Sample records for biopharmaceuticals

  1. Plasmid Biopharmaceuticals. (United States)

    Prazeres, Duarte Miguel F; Monteiro, Gabriel A


    Plasmids are currently an indispensable molecular tool in life science research and a central asset for the modern biotechnology industry, supporting its mission to produce pharmaceutical proteins, antibodies, vaccines, industrial enzymes, and molecular diagnostics, to name a few key products. Furthermore, plasmids have gradually stepped up in the past 20 years as useful biopharmaceuticals in the context of gene therapy and DNA vaccination interventions. This review provides a concise coverage of the scientific progress that has been made since the emergence of what are called today plasmid biopharmaceuticals. The most relevant topics are discussed to provide researchers with an updated overview of the field. A brief outline of the initial breakthroughs and innovations is followed by a discussion of the motivation behind the medical uses of plasmids in the context of therapeutic and prophylactic interventions. The molecular characteristics and rationale underlying the design of plasmid vectors as gene transfer agents are described and a description of the most important methods used to deliver plasmid biopharmaceuticals in vivo (gene gun, electroporation, cationic lipids and polymers, and micro- and nanoparticles) is provided. The major safety issues (integration and autoimmunity) surrounding the use of plasmid biopharmaceuticals is discussed next. Aspects related to the large-scale manufacturing are also covered, and reference is made to the plasmid products that have received marketing authorization as of today.

  2. Targeted biopharmaceuticals for cancer treatment. (United States)

    Zhou, Lufang; Xu, Ningning; Sun, Yan; Liu, Xiaoguang Margaret


    Cancer is a complex invasive genetic disease that causes significant mortality rate worldwide. Protein-based biopharmaceuticals have significantly extended the lives of millions of cancer patients. This article reviews the biological function and application of targeted anticancer biopharmaceuticals. We first discuss the specific antigens and core pathways that are used in the development of targeted cancer therapy. The innovative monoclonal antibodies, non-antibody proteins, and small molecules targeting these antigens or pathways are then reviewed. Finally, the current challenges in anticancer biopharmaceuticals development and the potential solutions to address these challenges are discussed.

  3. Assessing the Immunogenicity of Biopharmaceuticals. (United States)

    Pineda, Carlos; Castañeda Hernández, Gilberto; Jacobs, Ira A; Alvarez, Daniel F; Carini, Claudio


    Biopharmaceuticals have the potential to raise an immunogenic response in treated individuals, which may impact the efficacy and safety profile of these drugs. As a result, it is essential to evaluate immunogenicity throughout the different phases of the clinical development of a biopharmaceutical, including post-marketing surveillance. Although rigorous evaluation of biopharmaceutical immunogenicity is required by regulatory authorities, there is a lack of uniform standards for the type, quantity, and quality of evidence, and for guidance on experimental design for immunogenicity assays or criteria to compare immunogenicity of biopharmaceuticals. Moreover, substantial technological advances in methods to assess immune responses have yielded higher immunogenicity rates with modern assays, and limit comparison of immunogenicity of biopharmaceuticals outside of head-to-head clinical trials. Accordingly, research programs, regulatory agencies, and clinicians need to keep pace with continuously evolving analyses of immunogenicity. Here, we review factors associated with immunogenicity of biopharmaceuticals, potential clinical ramifications, and current regulatory guidance for evaluating immunogenicity, and discuss methods to assess immunogenicity in non-clinical and clinical studies. We also describe special considerations for evaluating the immunogenicity of biosimilar candidates.

  4. Biopharmaceuticals as Challenges to the Regulatory System

    NARCIS (Netherlands)

    Ebbers, H.C.


    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

  5. Biopharmaceuticals from microorganisms: from production to purification

    Directory of Open Access Journals (Sweden)

    Angela Faustino Jozala

    Full Text Available ABSTRACT The use of biopharmaceuticals dates from the 19th century and within 5-10 years, up to 50% of all drugs in development will be biopharmaceuticals. In the 1980s, the biopharmaceutical industry experienced a significant growth in the production and approval of recombinant proteins such as interferons (IFN α, β, and γ and growth hormones. The production of biopharmaceuticals, known as bioprocess, involves a wide range of techniques. In this review, we discuss the technology involved in the bioprocess and describe the available strategies and main advances in microbial fermentation and purification process to obtain biopharmaceuticals.

  6. Bioethical issues in the development of biopharmaceuticals

    Directory of Open Access Journals (Sweden)

    Todorović Zoran


    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.

  7. Biosurfactants in cosmetics and biopharmaceuticals. (United States)

    Varvaresou, A; Iakovou, K


    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.

  8. Continuous downstream processing of biopharmaceuticals. (United States)

    Jungbauer, Alois


    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.

  9. Researcher eyeing tobacco for factory of biopharmaceuticals


    Gilbert, Karen


    The economics of producing biopharmaceuticals from transgenic plants such as tobacco is still a roadblock to producing large quantities of urgently needed medicines, especially for people in underdeveloped nations.

  10. Safety Pharmacology Evaluation of Biopharmaceuticals. (United States)

    Amouzadeh, Hamid R; Engwall, Michael J; Vargas, Hugo M


    Biotechnology-derived pharmaceuticals or biopharmaceuticals (BPs) are molecules such as monoclonal antibodies, soluble/decoy receptors, hormones, enzymes, cytokines, and growth factors that are produced in various biological expression systems and are used to diagnose, treat, or prevent various diseases. Safety pharmacology (SP) assessment of BPs has evolved since the approval of the first BP (recombinant human insulin) in 1982. This evolution is ongoing and is informed by various international harmonization guidelines. Based on these guidelines, the potential undesirable effect of every drug candidate (small molecule or BP) on the cardiovascular, central nervous, and respiratory systems, referred to as the "core battery," should be assessed prior to first-in-human administration. However, SP assessment of BPs poses unique challenges such as choice of test species and integration of SP parameters into repeat-dose toxicity studies. This chapter reviews the evolution of SP assessment of BPs using the approval packages of marketed BPs and discusses the past, current, and new and upcoming approach and methods that can be used to generate high-quality data for the assessment of SP of BPs.

  11. Lipid nanoparticles for the delivery of biopharmaceuticals. (United States)

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


    Biopharmaceuticals comprise therapeutic protein-based, nucleic acids and cell-based products. According to their therapeutic success, the clinical use of these products has been growing. Therefore, the development of efficient biopharmaceuticals delivery systems, which overcome their limitations for administration, remains an excellent prospect for pharmaceutical technologists. In this area, lipid nanoparticles have been increasingly recognized as one of the most promising delivery systems, due to their exclusive advantages. However, no clinical biopharmaceutical lipid nanoparticle-based products are yet available. This fact could be explained by the lack or failure of in vivo studies, regarding stability and toxicological concerns, and also by the complex regulatory issues that must be accomplished. The present review article focuses on the different classes of biopharmaceuticals, their characteristics and limitations for administration. A state of the art regarding the use of lipid nanoparticles to improve biopharmaceuticals delivery is presented and a critical prospect of the future directions that should be addressed by pharmaceutical technologists is also discussed.

  12. Process analytical technology (PAT) for biopharmaceuticals

    DEFF Research Database (Denmark)

    Glassey, Jarka; Gernaey, Krist; Clemens, Christoph;


    emphasizes the need for improved PAT solutions. We summarize recent progress in this area based on an expert workshop held at the 8(th) European Symposium on Biochemical Engineering Sciences (Bologna, 2010), and highlight new opportunities for exploiting PAT when applied in biopharmaceutical production. We......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...... models for interpretation of systems biology data and new sensor technologies for cellular states, are instrumental in exploiting this potential. Industrial biopharmaceutical production has gradually become dependent on large-scale processes using sensitive mammalian cell cultures. This further...

  13. Cell engineering and molecular pharming for biopharmaceuticals. (United States)

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


    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.

  14. Cell Engineering and Molecular Pharming for Biopharmaceuticals (United States)

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


    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

  15. Advanced monitoring and control in biopharmaceutical production

    NARCIS (Netherlands)

    Soons, Z.I.T.A.


    Bioprocesses are characterised by natural variability in raw materials, initial conditions, human intervention, and varying properties of the micro-organism. In traditional biopharmaceutical production quality of the product is currently tested at the end of the production process only. Recently the

  16. [Biopharmaceuticals in the treatment of rheumatoid arthritis

    DEFF Research Database (Denmark)

    Baslund, B.; Bendtzen, K.


    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...

  17. Traceability of biopharmaceuticals in spontaneous reporting systems

    DEFF Research Database (Denmark)

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


    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...

  18. Pharmaceutical technology, biopharmaceutics and drug delivery. (United States)

    Youn, Yu Seok; Lee, Beom-Jin


    The 40th annual international conference of the Korean Society of Pharmaceutical Sciences and Technology on Pharmaceutical Technology, Biopharmaceutics and Drug Delivery was held on 2-3 December 2010 in Jeju Special Self-Governing Providence, Korea, to celebrate its 40th anniversary. A comprehensive review of a wide spectrum of recent topics on pharmaceutical technology, biopharmaceutics and drug delivery was presented. Invited lectures and poster presentations over 2 days were divided into six parallel sessions covering areas such as biotechnology, biopharmaceutics, drug delivery, formulation/manufacture, regulatory science and frontier science. Among these, there were two sessions related to regulatory science and biopharmaceutics that were co-sponsored by the Korea Food and Drug Administration. In fact, this conference provided an opportunity for many investigators to discuss their research, collect new information and to promote the advancement of knowledge in each pharmaceutical area. This conference report summarizes the keynote podium presentations provided by many distinguished speakers, including Gordon L Amidon of the University of Michigan.

  19. [Biophysical Characterization of Biopharmaceuticals, Including Antibody Drugs]. (United States)

    Uchiyama, Susumu


    Biopharmaceuticals, including antibody drugs, are now popular because of their high specificity with low adverse effects, especially in the treatment of cancer and autoimmune diseases. However, because the active pharmaceutical ingredients of biopharmaceuticals are proteins, biophysical characterization of these therapeutic proteins should be required. In this manuscript, methods of chemical and physical characterization of therapeutic proteins are described. In terms of chemical characterization, analysis of chemical modifications of the constituent amino acids is explained. Physical characterization includes higher order structural analysis and assessment of protein aggregates. Quantification methods of aggregates with different sizes, recently encouraged by the U.S. Food and Drug Administration (FDA), are introduced. As for the stability of therapeutic proteins, the importance of chemical and physical stability is explained. Finally, the contribution of colloidal and structural stability to the production of an antibody drug less prone to aggregation is introduced.

  20. Locust bean gum: Exploring its potential for biopharmaceutical applications. (United States)

    Dionísio, Marita; Grenha, Ana


    Polysaccharides have been finding, in the last decades, very interesting and useful applications in the biomedical and, specifically, in the biopharmaceutical field. Locust bean gum is a polysaccharide belonging to the group of galactomannans, being extracted from the seeds of the carob tree (Ceratonia siliqua). This polymer displays a number of appealing characteristics for biopharmaceutical applications, among which its high gelling capacity should be highlighted. In this review, we describe critical aspects of locust bean gum, contributing for its role in biopharmaceutical applications. Physicochemical properties, as well as strong and effective synergies with other biomaterials are described. The potential for in vivo biodegradation is explored and the specific biopharmaceutical applications are discussed.

  1. Biopharmaceuticals. Official position of Russian Association of Endocrinologists

    Directory of Open Access Journals (Sweden)

    . Russian Association of Endocrinologists


    Full Text Available Some of the glucose-lowering drugs are biopharmaceuticals. This letter states the official position of the Russian Association of Endocrinologists about the treatment with biopharmaceuticals of patients with endocrine disorders. This topic has not yet beenadequately reflected in the legal regulation of the drug market in the Russian Federation 

  2. The biopharmaceutical industry in China: history and future perspectives. (United States)

    Gao, Kai; Wang, Junzhi


    Biopharmaceuticals reflect the rapid progress achieved in modern biomedical research. This area has also become one of the main criteria for assessing the development level of biotechnology for a particular country. Although it has been only three decades since the first biopharmaceutical, recombinant human insulin, was licensed by the US Food and Drug Administration, the biopharmaceutical industry has become the fastest growing, most dynamic and technology-intensive sector in the biomedical field. Since the licensing of recombinant human interferon α1b in 1989, the biopharmaceutical industry in China has gone through initial developments and gradually entered a period of rapid growth. This paper provides an overview of the status and development trends of biopharmaceuticals in China, and compares them with those observed in developed countries.

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

    DEFF Research Database (Denmark)

    Nielsen, Jens


    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 production of several large volume products. Insulin and insulin analogs are by far the dominating biopharmaceuticals produced by yeast, and this will increase as the global insulin market is expected to grow from USD12B in 2011 to more than USD32B by 2018. Other important biopharmaceuticals produced...... 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...

  4. 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: [Analytical Platform of the Faculty of Pharmacy and Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy, Universite Libre de Bruxelles (ULB), Brussels (Belgium)


    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.

  5. Nanofiltration of plasma-derived biopharmaceutical products. (United States)

    Burnouf, T; Radosevich, M


    This review presents the current status on the use and benefits of viral removal filtration systems--known as nanofiltration--in the manufacture of plasma-derived coagulation factor concentrates and other biopharmaceutical products from human blood origin. Nanofiltration of plasma products has been implemented at a production scale in the early 1990s to improve margin of viral safety, as a complement to the viral reduction treatments, such as solvent-detergent and heat treatments, already applied for the inactivation of human immunodeficiency virus, hepatitis B and hepatitis C virus. The main reason for the introduction of nanofiltration was the need to improve product safety against non-enveloped viruses and to provide a possible safeguard against new infectious agents potentially entering the human plasma pool. Nanofiltration has gained quick acceptance as it is a relatively simple manufacturing step that consists in filtering protein solution through membranes of a very small pore size (typically 15-40 nm) under conditions that retain viruses by a mechanism largely based on size exclusion. Recent large-scale experience throughout the world has now established that nanofiltration is a robust and reliable viral reduction technique that can be applied to essentially all plasma products. Many of the licensed plasma products are currently nanofiltered. The technology has major advantages as it is flexible and it may combine efficient and largely predictable removal of more than 4 to 6 logs of a wide range of viruses, with an absence of denaturing effect on plasma proteins. Compared with other viral reduction means, nanofiltration may be the only method to date permitting efficient removal of enveloped and non-enveloped viruses under conditions where 90-95% of protein activity is recovered. New data indicate that nanofiltration may also remove prions, opening new perspectives in the development and interest of this technique. Nanofiltration is increasingly becoming a

  6. Locust bean gum: Exploring its potential for biopharmaceutical applications

    Directory of Open Access Journals (Sweden)

    Marita Dionísio


    Full Text Available Polysaccharides have been finding, in the last decades, very interesting and useful applications in the biomedical and, specifically, in the biopharmaceutical field. Locust bean gum is a polysaccharide belonging to the group of galactomannans, being extracted from the seeds of the carob tree (Ceratonia siliqua. This polymer displays a number of appealing characteristics for biopharmaceutical applications, among which its high gelling capacity should be highlighted. In this review, we describe critical aspects of locust bean gum, contributing for its role in biopharmaceutical applications. Physicochemical properties, as well as strong and effective synergies with other biomaterials are described. The potential for in vivo biodegradation is explored and the specific biopharmaceutical applications are discussed.

  7. PEGylated Biopharmaceuticals: Current Experience and Considerations for Nonclinical Development. (United States)

    Ivens, Inge A; Achanzar, William; Baumann, Andreas; Brändli-Baiocco, Annamaria; Cavagnaro, Joy; Dempster, Maggie; Depelchin, B Olympe; Rovira, Armando R Irizarry; Dill-Morton, Laura; Lane, Joan H; Reipert, Birgit M; Salcedo, Theodora; Schweighardt, Becky; Tsuruda, Laurie S; Turecek, Peter L; Sims, Jennifer


    PEGylation (the covalent binding of one or more polyethylene glycol molecules to another molecule) is a technology frequently used to improve the half-life and other pharmaceutical or pharmacological properties of proteins, peptides, and aptamers. To date, 11 PEGylated biopharmaceuticals have been approved and there is indication that many more are in nonclinical or clinical development. Adverse effects seen with those in toxicology studies are mostly related to the active part of the drug molecule and not to polyethylene glycol (PEG). In 5 of the 11 approved and 10 of the 17 PEGylated biopharmaceuticals in a 2013 industry survey presented here, cellular vacuolation is histologically observed in toxicology studies in certain organs and tissues. No other effects attributed to PEG alone have been reported. Importantly, vacuolation, which occurs mainly in phagocytes, has not been linked with changes in organ function in these toxicology studies. This article was authored through collaborative efforts of industry toxicologists/nonclinical scientists to address the nonclinical safety of large PEG molecules (>10 kilo Dalton) in PEGylated biopharmaceuticals. The impact of the PEG molecule on overall nonclinical safety assessments of PEGylated biopharmaceuticals is discussed, and toxicological information from a 2013 industry survey on PEGylated biopharmaceuticals under development is summarized. Results will contribute to the database of toxicological information publicly available for PEG and PEGylated biopharmaceuticals.

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

    Directory of Open Access Journals (Sweden)

    Santhaseelan Henciya


    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.


    Directory of Open Access Journals (Sweden)

    Puranik Prashant K


    Full Text Available The biopharmaceutical classification system (BCS has been developed to provide a scientific approach for classifying drug compounds based on solubility as related to dose and intestinal permeability in combination with the dissolution properties of the oral immediate release dosage form. BCS is to provide a regulatory tool for replacing certain bioequivalence (BE studies by accurate in vitro dissolution tests. This review gives three dimensionless numbers which are used in BCS are absorption number, dissolution number, dose number.Biowaver is an important tool for formulation development. Bioavailability (BA and BE play a central role in pharmaceutical product development, and BE studies are presently being conducted for New Drug Applications (NDAs of new compounds, in supplementary NDAs for new medical indications and product line extensions, in Abbreviated New Drug Applications (ANDAs of generic products, and in applications for scale-up and post-approval changes. The principles of the BCS classification system can be applied to NDA and ANDA approvals as well as to scale-up and post approval changes in drug manufacturing. BCS classification can therefore save pharmaceutical companies a significant amount in development time and reduce costs. The aim of the present review is to present the status of BCS and discuss its future application in pharmaceutical product development.

  10. Characteristics of product recalls of biopharmaceuticals and small-molecule drugs in the USA. (United States)

    Ebbers, Hans C; de Tienda, Nina Fuentes; Hoefnagel, Marcel C; Nibbeling, Ria; Mantel-Teeuwisse, Aukje K


    Compared with chemically synthesized small-molecule drugs, the manufacturing process of biopharmaceuticals is more complex. Unexpected changes to product characteristics following manufacturing changes have given rise to calls for robust systems to monitor the postauthorization safety of biopharmaceuticals. We compared quality-related product recalls in the USA of biopharmaceuticals and of small molecules. Although the reasons for recalls for biopharmaceuticals differed from those for small molecules, adverse events were rarely reported. The relative contribution of recalls that could cause serious adverse health consequences was not greater for biopharmaceuticals than for small molecules. Therefore, these data do not give rise to concerns that biopharmaceuticals are more frequently associated with unexpected safety concerns.

  11. Forced degradation studies of biopharmaceuticals: Selection of stress conditions. (United States)

    Tamizi, Elnaz; Jouyban, Abolghasem


    Stability studies under stress conditions or forced degradation studies play an important role in different phases of development and production of biopharmaceuticals and biological products. These studies are mostly applicable to selection of suitable candidates and formulation developments, comparability studies, elucidation of possible degradation pathways and identification of degradation products, as well as, development of stability indicating methods. Despite the integral part of these studies in biopharmaceutical industry, there is no well-established protocol for the selection of stress conditions, timing of stress testing and required extent of degradation. Therefore, due to the present gap in the stability studies guidelines, it is the responsibility of researchers working in academia and biopharmaceutical industry to set up forced degradation experiments that could fulfill all the expectations from the stability studies of biopharmaceuticals under stress conditions. Concerning the importance of the function of desired stress conditions in forced degradation studies, the present review aims to provide a practical summary of the applicable stress conditions in forced degradation studies of biopharmaceuticals according to the papers published in a time period of 1992-2015 giving detailed information about the experimental conditions utilized to induce required stresses.

  12. Thirty years of preclinical safety evaluation of biopharmaceuticals: did scientific progress lead to appropriate regulatory guidance?

    NARCIS (Netherlands)

    Kooijman, M.; Meer, P.J.K. van; Moors, E.H.M.; Schellekens, H.


    Introduction: The first biopharmaceuticals were developed 30 years ago. Biopharmaceuticals differ significantly from small molecule therapeutics (SMTs). Because of such differences, it was expected that classical preclinical safety evaluation procedures applied to SMTs would not predict the adverse

  13. Thirty years of preclinical safety evaluation of biopharmaceuticals: did scientific progress lead to appropriate regulatory guidance?


    Kooijman, M.; van Meer, P.J.K.; E. H. M. MOORS; Schellekens, H.


    Introduction: The first biopharmaceuticals were developed 30 years ago. Biopharmaceuticals differ significantly from small molecule therapeutics (SMTs). Because of such differences, it was expected that classical preclinical safety evaluation procedures applied to SMTs would not predict the adverse effects of biopharmaceuticals. Therefore, until sufficient experience was gained, the preclinical safety evaluation of biopharmaceuticals was carried out on a case-by-case basis. 30 years of experi...

  14. Chemically defined media modifications to lower tryptophan oxidation of biopharmaceuticals. (United States)

    Hazeltine, Laurie B; Knueven, Kristine M; Zhang, Yan; Lian, Zhirui; Olson, Donald J; Ouyang, Anli


    Oxidation of biopharmaceuticals is a major product quality issue with potential impacts on activity and immunogenicity. At Eli Lilly and Company, high tryptophan oxidation was observed for two biopharmaceuticals in development produced in Chinese hamster ovary cells. A switch from historical hydrolysate-containing media to chemically defined media with a reformulated basal powder was thought to be responsible, so mitigation efforts focused on media modification. Shake flask studies identified that increasing tryptophan, copper, and manganese and decreasing cysteine concentrations were individual approaches to lower tryptophan oxidation. When amino acid and metal changes were combined, the modified formulation had a synergistic impact that led to substantially less tryptophan oxidation for both biopharmaceuticals. Similar results were achieved in shake flasks and benchtop bioreactors, demonstrating the potential to implement these modifications at manufacturing scale. The modified formulation did not negatively impact cell growth and viability, product titer, purity, charge variants, or glycan profile. A potential mechanism of action is presented for each amino acid or metal factor based on its role in oxidation chemistry. This work served not only to mitigate the tryptophan oxidation issue in two Lilly biopharmaceuticals in development, but also to increase our knowledge and appreciation for the impact of media components on product quality.

  15. Current practice of therapeutic drug monitoring of biopharmaceuticals in spondyloarthritis. (United States)

    Medina, Frédéric; Placensia, Chamaida; Goupille, Philippe; Paintaud, Gilles; Balsa, Alejandro; Mulleman, Denis


    Treatment of spondyloarthritis (SpA) has greatly improved in the biopharmaceutical era. These compounds, primarily tumor necrosis factor (TNF) inhibitors, are effective, but some patients may show poor response, sometimes due to the presence of anti-drug antibodies (ADAs). In some instances, clinicians may increase or taper the dose, depending on the clinical response. Besides the current clinical practice, a tailored strategy based on drug monitoring is emerging as a way to improve the use of these drugs. However, the relevance of this therapeutic drug monitoring (TDM) of biopharmaceuticals for SpA is still unknown. In this literature review, we examined the most relevant articles dealing with the concentration-response relation, ADA detection, and pharmacokinetics in SpA treated with biopharmaceuticals. ADAs were associated with low or undetectable concentration of monoclonal antibodies. The relation between drug concentration and clinical response in SpA is debated, some studies showing an association and others not. Therefore, TDM of biopharmaceuticals for SpA requires a better understanding of the association among the pharmacokinetics, pharmacodynamics, and immunogenicity of these drugs.

  16. Biopharmaceutic Risk Assessment of Brand and Generic Lamotrigine Tablets. (United States)

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


    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.

  17. Biopharmaceutical Innovation System in China: System Evolution and Policy Transitions (Pre-1990s-2010s

    Directory of Open Access Journals (Sweden)

    Hao Hu


    Full Text Available Background: This article sets up the initial discussion of the evolution of biopharmaceutical innovation in China through the perspective of sectoral innovation system (SIS. Methods: Two data sources including archival documentary data and field interviews were used in this study. Archival documentary data was collected from China Food and Drug Administration (CFDA and Chinese National Knowledge Infrastructure (CNKI. In addition, industrial practitioners and leading researchers in academia were interviewed. Results: Biopharmaceutical in China was established through international knowledge transfer. The firms played more active role in commercializing biopharmaceutical in China though universities and research institutes were starting to interact with local firms and make contribution to biopharmaceutical industrialization. The transition of the Chinese government’s policies continuously shapes the evolution of biopharmaceutical sector. Policies have been dramatic changes before and after 1980s to encourage developing biopharmaceutical as a competitive industry for China. Conclusion: A SIS for biopharmaceutical has been shaped in China. However, currently biopharmaceutical is still a small sector in China, and for the further growth of the industry more synthetic policies should be implemented. Not only the policy supports towards the research and innovation of biopharmaceuticals in the early stage of development should be attended, but also commercialization of biopharmaceutical products in the later stage of sales.

  18. Biopharmaceutical Innovation System in China: System Evolution and Policy Transitions (Pre-1990s-2010s) (United States)

    Hu, Hao; Chung, Chao-Chen


    Background: This article sets up the initial discussion of the evolution of biopharmaceutical innovation in China through the perspective of sectoral innovation system (SIS). Methods: Two data sources including archival documentary data and field interviews were used in this study. Archival documentary data was collected from China Food and Drug Administration (CFDA) and Chinese National Knowledge Infrastructure (CNKI). In addition, industrial practitioners and leading researchers in academia were interviewed. Results: Biopharmaceutical in China was established through international knowledge transfer. The firms played more active role in commercializing biopharmaceutical in China though universities and research institutes were starting to interact with local firms and make contribution to biopharmaceutical industrialization. The transition of the Chinese government’s policies continuously shapes the evolution of biopharmaceutical sector. Policies have been dramatic changes before and after 1980s to encourage developing biopharmaceutical as a competitive industry for China. Conclusion: A SIS for biopharmaceutical has been shaped in China. However, currently biopharmaceutical is still a small sector in China, and for the further growth of the industry more synthetic policies should be implemented. Not only the policy supports towards the research and innovation of biopharmaceuticals in the early stage of development should be attended, but also commercialization of biopharmaceutical products in the later stage of sales. PMID:26673466

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

    CERN Document Server

    Macheras, Panos


    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...

  20. [Construction of biopharmaceutics classification system of Chinese materia medica]. (United States)

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


    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.

  1. Russia through the prism of the world biopharmaceutical market. (United States)

    Bairamashvili, Dmitrij I; Rabinovich, Mikhail L


    Trends in the Russian pharmaceutical biotechnology and related fields representing the major sector of domestic biotech are reviewed through the prism of the world biopharmaceuticals market. A special emphasis is placed on biogenerics and follow-on biologics. The revival of national pharmbiotech is seen in close cooperation between private companies and the state, academia and industry. One of the first positive steps toward promoting development of domestic biopharmaceuticals is the Federal Program of subsidized supply of expensive pharmaceuticals (Dopolnitel'- noe Lekarstvennoe Obespechenie). The program allows the Russian government to purchases expensive drugs to be provided free of cost to certain preferential categories of individuals. As an example, production of recombinant human insulin by the largest Russian fundamental biotechnological institute, Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry under the trademark Insuran (Insulin produced by the Russian Academy of Science) is reviewed. Some prospects and problems of Russian biotech research related to medical area are briefly discussed.

  2. Hairy roots culture as a source of valuable biopharmaceuticals


    Tomasz Kowalczyk; Marta Łucka; Janusz Szemraj; Tomasz Sakowicz; Marek Masiuk; Ewelina Staniszewska; Katarzyna Sporniak- Tutak; Edyta Gołembiewska; Kazimierz Ciechanowski


    Plants have been exploited as a source of medicinal substances for years. Nowadays, achievements of modern science, including molecular biotechnology, allow their huge potential to be utilized. They have become a promising platform for the production of valuable compounds such as biopharmaceuticals. Among the various plant systems used for this purpose, hairy root cultures are also applied for the production of recombinant proteins and secondary metabolites. For this purpose plant cells of se...

  3. Cost Evaluation and Portfolio Management Optimization for Biopharmaceutical Product Development


    Nie, W.


    The pharmaceutical industry is suffering from declining R&D productivity and yet biopharmaceutical firms have been attracting increasing venture capital investment. Effective R&D portfolio management can deliver above average returns under increasing costs of drug development and the high risk of clinical trial failure. This points to the need for advanced decisional tools that facilitate decision-making in R&D portfolio management by efficiently identifying optimal solutions while accounting...


    Directory of Open Access Journals (Sweden)

    Rohilla Seema


    Full Text Available 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 low solubility, low permeability high solubility and low permeability low solubility. The present review summarizes the principles, objectives, benefits, classification and applications of BCS.

  5. Glyco-engineering for biopharmaceutical production in moss bioreactors

    Directory of Open Access Journals (Sweden)

    Eva L. Decker


    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.

  6. CHO gene expression profiling in biopharmaceutical process analysis and design. (United States)

    Schaub, Jochen; Clemens, Christoph; Schorn, Peter; Hildebrandt, Tobias; Rust, Werner; Mennerich, Detlev; Kaufmann, Hitto; Schulz, Torsten W


    Increase in both productivity and product yields in biopharmaceutical process development with recombinant protein producing mammalian cells can be mainly attributed to the advancements in cell line development, media, and process optimization. Only recently, genome-scale technologies enable a system-level analysis to elucidate the complex biomolecular basis of protein production in mammalian cells promising an increased process understanding and the deduction of knowledge-based approaches for further process optimization. Here, the use of gene expression profiling for the analysis of a low titer (LT) and high titer (HT) fed batch process using the same IgG producing CHO cell line was investigated. We found that gene expression (i) significantly differed in HT versus LT process conditions due to differences in applied chemically defined, serum-free media, (ii) changed over the time course of the fed batch processes, and that (iii) both metabolic pathways and 14 biological functions such as cellular growth or cell death were affected. Furthermore, detailed analysis of metabolism in a standard process format revealed the potential use of transcriptomics for rational media design as is shown for the case of lipid metabolism where the product titer could be increased by about 20% based on a lipid modified basal medium. The results demonstrate that gene expression profiling can be an important tool for mammalian biopharmaceutical process analysis and optimization.

  7. Analytical, biopharmaceutical and regulatory evaluation of topical testosterone preparations. (United States)

    Baert, B; Annavarapu, S; Burvenich, C; De Spiegeleer, B


    Testosterone-containing pharmaceutical products for topical use were obtained from the pharmacist or through the internet. The legal status of the different products obtained is discussed: some products through the internet were clearly a medicinal product according to the current definitions, while they are not registered as such. Assay and impurity profiles of each of the marketed samples were obtained using HPLC-UV and ESI-iontrap MS. The analytical results were evaluated relative to the reporting, identification and qualification thresholds as defined by the the International Conference on Harmonisation (ICH) and the European Pharmacopoeia (Ph. Eur.). Preparations with impurities above the qualification threshold were observed. Moreover, in vitro release profiles over an artificial membrane were obtained using a standardised cell in a paddle dissolution bath as well as in a static Franz diffusion cell, using phosphate buffered saline (PBS; pH 7.0) containing 5% bovine serum albumin (BSA) as dissolution or receptor fluid. This biopharmaceutical quality attribute differs significantly between the preparations tested. In conclusion, the equivalency of topical testosterone preparations is not assured, nor on their legal status, nor on their impurity profiling nor on their biopharmaceutical behaviour. This calls for an urgent trans-national product-class harmonisation approach.

  8. Downstream processing of biopharmaceutical proteins produced in plants (United States)

    Buyel, Johannes Felix; Fischer, Rainer


    All biological platforms for the manufacture of biopharmaceutical proteins produce an initially turbid extract that must be clarified to avoid fouling sensitive media such as chromatography resins. Clarification is more challenging if the feed stream contains large amounts of dispersed particles, because these rapidly clog the filter media typically used to remove suspended solids. Charged polymers (flocculants) can increase the apparent size of the dispersed particles by aggregation, facilitating the separation of solids and liquids, and thus reducing process costs. However, many different factors can affect the behavior of flocculants, including the pH and conductivity of the medium, the size and charge distribution of the particulates, and the charge density and molecular mass of the polymer. Importantly, these properties can also affect the recovery of the target protein and the overall safety profile of the process. We therefore used a design of experiments approach to establish reliable predictive models that characterize the impact of flocculants during the downstream processing of biopharmaceutical proteins. We highlight strategies for the selection of flocculants during process optimization. These strategies will contribute to the quality by design aspects of process development and facilitate the development of safe and efficient downstream processes for plant-derived pharmaceutical proteins. PMID:24637706

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

    CERN Document Server

    Macheras, Panos


    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...

  10. The application of MALDI TOF MS in biopharmaceutical research. (United States)

    Kafka, Alexandra P; Kleffmann, Torsten; Rades, Thomas; McDowell, Arlene


    The development and quality assessment of modern biopharmaceuticals, particularly protein and peptide drugs, requires an array of analytical techniques to assess the integrity of the bioactive molecule during formulation and administration. Mass spectrometry is one of these methods and is particularly suitable for determining chemical modifications of protein and peptide drugs. The emphasis of this review is the identification of covalent interactions between protein and peptide bioactives with polymeric pharmaceutical formulations using mass spectrometry with the main focus on matrix-assisted laser desorption/ionization (MALDI) coupled tandem time-of-flight (TOF/TOF) mass spectrometry (MS). The basics of MALDI TOF MS and collision-induced dissociation (CID)-based ion fragmentation will be explained and applications for qualitative characterization of protein and peptide drugs and their interactions with pharmaceutical polymers will be discussed using three case studies.

  11. The potential of the capillary electrophoresis techniques for quality control of biopharmaceuticals-a review. (United States)

    Tamizi, Elnaz; Jouyban, Abolghasem


    CE is considered as a powerful technique in biopharmaceutical industry, owing to its inherent advantages such as high resolution, efficient separation, and its flexibility to couple with high-sensitive detecting methods. Present review provides a summary of the applications of CE-based methods in the quality control of biopharmaceuticals according to the papers published between 1994 and July 2014. This article is divided into the sections based on different CE modes applied in the analysis of biopharmaceuticals and gives detailed information about the employed experimental conditions. At the end some overall conclusions and perspectives are given.

