens in the stomach through bioencapsulation and eliminate the need for expensive purification and sterile injections, in addition to development of both systemic and mucosal immunity. Chloroplast genetic engineering offers several advantages, including high levels of transgene expression, transgene containment via maternal inheritance and multi-gene expression in a single transformation event. Hyper-expression of vaccine antigens against cholera, tetanus, anthrax, plague or canine parvovirus (4-31% of total soluble protein, tsp) in transgenic chloroplasts (leaves) or non-green plastids (carrots, tomato), as well as the availability of antibiotic-free selectable markers or the ability to excise selectable marker genes, facilitate oral delivery. Hyper-expression of several therapeutic proteins, including human serum albumin (11.1% tsp), somatotropin (7% tsp), interferon-gamma (6% tsp), anti-microbial peptide (21.5% tsp), facilitates efficient and economic purification. Also, the presence of chaperones and enzymes in chloroplasts facilitate assembly of complex multi-subunit proteins and correct folding of human blood proteins with proper disulfide bonds. Functionality of chloroplast-derived vaccine antigens and therapeutic proteins has been demonstrated by several assays, including the macrophage lysis assay, GM1-ganglioside binding assay, protection of HeLa cells or human lung carcinoma cells against encephalomyocarditis virus, systemic immune response, protection against pathogen challenge, and growth or inhibition of cell cultures. Thus, transgenic chloroplasts are ideal bioreactors for production of functional human and animal therapeutic proteins in an environmentally friendly manner.

  18. Systematic review of drug administration costs and implications for biopharmaceutical manufacturing.

    Science.gov (United States)

    Tetteh, Ebenezer; Morris, Stephen

    2013-10-01

    The acquisition costs of biologic drugs are often considered to be relatively high compared with those of nonbiologics. However, the total costs of delivering these drugs also depend on the cost of administration. Ignoring drug administration costs may distort resource allocation decisions because these affect cost effectiveness. The objectives of this systematic review were to develop a framework of drug administration costs that considers both the costs of physical administration and the associated proximal costs; and, as a case example, to use this framework to evaluate administration costs for biologics within the UK National Health Service (NHS). We reviewed literature that reported estimates of administration costs for biologics within the UK NHS to identify how these costs were quantified and to examine how differences in dosage forms and regimens influenced administration costs. The literature reviewed were identified by searching the Centre for Review and Dissemination Databases (DARE, NHS EED and HTA); EMBASE (The Excerpta Medica Database); MEDLINE (using the OVID interface); Econlit (EBSCO); Tufts Medical Center Cost Effectiveness Analysis (CEA) Registry; and Google Scholar. We identified 4,344 potentially relevant studies, of which 43 studies were selected for this systematic review. We extracted estimates of the administration costs of biologics from these studies. We found evidence of variation in the way that administration costs were measured, and that this affected the magnitude of costs reported, which could then influence cost effectiveness. Our findings suggested that manufacturers of biologic medicines should pay attention to formulation issues and their impact on administration costs, because these affect the total costs of healthcare delivery and cost effectiveness.

  19. Biotechnologies based on simple and structured superlight water for use in biopharmaceutical and biocosmetic field

    International Nuclear Information System (INIS)

    Manzatu, I.; Olariu, L.; Rusu, M.; Zamfir, S.

    2000-01-01

    S.C. Biotehnos S.A. has developed studies to obtain structured aqueous solutions to find biotechnologies that were patented both in this country and abroad. An increasing interest concerning the action of superlight water on biological systems as well as the investigation of possibility of incorporating this type of water in pharmaceutical and cosmetic products encouraged research upon the processes of structuring the deuterium depleted water to establish non-conventional modern biotechnologies. Thus, physico-chemical parameters of interest (pH-value, conductivity, redox potential) were determined for the superlight water systems resulting from structuration process. Also, these studies have dealt with the effects of superlight water and structured aqueous solutions upon cellular breeding, studies of major importance in cell physiology

  20. Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals

    DEFF Research Database (Denmark)

    Rup, B; Pallardy, M; Sikkema, D

    2015-01-01

    scientists are involved in: interpretation and management of clinical and biological outcomes of BP immunogenicity, improvement of methods for describing, predicting and mitigating immunogenicity risk and elucidation of underlying causes. Collaboration and alignment of efforts across these communities...... the Risk; www.abirisk.eu] was formed by leading clinicians, academic scientists and EFPIA (European Federation of Pharmaceutical Industries and Associations) members to elucidate underlying causes, improve methods for immunogenicity prediction and mitigation and establish common definitions around terms...

  1. Characterization and optimization of single-use bioreactors and biopharmaceutical production processes using computational fluid dynamics

    OpenAIRE

    Kaiser, Stephan Christian

    2015-01-01

    Durch die örtliche und zeitliche Modellierung der auftretenden Strömungen bietet die numerische Fluiddynamik (engl. Computational Fluid Dynamics, CFD) das Potenzial detaillierte Untersuchungen der Hydrodynamik in Bioreaktoren durchzuführen. Allerdings sind bisher nur wenige Studien in Verbindung mit Einwegbioreaktoren, die sich durch konstruktiven Besonderheiten von ihren klassischen Gegenspielern aus Glas und/oder Edelstahl unterscheiden, publiziert. Die vorliegende Arbeit soll daher geeigne...

  2. Whole‐cell Escherichia coli lactate biosensor for monitoring mammalian cell cultures during biopharmaceutical production

    Science.gov (United States)

    Goers, Lisa; Ainsworth, Catherine; Goey, Cher Hui; Kontoravdi, Cleo; Freemont, Paul S.

    2017-01-01

    ABSTRACT Many high‐value added recombinant proteins, such as therapeutic glycoproteins, are produced using mammalian cell cultures. In order to optimize the productivity of these cultures it is important to monitor cellular metabolism, for example the utilization of nutrients and the accumulation of metabolic waste products. One metabolic waste product of interest is lactic acid (lactate), overaccumulation of which can decrease cellular growth and protein production. Current methods for the detection of lactate are limited in terms of cost, sensitivity, and robustness. Therefore, we developed a whole‐cell Escherichia coli lactate biosensor based on the lldPRD operon and successfully used it to monitor lactate concentration in mammalian cell cultures. Using real samples and analytical validation we demonstrate that our biosensor can be used for absolute quantification of metabolites in complex samples with high accuracy, sensitivity, and robustness. Importantly, our whole‐cell biosensor was able to detect lactate at concentrations more than two orders of magnitude lower than the industry standard method, making it useful for monitoring lactate concentrations in early phase culture. Given the importance of lactate in a variety of both industrial and clinical contexts we anticipate that our whole‐cell biosensor can be used to address a range of interesting biological questions. It also serves as a blueprint for how to capitalize on the wealth of genetic operons for metabolite sensing available in nature for the development of other whole‐cell biosensors. Biotechnol. Bioeng. 2017;114: 1290–1300. © 2017 The Authors. Biotechnology and Bioengineering Published by Wiley Periodicals, Inc. PMID:28112405

  3. Cell-penetrating peptides as tools to enhance non-injectable delivery of biopharmaceuticals

    DEFF Research Database (Denmark)

    Kristensen, Mie; Nielsen, Hanne Mørck

    2016-01-01

    Non-injectable delivery of peptide and protein drugs is hampered by their labile nature, hydrophilicity, and large molecular size; thus limiting their permeation across mucosae, which represent major biochemical and physical barriers to drugs administered via e.g. the oral, nasal, and pulmonary...... routes. However, in recent years cell-penetrating peptides (CPP) have emerged as promising tools to enhance mucosal delivery of co-administered or conjugated peptide and protein cargo and more advanced CPP-cargo formulations are emerging. CPPs act as transepithelial delivery vectors, but the mechanism...... understanding, documentation of CPP-mediated delivery in higher animal species than rodent as well as extensive toxicological studies are necessary for CPP-containing non-injectable DDSs to reach the clinic....

  4. Design of PLGA-based depot delivery systems for biopharmaceuticals prepared by spray drying

    DEFF Research Database (Denmark)

    Wan, Feng; Yang, Mingshi

    2016-01-01

    Currently, most of the approved protein and peptide-based medicines are delivered via conventional parenteral injection (intramuscular, subcutaneous or intravenous). A frequent dosing regimen is often necessary because of their short plasma half-lives, causing poor patient compliance (e.g. pain......, abscess, etc.), side effects owing to typical peak-valley plasma concentration time profiles, and increased costs. Among many sustained-release formulations poly lactic-co-glycolic acid (PLGA)-based depot microparticle systems may represent one of the most promising approaches to provide protein...... and peptide drugs with a steady pharmacokinetic/pharmacodynamic profile maintained for a long period. However, the development of PLGA-based microparticle systems is still impeded by lack of easy, fast, effective manufacturing technologies. The aim of this paper is to review recent advances in spray drying...

  5. BIOPHARMACEUTICAL STUDIES ON AUXILIARY COMPONENTS CHOICE FOR A GEL WITH RHAPONTICUM EXTRACT

    Directory of Open Access Journals (Sweden)

    A. A. Kostina

    2014-01-01

    Full Text Available The development of medical compositions with herbal drug raw materials is an urgent issue of today. The production technology offered considers the use of domestic raw materials and maximal extraction of accessory agents from them, i.e. low-waste method.The purpose of this research is a selection of the best possible carrier base for soft external dosage form with Rhaponticum carthamoides extract.Traditional equipment for soft dosage forms processing was used during this study.Organoleptic properties of ointments, their pharmacological availability were examined, and production cost components were taken into account.Hence the studies conducted an optimal carrier base for production of external drug dosage with Rhaponticum carthamoides extract was chosen.

  6. Preparation and the Biopharmaceutical Evaluation for the Metered Dose Transdermal Spray of Dexketoprofen

    Directory of Open Access Journals (Sweden)

    Wangding Lu

    2014-01-01

    Full Text Available The objective of the present work was to develop a metered dose transdermal spray (MDTS formulation for transdermal delivery of dexketoprofen (DE. DE release from a series of formulations was assessed in vitro. Various qualitative and quantitative parameters like spray pattern, pump seal efficiency test, average weight per metered dose, and dose uniformity were evaluated. The optimized formulation with good skin permeation and an appropriate drug concentration and permeation enhancer (PE content was developed incorporating 7% (w/w, % DE, 7% (v/v, % isopropyl myristate (IPM, and 93% (v/v, % ethanol. In vivo pharmacokinetic study indicated that the optimized formulation showed a more sustainable plasma-concentration profile compared with the Fenli group. The antiinflammatory effect of DE MDTS was evaluated by experiments involving egg-albumin-induced paw edema in rats and xylene-induced ear swelling in mice. Acetic acid-induced abdominal constriction was used to evaluate the anti-nociceptive actions of DE MDTS. Pharmacodynamic studies indicated that the DE MDTS has good anti-inflammatory and anti-nociceptive activities. Besides, skin irritation studies were performed using rat as an animal model. The results obtained show that the MDTS can be a promising and innovative therapeutic system used in transdermal drug delivery for DE.

  7. Characterization of glycoprotein biopharmaceutical products by Caliper LC90 CE-SDS gel technology.

    Science.gov (United States)

    Chen, Grace; Ha, Sha; Rustandi, Richard R

    2013-01-01

    Over the last decade, science has greatly improved in the area of protein sizing and characterization. Efficient high-throughput methods are now available to substitute for the traditional labor-intensive SDS-PAGE methods, which alternatively take days to analyze a very limited number of samples. Currently, PerkinElmer(®) (Caliper) has designed an automated chip-based fluorescence detection method capable of analyzing proteins in minutes with sensitivity similar to standard SDS-PAGE. Here, we describe the use and implementation of this technology to characterize and screen a large number of formulations of target glycoproteins in the 14-200 kDa molecular weight range.

  8. N-Linked Glycosylation is an Important Parameter for Optimal Selection of Cell Lines Producing Biopharmaceutical Human IgG

    NARCIS (Netherlands)

    van Berkel, Patrick H. C.; Gerritsen, Jolanda; Perdok, Gerrard; Valbjorn, Jesper; Vink, Tom; van de Winkel, Jan G. J.; Parren, Paul W. H. I.

    2009-01-01

    We studied the variations in N-linked glycosylation of human IgG molecules derived from 105 different stable cell lines each expressing one of the six different antibodies. Antibody expression was based on glutamine synthetase selection technology in suspension growing CHO-KISV cells. The glycans

  9. Biopharmaceutical characterisation of insulin and recombinant human growth hormone loaded lipid submicron particles produced by supercritical gas micro-atomisation.

    Science.gov (United States)

    Salmaso, Stefano; Bersani, Sara; Elvassore, Nicola; Bertucco, Alberto; Caliceti, Paolo

    2009-09-08

    Homogeneous dispersions of insulin and recombinant human growth hormone (rh-GH) in tristearin/phosphatidylcholine/PEG mixtures (1.3:1.3:0.25:0.15 w/w ratio) were processed by supercritical carbon dioxide gas micro-atomisation to produce protein-loaded lipid particles. The process yielded spherical particles, with a 197+/-94 nm mean diameter, and the insulin and rh-GH recovery in the final product was 57+/-8% and 48+/-5%, respectively. In vitro, the proteins were slowly released for about 70-80 h according to a diffusive mechanism. In vivo, the insulin and glucose profiles in plasma obtained by subcutaneous administration of a dose of particles containing 2 microg insulin to diabetic mice overlapped that obtained with 2 microg of insulin in solution. Administration of a dose of particles containing 5 microg insulin resulted in faster and longer glycaemia reduction. Oral administration of 20 and 50 microg insulin equivalent particles produced a significant hypoglycaemic effect. The glucose levels decreased since 2h after administration, reaching about 50% and 70% glucose reduction in 1-2h with the lower and higher dose, respectively. As compared to subcutaneous administration, the relative pharmacological bioavailability obtained with 20 and 50 microg equivalent insulin particles was 7.7% and 6.7%, respectively. Daily subcutaneous administration of 40 microg of rh-GH-loaded particles to hypophysectomised rats induced similar body weight increase as 40 microg rh-GH in solution. The daily oral administration of 400 microg rh-GH equivalent particles elicited a slight body weight increase, which corresponded to a relative pharmacological bioavailability of 3.4% compared to subcutaneous administration.

  10. Full automation and validation of a flexible ELISA platform for host cell protein and protein A impurity detection in biopharmaceuticals.

    Science.gov (United States)

    Rey, Guillaume; Wendeler, Markus W

    2012-11-01

    Monitoring host cell protein (HCP) and protein A impurities is important to ensure successful development of recombinant antibody drugs. Here, we report the full automation and validation of an ELISA platform on a robotic system that allows the detection of Chinese hamster ovary (CHO) HCPs and residual protein A of in-process control samples and final drug substance. The ELISA setup is designed to serve three main goals: high sample throughput, high quality of results, and sample handling flexibility. The processing of analysis requests, determination of optimal sample dilutions, and calculation of impurity content is performed automatically by a spreadsheet. Up to 48 samples in three unspiked and spiked dilutions each are processed within 24 h. The dilution of each sample is individually prepared based on the drug concentration and the expected impurity content. Adaptable dilution protocols allow the analysis of sample dilutions ranging from 1:2 to 1:2×10(7). The validity of results is assessed by automatic testing for dilutional linearity and spike recovery for each sample. This automated impurity ELISA facilitates multi-project process development, is easily adaptable to other impurity ELISA formats, and increases analytical capacity by combining flexible sample handling with high data quality. Copyright © 2012 Elsevier B.V. All rights reserved.

  11. Development of Science and Technology Parks in Poland: Opportunities for New Modes of Cooperation in the Biopharmaceutical Industry

    Directory of Open Access Journals (Sweden)

    Michal Staszkow

    2017-03-01

    Full Text Available The aim of the article is to verify the development of science and technology parks in Poland as well as the opportunities of development of new forms of cooperation with the use of science and technology parks in the bio pharmaceutical industry in Poland. The first section reviews the origins and definitions of science and technology parks in order to clarify and systematize the concepts used in existing research and practice. Subsequently, the ensuing sections discuss the evolution of science and technology parks and different organizational models of STPS. Further, the analysis centres on science and technology parks in Poland. Then the importance of science and technology parks for the development of new modes of cooperation in the bio pharmaceutical industry is elaborated upon. The paper ends with a set of implications and conclusions.

  12. Silicone-oil-based subvisible particles: their detection, interactions, and regulation in prefilled container closure systems for biopharmaceuticals.

    Science.gov (United States)

    Felsovalyi, Flora; Janvier, Sébastien; Jouffray, Sébastien; Soukiassian, Hervé; Mangiagalli, Paolo

    2012-12-01

    Recent increased regulatory scrutiny concerning subvisible particulates (SbVPs) in parenteral formulations of biologics has led to the publication of numerous articles about the sources, characteristics, implications, and approaches to monitoring and detecting SbVPs. Despite varying opinions on the level of associated risks and method of regulation, nearly all industry scientists and regulators agree on the need for monitoring and reporting visible and subvisible particles. As prefillable drug delivery systems have become a prominent packaging option, silicone oil, a common primary packaging lubricant, may play a role in the appearance of particles. The goal of this article is to complement the current SbVP knowledge base with new insights into the evolution of silicone-oil-related particulates and their interactions with components in prefillable systems. We propose a "toolbox" for improved silicone-oil-related particulate detection and enumeration, and discuss the benefits and limitations of approaches for lowering and controlling silicone oil release in parenterals. Finally, we present surface cross-linking of silicone as the recommended solution for achieving significant SbVP reduction without negatively affecting functional performance. Copyright © 2012 Wiley Periodicals, Inc.

  13. BIOPHARMACEUTICAL SUBSTANTIATION OF THE SOLVENT IN THE COMPOSITION OF THE IMMUNOBIOLOGICAL DRUG FOR PREVENTION AND TREATMENT OF CANDIDAL INFECTION

    Directory of Open Access Journals (Sweden)

    Rybalkin М. V

    2014-10-01

    Full Text Available Today diseases caused by potentially pathogenic microorganisms become increasingly important. This phenomenon is connected with increase of power of influence of the environment: chemical pollution, radiation, irrational use of antibiotics and hormone therapy; it leads to decrease of the immune response and human nonspecific resistance. For the last years one of the indicators of failure of the human body immune protection is chronic and local candidiases caused by potentially pathogenic fungi of Candida genus. Prevalence and risk of candidal infections determine the need for searching new medicines with a high efficiency and safety for human. Development of a vaccine for prevention and treatment of candidal infection is being actively conducted in many countries of the world. It should be noted that currently no domestic vaccine is produced in Ukraine and no candidiasis vaccines have been registered. Therefore, development of such vaccine is the topical issue of modern pharmacy and medicine. In our previous studies it was found that the immunobiological drug based on the antigens of fungi of C. albicans with the protein concentration of 3 mg/ml and C. tropicalis with the protein concentration of 5 mg/ml in the ratio of 1:1 possesses the protective and therapeutic effect. At the current stage of research it is necessary to substantiate the solvent in the composition of the immunobiological drug. The aim of this work is the experimental substantiation of the solvent in the composition of the immunobiological drug based on the antigens of C. albicans and C. tropicalis fungi. Materials and Methods. The immunobiological drug with the protein concentration of 4 mg/ml was investigated using various solvents. The following solvents was studied: water for injections, 0.9 % isotonic saline solution, phosphate buffer solution. To determine the protective and therapeutic activity of the immunobiological drug based on the antigens of C. albicans and C. tropicalis fungi the research was conducted in healthy two-month white mice with the body weight of 18-22 g. There were 6 animals in the control and test groups. Mice were intramuscularly injected 0.2 ml of the immunobiological drug twice with an interval of 14 days. To determine the protective activity of the immunobiological drug the animals were infected intraperitoneally in 3 months after the second introduction. For this purpose the suspension of Candida albicans fungi of ССМ 335-867 strain in the amount of 20 mln. of cells and Candida tropicalis of АТТС 20336 strain in the amount of 60 mln. of cells in the volume of 1 ml was used; they were introduced with the interval of 1 hour. After that in 14 days the animals were examined and the results were determined. To determine therapeutic activity of the immunobiological drug the animals were infected according to the scheme described, in 5 days a doulble injection of the drug was introduced to mice. After that in 14 days the animals were examined and the results were determined. As a result of the research conducted it was found that the immunobiological drug based on the antigens of C. albicans and C. tropicalis fungi with all solvents studied protected 100 % of animals from infection in 1 and 3 months. The therapeutic effect of the immunobiological drug based on the antigens of C. albicans and C. tropicalis fungi with all solvents was 100 %. The therapeutic effect started to exhibit in 8 - 14 days after the first introduction of the vaccine, and in 8 - 14 days after the repeated introduction of the vaccine the full recovery of animals occurred. In animals of the control group the signs of infection corresponding to the moderate form of the disease and the advanced form of the disease were registered. Taking into account the fact that the immunobiological drug with all solvents has shown the similar results the use of phosphate buffer solution is more expedient for further study because it preserves the constant value of the рН medium for a long period of time. Thus, it provides the drug stability since an insignificant change in рН can greatly affect the activity of antigens, and it will have an influence on the drug activity.

  14. Comparative Studies on the Dissolution Profiles of Oral Ibuprofen Suspension and Commercial Tablets using Biopharmaceutical Classification System Criteria

    Science.gov (United States)

    Rivera-Leyva, J. C.; García-Flores, M.; Valladares-Méndez, A.; Orozco-Castellanos, L. M.; Martínez-Alfaro, M.

    2012-01-01

    In vitro dissolution studies for solid oral dosage forms have recently widened the scope to a variety of special dosage forms such as suspensions. For class II drugs, like Ibuprofen, it is very important to have discriminative methods for different formulations in physiological conditions of the gastrointestinal tract, which will identify different problems that compromise the drug bioavailability. In the present work, two agitation speeds have been performed in order to study ibuprofen suspension dissolution. The suspensions have been characterised relatively to particle size, density and solubility. The dissolution study was conducted using the following media: buffer pH 7.2, pH 6.8, 4.5 and 0.1 M HCl. For quantitative analysis, the UV/Vis spectrophotometry was used because this methodology had been adequately validated. The results show that 50 rpm was the adequate condition to discriminate the dissolution profile. The suspension kinetic release was found to be dependent on pH and was different compared to tablet release profile at the same experimental conditions. The ibuprofen release at pH 1.0 was the slowest. PMID:23626386

  15. The biotechnology innovation machine: a source of intelligent biopharmaceuticals for the pharma industry--mapping biotechnology's success.

    Science.gov (United States)

    Evens, R P; Kaitin, K I

    2014-05-01

    The marriage of biotechnology and the pharmaceutical industry (pharma) is predicated on an evolution in technology and product innovation. It has come as a result of advances in both the science and the business practices of the biotechnology sector in the past 30 years. Biotechnology products can be thought of as "intelligent pharmaceuticals," in that they often provide novel mechanisms of action, new approaches to disease control, higher clinical success rates, improved patient care, extended patent protection, and a significant likelihood of reimbursement. Although the first biotechnology product, insulin, was approved just 32 years ago in 1982, today there are more than 200 biotechnology products commercially available. Research has expanded to include more than 900 biotechnology products in clinical trials. Pharma is substantially engaged in both the clinical development of these products and their commercialization.

  16. At-line process analytical technology (PAT) for more efficient scale up of biopharmaceutical microfiltration unit operations.

    Science.gov (United States)

    Watson, Douglas S; Kerchner, Kristi R; Gant, Sean S; Pedersen, Joseph W; Hamburger, James B; Ortigosa, Allison D; Potgieter, Thomas I

    2016-01-01

    Tangential flow microfiltration (MF) is a cost-effective and robust bioprocess separation technique, but successful full scale implementation is hindered by the empirical, trial-and-error nature of scale-up. We present an integrated approach leveraging at-line process analytical technology (PAT) and mass balance based modeling to de-risk MF scale-up. Chromatography-based PAT was employed to improve the consistency of an MF step that had been a bottleneck in the process used to manufacture a therapeutic protein. A 10-min reverse phase ultra high performance liquid chromatography (RP-UPLC) assay was developed to provide at-line monitoring of protein concentration. The method was successfully validated and method performance was comparable to previously validated methods. The PAT tool revealed areas of divergence from a mass balance-based model, highlighting specific opportunities for process improvement. Adjustment of appropriate process controls led to improved operability and significantly increased yield, providing a successful example of PAT deployment in the downstream purification of a therapeutic protein. The general approach presented here should be broadly applicable to reduce risk during scale-up of filtration processes and should be suitable for feed-forward and feed-back process control. © 2015 American Institute of Chemical Engineers.

  17. Development of a lectin binding assay to differentiate between recombinant and endogenous proteins in pharmacokinetic studies of protein-biopharmaceuticals.

    Science.gov (United States)

    Weber, Alfred; Minibeck, Eva; Scheiflinger, Friedrich; Turecek, Peter L

    2015-04-10

    Human glycoproteins, expressed in hamster cell lines, show similar glycosylation patterns to naturally occurring human molecules except for a minute difference in the linkage of terminal sialic acid: both cell types lack α2,6-galactosyl-sialyltransferase, abundantly expressed in human hepatocytes and responsible for the α2,6-sialylation of circulating glycoproteins. This minute difference, which is currently not known to have any physiological relevance, was the basis for the selective measurement of recombinant glycoproteins in the presence of their endogenous counterparts. The assay is based on using the lectin Sambucus nigra agglutinin (SNA), selectively binding to α2,6-sialylated N-glycans. Using von Willebrand factor (VWF), factor IX (FIX), and factor VIIa (FVIIa), it was demonstrated that (i) the plasma-derived proteins, but not the corresponding recombinant proteins, specifically bind to SNA and (ii) this binding can be used to deplete the plasma-derived proteins. The feasibility of this approach was confirmed in spike-recovery studies for all three recombinant coagulation proteins in human plasma and for recombinant VWF (rVWF) in macaque plasma. Analysis of plasma samples from macaques after administration of recombinant and a plasma-derived VWF demonstrated the suitability and robustness of this approach. Data showed that rVWF could be selectively measured without changing the ELISAs and furthermore revealed the limitations of baseline adjustment using a single measurement of the predose concentration only. The SNA gel-based depletion procedure can easily be integrated in existing procedures as a specific sample pre-treatment step. While ELISA-based methods were used to measure the recombinant coagulation proteins in the supernatants obtained by depletion, this procedure is applicable for all biochemical analyses. Copyright © 2015 Elsevier B.V. All rights reserved.

  18. A View on the Importance of "Multi-Attribute Method" for Measuring Purity of Biopharmaceuticals and Improving Overall Control Strategy.

    Science.gov (United States)

    Rogers, Richard S; Abernathy, Michael; Richardson, Douglas D; Rouse, Jason C; Sperry, Justin B; Swann, Patrick; Wypych, Jette; Yu, Christopher; Zang, Li; Deshpande, Rohini

    2017-11-30

    Today, we are experiencing unprecedented growth and innovation within the pharmaceutical industry. Established protein therapeutic modalities, such as recombinant human proteins, monoclonal antibodies (mAbs), and fusion proteins, are being used to treat previously unmet medical needs. Novel therapies such as bispecific T cell engagers (BiTEs), chimeric antigen T cell receptors (CARTs), siRNA, and gene therapies are paving the path towards increasingly personalized medicine. This advancement of new indications and therapeutic modalities is paralleled by development of new analytical technologies and methods that provide enhanced information content in a more efficient manner. Recently, a liquid chromatography-mass spectrometry (LC-MS) multi-attribute method (MAM) has been developed and designed for improved simultaneous detection, identification, quantitation, and quality control (monitoring) of molecular attributes (Rogers et al. MAbs 7(5):881-90, 2015). Based on peptide mapping principles, this powerful tool represents a true advancement in testing methodology that can be utilized not only during product characterization, formulation development, stability testing, and development of the manufacturing process, but also as a platform quality control method in dispositioning clinical materials for both innovative biotherapeutics and biosimilars.

  19. QbD-Enabled Development of Novel Stimuli-Responsive Gastroretentive Systems of Acyclovir for Improved Patient Compliance and Biopharmaceutical Performance.

    Science.gov (United States)

    Singh, Bhupinder; Kaur, Anterpreet; Dhiman, Shashi; Garg, Babita; Khurana, Rajneet Kaur; Beg, Sarwar

    2016-04-01

    The current studies entail systematic quality by design (QbD)-based development of stimuli-responsive gastroretentive drug delivery systems (GRDDS) of acyclovir using polysaccharide blends for attaining controlled drug release profile and improved patient compliance. The patient-centric quality target product profile was defined and critical quality attributes (CQAs) earmarked. Risk assessment studies, carried out through Ishikawa fish bone diagram and failure mode, effect, and criticality analysis, helped in identifying the plausible risks or failure modes affecting the quality attributes of the drug product. A face-centered cubic design was employed for systematic development and optimization of the concentration of sodium alginate (X 1) and gellan (X 2) as the critical material attributes (CMAs) in the stimuli-responsive formulations, which were evaluated for CQAs viz. viscosity, gel strength, onset of floatation, and drug release characteristics. Mathematical modeling was carried out for generation of design space, and optimum formulation was embarked upon, exhibiting formulation characteristics marked by excellent floatation and bioadhesion characteristics along with promising drug release control up to 24 h. Drug-excipient compatibility studies through FTIR and DSC revealed absence of any interaction(s) among the formulation excipients. In vivo pharmacokinetic studies in Wistar rats corroborated extension in the drug absorption profile from the optimized stimuli-responsive GR formulations vis-à-vis the marketed suspension (ZOVIRAX®). Establishment of in vitro/in vivo correlation (IVIVC) revealed a high degree of correlation between the in vitro and in vivo data. In a nutshell, the present investigations report the successful development of stimuli-responsive GRDDS of acyclovir, which can be applicable as a platform approach for other drugs too.

  20. High-sensitivity quantitation of a biopharmaceutical Nanobody® in plasma by single-cartridge multi-dimensional solid-phase extraction and UPLC-MS/MS

    NARCIS (Netherlands)

    Bronsema, Kees; Bischoff, Rainer; Bouche, Marie-Paule; Mortier, Kjell; van de Merbel, Nico C.

    2015-01-01

    Background: A major challenge in protein quantitation based on enzymatic digestion of complex biological samples and subsequent LC-MS/MS analysis of a signature peptide is dealing with the high complexity of the matrix after digestion, which can reduce sensitivity considerably. For the quantitation

  1. [The status of occupational health of female migrant workers in traditional Chinese medicine, western medicine and bio-pharmaceutical industry in Gansu province].

    Science.gov (United States)

    Liao, Ping-Tai; Kou, Zhen-Xia; Li, Zhi-Lan; He, Yu-Hong; Yu, Wen-Lan; Zho, An-Shou

    2011-09-01

    To understand the status of occupational health of female migrant workers in different kinds of pharmaceutical industries in Gansu province and to provide the basis for improving occupational health condition. One thousand eight hundreds and one female workers from 16 enterprises were selected by cluster sampling in Gansu province and investigated by interviewing and questionnaires. There were statistical significances of education level, status of residency registrations, employment relationship and occupational hazards among female workers in three types of enterprises (P < 0.05 or P < 0.01). The morbidities of skin disease in female workers for three kinds of enterprises were 4.46%, 2.53% and 3.70%, respectively. The morbidities of reproductive system disease in female workers for three kinds of enterprises were 48.57%, 36.70% and 36.11%, respectively. The levels of education and working conditions of female workers in the traditional Chinese medicine, western medicine plants are low. There are more severe occupational hazards in female workers of the traditional Chinese medicine plants.

  2. Transforming lipid-based oral drug delivery systems into solid dosage forms: an overview of solid carriers, physicochemical properties, and biopharmaceutical performance.

    Science.gov (United States)

    Tan, Angel; Rao, Shasha; Prestidge, Clive A

    2013-12-01

    The diversity of lipid excipients available commercially has enabled versatile formulation design of lipid-based drug delivery systems for enhancing the oral absorption of poorly water-soluble drugs, such as emulsions, microemulsions, micelles, liposomes, niosomes and various self-emulsifying systems. The transformation of liquid lipid-based systems into solid dosage forms has been investigated for several decades, and has recently become a core subject of pharmaceutical research as solidification is regarded as viable means for stabilising lipid colloidal systems while eliminating stringent processing requirements associated with liquid systems. This review describes the types of pharmaceutical grade excipients (silica nanoparticle/microparticle, polysaccharide, polymer and protein-based materials) used as solid carriers and the current state of knowledge on the liquid-to-solid conversion approaches. Details are primarily focused on the solid-state physicochemical properties and redispersion capacity of various dry lipid-based formulations, and how these relate to the in vitro drug release and solubilisation, lipid carrier digestion and cell permeation performances. Numerous in vivo proof-of-concept studies are presented to highlight the viability of these dry lipid-based formulations. This review is significant in directing future research work in fostering translation of dry lipid-based formulations into clinical applications.

  3. Biopharmaceutical characterisation of ciprofloxacin-metallic ion interactions: Comparative study into the effect of aluminium, calcium, zinc and iron on drug solubility and dissolution

    Directory of Open Access Journals (Sweden)

    Stojković Aleksandra

    2014-03-01

    Full Text Available Ciprofloxacin bioavailability may be reduced when ciprofloxacin is co-administered with metallic ion containing preparations. In our previous study, physicochemical interaction between ciprofloxacin and ferrous sulphate was successfully simulated in vitro. In the present work, comparative in vitro ciprofloxacin solubility and dissolution studies were performed in the reactive media containing aluminium hydroxide, calcium carbonate or zinc sulphate. Solid phases collected from the dissolution vessel with aluminium hydroxide, calcium carbonate and zinc sulphate were investigated for their properties. The results obtained indicate that different types of adducts may form and retard ciprofloxacin solubility and dissolution. In the case of aluminium, no phase changes were observed. The solid phase generated in the presence of calcium carbonate was identified as hydrated ciprofloxacin base. Similarly to iron, a new complex consistent with Zn(SO42(Cl2(ciprofloxacin2 × nH2O stoichiometry was generated in the presence of relatively high concentrations of ciprofloxacin hydrochloride and zinc sulphate, indicating that small volume dissolution experiments can be useful for biorelevant dissolution tests.

  4. Assessing the Financial Benefits of Faster Development Times: The Case of Single-source Versus Multi-vendor Outsourced Biopharmaceutical Manufacturing.