  12. Analysis of illegal peptide biopharmaceuticals frequently encountered by controlling agencies. (United States)

    Vanhee, Celine; Janvier, Steven; Desmedt, Bart; Moens, Goedele; Deconinck, Eric; De Beer, Jacques O; Courselle, Patricia


    Recent advances in genomics, recombinant expression technologies and peptide synthesis have led to an increased development of protein and peptide therapeutics. Unfortunately this goes hand in hand with a growing market of counterfeit and illegal biopharmaceuticals, including substances that are still under pre-clinical and clinical development. These counterfeit and illegal protein and peptide substances could imply severe health threats as has been demonstrated by numerous case reports. The Belgian Federal Agency for Medicines and Health Products (FAMHP) and customs are striving, together with their global counterparts, to curtail the trafficking and distributions of these substances. At their request, suspected protein and peptide preparations are analysed in our Official Medicines Control Laboratory (OMCL). It stands to reason that a general screening method would be beneficiary in the battle against counterfeit and illegal peptide drugs. In this paper we present such general screening method employing liquid chromatography-tandem mass spectrometry (LC-MS/MS) for the identification of counterfeit and illegal injectable peptide preparations, extended with a subsequent quantification method using ultra-high performance liquid chromatography with diode array detection (UHPLC-DAD). The screening method, taking only 30 min, is able to selectively detect 25 different peptides and incorporates the proposed minimum of five identification points (IP) as has been recommended for sports drug testing applications. The group of peptides represent substances which have already been detected in illegal and counterfeit products seized by different European countries as well as some biopharmaceutical peptides which have not been confiscated yet by the controlling agencies, but are already being used according to the many internet users forums. Additionally, we also show that when applying the same LC gradient, it is also possible to quantify these peptides without the need for

  13. Patent production is a prerequisite for successful exit of a biopharmaceutical company. (United States)

    Saotome, Chikako; Nakaya, Yurie; Abe, Seiji


    Patents are especially important for the business of drug discovery; however, their importance for biopharmaceutical companies has not been revealed quantitatively yet. To examine the correlation between patents and long-term business outcome of biopharmaceutical companies we analyze annual number of patent families and business conditions of 123 public-listed biopharmaceutical companies established from 1990 to 1995 in the USA. Our results show the number of patent families per year correlates well with the business condition: average of the bankruptcy group is significantly smaller than those of the continuing and the merger and acquisitions (M&A) groups. In the M&A by big pharma group, the acquisition cost correlates with the number of annual patent families. However, patentability and strategy of foreign patent application are not different among the groups. Therefore, the productivity of invention is the key factor for success of biopharmaceutical companies.

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

    DEFF Research Database (Denmark)

    Rup, B; Pallardy, M; Sikkema, D


    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...

  15. Development of Modes of Cooperation: An Opportunity for Open Innovation Alliances in Polish Biopharmaceutical Industry

    Directory of Open Access Journals (Sweden)

    Lukasz Puslecki


    Full Text Available This article presents development of modes of cooperation in biopharmaceutical industry, referring to the latest data from the asap (the Association of Strategic Alliance Professionals. Examples of different modes of cooperation in contemporary economy as well as potential cooperation between academia, institutions and business in the field of biopharmaceutical industry in Poland are discussed. Biopharmaceutical companies try to implement new strategies to transfer their research processes to a higher level, often using open innovation model as an additional tool for developing new products and services. Thanks to the cooperation with universities in the framework of open innovation alliances, through joint work with academic researchers, biopharmaceutical companies are more successful in identifying disease mechanisms, implementation of better medical therapy for patients as well as in development of new drugs.

  16. Biopharmaceutical considerations and characterizations in development of colon targeted dosage forms for inflammatory bowel disease. (United States)

    Malayandi, Rajkumar; Kondamudi, Phani Krishna; Ruby, P K; Aggarwal, Deepika


    Colon targeted dosage forms have been extensively studied for the localized treatment of inflammatory bowel disease. These dosage forms not only improve the therapeutic efficacy but also reduce the incidence of adverse drug reactions and hence improve the patient compliance. However, complex and highly variable gastro intestinal physiology limits the clinical success of these dosage forms. Biopharmaceutical characteristics of these dosage forms play a key role in rapid formulation development and ensure the clinical success. The complexity in product development and clinical success of colon targeted dosage forms are based on the biopharmaceutical characteristics such as physicochemical properties of drug substances, pharmaceutical characteristics of dosage form, physiological conditions and pharmacokinetic properties of drug substances as well as drug products. Various in vitro and in vivo techniques have been employed in past to characterize the biopharmaceutical properties of colon targeted dosage forms. This review focuses on the factors influencing the biopharmaceutical performances of the dosage forms, in vitro characterization techniques and in vivo studies.

  17. Innovator Organizations in New Drug Development: Assessing the Sustainability of the Biopharmaceutical Industry. (United States)

    Kinch, Michael S; Moore, Ryan


    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.

  18. A special report on India's biotech scenario: advancement in biopharmaceutical and health care sectors. (United States)

    Chakraborty, Chiranjib; Agoramoorthy, Govindasamy


    India's biotechnology industry has been growing towards new heights in conjunction with the recent economic outburst. The country has the potential to revolutionize biopharmaceutical and healthcare sectors. In this review, we have highlighted the achievements of India's biotechnology industry, especially biopharmaceutical and healthcare sectors that include therapeutics, diagnostics, stem cell research, human healthcare related bioinformatics and animal health care. We have also described regulatory mechanisms involved in India's health care biotech including manpower development.

  19. Approval of new biopharmaceuticals 1999-2006: comparison of the US, EU and Japan situations. (United States)

    Tsuji, Kaori; Tsutani, Kiichiro


    Biopharmaceuticals, defined as either proteins derived from recombinant DNA technology (rDNAs) or therapeutic monoclonal antibodies (mAbs), have become the therapeutics of significance in the 21st century. This article identifies the new biopharmaceuticals approved in the three major pharmaceutical markets (US, EU and Japan) and analyzes the so-called "drug lag" in said regions. Between 1999 and 2006, a total of 65 new biopharmaceuticals were approved. Of this total, 59 (90.8%) were approved in the US, 52 (80.0%) in EU and 22 (33.8%) in Japan. The mean approval lag was 3.7 months in the US, 7.5 months in EU and 52.6 months in Japan. The US was ahead of the two other regional markets in approvals of biopharmaceuticals, while there was a significant drug lag in Japan. The authors also found that US companies were the licensors of 42 out of 65 new biopharmaceuticals, followed by European companies with 21 licensors and Japanese companies with only 2 licensors. These figures suggest that Japanese companies are still weak in biopharmaceuticals innovation and licensing, and this weakness appears to be a major contributing factor to the drug lag in the country.

  20. Manufacture of biopharmaceutical proteins by mammalian cell culture systems. (United States)

    Tolbert, W R


    In the last several years, dramatic advances have been in the development of new biopharmaceuticals including monoclonal antibodies for diagnosis and treatment and such genetically engineered proteins as tPA, Factor VIIIc, erythropoietin and soluble CD4, an anti-AIDS protein. Currently, there are several hundred such candidate drugs in human clinical trials. In most cases, these protein-based drugs will require manufacture by mammalian cell culture due to the inability of lower organisms to properly glycosylate, fold, make correct disulfide bonds and secrete active biomolecular forms. The need for large scale production from cell culture will greatly increase as more of the products in clinical trials are approved for commercial production. This will require significant reduction in manufacturing costs per gram, concomitant with increased capacity to hundreds or perhaps even thousands of kilograms annually. As an example, Invitron's multi-reactor manufacturing facility has operated at greater than one-half million liters per year and has experience with more than 250 mammalian cell lines for producing protein drug products.

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

    Directory of Open Access Journals (Sweden)

    Lorena Barbosa Arrunátegui


    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.

  2. Medicines for Pediatric Patients-Biopharmaceutical, Developmental, and Regulatory Considerations. (United States)

    Elder, David P; Holm, René; Kuentz, Martin


    This commentary reflects current developments in pediatric medicine. The underpinning legislation in both Europe and the United States has led to the initiation of an increased number of clinical trials in the pediatric population, but there are still a number of outstanding issues within this field. These include the differences in the physiology between adults and the very heterogeneous nature of pediatric patients. There is an ongoing scientific debate on the applicability of a Pediatric Biopharmaceutical Classification System to define when waivers for bioequivalence studies can be supported by in vitro dissolution. However, a challenge is that in vitro models should adequately mimic the physiology of different pediatric age-groups and dose definition is another critical aspect. There is a tendency for off-label use of established adult medicines, resulting in increased adverse events and decreased efficacy in the target population. Recent advances in physiologically based pharmacokinetic modelling may be used to provide valuable input into these discussions, but there are currently still many knowledge gaps. It is encouraging that there is a global recognition of these deficiencies and substantial funding in the field of basic research is being provided, for example, within Europe the Innovative Medicines Initiative consortium.

  3. Caco-2 cells, biopharmaceutics classification system (BCS) and biowaiver. (United States)

    Smetanová, Libuse; Stĕtinová, Vĕra; Svoboda, Zbynek; Kvetina, Jaroslav


    Almost all orally administered drugs are absorbed across the intestinal mucosa. The Caco-2 monolayers are used as an in vitro model to predict drug absorption in humans and to explore mechanism of drug absorption. The Caco-2 cells are derived from a human colon adenocarcinoma and spontaneously differentiate to form confluent monolayer of polarized cells structurally and functionally resembling the small intestinal epithelium. For studying drug permeability, Caco-2 cells are seeded onto the Transwell inserts with semipermeable membrane and grown to late confluence (21 days). After determination of cell viability, the integrity of monolayer is checked by phenol red permeability and by 14C-mannitol permeability. The transport from apical to basolateral (AP-BL) and basolateral to apical (BL-AP) is studied by adding the diluted drug on the apical or basolateral side and withdrawing the samples from the opposite compartment, respectively, for HPLC analysis or liquid scintillation spectrometry. Ca2+ -free transport medium is used to determine paracellular component of the drug transport. On the basis of permeability and solubility, drugs can be categorized into four classes of Biopharmaceutics Classification System (BCS). For certain drugs, the BCS-based biowaiver approach can be used which enables to reduce in vivo bioequivalence studies.

  4. In vitro -in vivo correlation and biopharmaceutical classification system

    Directory of Open Access Journals (Sweden)

    R Tiwari


    Full Text Available In vitro dissolution has been extensively used as a quality control tool for solid oral dosage forms. In several cases, however, it is not known whether one can predict the in vivo performance of these products from in vitro dissolution data. In an effort to minimize unnecessary human testing, investigations of in vitro-in vivo correlations (IVIVC between in vitro dissolution and in vivo bioavailability are increasingly becoming an integral part of extended release drug product development. Development, rapidity in drug development can be achieved by researchers on finding a mathematical link between bioavailability and dissolution testing, which leads to the concept of IVIVC. IVIVC is a mathematical model that can be used to estimate in vivo behavior from its in vitro performance. Among all the five levels of correlation, Level A correlation is widely accepted by the regulatory agencies. Biopharmaceutical classification system explains the suitability of IVIVC. Dissolution method design plays a pivotal role in the estimation of correlations. Applications of IVIVC ranges from drug and product development, their scale up and postapproval changes. Hence, IVIVC should be considered as an important tool in drug development.

  5. Hairy roots culture as a source of valuable biopharmaceuticals

    Directory of Open Access Journals (Sweden)

    Tomasz Kowalczyk


    Full Text Available Plants have been exploited as a source of medicinal substances for years. Nowadays, achievements of modern science, including molecular biotechnology, allow their huge potential to be utilized. They have become a promising platform for the production of valuable compounds such as biopharmaceuticals. Among the various plant systems used for this purpose, hairy root cultures are also applied for the production of recombinant proteins and secondary metabolites. For this purpose plant cells of selected species are genetically transformed using different strains of Agrobacterium rhizogenes carrying the desired genes. The next steps of this process include stable and efficient expression of these genes. Hairy root cultures exhibit a number of features which make them attractive compared to various pro- and eukaryotic cell systems including other plant models. Their main advantages are: relatively low production costs, ease of scale-up, production of compounds typical for eukaryotic cells with post-translational modifications, biological safety, and in many cases there is no need for complex purification techniques of the final product. Several compounds that are successfully obtained using this production strategy are valuable pharmaceuticals. This group includes selected cytokines, vaccine antigens and antibodies.

  6. [Hairy roots culture as a source of valuable biopharmaceuticals]. (United States)

    Kowalczyk, Tomasz; Łucka, Marta; Szemraj, Janusz; Sakowicz, Tomasz


    Plants have been exploited as a source of medicinal substances for years. Nowadays, achievements of modern science, including molecular biotechnology, allow their huge potential to be utilized. They have become a promising platform for the production of valuable compounds such as biopharmaceuticals. Among the various plant systems used for this purpose, hairy root cultures are also applied for the production of recombinant proteins and secondary metabolites. For this purpose plant cells of selected species are genetically transformed using different strains of Agrobacterium rhizogenes carrying the desired genes. The next steps of this process include stable and efficient expression of these genes. Hairy root cultures exhibit a number of features which make them attractive compared to various pro- and eukaryotic cell systems including other plant models. Their main advantages are: relatively low production costs, ease of scale-up, production of compounds typical for eukaryotic cells with post-translational modifications, biological safety, and in many cases there is no need for complex purification techniques of the final product. Several compounds that are successfully obtained using this production strategy are valuable pharmaceuticals. This group includes selected cytokines, vaccine antigens and antibodies.


    Directory of Open Access Journals (Sweden)

    Budhwaar Vikaas


    Full Text Available 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 BCS approach is to determine the equilibrium solubility of drug substances under physiological environment. The BCS helps in mathematically analyzing the kinetics and dynamics of drug in gastrointestinal tract (GIT for New Drug Applications (NDA and Abbreviated New Drug Applications (ANDA filings and biowaivers. This step reduces time in the new drug development process. Further it helps to decide when the dissolution rate is likely to be the rate determining step. It also helps in the prediction of potential of inactive ingredients in the dosage form to alter the dissolution / absorption of the drug. The present review, apart from giving a brief overview of BCS classification system, highlights these and some of the more recent applications of BCS classification system.

  8. Ion-exchange chromatography for the characterization of biopharmaceuticals. (United States)

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


    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.

  9. With the help of a foreign ally: biopharmaceutical innovation in India after TRIPS. (United States)

    Angeli, Federica


    This article investigates the implications of the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS), which reached full-fledged implementation in 2005, for the patenting activity of Indian biopharmaceutical companies. The Indian biopharmaceutical industry is well-known for its generic producers, whose business models capitalize on the opportunity to reverse-engineer patented compounds and produce them at low costs through process innovation. By strengthening intellectual property rights, TRIPS determined a major regulative change, which presents the characteristics of an institutional shock. The examination of the patenting and alliance activity of 123 Indian biopharmaceutical firms between 1999 and 2009 reveals two important insights. First, the innovation outcome of Indian biopharmaceuticals has sharply increased during the transition to TRIPS-compliant regulation, suggesting that Indian companies have been capable and willing to transit from an imitation-based to an innovation-based business model. Second, those biopharmaceutical firms holding cross-border alliances to foreign partners have proved significantly more successful at enhancing their innovative capability. This research delivers a multifold contribution to the policy debate surrounding the enforcement of TRIPS in emerging economies. First, it suggests that such regulatory change may have encouraged biopharmaceutical innovation in India, despite the sceptical voices who did not foresee any benefits because of inherent inertia of the industry. Second, by arguing and testing the advantages of foreign partnerships, this research highlights that the much feared return of pharmaceutical foreign companies to India could instead favour adaptation to institutional change. Implications for Indian public health are particularly critical. The impact of TRIPS on drug pricing and on the capability--and willingness--of Indian biopharmaceuticals to invest in local health conditions are two

  10. [Immunogenicity of biopharmaceuticals: Which consequences during the treatment of rheumatoid arthritis?]. (United States)

    Goupille, P


    The biopharmaceuticals used in rheumatology are monoclonal antibodies, chimeric (-ximab), humanized (-zumab) or fully human (-[m]umab), or fusion proteins. The immunogenicity, that is the ability to develop an immune response towards biopharmaceuticals and leading to the production of anti-drug antibodies (ADA), may be observed in nearly 30% of patients with monoclonal antibodies, more rarely with fusion proteins. The immunogenicity may lead to an increase of clearance, a reduction of half-life and serum concentration of biopharmaceuticals, a decrease of clinical response and therapeutic maintenance, as well as the occurrence of immuno-allergic reactions. However, we must relativize the importance of this phenomenon because in registers with anti-TNFα, the survival curve of monoclonal antibodies is much closed to that of fusion proteins. The immunogenicity is only one of the factors allowing to explain the clinical response, or the lack of response, with biopharmaceuticals. This phenomenon may explain some clinical situations (secondary failures, adverse reactions), but other factors (weight, inflammatory activity, combination with an immunosuppressive agent, etc.) may influence, more importantly than immunogenicity, the dose-response relationship with biopharmaceuticals.

  11. Biopharmaceuticals for rheumatic diseases in Latin America, Europe, Russia, and India: innovators, biosimilars, and intended copies. (United States)

    Castañeda-Hernández, Gilberto; Szekanecz, Zoltan; Mysler, Eduardo; Azevedo, Valderilio F; Guzman, Renato; Gutierrez, Miguel; Rodríguez, Wilfredo; Karateev, Dmitry


    A biosimilar is a biopharmaceutical product intended to be comparable to a previously licensed biopharmaceutical agent. The goal of such products is to increase the accessibility of biopharmaceutical therapy for rheumatoid arthritis by reducing costs. They are not like generic drugs, in that they may differ from the reference products in manufacturing, composition, and formulation. Regulatory authorities strive to ensure the absence of clinically meaningful differences between biosimilars and their reference drugs. However, small molecular differences may potentially affect pharmacodynamics (including affinity), pharmacokinetics, and immunogenicity. Intended copies are non-innovator biopharmaceutical products that, unlike biosimilars, do not have enough clinical evidence to demonstrate biosimilarity. For approval of a biosimilar, most countries require preclinical and clinical studies demonstrating comparability with the reference drug. The margin for determining equivalence or non-inferiority is determined on a case-by-case basis in each country, as there are no general criteria. The European Medicines Agency and US Food and Drug Administration have stringent regulatory processes to ensure comparability of biosimilars with their reference drugs. There are also post-marketing surveillance requirements to monitor safety. Only one biosimilar, CT-P13, has been approved for rheumatoid arthritis. However, in countries with less stringent regulation, intended copies are being commercialized and safety problems have been documented. Consequently, in such countries, there is an urgent need for appropriate regulatory processes to be established. Attempts to close the affordability gap of biopharmaceuticals should not open another gap between patients treated with an innovator drug and an intended copy.

  12. Biopharmaceutical Potential of Two Ramalina Lichens and their Metabolites. (United States)

    Ristic, Svetlana; Rankovic, Branislav; Kosanić, Marijana; Stamenkovic, Slavisa; Stanojković, Tatjana; Sovrlić, Miroslav; Manojlović, Nedeljko

    This paper studies the phytochemical analysis of the acetone extracts of the Ramalina fraxinea and Ramalina fastigiata lichens and the antioxidant, antimicrobial and antitumour activities of these species and their constituents. The phytochemical analysis of two Ramalina species was evaluated using HPLC-UV test. The depsides (evernic acid, obtusatic acid, sekikaic acid and atranorin), depsidones (protocetraric acid) and dibenzofurane (usnic acid) were identified from these lichens. Antioxidant activity was evaluated by DPPH assay, reducing power assay and by measuring the amounts of total phenolics in extracts. Antimicrobial activity was tested towards five bacterial and 10 fungal species, using broth microdilution method to determine the minimum inhibitory concentration. Cytotoxic activity was tested using MTT method on the human epithelial carcinoma (Hela), human lung carcinoma (A549) and human colon carcinoma (LS174) cells. As a result of the study, tested samples showed strong free radical scavenging activity with I50 values within the range of 285.45-423.51 μg/mL. Absorbance for reducing power was found to be from 0.0043 to 0.1747. The total amount of phenol concentrations in extracts of Ramalina fraxinea and Ramalina fastigiata was 32.63 and 33.49 μg PE/mg, respectively. Methyl evernate showed the strongest antimicrobial properties with the least measured MIC value being 0.125 mg/mL. In addition, all samples exhibited strong anticancer activities against tested cells (I50 values were between 24.63 and 161.37 μg/mL). These results indicate that lichen appears to be a possible natural biopharmaceutical.

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

  14. Semliki forest virus as a vector: pros and cons for its use in biopharmaceuticals production

    Directory of Open Access Journals (Sweden)

    Eutimio Gustavo Fernández Núñez


    Full Text Available The number of biopharmaceuticals for medical and veterinarian use produced in mammalian cells is increasing year after year. All of them are obtained by stable recombinant cell lines. However, it is recognized that transient gene expression produces high level expression in a short time. In that sense, viral vectors have been extensively used for producing recombinant proteins on lab-scale. Among them, Semliki Forest virus is commonly employed for this purpose. This review discusses the main aspects related to the use of Semliki Forest virus technology as well as its advantages and drawbacks which limit currently its utilization in biopharmaceutical industry on large-scale.

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

    DEFF Research Database (Denmark)

    Cun, Dongmei; Wan, Feng; Yang, Mingshi


    remains the most significant challeng to their clinical adoption due to their unfavorable intrinsic physicochemical properties. Among noninvasive administration routes the lung has been attempted intensively to be an alternative to injection to deliver the biopharmaceuticals, and has shown to be promising....... 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....

  16. Biotechnology and Biopharmaceutical Industry in the 21st Century-Development on Biopharmaceuticals%21世纪生物技术和生物制药

    Institute of Scientific and Technical Information of China (English)

    吴梧桐; 王友同; 吴文俊


    根据最新信息资料,评价了生物技术产业在国民经济发展中的重要地位,重点介绍了生物技术产业市场发展状况,对于了解国内外生物技术发展动态与客观决策具有参考价值。%Based on a thorough review,authors analized and categorized thetrend for the development on biotech-drugs and biopharmaceuticals market,also evaluated the importance of biotechnology in the national economic of China and illustrated their opinion on the direction of development on biopharmaceutical market and biophar maceutical industry in China.

  17. Guidance to Achieve Accurate Aggregate Quantitation in Biopharmaceuticals by SV-AUC. (United States)

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


    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.

  18. The long road of biopharmaceutical drug development: from inception to marketing. (United States)

    Mundae, M K; Ostör, A J K


    The development of therapeutics is costly, time-consuming and has high attrition rates. Biopharmaceutical medications differ from traditional agents in their discovery, design, structure and formulation. Prior to marketing a drug must show efficacy and acceptable toxicity in both preclinical and clinical trials. Regulatory bodies have a pivotal role in the licensing, naming and marketing of an agent.

  19. The publishing and patenting strategies of successful university spinoffs in the biopharmaceutical industry. (United States)

    Erden, Zeynep


    Firms in the biopharmaceutical industry send signals to investors about the value of their knowledge by disclosing it in the form of patents and publications. In this way, they can gain reputation even before having products on the market. This paper compares the patenting and publishing activities of university spinoffs with other biopharmaceutical firms. The findings suggest that successful university spinoffs and successful other firms (not university spinoffs) tend to follow different knowledge disclosure strategies. Whereas successful university spinoffs tend to emphasize the scientific value of their knowledge and gain reputation through their high-quality publications, other successful firms tend to emphasize the commercial value of their knowledge and gain reputation through high-quality patents.

  20. Cell-specific biomarkers and targeted biopharmaceuticals for breast cancer treatment. (United States)

    Liu, Mei; Li, Zhiyang; Yang, Jingjing; Jiang, Yanyun; Chen, Zhongsi; Ali, Zeeshan; He, Nongyue; Wang, Zhifei


    Breast cancer is the second leading cause of cancer death among women, and its related treatment has been attracting significant attention over the past decades. Among the various treatments, targeted therapy has shown great promise as a precision treatment, by binding to cancer cell-specific biomarkers. So far, great achievements have been made in targeted therapy of breast cancer. In this review, we first discuss cell-specific biomarkers, which are not only useful for classification of breast cancer subtyping but also can be utilized as goals for targeted therapy. Then, the innovative and generic-targeted biopharmaceuticals for breast cancer, including monoclonal antibodies, non-antibody proteins and small molecule drugs, are reviewed. Finally, we provide our outlook on future developments of biopharmaceuticals, and provide solutions to problems in this field.

  1. Organizational Scope and Investment: Evidence from the Drug Development Strategies and Performance of Biopharmaceutical Firms


    Ilan Guedj; David Scharfstein


    This paper compares the clinical trial strategies and performance of large, established ("mature") biopharmaceutical firms to those of smaller ("early stage") firms that have not yet successfully developed a drug. We study a sample of 235 cancer drug candidates that entered clinical trials during the period 1990-2002 and were sponsored by public firms. Early stage firms are more likely than mature firms to advance drug candidates from Phase I to Phase II clinical trials. However, early stage ...

  2. A comparative analysis of biopharmaceutics classification system and biopharmaceutics drug disposition classification system: a cross-sectional survey with 500 bioequivalence studies. (United States)

    Cristofoletti, Rodrigo; Chiann, Chang; Dressman, Jennifer B; Storpirtis, Silvia


    Although policies of waiving bioequivalence studies are part of the legal framework of various regulatory agencies, there is no harmonization with regard to extension of the biowaiver to drugs other than those with high solubility and high permeability, nor is there any consensus or official endorsement of the biopharmaceutics drug disposition classification system (BDDCS). To better understand the applicability of the biowaiver, we carried out a cross-sectional survey to estimate the relative risk of obtaining nonbioequivalent (non-BE) or bioinequivalent (BIE) results for drug products containing drugs belonging to each of the biopharmaceutics classification system (BCS) and BDDCS classes. Five hundred bioequivalence studies were randomly sampled from a database of the Brazilian Health Surveillance Agency (ANVISA). The drugs were classified according to the BCS and BDDCS, to evaluate how characteristics related to drug and dosage form influence the outcome of bioequivalence studies. The relative risk of obtaining a non-BE result was approximately four times lower for drugs in classes 1 and 3 of BCS or BDDCS when compared with class 2 drugs. Thus, it seems that the final outcome of a bioequivalence study is strongly influenced by the solubility of the drug, but not by its intestinal permeability or extent of metabolism.

  3. Delivery systems for biopharmaceuticals. Part II: Liposomes, Micelles, Microemulsions and Dendrimers. (United States)

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


    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.

  4. Nonclinical safety testing of biopharmaceuticals--Addressing current challenges of these novel and emerging therapies. (United States)

    Brennan, Frank R; Baumann, Andreas; Blaich, Guenter; de Haan, Lolke; Fagg, Rajni; Kiessling, Andrea; Kronenberg, Sven; Locher, Mathias; Milton, Mark; Tibbitts, Jay; Ulrich, Peter; Weir, Lucinda


    Non-clinical safety testing of biopharmaceuticals can present significant challenges to human risk assessment with these often innovative and complex drugs. Hot Topics in this field were discussed recently at the 4th Annual European Biosafe General Membership meeting. In this feature article, the presentations and subsequent discussions from the main sessions are summarized. The topics covered include: (i) wanted versus unwanted immune activation, (ii) bi-specific protein scaffolds, (iii) use of Pharmacokinetic (PK)/Pharmacodynamic (PD) data to impact/optimize toxicology study design, (iv) cytokine release and challenges to human translation (v) safety testing of cell and gene therapies including chimeric antigen receptor T (CAR-T) cells and retroviral vectors and (vi) biopharmaceutical development strategies encompassing a range of diverse topics including optimizing entry of monoclonal antibodies (mAbs) into the brain, safety testing of therapeutic vaccines, non-clinical testing of biosimilars, infection in toxicology studies with immunomodulators and challenges to human risk assessment, maternal and infant anti-drug antibody (ADA) development and impact in non-human primate (NHP) developmental toxicity studies, and a summary of an NC3Rs workshop on the future vision for non-clinical safety assessment of biopharmaceuticals.

  5. A novel in vitro method to model the fate of subcutaneously administered biopharmaceuticals and associated formulation components. (United States)

    Kinnunen, Hanne M; Sharma, Vikas; Contreras-Rojas, Luis Rodrigo; Yu, Yafei; Alleman, Chlöe; Sreedhara, Alavattam; Fischer, Stefan; Khawli, Leslie; Yohe, Stefan T; Bumbaca, Daniela; Patapoff, Thomas W; Daugherty, Ann L; Mrsny, Randall J


    Subcutaneous (SC) injection is becoming a more common route for the administration of biopharmaceuticals. Currently, there is no reliable in vitro method that can be used to anticipate the in vivo performance of a biopharmaceutical formulation intended for SC injection. Nor is there an animal model that can predict in vivo outcomes such as bioavailability in humans. We address this unmet need by the development of a novel in vitro system, termed Scissor (Subcutaneous Injection Site Simulator). The system models environmental changes that a biopharmaceutical could experience as it transitions from conditions of a drug product formulation to the homeostatic state of the hypodermis following SC injection. Scissor uses a dialysis-based injection chamber, which can incorporate various concentrations and combinations of acellular extracellular matrix (ECM) components that may affect the release of a biopharmaceutical from the SC injection site. This chamber is immersed in a container of a bicarbonate-based physiological buffer that mimics the SC injection site and the infinite sink of the body. Such an arrangement allows for real-time monitoring of the biopharmaceutical within the injection chamber, and can be used to characterize physicochemical changes of the drug and its interactions with ECM components. Movement of a biopharmaceutical from the injection chamber to the infinite sink compartment simulates the drug migration from the injection site and uptake by the blood and/or lymph capillaries. Here, we present an initial evaluation of the Scissor system using the ECM element hyaluronic acid and test formulations of insulin and four different monoclonal antibodies. Our findings suggest that Scissor can provide a tractable method to examine the potential fate of a biopharmaceutical formulation after its SC injection in humans and that this approach may provide a reliable and representative alternative to animal testing for the initial screening of SC formulations.

  6. Physiologically Based Absorption Modeling to Impact Biopharmaceutics and Formulation Strategies in Drug Development-Industry Case Studies. (United States)

    Kesisoglou, Filippos; Chung, John; van Asperen, Judith; Heimbach, Tycho


    In recent years, there has been a significant increase in use of physiologically based pharmacokinetic models in drug development and regulatory applications. Although most of the published examples have focused on aspects such as first-in-human (FIH) dose predictions or drug-drug interactions, several publications have highlighted the application of these models in the biopharmaceutics field and their use to inform formulation development. In this report, we present 5 case studies of use of such models in this biopharmaceutics/formulation space across different pharmaceutical companies. The case studies cover different aspects of biopharmaceutics or formulation questions including (1) prediction of absorption prior to FIH studies; (2) optimization of formulation and dissolution method post-FIH data; (3) early exploration of a modified-release formulation; (4) addressing bridging questions for late-stage formulation changes; and (5) prediction of pharmacokinetics in the fed state for a Biopharmaceutics Classification System class I drug with fasted state data. The discussion of the case studies focuses on how such models can facilitate decisions and biopharmaceutic understanding of drug candidates and the opportunities for increased use and acceptance of such models in drug development and regulatory interactions.

  7. Protein N-glycosylation in eukaryotic microalgae and its impact on the production of nuclear expressed biopharmaceuticals. (United States)

    Mathieu-Rivet, Elodie; Kiefer-Meyer, Marie-Christine; Vanier, Gaëtan; Ovide, Clément; Burel, Carole; Lerouge, Patrice; Bardor, Muriel


    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 remodeling 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.

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


    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. PMID:24776763

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

    Directory of Open Access Journals (Sweden)

    Yang Yang


    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.

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


    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.

  11. PEGylation of Biopharmaceuticals: A Review of Chemistry and Nonclinical Safety Information of Approved Drugs. (United States)

    Turecek, Peter L; Bossard, Mary J; Schoetens, Freddy; Ivens, Inge A


    Modification of biopharmaceutical molecules by covalent conjugation of polyethylene glycol (PEG) molecules is known to enhance pharmacologic and pharmaceutical properties of proteins and other large molecules and has been used successfully in 12 approved drugs. Both linear and branched-chain PEG reagents with molecular sizes of up to 40 kDa have been used with a variety of different PEG derivatives with different linker chemistries. This review describes the properties of PEG itself, the history and evolution of PEGylation chemistry, and provides examples of PEGylated drugs with an established medical history. A trend toward the use of complex PEG architectures and larger PEG polymers, but with very pure and well-characterized PEG reagents is described. Nonclinical toxicology findings related to PEG in approved PEGylated biopharmaceuticals are summarized. The effect attributed to the PEG part of the molecules as observed in 5 of the 12 marketed products was cellular vacuolation seen microscopically mainly in phagocytic cells which is likely related to their biological function to absorb and remove particles and macromolecules from blood and tissues. Experience with marketed PEGylated products indicates that adverse effects in toxicology studies are usually related to the active part of the drug but not to the PEG moiety.

  12. Potential of hydrophilic interaction chromatography for the analytical characterization of protein biopharmaceuticals. (United States)

    Periat, Aurélie; Fekete, Szabolcs; Cusumano, Alessandra; Veuthey, Jean-Luc; Beck, Alain; Lauber, Matthew; Guillarme, Davy


    A new stationary phase based on wide-pore hybrid silica bonded with amide ligand has been used to explore the utility of HILIC for the analytical characterization of protein biopharmaceuticals. Various, highly-relevant samples were tested, including different insulins, interferon α-2b and trastuzumab. This work shows that HILIC can be successfully employed for the analysis of therapeutic proteins and mAbs, using mobile phase compositions comprised of between 65 and 80% ACN and 0.1% TFA. In terms of elution order and selectivity, these HILIC separations have proven to be highly orthogonal to RPLC, while the kinetic performance remains comparable. In the case of characterizing trastuzumab, HILIC was uniquely able to resolve several important glycoforms at the middle-up level of analysis (fragments of 25-100kDa). Such a separation of glycoforms has been elusive by other separation mechanisms, such as RPLC and IEX. Besides showing orthogonality to RPLC and improved separations of glycoforms, HILIC offers several additional benefits for biopharmaceutical characterization: i) an inherent compatibility with MS, ii) a reduced requirement for very high mobile phase temperatures that are otherwise needed in RPLC to limit undesirably strong adsorption to the surface of the stationary phase, and iii) the possibility to couple several columns in series to improve resolving power, thanks to comparatively low mobile phase viscosity.

  13. Stem cells and biopharmaceuticals: vital roles in the growth of tissue-engineered small intestine. (United States)

    Belchior, Gustavo Gross; Sogayar, Mari Cleide; Grikscheit, Tracy Cannon


    Tissue engineering currently constitutes a complex, multidisciplinary field exploring ideal sources of cells in combination with scaffolds or delivery systems in order to form a new, functional organ to replace native organ lack or loss. Short bowel syndrome (SBS) is a life-threatening condition with high morbidity and mortality rates in children. Current therapeutic strategies consist of costly and risky allotransplants that demand lifelong immunosuppression. A promising alternative is the implantation of autologous organoid units (OU) to create a tissue-engineered small intestine (TESI). This strategy is proven to be stem cell and mesenchyme dependent. Intestinal stem cells (ISCs) are located at the base of the crypt and are responsible for repopulating the cycling mucosa up to the villus tip. The stem cell niche governs the biology of ISCs and, together with the rest of the epithelium, communicates with the underlying mesenchyme to sustain intestinal homeostasis. Biopharmaceuticals are broadly used in the clinic to activate or enhance known signaling pathways and may greatly contribute to the development of a full-thickness intestine by increasing mucosal surface area, improving blood supply, and determining stem cell fate. This review will focus on tissue engineering as a means of building the new small intestine, highlighting the importance of stem cells and recombinant peptide growth factors as biopharmaceuticals.

  14. The biopharmaceutics risk assessment roadmap for optimizing clinical drug product performance. (United States)

    Selen, Arzu; Dickinson, Paul A; Müllertz, Anette; Crison, John R; Mistry, Hitesh B; Cruañes, Maria T; Martinez, Marilyn N; Lennernäs, Hans; Wigal, Tim L; Swinney, David C; Polli, James E; Serajuddin, Abu T M; Cook, Jack A; Dressman, Jennifer B


    The biopharmaceutics risk assessment roadmap (BioRAM) optimizes drug product development and performance by using therapy-driven target drug delivery profiles as a framework to achieve the desired therapeutic outcome. Hence, clinical relevance is directly built into early formulation development. Biopharmaceutics tools are used to identify and address potential challenges to optimize the drug product for patient benefit. For illustration, BioRAM is applied to four relatively common therapy-driven drug delivery scenarios: rapid therapeutic onset, multiphasic delivery, delayed therapeutic onset, and maintenance of target exposure. BioRAM considers the therapeutic target with the drug substance characteristics and enables collection of critical knowledge for development of a dosage form that can perform consistently for meeting the patient's needs. Accordingly, the key factors are identified and in vitro, in vivo, and in silico modeling and simulation techniques are used to elucidate the optimal drug delivery rate and pattern. BioRAM enables (1) feasibility assessment for the dosage form, (2) development and conduct of appropriate "learning and confirming" studies, (3) transparency in decision-making, (4) assurance of drug product quality during lifecycle management, and (5) development of robust linkages between the desired clinical outcome and the necessary product quality attributes for inclusion in the quality target product profile.

  15. Artificial neural network associated to UV/Vis spectroscopy for monitoring bioreactions in biopharmaceutical processes. (United States)

    Takahashi, Maria Beatriz; Leme, Jaci; Caricati, Celso Pereira; Tonso, Aldo; Fernández Núñez, Eutimio Gustavo; Rocha, José Celso


    Currently, mammalian cells are the most utilized hosts for biopharmaceutical production. The culture media for these cell lines include commonly in their composition a pH indicator. Spectroscopic techniques are used for biopharmaceutical process monitoring, among them, UV-Vis spectroscopy has found scarce applications. This work aimed to define artificial neural networks architecture and fit its parameters to predict some nutrients and metabolites, as well as viable cell concentration based on UV-Vis spectral data of mammalian cell bioprocess using phenol red in culture medium. The BHK-21 cell line was used as a mammalian cell model. Off-line spectra of supernatant samples taken from batches performed at different dissolved oxygen concentrations in two bioreactor configurations and with two pH control strategies were used to define two artificial neural networks. According to absolute errors, glutamine (0.13 ± 0.14 mM), glutamate (0.02 ± 0.02 mM), glucose (1.11 ± 1.70 mM), lactate (0.84 ± 0.68 mM) and viable cell concentrations (1.89 10(5) ± 1.90 10(5) cell/mL) were suitably predicted. The prediction error averages for monitored variables were lower than those previously reported using different spectroscopic techniques in combination with partial least squares or artificial neural network. The present work allows for UV-VIS sensor development, and decreases cost related to nutrients and metabolite quantifications.

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

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


    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.

  17. [Development of technology, of rheological and biopharmaceutical properties of new gel]. (United States)

    Mekhralieva, S Dzh


    The purpose of this research is the development of technology for preparation of hydrogel Glysotrical and study its rheological and biopharmaceutical characteristics. Based on gel-forming chitosan, PEG-400, glycerol and Tween-80 a new composition of hydrogel - Glysotrical was developed. Rheological properties of Glysotrical, as well as biopharmaceutical properties of artificial (cellophane) and natural membrane (chicken and pork skin) were investigated by dialysis. Rheological properties of different concentrations of chitosan solution and gel Glysotrical prepared on their basis were studied. It was determined that gel derived from the 5% solution of chitosan meets the technological requirements (pH-5,5-6,0, melting point-75,0±1,07°C, dynamic viscosity - 890,6 ± 3,57 cps). Rheological properties of the hydrogel Glysotrical, prepared on the basis of a multi-component composition in different temperatures (20, 40, 60°C) were identified. It was found that shear of helium drug (458 H/m2, 355 H/m2) at 20° and 40°C is lower, and the value of dynamic viscosity (912spz, 602spz) higher than that of chitosan gel; the hydrogel is stable at 20° and 40°C. High kinetic activity of hydrogel with Tween-80 is observed. During 5 hours membrane maximum quantity of routine diffusion from helium mass into dialysate in cellophane is 57,54 ±0,51%; in normal skin chicken - 20,04±0,55%; in the skin of chicken treated with 2% citric acid - 23,14±0,45%; normal pig skin - 12,64±0,09%; in the skin of pigs, treated with acid - 15,08± 0,11%. The study showed that the gel Glysotrical at 10-22°C is maintained for 2 years. Physico-chemical, rheological, technological and biopharmaceutical research showed that 4% gel Glysotrical was good in treatment of dermatological diseases.


    Directory of Open Access Journals (Sweden)



    Full Text Available A major challenge confronting pharmaceutical scientists in the future will be to design successful dosage forms for the next generation of drugs. Many of these drugs will be complex polymers of amino acids (e.g., peptides, proteins, nucleosides (e.g., antisense molecules, carbohydrates (e.g., polysaccharides, or complex lipids. Protein and peptide therapeutics currently represent eight of the top 100 prescription pharmaceuticals in the US, and biotechnology products are projected to account for 15% of the total US Prescription drug market by 2003. Conventional drug formulation has the same focus but, due to the unique structures of peptide and protein molecules, formulation of these compounds is more complex and challenging. Therapeutic peptides and proteins always enjoyed unique place in pharmaceutical biotechnology. Peptides and proteins are expected to mitigate suffering in coming years as anticancer, hormones, analgesic antihypertensive, thrombolytics, growth factors, and many others. This review represents outstanding contributions in the field of biopharmaceuticals.

  19. The importance of patents to innovation: updated cross-industry comparisons with biopharmaceuticals. (United States)

    Cockburn, Iain; Long, Genia


    Patents have long been considered essential incentives to foster innovation, particularly the development of new prescription drugs, due to the lengthy, costly, and risky nature of the research and development (R&D) process as compared to the lower levels of investment and risk associated with generic drug entry. Compared with other forms of intellectual property protection (such as trade secrets, trademarks, and copyrights) and strategic complementary assets (such as lead time, sales and service, and manufacturing advantages), researchers focused on the US since the 1980s consistently have found patents to be relatively more important to R&D in pharmaceuticals than in other industries. Despite many changes in the market and patent landscape, the most recent data from government surveys and annual surveys of licensing professionals continue to find differential and high importance of patents to biopharmaceutical innovation.

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

    DEFF Research Database (Denmark)

    Minssen, Timo

    “The implications and applications of biotechnology continue to be at the centre of public debate. In the light of rapid scientific advances and novel insights, the multi-faceted discussions are particularly fierce with regard to patents on DNA–related technology. In the often very emotionally...... 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...... basically followed this line of thinking. Thus, the grant of patents on DNA- and protein- related technology had become routine. While it almost seems impossible to reconcile these fundamentally diverging views, the purpose of this thesis is related to a third area of debate. It focuses on the fierce...

  1. Biopharmaceutical classification system: A strategic tool for oral drug delivery technology

    Directory of Open Access Journals (Sweden)

    Sachan Nikhil


    Full Text Available The biopharmaceutical classification system (BCS is a new concept in the field of pharmaceutical science and technology. This is a valuable tool for the formulation scientists, for the selection and design of the formulation of any drug substance. The recent developments have also enabled us to predict the solubility and permeability characteristics of the drug molecule in the early development stages so that the necessary structural changes can be made to the molecule in order to optimize the pharmacokinetic parameters. The BCS has also got a place in various guidance documents of regulatory importance. This article reviews the criteria for classifying drugs according to the BCS and discusses further potential applications of the BCS, including the developments of new drugs and controlled release products.

  2. Microtools for single-cell analysis in biopharmaceutical development and manufacturing. (United States)

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


    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.

  3. Automated Antibody De Novo Sequencing and Its Utility in Biopharmaceutical Discovery (United States)

    Sen, K. Ilker; Tang, Wilfred H.; Nayak, Shruti; Kil, Yong J.; Bern, Marshall; Ozoglu, Berk; Ueberheide, Beatrix; Davis, Darryl; Becker, Christopher


    Applications of antibody de novo sequencing in the biopharmaceutical industry range from the discovery of new antibody drug candidates to identifying reagents for research and determining the primary structure of innovator products for biosimilar development. When murine, phage display, or patient-derived monoclonal antibodies against a target of interest are available, but the cDNA or the original cell line is not, de novo protein sequencing is required to humanize and recombinantly express these antibodies, followed by in vitro and in vivo testing for functional validation. Availability of fully automated software tools for monoclonal antibody de novo sequencing enables efficient and routine analysis. Here, we present a novel method to automatically de novo sequence antibodies using mass spectrometry and the Supernovo software. The robustness of the algorithm is demonstrated through a series of stress tests.

  4. [Impacts of multicomponent environment on solubility of puerarin in biopharmaceutics classification system of Chinese materia medica]. (United States)

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


    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.

  5. Endotoxin inactivation via steam-heat treatment in dilute simethicone emulsions used in biopharmaceutical processes. (United States)

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


    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.

  6. 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


    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.

  7. License Compliance Issues For Biopharmaceuticals: Special Challenges For Negotiations Between Companies And Non-Profit Research Institutions. (United States)

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


    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

  8. Hybrid modeling for quality by design and PAT-benefits and challenges of applications in biopharmaceutical industry. (United States)

    von Stosch, Moritz; Davy, Steven; Francois, Kjell; Galvanauskas, Vytautas; Hamelink, Jan-Martijn; Luebbert, Andreas; Mayer, Martin; Oliveira, Rui; O'Kennedy, Ronan; Rice, Paul; Glassey, Jarka


    This report highlights the drivers, challenges, and enablers of the hybrid modeling applications in biopharmaceutical industry. It is a summary of an expert panel discussion of European academics and industrialists with relevant scientific and engineering backgrounds. Hybrid modeling is viewed in its broader sense, namely as the integration of different knowledge sources in form of parametric and nonparametric models into a hybrid semi-parametric model, for instance the integration of fundamental and data-driven models. A brief description of the current state-of-the-art and industrial uptake of the methodology is provided. The report concludes with a number of recommendations to facilitate further developments and a wider industrial application of this modeling approach. These recommendations are limited to further exploiting the benefits of this methodology within process analytical technology (PAT) applications in biopharmaceutical industry.

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


    Catherine Tomaro-Duchesneau; Shyamali Saha; Meenakshi Malhotra; Imen Kahouli; Satya Prakash


    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 ...

  10. Oral biopharmaceutics tools - time for a new initiative - an introduction to the IMI project OrBiTo. (United States)

    Lennernäs, H; Aarons, L; Augustijns, P; Beato, S; Bolger, M; Box, K; Brewster, M; Butler, J; Dressman, J; Holm, R; Julia Frank, K; Kendall, R; Langguth, P; Sydor, J; Lindahl, A; McAllister, M; Muenster, U; Müllertz, A; Ojala, K; Pepin, X; Reppas, C; Rostami-Hodjegan, A; Verwei, M; Weitschies, W; Wilson, C; Karlsson, C; Abrahamsson, B


    OrBiTo is a new European project within the IMI programme in the area of oral biopharmaceutics tools that includes world leading scientists from nine European universities, one regulatory agency, one non-profit research organization, four SMEs together with scientists from twelve pharmaceutical companies. The OrBiTo project will address key gaps in our knowledge of gastrointestinal (GI) drug absorption and deliver a framework for rational application of predictive biopharmaceutics tools for oral drug delivery. This will be achieved through novel prospective investigations to define new methodologies as well as refinement of existing tools. Extensive validation of novel and existing biopharmaceutics tools will be performed using active pharmaceutical ingredient (API), formulations and supporting datasets from industry partners. A combination of high quality in vitro or in silico characterizations of API and formulations will be integrated into physiologically based in silico biopharmaceutics models capturing the full complexity of GI drug absorption. This approach gives an unparalleled opportunity to initiate a transformational change in industrial research and development to achieve model-based pharmaceutical product development in accordance with the Quality by Design concept. Benefits include an accelerated and more efficient drug candidate selection, formulation development process, particularly for challenging projects such as low solubility molecules (BCS II and IV), enhanced and modified-release formulations, as well as allowing optimization of clinical product performance for patient benefit. In addition, the tools emerging from OrBiTo are expected to significantly reduce demand for animal experiments in the future as well as reducing the number of human bioequivalence studies required to bridge formulations after manufacturing or composition changes.

  11. Biopharmaceutics data management system for anonymised data sharing and curation: First application with orbito IMI project. (United States)

    Lacy-Jones, Kristin; Hayward, Philip; Andrews, Steve; Gledhill, Ian; McAllister, Mark; Abrahamsson, Bertil; Rostami-Hodjegan, Amin; Pepin, Xavier


    The OrBiTo IMI project was designed to improve the understanding and modelling of how drugs are absorbed. To achieve this 13 pharmaceutical companies agreed to share biopharmaceutics drug properties and performance data, as long as they were able to hide certain aspects of their dataset if required. This data was then used in simulations to test how three in silico Physiological Based Pharmacokinetic (PBPK) tools performed. A unique database system was designed and implemented to store the drug data. The database system was unique, in that it had the ability to make different sections of a dataset visible or hidden depending on the stage of the project. Users were also given the option to hide identifying API attributes, to help prevent identification of project members from previously published data. This was achieved by applying blinding strategies to data parameters and the adoption of a unique numbering system. An anonymous communication tool was proposed to exchange comments about data, which enabled its curation and evolution. This paper describes the strategy adopted for numbering and blinding of the data, the tools developed to gather and search data as well as the tools used for communicating around the data with the aim of publicising the approach for other pre-competitive research between organisations.

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

    Directory of Open Access Journals (Sweden)

    Ya-Shan Chen


    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.

  13. Production of Biopharmaceuticals in E. coli: Current Scenario and Future Perspectives. (United States)

    Baeshen, Mohammed N; Al-Hejin, Ahmed M; Bora, Roop S; Ahmed, Mohamed M M; Ramadan, Hassan A I; Saini, Kulvinder S; Baeshen, Nabih A; Redwan, Elrashdy M


    Escherichia coli is the most preferred microorganism to express heterologous proteins for therapeutic use, as around 30% of the approved therapeutic proteins are currently being produced using it as a host. Owing to its rapid growth, high yield of the product, cost-effectiveness, and easy scale-up process, E. coli is an expression host of choice in the biotechnology industry for large-scale production of proteins, particularly non-glycosylated proteins, for therapeutic use. The availability of various E. coli expression vectors and strains, relatively easy protein folding mechanisms, and bioprocess technologies, makes it very attractive for industrial applications. However, the codon usage in E. coli and the absence of post-translational modifications, such as glycosylation, phosphorylation, and proteolytic processing, limit its use for the production of slightly complex recombinant biopharmaceuticals. Several new technological advancements in the E. coli expression system to meet the biotechnology industry requirements have been made, such as novel engineered strains, genetically modifying E. coli to possess capability to glycosylate heterologous proteins and express complex proteins, including full-length glycosylated antibodies. This review summarizes the recent advancements that may further expand the use of the E. coli expression system to produce more complex and also glycosylated proteins for therapeutic use in the future.

  14. Biopharmaceutics classification system-based biowaivers for generic oncology drug products: case studies. (United States)

    Tampal, Nilufer; Mandula, Haritha; Zhang, Hongling; Li, Bing V; Nguyen, Hoainhon; Conner, Dale P


    Establishing bioequivalence (BE) of drugs indicated to treat cancer poses special challenges. For ethical reasons, often, the studies need to be conducted in cancer patients rather than in healthy volunteers, especially when the drug is cytotoxic. The Biopharmaceutics Classification System (BCS) introduced by Amidon (1) and adopted by the FDA, presents opportunities to avoid conducting the bioequivalence studies in humans. This paper analyzes the application of the BCS approach by the generic pharmaceutical industry and the FDA to oncology drug products. To date, the FDA has granted BCS-based biowaivers for several drug products involving at least four different drug substances, used to treat cancer. Compared to in vivo BE studies, development of data to justify BCS waivers is considered somewhat easier, faster, and more cost effective. However, the FDA experience shows that the approval times for applications containing in vitro studies to support the BCS-based biowaivers are often as long as the applications containing in vivo BE studies, primarily because of inadequate information in the submissions. This paper deliberates some common causes for the delays in the approval of applications requesting BCS-based biowaivers for oncology drug products. Scientific considerations of conducting a non-BCS-based in vivo BE study for generic oncology drug products are also discussed. It is hoped that the information provided in our study would help the applicants to improve the quality of ANDA submissions in the future.

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

    Directory of Open Access Journals (Sweden)

    Jesús Zurdo


    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.

  16. Mass Spectrometry Based Mechanistic Insights into Formation of Tris Conjugates: Implications on Protein Biopharmaceutics (United States)

    Kabadi, Pradeep G.; Sankaran, Praveen Kallamvalliillam; Palanivelu, Dinesh V.; Adhikary, Laxmi; Khedkar, Anand; Chatterjee, Amarnath


    We present here extensive mass spectrometric studies on the formation of a Tris conjugate with a therapeutic monoclonal antibody. The results not only demonstrate the reactive nature of the Tris molecule but also the sequence and reaction conditions that trigger this reactivity. The results corroborate the fact that proteins are, in general, prone to conjugation and/or adduct formation reactions and any modification due to this essentially leads to formation of impurities in a protein sample. Further, the results demonstrate that the conjugation reaction happens via a succinimide intermediate and has sequence specificity. Additionally, the data presented in this study also shows that the Tris formation is produced in-solution and is not an in-source phenomenon. We believe that the facts given here will open further avenues on exploration of Tris as a conjugating agent as well as ensure that the use of Tris or any ionic buffer in the process of producing a biopharmaceutical drug is monitored closely for the presence of such conjugate formation.

  17. Early implementation of QbD in biopharmaceutical development: a practical example. (United States)

    Zurdo, Jesús; Arnell, Andreas; Obrezanova, Olga; Smith, Noel; Gómez de la Cuesta, Ramón; Gallagher, Thomas R A; Michael, Rebecca; Stallwood, Yvette; Ekblad, Caroline; Abrahmsén, Lars; Höidén-Guthenberg, Ingmarie


    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.

  18. Biopharmaceutical constants for carbamazepine immediate release tablets in simplifying bioequivalence studies

    Directory of Open Access Journals (Sweden)

    Nanayakkara Mangala


    Full Text Available Current study was undertaken in order to determine model biopharmaceutical constants for carbamazepine immediate release tablets (200 mg from documented data of plasma concentration vs time curves. The constants and the proposed methodology simplify bioequivalence determinations to blood sampling restricted only to two time points. Twelve volunteer drug plasma concentration (Cp determinations from a crossover design bioequivalence study were fitted into equations containing two rate processes. The optimized rate constants were used to generate the Cp vs time curves (generated curves. Generated curves were then differentiated (dCp/dt to obtain the first derivative curve for each volunteer from which times for highest rate of absorption (TAmaxn and highest rate of elimination (TEmaxn were determined. The corresponding highest rate of absorption and the highest rate of elimination for each individual were then obtained from the generated curve and named as Amaxn and Emaxn. Individual Amaxn and Emaxn values were then averaged to obtain the mean Amax and Emax. Out of the 24 determinations, a total of 13 Amaxn and 20 Emaxn values fell within ±20% of the overall mean. Final Amax and Emax values ware arrived at by averaging each set of individual 13 values and 20 values respectively. From these two mean coordinates, the corresponding constants, plasma drug concentration at the point of highest rate of absorption (CpAmax and corresponding time TAmax, as well as the plasma drug concentration at the point of highest rate of elimination (CpEmax and the corresponding time TEmax, were determined.

  19. Isolation and characterization of bioactive fungi from shark Carcharodon carcharias' gill with biopharmaceutical prospects (United States)

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


    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.

  20. Continuous counter-current chromatography for capture and polishing steps in biopharmaceutical production. (United States)

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


    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.

  1. Regulatory policy and the location of bio-pharmaceutical foreign direct investment in Europe. (United States)

    Koenig, Pamina; Macgarvie, Megan


    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.

  2. The human rhabdomyosarcoma cell line TE671--Towards an innovative production platform for glycosylated biopharmaceuticals. (United States)

    Rosenlöcher, Julia; Weilandt, Constanze; Sandig, Grit; Reinke, Stefan O; Blanchard, Véronique; Hinderlich, Stephan


    The market of therapeutic glycoproteins (including coagulation factors, antibodies, cytokines and hormones) is one of the profitable, fast-growing and challenging sectors of the biopharmaceutical industry. Although mammalian cell culture is still expensive and technically complex, the ability to produce desired post-translational modifications, in particular glycosylation, is a major issue. Glycans can influence ligand binding, serum half-life as well as biological activity or product immunogenicity. Aiming to establish a novel production platform for recombinant glycoproteins, the human TE671 cell line was investigated. Since the initial analysis of cell membrane proteins showed a promising glycosylation of TE671 cells for biotechnological purposes, we focused on the recombinant expression of two model glycoproteins of therapeutical relevance. The optimization of the cell transfection procedure and serum-free expression succeeded for the human serine protease inhibitor alpha-1-antitrypsin (A1AT) and the hematopoietic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). N-glycan analyses of both purified proteins by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry provided first fundamental insights into the TE671 glycosylation potential. Besides protein specific pattern, strong distinctions - in particular for N-glycan fucosylation and sialylation - were observed depending on the medium conditions of the respective TE671 cell cultivations. The cell line's ability to synthesize complex and highly sialylated N-glycan structures has been shown. Our results demonstrate the TE671 cell line as a serious alternative to other existing human expression systems.

  3. Capillary electrophoresis-mass spectrometry using noncovalently coated capillaries for the analysis of biopharmaceuticals. (United States)

    Haselberg, R; Brinks, V; Hawe, A; de Jong, G J; Somsen, G W


    In this work, the usefulness of capillary electrophoresis-electrospray ionization time-of-flight-mass spectrometry for the analysis of biopharmaceuticals was studied. Noncovalently bound capillary coatings consisting of Polybrene-poly(vinyl sulfonic acid) or Polybrene-dextran sulfate-Polybrene were used to minimize protein and peptide adsorption, and achieve good separation efficiencies. The potential of the capillary electrophoresis-mass spectrometry (CE-MS) system to characterize degradation products was investigated by analyzing samples of the drugs, recombinant human growth hormone (rhGH) and oxytocin, which had been subjected to prolonged storage, heat exposure, and/or different pH values. Modifications could be assigned based on accurate masses as obtained with time-of-flight-mass spectrometry (TOF-MS) and migration times with respect to the parent compound. For heat-exposed rhGH, oxidations, sulfonate formation, and deamidations were observed. Oxytocin showed strong deamidation (up to 40%) upon heat exposure at low pH, whereas at medium and high pH, mainly dimer (>10%) and trisulfide formation (6-7%) occurred. Recombinant human interferon-β-1a (rhIFN-β) was used to evaluate the capability of the CE-MS method to assess glycan heterogeneity of pharmaceutical proteins. Analysis of this N-glycosylated protein revealed a cluster of resolved peaks which appeared to be caused by at least ten glycoforms differing merely in sialic acid and hexose N-acetylhexosamine composition. Based on the relative peak area (assuming an equimolar response per glycoform), a quantitative profile could be derived with the disialytated biantennary glycoform as most abundant (52%). Such a profile may be useful for in-process and quality control of rhIFN-β batches. It is concluded that the separation power provided by combined capillary electrophoresis and TOF-MS allows discrimination of highly related protein species.

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

    Wolk, Omri; Agbaria, Riad; Dahan, Arik


    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.

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

    Directory of Open Access Journals (Sweden)

    Nancy Vara-Gama


    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.

  6. Density dependent mechanical properties and structures of a freeze dried biopharmaceutical excipient--sucrose. (United States)

    Devi, Sharmila; Williams, Daryl R


    Knowledge of the mechanical behaviour of freeze dried biopharmaceutical products is essential for designing of products with physical robustness that will not to crack, crumble or collapse during processing or transportation. The compressive mechanical deformation behaviour for freeze-dried sucrose cakes has been experimentally studied from a relative density (ρf/ρs) of 0.01-0.30 using a novel in-vial indentation test. Cakes exhibited more open like structures at lower densities and more closed structures at higher densities with some faces being present at all densities, as confirmed by SEM. The reduced elastic modulus Ef/Es=0.0044(ρf/ρs)(1) for all cake densities, indicating that face stretching was the dominant deformation mode assuming Gibson and Ashby's closed cell model. This linear scaling for the reduced elastic modulus is in line with various theoretical treatments based on tetrakaidecahedral cells and other experimental studies. Consistently, the wall thickness to cell diameter ratio scaled ρf/ρs with a power constant of 1.05. The maximum crushing stress was given by σmax=3800(ρf/ρs)(1.48) which agrees with a strut bending failure stress, assuming Gibson and Ashby's open cell model. Overall, the freeze dried cakes behaved as neither classic closed cell nor open cell materials, with their compressive elastic moduli reflecting a closed cell elastic response whilst their failure stresses reflecting an open cell failure mode. It was concluded that the mechanical response of freeze dried cellular materials depends upon their complex cellular structures and morphologies, and they cannot be rationalised using simple limiting case models of open or closed cell solids.

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


    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

  8. Superficial Talk Biopharmaceutical Technology in Medicine Pharmacy%浅谈生物制药技术在西药制药中的应用

    Institute of Scientific and Technical Information of China (English)



    随着生物技术的不断发展,生物制药技术逐渐在药物生产制造领域得到了广泛的应用。在西药的生产与研发过程中,生物制药技术的应用具有重要的推动作用。就生物制药技术在西药制药中的应用进行了分析与探讨。%With the development of biotechnology, biopharmaceutical technology is increasingly in the pharmaceutical manufacturing areas has been widely used. In Western medicine production and development process, the application of bio-pharmaceutical technology has an important role. You biopharmaceutical technology application in western medicine were analyzed and discussed.

  9. A study of physicochemical and biopharmaceutical properties of amoxicillin tablets using full factorial design and PCA biplot. (United States)

    Pasqualoto, Kerly F M; Teófilo, Reinaldo F; Guterres, Marcos; Pereira, Flávia S; Ferreira, Márcia M C


    The variables that influence the tablets obtained by direct compression method deserve to be studied to minimize formulations costs and to improve the physicochemical and biopharmaceutical properties of the compacts. Here, we explore the adjuvants effects on amoxicillin tablet formulations considering multiple responses, and indicate the most suitable formulation composition. A 2(3) full factorial design was built to different amoxicillin formulations, each one containing three replicate batches, and eight responses (physicochemical and biopharmaceutical parameters) were obtained. The microcrystalline cellulose (MCC) type Avicel PH-102 (low) or PH-200 (high), the absence (low) or presence (high) of spray-dried lactose (LAC), and the absence (low) or presence (high) of disintegrant (DIS) were the levels investigated. The more relevant responses to the distinct formulations from the experimental design were hardness, friability, and the amount of amoxicillin dissolved during the first hour. PCA biplot indicated high values of amount of drug dissolved in 60 min as advantageous responses for the investigated amoxicillin tablet formulations and high values of friability as not desirable. Considering the individual response evaluation, the most suitable amoxicillin tablet formulation should present in its composition the MCC type Avicel PH-102 (low level) and the superdisintegrant agent (DIS high level), croscarmellose sodium, but no LAC (low level).

  10. The biopharmaceutics of successful controlled release drug product: Segmental-dependent permeability of glipizide vs. metoprolol throughout the intestinal tract. (United States)

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


    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.

  11. Generic chromatography-based purification strategies accelerate the development of downstream processes for biopharmaceutical proteins produced in plants. (United States)

    Buyel, Johannes F; Fischer, Rainer


    Plants offer a valuable alternative to cultured mammalian cells for the production of recombinant biopharmaceutical proteins. However, the target protein typically represents only a minor fraction of the total protein in the initial plant extract, which means that the development of product-specific chromatography-based purification strategies is often laborious and expensive. To address this challenge, we designed a generic downstream process that is suitable for the purification of recombinant proteins with diverse properties from plant production platforms. This was achieved by focusing on the binding behavior of tobacco host cell proteins (HCPs) to a broad set of chromatography resins under different pH and conductivity conditions. Strong cation exchanger and salt-tolerant anion exchanger resins exhibited the best resolution of tobacco HCPs among the 13 tested resins, and their selectivity was easy to manipulate through the adjustment of pH and conductivity. The advantages, such as direct capture of a target protein from leaf extract, and limitations, such as low binding capacity, of various chromatography ligands and resins are discussed. We also address the most useful applications of the chromatography ligands, namely recovery of proteins with a certain pI, in a downstream process that aims to purify diverse plant-derived biopharmaceutical proteins. Based on these results, we describe generic purification schemes that are suitable for acidic, neutral, and basic target proteins, as a first step toward the development of industrial platform processes.

  12. Novel insights into excipient effects on the biopharmaceutics of APIs from different BCS classes: Lactose in solid oral dosage forms. (United States)

    Kubbinga, Marlies; Moghani, Laura; Langguth, Peter


    Excipients encompass a wide range of properties that are of importance for the resulting drug product. Regulatory guidelines on biowaivers for immediate release formulations require an in depth understanding of the biopharmaceutic effects of excipients in order to establish bioequivalence between two different products carrying the same API based on dissolution tests alone. This paper describes a new approach in evaluating biopharmaceutic excipient effects. Actually used quantities of a model excipient, lactose, formulated in combination with APIs from different BCS classes were evaluated. The results suggest that companies use different (relative) amounts depending on the characteristics of the API. The probability of bioinequivalence due to a difference in lactose content between test and reference products was classified as low for BCS class I APIs and medium for BCS class II and III APIs, whereas a high probability was assigned to the combination of lactose and BCS class IV APIs. If repeated for other excipients, this retrospective, top-down approach may lead to a new database and more widespread applications of the biowaiver approach.

  13. Granulocyte-macrophage colony stimulating factor: Evaluation of biopharmaceutical formulations by stability-indicating RP-LC method and bioassay. (United States)

    Leal, Diogo Paim; Souto, Ricardo Bizogne; Schutkoski, Renato; Bergamo, Ana Cláudia; Dalmora, Sérgio Luiz


    The granulocyte-macrophage colony stimulating factor (GM-CSF) is a cytokine that regulates the proliferation and differentiation of hematopoietic cells and activates granulocytes and macrophages. A reversed-phase liquid chromatography (RP-LC) method was validated for the assessing of the stability of non-glycosylated recombinant rhGM-CSF (Molgramostim) in biopharmaceutical formulations. The RP-LC method was carried out on a Jupiter C(4) column (250 mm × 4.6 mm i.d.), maintained at 45 °C. The mobile phase A consisted of 0.1% TFA and the mobile phase B was acetonitrile with 0.1% TFA in acetonitrile, run at a flow rate of 1 mL/min, and using photodiode array (PDA) detection at 214 nm. Chromatographic separation was obtained with a retention time of 29.2 min, and was linear over the concentration range of 2-300 μg/mL (r(2) = 0.9992). Specificity was established in degradation studies. Moreover, the in vitro cytotoxicity test of the degraded products showed significant differences (p method was applied to the assessment of rhGM-CSF and related proteins in biopharmaceutical dosage forms, and the results were correlated to those of a bioassay. It is concluded that the employment of RP-LC in conjunction with current methods allows a great improvement in monitoring stability, quality control and thereby assures the therapeutic efficacy.

  14. Optimizing novel implant formulations for the prolonged release of biopharmaceuticals using in vitro and in vivo imaging techniques. (United States)

    Beyer, Susanne; Xie, Li; Schmidt, Mike; de Bruin, Natasja; Ashtikar, Mukul; Rüschenbaum, Sabrina; Lange, Christian M; Vogel, Vitali; Mäntele, Werner; Parnham, Michael J; Wacker, Matthias G


    As a rapidly growing class of therapeutics, biopharmaceuticals have conquered the global market. Despite the great potential from a therapeutic perspective, such formulations often require frequent injections due to their short half-life. Aiming to establish a parenteral dosage form with prolonged release properties, a biodegradable implant was developed, based on a combination of nanoencapsulation of protein-heparin complexes, creation of a slow release matrix by freeze-drying, and compression using hyaluronan and methylcellulose. In order to investigate this novel delivery system, formulations containing IFN-β-1a and trypsinogen as model proteins were developed. No degradation of the proteins was observed at any stage of the formulation processing. The potential of the delivery system was evaluated in vivo and in vitro after fluorescence-labeling of the biopharmaceuticals. An optimized agarose gel was utilized as in vitro release medium to simulate the subcutaneous environment in a biorelevant manner. In addition, the formulations were administered to female SJL mice and release was innovatively tracked by fluorescence imaging, setting up an in vitro-in vivo correlation. A prolonged time of residence of approximately 12days was observed for the selected formulation design.