    Science.gov (United States)

    DiMasi, Joseph A; Smith, Zachary; Getz, Kenneth A

    2018-05-10

    The extent to which new drug developers can benefit financially from shorter development times has implications for development efficiency and innovation incentives. We provided a real-world example of such gains by using recent estimates of drug development costs and returns. Time and fee data were obtained on 5 single-source manufacturing projects. Time and fees were modeled for these projects as if the drug substance and drug product processes had been contracted separately from 2 vendors. The multi-vendor model was taken as the base case, and financial impacts from single-source contracting were determined relative to the base case. The mean and median after-tax financial benefits of shorter development times from single-source contracting were $44.7 million and $34.9 million, respectively (2016 dollars). The after-tax increases in sponsor fees from single-source contracting were small in comparison (mean and median of $0.65 million and $0.25 million). For the data we examined, single-source contracting yielded substantial financial benefits over multi-source contracting, even after accounting for somewhat higher sponsor fees. Copyright © 2018 Elsevier HS Journals, Inc. All rights reserved.

  5. Biopharmaceutical characterisation of ciprofloxacin-metallic ion interactions: comparative study into the effect of aluminium, calcium, zinc and iron on drug solubility and dissolution.

    Science.gov (United States)

    Stojković, Aleksandra; Tajber, Lidia; Paluch, Krzysztof J; Djurić, Zorica; Parojčić, Jelena; Corrigan, Owen I

    2014-03-01

    Ciprofloxacin bioavailability may be reduced when ciprofloxacin is co-administered with metallic ion containing preparations. In our previous study, physicochemical interaction between ciprofloxacin and ferrous sulphate was successfully simulated in vitro. In the present work, comparative in vitro ciprofloxacin solubility and dissolution studies were performed in the reactive media containing aluminium hydroxide, calcium carbonate or zinc sulphate. Solid phases collected from the dissolution vessel with aluminium hydroxide, calcium carbonate and zinc sulphate were investigated for their properties. The results obtained indicate that different types of adducts may form and retard ciprofloxacin solubility and dissolution. In the case of aluminium, no phase changes were observed. The solid phase generated in the presence of calcium carbonate was identified as hydrated ciprofloxacin base. Similarly to iron, a new complex consistent with Zn(SO4)2(Cl)2(ciprofloxacin)2 × nH2O stoichiometry was generated in the presence of relatively high concentrations of ciprofloxacin hydrochloride and zinc sulphate, indicating that small volume dissolution experiments can be useful for biorelevant dissolution tests.

  6. Quick generation of Raman spectroscopy based in-process glucose control to influence biopharmaceutical protein product quality during mammalian cell culture.

    Science.gov (United States)

    Berry, Brandon N; Dobrowsky, Terrence M; Timson, Rebecca C; Kshirsagar, Rashmi; Ryll, Thomas; Wiltberger, Kelly

    2016-01-01

    Mitigating risks to biotherapeutic protein production processes and products has driven the development of targeted process analytical technology (PAT); however implementing PAT during development without significantly increasing program timelines can be difficult. The development of a monoclonal antibody expressed in a Chinese hamster ovary (CHO) cell line via fed-batch processing presented an opportunity to demonstrate capabilities of altering percent glycated protein product. Glycation is caused by pseudo-first order, non-enzymatic reaction of a reducing sugar with an amino group. Glucose is the highest concentration reducing sugar in the chemically defined media (CDM), thus a strategy controlling glucose in the production bioreactor was developed utilizing Raman spectroscopy for feedback control. Raman regions for glucose were determined by spiking studies in water and CDM. Calibration spectra were collected during 8 bench scale batches designed to capture a wide glucose concentration space. Finally, a PLS model capable of translating Raman spectra to glucose concentration was built using the calibration spectra and spiking study regions. Bolus feeding in mammalian cell culture results in wide glucose concentration ranges. Here we describe the development of process automation enabling glucose setpoint control. Glucose-free nutrient feed was fed daily, however glucose stock solution was fed as needed according to online Raman measurements. Two feedback control conditions were executed where glucose was controlled at constant low concentration or decreased stepwise throughout. Glycation was reduced from ∼9% to 4% using a low target concentration but was not reduced in the stepwise condition as compared to the historical bolus glucose feeding regimen. © 2015 American Institute of Chemical Engineers.

  7. Optimization of a micro-scale, high throughput process development tool and the demonstration of comparable process performance and product quality with biopharmaceutical manufacturing processes.

    Science.gov (United States)

    Evans, Steven T; Stewart, Kevin D; Afdahl, Chris; Patel, Rohan; Newell, Kelcy J

    2017-07-14

    In this paper, we discuss the optimization and implementation of a high throughput process development (HTPD) tool that utilizes commercially available micro-liter sized column technology for the purification of multiple clinically significant monoclonal antibodies. Chromatographic profiles generated using this optimized tool are shown to overlay with comparable profiles from the conventional bench-scale and clinical manufacturing scale. Further, all product quality attributes measured are comparable across scales for the mAb purifications. In addition to supporting chromatography process development efforts (e.g., optimization screening), comparable product quality results at all scales makes this tool is an appropriate scale model to enable purification and product quality comparisons of HTPD bioreactors conditions. The ability to perform up to 8 chromatography purifications in parallel with reduced material requirements per run creates opportunities for gathering more process knowledge in less time. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

  8. Capillary electrophoresis coupled to fluorescence spectroscopy for protein characterisation

    NARCIS (Netherlands)

    de Kort, B.J.

    2012-01-01

    Proteins are essential molecules in all living organisms. Their involvement in numerous biological processes has led to the development of protein-based medicines (biopharmaceuticals). For good understanding of the properties and function of endogenous proteins and biopharmaceuticals, extensive

  9. High-Throughput Analysis and Automation for Glycomics Studies

    NARCIS (Netherlands)

    Shubhakar, A.; Reiding, K.R.; Gardner, R.A.; Spencer, D.I.R.; Fernandes, D.L.; Wuhrer, M.

    2015-01-01

    This review covers advances in analytical technologies for high-throughput (HTP) glycomics. Our focus is on structural studies of glycoprotein glycosylation to support biopharmaceutical realization and the discovery of glycan biomarkers for human disease. For biopharmaceuticals, there is increasing

  10. Determination of Regional Intestinal Permeability of Diclofenac and ...

    African Journals Online (AJOL)

    Keywords: Biopharmaceutics classification system, Diclofenac, Metoprolol tartrate, ... intestinal transit of drug formulations is about 3 - ... delivery of perfusion medium to the excised ..... of diclofenac in transdermal therapeutic preparations.

  11. Model-based optimization of the primary drying step during freeze-drying

    DEFF Research Database (Denmark)

    Mortier, Séverine Thérèse F.C.; Van Bockstal, Pieter-Jan; Nopens, Ingmar

    2015-01-01

    Since large molecules are considered the key driver for growth of the pharmaceutical industry, the focus of the pharmaceutical industry is shifting from small molecules to biopharmaceuticals: around 50% of the approved biopharmaceuticals are freeze-dried products. Therefore, freeze- drying is an ...

  12. Aspectos biofarmacêuticos da formulação de medicamentos para neonatos: fundamentos da complexação de indometacina com hidroxipropil-beta-ciclodextrina para tratamento oral do fechamento do canal arterial Biopharmaceutical aspects of drug formulation for neonatology: rational for indomethacin's complexation with hydroxypropyl-beta-cyclodextrin to treat patent ductus arteriosus

    Directory of Open Access Journals (Sweden)

    Ana Cristina Ribeiro Rama

    2005-09-01

    Full Text Available A terapêutica farmacológica em recém-nascidos confronta-se, por um lado, com um organismo sujeito a marcadas alterações biológicas, resultantes da composição orgânica e da maturação funcional, que decorre a diferentes graus em crianças com a mesma idade, determinando modificações no perfil farmacocinético e farmacodinâmico e, por outro lado, com a necessidade efetiva da utilização de fármacos. Para dar resposta à necessidade de tratamento destes doentes, recorre-se à utilização de medicamentos "off label", sendo esta uma prática com um elevado risco de segurança e de eficácia, na ausência de informação acerca da estabilidade, solubilidade e biodisponibilidade. Considerou-se, assim, que a utilização de derivados das ciclodextrinas altamente solúveis em água seria uma alternativa para a formulação de preparações líquidas aquosas de fármacos fracamente solúveis, aliada à melhoria de biodisponibilidade e de segurança. Esta revisão pretende fundamentar a possibilidade de recurso à complexação de indometacina com hidroxipropil-beta-ciclodextrina, com o objetivo de melhorar as características de biodisponibilidade e de segurança e permitir a administração por via oral para o tratamento farmacológico do fechamento do canal arterial em prematuros ou em recém-nascidos com esta patologia.Pharmacological therapy for newborns is faced on one hand, with an organism characterized by biological differences and functional immaturity with various grades of evolution for the same age, implying changes on the pharmacokinetic and pharmacodinamic medicine profiles. On the other hand, there is the effective need for pharmacotherapy. The "off label" use of medicines is therefore the only thing left to do, having in mind the risk of using therapeutic agents not studied for this special group of people. On this context it has been considered the use of cyclodextrin derivatives like hydroxypropyl-beta-cyclodextrin as an alternative to prepare oral formulations. With this review we intend to evaluate the rational for using indomethacin's complexation with hydroxypropyl-beta-cyclodextrin, to enhance bioavailability and reduce gastric toxicity characteristics, allowing its oral administration to treat patent ductus arteriosus on preterm and full-term newborns.

  13. Biosimilars: current perspectives and future implications.

    Science.gov (United States)

    Misra, Monika

    2012-01-01

    Biosimilars are biological products that are the replicas of their innovator biopharmaceuticals. These are developed after patent expiration of innovator biopharmaceuticals and are submitted for separate marketing approval. In view of the structural and manufacturing complexities of biopharmaceuticals, biosimilars should not be considered as "biological generics". These are rather unique molecules with limited data at time of approval, so there are concerns about the safety and efficacy of biosimilars. This article will address the differences between biosimilars and chemical generics, issues of concern with the use of biosimilars and need of appropriate regulations for their approval.

  14. Assessment of near infrared and "software sensor" for biomass monitoring and control

    NARCIS (Netherlands)

    Soons, Z.I.T.A.; Streefland, M.; Straten, van G.; Boxtel, van A.J.B.

    2008-01-01

    Spectroscopic instrumentation is often seen as promising for process analytical technology (PAT) to enhance control of manufacturing (bio)pharmaceuticals. The interpretation of near infrared spectra is challenging due to the large number of wavelengths recorded and the overlapping absorbance

  15. In vitro models for the prediction of in vivo performance of oral dosage forms

    NARCIS (Netherlands)

    Kostewicz, E.S.; Abrahamsson, B.; Brewster, M.; Brouwers, J.; Butler, J.; Carlert, S.; Dickinson, P.A.; Dressman, J.; Holm, R.; Klein, S.; Mann, J.; McAllister, M.; Minekus, M.; Muenster, U.; Müllertz, A.; Verwei, M.; Vertzoni, M.; Weitschies, W.; Augustijns, P.

    2014-01-01

    Accurate prediction of the in vivo biopharmaceutical performance of oral drug formulations is critical to efficient drug development. Traditionally, in vitro evaluation of oral drug formulations has focused on disintegration and dissolution testing for quality control (QC) purposes. The connection

  16. Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Proguanil Hydrochloride.

    NARCIS (Netherlands)

    Plöger, Gerlinde F; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, D I R K W; Langguth, Peter; Mehta, Mehul U; Parr, Alan; Polli, James E; Shah, Vinod P; Tajiri, Tomokazu; Dressman, Jennifer B

    2018-01-01

    Literature data relevant to the decision to waive in vivo bioequivalence testing for the approval of generic immediate release solid oral dosage forms of proguanil hydrochloride are reviewed. To clarify the Biopharmaceutics Classification System (BCS) classification, experimental solubility and

  17. Assessment of Protective Properties of Optimized Flagellin Derivative Against Biologically Harmful Effects of Ionizing Irradiation During Space Flight, Phase I

    Data.gov (United States)

    National Aeronautics and Space Administration — The goal of this proposal is to explore a novel proprietary biopharmaceutical agent, named deltaFL-AA', a first in the series of innovative radioprotectors to act as...

  18. Stability and drug dissolution evaluation of Qingkailing soft/hard ...

    African Journals Online (AJOL)

    HPLC-DAD) method was developed ... stability and drug dissolution, which may affect the biopharmaceutics and the clinical effects of the drug. ... behavior may also affect the pharmacokinetic ..... of enzymes and intrinsic factors in stomach and.

  19. The African perspective I: Using the new biosciences to support the African development agenda

    CSIR Research Space (South Africa)

    Morris, EJ

    2016-09-01

    Full Text Available Biopharmaceutical proteins and vaccines are traditionally produced in bacteria, eggs, yeast and animal cell cultures and are well established industries. More recently, these molecules are produced in plants and became known as biopharming. Plant...

  20. Immunogenicity of Anti-TNF-α Biotherapies

    DEFF Research Database (Denmark)

    Bendtzen, Klaus

    2015-01-01

    Immunogenicity of biopharmaceuticals is complex and influenced by both structural and pharmacological factors, and by patient-related conditions such as disease being treated, previous and concomitant therapies, and individual immune responsiveness. Essential for tailored therapeutic strategies b...

  1. Prospects and Trends in the Brazilian Market for Biologically Sourced Products

    Directory of Open Access Journals (Sweden)

    Luciana da Silva Madeira

    2012-09-01

    Full Text Available The aim of this paper was to select the most interesting Brazilian biopharmaceuticals, with the best market opportunity for production. The biopharmaceuticals filgrastim, infliximab, somatropin, imiglucerase, betainterferon and factor VIII were selected because they are not produced in Brazil and thus could increase the technological capacity of domestic production. The use of a data mining tool facilitated the results achieved here, using the patents deposited in several banks worldwide as the source information. The prospects and trends of producing biopharmaceuticals in Brazil are of great interest to the country to establish a competitive industry and reduce the vulnerability of the National Health System, such as display windows of opportunity, showing the possibility of moving towards the production of biopharmaceuticals.

  2. Incorporation of Developability into Cell Line Selection

    OpenAIRE

    Betts, J. P. J.

    2015-01-01

    The pharmaceutical industry is under increasing pressure to deliver new medicines quickly and cost effectively; traditional small molecule product pipelines have dried up and companies are increasingly investing into biopharmaceuticals. To date, the most successful biopharmaceuticals have been monoclonal antibodies. The ability to construct common manufacturing platforms for a range of antibody products has underpinned this interest. Antibodies are most often produced as heterologous proteins...

  3. Human Granulocyte Colony-Stimulating Factor (hG-CSF) Expression in Plastids of Lactuca sativa

    OpenAIRE

    Sharifi Tabar, Mehdi; Habashi, Ali Akbar; Rajabi Memari, Hamid

    2013-01-01

    Background: Human granulocyte colony-stimulating factor (hG-CSF) can serve as valuable biopharmaceutical for research and treatment of the human blood cancer. Transplastomic plants have been emerged as a new and high potential candidate for production of recombinant biopharmaceutical proteins in comparison with transgenic plants due to extremely high level expression, biosafety and many other advantages. Methods: hG-CSF gene was cloned into pCL vector between prrn16S promoter and TpsbA ter...

  4. Biotechnology

    International Nuclear Information System (INIS)

    2008-01-01

    The guidelines of the Biotechnology Program are research and development aiming to develop and manufacture products of pharmaceutical interest. This program has two main research areas, namely Pituitary Hormones and Biopharmaceuticals. The first one comprises a group with a long experience on Recombinant Human Pituitary Hormone synthesis, purification and characterization. The Biopharmaceutical area is dedicated to the research of isolation, structural analysis and biological activities in different biological system of macromolecules

  5. Repurposing pharma assets: an accelerated mechanism for strengthening the schistosomiasis drug development pipeline.

    Science.gov (United States)

    Ramamoorthi, Roopa; Graef, Katy M; Dent, Jennifer

    2015-01-01

    Schistosomiasis, one of 17 diseases deemed to be neglected by the World Health Organization, has received little attention from the biopharmaceutical industry. Due to this, only a handful of drugs have been developed to treat schistosomiasis, with only one, praziquantel, used in most endemic regions. Growing concern over resistance coupled with praziquantel's incomplete efficacy across all stages of the Schistosoma platyhelminth life cycle highlights the urgent need for new drugs. The WIPO Re:Search consortium is a platform whereupon biopharmaceutical company compounds are being repurposed to efficiently and cost-effectively develop new drugs for neglected diseases such as schistosomiasis. This article summarizes recent clinical-stage efforts to identify new antischistosomals and highlights biopharmaceutical company compounds with potential for repurposing to treat schistosomiasis.

  6. Active compounds from cyanobacteria and microalgae: properties and potential applications in biomedicine

    Directory of Open Access Journals (Sweden)

    Alexey Llopiz

    2016-05-01

    Full Text Available Cyanobacteria and microalgae are source of many chemicals substances with potential applications on biopharmaceutical industry. Many structures have been characterized in these organism, such as: peptides, proteins, carbohydrates, terpenoids, polyinsatured fatty acids, flavonoids, phenolic compounds, vitamins, porfirins and other organic substances. Chemicals structures of isolated compounds are diverse and it depends of microalgae habitats. Pharmacological activities located in microalgae are bactericides, immunomodulatory, antioxidants, cytoprotective, fungicides and antivirals. These properties may possible the potential treatment of many diseases including autoimmunes disorders, tumoral, and infectious process. In this review are presented and discussed some elements associated to chemical structure and biological activities around of compounds with potential uses as biopharmaceuticals.

  7. AN OVERVIEW OF BIOLOGICS: SCIENCE BEHIND PROTEIN THERAPEUTICS

    Directory of Open Access Journals (Sweden)

    Inderjeet Kaur

    2012-12-01

    Full Text Available Biosimilars or ‘follow-on biologics’ are new biopharmaceutical agents that are ‘similar’ but not identical to a reference biopharmaceutical product. Biosimilars are considered ‘comparable’ to the reference product, but this does not ensure therapeutic equivalence. Inherent differences between biosimilars may produce dissimilarities in clinical efficacy, safety, and immunogenicity. Therefore accurate measurement and characterization of these differences and absolute quantification of biosimilars is the significant requirement at present. Mass spectrometry coupled with high performance liquid chromatography offers the most sensitive and accurate solution for this. This review discusses the potential strategies for the absolute quantification of biosimilars using mass spectrometry.

  8. Biotechnology

    International Nuclear Information System (INIS)

    2011-01-01

    The guidelines of the Biotechnology Program are research and development aiming to develop and manufacture products of pharmaceutical interest. This Program has two main research areas, namely Pituitary Hormones and Biopharmaceuticals. The first one comprises a group with a long experience on Recombinant Human Pituitary Hormone synthesis, purification and characterization. The Biopharmaceutical area is dedicated to the research of isolation, structural analysis and biological activities in different biological system of macromolecules. The Animal Laboratory Division of IPEN is responsible for the breeding and production of small laboratory animal.

  9. In vitro models to evaluate the permeability of poorly soluble drug entities: Challenges and perspectives

    DEFF Research Database (Denmark)

    Buckley, S. T.; Fischer, S. M.; Fricker, G.

    2012-01-01

    The application of in vitro models in drug permeability studies represents a useful screening tool for assessing the biopharmaceutical appropriateness of new chemical entities (NCEs). Of note, there remains an ever-increasing number of NCEs which exhibit poor aqueous solubility. However, in their......The application of in vitro models in drug permeability studies represents a useful screening tool for assessing the biopharmaceutical appropriateness of new chemical entities (NCEs). Of note, there remains an ever-increasing number of NCEs which exhibit poor aqueous solubility. However...

  10. In vitro solubility, dissolution and permeability studies combined with semi-mechanistic modeling to investigate the intestinal absorption of desvenlafaxine from an immediate- and extended release formulation

    DEFF Research Database (Denmark)

    Franek, F; Jarlfors, A; Larsen, F.

    2015-01-01

    Desvenlafaxine is a biopharmaceutics classification system (BCS) class 1 (high solubility, high permeability) and biopharmaceutical drug disposition classification system (BDDCS) class 3, (high solubility, poor metabolism; implying low permeability) compound. Thus the rate-limiting step...... not imply low intestinal permeability, as indicated by the BDDCS, merely low duodenal/jejunal permeability....... for desvenlafaxine absorption (i.e. intestinal dissolution or permeation) is not fully clarified. The aim of this study was to investigate whether dissolution and/or intestinal permeability rate-limit desvenlafaxine absorption from an immediate-release formulation (IRF) and Pristiq®, an extended release formulation...

  11. The Membrane Gradostat Reactor: Secondary metabolite production ...

    African Journals Online (AJOL)

    This manuscript focuses on the aspect of a membrane gradostat as an entirely different concept compared to submerged hollow fibre modules. The use of membrane bioreactor (MBR) technology is rapidly advancing in the wastewater treatment industries. However, this is not the case in the biopharmaceutical ...

  12. Lysine conjugation properties in human IgGs studied by integrating high-resolution native mass spectrometry and bottom-up proteomics

    NARCIS (Netherlands)

    Gautier, Violette|info:eu-repo/dai/nl/372660851; Boumeester, Anja J.; Lössl, Philip|info:eu-repo/dai/nl/371559693; Heck, Albert J R|info:eu-repo/dai/nl/105189332

    2015-01-01

    Antibody-drug conjugates (ADCs) are a novel class of biopharmaceuticals several of which are now being investigated in clinical studies. In ADCs, potent cytotoxic drugs are coupled via a linker to reactive residues in IgG monoclonal antibodies. Linkage to lysine residues in the IgGs, using

  13. Good Pharma? How Business Communication Research Can Help Bridge the Gap between Students and Practitioners

    Science.gov (United States)

    Bruyer, Tom; Jacobs, Geert; Vandendaele, Astrid

    2016-01-01

    This article presents a case-based exploration of the complex interactions between learning, research, and practice in the field of business and professional communication. It focuses on a student research project in the area of corporate social responsibility in the biopharmaceutical industry. Adopting an autoethnographic approach, we aim to…

  14. Scaled-up manufacturing of recombinant antibodies produced by plant cells in a 200-L orbitally-shaken disposable bioreactor

    NARCIS (Netherlands)

    Raven, N.; Rasche, F.; Kuehn, C.; Anderlei, T.; Klöckner, W.; Schuster, F.; Henquet, M.G.L.; Bosch, H.J.; Büchs, J.; Fischer, R.; Schillberg, S.

    2015-01-01

    Tobacco BY-2 cells have emerged as a promising platform for the manufacture of biopharmaceutical proteins, offering efficient protein secretion, favourable growth characteristics and cultivation in containment under a controlled environment. The cultivation of BY-2 cells in disposable bioreactors is

  15. Therapeutic miRNA and siRNA: Moving from Bench to Clinic as Next Generation Medicine

    Directory of Open Access Journals (Sweden)

    Chiranjib Chakraborty

    2017-09-01

    Full Text Available In the past few years, therapeutic microRNA (miRNA and small interfering RNA (siRNA are some of the most important biopharmaceuticals that are in commercial space as future medicines. This review summarizes the patents of miRNA- and siRNA-based new drugs, and also provides a snapshot about significant biopharmaceutical companies that are investing for the therapeutic development of miRNA and siRNA molecules. An insightful view about individual siRNA and miRNA drugs has been depicted with their present status, which is gaining attention in the therapeutic landscape. The efforts of the biopharmaceuticals are discussed with the status of their preclinical and/or clinical trials. Here, some of the setbacks have been highlighted during the biopharmaceutical development of miRNA and siRNA as individual therapeutics. Finally, a snapshot is illustrated about pharmacokinetics, pharmacodynamics with absorption, distribution, metabolism, and excretion (ADME, which is the fundamental development process of these therapeutics, as well as the delivery system for miRNA- and siRNA-based drugs. Keywords: miRNA, siRNA, drug development

  16. Proceedings of the International Symposium on Biotechnology

    International Nuclear Information System (INIS)

    2008-01-01

    This is a book of abstracts of oral communications and posters that were presented during the International Symposium on Biotechnology that was held in Sfax, Tunisia from May 4th to 8th, 2008. The following themes were covered : - Biotechnology for animal and human health and biopharmaceuticals; - Microbial and environmental biotechnology; - Agricultural, Food and marine biotechnology

  17. Economic viability of Stratified Medicine concepts : An investor perspective on drivers and conditions that favour using Stratified Medicine approaches in a cost-contained healthcare environment

    NARCIS (Netherlands)

    Fugel, Hans-Joerg; Nuijten, Mark; Postma, Maarten

    2016-01-01

    RATIONALE: Stratified Medicine (SM) is becoming a natural result of advances in biomedical science and a promising path for the innovation-based biopharmaceutical industry to create new investment opportunities. While the use of biomarkers to improve R&D efficiency and productivity is very much

  18. Monomeric CH3: A Small, Stable Antibody Domain with Therapeutic Promise | Poster

    Science.gov (United States)

    By Ashley DeVine, Staff Writer Antibody domains are emerging as promising biopharmaceuticals because of their relatively small size compared to full-sized antibodies, which are too large to effectively penetrate tumors and bind to sterically restricted therapeutic targets. In an article published in The Journal of Biological Chemistry, Tianlei Ying, Ph.D., Dimiter Dimitrov,

  19. In vitro investigations of α-amylase mediated hydrolysis of cyclodextrins in the presence of ibuprofen, flurbiprofen, or benzo[a]pyrene

    DEFF Research Database (Denmark)

    Riisager, Ludmilla Lumholdt; Holm, R.; Jørgensen, E. B.

    2012-01-01

    -γ-cyclodextrins have different biopharmaceutical behaviours than the other evaluated cyclodextrins. The rate of degradation was affected by the addition of the inclusion complex forming additives flurbiprofen, ibuprofen and benzo[a]pyrene. This effect between the degradation dynamics and the included additives...

  20. [Biological treatment of multiple sclerosis

    DEFF Research Database (Denmark)

    Sorensen, P.S.; Sellebjerg, F.

    2008-01-01

    In 1996 interferon (IFN)beta was the first biopharmaceutical product to be approved for the treatment of relapsing-remitting multiple sclerosis (MS). In 2006 the more potent monoclonal antibody natalizumab was approved. Presently, a number of monoclonal antibodies are being studied, including ale...

  1. A Methods-Based Biotechnology Course for Undergraduates

    Science.gov (United States)

    Chakrabarti, Debopam

    2009-01-01

    This new course in biotechnology for upper division undergraduates provides a comprehensive overview of the process of drug discovery that is relevant to biopharmaceutical industry. The laboratory exercises train students in both cell-free and cell-based assays. Oral presentations by the students delve into recent progress in drug discovery.…

  2. Recent advances in smart biotechnology

    DEFF Research Database (Denmark)

    Milcovich, Gesmi; Lettieri, Stefania; Antunes, Filipe E.

    2017-01-01

    Over the past ten years, the global biopharmaceutical market has remarkably grown, with ten over the top twenty worldwide high performance medical treatment sales being biologics. Thus, biotech R&D (research and development) sector is becoming a key leading branch, with expanding revenues. Biotec...

  3. Genetic or chemical protease inhibition causes significant changes in the Bacillus subtilis exoproteome

    NARCIS (Netherlands)

    Westers, Lidia; Westers, Helga; Zanen, Geeske; Antelmann, Haike; Hecker, Michael; Noone, David; Devine, Kevin M.; van Dijl, Jan Maarten; Quax, Wim J.

    Bacillus subtilis is a prolific producer of enzymes and biopharmaceuticals. However, the susceptibility of heterologous proteins to degradation by (extracellular) proteases is a major limitation for use of B. subtilis as a protein cell factory. An increase in protein production levels has previously

  4. Biofarmaka til behandling af reumatoid artritis

    DEFF Research Database (Denmark)

    Baslund, Bo; Bendtzen, Klaus

    2008-01-01

    The current status on the use of biopharmaceuticals in the treatment of rheumatoid arthritis is reviewed. Blocking of TNF-alpha, co-stimulation of CD28+ T-cells and depletion of CD20+ B-cells are all effective ways to diminish inflammation and joint damage. However, not all patients react to thes...

  5. High-Pressure Biotechnology in Medicine and Pharmaceutical Science

    Directory of Open Access Journals (Sweden)

    Patrick Masson

    2001-01-01

    inactivation of biological agents is expected to be applicable to sterilization of fragile biopharmaceuticals, or medical compounds. The enhanced immunogenicity of some pressure-killed bacteria and viruses could be applied for making new vaccines. Finally, storage at subzero temperatures without freezing is another potential application of HP for cells, animal tissues, blood cells, organs for transplant, and so forth.

  6. Toward genome-scale models of the Chinese hamster ovary cells: incentives, status and perspectives

    DEFF Research Database (Denmark)

    Kaas, Christian Schrøder; Fan, Yuzhou; Weilguny, Dietmar

    2014-01-01

    Bioprocessing of the important Chinese hamster ovary (CHO) cell lines used for the production of biopharmaceuticals stands at the brink of several redefining events. In 2011, the field entered the genomics era, which has accelerated omics-based phenotyping of the cell lines. In this review we...

  7. Concept of Green Chemistry

    Indian Academy of Sciences (India)

    Srimath

    water or supercritical water and also solvent-free systems that utilize the surfaces or ... extent by the renewable and nontoxic glucose and the reaction is carried out in water. ... chemically modified penicillins, amino acids, vitamins, fructose syrup and many biopharmaceuticals are obtained by this method. A milestone in this ...

  8. DNA molecules and human therapeutics | Danquah | African Journal ...

    African Journals Online (AJOL)

    Nucleic acid molecules are championing a new generation of reverse engineered biopharmaceuticals. In terms of potential application in gene medicine, plasmid DNA (pDNA) vectors have exceptional therapeutic and immunological profiles as they are free from safety concerns associated with viral vectors, display ...

  9. A novel microdialysis-dissolution/permeation system for testing oral dosage forms

    DEFF Research Database (Denmark)

    Fong, Sophia Yui Kau; Poulsen, Jessie; Brandl, Martin

    2016-01-01

    A novel microdialysis-dissolution/permeation (M-D/P) system was developed for the biopharmaceutical assessment of oral drug formulations. This system consists of a side-by-side diffusion chamber, a microdialysis unit fixed within the dissolution chamber for continuous sampling, and a biomimetic P...

  10. Mapping the interactions of selective biochemical probes of antibody conformation by hydrogen-deuterium exchange mass spectrometry

    DEFF Research Database (Denmark)

    Leurs, Ulrike; Beck, Hermann; Bonnington, Lea

    2017-01-01

    Protein-based pharmaceuticals represent the fastest growing group of drugs in development in the pharmaceutical industry. One of the major challenges in the discovery, development and distribution of biopharmaceuticals is the assessment of changes in their higher-order structure due to chemical...

  11. Sparging - shear sensitivity of animal cells

    NARCIS (Netherlands)

    Pol, van der L.A.

    1998-01-01

    Biopharmaceuticals are increasingly produced by modern biotechnological techniques. The in-vitro culture of animal cells in stirred tanks is one of the feasible systems, especially for proteins that require specific post-tanslational modifications to evoke a desired respons in patients.

  12. Nanoparticle formulation of a poorly soluble cannabinoid receptor 1 antagonist improves absorption by rat and human intestine

    NARCIS (Netherlands)

    Siissalo, Sanna; De Waard, Hans; De Jager, Marina H.; Hayeshi, Rose; Frijlink, Henderik W.; Hinrichs, Wouter L.J.; Dinter-Heidorn, Heike; Van Dam, Annie; Proost, Johannes H.; Groothuis, Geny M.M.; De Graaf, Inge A.M.

    The inclusion of nanoparticles dispersed in a hydrophilic matrix is one of the formulation strategies to improve the bioavailability of orally administered Biopharmaceutics Classification System (BCS) class II and IV drugs by increasing their dissolution rate in the intestine. To confirm that the

  13. Biosimilars: a regulatory perspective from America.

    Science.gov (United States)

    Kay, Jonathan

    2011-05-12

    Biosimilars are protein products that are sufficiently similar to a biopharmaceutical already approved by a regulatory agency. Several biotechnology companies and generic drug manufacturers in Asia and Europe are developing biosimilars of tumor necrosis factor inhibitors and rituximab. A biosimilar etanercept is already being marketed in Colombia and China. In the US, several natural source products and recombinant proteins have been approved as generic drugs under Section 505(b)(2) of the Food, Drug, and Cosmetic Act. However, because the complexity of large biopharmaceuticals makes it difficult to demonstrate that a biosimilar is structurally identical to an already approved biopharmaceutical, this Act does not apply to biosimilars of large biopharmaceuticals. Section 7002 of the Patient Protection and Affordable Care Act of 2010, which is referred to as the Biologics Price Competition and Innovation Act of 2009, amends Section 351 of the Public Health Service Act to create an abbreviated pathway that permits a biosimilar to be evaluated by comparing it with only a single reference biological product. This paper reviews the processes for approval of biosimilars in the US and the European Union and highlights recent changes in federal regulations governing the approval of biosimilars in the US.

  14. Bioprocess scale-up/down as integrative enabling technology : from fluid mechanics to systems biology and beyond

    NARCIS (Netherlands)

    Delvigne, Frank; Takors, Ralf; Mudde, R.F.; van Gulik, W.M.; Noorman, H.J.

    2017-01-01

    Efficient optimization of microbial processes is a critical issue for achieving a number of sustainable development goals, considering the impact of microbial biotechnology in agrofood, environment, biopharmaceutical and chemical industries. Many of these applications require scale-up after proof

  15. Expression of natural human b1,4-GalT1 variants and of non-mammalian homologues in plants leads to differences in galactosylation of N-glycans

    NARCIS (Netherlands)

    Hesselink, T.; Rouwendal, G.J.A.; Henquet, M.G.L.; Florack, D.E.A.; Helsper, J.P.F.G.; Bosch, H.J.

    2014-01-01

    b1,4-Galactosylation of plant N-glycans is a prerequisite for commercial production of certain biopharmaceuticals in plants. Two different types of galactosylated N-glycans have initially been reported in plants as the result of expression of human b1,4-galactosyltransferase 1 (GalT). Here we show

  16. Dual substrate feedback control of specific growth-rate in vaccine production

    NARCIS (Netherlands)

    Neeleman, R.; Beuvery, E.C.; Vries, D.; Straten, van G.; Boxtel, van A.J.B.