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

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


    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 Development Status and Trend of Chinese Biopharmaceutical Industry%我国生物制药产业的发展现状与趋势

    Institute of Scientific and Technical Information of China (English)

    杨延云; 朱超


    Biopharmaceutical industry, which was the nucleus of the sunrise industry, had a strong pushing effect on pharmaceutical industry even in social and economic development. Chinese biopharmaceutical industry was facing opportu- nities and challenges. The development status of Chinese biopharmaceutical industry was reviewed and the future trend was analyzed with reference to the development of biopharmaceutical industry.%生物制药产业是“朝阳产业”的核心,对医药行业乃至整个社会经济的发展具有强大的推动作用。我国生物制药产业机遇与挑战并存。本文主要阐述了我国生物制药产业的发展现状,并分析了其未来的发展趋势,对生物制药产业的发展具有借鉴意义。

  17. Enhancing biopharmaceutical attributes of phospholipid complex-loaded nanostructured lipidic carriers of mangiferin: Systematic development, characterization and evaluation. (United States)

    Khurana, Rajneet Kaur; Bansal, Arvind K; Beg, Sarwar; Burrow, Andrea Julie; Katare, O P; Singh, Kamalinder K; Singh, Bhupinder


    Mangiferin (Mgf), largely expressed out from the leaves and stem bark of Mango, is a potent antioxidant. However, its in vivo activity gets tremendously reduced owing to poor aqueous solubility and inconsistent gastrointestinal absorption, high hepatic first-pass metabolism and high P-gp efflux. The current research work, therefore, was undertaken to overcome the biopharmaceutical hiccups by developing the Mgf-phospholipid complex (PLCs) loaded in nanostructured lipidic carriers (NLCs). The PLCs and NLCs were prepared using refluxing, solvent evaporation and hot emulsification technique, respectively with three molar ratios of Mgf and Phospholipon 90G, i.e., 1:1; 1:2; and 1:3. The complex was evaluated for various physicochemical parameters like drug content (96.57%), aqueous solubility (25-fold improved) and oil-water partition coefficient (10-fold enhanced). Diverse studies on the prepared complex using FTIR, DSC, PXRD and SEM studies ratified the formation of PLCs at 1:1 ratio. The PLCs were further incorporated onto NLCs, which were systematically optimized employing a face centered cubic design (FCCD), while evaluating for particle size, zeta potential, encapsulation efficiency and in vitro drug release as the CQAs. Caco-2 cell line studies indicated insignificant cytotoxicity, and P-gp efflux, while bi-directional permeability model and in situ perfusion studies specified enhanced intestinal permeation parameters. In vivo pharmacokinetic studies revealed notable increase in the values of Cmax (4.7-fold) and AUC (2.1-fold), respectively, from PLCs-loaded NLCs vis-à-vis Mgf solution. In a nutshell, the promising results observed from the present research work signify enhanced biopharmaceutical attributes of the novel PLCs-loaded NLCs for potentially augmenting the therapeutic efficacy of Mgf.

  18. 基因工程在生物制药领域的应用探讨%To Investigate the Genetic Engineering in the Field of Biopharmaceuticals

    Institute of Scientific and Technical Information of China (English)



    随着基因工程技术的进步和发展,其在生物制药领域发挥着重要的作用。从基因操作技术入手,详细阐述了大分子分离技术、PCR技术、基因芯片技术和外源基因的导入技术等,并详细分析和研究了一些具体的基因生物药物。%With the advancement and development of genetic engineering technology, which plays an important role in the biopharmaceutical field. Starting with the genetic manipulation techniques, elaborated macromolecular separation technology, PCR, gene chip technology and exogenous gene into technology, and a detailed analysis and study some specific genes biopharmaceuticals.

  19. Three-dimensional Collaborative Innovation Model in Biopharmaceutical Supply Chain%生物制药供应链三维立体协同创新模式

    Institute of Scientific and Technical Information of China (English)



    基于中国生物制药产业协同创新的现实需求,通过大量现实案例总结与文献分析,识别了生物制药供应链的基本结构和协同创新机会,开发了包含“横向协同创新”“纵向协同创新”和“深度协同创新”的生物制药供应链三维立体协同创新模式。从实践操作层面入手,构建了生物制药供应链三维立体协同创新平台,并分析了该平台的组织运行模式和功能。%Based on the realistic demand for collaborative innovation in biopharmaceutical industry of China ,through the case summary and lit‐erature analysis ,this paper discriminates the basic structure of integrated biopharmaceutical supply chain and the opportunities in it.Then it puts forward a three‐dimensional collaborative innovation mode of biopharmaceutical supply chain which includes horizontal collaborative innovation , vertical collaborative innovation and depth collaborative innovation.Finally ,according to the law of this study ,starting from the practice ,it con‐structs a three‐dimensional collaborative innovation platform of biopharmaceutical supply chain ,and analyzes the organizational operation mode and function of it .

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

    Directory of Open Access Journals (Sweden)

    Thomas J Hwang

    Full Text Available BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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

  1. 我国生物制药研究进展及展望%Present and Expectation of Biopharmaceuticals in China

    Institute of Scientific and Technical Information of China (English)

    靳坤; 李洋; 李乾; 范一文


    To review the present of Biopharmaceuticals in China. The problems in development of Chinese biopharmaceutical research were discussed. Raise the way to solve the problem in a certain extent and make expectation. Sum up the achievement of Chinese biopharmaceutical in recent years. Literatures on this field were summarized and evaluated. With the rapid development of biology science and technology, biological pharmacy industry has a bright future. Using each related research achievements broadly, constantly develop new technology is our country's biological pharmaceutical research will make great progress.%比较全面的介绍我国生物制药研究的进展,讨论我国在生物制药研究中存在的问题,一定程度的提出解决办法以及展望.通过大量调研相关文献资料,对近几年我国在生物制药研究上的成果进行总结.综合利用各个相关学科的研究成果、不断研发新技术是我国的生物制药研究取得长足进步的关键.

  2. Development Status and Prospect of Chinese Biopharmaceutical Industry%我国生物制药产业的发展现状与展望

    Institute of Scientific and Technical Information of China (English)

    石飞飞; 崔淑芹


    生物制药产业是我国七大新兴战略性产业之一,是我国朝阳产业的核心。未来我国生物制药产业的开发将会在治疗目前世界上无法攻克的顽疾方面表现出独特的优势,在医药行业具有广阔前景。本文通过对我国生物制药产业的初步探析,阐述我国生物制药产业的现状和发展趋势,展望我国生物制药产业的行业前景,对生物制药产业的发展具有一定借鉴意义。%Biopharmaceutical industry, which is one of the seven major strategic emerging industry and the nucleus of the sunrise industry in China, has broad prospects in the pharmaceutical industry with the unique advantage in the treatment of the unable to be conquered ills. The development status and the future trend of Chinese biopharmaceutical industry were reviewed with reference to the development of biopharmaceutical industry.

  3. Quantifying Trace Amounts of Aggregates in Biopharmaceuticals Using Analytical Ultracentrifugation Sedimentation Velocity: Bayesian Analyses and F Statistics. (United States)

    Wafer, Lucas; Kloczewiak, Marek; Luo, Yin


    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.

  4. High-intensity static magnetic field exposure devices for in vitro experiments on biopharmaceutical plant factories in aerospace environments. (United States)

    Lopresto, Vanni; Merla, Caterina; Pinto, Rosanna; Benvenuto, Eugenio


    Three high-intensity static magnetic field (SMF) exposure devices have been designed and realized for application to in vitro experimental research on hairy root cultures, supposed to grow in extreme environments- as those of space aircrafts- for producing biopharmaceutical molecules. The devices allow the exposure at two different levels of induction magnetic (B) field (250 mT and 500 mT) plus sham for blind exposure. The exposure levels can be considered representative of possible B-fields experienced within the habitat of a spacecraft in presence of active magnetic shielding systems. Each device can house a single 85-mm diameter Petri dish. Numerical simulations have been performed to accurately evaluate the B-field distribution in the biological target. Numerical results have been confirmed by measured data, proving that designed setups allows exposure to SMFs with a homogeneity better than 90%. The exposure devices will be employed for experiments scheduled within BIOxTREME research project, funded by the Italian Space Agency (ASI).

  5. Biopharmaceutical characterization of oral controlled/modified-release drug products. In vitro/in vivo correlation of roxatidine. (United States)

    Frick, A; Möller, H; Wirbitzki, E


    From the marketed drug product Roxane(R) 75 mg C/MR capsules (roxatidine controlled/modified-release capsules), an in vitro/in vivo comparison was performed to demonstrate a 1:1 correlation between in vitro and in vivo dissolution, and, furthermore, to ensure bioequivalence of the roxatidine controlled/modified-release (C/MR) capsules exhibiting dissolution profiles within the defined acceptance criteria. This 1:1 in vitro/in vivo comparison was calculated using a model independent numerical deconvolution method. The high degree of correlation is extremely rare, nevertheless it allows to omit the testing of clinical side batches for the setting of acceptance criteria for the in vitro dissolution of roxatidine controlled/modified-release (C/MR) capsules. The 1:1 in vitro/in vivo correlation can be explained by the biopharmaceutical characteristics of the drug substance as well as the drug product, that is, pH-independent high solubility of the drug substance as well as dissolution which is independent of pH and agitation. These facts lead to a controlled/modified-release formulation. Therefore, it is important to keep in mind that in most cases in which a pH-dependent solubility/dissolution as well as permeability characteristics can be found, a 1:1 in vitro/in vivo correlation could not be expected.

  6. Formation and Biopharmaceutical Characterization of Electrospun PVP Mats with Propolis and Silver Nanoparticles for Fast Releasing Wound Dressing

    Directory of Open Access Journals (Sweden)

    Erika Adomavičiūtė


    Full Text Available Antibacterial, antiviral, antifungal, antioxidant, anti-inflammatory, and anticancer activities of propolis and its ability to stimulate the immune system and promote wound healing make it a proper component for wound dressing materials. Silver nanoparticles are recognized to demonstrate strong antiseptic and antimicrobial activity; thus, it also could be considered in the development of products for wound healing. Combining propolis and silver nanoparticles can result in improved characteristics of products designed for wound healing and care. The aim of this study was to formulate electrospun fast dissolving mats for wound dressing containing propolis ethanolic extract and silver nanoparticles. Produced electrospun nano/microfiber mats were evaluated studying their structure, dissolution rate, release of propolis phenolic compounds and silver nanoparticles, and antimicrobial activity. Biopharmaceutical characterization of electrospun mats demonstrated fast release of propolis phenolic compounds and silver nanoparticles. Evaluation of antimicrobial activity on Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris, Bacillus subtilis, Bacillus cereus, and Candida albicans strains confirmed the ability of electrospun mats to inhibit the growth of the tested microorganisms.

  7. Formation and Biopharmaceutical Characterization of Electrospun PVP Mats with Propolis and Silver Nanoparticles for Fast Releasing Wound Dressing. (United States)

    Adomavičiūtė, Erika; Stanys, Sigitas; Žilius, Modestas; Juškaitė, Vaida; Pavilonis, Alvydas; Briedis, Vitalis


    Antibacterial, antiviral, antifungal, antioxidant, anti-inflammatory, and anticancer activities of propolis and its ability to stimulate the immune system and promote wound healing make it a proper component for wound dressing materials. Silver nanoparticles are recognized to demonstrate strong antiseptic and antimicrobial activity; thus, it also could be considered in the development of products for wound healing. Combining propolis and silver nanoparticles can result in improved characteristics of products designed for wound healing and care. The aim of this study was to formulate electrospun fast dissolving mats for wound dressing containing propolis ethanolic extract and silver nanoparticles. Produced electrospun nano/microfiber mats were evaluated studying their structure, dissolution rate, release of propolis phenolic compounds and silver nanoparticles, and antimicrobial activity. Biopharmaceutical characterization of electrospun mats demonstrated fast release of propolis phenolic compounds and silver nanoparticles. Evaluation of antimicrobial activity on Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecalis, Escherichia coli, Pseudomonas aeruginosa, Proteus vulgaris, Bacillus subtilis, Bacillus cereus, and Candida albicans strains confirmed the ability of electrospun mats to inhibit the growth of the tested microorganisms.

  8. Effect on the Gastrointestinal Absorption of Drugs from Different Classes in the Biopharmaceutics Classification System, When Treating with Liraglutide. (United States)

    Malm-Erjefält, Monika; Ekblom, Marianne; Vouis, Jan; Zdravkovic, Milan; Lennernäs, Hans


    Like other GLP-1 receptor agonists used for treatment of type 2 diabetes, liraglutide delays gastric emptying. In this clinical absorption study, the primary objective was to investigate the effect of liraglutide (at steady state) on the rate and/or extent of gastrointestinal (GI) absorption of concomitantly orally taken drugs from three classes of the Biopharmaceutics Classification System (BCS). To provide a general prediction on liraglutide drug-drug absorption interaction, single-dose pharmacokinetics of drugs representing BCS classes II (low solubility-high permeability; atorvastatin 40 mg and griseofulvin 500 mg), III (high solubility-low permeability; lisinopril 20 mg), and IV (low solubility-low permeability; digoxin 1 mg) were studied in healthy subjects at steady state of liraglutide 1.8 mg, or placebo, in a two-period crossover design. With liraglutide, the oral drugs atorvastatin, lisinopril, and digoxin showed delayed tmax (by ≤2 h) and did not meet the criterion for bioequivalence for Cmax (reduced Cmax by 27-38%); griseofulvin had similar tmax and 37% increased Cmax. Although the prespecified bioequivalence criterion was not met by all drugs, the overall plasma exposure (AUC) of griseofulvin, atorvastatin, lisinopril, and digoxin only exhibited minor changes and was not considered to be of clinical relevance.

  9. Formulation of controlled-release capsules of biopharmaceutical classification system I drugs using niacin as a model. (United States)

    Chuong, Monica C; Palugan, Luca; Su, Tiffany M; Busano, Claudelle; Lee, Ronald; Di Pretoro, Giustino; Shah, Anee


    Vitamin B(3) is made up of niacin (nicotinic acid) and its amide, niacinamide. Both have equivalent vitamin activity, but only niacin (not niacinamide) is effective in lowering elevated low-density lipoprotein cholesterol and triglyceride levels in the blood. Administration of an extended-release (ER) oral tablet would frequently encounter food. If hydrogel is used to formulate the matrix of a biopharmaceutical classification system I drug (high solubility and high permeability), the dosage form absorbs water and swells.. The softened outer layer may be slashed off by food present in the stomach, thus, exposing the core tablet more readily for water absorption and speeding up drug release from its original designed rate. This project aimed to formulate niacin CR pellets made of hydrophobic inert matrix. After niacin was melted with excipients and cooled, the mass was extruded and spheronized into pellets. Size distribution and flowability were determined before pellets were filled into hard gelatin capsule. The USP dissolution study revealed that a candidate formulation of 250 mg in strength released similar amount of niacin as its commercial reference, niacin controlled-release 500 mg tablet, in 6 h (223.9 ± 23.8 mg, n = 4 versus 259.4 ± 2.6 mg, n = 3). The differential scanning calorimetry study of the pellets in capsules stored in 40°C for 4 weeks, and the content assay of capsules in 40°C up to 6 months suggested that niacin was stable within the innovative formulation. In vitro release from this innovative ER capsules stored at 40°C up to 4 weeks were also investigated.

  10. Formulation and physiological and biopharmaceutical issues in the development of oral lipid-based drug delivery systems. (United States)

    Wasan, K M


    The rapidly increasing availability of drug receptor structural characteristics has permitted the receptor-guided synthesis of potential new drug molecules. This synthesis strategy frequently results in the creation of polycyclic and highly hydrophobic compounds, with attendant poor oral bioavailability resulting from low solubility and slow dissolution rate in the primarily aqueous contents of the gastrointestinal (GI) tract. In an attempt to improve the solubility-limited bioavailabiliy associated with these compounds, formulators have turned to the use of lipid excipients in which the compounds can be solubilized prior to oral administration. This new class of excipients presents the pharmaceutical scientist with a number of new challenges at all stages of the formulation development process, beginning with the excipient selection and stability assessment of the prototype formulation, up to and including scale-up and mass production of the final market-image product. The interaction of lipid-based formulations with the gastrointestinal system and associated digestive processes presents additional challenges and opportunities that will be understood more fully as we begin to unravel the intricacies of the GI processing of lipid excipients. For example, an increasing body of evidence has shown that certain lipids are capable of inhibiting both presystemic drug metabolism and drug efflux by the gut wall mediated by p-glycoprotein (PGP). And, it is well known that lipids are capable of enhancing lymphatic transport of hydrophobic drugs, thereby reducing drug clearance resulting from hepatic first-pass metabolism. This review addresses the current state of knowledge regarding oral lipid-based formulation development and scale-up issues and the physiological and biopharmaceutical aspects pertinent to the development of an orally bioavailable and efficacious dosage form.

  11. QbD-Oriented Development of Self-Nanoemulsifying Drug Delivery Systems (SNEDDS) of Valsartan with Improved Biopharmaceutical Performance. (United States)

    Bandyopadhyay, Shantanu; Beg, Sarwar; Katare, O P; Sharma, Gajanand; Singh, Bhupinder


    The objectives of the present studies were to develop the systematically optimized selfnanoemulsifying drug delivery systems (SNEDDS) of valsartan employing the holistic QbD approach. The quality profile target product (QTPP) was defined and critical quality attributes (CQAs) earmarked. Preformulation studies including the equilibrium solubility and pseudoternary phase titration studies facilitated the selection of suitable lipids and emulgents for formulation of SNEDDS. Risk assessment and factor screening studies facilitated the selection of Lauroglycol FCC and Capmul MCM L8 (i.e., lipid), Tween 40 and Tween 80 (i.e., emulgent) as the critical material attributes (CMAs) for SNEDDS prepared using medium-chain triglycerides (MCTs) and long-chain triglycerides (LCTs). A central composite design (CCD) was employed for systematic optimization of SNEDDS, taking globule size (Dnm), drug release in 10 min (Q10min) and amount permeated in 45 min (%Perm45min) as the CQAs. Design space was generated using apt mathematical models to embark upon the optimized formulations and validation of the QbD. In situ SPIP studies revealed significant improvement in the absorptivity and permeability parameters of SNEDDS owing to the inhibition of P-gp/MRP2 efflux vis-à-vis the conventional marketed formulation and pure drug. In vivo pharmacokinetic studies corroborated marked enhancement in the oral bioavailability drug from SNEDDS vis-à-vis the marketed formulation. Establishment of various levels of in vitro/in vivo correlations (IVIVC) indicated excellent goodness of fit between the in vitro drug release data with the in vivo absorption parameters. In a nutshell, the present studies report successful QbD-based development of MCT and LCT-SNEDDS of valsartan with improved biopharmaceutical performance.

  12. Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: verapamil hydrochloride, propranolol hydrochloride, and atenolol. (United States)

    Vogelpoel, H; Welink, J; Amidon, G L; Junginger, H E; Midha, K K; Möller, H; Olling, M; Shah, V P; Barends, D M


    Literature data related to the Biopharmaceutics Classification System (BCS) are presented on verapamil hydrochloride, propranolol hydrochloride, and atenolol in the form of BCS-monographs. Data on the qualitative composition of immediate release (IR) tablets containing these active substances with a Marketing Authorization (MA) in the Netherlands (NL) are also provided; in view of these MA's the assumption was made that these tablets were bioequivalent to the innovator product. The development of a database with BCS-related data is announced by the International Pharmaceutical Federation (FIP).

  13. 建立高校生物制药人才创新培养平台的途径%Strategic Approaches in Higher Education Reform to Cultivate Innovative Specialists in Biopharmaceutical Industry

    Institute of Scientific and Technical Information of China (English)

    王永中; 孔小卫; 张敏


    基于当前全球生物医药行业的创新发展,探讨如何在综合性大学培养创新型生物制药人才,以适应并满足当前生物医药行业的内在创新需求。在全面分析生物医药产业的发展特点及其内在创新需求的基础上,介绍当前欧美与国内高等教育机构在改革与发展生物制药相关专业的现状,提出建立国内高校生物制药人才创新培养平台的途径和策略。%The current biopharmaceutical market worldwide has shown continuous growth under the inten-sive innovation in biomedical industry.To meet the unmet demands of globally biopharmaceutical innova-tion,this article aims to propose feasible strategic approaches to build an innovation platform in higher education institutes of China for talents cultivation in biopharmaceutical research and development.The globally developmental feathers and inherent innovation demands of biopharmaceutical industry were first analyzed,and the current status on higher education practices in the western countries and China to develop innovative education and training system to cultivate biopharmaceutical specialists were discussed.Based on these development and status,strategic approaches to build an innovative talents cultivation platform to train biopharmaceutical specialists in China's higher education system were proposed.

  14. Analysis, biomedicine, collaboration, and determinism challenges and guidance: wish list for biopharmaceuticals on the interface of computing and statistics. (United States)

    Goodman, Arnold F


    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

  15. Statistical investigation of simulated intestinal fluid composition on the equilibrium solubility of biopharmaceutics classification system class II drugs. (United States)

    Khadra, Ibrahim; Zhou, Zhou; Dunn, Claire; Wilson, Clive G; Halbert, Gavin


    A drug's solubility and dissolution behaviour within the gastrointestinal tract is a key property for successful administration by the oral route and one of the key factors in the biopharmaceutics classification system. This property can be determined by investigating drug solubility in human intestinal fluid (HIF) but this is difficult to obtain and highly variable, which has led to the development of multiple simulated intestinal fluid (SIF) recipes. Using a statistical design of experiment (DoE) technique this paper has investigated the effects and interactions on equilibrium drug solubility of seven typical SIF components (sodium taurocholate, lecithin, sodium phosphate, sodium chloride, pH, pancreatin and sodium oleate) within concentration ranges relevant to human intestinal fluid values. A range of poorly soluble drugs with acidic (naproxen, indomethacin, phenytoin, and piroxicam), basic (aprepitant, carvedilol, zafirlukast, tadalafil) or neutral (fenofibrate, griseofulvin, felodipine and probucol) properties have been investigated. The equilibrium solubility results determined are comparable with literature studies of the drugs in either HIF or SIF indicating that the DoE is operating in the correct space. With the exception of pancreatin, all of the factors individually had a statistically significant influence on equilibrium solubility with variations in magnitude of effect between the acidic and basic or neutral compounds and drug specific interactions were evident. Interestingly for the neutral compounds pH was the factor with the second largest solubility effect. Around one third of all the possible factor combinations showed a significant influence on equilibrium solubility with variations in interaction significance and magnitude of effect between the acidic and basic or neutral compounds. The least number of significant media component interactions were noted for the acidic compounds with three and the greatest for the neutral compounds at seven

  16. 细胞工程在生物制药工业中的地位%The status of cytotechnology in biopharmaceutical industry

    Institute of Scientific and Technical Information of China (English)

    胡显文; 肖成祖


    细胞工程是生物制药工业中的关键技术,它是利用动物细胞体外培养和扩增来生产生物产品,或者作为发现和测试新药的工具。本文综述了细胞工程发展的历史、现状和未来,以及它在生物制药领域中的应用和局限。%Animal cell technology plays a substantial role in the field of biopharmaceuticals and may be defined as the use of animal cells propagated in-vitro for the manufacture of bioproducts and as vehicles in the discovery and/or the testing of medicines. This paper summarized the overview of the past, present and future of animal cell technology, its potential and its limitations in biopharmaceutical industry.

  17. Limited proteolysis and peptide mapping for comparability of biopharmaceuticals: An evaluation of repeatability, intra-assay precision and capability to detect structural change. (United States)

    Perrin, Camille; Burkitt, Will; Perraud, Xavier; O'Hara, John; Jone, Carl


    The use of limited proteolysis followed by peptide mapping for the comparability of the higher-order structure of biopharmaceuticals was investigated. In this approach the proteolysis is performed under non-reducing and non-denaturing conditions, and the resulting peptide map is determined by the samples primary and higher order structures. This allows comparability of biopharmaceuticals to be made in terms of their higher order structure, using a method that is relatively simple to implement. The digestion of a monoclonal antibody under non-denaturing conditions was analyzed using peptide mapping, circular dichroism (CD) and sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). This allowed an optimal digestion time to be chosen. This method was then assessed for its ability to detect structural change using a monoclonal antibody, which had been subjected to a range of stresses; deglycosylation, mild denaturation and a batch that had failed specifications due to in-process reduction. The repeatability and inter-assay precision were assessed. It was demonstrated that the limited proteolysis peptide maps of the three stressed samples were significantly different to control samples and that the differences observed were consistent between the occasions when the assays were run. A combination of limited proteolysis and CD or SDS-PAGE analysis was shown to enhance the capacity of these techniques to detect structural change, which otherwise would not have been observed.

  18. Formulation and the in-vitro and biopharmaceutical evaluation of sustained release tablet of verapamil HCL using precirol ATO 5 through melt granulation technique

    Directory of Open Access Journals (Sweden)

    Bhagwat Durgacharan


    Full Text Available Sustained release tablet of Verapamil hydrochloride (VPH was prepared by using Precirol ATO 5 (PREC by direct compression of matrices prepared by using the melt granulation technique. The effect of different concentrations of PREC on the in-vitro drug release of VPH was studied by comparing it with the marketed formulation and percent release given in USP for VPH extended release tablets. Effect of release enhancers such as microcrystalline cellulose (MCC and lactose on in-vitro drug release was also studied. Biopharmaceutical evaluation of the satisfactory formulation was also performed in order to estimate the maximum concentration of drug in plasma (C max , time required to reach maximum concentration (t max , elimination rate constant (k, elimination rate constant (t 1/2 , area under curve (AUC (0-t and AUC (02a, apparent volume of distribution (V d and mean residence time. The results showed that PREC can be utilized as the matrix forming agent to sustain the release of VPH. The results of biopharmaceutical evaluation showed that the rate of absorption appeared to be more sustained, resulting in a more uniform plasma concentration profile of VPH. More bioavailability was noted with the sustained release formulation even though the drug has substantial first pass metabolism. The results indicated that it is possible to make once-a-day sustained-release tablet of VPH by using the melt granulation technique.

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

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


    (14)C has long been used as a tracer for quantifying the in vivo human metabolism of food components, biopharmaceuticals, and nutrients. Minute amounts (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.

  20. Characterization of intact protein conjugates and biopharmaceuticals using ion-exchange chromatography with online detection by native electrospray ionization mass spectrometry and top-down tandem mass spectrometry. (United States)

    Muneeruddin, Khaja; Nazzaro, Mark; Kaltashov, Igor A


    Characterization of biopharmaceutical products is a challenging task, which needs to be carried out at several different levels (including both primary structure and conformation). An additional difficulty frequently arises due to the structural heterogeneity inherent to many protein-based therapeutics (e.g., extensive glycosylation or "designer" modifications such as chemical conjugation) or introduced postproduction as a result of stress (e.g., oxidation and deamidation). A combination of ion-exchange chromatography (IXC) with online detection by native electrospray ionization mass spectrometry (ESI MS) allows characterization of complex and heterogeneous therapeutic proteins and protein conjugates to be accomplished at a variety of levels without compromising their conformational integrity. The IXC/ESI MS measurements allow protein conjugates to be profiled by analyzing conjugation stoichiometry and the presence of multiple positional isomers, as well as to establish the effect of chemical modifications on the conformational integrity of each species. While mass profiling alone is not sufficient for identification of nonenzymatic post-translational modifications (PTMs) that result in a very small mass change of the eluting species (e.g., deamidation), this task can be completed using online top-down structural analysis, as demonstrated using stressed interferon-β as an example. The wealth of information that can be provided by IXC/native ESI MS and tandem mass spectrometry (MS/MS) on protein-based therapeutics will undoubtedly make it a very valuable addition to the experimental toolbox of biopharmaceutical analysis.

  1. Biopharmaceutical aspects of Depogen. (United States)

    Szentmiklósi, P; Marton, S


    The absorption of Depogen was studied on an in vitro model and in various laboratory animals using stoichiometrically equivalent doses of drotaverin (No-Spa) calculated for drotaverin base for comparison. Blood levels of the drug were assessed by radiochemical and microchemical methods. Based on the results obtained and pharmacokinetic properties, the expectable optimal dosage and formulations for the possible field of indication were elaborated.

  2. Quantification of biopharmaceuticals and biomarkers in complex biological matrices: a comparison of liquid chromatography coupled to tandem mass spectrometry and ligand binding assays. (United States)

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


    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 post-translational modifications. This review describes and compares the two main approaches, namely, ligand binding assays (LBAs) and liquid chromatography coupled to tandem mass spectrometry in the selected reaction monitoring (SRM) mode. While LBAs remain the most widely used approach, SRM assays are gaining interest due to their generally better analytical performance (precision and accuracy) and their capacity for multiplex analyses. This article focuses on the possible reasons for the discrepancies between results obtained by LBAs and SRM assays.

  3. Implementing the Biopharmaceutics Classification System in Drug Development: Reconciling Similarities, Differences, and Shared Challenges in the EMA and US-FDA-Recommended Approaches. (United States)

    Cardot, J-M; Garcia Arieta, A; Paixao, P; Tasevska, I; Davit, B


    The US-FDA recently posted a draft guideline for industry recommending procedures necessary to obtain a biowaiver for immediate-release oral dosage forms based on the Biopharmaceutics Classification System (BCS). This review compares the present FDA BCS biowaiver approach, with the existing European Medicines Agency (EMA) approach, with an emphasis on similarities, difficulties, and shared challenges. Some specifics of the current EMA BCS guideline are compared with those in the recently published draft US-FDA BCS guideline. In particular, similarities and differences in the EMA versus US-FDA approaches to establishing drug solubility, permeability, dissolution, and formulation suitability for BCS biowaiver are critically reviewed. Several case studies are presented to illustrate the (i) challenges of applying for BCS biowaivers for global registration in the face of differences in the EMA and US-FDA BCS biowaiver criteria, as well as (ii) challenges inherent in applying for BCS class I or III designation and common to both jurisdictions.

  4. Multiplex RT Q-PCR assay for simultaneous quantification of three viruses used for validation of virus clearance by biopharmaceutical production. (United States)

    Lute, Scott; Wang, Hua; Sanchez, Davonie; Barletta, Janet; Chen, Qi; Brorson, Kurt


    Virus removal studies are used to insure the safety of biopharmaceutical products by quantitatively estimating the viral clearance capacity by the manufacturing process. Virus quantification assays are used to measure the log(10) clearance factor of individual purification unit operations in spike recovery studies. We have developed a multiplex RT Q-PCR assay that detects and quantifies three commonly used model viruses X-MuLV, SV40, and MMV simultaneously. This RT Q-PCR multiplex assay has a 6log(10) dynamic range with a limit of detection (LOD) of approximately 1 genome copy/microL. Amplification profiles are similar to existing singleplex assays. Overall, this RT Q-PCR multiplex assay is highly quantitative, accurately identifies multiple viruses simultaneously, and may prove useful to validate viral clearance of biological products in small scale studies.

  5. Investigating a new drug delivery nano composite membrane system based on PVA/PCL and PVA/HA(PEG) for the controlled release of biopharmaceuticals for bone infections. (United States)

    Wan, Taoyu; Stylios, George K; Giannoudi, Marilena; Giannoudis, Peter V


    The capability for sustained and gradual release of pharmaceuticals is a major requirement in the development of a guided antimicrobial bacterial control system for clinical applications. In this study, PVA gels with varying constituents that were manufactured via a refreeze/thawing route, were found to have excellent potential for antimicrobial delivery for bone infections. Cefuroxime Sodium with poly(ethylene glycol) was incorporated into 2 delivery systems poly(e-caprolactone) (PCL) and hydroxyapatite (HA), by a modified emulsion process. Our results indicate that the Cefuroxime Sodium released from poly(e-caprolactone) in PVA was tailored to a sustained release over more than 45 days, while the release from hydroxyapatite PVA reach burst maximum after 20 days. These PVA hydrogel-systems were also capable of controlled and sustained release of other biopharmaceuticals.

  6. Biowaiver monographs for immediate release solid oral dosage forms based on biopharmaceutics classification system (BCS) literature data: chloroquine phosphate, chloroquine sulfate, and chloroquine hydrochloride. (United States)

    Verbeeck, R K; Junginger, H E; Midha, K K; Shah, V P; Barends, D M


    Literature data on the properties of chloroquine phosphate, chloroquine sulfate, and chloroquine hydrochloride related to the Biopharmaceutics Classification System (BCS) are reviewed. The available information indicates that these chloroquine salts can be classified as highly soluble and highly permeable, i.e., BCS class I. The qualitative composition of immediate release (IR) tablets containing these Active Pharmaceutical Ingredients (APIs) with a Marketing Authorization (MA) in Belgium (BE), Germany (DE), Finland (FI), and The Netherlands (NL) is provided. In view of these MA's and the critical therapeutic indication of chloroquine, it is assumed that the registration authorities had evidence that these formulations are bioequivalent to the innovator. It is concluded that IR tablets formulated with these excipients are candidates for a biowaiver.

  7. 胶束液相色谱在体内药物分析中的应用%Micellar Liquid Chromatography and its Application in Biopharmaceutical Analysis

    Institute of Scientific and Technical Information of China (English)

    朱斌; 杨贤帅; 章仕龙


    胶束液相色谱法(MLC)是采用高于临界胶束浓度(cmc)的表面活性剂溶液作为流动相的反相液相色谱方法。本文概述了胶束液相色谱的基本原理和优势,重点介绍了其在体内药物分析中的应用。%Micellar liquid chromatography (MLC) was a reversed phase liquid chromatography (RPLC) with mobile phases containing surfactant above its critical micellar concentration (cmc). The principle and advantages of MLC were reviewed; and its applications in biopharmaceutical analysis were mainly introduced.

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


    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;, ABIRISK consortium [Anti-Biopharmaceutical (BP) Immunization Prediction and Clinical Relevance to Reduce the Risk;] 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 (

  9. Discussionon Envi ronmental ImpactAssessment Emphases of Biopharmaceutical Park Construction Projects%生物制药园区建设项目环评编制要点

    Institute of Scientific and Technical Information of China (English)

    李金波; 王安


    Combining with anexample ofbiopharmaceutical projectin western China ,this articlesummarizes theenvironmental impact assessment (EIA )points of Biopharmaceutical park construction projects ,according tothe characteristics of biopharmaceutical projects ,and comparing with national policies ,laws and regula-tions ,andindustry standards .%根据生物制药项目的特征,对照国家政策、法律法规、行业规范,结合西部某生物制药园区建设项目实例,分析并总结了生物制药园区建设项目环评的评价要素及报告编制要点。

  10. Reform and Investigation on the Biopharmaceutical Technology of Biological Engineering Specialty%生物工程专业生物制药工艺学课程的教学改革探索

    Institute of Scientific and Technical Information of China (English)



    Technology of biopharmaceutics is an important practical subject in bioengineering. This paper according to the characteristics of biopharmaceutical technology of biological engineering, the teaching content, teaching method and teach-ing means were explored from the theory teaching and the practice teaching was summarized.%生物制药工艺学是生物工程专业实践应用的重要分支。文章根据生物工程专业生物制药工艺学特点,从理论教学方面进行了教材内容、教学方法及教学手段的探索,并对实践教学方面进行了总结。

  11. 中药组分与组分生物药剂学分类系统构建%Traditional Chinese medicine components and construction of components biopharmaceutical classification system

    Institute of Scientific and Technical Information of China (English)

    刘丹; 郁丹红; 孙娥; 贾晓斌


    中药复方物质基础是多组分,在研究中药生物药剂学性质时,应该以组分为研究对象.针对中药多组分生物药剂学研究,该文提出科学代表中药组分综合性质的有限成分的选择思路;其次,引入“离散度”的概念,以考察组分中各代表性成分个体性质之间的差异,从而更科学全面地评价中药组分的性质;最终结合组分综合性质值及离散度,初步构建中药组分生物药剂学分类系统,为中药多组分生物药剂学性质研究提出新的思路与方法.%Traditional Chinese medicine compound of material base is multi-components. It should be divided into groups to study traditional Chinese medicine biopharmaceutical properties. To study traditional Chinese medicine multi-component biopharmaceu-tical, this paper puts forward the scientific representative Chinese medicine integrated nature of the components of the composition, choose ideas. Secondly, this paper introduces the concept of " discrete degree" to examine difference about representative nature of each component. It should be more comprehensive evaluation of traditional Chinese medicine scientific nature of the components. With the comprehensive property value final components and discrete degrees, setting up a part of traditional Chinese medicine biopharmaceutical classification system, traditional Chinese medicine for the multi-composition biopharmaceutical nature study puts forward a new way and method.