    2004-01-01

    Abstract: Unexpectedly, primary concern of bio-pharmaceutical industry is not optimisation of product yield or cost reduction, but consistency in production and product quality. This paper describes the methodology and experimental results of specific growth-rate control for vaccine production. The

  17. Uninformed and disinformed society and the GMO market.

    Science.gov (United States)

    Twardowski, Tomasz; Małyska, Aleksandra

    2015-01-01

    The EU has a complicated regulatory framework, and this is slowing down the approval process of new genetically modified (GM) crops. Currently, labeling of GM organisms (GMOs) is mandatory in all Member States. However, the USA, in which GMO labeling is not mandatory, continues to lead the production of biotech crops, biopharmaceuticals, biomaterials, and bioenergy. Copyright © 2014 Elsevier Ltd. All rights reserved.

  18. Occurrence of Anti-Drug Antibodies against Interferon-Beta and Natalizumab in Multiple Sclerosis

    DEFF Research Database (Denmark)

    Bachelet, Delphine; Hässler, Signe; Mbogning, Cyprien

    2016-01-01

    Immunogenicity of biopharmaceutical products in multiple sclerosis is a frequent side effect which has a multifactorial etiology. Here we study associations between anti-drug antibody (ADA) occurrence and demographic and clinical factors. Retrospective data from routine ADA test laboratories in S...

  19. The Impact of Biotechnology on Pharmaceutics.

    Science.gov (United States)

    Block, Lawrence H.

    1990-01-01

    The emergence of bioactive peptides and proteins as new drug species poses formidable problems for the pharmaceutical scientist. Implications for revision or change in undergraduate and graduate pharmaceutics curricula derive from the biopharmaceutical, pharmacokinetic, and physiochemical aspects of the new drug species, which differ from…

  20. Venture capitalists as gatekeepers for biotechnological innovation

    NARCIS (Netherlands)

    Fernald, Kenneth; Hoeben, Ruud; Claassen, H.J.H.M.

    2015-01-01

    Venture capitalists (VCs) aim at trade sales as a preferred exit-strategy for biotechnology companies they invest in. Therefore, VCs pay close attention to the wishes of larger (bio)pharmaceutical acquirers. In this paper we explore VCs' behavior and strategies by analyzing the technology fields and

  1. Biowaiver monographs for immediate release solid oral dosage forms: acetaminophen (paracetamol).

    NARCIS (Netherlands)

    Kalantzi, L; Reppas, C; Dressman, J B; Amidon, G L; Junginger, H E; Midha, K K; Shah, V P; Stavchansky, S A; Barends, Dirk M

    2006-01-01

    Literature data are reviewed on the properties of acetaminophen (paracetamol) related to the biopharmaceutics classification system (BCS). According to the current BCS criteria, acetaminophen is BCS Class III compound. Differences in composition seldom, if ever, have an effect on the extent of

  2. Biowaiver monographs for immediate release solid oral dosage forms: cimetidine.

    NARCIS (Netherlands)

    Jantratid, E; Prakongpan, S; Dressman, J B; Amidon, G L; Junginger, H E; Midha, K K; Barends, D M

    2006-01-01

    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release (IR) solid oral dosage forms containing cimetidine are reviewed. According to the current Biopharmaceutics Classification System (BCS), cimetidine would be assigned

  3. Pharmaceutical biotechnology: drug discovery and clinical applications

    National Research Council Canada - National Science Library

    Kayser, Oliver; Müller, Rainer H

    2004-01-01

    .... The biopharmaceutical industry has changed dramatically since the first recombinant ® protein (Humulin ) was approved for marketing in 1982. The range of resources required for the pharmaceutical industry has expanded from its traditional fields. Advances in the field of recombinant genetics allows scientists to routinely clone genes and create ge...

  4. Recombinant organisms for production of industrial products

    OpenAIRE

    Adrio, Jose-Luis; Demain, Arnold L

    2009-01-01

    A revolution in industrial microbiology was sparked by the discoveries of ther double-stranded structure of DNA and the development of recombinant DNA technology. Traditional industrial microbiology was merged with molecular biology to yield improved recombinant processes for the industrial production of primary and secondary metabolites, protein biopharmaceuticals and industrial enzymes. Novel genetic techniques such as metabolic engineering, combinatorial biosynthesis and molecular breeding...

  5. Digitizing and Securing Archived Laboratory Notebooks

    Science.gov (United States)

    Caporizzo, Marilyn

    2008-01-01

    The Information Group at Millipore has been successfully using a digital rights management tool to secure the email distribution of archived laboratory notebooks. Millipore is a life science leader providing cutting-edge technologies, tools, and services for bioscience research and biopharmaceutical manufacturing. Consisting of four full-time…

  6. A Dynamic Design Space for Primary Drying During Batch Freeze-Drying

    DEFF Research Database (Denmark)

    Mortier, Séverine Thérèse F C; Van Bockstal, Pieter Jan; Nopens, Ingmar

    2016-01-01

    Biopharmaceutical products are emerging within the pharmaceutical industry. However, biopharmaceuticals are often unstable in aqueous solution. Freeze-drying (lyophilisation) is the preferred method to achieve a stable product with an increased shelf-life. During batch freeze-drying, there are only...... two adaptable process variables, i.e. the shelf temperature and the pressure in the drying chamber. The value of both should be optimized, preferably in a dynamic way, to minimise the primary drying time while respecting process and equipment constraints and ensuring end product quality. A mechanistic...... model is used to determine the optimal values for the adaptable variables, hereby accounting for the uncertainty in all involved model parameters. A dynamic Design Space was constructed with a risk of failure acceptance level of 0.01%, i.e. a 'zero-failure' situation. Even for a risk of failure of 0...

  7. Monoclonal Antibodies Production Platforms: An Opportunity Study of a Non-Protein-A Chromatographic Platform Based on Process Economics.

    Science.gov (United States)

    Grilo, António L; Mateus, Marília; Aires-Barros, Maria R; Azevedo, Ana M

    2017-12-01

    Monoclonal antibodies currently dominate the biopharmaceutical market with growing sales having reached 80 billion USD in 2016. As most top-selling mAbs are approaching the end of their patent life, biopharmaceutical companies compete fiercely in the biosimilars market. These two factors present a strong motivation for alternative process strategies and process optimization. In this work a novel purification strategy for monoclonal antibodies comprising phenylboronic acid multimodal chromatography for capture followed by polishing by ion-exchange monolithic chromatography and packed bed hydrophobic interaction chromatography is presented and compared to the traditional protein-A-based process. Although the capital investment is similar for both processes, the operation cost is 20% lower for the novel strategy. This study shows that the new process is worthwhile investing in and could present a viable alternative to the platform process used by most industrial players. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  8. Biologicals versus biosimilars the future ahead

    Directory of Open Access Journals (Sweden)

    A Singhal

    2015-01-01

    Full Text Available Biosimilars are highly similar versions of already authorized innovator biological therapies. They demonstrate no clinically meaningful difference with their innovator products in terms of efficacy, safety and quality characteristics and biological activity. Biosimilars have demonstrated growing acceptance and use, especially in the developing countries due to severe cost constraints. Global market for Indian non-innovator products is approximately worth USD 1.5 Billion/annum with an annual growth rate of 27%. Estimated exports of Indian biopharmaceutical products have been increasing at a rate of 47%. In India, there is a good acceptance of non-innovator healthcare products amongst healthcare professionals and patients. Several home grown biopharmaceutical industries are now actively developing and marketing non innovator products in India.

  9. Early pharmaceutical profiling to predict oral drug absorption

    DEFF Research Database (Denmark)

    Bergström, Christel A S; Holm, René; Jørgensen, Søren Astrup

    2014-01-01

    Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the pharmac......Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary...... and state-of-the art methodologies to study API properties impacting on oral absorption are reviewed. Assays performed during early development, i.e. physicochemical characterization, dissolution profiles under physiological conditions, permeability assays and the impact of excipients on these properties...

  10. Industrial Production of Therapeutic Proteins: Cell Lines, Cell Culture, and Purification

    Science.gov (United States)

    Zhu, Marie M.; Mollet, Michael; Hubert, Rene S.

    The biotechnology and pharmaceutical industries have seen a recent surge in the development of biological drug products manufactured from engineered mammalian cell lines. Since the hugely successful launch of human tissue plasminogen activator in 1987 and erythropoietin in 1988, the biopharmaceutical market has grown immensely. Global sales in 2003 exceeded US 30 billion.1 Currently, a total of 108 biotherapeutics are approved and available to patients (Table 32.1). In addition, 324 medically related, biotechnology-derived medicines for nearly 150 diseases are in clinical trials or under review by the U.S. Food and Drug Administration.2 These biopharmaceutical candidates promise to bring more and better treatments to patients. Compared to small molecule drugs, biotherapeutics show exquisite specificity with fewer off-target interactions and improved safety profiles.

  11. Pharmacology profiling of chemicals and proteins

    DEFF Research Database (Denmark)

    Kringelum, Jens Vindahl

    between pharmaceuticals and proteins in vivo potential leads to unwanted adverse effects, toxicity and reduced half-life, but can also lead to novel therapeutic effects of already approved pharmaceuticals. Hence identification of in vivo targets is of importance in discovery, development and repurposing....... This limitation complicates adverse effect assessment in the early drug-development phase, thus contributing to drugattrition. Prediction models offer the possibility to close these gaps and provide more complete pharmacology profiles, however improvements in performances are required for these tools to serve...... to its nonself origin, which potentially alters the pharmacology profile of the substance. The neutralization of biopharmaceuticals by antidrug antibodies (ADAs) is an important element in the immune response cascade, however studies of ADA binding site on biopharmaceuticals, referred to as B...

  12. The interaction between thermodynamic stability and buried free cysteines in regulating the functional half-life of fibroblast growth factor-1.

    Science.gov (United States)

    Lee, Jihun; Blaber, Michael

    2009-10-16

    Protein biopharmaceuticals are an important and growing area of human therapeutics; however, the intrinsic property of proteins to adopt alternative conformations (such as during protein unfolding and aggregation) presents numerous challenges, limiting their effective application as biopharmaceuticals. Using fibroblast growth factor-1 as model system, we describe a cooperative interaction between the intrinsic property of thermostability and the reactivity of buried free-cysteine residues that can substantially modulate protein functional half-life. A mutational strategy that combines elimination of buried free cysteines and secondary mutations that enhance thermostability to achieve a substantial gain in functional half-life is described. Furthermore, the implementation of this design strategy utilizing stabilizing mutations within the core region resulted in a mutant protein that is essentially indistinguishable from wild type as regard protein surface and solvent structure, thus minimizing the immunogenic potential of the mutations. This design strategy should be generally applicable to soluble globular proteins containing buried free-cysteine residues.

  13. New Cooperation Modes: An Opportunity for Polish Biotechnological Clusters

    Directory of Open Access Journals (Sweden)

    Lukasz Puslecki

    2015-06-01

    Full Text Available This article reviews new cooperation forms between companies, referring to the latest data from the asap (the Association of Strategic Alliance Professionals. Potential cooperation between companies, universities and research institutes in the field of biotechnology in Poland based on a model of open innovation alliances are presented. Biopharmaceutical companies are looking for new and innovative paths of development. They try to implement new strategies to transfer their research processes to a higher level. To achieve this, biopharmaceutical companies often use open innovation model as an additional tool for developing new products. Thanks to the cooperation with universities in the framework of open innovation alliances, they can significantly reduce the risk, the cost of research, and most of all, through joint work with academic researchers on identifying disease mechanisms and on development of new drugs, they are able to create improved and appropriate medical therapy for patients.

  14. Vaccination via Chloroplast Genetics: Affordable Protein Drugs for the Prevention and Treatment of Inherited or Infectious Human Diseases.

    Science.gov (United States)

    Daniell, Henry; Chan, Hui-Ting; Pasoreck, Elise K

    2016-11-23

    Plastid-made biopharmaceuticals treat major metabolic or genetic disorders, including Alzheimer's, diabetes, hypertension, hemophilia, and retinopathy. Booster vaccines made in chloroplasts prevent global infectious diseases, such as tuberculosis, malaria, cholera, and polio, and biological threats, such as anthrax and plague. Recent advances in this field include commercial-scale production of human therapeutic proteins in FDA-approved cGMP facilities, development of tags to deliver protein drugs to targeted human cells or tissues, methods to deliver precise doses, and long-term stability of protein drugs at ambient temperature, maintaining their efficacy. Codon optimization utilizing valuable information from sequenced chloroplast genomes enhanced expression of eukaryotic human or viral genes in chloroplasts and offered unique insights into translation in chloroplasts. Support from major biopharmaceutical companies, development of hydroponic production systems, and evaluation by regulatory agencies, including the CDC, FDA, and USDA, augur well for advancing this novel concept to the clinic and revolutionizing affordable healthcare.

  15. Uncertainty analysis as essential step in the establishment of the dynamic Design Space of primary drying during freeze-drying

    DEFF Research Database (Denmark)

    Mortier, Severine Therese F. C.; Van Bockstal, Pieter-Jan; Corver, Jos

    2016-01-01

    Large molecules, such as biopharmaceuticals, are considered the key driver of growth for the pharmaceutical industry. Freeze-drying is the preferred way to stabilise these products when needed. However, it is an expensive, inefficient, time- and energy-consuming process. During freeze-drying, the......Large molecules, such as biopharmaceuticals, are considered the key driver of growth for the pharmaceutical industry. Freeze-drying is the preferred way to stabilise these products when needed. However, it is an expensive, inefficient, time- and energy-consuming process. During freeze...... for pharmaceutical freeze-drying. Traditionally, the chamber pressure and shelf temperature are kept constant during primary drying, leading to less optimal process conditions. In this paper it is demonstrated how a mechanistic model of the primary drying step gives the opportunity to determine the optimal dynamic...

  16. The systems containing clays and clay minerals from modified drug release: a review.

    Science.gov (United States)

    Rodrigues, Luís Alberto de Sousa; Figueiras, Ana; Veiga, Francisco; de Freitas, Rivelilson Mendes; Nunes, Lívio César Cunha; da Silva Filho, Edson Cavalcanti; da Silva Leite, Cleide Maria

    2013-03-01

    Clays are materials commonly used in the pharmaceutical industry, either as ingredients or as active ingredients. It was observed that when they are administered concurrently, they may interact with drugs reducing their absorption. Therefore, such interactions can be used to achieve technological and biopharmaceutical advantages, regarding the control of release. This review summarizes bibliographic (articles) and technological (patents) information on the use of systems containing clays and clay minerals in modified drug delivery. In this area, formulations such natural clay, commercial clay, synthetic clay, composites clay-polymers, nanocomposites clay-polymers, films and hidrogels composites clay-polymers are used to slow/extend or vectorize the release of drugs and consequently they increase their bioavailability. Finally, this review summarizes the fields of technology and biopharmaceutical applications, where clays are applied. Copyright © 2012 Elsevier B.V. All rights reserved.

  17. The academic-industrial complex: navigating the translational and cultural divide.

    Science.gov (United States)

    Freedman, Stephen; Mullane, Kevin

    2017-07-01

    In general, the fruits of academic discoveries can only be realized through joint efforts with industry. However, the poor reproducibility of much academic research has damaged credibility and jeopardized translational efforts that could benefit patients. Meanwhile, journals are rife with articles bemoaning the limited productivity and increasing costs of the biopharmaceutical industry and its resultant predilection for mergers and reorganizations while decreasing internal research efforts. The ensuing disarray and uncertainty has created tremendous opportunities for academia and industry to form even closer ties, and to embrace new operational and financial models to their joint benefit. This review article offers a personal perspective on the opportunities, models and approaches that harness the increased interface and growing interdependency between biomedical research institutes, the biopharmaceutical industry and the technological world. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Development and Validation of an Enzyme-Linked Immunosorbent Assay for the Detection of Binding Anti-Drug Antibodies against Interferon Beta

    DEFF Research Database (Denmark)

    Ingenhoven, Kathleen; Kramer, Daniel; Jensen, Poul Erik Hyldgaard

    2017-01-01

    to be 26 ng/mL using commercially available polyclonal rabbit antihuman IFN-β in human sera as the positive control. CONCLUSION: An ultrasensitive ELISA for IFN-β-binding ADA testing has been validated. This will form the basis to assess anti-biopharmaceutical immunization toward IFN-β with regards to its......OBJECTIVE: To develop and validate a method for the detection of binding anti-drug antibodies (ADAs) against interferon beta (IFN-β) in human serum as part of a European initiative (ABIRISK) aimed at the prediction and analysis of clinical relevance of anti-biopharmaceutical immunization...... to minimize the risk. METHOD: A two-tiered bridging enzyme-linked immunosorbent assay (ELISA) format was selected and validated according to current recommendations. Screening assay: ADA in serum samples form complexes with immobilized IFN-β and biotinylated IFN-β, which are then detected using HRP labeled...

  19. Mechanochemical Synthesis and Crystal Structure of the Lidocaine-Phloroglucinol Hydrate 1:1:1 Complex

    OpenAIRE

    Nancy Evelyn Magaña-Vergara; Porfirio de la Cruz-Cruz; Ana Lilia Peraza-Campos; Francisco Javier Martínez-Martínez; Juan Saulo González-González

    2018-01-01

    Molecular complexation is a strategy used to modify the physicochemical or biopharmaceutical properties of an active pharmaceutical ingredient. Solvent assisted grinding is a common method used to obtain solid complexes in the form of cocrystals. Lidocaine is a drug used as an anesthetic and for the treatment of chronic pain, which bears in its chemical structure an amide functional group able to form hydrogen bonds. Polyphenols are used as cocrystal coformers due to their ability to form O–H...

  20. Progress on RNAi-based molecular medicines

    OpenAIRE

    Chen, Jing; Xie, Jianping

    2012-01-01

    Jing Chen, Jianping XieInstitute of Modern Biopharmaceuticals, State Key Laboratory Breeding Base of Ministry of Education Eco-Environment of the Three Gorges Reservoir Region, School of Life Sciences, Southwest University, Chongqing, ChinaAbstract: RNA interference (RNAi) is a promising strategy to suppress the expression of disease-relevant genes and induce post-transcriptional gene silencing. Their simplicity and stability endow RNAi with great advantages in molecular medicine. Several RNA...

  1. In vitro models for the prediction of in vivo performance of oral dosage forms

    DEFF Research Database (Denmark)

    Kostewicz, Edmund S; Abrahamsson, Bertil; Brewster, Marcus

    2014-01-01

    Accurate prediction of the in vivo biopharmaceutical performance of oral drug formulations is critical to efficient drug development. Traditionally, in vitro evaluation of oral drug formulations has focused on disintegration and dissolution testing for quality control (QC) purposes. The connection...... of formulations that rely on complex intraluminal processes (e.g. solubilization, supersaturation, precipitation…) remains extremely challenging. Concomitantly, the increasing demand for complex formulations to overcome low drug solubility or to control drug release rates urges the development of new in vitro...

  2. Membrane-Based Technologies in the Pharmaceutical Industry and Continuous Production of Polymer-Coated Crystals/Particles.

    Science.gov (United States)

    Chen, Dengyue; Sirkar, Kamalesh K; Jin, Chi; Singh, Dhananjay; Pfeffer, Robert

    2017-01-01

    Membrane technologies are of increasing importance in a variety of separation and purification applications involving liquid phases and gaseous mixtures. Although the most widely used applications at this time are in water treatment including desalination, there are many applications in chemical, food, healthcare, paper and petrochemical industries. This brief review is concerned with existing and emerging applications of various membrane technologies in the pharmaceutical and biopharmaceutical industry. The goal of this review article is to identify important membrane processes and techniques which are being used or proposed to be used in the pharmaceutical and biopharmaceutical operations. How novel membrane processes can be useful for delivery of crystalline/particulate drugs is also of interest. Membrane separation technologies are extensively used in downstream processes for bio-pharmaceutical separation and purification operations via microfiltration, ultrafiltration and diafiltration. Also the new technique of membrane chromatography allows efficient purification of monoclonal antibodies. Membrane filtration techniques of reverse osmosis and nanofiltration are being combined with bioreactors and advanced oxidation processes to treat wastewaters from pharmaceutical plants. Nanofiltration with organic solvent-stable membranes can implement solvent exchange and catalyst recovery during organic solvent-based drug synthesis of pharmaceutical compounds/intermediates. Membranes in the form of hollow fibers can be conveniently used to implement crystallization of pharmaceutical compounds. The novel crystallization methods of solid hollow fiber cooling crystallizer (SHFCC) and porous hollow fiber anti-solvent crystallization (PHFAC) are being developed to provide efficient methods for continuous production of polymer-coated drug crystals in the area of drug delivery. This brief review provides a general introduction to various applications of membrane technologies in

  3. Biochemical Characterization of Human Anti-Hepatitis B Monoclonal Antibody Produced in the Microalgae Phaeodactylum tricornutum.

    Directory of Open Access Journals (Sweden)

    Gaëtan Vanier

    Full Text Available Monoclonal antibodies (mAbs represent actually the major class of biopharmaceuticals. They are produced recombinantly using living cells as biofactories. Among the different expression systems currently available, microalgae represent an emerging alternative which displays several biotechnological advantages. Indeed, microalgae are classified as generally recognized as safe organisms and can be grown easily in bioreactors with high growth rates similarly to CHO cells. Moreover, microalgae exhibit a phototrophic lifestyle involving low production costs as protein expression is fueled by photosynthesis. However, questions remain to be solved before any industrial production of algae-made biopharmaceuticals. Among them, protein heterogeneity as well as protein post-translational modifications need to be evaluated. Especially, N-glycosylation acquired by the secreted recombinant proteins is of major concern since most of the biopharmaceuticals including mAbs are N-glycosylated and it is well recognized that glycosylation represent one of their critical quality attribute. In this paper, we assess the quality of the first recombinant algae-made mAbs produced in the diatom, Phaeodactylum tricornutum. We are focusing on the characterization of their C- and N-terminal extremities, their signal peptide cleavage and their post-translational modifications including N-glycosylation macro- and microheterogeneity. This study brings understanding on diatom cellular biology, especially secretion and intracellular trafficking of proteins. Overall, it reinforces the positioning of P. tricornutum as an emerging host for the production of biopharmaceuticals and prove that P. tricornutum is suitable for producing recombinant proteins bearing high mannose-type N-glycans.

  4. Interval-Censored Time-to-Event Data Methods and Applications

    CERN Document Server

    Chen, Ding-Geng

    2012-01-01

    Interval-Censored Time-to-Event Data: Methods and Applications collects the most recent techniques, models, and computational tools for interval-censored time-to-event data. Top biostatisticians from academia, biopharmaceutical industries, and government agencies discuss how these advances are impacting clinical trials and biomedical research. Divided into three parts, the book begins with an overview of interval-censored data modeling, including nonparametric estimation, survival functions, regression analysis, multivariate data analysis, competing risks analysis, and other models for interva

  5. Antibody-mediated delivery of interleukin 4 to the neo-vasculature reduces chronic skin inflammation

    OpenAIRE

    Hemmerle Teresa; Zgraggen Silvana; Matasci Mattia; Halin Cornelia; Detmar Michael; Neri Dario

    2014-01-01

    BACKGROUND: The antibody mediated delivery of cytokines (quot;immunocytokinesquot;) to sites of pathological angiogenesis represents an attractive strategy for the development of innovative biopharmaceuticals capable of modulating the activity of the immune system in cancer and in chronic inflammatory conditions. OBJECTIVE: Recombinant IL4 has previously been shown to be therapeutically active in patients with psoriasis. The antibody mediated delivery of this cytokine to sites of chronic skin...

  6. Biosimilar Drugs

    OpenAIRE

    Muradiye Nacak; Zafer Sezer; Aydın Erenmemisoglu

    2012-01-01

    Biotechnological (biopharmaceutical) products are complex macromolecules created through the genetic manipulation of living organisms using recombinant DNA technology, monocolonal antibodies and gene therapy. The patent expirations for many biotechnological medicines have prompted the development of copies of biological medicinal products. These new biotechnology medicines are known as %u201Cbiosimilars%u201D. Due to the complex method of production of biological medicines, biosimilar medicin...

  7. 2015/2016 Quality Risk Management Benchmarking Survey.

    Science.gov (United States)

    Waldron, Kelly; Ramnarine, Emma; Hartman, Jeffrey

    2017-01-01

    This paper investigates the concept of quality risk management (QRM) maturity as it applies to the pharmaceutical and biopharmaceutical industries, using the results and analysis from a QRM benchmarking survey conducted in 2015 and 2016. QRM maturity can be defined as the effectiveness and efficiency of a quality risk management program, moving beyond "check-the-box" compliance with guidelines such as ICH Q9 Quality Risk Management , to explore the value QRM brings to business and quality operations. While significant progress has been made towards full adoption of QRM principles and practices across industry, the full benefits of QRM have not yet been fully realized. The results of the QRM Benchmarking Survey indicate that the pharmaceutical and biopharmaceutical industries are approximately halfway along the journey towards full QRM maturity. LAY ABSTRACT: The management of risks associated with medicinal product quality and patient safety are an important focus for the pharmaceutical and biopharmaceutical industries. These risks are identified, analyzed, and controlled through a defined process called quality risk management (QRM), which seeks to protect the patient from potential quality-related risks. This paper summarizes the outcomes of a comprehensive survey of industry practitioners performed in 2015 and 2016 that aimed to benchmark the level of maturity with regard to the application of QRM. The survey results and subsequent analysis revealed that the pharmaceutical and biopharmaceutical industries have made significant progress in the management of quality risks over the last ten years, and they are roughly halfway towards reaching full maturity of QRM. © PDA, Inc. 2017.

  8. Teaching biomedical technology innovation as a discipline.

    Science.gov (United States)

    Yock, Paul G; Brinton, Todd J; Zenios, Stefanos A

    2011-07-20

    Recently, universities in the United States and abroad have developed dedicated educational programs in life science technology innovation. Here, we discuss the two major streams of educational theory and practice that have informed these programs: design thinking and entrepreneurship education. We make the case that the process of innovation for new medical technologies (medtech) is different from that for biopharmaceuticals and outline the challenges and opportunities associated with developing a discipline of medtech innovation.

  9. Growth strategy for an emerging biopharmaceutcal company

    OpenAIRE

    Winsborrow, Beatrice Gay

    2006-01-01

    Inimex Pharmaceuticals, Inc. is a privately held biopharmaceutical company dedicated to the discovery, development and commercialization of new human medicines based on the selective modulation of the innate immune response. Since Inimex’s background is in human drug development, no formal animal health activities have been a part of Inimex operations. This initial analysis shows that Inimex has opportunity in the animal health market. Inimex is in a good place to evaluate a potential re...

  10. Metal-free bioconjugation reactions.

    Science.gov (United States)

    van Berkel, Sander S; van Delft, Floris L

    2013-01-01

    The recent strategy to apply chemical reactions to address fundamental biological questions has led to the emergence of entirely new conjugation reactions that are fast and irreversible, yet so mild and selective that they can be performed even in living cells or organisms. These so-called bioorthogonal reactions open novel avenues, not only in chemical biology research, but also in many other life sciences applications, including the modulation of biopharmaceuticals by site-specific modification approaches.

  11. Pharmaceutical Cocrystals: New Solid Phase Modification Approaches for the Formulation of APIs

    OpenAIRE

    Anna Karagianni; Maria Malamatari; Kyriakos Kachrimanis

    2018-01-01

    Cocrystals can be used as an alternative approach based on crystal engineering to enhance specific physicochemical and biopharmaceutical properties of active pharmaceutical ingredients (APIs) when the approaches to salt or polymorph formation do not meet the expected targets. In this article, an overview of pharmaceutical cocrystals will be presented, with an emphasis on the intermolecular interactions in cocrystals and the methods for their preparation. Furthermore, cocrystals of direct phar...

  12. Controversy still simmers over plan to build plasma-fractionation plant in Nova Scotia.

    OpenAIRE

    Robb, N

    1995-01-01

    Controversy still simmers over a plan by the Canadian Red Cross Society and a US biopharmaceutical manufacturer to build a plasma-fractionation plant near Halifax. The unilateral decision to go ahead with the plant was taken as the Krever inquiry into Canada's blood-supply system was holding public hearings across the country. A panel created to evaluate the proposal has supported the fractionation plant, but made additional recommendations concerning product pricing, research and development...

  13. Inhibition of apoptosis using exosomes in Chinese hamster ovary cell culture.

    Science.gov (United States)

    Han, Seora; Rhee, Won Jong

    2018-05-01

    Animal cell culture technology for therapeutic protein production has shown significant improvement over the last few decades. Chinese hamster ovary (CHO) cells have been widely adapted for the production of biopharmaceutical drugs. In the biopharmaceutical industry, it is crucial to develop cell culture media and culturing conditions to achieve the highest productivity and quality. However, CHO cells are significantly affected by apoptosis in the bioreactors, resulting in a substantial decrease in product quantity and quality. Thus, to overcome the obstacle of apoptosis in CHO cell culture, it is critical to develop a novel method that does not have minimal concern of safety or cost. Herein, we showed for the first time that exosomes, which are nano-sized extracellular vesicles, derived from CHO cells inhibited apoptosis in CHO cell culture when supplemented to the culture medium. Flow cytometric and microscopic analyses revealed that substantial amounts of exosomes were delivered to CHO cells. Higher cell viability after staurosporine treatment was observed by exosome supplementation (67.3%) as compared to control (41.1%). Furthermore, exosomes prevented the mitochondrial membrane potential loss and caspase-3 activation, meaning that the exosomes enhanced cellular activities under pro-apoptotic condition. As the exosomes supplements are derived from CHO cells themselves, it is not only beneficial for the biopharmaceutical productivity of CHO cell culture to inhibit apoptosis, but also from a regulatory standpoint to diminish any safety concerns. Thus, we conclude that the method developed in this research may contribute to the biopharmaceutical industry where minimizing apoptosis in CHO cell culture is beneficial. © 2018 Wiley Periodicals, Inc.

  14. Low molecular weight poly (2-dimethylamino ethylmethacrylate) polymers with controlled.positioned fluorescent labeling: Synthesis, characterization and in vitro interaction with human endothelial cells

    DEFF Research Database (Denmark)

    Flebus, Luca; Lombart, Francois; Sevrin, Chantal

    2015-01-01

    Poly (2-dimethylamino ethylmethacrylate) (PDMAEMA) is an attractive non-degradable polymer studied as nonviral vector for gene delivery but it can be also adopted for delivery of other biopharmaceutical drugs. As a parenteral carrier, the PDMAEMA free form (FF) might interact with tissues and cells...... to a minor cytotoxicity compared to the higher ones.As main conclusion this study highlights the similitude in cell trafficking of FF PDMAEMA and data previously reported for PDMAEMA/DNA complexes....

  15. Procedure for the preparation of tritium-labelled insulins

    International Nuclear Information System (INIS)

    Bienert, M.; Haensicke, A.; Beyermann, M.; Kaufmann, K.D.; Oehlke, J.; Klauschenz, E.; Bespalowa, S.; Titov, M.; Pleiss, U.

    1986-01-01

    This invention is concerned with a procedure for the preparation of specific 3 H-labelled insulins with sequences of human, bovine or porcine insulins and without simultaneous chemical modifications of the insulin. On the basis of this procedure a 3 H 2 -Typ (B26)-insulin can be obtained in good yield and purity with a specific radioactivity appropriate to biopharmaceutical and pharmacokinetic purposes in medicine and pharmaceutical industry, resp

  16. DESIGN OF FILL AND FINISH FACILITY FOR ACTIVE PHARMACEUTICAL INGREDIENTS (API)

    OpenAIRE

    NUUR LAILA KHAIRUDDIN; NORLIZA ABD. RAHMAN; NUR SYAFIQAH KAMARUDIN

    2016-01-01

    Fill and finish operations continue to be one of the most heavily outsourced activities in the biopharmaceutical manufacturing market today. There are a few aspects that need to be consider in outsource activities like logistic, storage condition, facility certification and audit as regulations and standards which the manufacturer should adhere. Risk would be greater and extra care should be taken when outsource from foreign fill and finish facility. Thus, the internal aseptic fill and fin...

  17. Discussion on Reformation of Biotechnological Pharmacy Experimental Teaching

    Science.gov (United States)

    Wen, Zhang; Yanjun, Li; Qiao, Zeng

    This article constructs a "comprehensive-designable-innovation" multi-level experimental teaching model, through integrating related disciplines courses, updating biopharmaceutical experiment teaching content, adding designing and innovation experiment item. During the teaching, the teacher mobilizes and stimulates the students' learning interest, enthusiasm and initiative fully by adopting the opening experiment teaching mode. The experiment not only consolidates the students' theory knowledge, makes them master the basic skills of biological pharmacy experiment, but also cultivates the students' independent innovating and independent ability.

  18. Chitosan nanoparticles as drug delivery carriers for biomedical engineering

    International Nuclear Information System (INIS)

    Shi, L.E.S.; Chen, M.; XINF, L.Y.; Guo, X.F.; Zhao, L.M.

    2011-01-01

    Chitosan is a rather abundant material, which has been widely used in food industrial and bioengineering aspects, including in encapsulating active food ingredients, in enzyme immobilization, and as a carrier for drug delivery, due to its significant biological and chemical properties such as biodegradable, biocompatible, bioactive and polycationic. This review discussed preparation and applications of chitosan nanoparticles in the biomedical engineering field, namely as a drug delivery carrier for biopharmaceuticals. (author)

  19. Plastid transformation in lettuce (Lactuca sativa L.) by biolistic DNA delivery.

    Science.gov (United States)

    Ruhlman, Tracey A

    2014-01-01

    The interest in producing pharmaceutical proteins in a nontoxic plant host has led to the development of an approach to express such proteins in transplastomic lettuce (Lactuca sativa L.). A number of therapeutic proteins and vaccine antigen candidates have been stably integrated into the lettuce plastid genome using biolistic DNA delivery. High levels of accumulation and retention of biological activity suggest that lettuce may provide an ideal platform for the production of biopharmaceuticals.

  20. Novel Burkholderia mallei Virulence Factors Linked to Specific Host-Pathogen Protein Interactions

    Science.gov (United States)

    2013-06-23

    equine hosts. Thus, the genes retained in B. mallei share a high sequence similarity to genes common to B. pseudomallei (3), and many virulence...oppor- tunistic infections in mammalian hosts. Even for the equine - adapted and, thus, more genetically constrained, B. mallei pathogen, we cannot...BioDrugs: Clin. Immunotherapeut., Biopharmaceut. Gene Therapy 17, 413–424 88. Anderson, D. M., and Frank, D. W. (2012) Five mechanisms of manipula

  1. Molecular buckets: cyclodextrins for oral cancer therapy

    OpenAIRE

    Calleja, P. (Patricia); Huarte, J. (Judit); Agüeros, M. (Maite); Ruiz-Gaton, L. (Luisa); Espuelas, S. (Socorro); Irache, J.M. (Juan Manuel)

    2012-01-01

    The oral route is preferred by patients for drug administration due to its convenience, resulting in improved compliance. Unfortunately, for a number of drugs (e.g., anticancer drugs), this route of administration remains a challenge. Oral chemotherapy may be an attractive option and especially appropriate for chronic treatment of cancer. However, this route of administration is particularly complicated for the administration of anticancer drugs ascribed to Class IV of the Biopharmaceutical C...

  2. Reconceptualizing cancer immunotherapy based on plant production systems

    OpenAIRE

    Hefferon, Kathleen

    2017-01-01

    Plants can be used as inexpensive and facile production platforms for vaccines and other biopharmaceuticals. More recently, plant-based biologics have expanded to include cancer immunotherapy agents. The following review describes the current state of the art for plant-derived strategies to prevent or reduce cancers. The review discusses avenues taken to prevent infection by oncogenic viruses, solid tumors and lymphomas. Strategies including cancer vaccines, monoclonal antibodies and virus na...

  3. A Combination Tissue Engineering Strategy for Schwann Cell-Induced Spinal Cord Repair

    Science.gov (United States)

    2016-10-01

    and Biopharmaceutics, 2005. 61(3): p. 171-180. 6. Sellers, D.L., et al., Poly (lactic-co-glycolic) acid microspheres encapsulated in Pluronic F- 127...described (Greiner and Wendorff, 2007; Lee et al., 2011; Weber et al., 2010). 15% (w/v) of poly (vinylidene fluoride trifluoroethylene) (65/35) (PVDF...UK) was administrated twice a day for 3 days immediately after surgery to reduce pain . Gentamycin (APP Pharmaceuticals, LLC, Schaumburg, IL, 40 mg

  4. Whom to Choose as License Partner?

    DEFF Research Database (Denmark)

    Laursen, Keld; Reichstein, Toke; Trombini, Giulia

    2013-01-01

    benefits and obviate issues related to technology transfer and knowledge recombination. At the same time, firms wish to select a partner operating in a different product market to minimize competitive downside issues and to access other product markets, skills and resources. We contend interdependence...... between technology and market forces: if partners are market distant, the likelihood of technology license contractual partnership decreases with partners’ technological distance. Using data on the formation of license partnerships in the global biopharmaceutical industry over the period 1994...

  5. Near-Infrared Imaging for High-Throughput Screening of Moisture-Induced Changes in Freeze-Dried Formulations

    DEFF Research Database (Denmark)

    Trnka, Hjalte; Palou, Anna; Panouillot, Pierre Emanuel

    2014-01-01

    Evaluation of freeze-dried biopharmaceutical formulations requires careful analysis of multiple quality attributes. The aim of this study was to evaluate the use of near-infrared (NIR) imaging for fast analysis of water content and related physical properties in freeze-dried formulations. Model f...... tool for formulation development of freeze-dried samples. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci....

  6. Scalar mixing and strain dynamics methodologies for PIV/LIF measurements of vortex ring flows

    OpenAIRE

    Bouremel, Y.; Ducci, A.

    2017-01-01

    Fluid mixing operations are central to possibly all chemical, petrochemical, and pharmaceutical industries either being related to biphasic blending in polymerisation processes, cell suspension for biopharmaceuticals production, and fractionation of complex oil mixtures. This work aims at providing a fundamental understanding of the mixing and stretching dynamics occurring in a reactor in the presence of a vortical structure, and the vortex ring was selected as a flow paradigm of vortices com...

  7. Plant expression systems, a budding way to confront chikungunya and Zika in developing countries? [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Jaime A. Cardona-Ospina

    2016-08-01

    Full Text Available Plant expression systems could be used as biofactories of heterologous proteins that have the potential to be used with biopharmaceutical aims and vaccine design. This technology is scalable, safe and cost-effective and it has been previously proposed as an option for vaccine and protein pharmaceutical development in developing countries. Here we present a proposal of how plant expression systems could be used to address Zika and chikungunya outbreaks through development of vaccines and rapid diagnostic kits.

  8. The Portuguese Society of Rheumatology position paper on the use of biosimilars

    OpenAIRE

    Fonseca, JE; Gonçalves, J; Araújo, F; Cordeiro, I; Teixeira, F; Canhão, H; Pereira da Silva, JA; Garcês, S; Miranda, LC; Ramiro, Sofia; Roxo, Ana; Pimentel-Santos, FM; Tavares, V; Neto, A; Sepriano, A

    2014-01-01

    Biotechnological drugs have become a fundamental resource for the treatment of rheumatic patients. Patent expiry of some of these drugs created the opportunity for biopharmaceutical manufacturers to develop biosimilar drugs intended to be as efficacious as the originator product but with a lower cost to healthcare systems. Due to the complex manufacturing process and highly intricate structure of biologicals, a biosimilar can never be an exact copy of its reference product. Consequently, regu...

  9. Procedure for the preparation of tritium-labelled insulins. Verfahren zur Herstellung von Tritium-markierten Insulinen

    Energy Technology Data Exchange (ETDEWEB)

    Bienert, M; Haensicke, A; Beyermann, M; Kaufmann, K D; Oehlke, J; Klauschenz, E; Bespalowa, S; Titov, M; Pleiss, U

    1986-12-17

    This invention is concerned with a procedure for the preparation of specific /sup 3/H-labelled insulins with sequences of human, bovine or porcine insulins and without simultaneous chemical modifications of the insulin. On the basis of this procedure a /sup 3/H/sub 2/-Typ (B26)-insulin can be obtained in good yield and purity with a specific radioactivity appropriate to biopharmaceutical and pharmacokinetic purposes in medicine and pharmaceutical industry, resp.

  10. The Effect of Excipients on the Permeability of BCS Class III Compounds and Implications for Biowaivers

    OpenAIRE

    Parr, Alan; Hidalgo, Ismael J.; Bode, Chris; Brown, William; Yazdanian, Mehran; Gonzalez, Mario A.; Sagawa, Kazuko; Miller, Kevin; Jiang, Wenlei; Stippler, Erika S.

    2015-01-01

    Purpose Currently, the FDA allows biowaivers for Class I (high solubility and high permeability) and Class III (high solubility and low permeability) compounds of the Biopharmaceutics Classification System (BCS). Scientific evidence should be provided to support biowaivers for BCS Class I and Class III (high solubility and low permeability) compounds. Methods Data on the effects of excipients on drug permeability are needed to demonstrate that commonly used excipients do not affect the permea...

  11. Modulation of solubility and dissolution of furosemide by preparation of phospholipid complex

    OpenAIRE

    Mona Semalty; Prateeksha Badoni; Devendra Singh; Ajay Semalty

    2014-01-01

    Aim: The aim of this study is to improve the solubility and dissolution of furosemide (a potent high ceiling diuretic used for the treatment of hypertension and a Class IV drug that is low solubility and low permeability drug as per the Biopharmaceutical Classification System) by preparing its phospholipid complexes or pharmacosomes. Materials and Methods: Furosemide was complexed with phosphatidylcholine in four different molar ratios (1:1, 1:2, 1:3 and 1:4) by conventional solvent-evaporati...

  12. Scientific Perspectives on Extending the Provision for Waivers of In vivo Bioavailability and Bioequivalence Studies for Drug Products Containing High Solubility-Low Permeability Drugs (BCS-Class 3)

    OpenAIRE

    Stavchansky, Salomon

    2008-01-01

    Recently, there has been increased interest in extending the provision for waivers of in vivo bioavailability and bioequivalence (BA–BE) studies that appeared in the guidance published by the Food and Drug Administration (FDA) (1) to pharmaceutical products containing Class 3 drugs (High solubility–Low Permeability). The extension of the Biopharmaceutics Classification System (BCS) to Class 3 drugs is meritorious because of its impact on public health policy considerations. The rate limiting ...

  13. In Vitro Bioavailability Study of an Antiviral Compound Enisamium Iodide

    OpenAIRE

    Eleonore Haltner-Ukomadu; Svitlana Gureyeva; Oleksii Burmaka; Andriy Goy; Lutz Mueller; Grygorii Kostyuk; Victor Margitich

    2018-01-01

    An investigation into the biopharmaceutics classification and a study of the in vitro bioavailability (permeability and solubility) of the antiviral compound enisamium iodide (4-(benzylcarbamoyl)-1-methylpyridinium iodide) were carried out. The solubility of enisamium iodide was determined in four different buffers. Apparent intestinal permeability (Papp) of enisamium iodide was assessed using human colon carcinoma (Caco-2) cells at three concentrations. The solubility of enisamium iodide in ...

  14. Effect of Cyclodextrin Complexation on the Aqueous Solubility and Solubility/Dose Ratio of Praziquantel

    OpenAIRE

    Maragos, Stratos; Archontaki, Helen; Macheras, Panos; Valsami, Georgia

    2009-01-01

    Praziquantel (PZQ), the primary drug of choice in the treatment of schistosomiasis, is a highly lipophilic drug that possesses high permeability and low aqueous solubility and is, therefore, classified as a Class II drug according to the Biopharmaceutics Classification System (BCS). In this work, β-cyclodextrin (β-CD) and hydroxypropyl-β-cyclodextrin (HP-β-CD) were used in order to determine whether increasing the aqueous solubility of a drug by complexation with CDs, a BCS-Class II compound ...

  15. Cell factories for a sustainable world

    DEFF Research Database (Denmark)

    Kindtler, Jens William

    2016-01-01

    The Novo Nordisk Foundation Center for Biosustainability (CFB) is a university research center under the Technical University of Denmark within the field of design, engineering and construction of superior cell factories for the production of biopharmaceuticals, anti-infective compounds, industrial......-spectrum inhibitors against multi-drug resistant (MDR) Gram-negative bacterial pathogens using co-Adaptive Laboratory Evolution, 3. Design and engineering of E. coli and Saccharomyces cerevisiae for biobased production of various classes of chemicals. CFB has 230 employees....

  16. Human granulocyte colony-stimulating factor (hG-CSF) expression in plastids of Lactuca sativa.

    Science.gov (United States)

    Sharifi Tabar, Mehdi; Habashi, Ali Akbar; Rajabi Memari, Hamid

    2013-01-01

    Human granulocyte colony-stimulating factor (hG-CSF) can serve as valuable biopharmaceutical for research and treatment of the human blood cancer. Transplastomic plants have been emerged as a new and high potential candidate for production of recombinant biopharmaceutical proteins in comparison with transgenic plants due to extremely high level expression, biosafety and many other advantages. hG-CSF gene was cloned into pCL vector between prrn16S promoter and TpsbA terminator. The recombinant vector was coated on nanogold particles and transformed to lettuce chloroplasts through biolistic method. Callogenesis and regeneration of cotyledonary explants were obtained by Murashige and Skoog media containing 6-benzylaminopurine and 1-naphthaleneacetic acid hormones. The presence of hG-CSF gene in plastome was studied with four specific PCR primers and expression by Western immunoblotting. hG-CSF gene cloning was confirmed by digestion and sequencing. Transplastomic lettuce lines were regenerated and subjected to molecular analysis. The presence of hG-CSF in plastome was confirmed by PCR using specific primers designed from the plastid genome. Western immunoblotting of extracted protein from transplastomic plants showed a 20-kDa band, which verified the expression of recombinant protein in lettuce chloroplasts. This study is the first report that successfully express hG-CSF gene in lettuce chloroplast. The lettuce plastome can provide a cheap and safe expression platform for producing valuable biopharmaceuticals for research and treatment.

  17. The NISTmAb Reference Material 8671 lifecycle management and quality plan.

    Science.gov (United States)

    Schiel, John E; Turner, Abigail

    2018-03-01

    Comprehensive analysis of monoclonal antibody therapeutics involves an ever expanding cadre of technologies. Lifecycle-appropriate application of current and emerging techniques requires rigorous testing followed by discussion between industry and regulators in a pre-competitive space, an effort that may be facilitated by a widely available test metric. Biopharmaceutical quality materials, however, are often difficult to access and/or are protected by intellectual property rights. The NISTmAb, humanized IgG1κ Reference Material 8671 (RM 8671), has been established with the intent of filling that void. The NISTmAb embodies the quality and characteristics of a typical biopharmaceutical product, is widely available to the biopharmaceutical community, and is an open innovation tool for development and dissemination of results. The NISTmAb lifecyle management plan described herein provides a hierarchical strategy for maintenance of quality over time through rigorous method qualification detailed in additional submissions in the current publication series. The NISTmAb RM 8671 is a representative monoclonal antibody material and provides a means to continually evaluate current best practices, promote innovative approaches, and inform regulatory paradigms as technology advances. Graphical abstract The NISTmAb Reference Material (RM) 8671 is intended to be an industry standard monoclonal antibody for pre-competitive harmonization of best practices and designing next generation characterization technologies for identity, quality, and stability testing.

  18. Biomedical applications of yeast- a patent view, part one: yeasts as workhorses for the production of therapeutics and vaccines.

    Science.gov (United States)

    Roohvand, Farzin; Shokri, Mehdi; Abdollahpour-Alitappeh, Meghdad; Ehsani, Parastoo

    2017-08-01

    Yeasts, as Eukaryotes, offer unique features for ease of growth and genetic manipulation possibilities, making it an exceptional microbial host. Areas covered: This review provides general and patent-oriented insights into production of biopharmaceuticals by yeasts. Patents, wherever possible, were correlated to the original or review articles. The review describes applications of major GRAS (generally regarded as safe) yeasts for the production of therapeutic proteins and subunit vaccines; additionally, immunomodulatory properties of yeast cell wall components were reviewed for use of whole yeast cells as a new vaccine platform. The second part of the review will discuss yeast- humanization strategies and innovative applications. Expert opinion: Biomedical applications of yeasts were initiated by utilization of Saccharomyces cerevisiae, for production of leavened (fermented) products, and advanced to serve to produce biopharmaceuticals. Higher biomass production and expression/secretion yields, more similarity of glycosylation patterns to mammals and possibility of host-improvement strategies through application of synthetic biology might enhance selection of Pichia pastoris (instead of S. cerevisiae) as a host for production of biopharmaceutical in future. Immunomodulatory properties of yeast cell wall β-glucans and possibility of intracellular expression of heterologous pathogen/tumor antigens in yeast cells have expanded their application as a new platform, 'Whole Yeast Vaccines'.

  19. Small scale affinity purification and high sensitivity reversed phase nanoLC-MS N-glycan characterization of mAbs and fusion proteins.

    Science.gov (United States)

    Higel, Fabian; Seidl, Andreas; Demelbauer, Uwe; Sörgel, Fritz; Frieß, Wolfgang

    2014-01-01

    N-glycosylation is a complex post-translational modification with potential effects on the efficacy and safety of therapeutic proteins and known influence on the effector function of biopharmaceutical monoclonal antibodies (mAbs). Comprehensive characterization of N-glycosylation is therefore important in biopharmaceutical development. In early development, e.g. during pool or clone selection, however, only minute protein amounts of multiple samples are available for analytics. High sensitivity and high throughput methods are thus needed. An approach based on 96-well plate sample preparation and nanoLC-MS of 2- anthranilic acid or 2-aminobenzoic acid (AA) labeled N-glycans for the characterization of biopharmaceuticals in early development is reported here. With this approach, 192 samples can be processed simultaneously from complex matrices (e.g., cell culture supernatant) to purified 2-AA glycans, which are then analyzed by reversed phase nanoLC-MS. Attomolar sensitivity has been achieved by use of nanoelectrospray ionization, resulting in detailed glycan maps of mAbs and fusion proteins that are exemplarily shown in this work. Reproducibility, robustness and linearity of the approach are demonstrated, making use in a routine manner during pool or clone selection possible. Other potential fields of application, such as glycan biomarker discovery from serum samples, are also presented.

  20. Ectopic expression of human mTOR increases viability, robustness, cell size, proliferation, and antibody production of chinese hamster ovary cells.

    Science.gov (United States)

    Dreesen, Imke A J; Fussenegger, Martin

    2011-04-01

    Engineering of mammalian production cell lines to improve titer and quality of biopharmaceuticals is a top priority of the biopharmaceutical manufacturing industry providing protein therapeutics to patients worldwide. While many engineering strategies have been successful in the past decade they were often based on the over-expression of a single transgene and therefore limited to addressing a single bottleneck in the cell's production capacity. We provide evidence that ectopic expression of the global metabolic sensor and processing protein mammalian target of rapamycin (mTOR), simultaneously improves key bioprocess-relevant characteristics of Chinese hamster ovary (CHO) cell-derived production cell lines such as cell growth (increased cell size and protein content), proliferation (increased cell-cycle progression), viability (decreased apoptosis), robustness (decreased sensitivity to sub-optimal growth factor and oxygen supplies) and specific productivity of secreted human glycoproteins. Cultivation of mTOR-transgenic CHO-derived cell lines engineered for secretion of a therapeutic IgG resulted in antibody titers of up to 50 pg/cell/day, which represents a four-fold increase compared to the parental production cell line. mTOR-based engineering of mammalian production cell lines may therefore have a promising future in biopharmaceutical manufacturing of human therapeutic proteins. Copyright © 2010 Wiley Periodicals, Inc.

  1. A comprehensive screening platform for aerosolizable protein formulations for intranasal and pulmonary drug delivery.

    Science.gov (United States)

    Röhm, Martina; Carle, Stefan; Maigler, Frank; Flamm, Johannes; Kramer, Viktoria; Mavoungou, Chrystelle; Schmid, Otmar; Schindowski, Katharina

    2017-10-30

    Aerosolized administration of biopharmaceuticals to the airways is a promising route for nasal and pulmonary drug delivery, but - in contrast to small molecules - little is known about the effects of aerosolization on safety and efficacy of biopharmaceuticals. Proteins are sensitive against aerosolization-associated shear stress. Tailored formulations can shield proteins and enhance permeation, but formulation development requires extensive screening approaches. Thus, the aim of this study was to develop a cell-based in vitro technology platform that includes screening of protein quality after aerosolization and transepithelial permeation. For efficient screening, a previously published aerosolization-surrogate assay was used in a design of experiments approach to screen suitable formulations for an IgG and its antigen-binding fragment (Fab) as exemplary biopharmaceuticals. Efficient, dose-controlled aerosol-cell delivery was performed with the ALICE-CLOUD system containing RPMI 2650 epithelial cells at the air-liquid interface. We could demonstrate that our technology platform allows for rapid and efficient screening of formulations consisting of different excipients (here: arginine, cyclodextrin, polysorbate, sorbitol, and trehalose) to minimize aerosolization-induced protein aggregation and maximize permeation through an in vitro epithelial cell barrier. Formulations reduced aggregation of native Fab and IgG relative to vehicle up to 50% and enhanced transepithelial permeation rate up to 2.8-fold. Copyright © 2017 The Author(s). Published by Elsevier B.V. All rights reserved.

  2. Prediction of solubility and permeability class membership: provisional BCS classification of the world's top oral drugs.

    Science.gov (United States)

    Dahan, Arik; Miller, Jonathan M; Amidon, Gordon L

    2009-12-01

    The Biopharmaceutics Classification System (BCS) categorizes drugs into one of four biopharmaceutical classes according to their water solubility and membrane permeability characteristics and broadly allows the prediction of the rate-limiting step in the intestinal absorption process following oral administration. Since its introduction in 1995, the BCS has generated remarkable impact on the global pharmaceutical sciences arena, in drug discovery, development, and regulation, and extensive validation/discussion/extension of the BCS is continuously published in the literature. The BCS has been effectively implanted by drug regulatory agencies around the world in setting bioavailability/bioequivalence standards for immediate-release (IR) oral drug product approval. In this review, we describe the BCS scientific framework and impact on regulatory practice of oral drug products and review the provisional BCS classification of the top drugs on the global market. The Biopharmaceutical Drug Disposition Classification System and its association with the BCS are discussed as well. One notable finding of the provisional BCS classification is that the clinical performance of the majority of approved IR oral drug products essential for human health can be assured with an in vitro dissolution test, rather than empirical in vivo human studies.

  3. A practical discussion of risk management for manufacturing of pharmaceutical products.

    Science.gov (United States)

    Mollah, A Hamid; Baseman, Harold S; Long, Mike; Rathore, Anurag S

    2014-01-01

    Quality risk management (QRM) is now a regulatory expectation, and it makes good business sense. The goal of the risk assessment is to increase process understanding and deliver safe and effective product to the patients. Risk analysis and management is an acceptable and effective way to minimize patient risk and determine the appropriate level of controls in manufacturing. While understanding the elements of QRM is important, knowing how to apply them in the manufacturing environment is essential for effective process performance and control. This article will preview application of QRM in pharmaceutical and biopharmaceutical manufacturing to illustrate how QRM can help the reader achieve that objective. There are several areas of risk that a drug company may encounter in pharmaceutical manufacturing, specifically addressing oral solid and liquid formulations. QRM tools can be used effectively to identify the risks and develop strategy to minimize or control them. Risks are associated throughout the biopharmaceutical manufacturing process-from raw material supply through manufacturing and filling operations to final distribution via a controlled cold chain process. Assessing relevant attributes and risks for biotechnology-derived products is more complicated and challenging for complex pharmaceuticals. This paper discusses key risk factors in biopharmaceutical manufacturing. Successful development and commercialization of pharmaceutical products is all about managing risks. If a company was to take zero risk, most likely the path to commercialization would not be commercially viable. On the other hand, if the risk taken was too much, the product is likely to have a suboptimal safety and efficacy profile and thus is unlikely to be a successful product. This article addresses the topic of quality risk management with the key objective of minimizing patient risk while creating an optimal process and product. Various tools are presented to aid implementation of these

  4. Interactions between Therapeutic Proteins and Acrylic Acid Leachable.

    Science.gov (United States)

    Liu, Dengfeng; Nashed-Samuel, Yasser; Bondarenko, Pavel V; Brems, David N; Ren, Da

    2012-01-01

    Leachables are chemical compounds that migrate from manufacturing equipment, primary containers and closure systems, and packaging components into biopharmaceutical and pharmaceutical products. Acrylic acid (at concentration around 5 μg/mL) was detected as leachable in syringes from one of the potential vendors (X syringes). In order to evaluate the potential impact of acrylic acid on therapeutic proteins, an IgG 2 molecule was filled into a sterilized X syringe and then incubated at 45 °C for 45 days in a pH 5 acetate buffer. We discovered that acrylic acid can interact with proteins at three different sites: (1) the lysine side chain, (2) the N-terminus, and (3) the histidine side chain, by the Michael reaction. In this report, the direct interactions between acrylic acid leachable and a biopharmaceutical product were demonstrated and the reaction mechanism was proposed. Even thought a small amount (from 0.02% to 0.3%) of protein was found to be modified by acrylic acid, the modified protein can potentially be harmful due to the toxicity of acrylic acid. After being modified by acrylic acid, the properties of the therapeutic protein may change due to charge and hydrophobicity variations. Acrylic acid was detected to migrate from syringes (Vendor X) into a therapeutic protein solution (at a concentration around 5 μg/mL). In this study, we discovered that acrylic acid can modify proteins at three different sites: (1) the lysine side chain, 2) the N-terminus, and 3) the histidine side chain, by the Michael reaction. In this report, the direct interactions between acrylic acid leachable and a biopharmaceutical product were demonstrated and the reaction mechanism was proposed.

  5. Embryo-fetal transfer of bevacizumab (Avastin) in the rat over the course of gestation and the impact of neonatal Fc receptor (FcRn) binding.

    Science.gov (United States)

    Thorn, Mitchell; Piche-Nicholas, Nicole; Stedman, Donald; Davenport, Scott W; Zhang, Ning; Collinge, Mark; Bowman, Christopher J

    2012-10-01

    There is concern about embryo-fetal exposure to antibody-based biopharmaceuticals based on the increase of such therapies being prescribed to women of childbearing potential. Therefore, there is a desire to better characterize embryo-fetal exposure of these molecules. The pregnant rat is a standard model for evaluating the potential consequences of exposure but placental transfer of antibody-based biopharmaceuticals is not well understood in this model. The relative embryo-fetal distribution of an antibody-based biopharmaceutical was evaluated in the rat. Bevacizumab (Avastin) was chosen as a tool antibody since it does not have significant target binding in the rat that might influence embryo-fetal biodistribution. Avastin was labeled with a fluorescent dye, characterized, and injected into pregnant rats at different gestation ages. Labeled Avastin in fetal tissues was visualized ex vivo using an IVIS 200 (Caliper, A PerkinElmer Company, Alameda, CA). Avastin localized to the fetus as early as 24-hr post intravenous injection of the dam, and was taken up by the fetus in a dose-dependent manner. Avastin was detectable in the developing embryo as early as gestation day 13 and continued to be transferred until the end of gestation. Fetal transfer of Avastins mutated in the portion of the antibody that binds the neonatal Fc receptor (FcRn) was tested in late gestation and was found to correlate with affinities of the mutant Avastin antibody to FcRn. The novel application of this imaging technology was used to characterize the onset and duration of Avastin maternal-fetal transfer in rats and the importance of FcRn binding. © 2012 Wiley Periodicals, Inc.

  6. Biosimilar medicines and cost-effectiveness

    Directory of Open Access Journals (Sweden)

    Steven Simoens

    2011-02-01

    Full Text Available Steven SimoensResearch Centre for Pharmaceutical Care and Pharmaco-economics, Faculty of Pharmaceutical Sciences, Katholieke Universiteit Leuven, Leuven, BelgiumAbstract: Given that biosimilars are agents that are similar but not identical to the reference biopharmaceutical, this study aims to introduce and describe specific issues related to the economic evaluation of biosimilars by focusing on the relative costs, relative effectiveness, and cost-effectiveness of biosimilars. Economic evaluation assesses the cost-effectiveness of a medicine by comparing the costs and outcomes of a medicine with those of a relevant comparator. The assessment of cost-effectiveness of a biosimilar is complicated by the fact that evidence needed to obtain marketing authorization from a registration authority does not always correspond to the data requirements of a reimbursement authority. In particular, this relates to the availability of adequately powered equivalence or noninferiority studies, the need for comparative data about the effectiveness in a real-world setting rather than the efficacy in a structured setting, and the use of health outcome measures instead of surrogate endpoints. As a biosimilar is likely to be less expensive than the comparator (eg, the reference biopharmaceutical, the assessment of the cost-effectiveness of a biosimilar depends on the relative effectiveness. If appropriately designed and powered clinical studies demonstrate equivalent effectiveness between a biosimilar and the comparator, then a cost-minimization analysis identifies the least expensive medicine. If there are differences in the effectiveness of a biosimilar and the comparator, other techniques of economic evaluation need to be employed, such as cost-effectiveness analysis or cost-utility analysis. Given that there may be uncertainty surrounding the long-term safety (ie, risk of immunogenicity and rare adverse events and effectiveness of a biosimilar, the cost

  7. The Patient's Voice in Pharmacovigilance: Pragmatic Approaches to Building a Patient-Centric Drug Safety Organization.

    Science.gov (United States)

    Smith, Meredith Y; Benattia, Isma

    2016-09-01

    Patient-centeredness has become an acknowledged hallmark of not only high-quality health care but also high-quality drug development. Biopharmaceutical companies are actively seeking to be more patient-centric in drug research and development by involving patients in identifying target disease conditions, participating in the design of, and recruitment for, clinical trials, and disseminating study results. Drug safety departments within the biopharmaceutical industry are at a similar inflection point. Rising rates of per capita prescription drug use underscore the importance of having robust pharmacovigilance systems in place to detect and assess adverse drug reactions (ADRs). At the same time, the practice of pharmacovigilance is being transformed by a host of recent regulatory guidances and related initiatives which emphasize the importance of the patient's perspective in drug safety. Collectively, these initiatives impact the full range of activities that fall within the remit of pharmacovigilance, including ADR reporting, signal detection and evaluation, risk management, medication error assessment, benefit-risk assessment and risk communication. Examples include the fact that manufacturing authorization holders are now expected to monitor all digital sources under their control for potential reports of ADRs, and the emergence of new methods for collecting, analysing and reporting patient-generated ADR reports for signal detection and evaluation purposes. A drug safety department's ability to transition successfully into a more patient-centric organization will depend on three defining attributes: (1) a patient-centered culture; (2) deployment of a framework to guide patient engagement activities; and (3) demonstrated proficiency in patient-centered competencies, including patient engagement, risk communication and patient preference assessment. Whether, and to what extent, drug safety departments embrace the new patient-centric imperative, and the methods and

  8. Improvement of intestinal absorption of forsythoside A and chlorogenic acid by different carboxymethyl chitosan and chito-oligosaccharide, application to Flos Lonicerae-Fructus Forsythiae herb couple preparations.

    Directory of Open Access Journals (Sweden)

    Wei Zhou

    Full Text Available The current study aims to investigate the effect of chitosan derivatives on the intestinal absorption and bioavailabilities of forsythoside A (FTA and Chlorogenic acid (CHA, the major active components in Flos Lonicerae-Fructus Forsythiae herb couple. Biopharmaceutics and pharmacokinetics properties of the two compounds have been characterized in vitro, in situ as well as in rats. Based on the identified biopharmaceutics characteristics of the two compounds, the effect of chitosan derivatives as an absorption enhancer on the intestinal absorption and pharmacokinetics of FTA and CHA in pure compound form as well as extract form were investigated in vitro, in situ and in vivo. Both FTA and CHA demonstrated very limited intestinal permeabilities, leading to oral bioavailabilities being only 0.50% and 0.13% in rats, respectively. Results from both in vitro, in situ as well as in vivo studies consistently indicated that Chito-oligosaccharide (COS at dosage of 25 mg/kg could enhance intestinal permeabilities significantly as well as the in vivo bioavailabilities of both FTA and CHA than CMCs in Flos Lonicerae-Fructus Forsythiae herb couple preparations, and was safe for gastrointestine from morphological observation. Besides, treatment with Flos Lonicerae-Fructus Forsythiae herb couple preparations with COS at the dosage of 25 mg/kg prevented MDCK damage after influenza virus propagation, which was significantly better than control. The current findings not only identified the usefulness of COS for the improved delivery of Flos Lonicerae-Fructus Forsythiae preparations but also demonstrated the importance of biopharmaceutical characterization in the dosage form development of traditional Chinese medicine.

  9. A system identification approach for developing model predictive controllers of antibody quality attributes in cell culture processes.

    Science.gov (United States)

    Downey, Brandon; Schmitt, John; Beller, Justin; Russell, Brian; Quach, Anthony; Hermann, Elizabeth; Lyon, David; Breit, Jeffrey

    2017-11-01

    As the biopharmaceutical industry evolves to include more diverse protein formats and processes, more robust control of Critical Quality Attributes (CQAs) is needed to maintain processing flexibility without compromising quality. Active control of CQAs has been demonstrated using model predictive control techniques, which allow development of processes which are robust against disturbances associated with raw material variability and other potentially flexible operating conditions. Wide adoption of model predictive control in biopharmaceutical cell culture processes has been hampered, however, in part due to the large amount of data and expertise required to make a predictive model of controlled CQAs, a requirement for model predictive control. Here we developed a highly automated, perfusion apparatus to systematically and efficiently generate predictive models using application of system identification approaches. We successfully created a predictive model of %galactosylation using data obtained by manipulating galactose concentration in the perfusion apparatus in serialized step change experiments. We then demonstrated the use of the model in a model predictive controller in a simulated control scenario to successfully achieve a %galactosylation set point in a simulated fed-batch culture. The automated model identification approach demonstrated here can potentially be generalized to many CQAs, and could be a more efficient, faster, and highly automated alternative to batch experiments for developing predictive models in cell culture processes, and allow the wider adoption of model predictive control in biopharmaceutical processes. © 2017 The Authors Biotechnology Progress published by Wiley Periodicals, Inc. on behalf of American Institute of Chemical Engineers Biotechnol. Prog., 33:1647-1661, 2017. © 2017 The Authors Biotechnology Progress published by Wiley Periodicals, Inc. on behalf of American Institute of Chemical Engineers.

  10. Telomerase as an emerging target to fight cancer--opportunities and challenges for nanomedicine.

    Science.gov (United States)

    Philippi, C; Loretz, B; Schaefer, U F; Lehr, C M

    2010-09-01

    Telomerase as an enzyme is responsible for the renewal of the chromosomal ends, the so-called telomeres. By preventing them from shortening with each cell cycle, telomerase is able to inhibit cellular senescence and apoptosis. Telomerase activity, which is detectable in the majority of cancer cells, allows them to maintain their proliferative capacity. The thus obtained immortality of those cells again is a key to their malignancy. Based on these discoveries, it is obvious that telomerase inhibitors would represent an innovative approach to fight cancer, and a variety of such candidate molecules are currently in the pipeline. Telomerase inhibitors largely fall in two classes of compounds: small synthetic molecules and nucleotide-based biologicals. For several candidates, some proof of concept studies have been demonstrated, either on cell cultures or in animal models. But the same studies also revealed that inefficient delivery is largely limiting the translational step into the clinic. The most appealing feature of telomerase inhibitors, which distinguishes them from conventional anticancer drugs, is probably seen in their intrinsic non-toxicity to normal cells. Nevertheless, efficient delivery to the target cells, i.e. to the tumor, is still required. Here, some well-known biopharmaceutical problems such as insufficient solubility, permeability or even metabolic stability are frequently encountered. To address these challenges, there is a clear need for adequate delivery technologies, for example by using nanomedicines, that would allow to overcome their biopharmaceutical shortcomings and to warrant a sufficient bioavailability at the target side. This review first briefly explains the concept of telomerase and telomerase inhibition in cancer therapy. It secondly aims to provide an overview of the different currently known telomerase inhibitors. Finally, the biopharmaceutical limitations of these molecules are discussed as well as the possibilities to overcome

  11. Depth Filters Containing Diatomite Achieve More Efficient Particle Retention than Filters Solely Containing Cellulose Fibers.