  12. Glycoforms of Immunoglobulin G Based Biopharmaceuticals Are Differentially Cleaved by Trypsin Due to the Glycoform Influence on Higher-Order Structure. (United States)

    Falck, David; Jansen, Bas C; Plomp, Rosina; Reusch, Dietmar; Haberger, Markus; Wuhrer, Manfred


    It has been reported that glycosylation can influence the proteolytic cleavage of proteins. A thorough investigation of this phenomenon was conducted for the serine protease trypsin, which is essential in many proteomics workflows. Monoclonal and polyclonal immunoglobulin G biopharmaceuticals were employed as model substances, which are highly relevant for the bioanalytical applications. Relative quantitation of glycopeptides derived from the conserved Fc-glycosylation site allowed resolution of biases on the level of individual glycan compositions. As a result, a strong preferential digestion of high mannose, hybrid, alpha2-3-sialylated and bisected glycoforms was observed over the most abundant neutral, fucosylated glycoforms. Interestingly, this bias was, to a large extent, dependent on the intact higher order structure of the antibodies and, consequently, was drastically reduced in denatured versus intact antibodies. In addition, a cleavage protocol with acidic denaturation was tested, which featured reduced hands-on time and toxicity while showing highly comparable results to a published denaturation, reduction, and alkylation based protocol.


    Directory of Open Access Journals (Sweden)

    Y. A. Morozov


    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.

  14. Applications of fusion protein techniques in biopharmaceutical areas%融合蛋白技术在生物医药领域中的应用

    Institute of Scientific and Technical Information of China (English)



    在治疗性药物的研发中,效应分子与人免疫球蛋白IgG1 Fc片段或人血清白蛋白形成的融合蛋白疗效不变,但体内半衰期明显延长、药物耐受性增加、副作用减少.在疫苗研发中,抗原分子与毒素分子或Fc形成的融合蛋白是很好的新型疫苗,并能激发细胞免疫.%In the development of biopharmaceuticals, fusion proteins of effectors and IgG1 Fc fragment or human albumin have the same treatment efficacy as the effectors alone, much prolonged half-life, increased drug tolerance, and decreased side effects. In the studies of vaccines, the fusion proteins of antigens and toxins or IgG1 Fc will become new type of vaccines which can also stimulate T cell response.

  15. Polymeric Amorphous Solid Dispersions: A Review of Amorphization, Crystallization, Stabilization, Solid-State Characterization, and Aqueous Solubilization of Biopharmaceutical Classification System Class II Drugs. (United States)

    Baghel, Shrawan; Cathcart, Helen; O'Reilly, Niall J


    Poor water solubility of many drugs has emerged as one of the major challenges in the pharmaceutical world. Polymer-based amorphous solid dispersions have been considered as the major advancement in overcoming limited aqueous solubility and oral absorption issues. The principle drawback of this approach is that they can lack necessary stability and revert to the crystalline form on storage. Significant upfront development is, therefore, required to generate stable amorphous formulations. A thorough understanding of the processes occurring at a molecular level is imperative for the rational design of amorphous solid dispersion products. This review attempts to address the critical molecular and thermodynamic aspects governing the physicochemical properties of such systems. A brief introduction to Biopharmaceutical Classification System, solid dispersions, glass transition, and solubility advantage of amorphous drugs is provided. The objective of this review is to weigh the current understanding of solid dispersion chemistry and to critically review the theoretical, technical, and molecular aspects of solid dispersions (amorphization and crystallization) and potential advantage of polymers (stabilization and solubilization) as inert, hydrophilic, pharmaceutical carrier matrices. In addition, different preformulation tools for the rational selection of polymers, state-of-the-art techniques for preparation and characterization of polymeric amorphous solid dispersions, and drug supersaturation in gastric media are also discussed.

  16. 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


    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.

  17. [Factors affecting the adoption of ICT tools in experiments with bioinformatics in biopharmaceutical organizations: a case study in the Brazilian Cancer Institute]. (United States)

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


    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?

  18. A perspective for biowaivers of human bioequivalence studies on the basis of the combination of the ratio of AUC to the dose and the biopharmaceutics classification system. (United States)

    Sakuma, Shinji; Tachiki, Hidehisa; Uchiyama, Hitoshi; Fukui, Yasunobu; Takeuchi, Naohiro; Kumamoto, Kazuo; Satoh, Tomonori; Yamamoto, Yoshinobu; Ishii, Emi; Sakai, Yoshiyuki; Takeuchi, Susumu; Sugita, Masaru; Yamashita, Shinji


    The ratio of AUC to the dose (AUC/dose) was previously found as a parameter that predicts a risk of bioinequivalence of oral drug products. On the basis of the combination of this parameter and the biopharmaceutics classification system (BCS), a perspective for biowaivers of human bioequivalence studies is discussed. Databases of bioequivalence studies using immediate-release solid oral dosage forms were disclosed by 6 Japanese generic pharmaceutical companies, and the number of subjects required for demonstrating bioequivalence between generic and reference products was plotted as a function of AUC/dose for each BCS category. A small variation in the number of subjects was constantly observed in bioequivalence studies using dosage forms containing an identical BCS class 1 or class 3 drug, even though formulations of the generic product differ between companies. The variation was extremely enlarged when the drugs were substituted with BCS class 2 drugs. Rate-determining steps in oral absorption of highly water-soluble BCS class 1 and class 3 drugs are independent of formulations when there is no significant difference in the in vitro dissolution profiles between formulations. The small variation observed for both BCS categories indicates that the number of subjects converges into one value for each drug. Our analysis indicates the appropriateness of biowaiver of bioequivalence studies for immediate-release solid oral dosage forms containing not only BCS class 1 drugs but also class 3 drugs.

  19. QbD-based systematic development of novel optimized solid self-nanoemulsifying drug delivery systems (SNEDDS) of lovastatin with enhanced biopharmaceutical performance. (United States)

    Beg, Sarwar; Sandhu, Premjeet Singh; Batra, Rattandeep Singh; Khurana, Rajneet Kaur; Singh, Bhupinder


    Of late, solid self-nanoemulsifying drug delivery systems (S-SNEDDS) have been extensively sought-after owing to their superior portability, drug loading, stability and patient compliance. The current studies, therefore, entail systematic development, optimization and evaluation (in vitro, in situ and in vivo) of the solid formulations of (SNEDDS) lovastatin employing rational quality by design (QbD)-based approach of formulation by design (FbD). The patient-centric quality target product profile (QTPP) and critical quality attributes (CQAs) were earmarked. Preformulation studies along with initial risk assessment facilitated the selection of lipid (i.e. Capmul MCM), surfactant (i.e. Nikkol HCO-50) and co-surfactant (i.e. Lutrol F127) as CMAs for formulation of S-SNEDDS. A face-centered cubic design (FCCD) was employed for optimization using Nikkol-HCO50 (X1) and Lutrol-F127 (X2), evaluating CQAs like globule size, liquefaction time, emulsification time, MDT, dissolution efficiency and permeation parameter. The design space was generated using apt mathematical models, and the optimum formulation was located, followed by validation of the FbD methodology. In situ SPIP and in vivo pharmacodynamic studies on the optimized formulation carried out in unisex Wistar rats, corroborated superior drug absorption and enhanced pharmacodynamic potential in regulating serum lipid levels. In a nutshell, the present studies report successful QbD-oriented development of novel oral S-SNEDDS of lovastatin with distinctly improved biopharmaceutical performance.

  20. Biopharmaceutical profile of hydrogels containing pranoprofen-loaded PLGA nanoparticles for skin administration: In vitro, ex vivo and in vivo characterization. (United States)

    Abrego, Guadalupe; Alvarado, Helen; Souto, Eliana B; Guevara, Bessy; Bellowa, Lyda Halbaut; Garduño, Maria Luisa; Garcia, María Luisa; Calpena, Ana C


    Pranoprofen (PF)-loaded nanoparticles (PF-F1NPs and PF-F2NPs) have been formulated into blank hydrogels (HG_PF-F1NPs and HG_PF-F1NPs) or into hydrogels composed of 3% azone (HG_PF-F1NPs-Azone and HG_PF-F2NPs-Azone), as innovative strategy to improve the biopharmaceutical profile of the selected non-steroidal anti-inflammatory drug (Pranoprofen, PF) for topical application. The purpose of this approach has been to increase the contact of PF with the skin, improve its retention in deeper layers, thus enhancing its anti-inflammatory and analgesic effects. The physicochemical characterization of the developed hydrogels showed a non-Newtonian behaviour, typical of semi-solid formulations for skin administration, with sustained release profile. The results obtained from ex vivo skin human permeation and in vivo anti-inflammatory efficacy studies suggest that topical application of HG_PF-F2NPs has been more effective in the treatment of oedema on the skin' surface in comparison to other hydrogels. No signs of skin irritancy have been detected for all the semi-solid formulations containing 0% or 3% azone.

  1. Optimization and validation of DNA extraction and real-time PCR assay for the quantitative measurement of residual host cell DNA in biopharmaceutical products. (United States)

    Hu, B; Sellers, J; Kupec, J; Ngo, W; Fenton, S; Yang, T-Y; Grebanier, A


    Host cell DNA contamination occurs during the production of biopharmaceuticals and must be controlled and monitored for the purity and safety of the drug products. A sodium iodide-based DNA extraction and a subsequent real time PCR assay were developed and validated for the quantitative measurement of residual host cell DNA impurity in monoclonal antibody therapeutic products. A sodium iodide-based commercial kit was optimized for the removal of interfering matrices. Several incubation steps from the kit protocol were combined and a neutralization buffer was introduced to protein digestion step to eliminate any precipitation from the detergent. The elimination of the two washing steps significantly reduced assay variability from loss of DNA pellets. The optimized DNA extraction procedure can recover DNA close to 100% for DNA concentrations from 10 to 100,000pg/mL. Of the published sequences of repetitive interspersed nuclear elements, we identified a nucleotide mismatch from the published CHO probe. Correction of this nucleotide increased DNA amplification by a thousand fold. The optimized assay was further validated for the quantitation of residual CHO DNA according to ICH guidelines with preset assay acceptance criteria. The method met all assay acceptance criteria and was found linear, accurate and precise for the quantitation of residual CHO in the linear range of 10-100,000pg DNA/mL. LOQ was measured at 10pg DNA/mL and LOD at 1pg DNA/mL. No matrix interference to our validated assay was detected from bioreactor harvest, Protein A eluate or eluate from ion exchange columns.

  2. A Study on the Development of Nanning Biopharmaceutical Industry under GVC Background%全球价值链下南宁市生物医药产业发展对策研究

    Institute of Scientific and Technical Information of China (English)



      Biology industry is one of seven strategic emerging industries in China with biopharmaceutical as an important field. Based on the analysis of its past and current status, this paper emphasizes the major factors that affect the development of Nanning’s biopharmaceutical industry, i.e., external environment and internal operation mechanism, which indicating the Nanning biopharmaceutical cluster is still at the forming stage. To boost growth, this paper presents some policy suggestions such as strengthening cooperation between research institutes and pharmaceutical companies, improving risk investment system and public service platform as well as raising the quality and results of government.%  生物产业是我国七大战略新兴产业之一,而生物医药产业是其重点推进的一个领域。文章在对南宁市生物医药产业发展的历程与现状进行分析的基础上,重点剖析了其发展的外部环境与内部机制。虽然南宁市生物医药产业集群效益初步显现,但整体发展水平仍处于形成阶段。因此,应从加强产学研合作、健全风险投资体系、完善公共服务平台、提高政府服务质量等方面推动该产业的发展。

  3. 江西省生物医药产业发展对策研究%Study on Problems and Solutions in the Development of Bio-pharmaceutical Industry in Jiangxi

    Institute of Scientific and Technical Information of China (English)

    黄晓萍; 陈俊; 蔡汝林; 邱小忠


    生物医药产业是江西的重点发展产业和我国的战略性新兴产业,也是一个新兴产业,在金融危机中表现出较强的抗风险力和高增长率,已成为世界各国竞相争夺的产业战略制高点;分析江西省生物医药产业发展现状,深入分析制约江西生物医药产业进一步发展的因素在于研发投入不足、产学研合作不够紧密、缺乏技术市场中介和高素质的技术经营人等方面,并针对存在问题提出相应对策建议,以为实现江西经济的平稳较快发展创造有利条件。%Bio-pharmaceutical industry is one of the key industries in Jiangxi, it is also an emerging industries in China. Bio-pharmaceutical Industry is burgeoning industry, Its ability to guard against fi- nancial risks and high growth is powerful, has become the strategic industry in the world. The paper has analyzed status quo of bio-pharmaceutical Industry. It was pointed out the reasons restricting fur- ther development of the bio-pharmaceutical industry in Jiangxi, that is, inadequate investment in R&D,divorced between Production,learning and research, lack of effective technology market inter- mediary and high-quality technology intermediary. Last the paper has put forward the corresponding countermeasures and suggestions.

  4. Practice and Discussion of the Biopharmaceutical Technology Professional Certificate System Personnel Training%生物制药技术专业岗位证书制人才培养的研究与实践

    Institute of Scientific and Technical Information of China (English)



    高职生物制药技术专业人才培养的目标和规格凸显职业教育的针对性、实践性和先进性;与用人单位需求实现“零距离”对接,培养既具有高技能,又具有较好综合职业素质的高等技能型人才,是一个十分现实的课题。本文从生物制药技术专业人才培养中应该关注的职业岗位、职业资格证书问题等方面探讨了生物制药技术专业人才培养方案的制定,为生物制药技术专业人才培养提供了一定的参考。%Personnel training objectives and specifications of vocational biopharmaceuticai technology professional highlight the pertinence, practical and advanced nature of vocational education; to achieve the zero distance cooperation for employer needs, it is a very important realistic subject that to cultivate both a highly skilled, but also has good professional qualit), higher skilled personnel. Biopharmaceutical technology professional personnel training should focus on professional jobs, vocational qualification certificate problems of biopharmaceutical technology professional personnel training program development, and provide some reference to the cultivation of biopharmaceutical technology professionals.

  5. 基于"先进合同研究组织"的生物医药产业创新模式探讨%Advanced Contract Research Organization-Based Innovated Pattern of Biopharmaceutical Industry

    Institute of Scientific and Technical Information of China (English)

    蔡雨阳; 李际; 任军; 黄阳滨; 芮明杰


    目的:探索我国的生物医药产业创新模式.方法:分析我国生物医药产业的核心--新药研发中存在的研发基地建设薄弱、资金不足、成果转化难三大问题,基于"合同研究组织(CRO)"建立产业创新模式.结果:提出由"多并发CRO"的研发模式、风险投资与专利/新药证书对接的融资形式以及新药证书为导向的研发过程管理组成的产业创新模式,并整合为"先进合同研究组织(CRO+)".结论:该模式是一种开放性集成服务体系,有利于缩短生物医药研发周期,降低研发成本与研发风险,促进我国生物医药产业发展.%OBJECTIVE: To explore the innovation pattern of biopharmaceutical industry in China. METHODS: Three major problems encountered by the research and development (R&D) of new drug, the core of Chinese biopharmaceutical in-dustry, including the weak construction of operation base for R&D of new drug, insufficient fund, difficulty in the transfor-mation of achievements were analyzed. An innovation pattern of biopharmaceutical industry was founded based on the "Contract Research Organization(CRO)" . RESULTS: An innovation industry pattern consisting of multiple-concurrent CRO R&D mode, venture capital and patent/ new drug certificate tie-in financing form and new drug certificate oriented R& D process management has been put forward, which was integrated into an "advanced CRO"(CRO+ ) mode. CONCLUSION: The CRO+ mode is an open and integrative service system which can help shorten the R&D cycle, lower the cost and risk of R&D and promote the development of biopharmaceutical industry in China.

  6. Construction of biopharmaceutics classification system of Chinese materia medica%多成分体系下中药生物药剂学分类系统的构建分析

    Institute of Scientific and Technical Information of China (English)

    刘洋; 隗丽; 董玲; 朱美玲; 唐明敏; 张雷


    基于中药的多成分特点,借鉴化药领域的生物药剂学分类系统(biopharmaceutics classification system,BCS)理念、方法和技术,提出了中药生物药剂学分类系统(biopharmaceutics classification system of Chinese materia medica,CMMBCS)的科学框架.在学术思想阐述和理论分析的同时,构建了基于多成分层次差异比较法和中药整体CMMBCS研究法的方法流程,明确了该系统用于揭示中药多成分吸收的相互影响及相关机制的基础性作用,也为提高中药质量标准和开发中药新药提供了新的思路和方法.

  7. Sample preparation and biopharmaceutical analysis


    Farrelly, Gillian


    In chapter 1, an overview is given of sample preparation methods and analytical techniques in use today. Each one is discussed, and relevant examples are given. In chapter 2, the development of a method for the HPLC analysis of taurine in human plasma using acetonitrile precipitation and pre-column derivatisation with fluorescamine is presented. This procedure was found to be faster and easier to use than previous taurine assays. In chapter 3, the evaluation of novel aspirin derivativ...

  8. Avaliação biofarmacêutica in vitro de cápsulas de fluconazol In vitro biopharmaceutic evaluation of capsules containing fluconazole

    Directory of Open Access Journals (Sweden)

    Valentina Porta


    Full Text Available Atualmente, no mercado brasileiro, vários laboratórios farmacêuticos comercializam produtos a base do antifúngico fluconazol na forma de cápsulas de 150 mg. Pretendeu-se, neste trabalho, realizar avaliação biofarmacêutica in vitro de três formulações do mercado nacional contendo fluconazol, designadas por produtos A, B e C. Após desenvolvimento e padronização do método de dissolução, avaliou-se a cinética de dissolução de cápsulas de fluconazol provenientes de dois lotes de cada produto por meio dos parâmetros k (constante de velocidade de dissolução e t85% (tempo necessário para dissolução de 85% do fármaco presente na forma farmacêutica, derivados dos perfis de dissolução. Obteve-se k s de 0,1377 min-1 e 0,1079 min-1 para os lotes de A, 0,5421min-1 para os lotes de B e 0,0354 min-1 e 0,0146 min-1 para os lotes de C. t85% foi de 15,09 min e 20,06 min para os lotes de A, 5,64 min e 6,02 min para os lotes de B e 132,12 min e 56,05 min para os lotes de C. Concluiu-se que a dissolução de fluconazol em cápsulas segue cinética de primeira ordem para os três produtos avaliados, sendo que o produto B apresenta maior velocidade de dissolução do fármaco, seguido pelo produto A e pelo produto C.Many brazilian pharmaceutical industries manufacture capsules containing 150 mg of the antifungal agent fluconazole. The present study was designed to perform a in vitro biopharmaceutical evaluation of three commercial products available in Brazil, designated as products A, B and C. After a dissolution method was developed and standardized, the dissolution kinetics for samples of two batches of each product was analysed through k s (dissolution rate constant and t85% (time for dissolution of 85% of the drug in the dosage form, obtained from dissolution profiles. Results showed k s values of 0,1377 min-1 and 0,1079 min-1 for the tested batches of A, 0,5421min-1 for the tested batches of B and 0,0354 min-1 and 0,0146 min-1 for

  9. Classification Tree Model for Drug Penetrability Classification Identification of Biopharmaceutics Classification System%基于分类树模型鉴别药物在生物药剂分类系统的穿透性分类

    Institute of Scientific and Technical Information of China (English)

    曾垂宇; 王晓艳


    通过构建基于分子属性的分类树模型以鉴别化合物的生物药剂分类系统(biopharmaceutics classification system,BCS)的穿透性分类.将从不同文献采集的Caco-2穿透性数据构成训练集,建立分类树模型,并应用此模型对外部测试集——美国食品药品监督管理局BCS的标准化合物进行分类测试.由此建立的鉴别化合物的BCS穿透性分类的规则为如果氢键供体原子数量<4、正性范德华极性表面积和<40.71并且溶解能>-33.89,那么该化合物为高穿透性,否则为低穿透性.本分类结构属性关系模型的105个化合物的训练集和17个化合物的外部测试集的识别正确率分别91.43%和82.35%.本模型成功应用于鉴定BCS标准化合物高低穿透性分类药物的分子属性,为药物穿透性的识别提供了简便、有效的分类方法.

  10. Biopharmaceutics classification and absorption mechanisms primary study on four kinds of flavonoids%4种黄酮类中药有效成分BCS分类及吸收机制的初步研究

    Institute of Scientific and Technical Information of China (English)

    李慧芳; 张冬; 曲文君; 王海霖; 刘洋; 阿里穆斯; 崔箭; 董政起


    该研究根据生物药剂学分类系统(biopharmaceutics classification system,BCS),研究山柰酚、橙皮苷、芹菜素、染料木素等4种黄酮类中药有效成分的溶解性和渗透性,并对其进行BCS分类;同时对其吸收机制进行研究.参照《中国药典》2010年版中溶解度测定方法对4种黄酮类成分进行溶解度的测定,采用体外细胞培养法建立Caco-2细胞模型,利用MTT法筛选出合适的给药浓度进行细胞转运实验来检测表观渗透系数(Papp)以判断渗透性,并根据BCS对其进行分类;采用Caco-2细胞模型,选择高、中、低3组不同浓度化合物进行双向转运实验研究吸收机制.实验表明山柰酚、橙皮苷、芹菜素、染料木素等具有低溶解性、高渗透性,属于BCSⅡ类,其中山柰酚为主动转运吸收机制,而橙皮苷、芹菜素、染料木素等为被动吸收.该研究针对中药黄酮类单体有效成分的特性,对其溶解性及渗透性的评价方法进行了摸索,为进一步完善中药生物药剂学分类体系提供了理论依据.

  11. 基于药物体内处置的生物药剂学分类系统在预测药物体内过程中的应用%Appication of biopharmaceutics drug disposition classification system in predicting disposition of drugs in vivo

    Institute of Scientific and Technical Information of China (English)

    刘维; 杨丽; 闫婷婷; Leslie Benet; 翟所迪


    “生物药剂学分类系统(biopharmaceutics classification system,BCS)”和“基于药物体内处置的生物药剂学分类系统(biopharmaceutics drug disposition classification system,BDDCS)”是两个在欧美药品研发及监管领域使用非常广泛的系统,通过溶解度、渗透性或代谢程度指标,将药物分为简单的4类,即可以对药物的体内过程特点进行预测.本文将详细阐述和比较BCS和BDDCS在建立目的、分类标准和应用等方面的特点和差异,并着重介绍不同BDDCS分类药物体内过程特点与转运体之间的关系,以及转运体在药物吸收、分布、代谢和排泄过程中的作用.

  12. 京津沪生物医药产业比较研究及对天津的启示%A Comparative Study on Bio-Pharmaceutical Industry in Beijing-Tianjin-Shanghai Region and Its Enlightenment to Tianjin

    Institute of Scientific and Technical Information of China (English)

    周立群; 周晓波


    Through a comparative study on bio-pharmaceutical industry in Beijing , Tianjin and Shanghai , we found that the layout and structure of the bio-pharmaceutical industry in Tianjin has many advantages such as stronger competitiveness for individual enterprises , higher bio-pharmaceutical industry concentrating ratio , higher compound growth rate and greater scale efficiency , and it has formed “five-driven” development pattern of chemical drugs , traditional Chinese medicine , bio-medicine, medical equipment and health industry .But there also exist some defectives such as few pharmaceutical en-terprises, a small number of high added value products and irrational industrial structure etc .Therefore, in future of Tianjin we should implement a series of major projects by taking advantage of its industrial concentration features , so as to optimize the internal structure and key fields of bio-pharmaceutical industry .We would like to cultivate a group of pharmaceutical companies with enormous potentials and wide marketing prospect to encourage foreign enterprises to invest and build facto -ries in Tianjin.Relying on high-quality human resources in Beijing-Tianjin-Hebei region, we will expand industrial support and service platform , so that the bio-pharmaceutical industry could become a new growth point of economic development .%通过对京津沪3个直辖市的比较分析发现,天津生物医药产业的布局和结构呈现出单个企业实力较强、产业集中度高、产值复合增长率高、规模效率明显等优势。并已形成化学药、中药、生物药、医疗器械和健康产业“五轮驱动”的发展格局。但也存在医药企业数量少、过亿产品数量少、结构不合理等问题。因此,天津未来应借助产业和园区集中度高的优势,实施重大项目带动战略,调整优化医药产业的内部结构和重点领域,培育一批成长性好、市场潜力大的优势药企,把吸引跨国药企

  13. 基于财务视角的中小生物制药企业可持续增长能力实证分析%Factor analysis of sustainable growth ability in small and medium-sized biopharmaceutical enterprises based on financial perspective

    Institute of Scientific and Technical Information of China (English)

    王玉冬; 孙越


    中小生物制药企业的高风险性,使投资者、债权人和经营者等对企业可持续增长能力非常关注。本文采用实证分析的方法,从企业的财务状况和经营成果出发,对反映中小生物制药企业可持续增长能力的指标进行筛选的基础上,根据在中小板和创业板上市的44家中小生物制药企业财务数据,应用因子分析的方法对影响企业可持续增长能力的主成份囚素进行排序,并分析其对可持续增长能力的影响,对誉衡药业可持续增长能力进行评价,并提出其可持续增长能力提升的财务策略。本文的研究对于中小生物制药企业充分利用内外资源,进行资金优化配置和控制风险,促进企业可持续增长具有重要作用,可为中小生物制药企业和投资者、债权人等分析可持续增长能力提供借鉴。%The high risk of small and medium-sized biopharmaceutical enterprises makes investors,creditors,and operators concerned much about the sustainable growth ability of the company. This paper uses the method of factor analysis, sets out from the enterprises' financial position and operating results, on the basis of screening indexes which reflect the sustainable growth of the small and medium-sized biopharmaceutical enterprises,according to the financial data of 44 small and medium-sized biopharmaceutical enterprises listed on the SME Board and GEM Board. Then, factor analysis is applied to sort the principal component factors which affects the sustainable growth ability and analyzes their impact on sustainable growth ability,meanwhile,to evaluate sustainable growth ability of YuHeng Pharmaceuticals and propose the financial strategy of its sustainable growth ability. This paper plays an important role in making full use of the internal and external resources of small and medium-sized biopharmaceutical enterprises, optimizing the allocation of funds and control the risk, and promoting the

  14. Glycan characterization of biopharmaceuticals: Updates and perspectives. (United States)

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


    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.

  15. Biopharmaceutical aspects of oral drug delivery

    NARCIS (Netherlands)

    Faassen, Werenfriedus Adrianus


    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: rele

  16. Biopharmaceutical industry-sponsored global clinical trials in emerging countries Ensaios clínicos globais patrocinados pela indústria biofarmacêutica em países emergentes

    Directory of Open Access Journals (Sweden)

    Lenio Souza Alvarenga


    Full Text Available OBJECTIVE: 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. METHODS: Data regarding recruitment of subjects for clinical trials were retrieved from 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. RESULTS: 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 (pOBJETIVO: Avaliar ensaios clínicos patrocinados pela indústria biofarmacêutica alocados em países previamente definidos como emergentes em pesquisa clínica e possíveis diferenças naqueles alocados no Brasil. MÉTODOS: Dados de ensaios clínicos recrutando pacientes foram obtidos ( em 2 de fevereiro de 2009. As proporções de centros em cada país foram comparadas entre os países emergentes. Regressões logísticas múltiplas foram realizadas para avaliar a alocação do ensaio em outros países emergentes e as características do ensaio como preditores da presença de algum centro no Brasil RESULTADOS: No total, 8.501 ensaios clínicos estavam ativos à época, e 13,8% destes (N=1.170 incluíam centros em países emergentes (i.e., Argentina, Brasil, China, República Tcheca, Hungria, Índia, México, Polônia, Rússia, Coreia do Sul, e África do Sul. Coreia do Sul e China apresentaram uma proporção de centros significativamente superior aos outros países (p<0,05. Não se detectou correla

  17. Avaliação biofarmacotécnica in vitro de formas farmacêuticas sólidas contendo doxiciclina In vitro biopharmaceutical evaluation of solid dosage forms containing doxycycline

    Directory of Open Access Journals (Sweden)

    Geysa Aguiar


    Full Text Available A absorção de fármacos a partir de formas farmacêuticas sólidas, administradas por via oral, depende de sua liberação, da dissolução ou solubilização dos mesmos em condições fisiológicas e da permeabilidade das membranas do trato gastrintestinal. Portanto, a dissolução in vitro é fundamental para se prever o desempenho in vivo do fármaco. Pretendeu-se neste trabalho, realizar avaliação biofarmacotécnica in vitro através de testes físico-químicos e avaliação da cinética e eficiência de dissolução de quatro lotes de duas formulações do mercado nacional contendo 100 mg de doxiciclina. Utilizou-se o método descrito pela Farmacopéia Americana para realização do ensaio de dissolução. A análise da cinética de dissolução foi avaliada por meio dos parâmetros k s (constante de velocidade de dissolução e t50% (tempo necessário para dissolução de 50% do fármaco presente na forma farmacêutica. Calculou-se, também, a eficiência de dissolução (ED%. De acordo com os resultados obtidos, verificou-se que todas as amostras avaliadas apresentaram-se de acordo com os compêndios oficiais no que se referiu a peso médio, teor de fármaco, uniformidade de conteúdo e teste de dissolução. Em relação à cinética de dissolução observou-se que todos os produtos apresentaram cinética de primeira ordem. Para a eficiência de dissolução encontraram-se valores entre 58,48% e 78,39%.The process of drug absorption from solid dosage forms following oral administration depends on drug delivery from dosage form, its dissolution in gastrointestinal conditions and permeation through the intestinal membrane. Therefore, in vitro dissolution is very important to predict the in vivo performance of a drug contained in a solid dosage form. The purpose of this study was to perform an in vitro biopharmaceutical evaluation, through physicochemical, dissolution kinetics and dissolution efficacy tests of four batches of two

  18. 高职院校医药营销专业开设生物药品课程的探讨%An Inquiry into the Opening of "Biopharmaceutics" as a Compulsory Course in Pharmaceutical Marketing Spe-cialty of Higher Vocational College

    Institute of Scientific and Technical Information of China (English)


    This paper analyzes the necessity of Biopharmaceutics for pharmaceutical marketing majors as an compulsory course in higher vocational college, as well as the teaching aim, teaching contents, teaching design and teaching methods of this course. It also discusses the significance of the course for cultivating high-quality skilled talents of pharmaceutical industry.%  从高职院校医药营销专业开设生物药品课程的必要性、课程的教学目标、教学设计、教学内容以及取得的成效等进行探讨。分析了开设本门课程对培养从事药品营销、管理、服务等工作的高素质技能型人才的重要意义。

  19. Suggestions on Educational Model of Innovative Marine Biopharmaceutics Major Course--Taking Qinzhou University as an Example%创新海洋生物制药核心专业课程教学模式的建议——以钦州学院为例

    Institute of Scientific and Technical Information of China (English)



    Qinzhou University sets up the marine biopharmaceutics major course for the purpose of cultivating the marine biopharmaceuties-oriented high-level technical personnel in Guangxi. This paper puts forward some suggestions on the teaching of three major courses ( marine biopharmaceutics, manufacture of pharmaceutical equipment and principle, biological products ex- amination and analysis). The paper also stresses the application of multi-media courseware in teaching and the importance of theory must be combined with practice. This paper proposes that the contents of syllabus should be adjusted in order to meet the needs of professional talents; finally the paper explores different examination modes.%钦州学院开设海洋生物制药专业,承担起了为广西培养海洋生物制药方向高级技术人才的艰巨任务。就三门海洋生物制药专业课程(海洋生物制药、制药工程设备和原理、生物制品检验与分析)的教学提出了一些建议:强化多媒体课件在教学中的运用;探索多种教材的配合使用;结合企业对人才的需要适当调整教学大纲的内容;重视理论与实践相结合的作用;探索多种课程考核模式。

  20. An Analysis on the Institutional Environment of the US Biopharmaceutical Industry Boom%美国培育战略性新兴产业的制度供给及其启示要要以生物医药产业为例

    Institute of Scientific and Technical Information of China (English)

    宋韬; 楚天骄


      美国在培育战略性新兴产业方面卓有成效,这与其恰当的政策扶持密不可分,生物医药产业即是一个很典型的例证。二十世纪90年代后期以来,美国生物医药产业进入繁荣发展阶段,政府主导的制度供给和制度变迁是促成其繁荣的根本原因。首先,美国政府建立了基于政府基金的基础研究投资制度,巩固知识基础;其次,适时修改管制制度,促进知识产业化;再次,改革卫生保健制度,扩大市场需求。这一系列制度变革,从根本上解决了制约生物医药产业发展的几个关键性难题,为其发展营造了有利的制度环境。美国通过政府提供制度供给促进新兴产业发展的成功经验对我国有重要的启示和借鉴意义。%Biotechnology industry in the United States has been booming since 1990s. Institutional factors are the fundamental factors that contributed to the boom of U.S. bio-pharmaceutical industry. Firstly, the U.S. government has been a main investor through the system of NIH which consolidates the knowledge base. Secondly, the U.S. government changes their control system to facilitate the transfer of the knowledge into products that resulted from federally funded research. Thirdly, the U.S. government re-formed the health care system to expand market demand. Through a series of institutional supply, the U.S. government solved some key problems which constrained the develop-ment of bio-pharmaceutical industry, and created a favorable institutional environment. The successful experience of the United States provides an important reference for the development of strategic industries in China.

  1. Impacts of multicomponent environment on solubility of puerarin in biopharmaceutics classification system of Chinese materia medica%中药生物药剂学分类系统中多成分环境对葛根素溶解度的影响

    Institute of Scientific and Technical Information of China (English)

    侯成波; 汪国鹏; 张强; 杨文宁; 吕贝然; 隗丽; 董玲


    该研究针对中药生物药剂学分类系统(biopharmaceutics classification system of Chinese materia medica,CMMBCS)中的溶解度问题,实验考察人工制造的多成分环境对溶解度的影响,并利用所获数据进行数学建模总结相关规律.实验采用递进式设计,分别研究了单一成分背景(黄芩苷、小檗碱和甘草酸)、两成分背景(黄芩苷+甘草酸、黄芩苷+小檗碱和甘草酸+小檗碱)和三成分背景(黄芩苷+甘草酸+小檗碱)对葛根素溶解度影响的变化趋势,从而建立多成分环境对葛根素溶解度影响的数学回归模型方程.