    Science.gov (United States)

    Buyel, Johannes F; Gruchow, Hannah M; Fischer, Rainer

    2015-01-01

    The clarification of biological feed stocks during the production of biopharmaceutical proteins is challenging when large quantities of particles must be removed, e.g., when processing crude plant extracts. Single-use depth filters are often preferred for clarification because they are simple to integrate and have a good safety profile. However, the combination of filter layers must be optimized in terms of nominal retention ratings to account for the unique particle size distribution in each feed stock. We have recently shown that predictive models can facilitate filter screening and the selection of appropriate filter layers. Here we expand our previous study by testing several filters with different retention ratings. The filters typically contain diatomite to facilitate the removal of fine particles. However, diatomite can interfere with the recovery of large biopharmaceutical molecules such as virus-like particles and aggregated proteins. Therefore, we also tested filtration devices composed solely of cellulose fibers and cohesive resin. The capacities of both filter types varied from 10 to 50 L m(-2) when challenged with tobacco leaf extracts, but the filtrate turbidity was ~500-fold lower (~3.5 NTU) when diatomite filters were used. We also tested pre-coat filtration with dispersed diatomite, which achieved capacities of up to 120 L m(-2) with turbidities of ~100 NTU using bulk plant extracts, and in contrast to the other depth filters did not require an upstream bag filter. Single pre-coat filtration devices can thus replace combinations of bag and depth filters to simplify the processing of plant extracts, potentially saving on time, labor and consumables. The protein concentrations of TSP, DsRed and antibody 2G12 were not affected by pre-coat filtration, indicating its general applicability during the manufacture of plant-derived biopharmaceutical proteins.

  12. Depth filters containing diatomite achieve more efficient particle retention than filters solely containing cellulose fibers

    Directory of Open Access Journals (Sweden)

    Johannes Felix Buyel

    2015-12-01

    Full Text Available The clarification of biological feed stocks during the production of biopharmaceutical proteins is challenging when large quantities of particles must be removed, e.g. when processing crude plant extracts. Single-use depth filters are often preferred for clarification because they are simple to integrate and have a good safety profile. However, the combination of filter layers must be optimized in terms of nominal retention ratings to account for the unique particle size distribution in each feed stock. We have recently shown that predictive models can facilitate filter screening and the selection of appropriate filter layers. Here we expand our previous study by testing several filters with different retention ratings. The filters typically contain diatomite to facilitate the removal of fine particles. However, diatomite can interfere with the recovery of large biopharmaceutical molecules such as virus-like particles and aggregated proteins. Therefore, we also tested filtration devices composed solely of cellulose fibers and cohesive resin. The capacities of both filter types varied from 10 to 50 L m-2 when challenged with tobacco leaf extracts, but the filtrate turbidity was ~500-fold lower (~3.5 NTU when diatomite filters were used. We also tested pre coat filtration with dispersed diatomite, which achieved capacities of up to 120 L m-2 with turbidities of ~100 NTU using bulk plant extracts, and in contrast to the other depth filters did not require an upstream bag filter. Single pre-coat filtration devices can thus replace combinations of bag and depth filters to simplify the processing of plant extracts, potentially saving on time, labor and consumables. The protein concentrations of TSP, DsRed and antibody 2G12 were not affected by pre-coat filtration, indicating its general applicability during the manufacture of plant-derived biopharmaceutical proteins.

  13. Solid dispersions enhance solubility, dissolution, and permeability of thalidomide.

    Science.gov (United States)

    Barea, Silvana A; Mattos, Cristiane B; Cruz, Ariadne C C; Chaves, Vitor C; Pereira, Rafael N; Simões, Claudia M O; Kratz, Jadel M; Koester, Letícia S

    2017-03-01

    Thalidomide (THD) is a BCS class II drug with renewed and growing therapeutic applicability. Along with the low aqueous solubility, additional poor biopharmaceutical properties of the drug, i.e. chemical instability, high crystallinity, and polymorphism, lead to a slow and variable oral absorption. In this view, we developed solid dispersions (SDs) containing THD dispersed in different self-emulsifying carriers aiming at an enhanced absorption profile for the drug. THD was dispersed in lauroyl macrogol-32 glycerides (Gelucire ® 44/14) and α-tocopherol polyethylene glycol succinate (Kolliphor ® TPGS), in the presence or absence of the precipitation inhibitor polyvinylpyrrolidone K30 (PVP K30), by means of the solvent method. Physicochemical analysis revealed the formation of semicrystalline SDs. X-ray diffraction and infrared spectroscopy analyses suggest that the remaining crystalline fraction of the drug in the SDs did not undergo polymorphic transition. The impact of the solubility-enhancing formulations on the THD biopharmaceutical properties was evaluated by several in vitro techniques. The developed SDs were able to increase the apparent solubility of the drug (up to 2-3x the equilibrium solubility) for a least 4 h. Dissolution experiments (paddle method, 75 rpm) in different pHs showed that around 80% of drug dissolved after 120 min (versus 40% of pure crystalline drug). Additionally, we demonstrated the enhanced solubility obtained via SDs could be translated into increased flux in a parallel artificial membrane permeability assay (PAMPA). In summary, the results demonstrate that SDs could be considered an interesting and unexplored strategy to improve the biopharmaceutical properties of THD, since SDs of this important drug have yet to be reported.

  14. Current landscape of protein glycosylation analysis and recent progress toward a novel paradigm of glycoscience research.

    Science.gov (United States)

    Yamamoto, Sachio; Kinoshita, Mitsuhiro; Suzuki, Shigeo

    2016-10-25

    This review covers the basics and some applications of methodologies for the analysis of glycoprotein glycans. Analytical techniques used for glycoprotein glycans, including liquid chromatography (LC), capillary electrophoresis (CE), mass spectrometry (MS), and high-throughput analytical methods based on microfluidics, were described to supply the essentials about biopharmaceutical and biomarker glycoproteins. We will also describe the MS analysis of glycoproteins and glycopeptides as well as the chemical and enzymatic releasing methods of glycans from glycoproteins and the chemical reactions used for the derivatization of glycans. We hope the techniques have accommodated most of the requests from glycoproteomics researchers. Copyright © 2016 Elsevier B.V. All rights reserved.

  15. The emerging CHO systems biology era: harnessing the ‘omics revolution for biotechnology

    DEFF Research Database (Denmark)

    Kildegaard, Helene Faustrup; Baycin-Hizal, Deniz; Lewis, Nathan

    2013-01-01

    into mathematical models that describe CHO phenotypes will provide crucial biotechnology insights. As ‘omics technologies and computational systems biology mature, genome-scale approaches will lead to major innovations in cell line development and metabolic engineering, thereby improving protein production......Chinese hamster ovary (CHO) cells are the primary factories for biopharmaceuticals because of their capacity to correctly fold and post-translationally modify recombinant proteins compatible with humans. New opportunities are arising to enhance these cell factories, especially since the CHO-K1 cell...

  16. Improving the prediction of the brain disposition for orally administered drugs using BDDCS

    DEFF Research Database (Denmark)

    Broccatelli, Fabio; Larregieu, Caroline A.; Cruciani, Gabriele

    2012-01-01

    outcome. Passive permeability and P-glycoprotein (Pgp, ABCB1) efflux have been successfully recognized to impact xenobiotic extrusion from the brain, as Pgp is known to play a role in limiting the BBB penetration of oral drugs in humans. However, these two properties alone fail to explain the BBB...... penetration for a significant number of marketed central nervous system (CNS) agents. The Biopharmaceutics Drug Disposition Classification System (BDDCS) has proved useful in predicting drug disposition in the human body, particularly in the liver and intestine. Here we discuss the value of using BDDCS...

  17. Managing Innovation to Maximize Value Along the Discovery-Translation-Application Continuum.

    Science.gov (United States)

    Waldman, S A; Terzic, A

    2017-01-01

    Success in pharmaceutical development led to a record 51 drugs approved in the past year, surpassing every previous year since 1950. Technology innovation enabled identification and exploitation of increasingly precise disease targets ensuring next generation diagnostic and therapeutic products for patient management. The expanding biopharmaceutical portfolio stands, however, in contradistinction to the unsustainable costs that reflect remarkable challenges of clinical development programs. This annual Therapeutic Innovations issue juxtaposes advances in translating molecular breakthroughs into transformative therapies with essential considerations for lowering attrition and improving the cost-effectiveness of the drug-development paradigm. Realizing the discovery-translation-application continuum mandates a congruent approval, adoption, and access triad. © 2016 ASCPT.

  18. “Inclonals”: IgGs and IgG-enzyme fusion proteins produced in an E. coli expression-refolding system

    OpenAIRE

    Hakim, Rahely; Benhar, Itai

    2009-01-01

    Full-length antibodies and antibodies that ferry a cargo to target cells are desired biopharmaceuticals. We describe the production of full-length IgGs and IgG-toxin fusion proteins in E. coli. In the presented examples of anti CD30 and anti EGF-receptor antibodies, the antibody heavy and light chains or toxin fusions thereof were expressed in separate bacterial cultures, where they accumulated as insoluble inclusion bodies. Following refolding and purification, high yields (up to 50 mg/L of ...

  19. Validación de un método analítico empleando cromatografía líquida de alta eficiencia para la determinación de ibuprofeno en medios biorrelevantes Validation of an analytical method by liquid chromatography for determination of ibuprofen in biorelevant media

    Directory of Open Access Journals (Sweden)

    Sandra M. Gómez

    2010-01-01

    Full Text Available An analytical method by liquid chromatography has been proposed and validated to study the apparent solubility of ibuprofen in biorelevant dissolution media. The main properties of the studied media were pH values of 5.0 and 6.5 and the presence or absence of some natural surfactant agents. The parameters evaluated were specificity, linearity, precision, accuracy, and detection and quantification limits, as well as the drug stability under the analysis conditions. The developed method was useful to determine the apparent solubility of this drug as a function of temperature and surfactants concentration to demonstrate the validity of the Biopharmaceutics Classification System.

  20. FDA Approves Immunotherapy for a Cancer that Affects Infants and Children | Poster

    Science.gov (United States)

    By Frank Blanchard, Staff Writer The U.S. Food and Drug Administration (FDA) recently approved dinutuximab (ch14.18) as an immunotherapy for neuroblastoma, a rare type of childhood cancer that offers poor prognosis for about half of the children who are affected. The National Cancer Institute’s (NCI) Biopharmaceutical Development Program (BDP) at the Frederick National Laboratory for Cancer Research produced ch14.18 for the NCI-sponsored clinical trials that proved the drug’s effectiveness against the disease.

  1. Nanoemulsões como sistemas de liberação parenteral de fármacos

    Directory of Open Access Journals (Sweden)

    Fernanda Bruxel

    2012-01-01

    Full Text Available Lipid nanoemulsions have recently been proposed as parenteral delivery systems for poorly-soluble drugs. These systems consist of nanoscale oil/water dispersions stabilized by an appropriate surfactant system in which the drug is incorporated into the oil core and/or adsorbed at the interface. This article reviews technological aspects of such nanosystems, including their composition, preparation methods, and physicochemical properties. From this review, it was possible to identify five groups of nanoemulsions based on their composition. Biopharmaceutical aspects of formulations containing some commercially available drugs (diazepam, propofol, dexamethasone, etomidate, flurbiprofen and prostaglandin E1 were then discussed.

  2. Yeast biotechnology: teaching the old dog new tricks

    Science.gov (United States)

    2014-01-01

    Yeasts are regarded as the first microorganisms used by humans to process food and alcoholic beverages. The technology developed out of these ancient processes has been the basis for modern industrial biotechnology. Yeast biotechnology has gained great interest again in the last decades. Joining the potentials of genomics, metabolic engineering, systems and synthetic biology enables the production of numerous valuable products of primary and secondary metabolism, technical enzymes and biopharmaceutical proteins. An overview of emerging and established substrates and products of yeast biotechnology is provided and discussed in the light of the recent literature. PMID:24602262

  3. Pharmaceutical Cocrystals: New Solid Phase Modification Approaches for the Formulation of APIs

    Directory of Open Access Journals (Sweden)

    Anna Karagianni

    2018-01-01

    Full Text Available Cocrystals can be used as an alternative approach based on crystal engineering to enhance specific physicochemical and biopharmaceutical properties of active pharmaceutical ingredients (APIs when the approaches to salt or polymorph formation do not meet the expected targets. In this article, an overview of pharmaceutical cocrystals will be presented, with an emphasis on the intermolecular interactions in cocrystals and the methods for their preparation. Furthermore, cocrystals of direct pharmaceutical interest, along with their in vitro properties and available in vivo data and characterization techniques are discussed, highlighting the potential of cocrystals as an attractive route for drug development.

  4. Pharmaceutical Cocrystals: New Solid Phase Modification Approaches for the Formulation of APIs.

    Science.gov (United States)

    Karagianni, Anna; Malamatari, Maria; Kachrimanis, Kyriakos

    2018-01-25

    Cocrystals can be used as an alternative approach based on crystal engineering to enhance specific physicochemical and biopharmaceutical properties of active pharmaceutical ingredients (APIs) when the approaches to salt or polymorph formation do not meet the expected targets. In this article, an overview of pharmaceutical cocrystals will be presented, with an emphasis on the intermolecular interactions in cocrystals and the methods for their preparation. Furthermore, cocrystals of direct pharmaceutical interest, along with their in vitro properties and available in vivo data and characterization techniques are discussed, highlighting the potential of cocrystals as an attractive route for drug development.

  5. Internalization, Trafficking, Intracellular Processing and Actions of Antibody-Drug Conjugates.

    Science.gov (United States)

    Xu, Shi

    2015-11-01

    This review discusses the molecular mechanism involved in the targeting and delivery of antibody-drug conjugates (ADCs), the new class of biopharmaceuticals mainly designed for targeted cancer therapy. this review goes over major progress in preclinical and clinical studies of ADCs, in the past 5 years. The pharmacokinetics and pharmacodynamics of ADCs involve multiple mechanisms, including internalization of ADCs by target cells, intracellular trafficking, release of conjugated drugs, and payload. These mechanisms actually jointly determine the efficacy of ADCs. Therefore, the optimization of ADCs should take them as necessary rationales.

  6. Solid Phospholipid Dispersions for Oral Delivery of Poorly Soluble Drugs

    DEFF Research Database (Denmark)

    Fong, Sophia Yui Kau; Martins, Susana A. M.; Brandl, Martin

    2016-01-01

    Celecoxib (CXB) is a Biopharmaceutical Classification System class II drug in which its oral bioavailability is limited by poor aqueous solubility. Although a range of formulations aiming to increase the solubility of CXB have been developed, it is not completely understood, whether (1) an increase...... the importance of evaluating both, solubility and permeability, and the use of biorelevant medium for testing the candidate-enabling performance of liposomal formulations. Mechanisms at molecular level that may explain the effect of PL formulations on the permeability of CXB are also discussed....

  7. Brief Note on the Development of Biotechnology

    Directory of Open Access Journals (Sweden)

    Karl Bayer

    2014-01-01

    Full Text Available Biotechnology, with the main applications in food and nutrition, dates back to the early times of mankind. In the recent decades the progress in natural sciences, mathematics and computer science has led to a new branch termed molecular biotechnology, which finally developed as an autonomous scientific discipline. The field of biotechnology, in the past generally empirically driven, now largely benefits from molecular biotechnology by improved systems, knowledge and understanding. Thereby, compliance with the recently published initiatives of the regulatory authorities to accelerate the approval process for the manufacturing of biopharmaceuticals can be gained.

  8. The Innovative Medicines Initiative moves translational immunology forward.

    Science.gov (United States)

    Goldman, Michel; Wittelsberger, Angela; De Magistris, Maria-Teresa

    2013-02-01

    The Innovative Medicines Initiative (IMI) was established in 2008 as a public-private partnership between the European Union and the European Federation of Pharmaceutical Industries and Associations with the mission to promote the development of novel therapies through collaborative efforts based on the concept of pre-competitive research. Several consortia supported by IMI are dedicated to immuno-inflammatory disorders, immune-based biopharmaceuticals and vaccines. Herein, we present the key principles underlying IMI, briefly review the status of projects related to translational immunology, and present future topics of interest to immunologists.

  9. Reconceptualizing cancer immunotherapy based on plant production systems

    Science.gov (United States)

    Hefferon, Kathleen

    2017-01-01

    Plants can be used as inexpensive and facile production platforms for vaccines and other biopharmaceuticals. More recently, plant-based biologics have expanded to include cancer immunotherapy agents. The following review describes the current state of the art for plant-derived strategies to prevent or reduce cancers. The review discusses avenues taken to prevent infection by oncogenic viruses, solid tumors and lymphomas. Strategies including cancer vaccines, monoclonal antibodies and virus nanoparticles are described, and examples are provided. The review ends with a discussion of the implications of plant-based cancer immunotherapy for developing countries. PMID:28884013

  10. A novel sensitive sheathless CE-MS device for peptide and protein analysis

    DEFF Research Database (Denmark)

    Nguyen, Tam T. T. N.; Petersen, Nickolaj J.; Rand, Kasper Dyrberg

    analysis. By analysis of a model peptide (Leucine Enkephalin), a limit of detection (LOD) of 0.045 pmol/µL (corresponding to 67 attomol in a sample volume of ~ 15 nL) was obtained. The merit of the CE-MS approach was demonstrated by analysis of bovine serum albumin (BSA) tryptic peptides. A well......Ab (Rituximab) suggesting significant real-world applicability in biopharmaceutical research. Finally, by employing a native CE buffer (ammonium acetate, pH 6), we show that the CE-MS interface facilitates gentle ESI of proteins, opening up for native MS applications in combination with ion mobility and other...

  11. Yeast biotechnology: teaching the old dog new tricks.

    Science.gov (United States)

    Mattanovich, Diethard; Sauer, Michael; Gasser, Brigitte

    2014-03-06

    Yeasts are regarded as the first microorganisms used by humans to process food and alcoholic beverages. The technology developed out of these ancient processes has been the basis for modern industrial biotechnology. Yeast biotechnology has gained great interest again in the last decades. Joining the potentials of genomics, metabolic engineering, systems and synthetic biology enables the production of numerous valuable products of primary and secondary metabolism, technical enzymes and biopharmaceutical proteins. An overview of emerging and established substrates and products of yeast biotechnology is provided and discussed in the light of the recent literature.

  12. Clinical Case of Tocilizumab Use in a Patient with Systemic Juvenile Idiopathic Arthritis

    Directory of Open Access Journals (Sweden)

    Y. M. Spivakovskiy

    2015-01-01

    Full Text Available The article presents a case of using genetically engineered biopharmaceutical tocilizumab in a child with systemic juvenile idiopathic arthritis. On the initial stage, the treatment was characterized by resistance to high doses of glucocorticoids and cytostatic drugs. Successful termination of visceral and articular manifestations of systemic juvenile idiopathic arthritis and normalization of laboratory indicators of disease activity in the setting of use of interleukin 6 receptor blocker were described. We observed stable improvement of the child’s condition during a year-long follow-up in the setting of the selected anti-inflammatory therapy pattern. 

  13. Self-Assembled Hydrogel Nanoparticles for Drug Delivery Applications

    Directory of Open Access Journals (Sweden)

    Miguel Gama

    2010-02-01

    Full Text Available Hydrogel nanoparticles—also referred to as polymeric nanogels or macromolecular micelles—are emerging as promising drug carriers for therapeutic applications. These nanostructures hold versatility and properties suitable for the delivery of bioactive molecules, namely of biopharmaceuticals. This article reviews the latest developments in the use of self-assembled polymeric nanogels for drug delivery applications, including small molecular weight drugs, proteins, peptides, oligosaccharides, vaccines and nucleic acids. The materials and techniques used in the development of self-assembling nanogels are also described.

  14. Immunogenicity of Anti-TNF-α Biotherapies

    DEFF Research Database (Denmark)

    Bendtzen, Klaus

    2015-01-01

    % of patients do not respond and about 50% of those who do loose response with time. Furthermore, safety may be compromised by immunogenicity with the induction of anti-drug-antibodies (ADA). Assessment of drug pharmacokinetics and ADA is increasingly recognized as a requirement for safe and rational use...... article - and the accompanying article - is to discuss the reasons for recommending assessments of circulating drug and ADA levels in patients treated with anti-TNF biopharmaceuticals and to detail some of the methodological issues that obscure cost-effective and safer therapies....

  15. ANTIMICROBIAL PROPERTIES OF PLEUROTUS ERYNGII AND LENTINUS EDODES HYDRO-ALCOHOLIC EXTRACTS

    Directory of Open Access Journals (Sweden)

    Gabriela Popa

    2016-11-01

    Full Text Available Besides superior nutritional values mushrooms posed significant medicinal properties. Hydro-alcoholic extracts of several isolates of Pleurotus eryngii and Lentinus edodes mushroom species were investigated for their antimicrobial activities against pathogenic microorganisms with medicinal importance. Antimicrobial activities of the extracts were evaluated by the agar disk diffusion method. Results revealed that the 70% ethylic alcohol extracts have significant inhibitory activities against Bacillus subtilis var. spizizinii, Escherichia coli and Staphylococcus aureus. The results showed that the 70% ethanol extracts of Pleurotus eryngii and Lentinus edodes mushroom isolates may have biopharmaceutical potentiality.

  16. Quantification of protein concentration using UV absorbance and Coomassie dyes.

    Science.gov (United States)

    Noble, James E

    2014-01-01

    The measurement of a solubilized protein concentration in solution is an important assay in biochemistry research and development labs for applications ranging from enzymatic studies to providing data for biopharmaceutical lot release. Spectrophotometric protein quantification assays are methods that use UV and visible spectroscopy to rapidly determine the concentration of protein, relative to a standard, or using an assigned extinction coefficient. Where multiple samples need measurement, and/or the sample volume and concentration is limited, preparations of the Coomassie dye commonly known as the Bradford assay can be used. © 2014 Elsevier Inc. All rights reserved.

  17. Whom to Choose as License Partner?

    DEFF Research Database (Denmark)

    Laursen, Keld; Reichstein, Toke; Trombini, Giulia

    2013-01-01

    between technology and market forces: if partners are market distant, the likelihood of technology license contractual partnership decreases with partners’ technological distance. Using data on the formation of license partnerships in the global biopharmaceutical industry over the period 1994......This paper investigates the matching of firms on the market for technology. The paper forwards two dimensions along which license formation occurs: technology and product-market. Both sides of the market search for a partner representing potential for high technology synergies to maximize licensing...

  18. Regulatory guidelines for biosimilars in Malaysia.

    Science.gov (United States)

    Abas, Arpah

    2011-09-01

    The biosimilars sector continues to attract huge interest and controversy. Biosimilars are new biopharmaceuticals that are "similar" but not identical to the innovator product. Characteristics of biopharmaceuticals are closely related to the manufacturing process, which implies that the products cannot be exactly duplicated. Minuscule differences in the product's structure and manufacturing process can result in different clinical outcome. This raises concerns over the safety, efficacy and even pharmacovigilance of biosimilars. Thus, biosimilars are unique - they are not a true chemical generic and are regulated via a distinct regulatory framework. This report discusses the features of Malaysian regulatory oversight of biosimilars and experience acquired in the evaluation of some products from various countries. Ensuring regulatory position adequately reflects scientific advancement, expertise/resources is key. The regulatory situation is an evolving process. Various guidance documents are being prepared with the aim of developing a uniform global framework towards assuring the dual goal of lower costs and patient safety while expediting the availability of important biosimilar products. Copyright © 2011. Published by Elsevier Ltd.

  19. Very-large-scale production of antibodies in plants: The biologization of manufacturing.

    Science.gov (United States)

    Buyel, J F; Twyman, R M; Fischer, R

    2017-07-01

    Gene technology has facilitated the biologization of manufacturing, i.e. the use and production of complex biological molecules and systems at an industrial scale. Monoclonal antibodies (mAbs) are currently the major class of biopharmaceutical products, but they are typically used to treat specific diseases which individually have comparably low incidences. The therapeutic potential of mAbs could also be used for more prevalent diseases, but this would require a massive increase in production capacity that could not be met by traditional fermenter systems. Here we outline the potential of plants to be used for the very-large-scale (VLS) production of biopharmaceutical proteins such as mAbs. We discuss the potential market sizes and their corresponding production capacities. We then consider available process technologies and scale-down models and how these can be used to develop VLS processes. Finally, we discuss which adaptations will likely be required for VLS production, lessons learned from existing cell culture-based processes and the food industry, and practical requirements for the implementation of a VLS process. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  20. Scope of claim coverage in patents of fufang Chinese herbal drugs: Substitution of ingredients

    Directory of Open Access Journals (Sweden)

    Tian Jiaher

    2011-08-01

    Full Text Available Abstract Herbal ingredients in a Chinese fufang prescription are often replaced by one or several other herbal combinations. As there have been very few Chinese herbal patent infringement cases, it is still unclear how the Doctrine of Equivalents should be applied to determine the scope of 'equivalents' in Chinese fufang prescriptions. Case law principles from cases in other technical areas such as chemical patents and biological drug patents can be borrowed to ascertain a precise scope of a fufang patent. This article summarizes and discusses several chemical and biopharmaceutical patent cases. In cases where a certain herbal ingredient is substituted by another herb or a combination of herbs, accused infringers are likely to relate herbal drug patents to chemical drug patents with strict interpretation whereas patent owners may take advantage of the liberal application of Doctrine of Equivalence in biopharmaceutical patents by analogizing the complex nature of herbal drugs with biological drugs. Therefore, consideration should be given to the purpose of an ingredient in a patent, the qualities when combined with the other ingredients and the intended function. The scope of equivalents also depends on the stage of the prior art. Moreover, it is desirable to disclose any potential substitutes when drafting the application. Claims should be drafted in such a way that all foreseeable modifications are encompassed for the protection of the patent owner's intellectual property.

  1. The promising future of microalgae: current status, challenges, and optimization of a sustainable and renewable industry for biofuels, feed, and other products.

    Science.gov (United States)

    Khan, Muhammad Imran; Shin, Jin Hyuk; Kim, Jong Deog

    2018-03-05

    Microalgae have recently attracted considerable interest worldwide, due to their extensive application potential in the renewable energy, biopharmaceutical, and nutraceutical industries. Microalgae are renewable, sustainable, and economical sources of biofuels, bioactive medicinal products, and food ingredients. Several microalgae species have been investigated for their potential as value-added products with remarkable pharmacological and biological qualities. As biofuels, they are a perfect substitute to liquid fossil fuels with respect to cost, renewability, and environmental concerns. Microalgae have a significant ability to convert atmospheric CO 2 to useful products such as carbohydrates, lipids, and other bioactive metabolites. Although microalgae are feasible sources for bioenergy and biopharmaceuticals in general, some limitations and challenges remain, which must be overcome to upgrade the technology from pilot-phase to industrial level. The most challenging and crucial issues are enhancing microalgae growth rate and product synthesis, dewatering algae culture for biomass production, pretreating biomass, and optimizing the fermentation process in case of algal bioethanol production. The present review describes the advantages of microalgae for the production of biofuels and various bioactive compounds and discusses culturing parameters.

  2. Increased yield of heterologous viral glycoprotein in the seeds of homozygous transgenic tobacco plants cultivated underground.

    Science.gov (United States)

    Tackaberry, Eilleen S; Prior, Fiona; Bell, Margaret; Tocchi, Monika; Porter, Suzanne; Mehic, Jelica; Ganz, Peter R; Sardana, Ravinder; Altosaar, Illimar; Dudani, Anil

    2003-06-01

    The use of transgenic plants in the production of recombinant proteins for human therapy, including subunit vaccines, is being investigated to evaluate the efficacy and safety of these emerging biopharmaceutical products. We have previously shown that synthesis of recombinant glycoprotein B (gB) of human cytomegalovirus can be targeted to seeds of transgenic tobacco when directed by the rice glutelin 3 promoter, with gB retaining critical features of immunological reactivity (E.S. Tackaberry et al. 1999. Vaccine, 17: 3020-3029). Here, we report development of second generation transgenic plant lines (T1) homozygous for the transgene. Twenty progeny plants from two lines (A23T(1)-2 and A24T(1)-3) were grown underground in an environmentally contained mine shaft. Based on yields of gB in their seeds, the A23T(1)-2 line was then selected for scale-up in the same facility. Analyses of mature seeds by ELISA showedthat gB specific activity in A23T(1)-2 seeds was over 30-fold greater than the best T0 plants from the same transformation series, representing 1.07% total seed protein. These data demonstrate stable inheritance, an absence of transgene inactivation, and enhanced levels of gB expression in a homozygous second generation plant line. They also provide evidence for the suitability of using this environmentally secure facility to grow transgenic plants producing therapeutic biopharmaceuticals.

  3. Self assembling nanocomposites for protein delivery: supramolecular interactions of soluble polymers with protein drugs.

    Science.gov (United States)

    Salmaso, Stefano; Caliceti, Paolo

    2013-01-02

    Translation of therapeutic proteins to pharmaceutical products is often encumbered by their inadequate physicochemical and biopharmaceutical properties, namely low stability and poor bioavailability. Over the last decades, several academic and industrial research programs have been focused on development of biocompatible polymers to produce appropriate formulations that provide for enhanced therapeutic performance. According to their physicochemical properties, polymers have been exploited to obtain a variety of formulations including biodegradable microparticles, 3-dimensional hydrogels, bioconjugates and soluble nanocomposites. Several soluble polymers bearing charges or hydrophobic moieties along the macromolecular backbone have been found to physically associate with proteins to form soluble nanocomplexes. Physical complexation is deemed a valuable alternative tool to the chemical bioconjugation. Soluble protein/polymer nanocomplexes formed by physical specific or unspecific interactions have been found in fact to possess peculiar physicochemical, and biopharmaceutical properties. Accordingly, soluble polymeric systems have been developed to increase the protein stability, enhance the bioavailability, promote the absorption across the biological barriers, and prolong the protein residence in the bloodstream. Furthermore, a few polymers have been found to favour the protein internalisation into cells or boost their immunogenic potential by acting as immunoadjuvant in vaccination protocols. Copyright © 2011 Elsevier B.V. All rights reserved.

  4. Contrasting effects of cord injury on intravenous and oral pharmacokinetics of diclofenac: a drug with intermediate hepatic extraction.

    Science.gov (United States)

    Cruz-Antonio, L; Arauz, J; Franco-Bourland, R E; Guízar-Sahagún, G; Castañeda-Hernández, G

    2012-08-01

    Laboratory investigation in rats submitted to experimental spinal cord injury (SCI). To determine the effect of acute SCI on the pharmacokinetics of diclofenac, a marker drug of intermediate hepatic extraction, administered by the intravenous and the oral routes. Female Wistar rats were submitted to complete section of the spinal cord at the T8 level. SCI and sham-injured rats received 3.2 mg kg(-1) of diclofenac sodium either intravenously or orally, diclofenac concentration was measured in whole blood samples and pharmacokinetic parameters were estimated. Diclofenac was not selected as test drug because of its therapeutic properties, but because to its biopharmaceutical properties, that is, intermediate hepatic extraction. Diclofenac bioavailability after intravenous administration was increased in injured rats compared with controls due to a reduced clearance. In contrast, oral diclofenac bioavailability was diminished in SCI animals due to a reduction in drug absorption, which overrides the effect on clearance. Acute SCI induces significant pharmacokinetic changes for diclofenac, a marker drug with intermediate hepatic extraction. SCI-induced pharmacokinetic changes are not only determined by injury characteristics, but also by the route of administration and the biopharmaceutical properties of the studied drug.

  5. Effects of the TAT peptide orientation and relative location on the protein transduction efficiency.

    Science.gov (United States)

    Guo, Qingguo; Zhao, Guojie; Hao, Fengjin; Guan, Yifu

    2012-05-01

    To understand the protein transduction domain (PTD)-mediated protein transduction behavior and to explore its potential in delivering biopharmaceutic drugs, we prepared four TAT-EGFP conjugates: TAT(+)-EGFP, TAT(-)-EGFP, EGFP-TAT(+) and EGFP-TAT(-), where TAT(+) and TAT(-) represent the original and the reversed TAT sequence, respectively. These four TAT-EGFP conjugates were incubated with HeLa and PC12 cells for in vitro study as well as injected intraperitoneally to mice for in vivo study. Flow cytometric results showed that four TAT-EGFP conjugates were able to traverse HeLa and PC12 cells with almost equal transduction efficiency. The in vivo study showed that the TAT-EGFP conjugates could be delivered into different organs of mice with different transduction capabilities. Bioinformatic analyses and CD spectroscopic data revealed that the TAT peptide has no defined secondary structure, and conjugating the TAT peptide to the EGFP cargo protein would not alter the native structure and the function of the EGFP protein. These results conclude that the sequence orientation, the spatial structure, and the relative location of the TAT peptide have much less effect on the TAT-mediated protein transduction. Thus, the TAT-fused conjugates could be constructed in more convenient and flexible formats for a wide range of biopharmaceutical applications. © 2011 John Wiley & Sons A/S.

  6. Supramolecular Cocrystals of Gliclazide: Synthesis, Characterization and Evaluation.

    Science.gov (United States)

    Chadha, Renu; Rani, Dimpy; Goyal, Parnika

    2017-03-01

    To prepare the supramolecular cocrystals of gliclazide (GL, a BCS class II drug molecule) via mechanochemical route, with the goal of improving physicochemical and biopharmaceutical properties. Two cocrystals of GL with GRAS status coformers, sebacic acid (GL-SB; 1:1) and α-hydroxyacetic acid (GL-HA; 1:1) were screened out using liquid assisted grinding. The prepared cocrystals were characterized using thermal and analytical techniques followed by evaluation of antidiabetic activity and pharmacokinetic parameters. The generation of new, single and pure crystal forms was characterized by DSC and PXRD. The crystal structure determination from PXRD revealed the existence of both cocrystals in triclinic (P-1) crystal system. The hydrogen bonded network, determined by material studio was well supported by shifts in FTIR and SSNMR. Both the new solid forms displayed improved solubility, IDR, antidiabetic activity and pharmacokinetic parameters as compared to GL. The improvement in these physicochemical and biopharmaceutical properties corroborated the fact that the supramolecular cocrystallization may be useful in the development of pharmaceutical crystalline materials with interesting network and properties.

  7. Quality beyond compliance.

    Science.gov (United States)

    Centanni, N; Monroe, M; White, L; Larson, R

    1999-01-01

    The service sector within the biopharmaceutical industry has experienced phenomenal growth over the past decade. In the highly regulated Good Laboratory Practices environment, the need for timely, high-quality service, accurate results, and on-time deliverables becomes paramount for the success and profitability of biopharmaceutical companies. The quality assurance process is a vital component of this drug product-development cycle and ensures compliance to the highest domestic and international regulatory standards. Quality-assurance professionals historically have held the role of independent auditors of the processes, who certify that results meet current standards of practice. Covance, a contract research organization that includes Good Laboratory Practices laboratories, reorganized and expanded the functional responsibilities of its quality assurance team in 1997. Auditors and quality assurance professionals have assumed roles beyond traditional compliance auditing and are forging new leadership and mentoring roles as process-improvement specialists. The results have been tangible, measurable benefits for clients and the Covance organization. This article provides an overview of this cultural change and the processes put in place to improve efficiency, productivity, and customer and employee satisfaction.

  8. Polysorbates 20 and 80 used in the formulation of protein biotherapeutics: structure and degradation pathways.

    Science.gov (United States)

    Kerwin, Bruce A

    2008-08-01

    Polysorbates 20 and 80 (Tween 20 and Tween 80) are used in the formulation of biotherapeutic products for both preventing surface adsorption and as stabilizers against protein aggregation. The polysorbates are amphipathic, nonionic surfactants composed of fatty acid esters of polyoxyethylene sorbitan being polyoxyethylene sorbitan monolaurate for polysorbate 20 and polyoxyethylene sorbitan monooleate for polysorbate 80. The polysorbates used in the formulation of biopharmaceuticals are mixtures of different fatty acid esters with the monolaurate fraction of polysorbate 20 making up only 40-60% of the mixture and the monooleate fraction of polysorbate 80 making up >58% of the mixture. The polysorbates undergo autooxidation, cleavage at the ethylene oxide subunits and hydrolysis of the fatty acid ester bond. Autooxidation results in hydroperoxide formation, side-chain cleavage and eventually formation of short chain acids such as formic acid all of which could influence the stability of a biopharmaceutical product. Oxidation of the fatty acid moiety while well described in the literature has not been specifically investigated for polysorbate. This review focuses on the chemical structure of the polysorbates, factors influencing micelle formation and factors and excipients influencing stability and degradation of the polyoxyethylene and fatty acid ester linkages.

  9. High-throughput miniaturized bioreactors for cell culture process development: reproducibility, scalability, and control.

    Science.gov (United States)

    Rameez, Shahid; Mostafa, Sigma S; Miller, Christopher; Shukla, Abhinav A

    2014-01-01

    Decreasing the timeframe for cell culture process development has been a key goal toward accelerating biopharmaceutical development. Advanced Microscale Bioreactors (ambr™) is an automated micro-bioreactor system with miniature single-use bioreactors with a 10-15 mL working volume controlled by an automated workstation. This system was compared to conventional bioreactor systems in terms of its performance for the production of a monoclonal antibody in a recombinant Chinese Hamster Ovary cell line. The miniaturized bioreactor system was found to produce cell culture profiles that matched across scales to 3 L, 15 L, and 200 L stirred tank bioreactors. The processes used in this article involve complex feed formulations, perturbations, and strict process control within the design space, which are in-line with processes used for commercial scale manufacturing of biopharmaceuticals. Changes to important process parameters in ambr™ resulted in predictable cell growth, viability and titer changes, which were in good agreement to data from the conventional larger scale bioreactors. ambr™ was found to successfully reproduce variations in temperature, dissolved oxygen (DO), and pH conditions similar to the larger bioreactor systems. Additionally, the miniature bioreactors were found to react well to perturbations in pH and DO through adjustments to the Proportional and Integral control loop. The data presented here demonstrates the utility of the ambr™ system as a high throughput system for cell culture process development. © 2014 American Institute of Chemical Engineers.

  10. Susceptibility of mouse minute virus to inactivation by heat in two cell culture media types.

    Science.gov (United States)

    Schleh, Marc; Romanowski, Peter; Bhebe, Prince; Zhang, Li; Chinniah, Shivanthi; Lawrence, Bill; Bashiri, Houman; Gaduh, Asri; Rajurs, Viveka; Rasmussen, Brian; Chuck, Alice; Dehghani, Houman

    2009-01-01

    Viral contaminations of biopharmaceutical manufacturing cell culture facilities are a significant threat and one for which having a risk mitigation strategy is highly desirable. High temperature, short time (HTST) mammalian cell media treatment may potentially safeguard manufacturing facilities from such contaminations. HTST is thought to inactivate virions by denaturing proteins of the viral capsid, and there is evidence that HTST provides ample virucidal efficacy against nonenveloped or naked viruses such as mouse minute virus (MMV), a parvovirus. The aim of the studies presented herein was to further delineate the susceptibility of MMV, known to have contaminated mammalian cell manufacturing facilities, to heat by exposing virus-spiked cell culture media to a broad range of temperatures and for various times of exposure. The results of these studies show that HTST is capable of inactivating MMV by three orders of magnitude or more. Thus, we believe that HTST is a useful technology for the purposes of providing a barrier to adventitious contamination of mammalian cell culture processes in the biopharmaceutical industry. 2009 American Institute of Chemical Engineers

  11. Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Folic Acid.

    Science.gov (United States)

    Hofsäss, Martin A; Souza, Jacqueline de; Silva-Barcellos, Neila M; Bellavinha, Karime R; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, D W; Parr, Alan; Langguth, Peter; Polli, James E; Shah, Vinod P; Tajiri, Tomokazu; Mehta, Mehul U; Dressman, Jennifer B

    2017-12-01

    This work presents a review of literature and experimental data relevant to the possibility of waiving pharmacokinetic bioequivalence studies in human volunteers for approval of immediate-release solid oral pharmaceutical forms containing folic acid as the single active pharmaceutical ingredient. For dosage forms containing 5 mg folic acid, the highest dose strength on the World Health Organization Essential Medicines List, the dose/solubility ratio calculated from solubility studies was higher than 250 mL, corresponding to a classification as "not highly soluble." Small, physiological doses of folic acid (≤320 μg) seem to be absorbed completely via active transport, but permeability data for higher doses of 1-5 mg are inconclusive. Following a conservative approach, folic acid is classified as a Biopharmaceutics Classification System class IV compound until more reliable data become available. Commensurate with its solubility characteristics, the results of dissolution studies indicated that none of the folic acid products evaluated showed rapid dissolution in media at pH 1.2 or 4.5. Therefore, according to the current criteria of the Biopharmaceutics Classification System, the biowaiver approval procedure cannot be recommended for immediate-release solid oral dosage forms containing folic acid. Copyright © 2017 American Pharmacists Association®. All rights reserved.

  12. Yeast synthetic biology for the production of recombinant therapeutic proteins.

    Science.gov (United States)

    Kim, Hyunah; Yoo, Su Jin; Kang, Hyun Ah

    2015-02-01

    The production of recombinant therapeutic proteins is one of the fast-growing areas of molecular medicine and currently plays an important role in treatment of several diseases. Yeasts are unicellular eukaryotic microbial host cells that offer unique advantages in producing biopharmaceutical proteins. Yeasts are capable of robust growth on simple media, readily accommodate genetic modifications, and incorporate typical eukaryotic post-translational modifications. Saccharomyces cerevisiae is a traditional baker's yeast that has been used as a major host for the production of biopharmaceuticals; however, several nonconventional yeast species including Hansenula polymorpha, Pichia pastoris, and Yarrowia lipolytica have gained increasing attention as alternative hosts for the industrial production of recombinant proteins. In this review, we address the established and emerging genetic tools and host strains suitable for recombinant protein production in various yeast expression systems, particularly focusing on current efforts toward synthetic biology approaches in developing yeast cell factories for the production of therapeutic recombinant proteins. © FEMS 2015. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.

  13. Advanced technologies for improved expression of recombinant proteins in bacteria: perspectives and applications.

    Science.gov (United States)

    Gupta, Sanjeev K; Shukla, Pratyoosh

    2016-12-01

    Prokaryotic expression systems are superior in producing valuable recombinant proteins, enzymes and therapeutic products. Conventional microbial technology is evolving gradually and amalgamated with advanced technologies in order to give rise to improved processes for the production of metabolites, recombinant biopharmaceuticals and industrial enzymes. Recently, several novel approaches have been employed in a bacterial expression platform to improve recombinant protein expression. These approaches involve metabolic engineering, use of strong promoters, novel vector elements such as inducers and enhancers, protein tags, secretion signals, high-throughput devices for cloning and process screening as well as fermentation technologies. Advancement of the novel technologies in E. coli systems led to the production of "difficult to express" complex products including small peptides, antibody fragments, few proteins and full-length aglycosylated monoclonal antibodies in considerable large quantity. Wacker's secretion technologies, Pfenex system, inducers, cell-free systems, strain engineering for post-translational modification, such as disulfide bridging and bacterial N-glycosylation, are still under evaluation for the production of complex proteins and peptides in E. coli in an efficient manner. This appraisal provides an impression of expression technologies developed in recent times for enhanced production of heterologous proteins in E. coli which are of foremost importance for diverse applications in microbiology and biopharmaceutical production.

  14. Binding mechanisms for histamine and agmatine ligands in plasmid deoxyribonucleic acid purifications.

    Science.gov (United States)

    Sousa, Ângela; Pereira, Patrícia; Sousa, Fani; Queiroz, João A

    2014-10-31

    Histamine and agmatine amino acid derivatives were immobilized into monolithic disks, in order to combine the specificity and selectivity of the ligand with the high mass transfer and binding capacity offered by monolithic supports, to purify potential plasmid DNA biopharmaceuticals. Different elution strategies were explored by changing the type and salt concentration, as well as the pH, in order to understand the retention pattern of different plasmids isoforms The pVAX1-LacZ supercoiled isoform was isolated from a mixture of pDNA isoforms by using NaCl increasing stepwise gradient and also by ammonium sulfate decreasing stepwise gradient, in both histamine and agmatine monoliths. Acidic pH in the binding buffer mainly strengthened ionic interactions with both ligands in the presence of sodium chloride. Otherwise, for histamine ligand, pH values higher than 7 intensified hydrophobic interactions in the presence of ammonium sulfate. In addition, circular dichroism spectroscopy studies revealed that the binding and elution chromatographic conditions, such as the combination of high ionic strength with extreme pH values can reversibly influence the structural stability of the target nucleic acid. Therefore, ascending sodium chloride gradients with pH manipulation can be preferable chromatographic conditions to be explored in the purification of plasmid DNA biopharmaceuticals, in order to avoid the environmental impact of ammonium sulfate. Copyright © 2014. Published by Elsevier B.V.

  15. Regulation of biogenerics: a survey of viewpoints.

    Science.gov (United States)

    Nieminen, Outi; Nordström, Katrina

    2004-01-01

    'Biogenerics' regulation has brought about a heated debate within the EU as the first biopharmaceuticals are going off patent. This study aims to examine the opportunities and challenges offered by biogenerics by surveying the viewpoints of experts in regulatory agencies and in companies developing novel biopharmaceuticals and biogenerics. Oral interviews were conducted in 2002 and 2003 with experts including representatives of the European Generic Medicines Association (EGA) and the European Federation of Pharmaceutical Industries and Associations (EFPIA) in Brussels, three innovator biotech companies, and five other experts in Finland. Additionally, four biogenerics companies and one innovator company abroad answered a structured, written questionnaire. According to this study, biogenerics should be regulated on a case-by-case basis. The interviewees were not unanimous as to whether comparability can be addressed and which are the most challenging areas for proving comparability. Immunogenicity was considered to be a major problem for biogenerics. Therefore, a requirement for an intensified monitoring of the safety profile during post-marketing was thought to be justified in many cases.

  16. In vitro disposition profiling of heterocyclic compounds.

    Science.gov (United States)

    Keemink, Janneke; Wuyts, Benjamin; Nicolaï, Johan; Jonghe, Steven De; Stella, Alessandro; Herdewijn, Piet; Augustijns, Patrick; Annaert, Pieter

    2015-08-01

    Compound libraries that are screened for biological activity commonly contain heterocycles. Besides potency, drug-like properties need to be evaluated to ensure in vivo efficacy of test compounds. In this context, we determined hepatic and intestinal disposition profiles for 17 heterocyclic compounds. All studied compounds showed rapid uptake in suspended rat hepatocytes, whereas metabolism was poor and the rate-limiting step in hepatic elimination. In vitro assays demonstrated a relatively low solubility and high intestinal permeability. Based on these in vitro data, heterocycles were categorized in the biopharmaceutics classification system (BCS) and the biopharmaceutics drug disposition classification system (BDDCS) to predict disposition characteristics before clinical data are available. Our findings emphasized the importance to use hepatocytes in addition to microsomes to study metabolism, since the latter lack non-microsomal enzymes and cellular context. Moreover, intracellular exposure should be considered to gain insight in the relevant fraction of the compound available at the enzymatic site. Finally, the study reveals discrepancies associated with the classification of heterocycles in BCS versus BDDCS. These probably originate from the binary character of both systems. Copyright © 2015 Elsevier B.V. All rights reserved.

  17. Modeling the Downstream Processing of Monoclonal Antibodies Reveals Cost Advantages for Continuous Methods for a Broad Range of Manufacturing Scales.

    Science.gov (United States)

    Hummel, Jonathan; Pagkaliwangan, Mark; Gjoka, Xhorxhi; Davidovits, Terence; Stock, Rick; Ransohoff, Thomas; Gantier, Rene; Schofield, Mark

    2018-01-17

    The biopharmaceutical industry is evolving in response to changing market conditions, including increasing competition and growing pressures to reduce costs. Single-use (SU) technologies and continuous bioprocessing have attracted attention as potential facilitators of cost-optimized manufacturing for monoclonal antibodies. While disposable bioprocessing has been adopted at many scales of manufacturing, continuous bioprocessing has yet to reach the same level of implementation. In this study, the cost of goods of Pall Life Science's integrated, continuous bioprocessing (ICB) platform is modeled, along with that of purification processes in stainless-steel and SU batch formats. All three models include costs associated with downstream processing only. Evaluation of the models across a broad range of clinical and commercial scenarios reveal that the cost savings gained by switching from stainless-steel to SU batch processing are often amplified by continuous operation. The continuous platform exhibits the lowest cost of goods across 78% of all scenarios modeled here, with the SU batch process having the lowest costs in the rest of the cases. The relative savings demonstrated by the continuous process are greatest at the highest feed titers and volumes. These findings indicate that existing and imminent continuous technologies and equipment can become key enablers for more cost effective manufacturing of biopharmaceuticals. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Flexible Biomanufacturing Processes that Address the Needs of the Future.

    Science.gov (United States)

    Diel, Bernhard; Manzke, Christian; Peuker, Thorsten

    2014-01-01

    : As the age of the blockbuster drug recedes, the business model for the biopharmaceutical industry is evolving at an ever-increasing pace. The personalization of medicine, the emergence of biosimilars and biobetters, and the need to provide vaccines globally are just some of the factors forcing biomanufacturers to rethink how future manufacturing capability is implemented. One thing is clear: the traditional manufacturing strategy of constructing large-scale, purpose-built, capital-intensive facilities will no longer meet the industry's emerging production and economic requirements. Therefore, the authors of this chapter describe the new approach for designing and implementing flexible production processes for monoclonal antibodies and focus on the points to consider as well as the lessons learned from past experience in engineering such systems. A conceptual integrated design is presented that can be used as a blueprint for next-generation biomanufacturing facilities. In addition, this chapter discusses the benefits of the new approach with respect to flexibility, cost, and schedule. The concept presented here can be applied to other biopharmaceutical manufacturing processes and facilities, including-but not limited to-vaccine manufacturing, multiproduct and/or multiprocess capability, clinical manufacturing, and so on.

  19. The art of CHO cell engineering: A comprehensive retrospect and future perspectives.

    Science.gov (United States)

    Fischer, Simon; Handrick, René; Otte, Kerstin

    2015-12-01

    Chinese hamster ovary (CHO) cells represent the most frequently applied host cell system for industrial manufacturing of recombinant protein therapeutics. CHO cells are capable of producing high quality biologics exhibiting human-like post-translational modifications in gram quantities. However, production processes for biopharmaceuticals using mammalian cells still suffer from cellular limitations such as limited growth, low productivity and stress resistance as well as higher expenses compared to bacterial or yeast based expression systems. Besides bioprocess, media and vector optimizations, advances in host cell engineering technologies comprising introduction, knock-out or post-transcriptional silencing of engineering genes have paved the way for remarkable achievements in CHO cell line development. Furthermore, thorough analysis of cellular pathways and mechanisms important for bioprocessing steadily unravels novel target molecules which might be addressed by functional genomic tools in order to establish superior production cell factories. This review provides a comprehensive summary of the most fundamental achievements in CHO cell engineering over the past three decades. Finally, the authors discuss the potential of novel and innovative methodologies that might contribute to further enhancement of existing CHO based production platforms for biopharmaceutical manufacturing in the future. Copyright © 2015 Elsevier Inc. All rights reserved.

  20. Clarification technologies for monoclonal antibody manufacturing processes: Current state and future perspectives.

    Science.gov (United States)

    Singh, Nripen; Arunkumar, Abhiram; Chollangi, Srinivas; Tan, Zhijun George; Borys, Michael; Li, Zheng Jian

    2016-04-01

    Considerable progress has been made increasing productivity of cell cultures to meet the rapidly growing demand for antibody biopharmaceuticals through increased cell densities and longer culture times. This in turn has dramatically increased the burden of process and product related impurities on the purification processes. In addition, current trends in the biopharmaceutical industry point toward both increased productivity and targeting smaller patient populations for new indications. Taken together, these developments are driving the industry to explore alternative separation technologies as a future manufacturing strategy. Clarification technologies well established in other industries, such as flocculation and precipitation are increasingly considered as a viable solution to address this bottleneck in antibody processes. However, several technical issues need to be fully addressed including suitability as a platform application, robustness, process cost, toxicity, and clearance. This review will focus on recent efforts to incorporate new generation clarification technologies for mammalian cell cultures producing monoclonal antibodies as well as challenges to their implementation supported by a case study. © 2015 Wiley Periodicals, Inc.

  1. Biocorrosion of Endodontic Files through the Action of Two Species of Sulfate-reducing Bacteria: Desulfovibrio desulfuricans and Desulfovibrio fairfieldensis.

    Science.gov (United States)

    Heggendorn, Fabiano Luiz; Gonçalves, Lucio Souza; Dias, Eliane Pedra; de Oliveira Freitas Lione, Viviane; Lutterbach, Márcia Teresa Soares

    2015-08-01

    This study assessed the biocorrosive capacity of two bacteria: Desulfovibrio desulfuricans and Desulfovibrio fairfieldensis on endodontic files, as a preliminary step in the development of a biopharmaceutical, to facilitate the removal of endodontic file fragments from root canals. In the first stage, the corrosive potential of the artificial saliva medium (ASM), modified Postgate E medium (MPEM), 2.5 % sodium hypochlorite (NaOCl) solution and white medium (WM), without the inoculation of bacteria was assessed by immersion assays. In the second stage, test samples were inoculated with the two species of sulphur-reducing bacteria (SRB) on ASM and modified artificial saliva medium (MASM). In the third stage, test samples were inoculated with the same species on MPEM, ASM and MASM. All test samples were viewed under an infinite focus Alicona microscope. No test sample became corroded when immersed only in media, without bacteria. With the exception of one test sample between those inoculated with bacteria in ASM and MASM, there was no evidence of corrosion. Fifty percent of the test samples demonstrated a greater intensity of biocorrosion when compared with the initial assays. Desulfovibrio desulfuricans and D. fairfieldensis are capable of promoting biocorrosion of the steel constituent of endodontic files. This study describes the initial development of a biopharmaceutical to facilitate the removal of endodontic file fragments from root canals, which can be successfully implicated in endodontic therapy in order to avoiding parendodontic surgery or even tooth loss in such events.

  2. Purification of inclusion bodies using PEG precipitation under denaturing conditions to produce recombinant therapeutic proteins from Escherichia coli.

    Science.gov (United States)

    Chen, Huanhuan; Li, Ninghuan; Xie, Yueqing; Jiang, Hua; Yang, Xiaoyi; Cagliero, Cedric; Shi, Siwei; Zhu, Chencen; Luo, Han; Chen, Junsheng; Zhang, Lei; Zhao, Menglin; Feng, Lei; Lu, Huili; Zhu, Jianwei

    2017-07-01

    It has been documented that the purification of inclusion bodies from Escherichia coli by size exclusion chromatography (SEC) may benefit subsequent refolding and recovery of recombinant proteins. However, loading volume and the high cost of the column limits its application in large-scale manufacturing of biopharmaceutical proteins. We report a novel process using polyethylene glycol (PEG) precipitation under denaturing conditions to replace SEC for rapid purification of inclusion bodies containing recombinant therapeutic proteins. Using recombinant human interleukin 15 (rhIL-15) as an example, inclusion bodies of rhIL-15 were solubilized in 7 M guanidine hydrochloride, and rhIL-15 was precipitated by the addition of PEG 6000. A final concentration of 5% (w/v) PEG 6000 was found to be optimal to precipitate target proteins and enhance recovery and purity. Compared to the previously reported S-200 size exclusion purification method, PEG precipitation was easier to scale up and achieved the same protein yields and quality of the product. PEG precipitation also reduced manufacturing time by about 50 and 95% of material costs. After refolding and further purification, the rhIL-15 product was highly pure and demonstrated a comparable bioactivity with a rhIL-15 reference standard. Our studies demonstrated that PEG precipitation of inclusion bodies under denaturing conditions holds significant potential as a manufacturing process for biopharmaceuticals from E. coli protein expression systems.

  3. High-Throughput Analysis and Automation for Glycomics Studies.

    Science.gov (United States)

    Shubhakar, Archana; Reiding, Karli R; Gardner, Richard A; Spencer, Daniel I R; Fernandes, Daryl L; Wuhrer, Manfred

    This review covers advances in analytical technologies for high-throughput (HTP) glycomics. Our focus is on structural studies of glycoprotein glycosylation to support biopharmaceutical realization and the discovery of glycan biomarkers for human disease. For biopharmaceuticals, there is increasing use of glycomics in Quality by Design studies to help optimize glycan profiles of drugs with a view to improving their clinical performance. Glycomics is also used in comparability studies to ensure consistency of glycosylation both throughout product development and between biosimilars and innovator drugs. In clinical studies there is as well an expanding interest in the use of glycomics-for example in Genome Wide Association Studies-to follow changes in glycosylation patterns of biological tissues and fluids with the progress of certain diseases. These include cancers, neurodegenerative disorders and inflammatory conditions. Despite rising activity in this field, there are significant challenges in performing large scale glycomics studies. The requirement is accurate identification and quantitation of individual glycan structures. However, glycoconjugate samples are often very complex and heterogeneous and contain many diverse branched glycan structures. In this article we cover HTP sample preparation and derivatization methods, sample purification, robotization, optimized glycan profiling by UHPLC, MS and multiplexed CE, as well as hyphenated techniques and automated data analysis tools. Throughout, we summarize the advantages and challenges with each of these technologies. The issues considered include reliability of the methods for glycan identification and quantitation, sample throughput, labor intensity, and affordability for large sample numbers.

  4. Dissolving Microneedle Patch for Transdermal Delivery of Human Growth Hormone

    Science.gov (United States)

    Lee, Jeong Woo; Choi, Seong-O; Felner, Eric I.

    2014-01-01

    Clinical impact of biotechnology has been constrained by the limitations of traditional hypodermic injection of biopharmaceuticals. Microneedle patches have been proposed as a minimally invasive alternative. In this study, we assess the translation of a dissolving microneedle patch designed for simple, painless self-administration of biopharmacetucials that generates no sharp biohazardous waste. To study pharmacokinetics and safety of this approach, human growth hormone (hGH) was encapsulated in 600 μm long dissolving microneedles composed of carboxymethylcellulose and trehalose using an aqueous, moderate-temperature process that maintained complete hGH activity after encapsulation and retained most activity after storage for up to 15 months at room temperature and humidity. After manual insertion into the skin of hairless rats, hGH pharmacokinetics were similar to conventional subcutaneous injection. After patch removal, the microneedles had almost completely dissolved, leaving behind only blunt stubs. The dissolving microneedle patch was well tolerated, causing only slight, transient erythema. This study suggests that a dissolving microneedle patch can deliver hGH and other biopharmaceuticals in a manner suitable for self-administration without sharp biohazardous waste. PMID:21360810

  5. Intracellular Protein Delivery and Gene Transfection by Electroporation Using a Microneedle Electrode Array

    Science.gov (United States)

    Choi, Seong-O; Kim, Yeu-Chun; Lee, Jeong Woo; Park, Jung-Hwan

    2012-01-01

    The impact of many biopharmaceuticals, including protein- and gene-based therapies, has been limited by the need for better methods of delivery into cells within tissues. Here, we present intracellular delivery of molecules and transfection with plasmid DNA by electroporation using a novel microneedle electrode array designed for targeted treatment of skin and other tissue surfaces. The microneedle array is molded out of polylactic acid. Electrodes and circuitry required for electroporation are applied to the microneedle array surface by a new metal-transfer micromolding method. The microneedle array maintains mechanical integrity after insertion into pig cadaver skin and is able to electroporate human prostate cancer cells in vitro. Quantitative measurements show that increasing electroporation pulse voltage increases uptake efficiency of calcein and bovine serum albumin, whereas increasing pulse length has lesser effects over the range studied. Uptake of molecules by up to 50 % of cells and transfection of 12 % of cells with a gene for green fluorescent protein is demonstrated at high cell viability. We conclude that the microneedle electrode array is able to electroporate cells, resulting in intracellular uptake of molecules, and has potential applications to improve intracellular delivery of proteins, DNA and other biopharmaceuticals. PMID:22328093

  6. Development and Validation of an Enzyme-Linked Immunosorbent Assay for the Detection of Binding Anti-Drug Antibodies against Interferon Beta

    Directory of Open Access Journals (Sweden)

    Kathleen Ingenhoven

    2017-07-01

    Full Text Available ObjectiveTo develop and validate a method for the detection of binding anti-drug antibodies (ADAs against interferon beta (IFN-β in human serum as part of a European initiative (ABIRISK aimed at the prediction and analysis of clinical relevance of anti-biopharmaceutical immunization to minimize the risk.MethodA two-tiered bridging enzyme-linked immunosorbent assay (ELISA format was selected and validated according to current recommendations. Screening assay: ADA in serum samples form complexes with immobilized IFN-β and biotinylated IFN-β, which are then detected using HRP labeled Streptavidin and TMB substrate. Confirmation assay: Screen “putative positive” samples are tested in the presence of excess drug (preincubation of sera with 0.3 µg/mL of soluble IFN-β and percentage of inhibition is calculated.ResultsThe assay is precise, and the sensitivity of the assay was confirmed to be 26 ng/mL using commercially available polyclonal rabbit antihuman IFN-β in human sera as the positive control.ConclusionAn ultrasensitive ELISA for IFN-β-binding ADA testing has been validated. This will form the basis to assess anti-biopharmaceutical immunization toward IFN-β with regards to its clinical relevance and may allow for the development of predictive tools, key aims within the ABIRISK consortium.

  7. Spray drying of silica microparticles for sustained release application with a new sol-gel precursor.

    Science.gov (United States)

    Wang, Bifeng; Friess, Wolfgang

    2017-10-30

    A new precursor, tetrakis(2-methoxyethyl) orthosilicate (TMEOS) was used to fabricate microparticles for sustained release application, specifically for biopharmaceuticals, by spray drying. The advantages of TMEOS over the currently applied precursors are its water solubility and hydrolysis at moderate pH without the need of organic solvents or catalyzers. Thus a detrimental effect on biomolecular drug is avoided. By generating spray-dried silica particles encapsulating the high molecular weight model compound FITC-dextran 150 via the nano spray dryer Büchi-90, we demonstrated how formulation parameters affect and enable control of drug release properties. The implemented strategies to regulate release included incorporating different quantities of dextrans with varying molecular weight as well as adjusting the pH of the precursor solution to modify the internal microstructures. The addition of dextran significantly altered the released amount, while the release became faster with increasing dextran molecular weight. A sustained release over 35days could be achieved with addition of 60 kD dextran. The rate of FITC-Dextran 150 release from the dextran 60 containing particles decreased with higher precursor solution pH. In conclusion, the new precursor TMEOS presents a promising alternative sol-gel technology based carrier material for sustained release application of high molecular weight biopharmaceutical drugs. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Protein stability in pulmonary drug delivery via nebulization.

    Science.gov (United States)

    Hertel, Sebastian P; Winter, Gerhard; Friess, Wolfgang

    2015-10-01

    Protein inhalation is a delivery route which offers high potential for direct local lung application of proteins. Liquid formulations are usually available in early stages of biopharmaceutical development and nebulizers are the device of choice for atomization avoiding additional process steps like drying and enabling fast progression to clinical trials. While some proteins were proven to remain stable throughout aerosolization e.g. DNase, many biopharmaceuticals are more susceptible towards the stresses encountered during nebulization. The main reason for protein instability is unfolding and aggregation at the air-liquid interface, a problem which is of particular challenge in the case of ultrasound and jet nebulizers due to recirculation of much of the generated droplets. Surfactants are an important formulation component to protect the sensitive biomolecules. A second important challenge is warming of ultrasound and vibrating mesh devices, which can be overcome by overfilling, precooled solutions or cooling of the reservoir. Ultimately, formulation development has to go hand in hand with device evaluation. Copyright © 2014 Elsevier B.V. All rights reserved.

  9. [The role of biotechnology in pharmaceutical drug design].

    Science.gov (United States)

    Gaisser, Sibylle; Nusser, Michael

    2010-01-01

    Biotechnological methods have become an important tool in pharmaceutical drug research and development. Today approximately 15 % of drug revenues are derived from biopharmaceuticals. The most relevant indications are oncology, metabolic disorders and disorders of the musculoskeletal system. For the future it can be expected that the relevance of biopharmaceuticals will further increase. Currently, the share of substances in preclinical testing that rely on biotechnology is more than 25 % of all substances in preclinical testing. Products for the treatment of cancer, metabolic disorders and infectious diseases are most important. New therapeutic approaches such as RNA interference only play a minor role in current commercial drug research and development with 1.5 % of all biological preclinical substances. Investments in sustainable high technology such as biotechnology are of vital importance for a highly developed country like Germany because of its lack of raw materials. Biotechnology helps the pharmaceutical industry to develop new products, new processes, methods and services and to improve existing ones. Thus, international competitiveness can be strengthened, new jobs can be created and existing jobs preserved.

  10. Novel chemometric strategy based on the application of artificial neural networks to crossed mixture design for the improvement of recombinant protein production in continuous culture.

    Science.gov (United States)

    Didier, Caroline; Forno, Guillermina; Etcheverrigaray, Marina; Kratje, Ricardo; Goicoechea, Héctor

    2009-09-21

    The optimal blends of six compounds that should be present in culture media used in recombinant protein production were determined by means of artificial neural networks (ANN) coupled with crossed mixture experimental design. This combination constitutes a novel approach to develop a medium for cultivating genetically engineered mammalian cells. The compounds were collected in two mixtures of three elements each, and the experimental space was determined by a crossed mixture design. Empirical data from 51 experimental units were used in a multiresponse analysis to train artificial neural networks which satisfy different requirements, in order to define two new culture media (Medium 1 and Medium 2) to be used in a continuous biopharmaceutical production process. These media were tested in a bioreactor to produce a recombinant protein in CHO cells. Remarkably, for both predicted media all responses satisfied the predefined goals pursued during the analysis, except in the case of the specific growth rate (mu) observed for Medium 1. ANN analysis proved to be a suitable methodology to be used when dealing with complex experimental designs, as frequently occurs in the optimization of production processes in the biotechnology area. The present work is a new example of the use of ANN for the resolution of a complex, real life system, successfully employed in the context of a biopharmaceutical production process.

  11. The use of biosimilar medicines in oncology - position statement of the Brazilian Society of Clinical Oncology (SBOC).

    Science.gov (United States)

    Fernandes, G S; Sternberg, C; Lopes, G; Chammas, R; Gifoni, M A C; Gil, R A; Araujo, D V

    2018-01-11

    A biosimilar is a biologic product that is similar to a reference biopharmaceutical product, the manufacturing process of which hinders the ability to identically replicate the structure of the original product, and therefore, it cannot be described as an absolute equivalent of the original medication. The currently available technology does not allow for an accurate copy of complex molecules, but it does allow the replication of similar molecules with the same activity. As biosimilars are about to be introduced in oncology practice, these must be evaluated through evidence-based medicine. This manuscript is a position paper, where the Brazilian Society of Clinical Oncology (SBOC) aims to describe pertinent issues regarding the approval and use of biosimilars in oncology. As a working group on behalf of SBOC, we discuss aspects related to definition, labeling/nomenclature, extrapolation, interchangeability, switching, automatic substitution, clinical standards on safety and efficacy, and the potential impact on financial burden in healthcare. We take a stand in favor of the introduction of biosimilars, as they offer a viable, safe, and cost-effective alternative to the biopharmaceutical products currently used in cancer. We hope this document can provide valuable information to support therapeutic decisions that maximize the clinical benefit for the thousands of cancer patients in Brazil and can contribute to expedite the introduction of this new drug class in clinical practice. We expect the conveyed information to serve as a basis for further discussion in Latin America, this being the first position paper issued by a Latin American Oncology Society.

  12. In Vitro Bioavailability Study of an Antiviral Compound Enisamium Iodide

    Directory of Open Access Journals (Sweden)

    Eleonore Haltner-Ukomadu

    2018-01-01

    Full Text Available An investigation into the biopharmaceutics classification and a study of the in vitro bioavailability (permeability and solubility of the antiviral compound enisamium iodide (4-(benzylcarbamoyl-1-methylpyridinium iodide were carried out. The solubility of enisamium iodide was determined in four different buffers. Apparent intestinal permeability (Papp of enisamium iodide was assessed using human colon carcinoma (Caco-2 cells at three concentrations. The solubility of enisamium iodide in four buffer solutions from pH 1.2 to 7.5 is about 60 mg/mL at 25 °C, and ranges from 130 to 150 mg/mL at 37 °C, depending on the pH. Based on these results, enisamium iodide can be classified as highly soluble. Enisamium iodide demonstrated low permeability in Caco-2 experiments in all tested concentrations of 10–100 μM with permeability coefficients between 0.2 × 10−6 cm s−1 and 0.3 × 10−6 cm s−1. These results indicate that enisamium iodide belongs to class III of the Biopharmaceutics Classification System (BCS due to its high solubility and low permeability. The bioavailability of enisamium iodide needs to be confirmed in animal and human studies.

  13. Progress toward forecasting product quality and quantity of mammalian cell culture processes by performance-based modeling.