  2. 科学商业的范式分析及其创新轨道--以生物制药为例%The Analysis of Paradigm of Science Business and the Innovation Trajectories:Based on the Bio-pharmaceutical Industry

    Institute of Scientific and Technical Information of China (English)

    李天柱; 马佳; 侯锡林; 冯薇


    新兴产业发展正在涌现出一种科学与商业相融合的创新范式,可以称为“科学商业”。基于对生物制药产业的分析,以科技哲学领域的范式理论为指导,首先证明科学商业是一种创新范式,接下来研究科学商业的世界观、行为模式、形成机制、关键问题等,从而构建科学商业的理论框架以指导相关产业创新。在此基础上,定性归纳了科学商业的接力创新、专业化提供、发展利基市场这三条主要创新轨道,为创新参与者提供决策参考。%The innovation in biotechnology, nanotechnology and some other emerging industries, follows the rules of paradigm of science business. Based on the practical cases in bio-pharmaceutical industry, the science business has been proved to be as a paradigm of innovation, supported by the paradigm theory in philosophy of science and technology. Some general rules have been studied respectively, including the world outlook of science busi-ness, the behavior patterns, the formation mechanism, and the key problems of innovation community, which struc-ture the theoretic framework of science business to illuminate the innovation in related industries. On the basis of these, three main innovation trajectories in science business have been summarized, consisting of relay innovation, professionalized offer and niche market development, which provide the innovation participants the references for decision making in related industries.

  3. 中药生物药剂学分类系统中多成分环境对葛根素渗透性的影响%Effect of multicomponent environment on intestinal permeability of puerarin in biopharmaceutics classification system of Chinese materia medica

    Institute of Scientific and Technical Information of China (English)

    刘洋; 王刚; 董玲; 唐明敏; 朱美玲; 董红环; 侯成波


    中药生物药剂学分类系统(biopharmaceutics classification system of Chinese materia medica,CMMBCS)中的渗透性评价,需多成分作为整体来开展研究,即使在研究具体某一成分时,也应将其放在多成分环境中审视.该实验以此为原则,将葛根芩连汤中的高含量成分作为多成分环境影响因素,考察葛根素的肠渗透性,运用在体肠单向灌流模型,对葛根素肠渗透性的相关参数进行测定,评价其他高含量成分对其肠渗透性的影响.实验结果表明不同比例的黄芩苷、甘草酸和小檗碱对葛根素的肠渗透性均有一定的影响,甘草酸能显著抑制葛根素的肠吸收,高浓度小檗碱会促进葛根素的吸收.该研究结果表明中药生物药剂学分类系统的渗透性评价充分考虑多成分环境中其他成分的影响是重要的研究思想.

  4. Research on Cooperative Model of Service Towards Generic Technology in Biopharmaceutics Based on Biosimilar Monoclonal Antibody%基于抗体生物类似药研发的生物制药共性技术服务平台合作模式研究

    Institute of Scientific and Technical Information of China (English)

    张灿; 董丽


    目的:观察多领域专业人员协同配合在生物类似药开发,尤其是单克隆抗体类似药研究开发中的作用。方法通过抗体生物类似药在注册申报阶段与共性技术服务平台合作的内容和注意事项,分析研发企业与服务平台的合作模式。结果与结论对于广大中小型生物药品研发企业,部分或全部业务委托合同研究组织不仅是一种经营现象,也是现代专业分工的必然选择。外包后,研发企业可集中精力于核心业务,这样更专业、更有效、更易成功,且一定程度上降低了成本。有助于中小型研发企业合理安排研发工作及加快申报。%Objective To investigate the role of synergistic coordination in the development of biosimilar drugs,especially in monoclonal antibody-like drug research and development. Methods The cooperative model of R&D enterprise and service platform is analyzed through the content and precautions of the cooperation between the biosimilar drug and the common technical service platform in the registration and declaration phase. Result and Conclusion For the majority of small and medium-sized bio-pharmaceutical R&D enterprises,cooperation with contract research organization is not only a business phenomenon,but also the inevitable choice of modern professional division of labor. After outsourcing,R&D enterprises can focus on their core business,which is more professional,more effec-tive,easier to obtain results,more successful,and to a certain extent reduce costs. This can help small and medium R&D enterprises with reasonable arrangements for R&D work and speed up the registration and declaration.

  5. 中药生物药剂学分类系统的多成分溶出评价方法在葛根芩连片中的应用%Application of multicomponent dissolution evaluation method of biopharmaceutics classification system of Chinese materia medica in Gegen Qinlian tablets

    Institute of Scientific and Technical Information of China (English)

    隗丽; 汪国鹏; 董玲; 唐明敏; 张雷; 朱美玲; 刘洋


    该研究是中药生物药剂学分类系统(biopharmaceutics classification system of Chinese materia medica,CMMBCS)用于中成药评价的实例,重点评估可能影响多成分吸收时序的溶出同步性问题.实验采用HPLC测定复方葛根芩连片中9种成分在不同溶出介质中不同时间点的累积溶出百分率,绘制体外溶出曲线,采用相似因子(f2)和聚类分析进行溶出曲线的相似性比较分析,结果表明在水介质中,峰7和峰8(黄芩苷)所代表的成分与2号参比峰(葛根素)相似性较差,相似因子均为43;在pH7.4介质中,峰7和峰8(黄芩苷)所代表的成分与2号参比峰(葛根素)相似性较差,相似因子分别为31和45;其他介质中各峰所代表的成分与2号参比峰(葛根素)均相似性较好.该实验表明峰3,4,5和6(小檗碱)所代表的成分与2号参比峰(葛根素)具有完全同步溶出的特性;峰1和峰9所代表的成分与2号参比峰(葛根素)具有基本完全同步溶出的特性;峰7和峰8(黄芩苷)所代表的成分与2号参比峰(葛根素)不具有同步溶出的特性.

  6. R&D投入与公司价值相关性的实证分析—以我国生物制药和电子信息技术行业上市公司为例%Empirical Analysis of the Correlation between R&D Investment and Firm Value Analysis -An Example of Bio-pharmaceutical and Electronic Information Technology Listed Companies in China

    Institute of Scientific and Technical Information of China (English)

    龚志文; 陈金龙


    Using a firm-level dataset of Chinese bio-pharmaceutical and electronic information technology listed companies from 2007 to 2009 as sample, the paper empirically studies the correlation between R&-D investment and company's R&.D value. This paper first examines the role of R&-D investment on business performance, and then uses an improved model of Fama-French three-factor test R&D investment effects on the market valuation. The results show that, R&-D investment is related to operating profits in the same year. R&.D investment is also associated with the same and next year stock price, but not significant. It is found out that, with the implementation of new accounting standards and the completion of the split share reform, the value of R&D investment of the Bio-pharmaceutical and electronic information technology listed companies in China has not been effectively recognized by the market.%以2007-2009年我国生物制药和电子信息技术行业上市公司为研究样本,实证考察R&D投入与公司价值的相关性.首先检验R&D投入对公司经营业绩的作用,然后运用改进的Fama-French三因子模型,检验R&D投入的市场估值效应.结果显示,R&D投入与公司本年主营业务利润正相关,与同期股价和未来一年的股价变动正相关,但不显著.说明生物制药和电子信息技术企业研发投入的价值,在新会计准则实施和股权分置改革完成后,仍未得到市场的有效认可.

  7. Theoretical approximations and experimental extinction coefficients of biopharmaceuticals. (United States)

    Miranda-Hernández, Mariana P; Valle-González, Elba R; Ferreira-Gómez, David; Pérez, Néstor O; Flores-Ortiz, Luis F; Medina-Rivero, Emilio


    UV spectrophotometric measurement is a widely accepted and standardized routine analysis for quantitation of highly purified proteins; however, the reliability of the results strictly depends on the accuracy of the employed extinction coefficients. In this work, an experimental estimation of the differential refractive index (dn/dc), based on dry weight measurements, was performed in order to determine accurate extinction coefficients for four biotherapeutic proteins and one synthetic copolymer after separation in a size-exclusion ultra-performance liquid chromatograph coupled to an ultraviolet, multiangle light scattering and refractive index (SE-UPLC-UV-MALS-RI) multidetection system. The results showed small deviations with respect to theoretical values, calculated from the specific amino acid sequences, for all the studied immunoglobulins. Nevertheless, for proteins like etanercept and glatiramer acetate, several considerations, such as glycan content, partial specific volume, polarizability, and higher order structure, should be considered to properly calculate theoretical extinction coefficient values. Herein, these values were assessed with simple approximations. The precision of the experimentally obtained extinction coefficients, and its convergence towards the theoretical values, makes them useful for characterization and comparability exercises. Also, these values provide insight into the absorbance and scattering properties of the evaluated proteins. Overall, this methodology is capable of providing accurate extinction coefficients useful for development studies.

  8. The Modern Merits of South Koreas Biopharmaceutical Industry


    Benjamin Rymzo; Nathan Dowden; Regina Salvat; Tom Lee


    The overview: In recent years, the South Korean economy has evolved from light goods, to heavy industry, to high tech and biotech. Along the way, the country has built a thoroughly modern legal and regulatory framework, an arguably world class educational infrastructure, and an unusually productive level of public-private partnership activity. How did it get here?: Migrating from a heavy manufacturing economy in the aftermath of the Korean War, South Korea began turning its attention to bioph...

  9. Drug-sensing hydrogels for the inducible release of biopharmaceuticals (United States)

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


    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.

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

    Directory of Open Access Journals (Sweden)

    Aníbal Domínguez Odio


    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.

  11. [Study of biopharmaceutic characteristics of cromoglycate eye drops]. (United States)

    Klimas, Rimantas; Inkeniene, Asta Marija; Briedis, Vitalis; Gerbutaviciene, Rima Jūrate


    One of the factors influencing the release of active substance from the drug formulation is presence of polymeric substance resulting in increase of viscosity of eye drops. Diffusion of sodium cromoglycate from polyvinyl alcohol 1.4%, 3% solutions and hypromellose 1% aqueous solution was investigated using in vitro method and diffusion coefficients were evaluated. Release of sodium cromoglycate from polyvinyl alcohol 1.4%, 3% solutions and hypromellose 1% aqueous solution was slower than the release from aqueous solution of sodium cromoglycate. The sodium cromoglycate diffusion from ophthalmic vehicle process kinetics was influenced by viscosity of these solutions and nature of the used polymers. The diffusion process of sodium cromoglycate from 1.4% PVA solution was more intensive if compared to diffusion from 1% hypromellose solution. The influence of excipients on sodium cromoglycate diffusion from eye drop formulation was evaluated when polymeric solutions have been used as vehicles.

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

    DEFF Research Database (Denmark)

    Kaltenbrunner, Oliver; McCue, Justin; Engel, Philip;


    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...

  13. "Follow-On Biologic Competition in the Biopharmaceutical Marketplace (United States)


    and recombinant erythropoietin for management of anemia during end-stage renal disease. Both products yielded significant improvements over previously available therapeutic alternatives for each condition.

  14. Carrier peptide-mediated transepithelial permeation of biopharmaceuticals

    DEFF Research Database (Denmark)

    Kristensen, Mie; Nielsen, Hanne Mørck


    of the molar mixing ratio between the carrier peptide and the therapeutic cargo, whereas the direct conjugation approach ensures an inherent proximity of the carrier peptide to its therapeutic cargo. So far studies addressing the choice of using the co-administration approach over the conjugation approach......-34)) and the widely studied CPP penetratin were employed as therapeutic cargo and carrier peptide, respectively....

  15. Application of solution calorimetry in pharmaceutical and biopharmaceutical research. (United States)

    Royall, P G; Gaisford, S


    In solution calorimetry the heat of solution (Delta(sol)H) is recorded as a solute (usually a solid) dissolves in an excess of solvent. Such measurements are valuable during all the phases of pharmaceutical formulation and the number of applications of the technique is growing. For instance, solution calorimetry is extremely useful during preformulation for the detection and quantification of polymorphs, degrees of crystallinity and percent amorphous content; knowledge of all of these parameters is essential in order to exert control over the manufacture and subsequent performance of a solid pharmaceutical. Careful experimental design and data interpretation also allows the measurement of the enthalpy of transfer (Delta(trans)H) of a solute between two phases. Because solution calorimetry does not require optically transparent solutions, and can be used to study cloudy or turbid solutions or suspensions directly, measurement of Delta(trans)H affords the opportunity to study the partitioning of drugs into, and across, biological membranes. It also allows the in-situ study of cellular systems. Furthermore, novel experimental methodologies have led to the increasing use of solution calorimetry to study a wider range of phenomena, such as the precipitation of drugs from supersaturated solutions or the formation of liposomes from phospholipid films. It is the purpose of this review to discuss some of these applications, in the context of pharmaceutical formulation and preformulation, and highlight some of the potential future areas where solution calorimetry might find applications.

  16. In vitro -in vivo correlation and biopharmaceutical classification system



    In vitro dissolution has been extensively used as a quality control tool for solid oral dosage forms. In several cases, however, it is not known whether one can predict the in vivo performance of these products from in vitro dissolution data. In an effort to minimize unnecessary human testing, investigations of in vitro-in vivo correlations (IVIVC) between in vitro dissolution and in vivo bioavailability are increasingly becoming an integral part of extended release drug product development. ...

  17. High-level expression and preparation of recombinant human fibrinogen as biopharmaceuticals. (United States)

    Hirashima, Masaki; Imamura, Takayuki; Yano, Kentaro; Kawamura, Ryoichi; Meta, Akihiro; Tokieda, Yoshiyuki; Nakashima, Toshihiro


    Fibrinogen is a large and complex glycoprotein containing two sets of each of three different chains (α, β and γ). There have been no reports of high-level expression of fibrinogen at commercial levels using mammalian cultured cells such as CHO cells because of the difficulty in highly expressing a protein with such a complex structure. We achieved high-level (1.3 g/l or higher) expression of recombinant human fibrinogen using CHO DG44 cells by optimizing the expression system and culture conditions. We also succeeded in establishing a high-recovery preparation method for recombinant fibrinogen that rarely yields degraded products. To characterize the properties of the recombinant human fibrinogen, we performed SDS-PAGE; western blotting of the α, β and γ chains using specific antibodies and scanning electron microscopy observations of fibrin fibres. We also evaluated the functional equivalence between recombinant fibrinogen and plasma fibrinogen with respect to the release of fibrinopeptides initiated by thrombin and its cross-linking properties. The basic properties of recombinant fibrinogen showed no apparent differences from those of plasma fibrinogen. Here, we report the development of methods for the culture and preparation of recombinant human fibrinogen of satisfactory quality that can be scaled up to the commercial level.

  18. From the bench to clinical practice: understanding the challenges and uncertainties in immunogenicity testing for biopharmaceuticals. (United States)

    Gunn, G R; Sealey, D C F; Jamali, F; Meibohm, B; Ghosh, S; Shankar, G


    Unlike conventional chemical drugs where immunogenicity typically does not occur, the development of anti-drug antibodies following treatment with biologics has led to concerns about their impact on clinical safety and efficacy. Hence the elucidation of the immunogenicity of biologics is required for drug approval by health regulatory authorities worldwide. Published ADA 'incidence' rates can vary greatly between same-class products and different patient populations. Such differences are due to disparate bioanalytical methods and interpretation approaches, as well as a plethora of product-specific and patient-specific factors that are not fully understood. Therefore, the incidence of ADA and their association with clinical consequences cannot be generalized across products. In this context, the intent of this review article is to discuss the complex nature of ADA and key nuances of the methodologies used for immunogenicity assessments, and to dispel some fallacies and myths.

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

    Directory of Open Access Journals (Sweden)

    Jhoany Acosta


    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.

  20. Novel biocompatible and self-buffering ionic liquids for biopharmaceutical applications. (United States)

    Taha, Mohamed; Almeida, Mafalda R; Silva, Francisca A E; Domingues, Pedro; Ventura, Sónia P M; Coutinho, João A P; Freire, Mara G


    Antibodies obtained from egg yolk of immunized hens, immunoglobulin Y (IgY), are an alternative to the most focused mammal antibodies, because they can be obtained in higher titers by less invasive approaches. However, the production cost of high-quality IgY for large-scale applications remains higher than that of other drug therapies due to the lack of efficient purification methods. The search for new purification platforms is thus vital. The solution could be liquid-liquid extraction by using aqueous biphasic systems (ABS). Herein, we report the extraction and attempted purification of IgY from chicken egg yolk by using a new ABS composed of polymers and Good's buffer ionic liquids (GB-ILs). New self-buffering and biocompatible ILs based on the cholinium cation and anions derived from Good's buffers were synthesized and the self-buffering characteristics and toxicity were characterized. Moreover, when these GB-ILs are combined with PPG 400 (poly(propylene) glycol with a molecular weight of 400 g mol(-1)) to form ABS, extraction efficiencies, of the water-soluble fraction of proteins, ranging between 79 and 94% were achieved in a single step. Based on computational investigations, we also demonstrate that the preferential partitioning of IgY for the GB-IL-rich phase is dominated by hydrogen-bonding and van der Waals interactions.

  1. New drug development in biopharmaceutical companies : the role of private and external funding


    Vernalls, Saara


    Biotech industry is characterized by unique elements as the companies operate in high risk environment attempting to accomplish scientific developments trough lengthy and expensive R&D cycles while facing insufficient funding. Most companies develop new drugs while not generating any revenue, however, the need for funding is critical at each stage of the new drug development process. The overall purpose of this study is to describe the challenges in new drug development and identify main sour...

  2. Integrated Teaching of Structure-Based Drug Design and Biopharmaceutics: A Computer-Based Approach (United States)

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


    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…

  3. Efficient Agrobacterium-based transient expression system for the production of biopharmaceuticals in plants (United States)

    Circelli, Patrizia; Donini, Marcello; Villani, Maria Elena; Benvenuto, Eugenio


    We have recently described an efficient transient expression system mediated by Agrobacterium tumefaciens for the production of HIV-1 Nef protein in Nicotiana benthamiana plants. In order to enhance the yield of recombinant protein we assayed the effect of three gene-silencing viral suppressor proteins (P25 of Potato Virus X, P19 of Artichoke Mottled Crinckle virus and Tomato Bushy Stunt virus) on Nef expression levels. Results demonstrated that AMCV-P19 gave the highest Nef yield (1.3% of total soluble protein) and that this effect was correlated to a remarkable decrease of Nef-specific small interfering RNAs (siRNAs) indicating an effective modulation of RNA silencing mechanisms. Here we report additional data on the production of different heterologous proteins including human immunoglobulin heavy and light chains and a virus coat protein that demonstrate the robustness of this co-agroinfiltration expression system boosted by the AMCV-P19 gene-silencing suppressor. PMID:21326930

  4. Endophyte bioprospecting in South Asian medicinal plants: an attractive resource for biopharmaceuticals. (United States)

    Tanvir, Rabia; Javeed, Aqeel; Bajwa, Aamir Ghafoor


    From the last several years, there has been an increasing interest in plant-associated bacteria commonly referred to as endophytes that reside asymptomatically in the internal plant tissues. This interest peaked since the last two decades due to the recognition that endophytes within medicinal plants have the capability to mimic and produce the bioactive metabolites of the host plant. A number of medicinal plants have been used for centuries by the people of South Asia to cure various diseases and this has led to abundant usage experience. Relating to prior ethanopharmacological experiences, scientists have searched for medicinal plants that could be valued sources for endophytes yielding novel metabolites of pharmaceutical importance. This review is therefore an effort to encompass the most recent efforts in the exploration of medicinal plants of South Asia and their endophytes.

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

    DEFF Research Database (Denmark)

    Wan, Feng; Yang, Mingshi


    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...... parameters on the critical quality attributes of the spray-dried microparticles....

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

    Directory of Open Access Journals (Sweden)

    Wangding Lu


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

    DEFF Research Database (Denmark)

    Kristensen, Mie; Nielsen, Hanne Mørck


    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...

  8. Establishment of a design space for biopharmaceutical purification processes using DoE. (United States)

    Amadeo, Ignacio; Mauro, Laura; Ortí, Eduardo; Forno, Guillermina


    Recent trends in the pharmaceutical sector are changing the way protein purification processes are designed and executed, moving from operating the process in a fixed point to allowing a permissible region in the operating space known as design space. This trend is driving product development to design quality into the manufacturing process (Quality by Design) and not to rely exclusively on testing quality in the product. A typical purification step has numerous operating parameters that can impact its performance. Therefore, optimization and robustness analysis in purification processes can be time-consuming since they are mainly grounded on experimental work. A valuable approach consists in the combination of an adequate risk analysis technique for selecting the relevant factors influencing process performance and the design of experiment methodology. The latter allows for many process variables which can be studied at the same time; thus, the number of tests will be reduced in comparison with the conventional approach based on trial and error. These multivariate studies permit a detailed exploration in the experimental range and lay the foundation of Quality by Design principles application. This article outlines a recommended sequence of activities toward the establishment of an expanded design space for a purification process.

  9. Process analytical technology (PAT) for biopharmaceutical products: Part II. Concepts and applications. (United States)

    Read, E K; Shah, R B; Riley, B S; Park, J T; Brorson, K A; Rathore, A S


    Implementing real-time product quality control meets one or both of the key goals outlined in FDA's PAT guidance: "variability is managed by the process" and "product quality attributes can be accurately and reliably predicted over the design space established for materials used, process parameters, manufacturing, environmental, and other conditions." The first part of the paper presented an overview of PAT concepts and applications in the areas of upstream and downstream processing. In this second part, we present principles and case studies to illustrate implementation of PAT for drug product manufacturing, rapid microbiology, and chemometrics. We further present our thoughts on how PAT will be applied to biotech processes going forward. The role of PAT as an enabling component of the Quality by Design framework is highlighted. Integration of PAT with the principles stated in the ICH Q8, Q9, and Q10 guidance documents is also discussed.

  10. N(pro) fusion technology: On-column complementation to improve efficiency in biopharmaceutical production. (United States)

    Schindler, S; Missbichler, B; Walther, C; Sponring, M; Cserjan-Puschmann, M; Auer, B; Schneider, R; Dürauer, A


    N(pro) fusion technology, a highly efficient system for overexpression of proteins and peptides in Escherichia coli, was further developed by splitting the autoprotease N(pro) into two fragments to generate a functional complementation system. The size of the expression tag is thus reduced from 168 to 58 amino acids, so by 66%. Upon complementation of the fragments auto-proteolytic activity is restored. This process has been shown for three model proteins of different size, a short 16 aa-peptide, MCP-1, and lysozyme. Moreover, the complementation was still functional after immobilization of the N-terminal fragment to a solid support which enables recycling of the immobilized fragment. This strategy enhances overall productivity of N(pro) Fusion Technology and thus allows more efficient production of recombinant proteins with reduced costs and in higher yields. Overall, the N(pro) complementation system has, depending on the size of the target molecule, potential to increase the productivity up to 4 fold for batch refolding and even more for on-column refolding strategies by the proven possibility of regeneration of the immobilized fragment.

  11. Comparability of a Three-Dimensional Structure in Biopharmaceuticals Using Spectroscopic Methods

    Directory of Open Access Journals (Sweden)

    Víctor Pérez Medina Martínez


    Full Text Available Protein structure depends on weak interactions and covalent bonds, like disulfide bridges, established according to the environmental conditions. Here, we present the validation of two spectroscopic methodologies for the measurement of free and unoxidized thiols, as an attribute of structural integrity, using 5,5′-dithionitrobenzoic acid (DTNB and DyLight Maleimide (DLM as derivatizing agents. These methods were used to compare Rituximab and Etanercept products from different manufacturers. Physicochemical comparability was demonstrated for Rituximab products as DTNB showed no statistical differences under native, denaturing, and denaturing-reducing conditions, with Student’s t-test P values of 0.6233, 0.4022, and 0.1475, respectively. While for Etanercept products no statistical differences were observed under native (P=0.0758 and denaturing conditions (P=0.2450, denaturing-reducing conditions revealed cysteine contents of 98% and 101%, towards the theoretical value of 58, for the evaluated products from different Etanercept manufacturers. DLM supported equality between Rituximab products under native (P=0.7499 and denaturing conditions (P=0.8027, but showed statistical differences among Etanercept products under native conditions (P<0.001. DLM suggested that Infinitam has fewer exposed thiols than Enbrel, although DTNB method, circular dichroism (CD, fluorescence (TCSPC, and activity (TNFα neutralization showed no differences. Overall, this data revealed the capabilities and drawbacks of each thiol quantification technique and their correlation with protein structure.

  12. Biopharmaceutical protein production bySaccharomyces cerevisiae: current state and future prospects

    DEFF Research Database (Denmark)

    Huang, Mingtao; Bao, Jichen; Nielsen, Jens


    tasks with low cost, high productivity and proper post-translational modifications. The yeast Saccharomyces cerevisiae is one of these preferred cell factories as it meets many of the requirements. There are several reports on improvement of recombinant protein production by S. cerevisiae through...

  13. Engineering of Escherichia coli strains for plasmid biopharmaceutical production: scale-up challenges. (United States)

    Gonçalves, Geisa A L; Prather, Kristala L J; Monteiro, Gabriel A; Prazeres, Duarte M F


    Plasmid-based vaccines and therapeutics have been making their way into the clinic in the last years. The existence of cost-effective manufacturing processes capable of delivering high amounts of high-quality plasmid DNA (pDNA) is essential to generate enough material for trials and support future commercialization. However, the development of pDNA manufacturing processes is often hampered by difficulties in predicting process scale performance of Escherichia coli cultivation on the basis of results obtained at lab scale. This paper reports on the differences observed in pDNA production when using shake flask and bench-scale bioreactor cultivation of E. coli strains MG1655ΔendAΔrecA and DH5α in complex media with 20 g/L of glucose. MG1655ΔendAΔrecA produced 5-fold more pDNA (9.8 mg/g DCW) in bioreactor than in shake flask (1.9 mg/g DCW) and DH5α produced 4-fold more pDNA (8 mg/g DCW) in bioreactor than in shake flask (2 mg/g DCW). Accumulation of acetate was also significant in shake flasks but not in bioreactors, a fact that was attributed to a lack of control of pH.


    Directory of Open Access Journals (Sweden)

    A. A. Kostina


    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.

  15. Formulation of Propolis Phenolic Acids Containing Microemulsions and Their Biopharmaceutical Characterization

    Directory of Open Access Journals (Sweden)

    Modestas Žilius


    Full Text Available Microemulsions (MEs were formulated using PEG-8 caprylic/capric glycerides and ethanolic propolis extracts. Characterization of MEs was performed by determining mean droplet size, polydispersity index, stability under varying external factors, and formulation effect on delivery of phenolic compounds into the skin ex vivo. Essential oils were included into the formulations of MEs and their influence on physical characteristics of the nanostructured systems as well as penetration into epidermis and dermis were evaluated. The droplet size, their distribution, and stability of the formulated MEs were not affected. Presence of essential oils in the formulation increased penetration of phenolic compounds in general, but only the amount of ferulic acid increased significantly. Mean droplet size increased with increase of oily phase amount, suggesting that phenolic compounds and components of essential oils were not modifying the formation of the interphase film composition and/or structure. Phenolic compounds were predominantly located in the lipid phase of the MEs thus minimizing their availability at the surface of the skin.

  16. Optimization of biopharmaceutical downstream processes supported by mechanistic models and artificial neural networks. (United States)

    Pirrung, Silvia M; van der Wielen, Luuk A M; van Beckhoven, Ruud F W C; van de Sandt, Emile J A X; Eppink, Michel H M; Ottens, Marcel


    Downstream process development is a major area of importance within the field of bioengineering. During the design of such a downstream process, important decisions have to be made regarding the type of unit operations as well as their sequence and their operating conditions. Current computational approaches addressing these issues either show a high level of simplification or struggle with computational speed. Therefore, this article presents a new approach that combines detailed mechanistic models and speed-enhancing artificial neural networks. This approach was able to simultaneously optimize a process with three different chromatographic columns toward yield with a minimum purity of 99.9%. The addition of artificial neural networks greatly accelerated this optimization. Due to high computational speed, the approach is easily extendable to include more unit operations. Therefore, it can be of great help in the acceleration of downstream process development. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 2017.

  17. Advancing biopharmaceutical process development by system-level data analysis and integration of omics data. (United States)

    Schaub, Jochen; Clemens, Christoph; Kaufmann, Hitto; Schulz, Torsten W


    Development of efficient bioprocesses is essential for cost-effective manufacturing of recombinant therapeutic proteins. To achieve further process improvement and process rationalization comprehensive data analysis of both process data and phenotypic cell-level data is essential. Here, we present a framework for advanced bioprocess data analysis consisting of multivariate data analysis (MVDA), metabolic flux analysis (MFA), and pathway analysis for mapping of large-scale gene expression data sets. This data analysis platform was applied in a process development project with an IgG-producing Chinese hamster ovary (CHO) cell line in which the maximal product titer could be increased from about 5 to 8 g/L.Principal component analysis (PCA), k-means clustering, and partial least-squares (PLS) models were applied to analyze the macroscopic bioprocess data. MFA and gene expression analysis revealed intracellular information on the characteristics of high-performance cell cultivations. By MVDA, for example, correlations between several essential amino acids and the product concentration were observed. Also, a grouping into rather cell specific productivity-driven and process control-driven processes could be unraveled. By MFA, phenotypic characteristics in glycolysis, glutaminolysis, pentose phosphate pathway, citrate cycle, coupling of amino acid metabolism to citrate cycle, and in the energy yield could be identified. By gene expression analysis 247 deregulated metabolic genes were identified which are involved, inter alia, in amino acid metabolism, transport, and protein synthesis.

  18. Monitoring patients treated with anti-TNF-alpha biopharmaceuticals: assessing serum infliximab and anti-infliximab antibodies

    DEFF Research Database (Denmark)

    Svenson, M; Geborek, P; Saxne, T;


    Infliximab is an anti-tumour necrosis factor-alpha (TNF-alpha) mouse-human IgG1/kappa antibody used to treat patients with rheumatoid arthritis (RA) and other inflammatory diseases. Unfortunately, response failure and side-effects due to immunogenicity of the drug are not rare. In this study, we ...

  19. The biotechnology innovation machine: a source of intelligent biopharmaceuticals for the pharma industry--mapping biotechnology's success. (United States)

    Evens, R P; Kaitin, K I


    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.

  20. Enabling Low Cost Biopharmaceuticals: A Systematic Approach to Delete Proteases from a Well-Known Protein Production Host Trichoderma reesei.

    Directory of Open Access Journals (Sweden)

    Christopher P Landowski

    Full Text Available The filamentous fungus Trichoderma reesei has tremendous capability to secrete proteins. Therefore, it would be an excellent host for producing high levels of therapeutic proteins at low cost. Developing a filamentous fungus to produce sensitive therapeutic proteins requires that protease secretion is drastically reduced. We have identified 13 major secreted proteases that are related to degradation of therapeutic antibodies, interferon alpha 2b, and insulin like growth factor. The major proteases observed were aspartic, glutamic, subtilisin-like, and trypsin-like proteases. The seven most problematic proteases were sequentially removed from a strain to develop it for producing therapeutic proteins. After this the protease activity in the supernatant was dramatically reduced down to 4% of the original level based upon a casein substrate. When antibody was incubated in the six protease deletion strain supernatant, the heavy chain remained fully intact and no degradation products were observed. Interferon alpha 2b and insulin like growth factor were less stable in the same supernatant, but full length proteins remained when incubated overnight, in contrast to the original strain. As additional benefits, the multiple protease deletions have led to faster strain growth and higher levels of total protein in the culture supernatant.


    Directory of Open Access Journals (Sweden)

    Rybalkin М. V


    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.

  2. Monitoring patients treated with anti-TNF-alpha biopharmaceuticals: assessing serum infliximab and anti-infliximab antibodies

    DEFF Research Database (Denmark)

    Svenson, M; Geborek, P; Saxne, T


    Infliximab is an anti-tumour necrosis factor-alpha (TNF-alpha) mouse-human IgG1/kappa antibody used to treat patients with rheumatoid arthritis (RA) and other inflammatory diseases. Unfortunately, response failure and side-effects due to immunogenicity of the drug are not rare. In this study, we...

  3. Comparative studies on the dissolution profiles of oral ibuprofen suspension and commercial tablets using biopharmaceutical classification system criteria

    Directory of Open Access Journals (Sweden)

    J C Rivera-Leyva


    Full Text Available 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.

  4. In situ protein secondary structure determination in ice: Raman spectroscopy-based process analytical tool for frozen storage of biopharmaceuticals. (United States)

    Roessl, Ulrich; Leitgeb, Stefan; Pieters, Sigrid; De Beer, Thomas; Nidetzky, Bernd


    A Raman spectroscopy-based method for in situ monitoring of secondary structural composition of proteins during frozen and thawed storage was developed. A set of reference proteins with different α-helix and β-sheet compositions was used for calibration and validation in a chemometric approach. Reference secondary structures were quantified with circular dichroism spectroscopy in the liquid state. Partial least squares regression models were established that enable estimation of secondary structure content from Raman spectra. Quantitative secondary structure determination in ice was accomplished for the first time and correlation with existing (qualitative) protein structural data from the frozen state was achieved. The method can be used in the presence of common stabilizing agents and is applicable in an industrial freezer setup. Raman spectroscopy represents a powerful, noninvasive, and flexibly applicable tool for protein stability monitoring during frozen storage.

  5. Quick generation of Raman spectroscopy based in-process glucose control to influence biopharmaceutical protein product quality during mammalian cell culture. (United States)

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


    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.

  6. Study on the Prediction of Biopharmaceutics Classification System%应用人工神经网络预测药物的生物药剂学分类

    Institute of Scientific and Technical Information of China (English)

    陈敏燕; 金芝贵; 吴飞华; 梁文权


    目的 建立药物生物药剂学分类的预测模型.方法 采集60个样本建立药物特征溶解度神经网络模型,采集214个样本建立药物渗透性遗传神经网络模型,并在此2个模型基础上,构建生物药剂学分类系统预测模型.结果 生物药剂学分类系统预测模型中,溶解度预测准确度为93.8%,渗透性预测准确性为81.2%,生物药剂学分类预测准确性为75.0%.结论 本模型可以较好地预测药物的生物药剂学分类,预测效能较高.

  7. Introduction of biopharmaceutics classification system(BCS)and its application progress%生物药剂分类系统(BCS)及应用进展介绍

    Institute of Scientific and Technical Information of China (English)

    张宁; 平其能



  8. QbD-Enabled Development of Novel Stimuli-Responsive Gastroretentive Systems of Acyclovir for Improved Patient Compliance and Biopharmaceutical Performance. (United States)

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


    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.