    Science.gov (United States)

    Schmidberger, Timo; Posch, Christoph; Sasse, Alexandra; Gülch, Carina; Huber, Robert

    2015-01-01

    The production of biopharmaceuticals requires highly sophisticated, complex cell based processes. Once a process has been developed, acceptable ranges for various control parameters are typically defined based on process characterization studies often comprising several dozens of small scale bioreactor cultivations. A lot of data is generated during these studies and usually only the information needed to define acceptable ranges is processed in more detail. Making use of the wealth of information contained in such data sets, we present here a methodology that uses performance data (such as metabolite profiles) to forecast the product quality and quantity of mammalian cell culture processes based on a toolbox of advanced statistical methods. With this performance based modeling (PBM) the final product concentration and 12 quality attributes (QAs) for two different biopharmaceutical products were predicted in daily intervals throughout the main stage process. The best forecast was achieved for product concentration in a very early phase of the process. Furthermore, some glycan isoforms were predicted with good accuracy several days before the bioreactor was harvested. Overall, PBM clearly demonstrated its capability of early process endpoint prediction by only using commonly available data, even though it was not possible to predict all QAs with the desired accuracy. Knowing the product quality prior to the harvest allows the manufacturer to take counter measures in case the forecasted quality or quantity deviates from what is expected. This would be a big step towards real-time release, an important element of the FDA's PAT initiative. © 2015 American Institute of Chemical Engineers.

  14. Empirical investigation of the ethical reasoning of physicians and molecular biologists – the importance of the four principles of biomedical ethics

    Science.gov (United States)

    Ebbesen, Mette; Pedersen, Birthe D

    2007-01-01

    Background This study presents an empirical investigation of the ethical reasoning and ethical issues at stake in the daily work of physicians and molecular biologists in Denmark. The aim of this study was to test empirically whether there is a difference in ethical considerations and principles between Danish physicians and Danish molecular biologists, and whether the bioethical principles of the American bioethicists Tom L. Beauchamp and James F. Childress are applicable to these groups. Method This study is based on 12 semi-structured interviews with three groups of respondents: a group of oncology physicians working in a clinic at a public hospital and two groups of molecular biologists conducting basic research, one group employed at a public university and the other in a private biopharmaceutical company. Results In this sample, the authors found that oncology physicians and molecular biologists employed in a private biopharmaceutical company have the specific principle of beneficence in mind in their daily work. Both groups are motivated to help sick patients. According to the study, molecular biologists explicitly consider nonmaleficence in relation to the environment, the researchers' own health, and animal models; and only implicitly in relation to patients or human subjects. In contrast, considerations of nonmaleficence by oncology physicians relate to patients or human subjects. Physicians and molecular biologists both consider the principle of respect for autonomy as a negative obligation in the sense that informed consent of patients should be respected. However, in contrast to molecular biologists, physicians experience the principle of respect for autonomy as a positive obligation as the physician, in dialogue with the patient, offers a medical prognosis based upon the patients wishes and ideas, mutual understanding, and respect. Finally, this study discloses utilitarian characteristics in the overall conception of justice as conceived by oncology

  15. Essays on measurement and evaluation of demand side management programs in the electricity industry, and impacts of firm strategy on stock price in the biotechnology industry

    Science.gov (United States)

    Bandres Motola, Miguel A.

    Essay one estimates changes in small business customer energy consumption (kWh) patterns resulting from a seasonally differentiated pricing structure. Econometric analysis leverages cross-sectional time series data across the entire population of affected customers, from 2007 through the present. Observations include: monthly energy usage (kWh), relevant customer segmentations, local daily temperature, energy price, and region-specific economic conditions, among other variables. The study identifies the determinants of responsiveness to seasonal price differentiation. In addition, estimated energy consumption changes occurring during the 2010 summer season are reported for the average customer and in aggregate grouped by relevant customer segments, climate zone, and total customer base. Essay two develops an econometric modeling methodology to evaluate load impacts for short duration demand response events. The study analyzes time series data from a season of direct load control program tests aimed at integrating demand response into the wholesale electricity market. I have combined "fuzzy logic" with binary variables to create "fuzzy indicator variables" that allow for measurement of short duration events while using industry standard model specifications. Typically, binary variables for every hour are applied in load impact analysis of programs dispatched in hourly intervals. As programs evolve towards integration with the wholesale market, event durations become irregular and often occur for periods of only a few minutes. This methodology is innovative in that it conserves the degrees of freedom in the model while allowing for analysis of high frequency data using fixed effects. Essay three examines the effects of strategies, intangibles, and FDA news on the stocks of young biopharmaceutical firms. An event study methodology is used to explore those effects. This study investigates 20,839 announcements from 1990 to 2005. Announcements on drug development

  16. Clinical data management: Current status, challenges, and future directions from industry perspectives

    Directory of Open Access Journals (Sweden)

    Zhengwu Lu

    2010-06-01

    Full Text Available Zhengwu Lu1, Jing Su21Smith Hanley Consulting, Houston, Texas; 2Department of Chemical Engineering, University of Massachusetts, Amherst, MA, USAAbstract: To maintain a competitive position, the biopharmaceutical industry has been facing the challenge of increasing productivity both internally and externally. As the product of the clinical development process, clinical data are recognized to be the key corporate asset and provide critical evidence of a medicine’s efficacy and safety and of its potential economic value to the market. It is also well recognized that using effective technology-enabled methods to manage clinical data can enhance the speed with which the drug is developed and commercialized, hence enhancing the competitive advantage. The effective use of data-capture tools may ensure that high-quality data are available for early review and rapid decision-making. A well-designed, protocol-driven, standardized, site workflow-oriented and documented database, populated via efficient data feed mechanisms, will ensure regulatory and commercial questions receive rapid responses. When information from a sponsor’s clinical database or data warehouse develops into corporate knowledge, the value of the medicine can be realized. Moreover, regulators, payer groups, patients, activist groups, patient advocacy groups, and employers are becoming more educated consumers of medicine, requiring monetary value and quality, and seeking out up-todate medical information supplied by biopharmaceutical companies. All these developments in the current biopharmaceutical arena demand that clinical data management (CDM is at the forefront, leading change, influencing direction, and providing objective evidence. Sustaining an integrated database or data repository for initial product registration and subsequent postmarketing uses is a long-term process to maximize return on investment for organizations. CDM should be the owner of driving clinical data

  17. Extractables analysis of single-use flexible plastic biocontainers.

    Science.gov (United States)

    Marghitoiu, Liliana; Liu, Jian; Lee, Hans; Perez, Lourdes; Fujimori, Kiyoshi; Ronk, Michael; Hammond, Matthew R; Nunn, Heather; Lower, Asher; Rogers, Gary; Nashed-Samuel, Yasser

    2015-01-01

    Studies of the extractable profiles of bioprocessing components have become an integral part of drug development efforts to minimize possible compromise in process performance, decrease in drug product quality, and potential safety risk to patients due to the possibility of small molecules leaching out from the components. In this study, an effective extraction solvent system was developed to evaluate the organic extractable profiles of single-use bioprocess equipment, which has been gaining increasing popularity in the biopharmaceutical industry because of the many advantages over the traditional stainless steel-based bioreactors and other fluid mixing and storage vessels. The chosen extraction conditions were intended to represent aggressive conditions relative to the application of single-use bags in biopharmaceutical manufacture, in which aqueous based systems are largely utilized. Those extraction conditions, along with a non-targeted analytical strategy, allowed for the generation and identification of an array of extractable compounds; a total of 53 organic compounds were identified from four types of commercially available single-use bags, the majority of which are degradation products of polymer additives. The success of this overall extractables analysis strategy was reflected partially by the effectiveness in the extraction and identification of a compound that was later found to be highly detrimental to mammalian cell growth. The usage of single-use bioreactors has been increasing in biopharmaceutical industry because of the appealing advantages that it promises regarding to the cleaning, sterilization, operational flexibility, and so on, during manufacturing of biologics. However, compared to its conventional counterparts based mainly on stainless steel, single-use bioreactors are more susceptible to potential problems associated with compound leaching into the bioprocessing fluid. As a result, extractable profiling of the single-use system has become

  18. Empirical investigation of the ethical reasoning of physicians and molecular biologists – the importance of the four principles of biomedical ethics

    Directory of Open Access Journals (Sweden)

    Ebbesen Mette

    2007-10-01

    Full Text Available Abstract Background This study presents an empirical investigation of the ethical reasoning and ethical issues at stake in the daily work of physicians and molecular biologists in Denmark. The aim of this study was to test empirically whether there is a difference in ethical considerations and principles between Danish physicians and Danish molecular biologists, and whether the bioethical principles of the American bioethicists Tom L. Beauchamp and James F. Childress are applicable to these groups. Method This study is based on 12 semi-structured interviews with three groups of respondents: a group of oncology physicians working in a clinic at a public hospital and two groups of molecular biologists conducting basic research, one group employed at a public university and the other in a private biopharmaceutical company. Results In this sample, the authors found that oncology physicians and molecular biologists employed in a private biopharmaceutical company have the specific principle of beneficence in mind in their daily work. Both groups are motivated to help sick patients. According to the study, molecular biologists explicitly consider nonmaleficence in relation to the environment, the researchers' own health, and animal models; and only implicitly in relation to patients or human subjects. In contrast, considerations of nonmaleficence by oncology physicians relate to patients or human subjects. Physicians and molecular biologists both consider the principle of respect for autonomy as a negative obligation in the sense that informed consent of patients should be respected. However, in contrast to molecular biologists, physicians experience the principle of respect for autonomy as a positive obligation as the physician, in dialogue with the patient, offers a medical prognosis based upon the patients wishes and ideas, mutual understanding, and respect. Finally, this study discloses utilitarian characteristics in the overall conception of

  19. Establishing the pharmaceutical quality of Chinese herbal medicine: a provisional BCS classification.

    Science.gov (United States)

    Fong, Sophia Y K; Liu, Mary; Wei, Hai; Löbenberg, Raimar; Kanfer, Isadore; Lee, Vincent H L; Amidon, Gordon L; Zuo, Zhong

    2013-05-06

    The Biopharmaceutical Classification System (BCS), which is a scientific approach to categorize active drug ingredient based on its solubility and intestinal permeability into one of the four classes, has been used to set the pharmaceutical quality standards for drug products in western society. However, it has received little attention in the area of Chinese herbal medicine (CHM). This is likely, in part, due to the presence of multiple active components as well as lack of standardization of CHM. In this report, we apply BCS classification to CHMs provisionally as a basis for establishing improved in vitro quality standards. Based on a top-200 drugs selling list in China, a total of 31 CHM products comprising 50 official active marker compounds (AMCs) were provisionally classified according to BCS. Information on AMC content and doses of these CHM products were retrieved from the Chinese Pharmacopoeia. BCS parameters including solubility and permeability of the AMCs were predicted in silico (ACD/Laboratories). A BCS classification of CHMs according to biopharmaceutical properties of their AMCs is demonstrated to be feasible in the current study and can be used to provide a minimum set of quality standards. Our provisional results showed that 44% of the included AMCs were classified as Class III (high solubility, low permeability), followed by Class II (26%), Class I (18%), and Class IV (12%). A similar trend was observed when CHMs were classified in accordance with the BCS class of AMCs. Most (45%) of the included CHMs were classified as Class III, followed by Class II (16%), Class I (10%), and Class IV (6%); whereas 23% of the CHMs were of mixed class due to the presence of multiple individual AMCs with different BCS classifications. Moreover, about 60% of the AMCs were classified as high-solubility compounds (Class I and Class III), suggesting an important role for an in vitro dissolution test in setting quality control standards ensuring consistent

  20. Absolute quantification of Bovine Viral Diarrhea Virus (BVDV) RNA by the digital PCR technique

    Science.gov (United States)

    Flatschart, R. B.; Almeida, D. O.; Heinemann, M. B.; Medeiros, M. N.; Granjeiro, J. M.; Folgueras-Flatschart, A. V.

    2015-01-01

    The quality control of cell lines used in research and industry is critical to ensure confidence in experimental results and to guarantee the safety of biopharmaceuticals to consumers. The BVDV is a common adventitious agent in many cell lines. We preliminarly evaluate the use of Digital Droplet PCR (ddPCR) for the detection and enumeration of genome copies of BVDV in cell culture and on FBS. The application of a commercial Real-Time PCR kit with the ddPCR technique was successful on different matrices. The technique allowed the absolute quantification of the genome without the use of calibration standards, suggesting its promising application on the development of reference materials for quantification of nucleic acids.

  1. UHPLC: The Greening Face of Liquid Chromatography.

    Science.gov (United States)

    Cielecka-Piontek, Judyta; Zalewski, Przemysław; Jelińska, Anna; Garbacki, Piotr

    2013-01-01

    Pharmaceutical analysis based on chromatographic separation is an important part of studies aimed at developing routine quality analysis of drugs. High-performance liquid chromatography (HPLC) is one of the main analytical techniques recommended for drug analysis. Although it meets many criteria vital for analysis, it is time-consuming and uses a relatively high amount of organic solvents compared to other analytical techniques. Recently, Ultra-high-performance liquid chromatography (UHPLC) has been frequently proposed as an alternative to HPLC, which means introducing an environment-friendly approach to drug analysis achieved by reducing the consumption of solvents. It also offers greater chromatographic resolution and higher sensitivity as well as requiring less time due to faster analysis. This review focuses on the basics of UHPLC, compares that technique with HPLC and discusses the possibilities of applying UHPLC for the analysis of different pharmaceuticals and biopharmaceuticals.

  2. In vitro testing of thiolated poly(aspartic acid) from ophthalmic formulation aspects.

    Science.gov (United States)

    Budai-Szű Cs, Mária; Horvát, Gabriella; Gyarmati, Benjámin; Szilágyi, Barnabás Áron; Szilágyi, András; Csihi, Tímea; Berkó, Szilvia; Szabó-Révész, Piroska; Mori, Michela; Sandri, Giuseppina; Bonferoni, Maria Cristina; Caramella, Carla; Csányi, Erzsébet

    2016-08-01

    Ocular drug delivery formulations must meet anatomical, biopharmaceutical, patient-driven and regulatory requirements. Mucoadhesive polymers can serve as a better alternative to currently available ophthalmic formulations by providing improved bioavailability. If all requirements are addressed, a polymeric formulation resembling the tear film of the eye might be the best solution. The optimum formulation must not have high osmotic activity, should provide appropriate surface tension, pH and refractive index, must be non-toxic and should be transparent and mucoadhesive. We would like to highlight the importance of in vitro polymer testing from a pharmaceutical aspect. We, therefore, carried out physical-chemical investigations to verify the suitability of certain systems for ophthalmic formulations. In this work, in situ gelling, mucoadhesive thiolated poly(aspartic acid)s were tested from ophthalmic formulation aspects. The results of preformulation measurements indicate that these polymers can be used as potential carriers in ophthalmic drug delivery.

  3. Nanoemulsion: A new concept of delivery system

    Directory of Open Access Journals (Sweden)

    Nitin Sharma

    2010-01-01

    Full Text Available Nanoemulsion has been identified as a promising delivery system for various drugs including biopharmaceuticals. Nanoemulsion is a heterogeneous system composed of one immiscible liquid dispersed as droplets within another liquid. The droplets size of nano emulsion is between 20 to 500 nm. Diameter and surface properties of droplets of nanoemulsion plays an important role in the biological behavior of the formulation. Small droplet sizes lead to transparent emulsions so that product appearance is not altered by the addition of an oil phase. In this paper various aspects of nanoemulsion have been discussed including advantages, disadvantages and methods of preparation. Furthermore new approaches of stability of formulation, effect of types and concentration of surfactant, process variables and method are also discussed to improve the stability of nanoemulsion formulation

  4. The Nutraceutical Bioavailability Classification Scheme: Classifying Nutraceuticals According to Factors Limiting their Oral Bioavailability.

    Science.gov (United States)

    McClements, David Julian; Li, Fang; Xiao, Hang

    2015-01-01

    The oral bioavailability of a health-promoting dietary component (nutraceutical) may be limited by various physicochemical and physiological phenomena: liberation from food matrices, solubility in gastrointestinal fluids, interaction with gastrointestinal components, chemical degradation or metabolism, and epithelium cell permeability. Nutraceutical bioavailability can therefore be improved by designing food matrices that control their bioaccessibility (B*), absorption (A*), and transformation (T*) within the gastrointestinal tract (GIT). This article reviews the major factors influencing the gastrointestinal fate of nutraceuticals, and then uses this information to develop a new scheme to classify the major factors limiting nutraceutical bioavailability: the nutraceutical bioavailability classification scheme (NuBACS). This new scheme is analogous to the biopharmaceutical classification scheme (BCS) used by the pharmaceutical industry to classify drug bioavailability, but it contains additional factors important for understanding nutraceutical bioavailability in foods. The article also highlights potential strategies for increasing the oral bioavailability of nutraceuticals based on their NuBACS designation (B*A*T*).

  5. Delivering advanced therapies: the big pharma approach.

    Science.gov (United States)

    Tarnowski, J; Krishna, D; Jespers, L; Ketkar, A; Haddock, R; Imrie, J; Kili, S

    2017-09-01

    After two decades of focused development and some recent clinical successes, cell and gene therapy (CGT) is emerging as a promising approach to personalized medicines. Genetically engineered cells as a medical modality are poised to stand alongside or in combination with small molecule and biopharmaceutical approaches to bring new therapies to patients globally. Big pharma can have a vital role in industrializing CGT by focusing on diseases with high unmet medical need and compelling genetic evidence. Pharma should invest in manufacturing and supply chain solutions that deliver reproducible, high-quality therapies at a commercially viable cost. Owing to the fast pace of innovation in this field proactive engagement with regulators is critical. It is also vital to understand the needs of patients all along the patient care pathway and to establish product pricing that is accepted by prescribers, payers and patients.

  6. The development of cream-mask base composition for androgenetic alopecia prevention and treatment

    Directory of Open Access Journals (Sweden)

    M. I. Fedorovska

    2014-08-01

    Full Text Available Aim. Androgenetic Alopecia (AA treatment nowadays is still a difficult task of dermatology as the range of drugs that affect the pathological link of disease and are safe for prolonged use, is limited. Methods and results. The purpose of the work was to study the optimal composition of the cream-mask base with Saw palmetto dry extract and the tincture of Sophora Japonica intended for prophylactic and therapeutic use in AA. The work presents a complex of physical, biopharmaceutical and microscopic research on the choice of the optimal cream-mask base. Conclusion. It has been established that the best consumer and pharmaco-technological properties are characterized with the bases, to which a complex of emulsifiers MONTANOV 68 and NatureMulse or Olivem 1000 polymers; Carbopol (0,5% and guar gum (1% is introduced;

  7. Efficient micropropagation and assessment of genetic fidelity of Boerhaavia diffusa L- High trade medicinal plant.

    Science.gov (United States)

    Patil, Kapil S; Bhalsing, Sanjivani R

    2015-07-01

    Boerhaavia diffusa L is a medicinal herb with immense pharmaceutical significance. The plant is used by many herbalist, Ayurvedic and pharmaceutical industries for production biopharmaceuticals. It is among the 46 medicinal plant species in high trade sourced mainly from wastelands and generally found in temperate regions of the world. However, the commercial bulk of this plant shows genetic variations which are the main constraint to use this plant as medicinal ingredient and to obtain high value products of pharmaceutical interest from this plant. In this study, we have regenerated the plant of Boerhaavia diffusa L through nodal explants and evaluated genetic fidelity of the micropropagated plants of Boerhaavia diffusa L with the help of random amplified polymorphic DNA (RAPD) markers. The results obtained using RAPD showed monomorphic banding pattern revealing genetic stability among the mother plant and in vitro regenerated plants of Boerhaavia diffusa L.

  8. Soft sensors in bioprocessing: A status report and recommendations

    DEFF Research Database (Denmark)

    Luttmann, Reiner; Bracewell, Daniel G.; Cornelissen, Gesine

    2012-01-01

    The following report with recommendations is the result of an expert panel meeting on soft sensor applications in bioprocess engineering that was organized by the Measurement, Monitoring, Modelling and Control (M3C) Working Group of the European Federation of Biotechnology - Section of Biochemical...... Engineering Science (ESBES). The aim of the panel was to provide an update on the present status of the subject and to identify critical needs and issues for the furthering of the successful development of soft sensor methods in bioprocess engineering research and for industrial applications, in particular...... with focus on biopharmaceutical applications. It concludes with a set of recommendations, which highlight current prospects for the extended use of soft sensors and those areas requiring development....

  9. Industrial systems biology and its impact on synthetic biology of yeast cell factories.

    Science.gov (United States)

    Fletcher, Eugene; Krivoruchko, Anastasia; Nielsen, Jens

    2016-06-01

    Engineering industrial cell factories to effectively yield a desired product while dealing with industrially relevant stresses is usually the most challenging step in the development of industrial production of chemicals using microbial fermentation processes. Using synthetic biology tools, microbial cell factories such as Saccharomyces cerevisiae can be engineered to express synthetic pathways for the production of fuels, biopharmaceuticals, fragrances, and food flavors. However, directing fluxes through these synthetic pathways towards the desired product can be demanding due to complex regulation or poor gene expression. Systems biology, which applies computational tools and mathematical modeling to understand complex biological networks, can be used to guide synthetic biology design. Here, we present our perspective on how systems biology can impact synthetic biology towards the goal of developing improved yeast cell factories. Biotechnol. Bioeng. 2016;113: 1164-1170. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.

  10. Testing of resveratrol microemulsion photostability and protective effect against UV induced oxidative stress.

    Science.gov (United States)

    Juškaitė, Vaida; Ramanauskienė, Kristina; Briedis, Vitalis

    2017-06-27

    Resveratrol is well known for its antioxidant activity and susceptibility to ultraviolet radiation. Development of formulations providing improved stability and relevant drug delivery of resveratrol is still a challenging task. The aim of this study was to determine protective characteristics of formulated microemulsions by evaluating photoisomerization of resveratrol and to investigate the effects of resveratrol on human keratinocyte cells under oxidative stress caused by ultraviolet radiation. Incorporation of resveratrol into microemulsions resulted in increased photostability of active compounds and the results demonstrated that photodegradation of resveratrol was significantly delayed. Results of biopharmaceutical evaluation in vitro demonstrated that up to 60 % of resveratrol was released from microemulsions within 6 hours under a constant release rate profile. In vivo biological testing confirmed the ability of resveratrol to protect cells from oxidative stress and to increase cell viability. It was concluded that microemulsions might be considered in the development of UV light sensitive compounds.

  11. Testing of resveratrol microemulsion photostability and protective effect against UV induced oxidative stress

    Directory of Open Access Journals (Sweden)

    Juškaitė Vaida

    2017-06-01

    Full Text Available Resveratrol is well known for its antioxidant activity and susceptibility to ultraviolet radiation. Development of formulations providing improved stability and relevant drug delivery of resveratrol is still a challenging task. The aim of this study was to determine protective characteristics of formulated microemulsions by evaluating photoisomerization of resveratrol and to investigate the effects of resveratrol on human keratinocyte cells under oxidative stress caused by ultraviolet radiation. Incorporation of resveratrol into microemulsions resulted in increased photostability of active compounds and the results demonstrated that photodegradation of resveratrol was significantly delayed. Results of biopharmaceutical evaluation in vitro demonstrated that up to 60 % of resveratrol was released from microemulsions within 6 hours under a constant release rate profile. In vivo biological testing confirmed the ability of resveratrol to protect cells from oxidative stress and to increase cell viability. It was concluded that microemulsions might be considered in the development of UV light sensitive compounds.

  12. Clinical practice of analysis of anti-drug antibodies against interferon beta and natalizumab in multiple sclerosis patients in Europe

    DEFF Research Database (Denmark)

    Link, Jenny; Ramanujam, Ryan; Auer, Michael

    2017-01-01

    Antibodies against biopharmaceuticals (anti-drug antibodies, ADA) have been a well-integrated part of the clinical care of multiple sclerosis (MS) in several European countries. ADA data generated in Europe during the more than 10 years of ADA monitoring in MS patients treated with interferon beta...... positive test. Shorter times were observed for IFNβ-1b-Extavia s.c. (0.99 and 0.94 years) and natalizumab (0.25 and 0.23 years), which were introduced on the market when ADA testing was already available, as compared to IFNβ-1a i.m. (1.41 and 2.27 years), IFNβ-1b-Betaferon s.c. (2.51 and 1.96 years...

  13. Heterologous production of peptides in plants: fusion proteins and beyond.

    Science.gov (United States)

    Viana, Juliane Flávia Cançado; Dias, Simoni Campos; Franco, Octávio Luiz; Lacorte, Cristiano

    2013-11-01

    Recombinant DNA technology has allowed the ectopic production of proteins and peptides of different organisms leading to biopharmaceutical production in large cultures of bacterial, yeasts and mammalian cells. Otherwise, the expression of recombinant proteins and peptides in plants is an attractive alternative presenting several advantages over the commonly used expression systems including reduced production costs, easy scale-up and reduced risks of pathogen contamination. Different types of proteins and peptides have been expressed in plants, including antibodies, antigens, and proteins and peptides of medical, veterinary and industrial applications. However, apart from providing a proof of concept, the use of plants as platforms for heterologous protein and peptide production still depends on key steps towards optimization including the enhancement of expression levels, manipulation of post-transcriptional modifications and improvements in purification methods. In this review, strategies to increase heterologous protein and peptide stability and accumulation are discussed, focusing on the expression of peptides through the use of gene fusions.

  14. Challenges and advances in the assessment of the disposition of antibody‐drug conjugates

    Science.gov (United States)

    Iyer, Suhasini

    2015-01-01

    Abstract Antibody‐drug conjugates (ADCs) are a rapidly growing therapeutic platform for the treatment of cancer. ADCs consist of a cytotoxic small molecule drug linked to an antibody to provide targeted delivery of the cytotoxic agent to the tumor. Understanding the pharmacokinetics (PK) and pharmacodynamics (PD) of ADCs is crucial in their design to optimize dose and regimen, to maximize efficacy and to minimize toxicity in patients. Significant progress has been made in recent years in this area, however, many fundamental questions still remain. This review discusses factors to consider while assessing the disposition of ADCs, and the unique challenges associated with these therapeutics. Current tools that are available and strategies to enable appropriate assessment are also discussed. © 2015 Genentech Inc. Biopharmaceutics & Drug Disposition Published by John Wiley & Sons Ltd. PMID:25904406

  15. Advances in combination therapy of lung cancer

    DEFF Research Database (Denmark)

    Wu, Lan; Leng, Donglei; Cun, Dongmei

    2017-01-01

    Lung cancer is a complex disease caused by a multitude of genetic and environmental factors. The progression of lung cancer involves dynamic changes in the genome and a complex network of interactions between cancer cells with multiple, distinct cell types that form tumors. Combination therapy......, including small molecule drugs and biopharmaceuticals, which make the optimization of dosing and administration schedule challenging. This article reviews the recent advances in the design and development of combinations of pharmaceuticals for the treatment of lung cancer. Focus is primarily on rationales...... for the selection of specific combination therapies for lung cancer treatment, and state of the art of delivery technologies and dosage regimens for the combinations, tested in preclinical and clinical trials....

  16. Electrospun fish protein fibers as a biopolymer-based carrier – implications for oral protein delivery

    DEFF Research Database (Denmark)

    Boutrup Stephansen, Karen; García-Díaz, María; Jessen, Flemming

    2014-01-01

    Purpose: Protein-based electrospun fibers have emerged as novel nanostructured materials for tissue engineering and drug delivery due to their unique structural characteristics, biocompatibility and biodegradability. The aim of this study was to explore the use of electrospun fibers based on fish...... sarcoplasmic proteins as an oral delivery platform for biopharmaceuticals, using insulin as a model protein. Methods: Fish sarcoplasmic proteins (FSP) were isolated from fresh cod and electrospun into nanomicrofibers using insulin as a model payload. The morphology of FSP fibers was characterized using...... differentiated Caco-2 cell monolayers was followed by RP-HPLC and ELISA, and the transepithelial electrical resistance (TEER) was measured before and after the experiment. Cell viability was assessed by the MTS/PMS assay. Results: Insulin was encapsulated in the electrospun FSP fibers with high efficiency, high...

  17. Determination of Disulfide Bond Connectivity of Cysteine-rich Peptide IpTx{sub a}

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Chul Won; Kim, Jim Il [Chonnam National Univ., Gwangju (Korea, Republic of); Sato, Kazuki [Fukuoka Women' s Univ., Fukuoka (Japan)

    2013-06-15

    Cysteine-rich peptides stabilized by intramolecular disulfide bonds have often been isolated from venoms of microbes, animals and plants. These peptides typically have much higher stability and improved biopharmaceutical properties compared to their linear counterparts. Therefore the correct disulfide bond formation of small proteins and peptides has been extensively studied for a better understanding of their folding mechanism and achieving efficient generation of the naturally occurring biologically active product. Imperatoxin A (IpTx{sub a}), a peptide toxin containing 6 cysteine residues, was isolated from the venom of scorpion Pandinus imperator, selectively binds the ryanodine receptors and activates Ca{sup 2+} release from sarcoplasmic reticulum (SR). IpTx{sub a} increases the binding of ryanodine to ryanodine receptors (RyRs) and encourages reconstituted single channel to induce subconductance states.

  18. Conformational Assessment of Adnectin and Adnectin-Drug Conjugate by Hydrogen/Deuterium Exchange Mass Spectrometry

    Science.gov (United States)

    Huang, Richard Y.-C.; O'Neil, Steven R.; Lipovšek, Daša; Chen, Guodong

    2018-05-01

    Higher-order structure (HOS) characterization of therapeutic protein-drug conjugates for comprehensive assessment of conjugation-induced protein conformational changes is an important consideration in the biopharmaceutical industry to ensure proper behavior of protein therapeutics. In this study, conformational dynamics of a small therapeutic protein, adnectin 1, together with its drug conjugate were characterized by hydrogen/deuterium exchange mass spectrometry (HDX-MS) with different spatial resolutions. Top-down HDX allows detailed assessment of the residue-level deuterium content in the payload conjugation region. HDX-MS dataset revealed the ability of peptide-based payload/linker to retain deuterium in HDX experiments. Combined results from intact, top-down, and bottom-up HDX indicated no significant conformational changes of adnectin 1 upon payload conjugation. [Figure not available: see fulltext.

  19. Organic solute carrier 22 (SLC22 family: Potential for interactions with food, herbal/dietary supplements, endogenous compounds, and drugs

    Directory of Open Access Journals (Sweden)

    Raymond E. Lai

    2018-04-01

    Full Text Available Many drugs, hormones, components of herbal medicines, environmental pesticides and toxins are Solute Carrier family 22 (SLC22 substrates. The last twenty years has seen great progress in determining SLC22 tissue expression profiles, membrane localization, energetics, substrate profiles and biopharmaceutical significance. However, much still remains to be answered in terms of SLC22 family member's roles in ‘normal’ physiology as compared to pathophysiological states, as well as in drug interactions that impact pharmacokinetics, efficacy and toxicity. This review begins with a brief synopsis of SLC22 family discovery, function and tissue expression. Subsequent sections provide examples establishing a role for SLC22 transporters in food-drug, herbal supplement-drug, endogenous substrate-drug and drug–drug interactions. Keywords: Hepatic transport, Nephrotoxicity, Organic anion transporter, Organic cation transporter, Renal transport

  20. Optimizing clinical drug product performance

    DEFF Research Database (Denmark)

    Dickinson, Paul A.; Kesisoglou, Filippos; Flanagan, Talia

    2016-01-01

    The aim of Biopharmaceutics Risk Assessment Roadmap (BioRAM) and the BioRAM Scoring Grid is to facilitate optimization of clinical performance of drug products. BioRAM strategy relies on therapy-driven drug delivery and follows an integrated systems approach for formulating and addressing critical...... questions and decision-making (J Pharm Sci. 2014,103(11): 3777-97). In BioRAM, risk is defined as not achieving the intended in vivo drug product performance, and success is assessed by time to decision-making and action. Emphasis on time to decision-making and time to action highlights the value of well....... Application of the BioRAM Scoring Grid is illustrated using published literature. Organizational considerations for implementing BioRAM strategy, including the interactions, function, and skillsets of the BioRAM group members, are also reviewed. As a creative and innovative systems approach, we believe...

  1. Immunogenicity of biologically-derived therapeutics: assessment and interpretation of nonclinical safety studies.

    Science.gov (United States)

    Ponce, Rafael; Abad, Leslie; Amaravadi, Lakshmi; Gelzleichter, Thomas; Gore, Elizabeth; Green, James; Gupta, Shalini; Herzyk, Danuta; Hurst, Christopher; Ivens, Inge A; Kawabata, Thomas; Maier, Curtis; Mounho, Barbara; Rup, Bonita; Shankar, Gopi; Smith, Holly; Thomas, Peter; Wierda, Dan

    2009-07-01

    An evaluation of potential antibody formation to biologic therapeutics during the course of nonclinical safety studies and its impact on the toxicity profile is expected under current regulatory guidance and is accepted standard practice. However, approaches for incorporating this information in the interpretation of nonclinical safety studies are not clearly established. Described here are the immunological basis of anti-drug antibody formation to biopharmaceuticals (immunogenicity) in laboratory animals, and approaches for generating and interpreting immunogenicity data from nonclinical safety studies of biotechnology-derived therapeutics to support their progression to clinical evaluation. We subscribe that immunogenicity testing strategies should be adapted to the specific needs of each therapeutic development program, and data generated from such analyses should be integrated with available clinical and anatomic pathology, pharmacokinetic, and pharmacodynamic data to properly interpret nonclinical studies.

  2. Mechanistic failure mode investigation and resolution of parvovirus retentive filters.

    Science.gov (United States)

    LaCasse, Daniel; Lute, Scott; Fiadeiro, Marcus; Basha, Jonida; Stork, Matthew; Brorson, Kurt; Godavarti, Ranga; Gallo, Chris

    2016-07-08

    Virus retentive filters are a key product safety measure for biopharmaceuticals. A simplistic perception is that they function solely based on a size-based particle removal mechanism of mechanical sieving and retention of particles based on their hydrodynamic size. Recent observations have revealed a more nuanced picture, indicating that changes in viral particle retention can result from process pressure and/or flow interruptions. In this study, a mechanistic investigation was performed to help identify a potential mechanism leading to the reported reduced particle retention in small virus filters. Permeate flow rate or permeate driving force were varied and analyzed for their impact on particle retention in three commercially available small virus retentive filters. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:959-970, 2016. © 2016 American Institute of Chemical Engineers.

  3. Analysis of carbohydrates and glycoconjugates by matrix-assisted laser desorption/ionization mass spectrometry: an update for 2009-2010.

    Science.gov (United States)

    Harvey, David J

    2015-01-01

    This review is the sixth update of the original article published in 1999 on the application of MALDI mass spectrometry to the analysis of carbohydrates and glycoconjugates and brings coverage of the literature to the end of 2010. General aspects such as theory of the MALDI process, matrices, derivatization, MALDI imaging, arrays and fragmentation are covered in the first part of the review and applications to various structural typed constitutes the remainder. The main groups of compound that are discussed in this section are oligo and polysaccharides, glycoproteins, glycolipids, glycosides and biopharmaceuticals. Many of these applications are presented in tabular form. Also discussed are medical and industrial applications of the technique, studies of enzyme reactions and applications to chemical synthesis. © 2014 Wiley Periodicals, Inc.

  4. Money and morals: ending clinical trials for financial reasons.

    Science.gov (United States)

    Eaton, Margaret L; Kwon, Brian K; Scott, Christopher Thomas

    2015-01-01

    Too often, biopharmaceutical companies stop their clinical trials solely for financial reasons. In this chapter, we discuss this phenomenon against the backdrop of a 2011 decision by Geron Corporation to abandon its stem cell clinical trial for spinal cord injury (SCI), the preliminary results of which were released in May 2014. We argue that the resultant harms are widespread and are different in nature from the consequences of stopping trials for scientific or medical reasons. We examine the ethical and social effects that arise from such decisions and discuss them in light of ethical frameworks, including duties of individual stakeholders and corporate sponsors. We offer ways that sponsors and clinical sites can ensure that trials are responsibly started, and once started adequately protect the interests of participants. We conclude with recommendations that industry sponsors of clinical trials should adopt in order to advance a collective and patient-centered research ethic.

  5. [Research progress on current pharmacokinetic evaluation of Chinese herbal medicines].

    Science.gov (United States)

    Li, Guofu; Zhao, Haoru; Yang, Jin

    2011-03-01

    In order to prove safety and efficacy, herbal medicines must undergo the rigorous scientific researches such as pharmacokinetic and bioavailability, before they are put on the market in the foreign countries. Botanical Drug Products promulgated by the US FDA could guide industry sponsors to develop herbal drugs, which was also an important reference for investigating Chinese herbal medicines. This paper reviews and discusses novel approaches for how to assess systemic exposure and pharmacokinetic of Chinese herbal medicines, which were in line with FDA guidance. This mainly focus on identifying pharmacokinetic markers of botanical products, integral pharmacokinetic study of multiple components, Biopharmaceutics drug disposition classification system, and population pharmacokinetic-pharmacodynamic study in herb-drug interaction.

  6. Routes for drug translocation across the blood-brain barrier

    DEFF Research Database (Denmark)

    Kristensen, Mie; Brodin, Birger

    2017-01-01

    A number of potent drugs for the treatment of brain diseases are available. However, in order for them to reach their target site of action, they must pass the blood-brain barrier (BBB). The capillary endothelium comprises the major barrier of the BBB and allows only passive permeation of some...... small lipophilic molecules. Brain delivery of the larger biopharmaceuticals, which today includes an increasing number of novel drug entities, is therefore restricted; both due to their molecular size and their hydrophilic nature. Thus, the development of novel drug entities intended for the treatment...... of brain diseases such as neurodegenerative diseases or brain cancers, require a delivery strategy for overcoming the BBB before reaching its final target within the brain. Peptide-based delivery vectors is an emerging tool as shuttles for drug delivery across the BBB and one may explore receptor...

  7. Trends in Process Analytical Technology: Present State in Bioprocessing.

    Science.gov (United States)

    Jenzsch, Marco; Bell, Christian; Buziol, Stefan; Kepert, Felix; Wegele, Harald; Hakemeyer, Christian

    2017-08-04

    Process analytical technology (PAT), the regulatory initiative for incorporating quality in pharmaceutical manufacturing, is an area of intense research and interest. If PAT is effectively applied to bioprocesses, this can increase process understanding and control, and mitigate the risk from substandard drug products to both manufacturer and patient. To optimize the benefits of PAT, the entire PAT framework must be considered and each elements of PAT must be carefully selected, including sensor and analytical technology, data analysis techniques, control strategies and algorithms, and process optimization routines. This chapter discusses the current state of PAT in the biopharmaceutical industry, including several case studies demonstrating the degree of maturity of various PAT tools. Graphical Abstract Hierarchy of QbD components.

  8. Strategies to improve drug delivery across the blood-brain barrier.

    Science.gov (United States)

    de Boer, Albertus G; Gaillard, Pieter J

    2007-01-01

    The blood-brain barrier (BBB), together with the blood-cerebrospinal-fluid barrier, protects and regulates the homeostasis of the brain. However, these barriers also limit the transport of small-molecule and, particularly, biopharmaceutical drugs such as proteins, genes and interference RNA to the brain, thereby limiting the treatment of many brain diseases. As a result, various drug delivery and targeting strategies are currently being developed to enhance the transport and distribution of drugs into the brain. In this review, we discuss briefly the biology and physiology of the BBB as the most important barrier for drug transport to the brain and, in more detail, the possibilities for delivering large-molecule drugs, particularly genes, by receptor-mediated nonviral drug delivery to the (human) brain. In addition, the systemic and intracellular pharmacokinetics of nonviral gene delivery, together with targeted brain imaging, are reviewed briefly.

  9. Amino acid and glucose metabolism in fed-batch CHO cell culture affects antibody production and glycosylation

    DEFF Research Database (Denmark)

    Fan, Yuzhou; Jimenez Del Val, Ioscani; Müller, Christian

    2015-01-01

    optimization, especially media optimization. Gaining knowledge on their interrelations could provide insight for obtaining higher immunoglobulin G (IgG) titer and better controlling glycosylationrelated product quality. In this work, different fed-batch processes with two chemically defined proprietary media......Fed-batch Chinese hamster ovary (CHO) cell culture is the most commonly used process for IgG production in the biopharmaceutical industry. Amino acid and glucose consumption, cell growth, metabolism, antibody titer, and N-glycosylation patterns are always the major concerns during upstream process...... and glutamine concentrations and uptake rates were positively correlated with intracellular UDP-Gal availability. All these findings are important for optimization of fed-batch culture for improving IgG production and directing glycosylation quality....

  10. The yeast stands alone: the future of protein biologic production.

    Science.gov (United States)

    Love, Kerry R; Dalvie, Neil C; Love, J Christopher

    2017-12-22

    Yeasts are promising alternative hosts for the manufacturing of recombinant protein therapeutics because they simply and efficiently meet needs for both platform and small-market drugs. Fast accumulation of biomass and low-cost media reduce the cost-of-goods when using yeast, which in turn can enable agile, small-volume manufacturing facilities. Small, tractable yeast genomes are amenable to rapid process development, facilitating strain and product quality by design. Specifically, Pichia pastoris is becoming a widely accepted yeast for biopharmaceutical manufacturing in much of the world owing to a clean secreted product and the rapidly expanding understanding of its cell biology as a host organism. We advocate for a near term partnership spanning industry and academia to promote open source, timely development of yeast hosts. Copyright © 2017. Published by Elsevier Ltd.

  11. Bile Salt Micelles and Phospholipid Vesicles Present in Simulated and Human Intestinal Fluids

    DEFF Research Database (Denmark)

    Elvang, Philipp A; Hinna, Askell H; Brouwers, Joachim

    2016-01-01

    Knowledge about colloidal assemblies present in human intestinal fluids (HIFs), such as bile salt micelles and phospholipid vesicles, is regarded of importance for a better understanding of the in vivo dissolution and absorption behavior of poorly soluble drugs (Biopharmaceutics Classification...... System class II/IV drugs) because of their drug-solubilizing ability. The characterization of these potential drug-solubilizing compartments is a prerequisite for further studies of the mechanistic interplays between drug molecules and colloidal structures within HIFs. The aim of the present study...... and HIF indicate that the simulated intestinal fluids (FaSSIF-V1 and FeSSIF-V1) represent rather simplified models of the real human intestinal environment in terms of coexisting colloidal particles. It is hypothesized that the different supramolecular assemblies detected differ in their lipid composition...

  12. Facilitating a More Efficient Commercial Review Process for Pediatric Drugs and Biologics

    Directory of Open Access Journals (Sweden)

    Ryan D. Rykhus

    2017-12-01

    Full Text Available Over the past two decades, the biopharmaceutical industry has seen unprecedented expansion and innovation in concert with significant technological advancements. While the industry has experienced marked growth, the regulatory system in the United States still operates at a capacity much lower than the influx of new drug and biologic candidates. As a result, it has become standard for months or even years of waiting for commercial approval by the U.S. Food and Drug Administration. These regulatory delays have generated a system that stifles growth and innovation due to the exorbitant costs associated with awaiting approval from the nation’s sole regulatory agency. The recent re-emergence of diseases that impact pediatric demographics represents one particularly acute reason for developing a regulatory system that facilitates a more efficient commercial review process. Herein, we present a range of initiatives that could represent early steps toward alleviating the delays in approving life-saving therapeutics.

  13. The functional and biological properties of whey proteins: prospects for the development of functional foods

    Directory of Open Access Journals (Sweden)

    H. J. T. KORHONEN

    2008-12-01

    Full Text Available Advances in processing technologies and the accumulation of scientific data on the functional and biological properties of whey components have contributed to the growing commercial valuation of cheese whey over the last decade. New membrane separation and chromatographic techniques have made it possible to fractionate and enrich various components of whey more efficiently than before. The specific properties of these components can now be examined in greater detail and new applications developed accordingly. The utilisation of cheese whey is evolving into a new industry producing a multitude of purified ingredients for numerous purposes. The most significant areas of R&D related to whey proteins include functional foods, the rheological properties of foodstuffs, and biopharmaceuticals.

  14. Anti-TNF-α biotherapies

    DEFF Research Database (Denmark)

    Bendtzen, Klaus

    2012-01-01

    This article discusses the rationale behind recommending immunopharmacological guidance of long-term therapies with genetically engineered anti-TNF-α immunoglobulin constructs. Arguments why therapeutic decision-making should not rely on clinical outcome alone are presented. Central...... to this is that the use of theranostics (i.e., monitoring circulating levels of functional anti-TNF-α drugs and antidrug antibodies) would markedly improve treatment because therapies can be tailored to individual patients and provide more effective and economical long-term therapies with minimal risk of side effects....... Large-scale immunopharmacological knowledge of how patients 'handle' TNF-α biopharmaceuticals would also help industry develop more effective and safer TNF-α inhibitors....

  15. Use of a charge reducing agent to enable intact mass analysis of cysteine-linked antibody-drug-conjugates by native mass spectrometry

    Directory of Open Access Journals (Sweden)

    Kamila J. Pacholarz

    2016-06-01

    Full Text Available Antibody-drug-conjugates (ADC are a growing class of anticancer biopharmaceuticals. Conjugation of cysteine linked ADCs, requires initial reduction of mAb inter-chain disulfide bonds, as the drugs are attached via thiol chemistry. This results in the active mAb moiety being transformed from a covalently linked tetramer to non-covalently linked complexes, which hinders precise determination of drug load with LC–MS. Here, we show how the addition of the charge reducing agent triethylammonium acetate (TEAA preserves the intact mAb structure, is well suited to the study of cysteine linked conjugates and facilitates easy drug load determination by direct infusion native MS.

  16. Glycotherapy: new advances inspire a reemergence of glycans in medicine.

    Science.gov (United States)

    Hudak, Jason E; Bertozzi, Carolyn R

    2014-01-16

    The beginning of the 20(th) century marked the dawn of modern medicine with glycan-based therapies at the forefront. However, glycans quickly became overshadowed as DNA- and protein-focused treatments became readily accessible. The recent development of new tools and techniques to study and produce structurally defined carbohydrates has spurred renewed interest in the therapeutic applications of glycans. This review focuses on advances within the past decade that are bringing glycan-based treatments back to the forefront of medicine and the technologies that are driving these efforts. These include the use of glycans themselves as therapeutic molecules as well as engineering protein and cell surface glycans to suit clinical applications. Glycan therapeutics offer a rich and promising frontier for developments in the academic, biopharmaceutical, and medical fields. Copyright © 2014 Elsevier Ltd. All rights reserved.

  17. Biosimilars design and analysis of follow-on biologics

    CERN Document Server

    2013-01-01

    "This book extensively covers both statistical and regulatory considerations from design to analysis of biosimilarity. … it is well presented and comprehensively covers fundamental issues and some of the newly developed methods for biosimilarity studies. The book is very balanced between scientific aspects and regulatory requirements. In addition, the reference lists give readers helpful information. … a valuable resource for anyone interested and involved in biosimilarity studies."-Biometrics, September 2014"[Professor] Chow's book Biosimilars: Design and Analysis of Follow-On Biologics … is the first book ever written on this topic. I commend Professor Chow for his effort to introduce the topic … Overall, this is a worthwhile reference book for statisticians interested in understanding biosimilar product development and evaluation." -Yi Tsong, PhD, Center for Drug Evaluation and Research, US Food and Drug Administration, USA, in Journal of Biopharmaceutical Statistics>.

  18. Metal ion controlled self-assembly of a chemically reengineered protein drug studied by small-angle X-ray scattering

    DEFF Research Database (Denmark)

    Jesper, Nygaard; Munch, Henrik K.; Thulstrup, Peter W.

    2012-01-01

    . A small-angle X-ray scattering analysis of the bipyridine-modified insulin system confirmed an organization into a novel well-ordered structure based on insulin trimers, as induced by the addition of Fe(II). In contrast, unmodified monomeric insulin formed larger and more randomly structured assemblies......Precise control of the oligomeric state of proteins is of central importance for biological function and for the properties of biopharmaceutical drugs. Here, the self-assembly of 2,2′-bipyridine conjugated monomeric insulin analogues, induced through coordination to divalent metal ions, was studied....... This protein drug system was designed to form non-native homo-oligomers through selective coordination of two divalent metal ions, Fe(II) and Zn(II), respectively. The insulin type chosen for this study is a variant designed for a reduced tendency toward native dimer formation at physiological concentrations...

  19. Gene Therapy for Advanced Melanoma: Selective Targeting and Therapeutic Nucleic Acids

    Directory of Open Access Journals (Sweden)

    Joana R. Viola

    2013-01-01

    Full Text Available Despite recent advances, the treatment of malignant melanoma still results in the relapse of the disease, and second line treatment mostly fails due to the occurrence of resistance. A wide range of mutations are known to prevent effective treatment with chemotherapeutic drugs. Hence, approaches with biopharmaceuticals including proteins, like antibodies or cytokines, are applied. As an alternative, regimens with therapeutically active nucleic acids offer the possibility for highly selective cancer treatment whilst avoiding unwanted and toxic side effects. This paper gives a brief introduction into the mechanism of this devastating disease, discusses the shortcoming of current therapy approaches, and pinpoints anchor points which could be harnessed for therapeutic intervention with nucleic acids. We bring the delivery of nucleic acid nanopharmaceutics into perspective as a novel antimelanoma therapeutic approach and discuss the possibilities for melanoma specific targeting. The latest reports on preclinical and already clinical application of nucleic acids in melanoma are discussed.

  20. DESIGN OF FILL AND FINISH FACILITY FOR ACTIVE PHARMACEUTICAL INGREDIENTS (API

    Directory of Open Access Journals (Sweden)

    NUUR LAILA KHAIRUDDIN

    2016-08-01

    Full Text Available Fill and finish operations continue to be one of the most heavily outsourced activities in the biopharmaceutical manufacturing market today. There are a few aspects that need to be consider in outsource activities like logistic, storage condition, facility certification and audit as regulations and standards which the manufacturer should adhere. Risk would be greater and extra care should be taken when outsource from foreign fill and finish facility. Thus, the internal aseptic fill and finish facility with audit checklist will help to minimize the risk during logistic and storage and also minimize the cost for outsource fill and finish facility. The data collections are through survey and conceptual design with simulation as the execution part.

  1. Toward greener analytical techniques for the absolute quantification of peptides in pharmaceutical and biological samples.

    Science.gov (United States)

    Van Eeckhaut, Ann; Mangelings, Debby

    2015-09-10

    Peptide-based biopharmaceuticals represent one of the fastest growing classes of new drug molecules. New reaction types included in the synthesis strategies to reduce the rapid metabolism of peptides, along with the availability of new formulation and delivery technologies, resulted in an increased marketing of peptide drug products. In this regard, the development of analytical methods for quantification of peptides in pharmaceutical and biological samples is of utmost importance. From the sample preparation step to their analysis by means of chromatographic or electrophoretic methods, many difficulties should be tackled to analyze them. Recent developments in analytical techniques emphasize more and more on the use of green analytical techniques. This review will discuss the progresses in and challenges observed during green analytical method development for the quantification of peptides in pharmaceutical and biological samples. Copyright © 2015 Elsevier B.V. All rights reserved.

  2. The genomic sequence of the Chinese hamster ovary (CHO)-K1 cell line

    DEFF Research Database (Denmark)

    Xu, Xun; Pan, Shengkai; Liu, Xin

    2011-01-01

    Chinese hamster ovary (CHO)-derived cell lines are the preferred host cells for the production of therapeutic proteins. Here we present a draft genomic sequence of the CHO-K1 ancestral cell line. The assembly comprises 2.45 Gb of genomic sequence, with 24,383 predicted genes. We associate most....... Homologs of most human glycosylation-associated genes are present in the CHO-K1 genome, although 141 of these homologs are not expressed under exponential growth conditions. Many important viral entry genes are also present in the genome but not expressed, which may explain the unusual viral resistance...... property of CHO cell lines. We discuss how the availability of this genome sequence may facilitate genome-scale science for the optimization of biopharmaceutical protein production....

  3. Microbials for the production of monoclonal antibodies and antibody fragments.

    Science.gov (United States)

    Spadiut, Oliver; Capone, Simona; Krainer, Florian; Glieder, Anton; Herwig, Christoph

    2014-01-01

    Monoclonal antibodies (mAbs) and antibody fragments represent the most important biopharmaceutical products today. Because full length antibodies are glycosylated, mammalian cells, which allow human-like N-glycosylation, are currently used for their production. However, mammalian cells have several drawbacks when it comes to bioprocessing and scale-up, resulting in long processing times and elevated costs. By contrast, antibody fragments, that are not glycosylated but still exhibit antigen binding properties, can be produced in microbial organisms, which are easy to manipulate and cultivate. In this review, we summarize recent advances in the expression systems, strain engineering, and production processes for the three main microbials used in antibody and antibody fragment production, namely Saccharomyces cerevisiae, Pichia pastoris, and Escherichia coli. Copyright © 2013 Elsevier Ltd. All rights reserved.

  4. Teaching and implementing autonomous robotic lab walkthroughs in a biotech laboratory through model-based visual tracking

    Science.gov (United States)

    Wojtczyk, Martin; Panin, Giorgio; Röder, Thorsten; Lenz, Claus; Nair, Suraj; Heidemann, Rüdiger; Goudar, Chetan; Knoll, Alois

    2010-01-01

    After utilizing robots for more than 30 years for classic industrial automation applications, service robots form a constantly increasing market, although the big breakthrough is still awaited. Our approach to service robots was driven by the idea of supporting lab personnel in a biotechnology laboratory. After initial development in Germany, a mobile robot platform extended with an industrial manipulator and the necessary sensors for indoor localization and object manipulation, has been shipped to Bayer HealthCare in Berkeley, CA, USA, a global player in the sector of biopharmaceutical products, located in the San Francisco bay area. The determined goal of the mobile manipulator is to support the off-shift staff to carry out completely autonomous or guided, remote controlled lab walkthroughs, which we implement utilizing a recent development of our computer vision group: OpenTL - an integrated framework for model-based visual tracking.

  5. Recent patents in plant biotechnology: impact on global health.

    Science.gov (United States)

    Hefferon, Kathleen L

    2012-08-01

    Agricultural biotechnology offers a robust series of tools by which to address global concerns such as food security, crop protection, and fuel/energy requirements. A number of advances made recently in plant molecular biology also have resulted in applications which largely focus on improving global human health. This review describes some of the recent innovations in plant biotechnology that have come to the forefront over the past year. Included are novel techniques by which plants can be improved as platforms for biopharmaceutical protein production, a growing field also referred to as 'molecular pharming'. The metabolic engineering of plants to produce compounds which have additional nutritional benefits is also outlined. The review concludes with a discussion of the future impact that these innovations may have both on global health and on the development of our future intellectual property landscape.

  6. Preparative Purification of Recombinant Proteins: Current Status and Future Trends

    Directory of Open Access Journals (Sweden)

    Mayank Saraswat

    2013-01-01

    Full Text Available Advances in fermentation technologies have resulted in the production of increased yields of proteins of economic, biopharmaceutical, and medicinal importance. Consequently, there is an absolute requirement for the development of rapid, cost-effective methodologies which facilitate the purification of such products in the absence of contaminants, such as superfluous proteins and endotoxins. Here, we provide a comprehensive overview of a selection of key purification methodologies currently being applied in both academic and industrial settings and discuss how innovative and effective protocols such as aqueous two-phase partitioning, membrane chromatography, and high-performance tangential flow filtration may be applied independently of or in conjunction with more traditional protocols for downstream processing applications.

  7. A step-up test procedure to find the minimum effective dose.

    Science.gov (United States)

    Wang, Weizhen; Peng, Jianan

    2015-01-01

    It is of great interest to find the minimum effective dose (MED) in dose-response studies. A sequence of decreasing null hypotheses to find the MED is formulated under the assumption of nondecreasing dose response means. A step-up multiple test procedure that controls the familywise error rate (FWER) is constructed based on the maximum likelihood estimators for the monotone normal means. When the MED is equal to one, the proposed test is uniformly more powerful than Hsu and Berger's test (1999). Also, a simulation study shows a substantial power improvement for the proposed test over four competitors. Three R-codes are provided in Supplemental Materials for this article. Go to the publishers online edition of Journal of Biopharmaceutical Statistics to view the files.

  8. Sherlock Holmes and the proteome--a detective story.

    Science.gov (United States)

    Righetti, Pier Giorgio; Boschetti, Egisto

    2007-02-01

    The performance of a hexapeptide ligand library in capturing the 'hidden proteome' is illustrated and evaluated. This library, insolubilized on an organic polymer and available under the trade name 'Equalizer Bead Technology', acts by capturing all components of a given proteome, by concentrating rare and very rare proteins, and simultaneously diluting the abundant ones. This results in a proteome of 'normalized' relative abundances, amenable to analysis by MS and any other analytical tool. Examples are given of analysis of human urine and serum, as well as cell and tissue lysates, such as Escherichia coli and Saccharomyces cerevisiae extracts. Another important application is impurity tracking and polishing of recombinant DNA products, especially biopharmaceuticals meant for human consumption.

  9. Clinical pharmacology of CAR-T cells: Linking cellular pharmacodynamics to pharmacokinetics and antitumor effects.

    Science.gov (United States)

    Norelli, M; Casucci, M; Bonini, C; Bondanza, A

    2016-01-01

    Adoptive cell transfer of T cells genetically modified with tumor-reactive chimeric antigen receptors (CARs) is a rapidly emerging field in oncology, which in preliminary clinical trials has already shown striking antitumor efficacy. Despite these premises, there are still a number of open issues related to CAR-T cells, spanning from their exact mechanism of action (pharmacodynamics), to the factors associated with their in vivo persistence (pharmacokinetics), and, finally, to the relative contribution of each of the two in determining the antitumor effects and accompanying toxicities. In light of the unprecedented curative potential of CAR-T cells and of their predicted wide availability in the next few years, in this review we will summarize the current knowledge on the clinical pharmacology aspects of what is anticipated to be a brand new class of biopharmaceuticals to join the therapeutic armamentarium of cancer doctors. Copyright © 2015. Published by Elsevier B.V.

  10. Quantitative intracellular flux modeling and applications in biotherapeutic development and production using CHO cell cultures.

    Science.gov (United States)

    Huang, Zhuangrong; Lee, Dong-Yup; Yoon, Seongkyu

    2017-12-01

    Chinese hamster ovary (CHO) cells have been widely used for producing many recombinant therapeutic proteins. Constraint-based modeling, such as flux balance analysis (FBA) and metabolic flux analysis (MFA), has been developing rapidly for the quantification of intracellular metabolic flux distribution at a systematic level. Such methods would produce detailed maps of flows through metabolic networks, which contribute significantly to better understanding of metabolism in cells. Although these approaches have been extensively established in microbial systems, their application to mammalian cells is sparse. This review brings together the recent development of constraint-based models and their applications in CHO cells. The further development of constraint-based modeling approaches driven by multi-omics datasets is discussed, and a framework of potential modeling application in cell culture engineering is proposed. Improved cell culture system understanding will enable robust developments in cell line and bioprocess engineering thus accelerating consistent process quality control in biopharmaceutical manufacturing. © 2017 Wiley Periodicals, Inc.

  11. Improved Production of a Heterologous Amylase in Saccharomyces cerevisiae by Inverse Metabolic Engineering

    DEFF Research Database (Denmark)

    Liu, Zihe; Liu, Lifang; Osterlund, Tobias

    2014-01-01

    this modification alone, the amylase secretion could be improved by 35%. As a complement to the identification of genomic variants, transcriptome analysis was also performed in order to understand on a global level the transcriptional changes associated with the improved amylase production caused by UV mutagenesis.......The increasing demand for industrial enzymes and biopharmaceutical proteins relies on robust production hosts with high protein yield and productivity. Being one of the best-studied model organisms and capable of performing posttranslational modifications, the yeast Saccharomyces cerevisiae...... is widely used as a cell factory for recombinant protein production. However, many recombinant proteins are produced at only 1% (or less) of the theoretical capacity due to the complexity of the secretory pathway, which has not been fully exploited. In this study, we applied the concept of inverse metabolic...

  12. Differential Mobility Spectrometry-Hydrogen Deuterium Exchange (DMS-HDX) as a Probe of Protein Conformation in Solution.

    Science.gov (United States)

    Zhu, Shaolong; Campbell, J Larry; Chernushevich, Igor; Le Blanc, J C Yves; Wilson, Derek J

    2016-06-01

    Differential mobility spectrometry (DMS) is an ion mobility technique that has been adopted chiefly as a pre-filter for small- to medium-sized analytes (DMS-field asymmetric waveform ion mobility spectroscopy (FAIMS)-the application of DMS to intact biomacromolecules remains largely unexplored. In this work, we employ DMS combined with gas-phase hydrogen deuterium exchange (DMS-HDX) to probe the gas-phase conformations generated from proteins that were initially folded, partially-folded, and unfolded in solution. Our findings indicate that proteins with distinct structural features in solution exhibit unique deuterium uptake profiles as function of their optimal transmission through the DMS. Ultimately we propose that DMS-HDX can, if properly implemented, provide rapid measurements of liquid-phase protein structural stability that could be of use in biopharmaceuticals development. Graphical Abstract ᅟ.

  13. Correlation of cell growth and heterologous protein production by Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Liu, Zihe; Hou, Jin; Martinez Ruiz, José Luis

    2013-01-01

    .g., metabolic and cellular stresses have a strong impact on recombinant protein production. In this work, we investigated the effect of the specific growth rate on the production of two different recombinant proteins. Our results show that human insulin precursor is produced in a growth-associated manner...... turnover, cell cycle, and global stress response. We also found that there is a shift at a specific growth rate of 0.1 h−1 that influences protein production. Thus, for lower specific growth rates, the α-amylase and insulin precursor-producing strains present similar cell responses and phenotypes, whereas......With the increasing demand for biopharmaceutical proteins and industrial enzymes, it is necessary to optimize the production by microbial fermentation or cell cultures. Yeasts are well established for the production of a wide range of recombinant proteins, but there are also some limitations; e...

  14. Avelumab: First Global Approval.

    Science.gov (United States)

    Kim, Esther S

    2017-05-01

    Avelumab (Bavencio ® ) is an intravenously administered programmed cell death ligand-1-blocking human antibody initially developed by EMD Serono Inc. (the biopharmaceutical division of Merck KGaA, Darmstadt, Germany) [now jointly developed and commercialized by EMD Serono Inc. and Pfizer] for the treatment of various tumours. It has received accelerated approval in the USA for the treatment of metastatic Merkel cell carcinoma (mMCC) in adults and paediatric patients aged ≥12 years. The marketing authorization application for avelumab in the treatment of mMCC is undergoing regulatory review in the EU, the biologics license application for avelumab in the treatment of urothelial carcinoma is undergoing priority review by the FDA, and avelumab is in various stages of development internationally for a variety of cancers. This article summarizes the milestones in the development of avelumab leading to this first approval for mMCC.

  15. AMCP Partnership Forum: FDAMA Section 114-Improving the Exchange of Health Care Economic Data.

    Science.gov (United States)

    2016-07-01

    The Food and Drug Administration Modernization Act (FDAMA) of 1997 included Section 114 as a regulatory safe harbor with the goal of increasing the dissemination of health care economic information (HCEI) to those responsible for formulary decision making. HCEI is typically not included within FDA-approved labeling. Although it has been nearly 20 years since passage and enactment of Section 114, proactive distribution of HCEI has been underutilized by biopharmaceutical companies partly because of (a) vague wording in the statute and (b) the absence of FDA-implementing regulations. Consequently, companies and health care decisions makers have had to speculate about the scope of the provisions. As a result, the biopharmaceutical industry has significant concerns about stepping over the line when using the safe harbor. Also, payers and other "payer-like" decision makers (e.g., self-funded corporate insurers) who are trying to make appropriate coverage and utilization decisions are demanding this information but are not receiving it because of the uncertainties in the statute. Considering this renewed interest by multiple stakeholders regarding the need for revisions and/or guidance pertaining to Section 114, the Academy of Managed Care Pharmacy held a partnership forum on March 1-2, 2016, with a diverse group of health care stakeholders to provide the FDA with considerations for disseminating a guidance document on current thinking for the sharing of HCEI with health care decision makers. Forum participants represented the managed care industry, biopharmaceutical industry, health care providers, pharmacoeconomic experts, policy experts, and patient advocacy groups with specific expertise in the development, use, and dissemination of HCEI. The multistakeholder group represented the key professionals and entities affected by the provisions of Section 114 and present the collective credibility necessary for Congress and the FDA to modernize and operationalize the safe

  16. Recent Advances in Drug Development and Regulatory Science in China.

    Science.gov (United States)

    Chen, Jie; Zhao, Naiqing

    2018-01-01

    As the second largest pharmaceutical market with a great potential for future growth, China has drawn much attention from the global pharmaceutical community. With an increasing government investment in biomedical research, the domestic biopharmaceutical (biotechnological) companies in China are turning their attention to the development of innovative medicines and targeting the global market. To introduce innovative products to Chinese patients sooner, to improve the efficiency of its review and approval processes, and to harmonize its regulatory science with international standards, the China Food and Drug Administration (CFDA) has initiated a series of major changes to its policies and regulations. This paper presents a snapshot of China's pharmaceutical market, and research and development status, and introduces technical guidelines pertaining to clinical trials and new drug applications. The recent wave of ground-breaking reforms in CFDA's regulatory science is discussed. Examples of clinical trials and new drug applications are provided throughout the discussion.

  17. Rational and systematic protein purification process development: the next generation.

    Science.gov (United States)

    Nfor, Beckley K; Verhaert, Peter D E M; van der Wielen, Luuk A M; Hubbuch, Jürgen; Ottens, Marcel

    2009-12-01

    Current biopharmaceutical manufacturing strongly relies on using purification platform processes, offering harmonization of practices and speed-to-market. However, the ability of such processes to respond quickly to anticipated higher quality and capacity demands is under question. Here, we describe novel approaches for purification process development that incorporate biothermodynamics, modern high throughput experimentation and simulation tools. Such development leads to production platform-specific databases containing thermodynamic protein descriptors of major host cell proteins over a range of experimental conditions. This will pave the way for in silico purification process development, providing better process understanding and the potential to respond quickly to product quality and market demands. Future efforts will focus on improving this field further and enabling more rationale in process development.

  18. Disposable bioprocessing: the future has arrived.

    Science.gov (United States)

    Rao, Govind; Moreira, Antonio; Brorson, Kurt

    2009-02-01

    Increasing cost pressures are driving the rapid adoption of disposables in bioprocessing. While well ensconced in lab-scale operations, the lower operating/ validation costs at larger scale and relative ease of use are leading to these systems entering all stages and operations of a typical biopharmaceutical manufacturing process. Here, we focus on progress made in the incorporation of disposable equipment with sensor technology in bioprocessing throughout the development cycle. We note that sensor patch technology is mostly being adapted to disposable cell culture devices, but future adaptation to downstream steps is conceivable. Lastly, regulatory requirements are also briefly assessed in the context of disposables and the Process Analytical Technologies (PAT) and Quality by Design (QbD) initiatives.

  19. Displacement of Drugs From Cyclodextrin Complexes by Bile Salts

    DEFF Research Database (Denmark)

    Olesen, Niels Erik; Westh, Peter; Holm, Rene

    2016-01-01

    of drug from the cyclodextrin cavity by bile salts present in the small intestine. As bile salts in the intestine are present at concentrations above the critical micelle concentration, an understanding of the interaction between cyclodextrins and bile salts at such supramicellar concentrations (SMC......) is required for a better biopharmaceutical understanding of the release mechanism from orally dosed cyclodextrin complexes. To address this, experiments were conducted by isothermal titration calorimetry to determine how various b-cyclodextrins and bile salt interacts at SMC. Combined analysis of the current...... results and earlier data demonstrated that direct interactions between bile salt micelles and cyclodextrin were negligible. From this knowledge, an extended form of the UCD was suggested to describe the concentration of cyclodextrins to achieve full drug solubilization in the intestine where bile salts...

  20. Venture Capital Investment in the Life Sciences in Switzerland.

    Science.gov (United States)

    Hosang, Markus

    2014-12-01

    Innovation is one of the main driving factors for continuous and healthy economic growth and welfare. Switzerland as a resource-poor country is particularly dependent on innovation, and the life sciences, which comprise biotechnologies, (bio)pharmaceuticals, medical technologies and diagnostics, are one of the key areas of innovative strength of Switzerland. Venture capital financing and venture capitalists (frequently called 'VCs') and investors in public equities have played and still play a pivotal role in financing the Swiss biotechnology industry. In the following some general features of venture capital investment in life sciences as well as some opportunities and challenges which venture capital investors in Switzerland are facing are highlighted. In addition certain means to counteract these challenges including the 'Zukunftsfonds Schweiz' are discussed.