  9. Capillary electrophoresis coupled to fluorescence spectroscopy for protein characterisation

    NARCIS (Netherlands)

    de Kort, B.J.


    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 prot

  10. Biosimilars: controversies as illustrated by rhGH.

    NARCIS (Netherlands)

    Declerck, P.J.; Darendeliler, F.; Goth, M.; Kolouskova, S.; Micle, I.; Noordam, C.; Peterkova, V.; Volevodz, N.N.; Zapletalova, J.; Ranke, M.B.


    Abstract Background and scope: Similar biological medicinal products, also called 'biosimilars', are copies of biopharmaceutical products whose patent has expired. Whether biosimilars are truly comparable and interchangeable with their reference biopharmaceutical products in terms of quality, effica

  11. 纳米技术在生物制药领域中的应用研究%Study on the Application of Nanotechnology in the Bio-pharmaceutical Field

    Institute of Scientific and Technical Information of China (English)

    李向辉; 王宏魁


    纳米技术在生物领域的广泛应用形成了纳米生物技术,而纳米药物载体和纳米中药的研究也成为近年来生物制药领域的研究热点之一。综述了纳米技术、纳米生物技术的定义,详细介绍了纳米药物载体和纳米中药的相关研究进展,以期为该技术的进一步应用提供理论依据。%With the wide application of nano-technology in the field of biology,nanobiotechnology as a new subject is formed. The studies on nano-drug carrier and nano-traditional Chinese medicine have been one of research hotspots in the field of biological pharmacy in recent years. The definition of nano-technology and nanobiotechnology were summarized. The related research progresses on nano-drug carrier and nano-traditional Chinese medicine were introduced in detail,so as to provide theoretical basis for further application of this technology.

  12. The Probe on Air Conditioning System and Differential Pressure Control in Bio-pharmaceutical Cleanroom%生物制药洁净厂房空调系统与压差控制方案探讨

    Institute of Scientific and Technical Information of China (English)

    胡汉江; 白晓明



  13. 基于生物药剂学分类系统的口服固体速释制剂生物豁免%Biowaiver for immediate-release solid oral dosage forms based on biopharmaceutics classification system

    Institute of Scientific and Technical Information of China (English)

    刘曼; 张文萍; 张丽娜; 刘会臣



  14. 基于药物体内处置的生物药剂学分类系统(BDDCS)简介%Introduction to biopharmaceutics drug disposition classification system (BDDCS)

    Institute of Scientific and Technical Information of China (English)

    刘维; 杨丽; BENET Leslie Z.; 翟所迪



  15. 盐酸小檗碱在黄连水煎液中的生物药剂学分类系统属性研究%Study on property of biopharmaceutics classification system of berberine in Huanglian decoction

    Institute of Scientific and Technical Information of China (English)

    隗丽; 朱美玲; 董月柳; 董玲; 刘洋; 陈江鹏; 尹秀文



  16. Patent Quality Evaluation Index:an Case of Chinese Bio-pharmaceutical Industry%专利质量综合评价指数--以我国生物医药行业为例

    Institute of Scientific and Technical Information of China (English)

    吴菲菲; 张广安; 张辉; 黄鲁成


    专利质量问题已引起世界各国的广泛关注。利用文献计量方法确定专利质量评价指标和权重,并给出了专利质量评价指数。根据数据的可得性对指标进行删减,利用 OECD 给出的生物技术专利IPC分类号,结合医药特征关键词对专利进行筛选,最终得到全国不同省(区、市)生物医药行业专利质量评价指数。研究结果表明,所确定的专利质量指数是有效的,我国生物医药行业专利质量排名前五位的分别是:北京、上海、台湾、香港和江苏。最后提出提高专利质量的对策建议。%Attentions to patent quality has arisen around the world.This paper determines the patent quality evaluation indi-cators and their weight with the method of bibliometrics.It also puts forward the patent evaluation index.After deletion of indicators according to their accessibility,It filters all patents by using the IPC numbers included in biotechnology given by OECD and reference keywords which can represent the character of pharmaceuticals industry.After that,the paper con-clude the pharmaceuticals industry's patent quality evaluation indices of all provinces (districts or cities).The results show that the patent quality indices are valid.The top five of pharmaceuticals industry's patent quality are Beijing,Shanghai, Taiwan,Hong Kong and Jiangsu.Suggestions to improve the patent quality are proposed in the end of the paper.

  17. 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;


    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 ...

  18. Exploration of the Ecological Planning for Partial Section: Case Study of Shangluo Bio-pharmaceutical Industry Park Planning%局部地段生态规划的探索--以商洛生物医药工业园规划为例

    Institute of Scientific and Technical Information of China (English)

    洪亘伟; 段德罡



  19. Considerations for biowaiver of oral immediate-release solid products based on biopharmaceutics classification system%基于生物药剂分类系统对普通口服固体制剂免除生物等效性研究的考虑

    Institute of Scientific and Technical Information of China (English)

    张宁; 平其能



  20. 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


    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.

  1. A Simulation Research of Firms' Capacity Mecharism of Actions under Open Innovation Background——Take Biopharmaceutical SMEs for Example%开放式创新视角下企业能力作用机理的仿真研究——以中小型生物制药企业为例

    Institute of Scientific and Technical Information of China (English)

    莫燕; 郑旻



  2. Biosimilars: Current perspectives and future implications

    Directory of Open Access Journals (Sweden)

    Monika Misra


    Full Text Available 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.

  3. Systems glycobiology for glycoengineering

    DEFF Research Database (Denmark)

    Spahn, Philipp N.; Lewis, Nathan


    Glycosylation serves essential functions on many proteins produced in biopharmaceutical manufacturing, making it mandatory to thoroughly consider its biogenesis during the production process. Glycoengineering efforts involve the rational design of glycosylation through adjustments in culturing...

  4. Metabolic-flux analysis of mammalian-cell culture.

    NARCIS (Netherlands)

    Bonarius, H.P.J.


    In the biopharmaceutical industry mammalian cells are cultivated for the production of recombinant glycoproteins, vaccines, and monoclonal antibodies. In contrast to other expression systems, such as prokaryotes or yeasts, mammalian cells are able to glycosylate and fold therapeutic proteins correct

  5. 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.;


    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 for desve......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...... of desvenlafaxine pharmacokinetics after IRF and ERF administration were compared with published clinical data from 14 trials. Desvenlafaxine in vivo dissolution from the IRF and ERF was predicted from in vitro solubility studies and biorelevant dissolution studies (using the USP3 dissolution apparatus...

  6. Intracellular degradation of microspheres based on cross-linked dextran hydrogels or amphiphilic block copolymers: A comparative Raman microscopy study

    NARCIS (Netherlands)

    Manen, van Henk-Jan; Apeldoorn, van Aart A.; Verrijk, Ruud; Blitterswijk, van Clemens A.; Otto, Cees


    Micro- and nanospheres composed of biodegradable polymers show promise as versatile devices for the controlled delivery of biopharmaceuticals. Whereas important properties such as drug release profiles, biocompatibility, and (bio)degradability have been determined for many types of biodegradable par

  7. In-situ product removal by membrane extraction

    NARCIS (Netherlands)

    Heerema, L. D.


    In bioproduction processes of chemicals and pharmaceuticals, downstream processing usually is a significant cost factor. The products require a high purity (especially biopharmaceutical products), therefore, the process usually contains a large number of separation steps. Moreover, the high costs in

  8. Assessment of Protective Properties of Optimized Flagellin Derivative Against Biologically Harmful Effects of Ionizing Irradiation During Space Flight Project (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...

  9. Applications of recombinant Pichia pastoris in the healthcare industry


    Daniel Weinacker; Claudia Rabert; Andrea B. Zepeda; Figueroa, Carolina A.; Adalberto Pessoa; Farías,Jorge G.


    Since the 1970s, the establishment and development of the biotech industry has improved exponentially, allowing the commercial production of biopharmaceutical proteins. Nowadays, new recombinant protein production is considered a multibillion-dollar market, in which about 25% of commercial pharmaceuticals are biopharmaceuticals. But to achieve a competitive production process is not an easy task. Any production process has to be highly productive, efficient and economic. Despite that the perf...

  10. Strategic funding priorities in the pharmaceutical sciences allied to Quality by Design (QbD) and Process Analytical Technology (PAT)

    DEFF Research Database (Denmark)

    Aksu, Buket; De Beer, Thomas; Folestad, Staffan


    Substantial changes in Pharmaceutical R&D strategy are required to address existing issues of low productivity, imminent patent expirations and pressures on pricing. Moves towards personalized healthcare and increasing diversity in the nature of portfolios including the rise of biopharmaceuticals......, include product design and development for personalized healthcare, continuous-processing in pharmaceutical product manufacture, quantitative quality risk assessment for pharmaceutical development including life cycle management and the downstream processing of biopharmaceutical products. Plans are being...

  11. Separation of Recombinant β-Glucuronidase from Transgenic Tobacco by Aqueous Two-Phase Extraction



    Separation of Recombinant à -Glucuronidase from Transgenic Tobacco by Aqueous Two-Phase Extraction Kristin Coby Ross Abstract Biopharmaceutical manufacturing is a rigorous and expensive process. Due to the medicinal nature of the product, a high purity level is required and several expensive purification steps must be utilized. Cost-effective production and purification is essential for any biopharmaceutical product to be successful and development of the fastest, most economical, ...

  12. Biotechnology

    Energy Technology Data Exchange (ETDEWEB)



    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.

  13. Getting to the core of protein pharmaceuticals – comprehensive structure analysis by mass spectrometry

    DEFF Research Database (Denmark)

    Leurs, Ulrike; Mistarz, Ulrik Hvid; Rand, Kasper Dyrberg


    Protein pharmaceuticals are the fastest growing class of novel therapeutic agents, and have been a major research and development focus in the (bio)pharmaceutical industry. Due to their large size and structural diversity, biopharmaceuticals represent a formidable challenge regarding analysis....... Mass spectrometry has evolved as a powerful tool for the characterization of both primary and higher order structures of protein pharmaceuticals. Furthermore, the chemical and physical stability of protein drugs, as well as their pharmacokinetics are nowadays routinely determined by mass spectrometry...

  14. Effect of Equity Structure and Board Independence on Corporate Performances --Based on Comparative Study between Pre-financial Crisis and Post-financial Crisis in Bio-pharmaceutical Industry%股权结构与董事会独立性对企业绩效的影响——基于危机前后生物医药行业的比较研究

    Institute of Scientific and Technical Information of China (English)

    丁明智; 张浩


    The different influence of equity structure and board independence of bio- pharmaceutical industry on corporate performance is investigated in pre-financial crisis and post-financial crisis environment. The empirical results indicate that both equity concentration and balance promote corporate performances. It is found that equity balance's promotion on corporate performances is more significant and stronger, and equity concentration's promotion on corporate performances is less significant and weaker in post- financial crisis environment than in pre-financial crisis environment. The proportion of independent directors and corporate performance is negatively related, and in the crisis, the negative effects become more significant.%分析了危机前后生物医药行业股权结构,董事会独立性与企业绩效情况,认为股权制衡与股权集中对企业绩效的增长均具有促进作用,但是相对于危机之前的环境来说,在危机发生后股权制衡对企业绩效促进作用的显著性增大,作用力度也增强;而股权集中对企业绩效促进作用的显著性降低,作用力度也减弱。独立董事比例与企业绩效呈负相关,但在危机之前该作用不显著,在危机发生后,该负向作用才变得显著。

  15. A European perspective on the market accessibility of biosimilars

    Directory of Open Access Journals (Sweden)

    Declerck PJ


    Full Text Available Paul J Declerck,1 Steven Simoens21Laboratory for Pharmaceutical Biology, 2Research Centre for Pharmaceutical Care and Pharmacoeconomics, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven, Leuven, BelgiumAbstract: Biopharmaceuticals are complex molecules produced by living cells. Copies of these drugs, called biosimilars, are not identical to their reference medicine, and therefore specific regulatory requirements for registration apply. Pharmaceutical quality evaluation requires a complete dossier and a detailed comparative analysis to the reference drug. However, nonclinical and clinical requirements are much less extensive compared to the requirements for an innovator. Therefore, at the time of introduction onto the market, only limited clinical experience is available for the biosimilar. Differences of 15%–30% between the acquisition price of biosimilars and their corresponding reference biopharmaceuticals have been suggested in the literature. Although the percentage price difference between reference biopharmaceuticals and biosimilar medicines may be limited, absolute savings are still likely to be substantial when calculated with respect to expensive reference biopharmaceutical medicines. Although an economic evaluation needs to be carried out in an increasing number of European countries to inform reimbursement decisions, uncertainty exists about how such an economic evaluation should be conducted for a biosimilar. The assessment of the cost-effectiveness of a biosimilar for reimbursement purposes depends primarily on the relative efficacy, given that a biosimilar is likely to be less expensive than the reference biopharmaceutical. To date, the question of meaningful differences in efficacy between biosimilar and biopharmaceutical drugs has not been answered. Due to a lack of demand-side incentives, biosimilar medicines have enjoyed limited success in Europe to date. Other factors that inhibit the market accessibility

  16. Protein pharmaceuticals: discovery and preclinical development. (United States)

    Gill, Davinder S


    Proteins are natural molecules that carry out important cellular functions within our bodies. Their precise role is crucial to the maintenance of good health. Malfunctioning proteins or those not produced optimally result in disease. The foundation of biopharmaceutical drug therapy has therefore been to modulate cellular function by targeting specific proteins expressed on or outside the cell. Because most biopharmaceuticals are natural in origin, they are biologically and chemically very different from conventional medicines. In addition to differences in mechanism of action, biopharmaceuticals differ in the process by which they get manufactured and delivered. Because of their large, complex structure, they must often be produced by culturing cells and then purified from a host of cellular components. This can be time-consuming and costly. Also, most biopharmaceuticals are given by injection under the skin or by infusion into the veins. This creates significant limitations to their utility. Nonetheless, biopharmaceuticals can be very powerful and selective in disease applications such as in rheumatoid arthritis or cancer. This chapter describes methods by which proteins drugs are discovered, optimized and developed. It also covers novel agents and next generation proteins as well as some of the challenges and opportunities in the area.

  17. Scientific considerations concerning the EMA change in the definition of "dose" of the BCS-based biowaiver guideline and implications for bioequivalence. (United States)

    Daousani, Chrysa; Macheras, Panos


    This work discusses the scientific aspects of the definition of dose as the 'highest single oral IR dose' recommended for administration in the SmPC (summary of product characteristics) in the current European Medicines Agency (EMA) 2010 Guideline, for the purpose of biopharmaceutics classification system (BCS)-based biowaiver decision making. Analysis of theoretical and experimental data dealing with drug dissolution and biopharmaceutic drug classification reveals that the drug dose is an important parameter for both drug dissolution and biopharmaceutic classification. The relevant implications for the dose considerations in bioequivalence studies are also discussed briefly. It is suggested that the concept of "the highest single dose oral IR dose recommended for administration in the SmPC" of the EMA 2010 Guideline be abolished. It is advisable, each dose strength be considered separately i.e., whether or not it meets the solubility-dissolution regulatory criteria.

  18. 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;


    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...... with in vivo biopharmaceutical performance has often been ignored. More recently, the switch to assessing drug products in a more biorelevant and mechanistic manner has advanced the understanding of drug formulation behavior. Notwithstanding this evolution, predicting the in vivo biopharmaceutical performance...... 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...

  19. Biotechnology

    Energy Technology Data Exchange (ETDEWEB)



    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.

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

    Directory of Open Access Journals (Sweden)

    Alexey Llopiz


    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.

  1. Formulation and stability of cytokine therapeutics. (United States)

    Lipiäinen, Tiina; Peltoniemi, Marikki; Sarkhel, Sanjay; Yrjönen, Teijo; Vuorela, Heikki; Urtti, Arto; Juppo, Anne


    Cytokines are messenger proteins that regulate the proliferation and differentiation of cells and control immune responses. Interferons, interleukins, and growth factors have applications in cancer, autoimmune, and viral disease treatment. The cytokines are susceptible to chemical and physical instability. This article reviews the structure and stability issues of clinically used cytokines, as well as formulation strategies for improved stability. Some general aspects for identifying most probable stability concerns, selecting excipients, and developing stable cytokine formulations are presented. The vast group of cytokines offers possibilities for new biopharmaceuticals. The formulation approaches of the current cytokine products could facilitate development of new biopharmaceuticals.

  2. Characterization of Stress-Exposed Granulocyte Colony Stimulating Factor Using ELISA and Hydrogen/Deuterium Exchange Mass Spectrometry (United States)

    Tsuchida, Daisuke; Yamazaki, Katsuyoshi; Akashi, Satoko


    Information on the higher-order structure is important in the development of biopharmaceutical drugs. Recently, hydrogen/deuterium exchange coupled with mass spectrometry (HDX-MS) has been widely used as a tool to evaluate protein conformation, and unique automated systems for HDX-MS are now commercially available. To investigate the potential of this technique for the prediction of the activity of biopharmaceuticals, granulocyte colony stimulating factor (G-CSF), which had been subjected to three different stress types, was analyzed using HDX-MS and through comparison with receptor-binding activity. It was found that HDX-MS, in combination with ion mobility separation, was able to identify conformational changes in G-CSF induced by stress, and a good correlation with the receptor-binding activity was demonstrated, which cannot be completely determined by conventional peptide mapping alone. The direct evaluation of biological activity using bioassay is absolutely imperative in biopharmaceutical development, but HDX-MS can provide the alternative information in a short time on the extent and location of the structural damage caused by stresses. Furthermore, the present study suggests the possibility of this system being a versatile evaluation method for the preservation stability of biopharmaceuticals.

  3. High-Pressure Biotechnology in Medicine and Pharmaceutical Science

    Directory of Open Access Journals (Sweden)

    Patrick Masson


    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.

  4. Establishment of a mammalian cell line suitable for industrial production of recombinant protein using mutations induced by high-energy beam radiation


    Chida, Yasuhito; Takagi, Keiichi; Terada, Satoshi


    Mammalian cells are extensively used for production of biopharmaceuticals. Most cells used in industry have infinite proliferative capacity, which provides a high number of cells and corresponding productivity. However, infinite cells will continue to multiply even after cell density reaches sufficient levels. This excess proliferation aggravates the culture environment and induces low productivity. Therefore, after cell density reaches sufficient levels, downregulation of proliferation would...

  5. Manufacturing Vaccines: An Illustration of Using PAT Tools for Controlling the Cultivation of Bordetella pertussis

    NARCIS (Netherlands)

    Sprang, van E.N.M.; Streefland, M.; Ramaker, H.J.; Pol, van der L.A.; Beuvery, E.C.; Smilde, A.K.


    An illustration of the operational consistency of the upstream part of a biopharmaceutical process is given. For this purpose four batch cultivations of Bordetella pertussis have been executed under identical conditions. The batches have been monitored by means of two fundamentally different process

  6. A Methods-Based Biotechnology Course for Undergraduates (United States)

    Chakrabarti, Debopam


    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.…

  7. Plants as a production platform for high-value proteins

    NARCIS (Netherlands)

    Westerhof, L.B.


    Summary Current treatments of inflammatory disorders are often based on therapeutic proteins. These proteins, so-called biopharmaceuticals, are isolated from a natural resource or, more often, made using cell based fermentation systems. The most common production platforms are based

  8. Good Pharma? How Business Communication Research Can Help Bridge the Gap between Students and Practitioners (United States)

    Bruyer, Tom; Jacobs, Geert; Vandendaele, Astrid


    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…

  9. Radical Innovation and Network Evolution

    NARCIS (Netherlands)

    S.M.W. Phlippen (Sandra); M. Riccaboni


    textabstractThis paper examines how a radical technological innovation affects alliance formation of firms and subsequent network structures. We use longitudinal data of interfirm R&D collaborations in the biopharmaceutical industry in which a new technological regime is established. Our findings su

  10. LC-MS systems for quantitative bioanalysis

    NARCIS (Netherlands)

    Dongen, W.D. van; Niessen, W.M.A.


    LC-MS has become the method-of-choice in small-molecule drug bioanalysis (molecular mass <800 Da) and is also increasingly being applied as an alternative to ligand-binding assays for the bioanalytical determination of biopharmaceuticals. Triple quadrupole MS is the established bioanalytical techniq

  11. Process analytical technology tools for perfusion cell culture

    NARCIS (Netherlands)

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


    During cell cultivation processes for the production of biopharmaceuticals, good process performance and good product quality can be ensured by online monitoring of critical process parameters (e.g. temperature, pH, or dissolved oxygen). These data can be used in real-time for process control, as su

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


    Alexey Llopiz


    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 microalga...

  13. Biosimilar therapeutics: what do we need to consider?

    NARCIS (Netherlands)

    Schellekens, H.


    Patents for the first generation of approved biopharmaceuticals have either expired or are about to expire. Thus the market is opening for generic versions, referred to as ‘biosimilars’ (European Union) or ‘follow-on protein products’ (United States). Healthcare professionals need to understand the

  14. AgBase: a functional genomics resource for agriculture



    Abstract Background Many agricultural species and their pathogens have sequenced genomes and more are in progress. Agricultural species provide food, fiber, xenotransplant tissues, biopharmaceuticals and biomedical models. Moreover, many agricultural microorganisms are human zoonoses. However, systems biology from functional genomics data is hindered in agricultural species because agricultural genome sequences have relatively poor structural and functional annotation and agricultural researc...

  15. Size and molecular flexibility of sugars determine the storage stability of freeze-dried proteins

    NARCIS (Netherlands)

    Tonnis, W. F.; Mensink, M. A.; de Jager, A.; Maarschalk, K. van der Voort; Frijlink, H. W.; Hinrichs, W. L. J.


    Protein-based biopharmaceuticals are generally produced as aqueous solutions and stored refrigerated to obtain sufficient shelf life. Alternatively, proteins may be freeze-dried in the presence of sugars to allow storage stability at ambient conditions for prolonged periods. However, to act as a sta

  16. Cell factories for a sustainable world

    DEFF Research Database (Denmark)

    Kindtler, Jens William


    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...

  17. 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

  18. Uninformed and disinformed society and the GMO market. (United States)

    Twardowski, Tomasz; Małyska, Aleksandra


    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.

  19. 77 FR 72904 - In the Matter of HealthSport, Inc., Home Director, Inc., Home Theater Products International, Inc... (United States)


    ... From the Federal Register Online via the Government Publishing Office SECURITIES AND EXCHANGE COMMISSION In the Matter of HealthSport, Inc., Home Director, Inc., Home Theater Products International, Inc., House of Taylor Jewelry, Inc. (n/ k/a Global Jewelry Concepts, Inc.), and Huifeng Bio-Pharmaceutical Technology, Inc.; Order of Suspension...

  20. Solid Phospholipid Dispersions for Oral Delivery of Poorly Soluble Drugs

    DEFF Research Database (Denmark)

    Fong, Sophia Yui Kau; Martins, Susana M; Brandl, Martin;


    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...

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

    DEFF Research Database (Denmark)

    Bachelet, Delphine; Hässler, Signe; Mbogning, Cyprien


    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...

  2. From Fangs to Pharmacology: The Future of Snakebite Envenoming Therapy

    DEFF Research Database (Denmark)

    Laustsen, Andreas Hougaard; Engmark, Mikael; Milbo, Christina


    therapies for snakebite envenomings. In this review, current state-of-the-art in biopharmaceutical antitoxin development is presented together with an overview of available bioinformatics and structural data on snake venom toxins. This growing body of scientific and technological tools could define...

  3. 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


    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 absor

  4. 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


    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

  5. 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 in

  6. 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.


    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 feature

  7. Sparging-shear sensitivity of animal cells.

    NARCIS (Netherlands)

    Pol, van der L.A.


    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. Animal cell

  8. 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.


    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

  9. Advances and challenges in analytical characterization of biotechnology products: mass spectrometry-based approaches to study properties and behavior of protein therapeutics. (United States)

    Kaltashov, Igor A; Bobst, Cedric E; Abzalimov, Rinat R; Wang, Guanbo; Baykal, Burcu; Wang, Shunhai


    Biopharmaceuticals are a unique class of medicines due to their extreme structural complexity. The structure of these therapeutic proteins is critically important for their efficacy and safety, and the ability to characterize it at various levels (from sequence to conformation) is critical not only at the quality control stage, but also throughout the discovery and design stages. Biological mass spectrometry (MS) offers a variety of approaches to study structure and behavior of complex protein drugs and has already become a default tool for characterizing the covalent structure of protein therapeutics, including sequence and post-translational modifications. Recently, MS-based methods have also begun enjoying a dramatic growth in popularity as a means to provide information on higher order structure and dynamics of biotechnology products. In particular, hydrogen/deuterium exchange MS and charge state distribution analysis of protein ions in electrospray ionization (ESI) MS offer a convenient way to assess the integrity of protein conformation. Native ESI MS also allows the interactions of protein drugs with their therapeutic targets and other physiological partners to be monitored using simple model systems. MS-based methods are also applied to study pharmacokinetics of biopharmaceutical products, where they begin to rival traditional immunoassays. MS already provides valuable support to all stages of development of biopharmaceuticals, from discovery to post-approval monitoring, and its impact on the field of biopharmaceutical analysis will undoubtedly continue to grow.

  10. Biofarmaka til behandling af reumatoid artritis

    DEFF Research Database (Denmark)

    Baslund, Bo; Bendtzen, Klaus


    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...

  11. Deep sequencing reveals different compositions of mRNA transcribed from the F8 gene in a panel of FVIII-producing CHO cell lines

    DEFF Research Database (Denmark)

    Kaas, Christian Schrøder; Bolt, Gert; Hansen, Jens J;


    Coagulation factor VIII (FVIII) is one of the most complex biopharmaceuticals due to the large size, poor protein stability and extensive post-translational modifications. As a consequence, efficient production of FVIII in mammalian cells poses a major challenge, with typical yields two to three ...

  12. 计算生物学中有关基因组翻转距离的NPC问题%NPC Problems of the Reversal Distance between Genomes in Computational Biology

    Institute of Scientific and Technical Information of China (English)

    栾峻峰; 朱大铭; 马绍汉


    Problems of computing the reversal distance between genomes are discussed. Problems of computing the reversal distance between genomes are fundamental problems of Computational Biology, these problems have important meanings in studying the biological race evolution and the bio-pharmaceuticals etc. The problem of evolutionary trees based on reversal distance between genomes and it's NPC property are especially discussed.

  13. 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;


    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...

  14. Human in vivo regional intestinal permeability: importance for pharmaceutical drug development. (United States)

    Lennernäs, Hans


    Both the development and regulation of pharmaceutical dosage forms have undergone significant improvements and development over the past 25 years, due primarily to the extensive application of the biopharmaceutical classification system (BCS). The Biopharmaceutics Drug Disposition Classification System, which was published in 2005, has also been a useful resource for predicting the influence of transporters in several pharmacokinetic processes. However, there remains a need for the pharmaceutical industry to develop reliable in vitro/in vivo correlations and in silico methods for predicting the rate and extent of complex gastrointestinal (GI) absorption, the bioavailability, and the plasma concentration-time curves for orally administered drug products. Accordingly, a more rational approach is required, one in which high quality in vitro or in silico characterizations of active pharmaceutical ingredients and formulations are integrated into physiologically based in silico biopharmaceutics models to capture the full complexity of GI drug absorption. The need for better understanding of the in vivo GI process has recently become evident after an unsuccessful attempt to predict the GI absorption of BCS class II and IV drugs. Reliable data on the in vivo permeability of the human intestine (Peff) from various intestinal regions is recognized as one of the key biopharmaceutical requirements when developing in silico GI biopharmaceutics models with improved predictive accuracy. The Peff values for human jejunum and ileum, based on historical open, single-pass, perfusion studies are presented in this review. The main objective of this review is to summarize and discuss the relevance and current status of these human in vivo regional intestinal permeability values.

  15. In vitro models for the prediction of in vivo performance of oral dosage forms. (United States)

    Kostewicz, Edmund S; Abrahamsson, Bertil; Brewster, Marcus; Brouwers, Joachim; Butler, James; Carlert, Sara; Dickinson, Paul A; Dressman, Jennifer; Holm, René; Klein, Sandra; Mann, James; McAllister, Mark; Minekus, Mans; Muenster, Uwe; Müllertz, Anette; Verwei, Miriam; Vertzoni, Maria; Weitschies, Werner; Augustijns, Patrick


    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 with in vivo biopharmaceutical performance has often been ignored. More recently, the switch to assessing drug products in a more biorelevant and mechanistic manner has advanced the understanding of drug formulation behavior. Notwithstanding this evolution, predicting the in vivo biopharmaceutical performance 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 tools. Development and optimizing innovative, predictive Oral Biopharmaceutical Tools is the main target of the OrBiTo project within the Innovative Medicines Initiative (IMI) framework. A combination of physico-chemical measurements, in vitro tests, in vivo methods, and physiology-based pharmacokinetic modeling is expected to create a unique knowledge platform, enabling the bottlenecks in drug development to be removed and the whole process of drug development to become more efficient. As part of the basis for the OrBiTo project, this review summarizes the current status of predictive in vitro assessment tools for formulation behavior. Both pharmacopoeia-listed apparatus and more advanced tools are discussed. Special attention is paid to major issues limiting the predictive power of traditional tools, including the simulation of dynamic changes in gastrointestinal conditions, the adequate reproduction of gastrointestinal motility, the simulation of supersaturation and precipitation, and the implementation of the solubility-permeability interplay. It is

  16. Animal pharming, two decades on. (United States)

    Kind, Alexander; Schnieke, Angelika


    Since its inception 20 years ago, the animal pharming industry has promoted transgenic animals as a cost-effective method of biopharmaceutical production. However, it took until 2006 for the first therapeutic product to gain regulatory approval. This was an important milestone, but scepticism still abounds. Can pharming regain investor confidence, and will society accept transgenic livestock as a production method? There is some cause for optimism, biopharmaceuticals are a large, expanding market and animal pharming has already made considerable strides. A novel production platform has been established, groundbreaking technologies developed, a necessary regulatory framework put in place. Nevertheless, despite cost advantages, pharming has become a niche production method and its long term success may depend on products unique to transgenic animals.

  17. Recombinant plant-derived pharmaceutical proteins: current technical and economic bottlenecks. (United States)

    Sabalza, Maite; Christou, Paul; Capell, Teresa


    Molecular pharming is a cost-effective platform for the production of recombinant proteins in plants. Although the biopharmaceutical industry still relies on a small number of standardized fermentation-based technologies for the production of recombinant proteins there is now a greater awareness of the advantages of molecular pharming particularly in niche markets. Here we discuss some of the technical, economic and regulatory barriers that constrain the clinical development and commercialization of plant-derived pharmaceutical proteins. We also discuss strategies to increase productivity and product quality/homogeneity. The advantages of whole plants should be welcomed by the industry because this will help to reduce the cost of goods and therefore expand the biopharmaceutical market into untapped sectors.

  18. BDDCS Predictions, Self-Correcting Aspects of BDDCS Assignments, BDDCS Assignment Corrections, and Classification for more than 175 Additional Drugs. (United States)

    Hosey, Chelsea M; Chan, Rosa; Benet, Leslie Z


    The biopharmaceutics drug disposition classification system was developed in 2005 by Wu and Benet as a tool to predict metabolizing enzyme and drug transporter effects on drug disposition. The system was modified from the biopharmaceutics classification system and classifies drugs according to their extent of metabolism and their water solubility. By 2010, Benet et al. had classified over 900 drugs. In this paper, we incorporate more than 175 drugs into the system and amend the classification of 13 drugs. We discuss current and additional applications of BDDCS, which include predicting drug-drug and endogenous substrate interactions, pharmacogenomic effects, food effects, elimination routes, central nervous system exposure, toxicity, and environmental impacts of drugs. When predictions and classes are not aligned, the system detects an error and is able to self-correct, generally indicating a problem with initial class assignment and/or measurements determining such assignments.

  19. Recommendations on risk-based strategies for detection and characterization of antibodies against biotechnology products. (United States)

    Koren, Eugen; Smith, Holly W; Shores, Elizabeth; Shankar, Gopi; Finco-Kent, Deborah; Rup, Bonita; Barrett, Yu-Chen; Devanarayan, Viswanath; Gorovits, Boris; Gupta, Shalini; Parish, Thomas; Quarmby, Valerie; Moxness, Michael; Swanson, Steven J; Taniguchi, Gary; Zuckerman, Linda A; Stebbins, Christopher C; Mire-Sluis, Anthony


    The appropriate evaluation of the immunogenicity of biopharmaceuticals is of major importance for their successful development and licensure. Antibodies elicited by these products in many cases cause no detectable clinical effects in humans. However, antibodies to some therapeutic proteins have been shown to cause a variety of clinical consequences ranging from relatively mild to serious adverse events. In addition, antibodies can affect drug efficacy. In non-clinical studies, anti-drug antibodies (ADA) can complicate interpretation of the toxicity, pharmacokinetic (PK) and pharmacodynamic (PD) data. Therefore, it is important to develop testing strategies that provide valid assessments of antibody responses in both non-clinical and clinical studies. This document provides recommendations for antibody testing strategies stemming from the experience of contributing authors. The recommendations are intended to foster a more unified approach to antibody testing across the biopharmaceutical industry. The strategies proposed are also expected to contribute to better understanding of antibody responses and to further advance immunogenicity evaluation.

  20. 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;


    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......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...

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

    Directory of Open Access Journals (Sweden)

    Lukasz Puslecki


    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.

  2. Applications of recombinant Pichia pastoris in the healthcare industry

    Directory of Open Access Journals (Sweden)

    Daniel Weinacker


    Full Text Available Since the 1970s, the establishment and development of the biotech industry has improved exponentially, allowing the commercial production of biopharmaceutical proteins. Nowadays, new recombinant protein production is considered a multibillion-dollar market, in which about 25% of commercial pharmaceuticals are biopharmaceuticals. But to achieve a competitive production process is not an easy task. Any production process has to be highly productive, efficient and economic. Despite that the perfect host is still not discovered, several research groups have chosen Pichia pastoris as expression system for the production of their protein because of its many features. The attempt of this review is to embrace several research lines that have adopted Pichia pastoris as their expression system to produce a protein on an industrial scale in the health care industry.

  3. Maize (Zea mays)-derived bovine trypsin: characterization of the first large-scale, commercial protein product from transgenic plants. (United States)

    Woodard, Susan L; Mayor, Jocelyne M; Bailey, Michele R; Barker, Donna K; Love, Robert T; Lane, Jeffrey R; Delaney, Donna E; McComas-Wagner, Janet M; Mallubhotla, Hanuman D; Hood, Elizabeth E; Dangott, Lawrence J; Tichy, Shane E; Howard, John A


    Bovine trypsin (EC is an enzyme that is widely used for commercial purposes to digest or process other proteins, including some therapeutic proteins. The biopharmaceutical industry is trying to eliminate animal-derived proteins from manufacturing processes due to the possible contamination of these products by human pathogens. Recombinant trypsin has been produced in a number of systems, including cell culture, bacteria and yeast. To date, these expression systems have not produced trypsin on a scale sufficient to fulfill the need of biopharmaceutical manufacturers where kilogram quantities are often required. The present paper describes commercial-level production of trypsin in transgenic maize (Zea mays) and its physical and functional characterization. This protease, the first enzyme to be produced on a large-scale using transgenic plant technology, is functionally equivalent to native bovine pancreatic trypsin. The availability of this reagent should allow for the replacement of animal-derived trypsin in the processing of pharmaceutical proteins.

  4. Biowaiver Monographs for Immediate-Release Solid Oral Dosage Forms: Nifedipine. (United States)

    Gajendran, Jayachandar; Krämer, Johannes; Shah, Vinod P; Langguth, Peter; Polli, James; Mehta, Mehul; Groot, D W; Cristofoletti, Rodrigo; Abrahamsson, Bertil; Dressman, Jennifer B


    Literature data relevant to the biopharmaceutical properties of the active pharmaceutical ingredient (API) nifedipine are reviewed to evaluate whether a waiver of in vivo bioequivalence (BE) testing of immediate-release (IR) dosage forms formulated as tablets and soft gelatin capsules is warranted. Nifedipine's solubility and permeability, its therapeutic use and index, pharmacokinetics, food drug interactions, and any reported BE/bioavailability problems were all taken into consideration. Solubility and BA data indicate conclusively that nifedipine is a class II substance of biopharmaceutics classification system (BCS) and that the formulation of drug product plays a key role on the dissolution characteristics of the API. Therefore, a BCS biowaiver-based approval of nifedipine containing IR oral dosage forms cannot be recommended for reformulated/new multisource drug products or for major scale-up and postapproval changes to the existing drug products.

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


    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.

  6. 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...... of pharmaceuticals, a process referred to as pharmacology profiling. Pharmacology profiling of chemical and protein based pharmaceuticals has been proven valuable in a number studies [2], however missing values in the drug-protein interaction matrix limits the profile for novel or less studied compounds...... as an alternative to experimentally obtained measurements. Here I present several different tools that aid pharmacology profiling of the two main classes of pharmaceuticals; chemicals (small molecules) and proteins (biopharmaceuticals). Biopharmaceuticals have the inherent risks of eliciting an immune response due...

  7. Versatile microscale screening platform for improving recombinant protein productivity in Chinese hamster ovary cells

    DEFF Research Database (Denmark)

    Hansen, Henning Gram; Nilsson, Claes Nymand; Lund, Anne Mathilde


    of four techniques compatible with 96-well microplates: lipid-based transient transfection, cell cultivation in microplates, cell counting and antibody-independent product titer determination based on split-GFP complementation. We were able to demonstrate growth profiles and volumetric productivity of CHO......Chinese hamster ovary (CHO) cells are widely used as cell factories for the production of biopharmaceuticals. In contrast to the highly optimized production processes for monoclonal antibody (mAb)-based biopharmaceuticals, improving productivity of non-mAb therapeutic glycoproteins is more likely...... cells in 96-half-deepwell microplates comparable with those obtained in shake flasks. In addition, we demonstrate that split-GFP complementation can be used to accurately measure relative titers of therapeutic glycoproteins. Using this platform, we were able to detect target gene-specific increase...

  8. Molecular dynamics-based virtual screening: accelerating the drug discovery process by high-performance computing. (United States)

    Ge, Hu; Wang, Yu; Li, Chanjuan; Chen, Nanhao; Xie, Yufang; Xu, Mengyan; He, Yingyan; Gu, Xinchun; Wu, Ruibo; Gu, Qiong; Zeng, Liang; Xu, Jun


    High-performance computing (HPC) has become a state strategic technology in a number of countries. One hypothesis is that HPC can accelerate biopharmaceutical innovation. Our experimental data demonstrate that HPC can significantly accelerate biopharmaceutical innovation by employing molecular dynamics-based virtual screening (MDVS). Without using HPC, MDVS for a 10K compound library with tens of nanoseconds of MD simulations requires years of computer time. In contrast, a state of the art HPC can be 600 times faster than an eight-core PC server is in screening a typical drug target (which contains about 40K atoms). Also, careful design of the GPU/CPU architecture can reduce the HPC costs. However, the communication cost of parallel computing is a bottleneck that acts as the main limit of further virtual screening improvements for drug innovations.

  9. Mathematical modelling of protein precipitation based on the phase equilibrium for an antibody fragment from E. coli Lysis


    Zhou, Y.; Ji, Y.


    Precipitation is an important operation in biopharmaceutical purification yet the mechanism of protein precipitation in multi-component solutions is not well understood. Existing models lack fundamental understanding of the process. In this paper, a new model describing how the protein solubility changes in the protein precipitation is proposed and is based on the phase equilibrium of the light liquid phase and dense solid phase. The model structure is generic and robust. It adequately reflec...

  10. Biosimilars: company strategies to capture value from the biologics market. (United States)

    Calo-Fernández, Bruno; Martínez-Hurtado, Juan Leonardo


    Patents for several biologic blockbusters will expire in the next few years. The arrival of biosimilars, the biologic equivalent of chemical generics, will have an impact on the current biopharmaceuticals market. Five core capabilities have been identified as paramount for those companies aiming to enter the biosimilars market: research and development, manufacturing, supporting activities, marketing, and lobbying. Understanding the importance of each of these capabilities will be key to maximising the value generated from the biologics patent cliff.

  11. Joint position statement by "Sociedad Española de Patología Digestiva" (Spanish Society of Gastroenterology) and "Sociedad Española de Farmacología" (Spanish Society of Pharmacology) on biosimilar therapy for inflammatory bowel disease Posición conjunta de la Sociedad Española de Patología Digestiva y de la Sociedad Española de Farmacología sobre el tratamiento con biosimilares en la enfermedad inflamatoria intestinal


    Federico Argüelles-Arias; Manuel Barreiro-de-Acosta; Fernando Carballo; Joaquín Hinojosa; Teresa Tejerina


    Biological drugs or biopharmaceutical products, manufactured with or from living organisms using biotechnology, have represented a therapeutic revolution for the control of inflammatory bowel disease (IBD). At present, in this indication and in our country, only two biologicals are approved, infliximab (IFX) and adalimumab (ADA), both of them monoclonal antibodies against tumor necrosis factor alpha. Effectiveness data are strong for both therapies, with maximum levels of scientific evidence....

  12. Predicting when Biliary Excretion of Parent Drug is a Major Route of Elimination in Humans


    Hosey, Chelsea M.; Broccatelli, Fabio; Benet, Leslie Z.


    Biliary excretion is an important route of elimination for many drugs, yet measuring the extent of biliary elimination is difficult, invasive, and variable. Biliary elimination has been quantified for few drugs with a limited number of subjects, who are often diseased patients. An accurate prediction of which drugs or new molecular entities are significantly eliminated in the bile may predict potential drug-drug interactions, pharmacokinetics, and toxicities. The Biopharmaceutics Drug Disposi...

  13. 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


    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.

  14. Disulfide Linkage Characterization of Disulfide Bond-Containing Proteins and Peptides by Reducing Electrochemistry and Mass Spectrometry

    DEFF Research Database (Denmark)

    Cramer, Christian N; Haselmann, Kim F; Olsen, Jesper V;


    Unravelling of disulfide linkage patterns is a crucial part of protein characterization, whether it is for a previously uncharacterized protein in basic research or a recombinant pharmaceutical protein. In the biopharmaceutical industry, elucidation of the cysteine connectivities is a necessity...... in protein sequencing by tandem MS (MS/MS). Electrochemical (EC) reduction of disulfide bonds has recently been demonstrated to provide efficient reduction efficiencies, significantly enhancing sequence coverages in online coupling with MS characterization. In this study, the potential use of EC disulfide...

  15. Cell death in mammalian cell culture: molecular mechanisms and cell line engineering strategies


    Krampe, Britta; Al-Rubeai, Mohamed


    Cell death is a fundamentally important problem in cell lines used by the biopharmaceutical industry. Environmental stress, which can result from nutrient depletion, by-product accumulation and chemical agents, activates through signalling cascades regulators that promote death. The best known key regulators of death process are the Bcl-2 family proteins which constitute a critical intracellular checkpoint of apoptosis cell death within a common death pathway. Engineering of several members o...

  16. A perspective overview on lipospheres as lipid carrier systems


    Dudala, Thushara Bindu; Yalavarthi, Prasanna Raju; Vadlamudi, Harini Chowdary; Thanniru, Jyotsna; Yaga, Gowri; Mudumala, Naga Lakshmi; Pasupati, Vivek Kumar


    Both hydrophilic and lipophilic therapeutics can be delivered successfully into deep and peripheral tissues such as cerebrospinal fluid and central nervous system by encapsulating them with crystalline lipids as lipospheres. The advent of lipospheres was meant to deliver both therapeutic moieties with enhanced efficacy and added stability to reach out intended tissue areas. Although extensive information is available on physicochemical, analytical and biopharmaceutical aspects of lipospheres,...

  17. Biologicals and Fetal Cell Therapy for Wound and Scar Management


    Hirt-Burri, Nathalie; Ramelet, Albert-Adrien; Raffoul, Wassim; de Buys Roessingh, Anthony; Scaletta, Corinne; Pioletti, Dominique; Applegate, Lee Ann


    Few biopharmaceutical preparations developed from biologicals are available for tissue regeneration and scar management. When developing biological treatments with cellular therapy, selection of cell types and establishment of consistent cell banks are crucial steps in whole-cell bioprocessing. Various cell types have been used in treatment of wounds to reduce scar to date including autolog and allogenic skin cells, platelets, placenta, and amniotic extracts. Experience with fetal cells show ...

  18. Biosimilars: Company Strategies to Capture Value from the Biologics Market

    Directory of Open Access Journals (Sweden)

    Juan Leonardo Martínez-Hurtado


    Full Text Available Patents for several biologic blockbusters will expire in the next few years. The arrival of biosimilars, the biologic equivalent of chemical generics, will have an impact on the current biopharmaceuticals market. Five core capabilities have been identified as paramount for those companies aiming to enter the biosimilars market: research and development, manufacturing, supporting activities, marketing, and lobbying. Understanding the importance of each of these capabilities will be key to maximising the value generated from the biologics patent cliff.

  19. Teaching biomedical technology innovation as a discipline. (United States)

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


    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.

  20. 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.

  1. Nanosuspension: An approach to enhance solubility of drugs


    Patel, Vishal R.; Y K Agrawal


    One of the major problems associated with poorly soluble drugs is very low bioavailability. The problem is even more complex for drugs like itraconazole, simvastatin, and carbamazepine which are poorly soluble in both aqueous and nonaqueous media, belonging to BCS class II as classified by biopharmaceutical classification system. Formulation as nanosuspension is an attractive and promising alternative to solve these problems. Nanosuspension consists of the pure poorly water-soluble drug witho...

  2. Discussion on Reformation of Biotechnological Pharmacy Experimental Teaching (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.

  3. Mayo v. Prometheus: A Year Later. (United States)

    Dorn, Brian R


    Last year's U.S. Supreme Court decision in Mayo v. Prometheus regarding the patent eligibility of diagnostic method claims will probably have the most profound lasting effect of any recent court decision on the biopharmaceutical industry. The Mayo decision changed the evaluation of patent eligibility of a method claim under 35 U.S.C. § 101. The new evaluation is a more difficult standard to clear and needs to be considered prior to filing a patent application.



    McWilliams, Douglas E.


    Over the past decade, the infant biotechnology industry, led by small biotechnology companies, has produced numerous breakthrough drugs which have saved lives, reduced suffering and cut the cost of health care. Given that the biopharmaceutical industry has only been in existence for a little over 20 years, biotechnology holds enormous potential for the advancement of medical treatments. Unfortunately, even with biotechnology, as with the more traditional methods of drug development, the gover...

  5. バイオ産業の課題と展望(<特集>生命科学の事業化)


    藤原, 孝男


    An introductory and short explanation is summarized here for following five papers from the U.S.A., Germany, India, China, and Japan. Main topics include the reason of attention to biopharmaceutical industry, the global trend of commercialization of life science, the characteristics of advanced countries as the U.S.A. and Europe and of emerging countries as India and China, and Japan's trend of number of biotech start-ups, business areas, and venture capital.

  6. The Politics of Access to Expensive Drugs: INESSS and the Innovative Pharmaceutical Industry


    Hughes, David


    The innovative pharmaceutical industry employs thousands of people in Quebec and so has the ability to exert strong political pressure; the public statements of Sanofi-Aventis concerning the provincial reimbursement of certain expensive drugs are an example. “Maintaining a dynamic biopharmaceutical industry” is one of four main axes of the drug policy of Quebec's ministry of health. However, this role of government should not take precedence over the efficient and equitable management of heal...

  7. Plastid transformation in lettuce (Lactuca sativa L.) by biolistic DNA delivery. (United States)

    Ruhlman, Tracey A


    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.

  8. Common resources in open innovation model as the competition driving agents


    Elzbieta Pohulak-Zoledowska


    The hereby article is addressed to the problem of innovation in new, Academia rooted industries. The traditional models of innovation seem to fail, whilst R&D activity of companies is more and more risky, and expensive. An example of pharmaceutical industry is given here. Pharmaceutical (and especially biopharmaceutical) industry widely adopts the open innovation model in order to increase innovation. Opening of the innovation process is a novelty in these industries, as the secrecy and inwar...

  9. Statistics on BCS Classification of Generic Drug Products Approved Between 2000 and 2011 in the USA


    Nair, Anil K.; Anand, Om; Chun, Nam; Conner, Dale P.; Mehta, Mehul U.; Nhu, Duong T.; Polli, James E.; Yu, Lawrence X.; Davit, Barbara M.


    The Biopharmaceutics Classification system (BCS) classifies drug substances based on aqueous solubility and intestinal permeability. The objective of this study was to use the World Health Organization Model List of Essential Medicines to determine the distribution of BCS Class 1, 2, 3, and 4 drugs in Abbreviated New drug Applications (ANDA) submissions. To categorize solubility and intestinal permeability properties of generic drugs under development, we used a list of 61 drugs which were cl...

  10. Affitins as robust tailored reagents for affinity chromatography purification of antibodies and non-immunoglobulin proteins


    Béhar, Ghislaine; Renodon-Cornière, Axelle; Mouratou, Barbara; Pecorari, Frédéric


    International audience; Affinity chromatography is a convenient way of purifying proteins, as a high degree of purity can be reached in one step. The use of tags has greatly contributed to the popularity of this technique. However, the addition of tags may not be desirable or possible for the production of biopharmaceuticals. There is thus a need for tailored artificial affinity ligands. We have developed the use of archaeal extremophilic proteins as scaffolds to generate affinity proteins (A...

  11. Incorporation of Graphene-Related Carbon Nanosheets in Membrane Fabrication for Water Treatment: A Review


    Jenny Lawler


    The minimization of the trade-off between the flux and the selectivity of membranes is a key area that researchers are continually working to optimise, particularly in the area of fabrication of novel membranes. Flux versus selectivity issues apply in many industrial applications of membranes, for example the unwanted diffusion of methanol in fuel cells, retention of valuable proteins in downstream processing of biopharmaceuticals, rejection of organic matter and micro-organisms in water trea...

  12. 生物药剂学分类系统及其应用(上)2008年《中国药师》杂志国家级继续药学教育第1单元

    Institute of Scientific and Technical Information of China (English)

    斯陆勤; 黄建耿; 李高


    @@ 生物药剂学分类系统(biopharmaceutics classification system,BCS)的概念自从1995年被提出后,人们对其有效性和适用性进行了广泛而深入的研究.经过十多年的发展,BCS现已成为世界药品管理中一个越来越重要的工具[1].

  13. Membrane-less microfiltration using inertial microfluidics


    Majid Ebrahimi Warkiani; Andy Kah Ping Tay; Guofeng Guan; Jongyoon Han


    Microfiltration is a ubiquitous and often crucial part of many industrial processes, including biopharmaceutical manufacturing. Yet, all existing filtration systems suffer from the issue of membrane clogging, which fundamentally limits the efficiency and reliability of the filtration process. Herein, we report the development of a membrane-less microfiltration system by massively parallelizing inertial microfluidics to achieve a macroscopic volume processing rates (~ 500 mL/min). We demonstra...

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


    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.


    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 absorption. However, some studies show differences in rate of absorption between brands and formulations. In particular, sodium bicarbonate, present in some drug products, was reported to give an increa...

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


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


    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 to Class III. Cimetidine's therapeutic use and therapeutic index, its pharmacokinetic properties, data related to the possibility of excipient interactions, and reported BE/bioavailability (BA) pr...

  16. Industry 4.0 : a vision for personalized medicine supply chains?


    Branke, Jürgen; Farid, Suzanne S.; Shah, Nilay


    Industry 4.0 foresees a digital transformation of manufacturing resulting in smart factories and supply chains. At the heart of the concept lies the vision of interconnected materials, goods and machines, where goods find their way through the factory and the supply chain to the customer in a self-organized manner. Industry 4.0 is gaining traction in high value manufacturing sectors. This expert insight article explores what this technology-driven vision has to offer the biopharmaceutical ind...

  17. Sparging-shear sensitivity of animal cells.


    Pol, van de, F.C.M.


    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. Animal cell are usually capable to perform these modifications in contrast to bacteria and yeast. Another advantage of animal cells is that they secrete their product into the culture medium, which is greatly ...

  18. Chemoenzymatic Fc Glycosylation via Engineered Aldehyde Tags



    Glycoproteins with chemically defined glycosylation sites and structures are important biopharmaceutical targets and critical tools for glycobiology. One approach toward constructing such molecules involves chemical glycosylation of aldehyde-tagged proteins. Here, we report the installation of a genetically encoded aldehyde tag at the internal glycosylation site of the crystallizable fragment (Fc) of IgG1. We replaced the natural Fc N-glycosylation sequon with a five amino-acid sequence that ...

  19. In vitro-In vivo Correlation: Perspectives on Model Development



    In vitro – in vivo correlation (IVIVC) allows prediction of the in vivo performance of a drug based on the in vitro drug release profiles. To develop an effective IVIVC, the physicochemical and biopharmaceutical properties of the drug as well as the physiological environment in the body must be taken into consideration. Key factors include drug solubility, pKa, drug permeability, octanol-water partition coefficient and pH of environment. In general, construction of an IVIVC involves three sta...

  20. Generalized in vitro-in vivo relationship (IVIVR) model based on artificial neural networks



    Aleksander Mendyk,1 Pawel Tuszynski,1 Sebastian Polak,2 Renata Jachowicz1 1Department of Pharmaceutical Technology and Biopharmaceutics, 2Department of Social Pharmacy, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland Background: The aim of this study was to develop a generalized in vitro-in vivo relationship (IVIVR) model based on in vitro dissolution profiles together with quantitative and qualitative composition of dosage formulations as covariates. ...

  1. Comparison of ibuprofen release from minitablets and capsules containing ibuprofen: β-Cyclodextrin complex


    Salústio, Paulo; Marques, Helena Cabral; Costa, Paulo; Pinto, João


    NOTICE: this is the author’s version of a work that was accepted for publication in European Journal of Pharmaceutics and Biopharmaceutics. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in Eur J Pharm Biopharm. 2011 May;78(1):...

  2. The role of big data and advanced analytics in drug discovery, development, and commercialization. (United States)

    Szlezák, N; Evers, M; Wang, J; Pérez, L


    In recent years, few ideas have captured the imagination of health-care practitioners as much as the advent of "big data" and the advanced analytical methods and technologies used to interpret it-it is a trend seen as having the potential to revolutionize biology, medicine, and health care.(1,2,3) As new types of data and tools become available, a unique opportunity is emerging for smarter and more effective discovery, development, and commercialization of innovative biopharmaceutical drugs.

  3. Hot-Melt Extrusion: from Theory to Application in Pharmaceutical Formulation


    Patil, Hemlata; Tiwari, Roshan V.; Repka, Michael A.


    Hot-melt extrusion (HME) is a promising technology for the production of new chemical entities in the developmental pipeline and for improving products already on the market. In drug discovery and development, industry estimates that more than 50% of active pharmaceutical ingredients currently used belong to the biopharmaceutical classification system II (BCS class II), which are characterized as poorly water-soluble compounds and result in formulations with low bioavailability. Therefore, th...

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

    CERN Document Server

    Chen, Ding-Geng


    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. Prior-Learning, Cumulative Science Experiences and the Absorptive Capacity of Bio-Entrepreneurs: A Case of the East Midlands Region, England


    Simba, A


    In the modern healthcare and medical sectors corporate bio-pharmaceutical firms continue to scale down their\\ud in-house research and development (R&D) activities in favour of outsourcing the services to bio-tech ventures.\\ud These small but, entrepreneurial research-oriented organisations have increased dramatically. They are\\ud predominantly owned by bio-entrepreneurs who are extensively experienced scientists. In the science-based\\ud industry they operate in, innovation “ecosystems” consis...

  6. Unified superresolution experiments and stochastic theory provide mechanistic insight into protein ion-exchange adsorptive separations


    Kisley, Lydia; Chen, Jixin; Mansur, Andrea P.; Shuang, Bo; Kourentzi, Katerina; Poongavanam, Mohan-Vivekanandan; Chen, Wen-Hsiang; Dhamane, Sagar; Willson, Richard C.; Landes, Christy F.


    Adsorption of proteins underlies the purification of biopharmaceuticals, as well as therapeutic apheresis, immunoassays, and biosensors. In particular, separation of proteins by interactions with charged ligands on surfaces (ion-exchange chromatography) is an essential tool of the modern pharmaceutical industry. By quantifying the interactions of single proteins with individual charged ligands, we demonstrate that clusters of charges are necessary to create functional adsorption sites and tha...

  7. Clinical trial registration, reporting, publication and FDAAA compliance: a cross-sectional analysis and ranking of new drugs approved by the FDA in 2012


    Miller, Jennifer E.; Korn, David; Ross, Joseph S


    Objective: To evaluate clinical trial registration, reporting and publication rates for new drugs by: (1) legal requirements and (2) the ethical standard that all human subjects research should be publicly accessible to contribute to generalisable knowledge. Design: Cross-sectional analysis of all clinical trials submitted to the Food and Drug Administration (FDA) for drugs approved in 2012, sponsored by large biopharmaceutical companies. Data sources Information from Drugs@FDA, ClinicalTrial...


    Directory of Open Access Journals (Sweden)

    Shah Kalpesh


    Full Text Available Biopharmaceutical drugs have outperformed the pharmaceutical market as a whole largely due to two factors: they address areas of clinical need that are unmanageable with conventional therapeutics (including cancers and they are able to command a premium price. With expiry of patent of many biopharmaceutical drugs, the potential of a sizeable market will attract several generic companies. However the process to develop essentially generic version of biopharmaceuticals (biosimilars is more complex than that of developing a generic copy of a chemical-based compound. These products are approved through an abbreviated route which relies on limited safety and efficacy data enabling the generic companies to keep the production costs low and pass on the price benefit to the patient and make the product affordable to the masses. There are no common regulatory pathways and many countries have published guidelines and it is still evolving in other countries. WHO (World Health Organization, Europe and recently USA have published guidelines for the development and marketing of biosimilar products. These products undergo extensive head to head comparability testing with the reference biopharmaceutical product to show their similarity to the reference product in terms of quality, efficacy and safety. Regulators and administrators of different countries need to strike a balance in cost-to-benefit versus risks that are perceived for these products, keeping in mind global regulatory issues. India's biotechnology industry has been growing towards new heights in conjunction with the economic evolution. The practical way forward for approval of biosimilars in India would have to be unique to the Indian context as it should balance the scientific aspects and consider needs and limitation of the country.

  9. An approach to quality and security of supply for single-use bioreactors. (United States)

    Barbaroux, Magali; Gerighausen, Susanne; Hackel, Heiko


    Single-use systems (also referred to as disposables) have become a huge part of the bioprocessing industry, which raised concern in the industry regarding quality and security of supply. Processes must be in place to assure the supply and control of outsourced activities and quality of purchased materials along the product life cycle. Quality and security of supply for single-use bioreactors (SUBs) are based on a multidisciplinary approach. Developing a state-of-the-art SUB-system based on quality by design (QbD) principles requires broad expertise and know-how including the cell culture application, polymer chemistry, regulatory requirements, and a deep understanding of the biopharmaceutical industry. Using standardized products reduces the complexity and strengthens the robustness of the supply chain. Well-established supplier relations including risk mitigation strategies are the basis for achieving long-term security of supply. Well-developed quality systems including change control approaches aligned with the requirements of the biopharmaceutical industry are a key factor in supporting long-term product availability. This chapter outlines the approach to security of supply for key materials used in single-use production processes for biopharmaceuticals from a supplier perspective.

  10. Current trends in endotoxin detection and analysis of endotoxin-protein interactions. (United States)

    Dullah, Elvina Clarie; Ongkudon, Clarence M


    Endotoxin is a type of pyrogen that can be found in Gram-negative bacteria. Endotoxin can form a stable interaction with other biomolecules thus making its removal difficult especially during the production of biopharmaceutical drugs. The prevention of endotoxins from contaminating biopharmaceutical products is paramount as endotoxin contamination, even in small quantities, can result in fever, inflammation, sepsis, tissue damage and even lead to death. Highly sensitive and accurate detection of endotoxins are keys in the development of biopharmaceutical products derived from Gram-negative bacteria. It will facilitate the study of the intermolecular interaction of an endotoxin with other biomolecules, hence the selection of appropriate endotoxin removal strategies. Currently, most researchers rely on the conventional LAL-based endotoxin detection method. However, new methods have been and are being developed to overcome the problems associated with the LAL-based method. This review paper highlights the current research trends in endotoxin detection from conventional methods to newly developed biosensors. Additionally, it also provides an overview of the use of electron microscopy, dynamic light scattering (DLS), fluorescence resonance energy transfer (FRET) and docking programs in the endotoxin-protein analysis.

  11. A molecular simulation study of the protection of insulin bioactive structure by trehalose. (United States)

    Li, Daixi; Liu, Li; Yu, Huaxing; Zhai, Zhen; Zhang, Yan; Guo, Baisong; Yang, Chunsheng; Liu, Baolin


    Biopharmaceuticals are proteins with a crucial role in the treatment of many diseases. However, these protein medicines are often thermally labile and therefore unsuitable for long-term application and storage, as they tend to lose their activity under ambient conditions. Desiccation is one approach to improving protein stability, but the drying process itself can cause irreversible damage. In the current study, insulin was chosen as an example of a thermally sensitive biopharmaceutical to investigate whether the disaccharide, trehalose, can prevent loss of structural integrity due to drying. The experiment was performed using replica exchange molecular simulation and Gromacs software with a Gromos96 (53a6) force field. The results indicate that trehalose preserves the bioactive structure of insulin during drying, consistent with the use of trehalose as a protectant for thermally sensitive biopharmaceuticals. For instance, at the water content of 1.77%, insulin without any protectants yields the highest RMSD value as 0.451 nm, then the RMSD of insulin in presence of trehalose only ca. 0.100 nm.

  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


    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. Extraction and downstream processing of plant-derived recombinant proteins. (United States)

    Buyel, J F; Twyman, R M; Fischer, R


    Plants offer the tantalizing prospect of low-cost automated manufacturing processes for biopharmaceutical proteins, but several challenges must be addressed before such goals are realized and the most significant hurdles are found during downstream processing (DSP). In contrast to the standardized microbial and mammalian cell platforms embraced by the biopharmaceutical industry, there are many different plant-based expression systems vying for attention, and those with the greatest potential to provide inexpensive biopharmaceuticals are also the ones with the most significant drawbacks in terms of DSP. This is because the most scalable plant systems are based on the expression of intracellular proteins in whole plants. The plant tissue must therefore be disrupted to extract the product, challenging the initial DSP steps with an unusually high load of both particulate and soluble contaminants. DSP platform technologies can accelerate and simplify process development, including centrifugation, filtration, flocculation, and integrated methods that combine solid-liquid separation, purification and concentration, such as aqueous two-phase separation systems. Protein tags can also facilitate these DSP steps, but they are difficult to transfer to a commercial environment and more generic, flexible and scalable strategies to separate target and host cell proteins are preferable, such as membrane technologies and heat/pH precipitation. In this context, clarified plant extracts behave similarly to the feed stream from microbes or mammalian cells and the corresponding purification methods can be applied, as long as they are adapted for plant-specific soluble contaminants such as the superabundant protein RuBisCO. Plant-derived pharmaceutical proteins cannot yet compete directly with established platforms but they are beginning to penetrate niche markets that allow the beneficial properties of plants to be exploited, such as the ability to produce 'biobetters' with tailored

  14. Multiplexed, targeted gene editing in Nicotiana benthamiana for glyco-engineering and monoclonal antibody production. (United States)

    Li, Jin; Stoddard, Thomas J; Demorest, Zachary L; Lavoie, Pierre-Olivier; Luo, Song; Clasen, Benjamin M; Cedrone, Frederic; Ray, Erin E; Coffman, Andrew P; Daulhac, Aurelie; Yabandith, Ann; Retterath, Adam J; Mathis, Luc; Voytas, Daniel F; D'Aoust, Marc-André; Zhang, Feng


    Biopharmaceutical glycoproteins produced in plants carry N-glycans with plant-specific residues core α(1,3)-fucose and β(1,2)-xylose, which can significantly impact the activity, stability and immunogenicity of biopharmaceuticals. In this study, we have employed sequence-specific transcription activator-like effector nucleases (TALENs) to knock out two α(1,3)-fucosyltransferase (FucT) and the two β(1,2)-xylosyltransferase (XylT) genes within Nicotiana benthamiana to generate plants with improved capacity to produce glycoproteins devoid of plant-specific residues. Among plants regenerated from N. benthamiana protoplasts transformed with TALENs targeting either the FucT or XylT genes, 50% (80 of 160) and 73% (94 of 129) had mutations in at least one FucT or XylT allele, respectively. Among plants regenerated from protoplasts transformed with both TALEN pairs, 17% (18 of 105) had mutations in all four gene targets, and 3% (3 of 105) plants had mutations in all eight alleles comprising both gene families; these mutations were transmitted to the next generation. Endogenous proteins expressed in the complete knockout line had N-glycans that lacked β(1,2)-xylose and had a significant reduction in core α(1,3)-fucose levels (40% of wild type). A similar phenotype was observed in the N-glycans of a recombinant rituximab antibody transiently expressed in the homozygous mutant plants. More importantly, the most desirable glycoform, one lacking both core α(1,3)-fucose and β(1,2)-xylose residues, increased in the antibody from 2% when produced in the wild-type line to 55% in the mutant line. These results demonstrate the power of TALENs for multiplexed gene editing. Furthermore, the mutant N. benthamiana lines provide a valuable platform for producing highly potent biopharmaceutical products.

  15. 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.

  16. Telomerase as an emerging target to fight cancer--opportunities and challenges for nanomedicine. (United States)

    Philippi, C; Loretz, B; Schaefer, U F; Lehr, C M


    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

  17. Biosimilar medicines and cost-effectiveness

    Directory of Open Access Journals (Sweden)

    Steven Simoens


    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

  18. Self-Assembled Hydrogel Nanoparticles for Drug Delivery Applications

    Directory of Open Access Journals (Sweden)

    Miguel Gama


    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.

  19. 对抗埃博拉背后的黑色科技

    Institute of Scientific and Technical Information of China (English)



    近日,两名在利比里亚感染埃博拉病毒的美国医务人员,接受了名为ZMapp的实验性药物的治疗,病情出现好转。研发这种药物的公司是此前一家名不经传的小型医药公司……“Mapp Biopharmaceutical Inc”生物科技公司。

  20. Human gene therapy: Methods and materials. December 1985-April 1990 (A Bibliography from the Biobusiness data base). Report for December 1985-April 1990

    Energy Technology Data Exchange (ETDEWEB)


    This bibliography contains citations concerning the rapid evolution of technologies geared toward the genetic identification and treatment of diseases. Emphasis is placed upon development and application of genetic engineering techniques for the production of biopharmaceuticals. Other topics include the use of DNA (deoxyribonucleic acid) probes for gene isolation and disease marker identification, methods for replacing missing or defective genetic material, and mapping of the human genome. Governmental regulation, and moral and ethical implications are briefly reviewed. (Contains 299 citations fully indexed and including a title list.)

  1. R9 药物学

    Institute of Scientific and Technical Information of China (English)


    R91 2005062754生物制药的现状和未来(二):发展趋势与希望=The present and the future of biopharmaceuticals(2):trends and prospects;R93 2005062755栽培花锚中抗肝炎活性成分的含量在不同生长期变化的研究=Change of anti-hepatitis active substance during different growth period in cultivated Halenia allipitica……

  2. In situ modification of chromatography adsorbents using cold atmospheric pressure plasmas (United States)

    Olszewski, P.; Willett, T. C.; Theodosiou, E.; Thomas, O. R. T.; Walsh, J. L.


    Efficient manufacturing of increasingly sophisticated biopharmaceuticals requires the development of new breeds of chromatographic materials featuring two or more layers, with each layer affording different functions. This letter reports the in situ modification of a commercial beaded anion exchange adsorbent using atmospheric pressure plasma generated within gas bubbles. The results show that exposure to He-O2 plasma in this way yields significant reductions in the surface binding of plasmid DNA to the adsorbent exterior, with minimal loss of core protein binding capacity; thus, a bi-layered chromatography material exhibiting both size excluding and anion exchange functionalities within the same bead is produced.

  3. Anti-TNF-α biotherapies

    DEFF Research Database (Denmark)

    Bendtzen, Klaus


    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 th......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....... Large-scale immunopharmacological knowledge of how patients 'handle' TNF-α biopharmaceuticals would also help industry develop more effective and safer TNF-α inhibitors....

  4. In Vitro Study of Hexahydro-1,3,5-Trinitro-1,3,5-Triazine (RDX) Metabolism in Human Liver (United States)


    Casarett & Doull ’s Toxicology: The Basic Science of Poisons (2001) by Curtis D. Klaassen 6111 Edition, Chapter 13, The McGraw-Hill Companies, lnc. e. Lev...Rhodococcus sp. Strain DN22, Applied and Environ. Micro. 69(3): 1347-51. c. Helena M. B. Seth-Smith (2002): MICROBIAL DEGRADATION OF RDX, Ph.D. thesis...Li of In Vitro ADMET Laboratories, LLC, Rockville, MD )> Dr. David Kwok of Biopharmaceutical Research Inc, Canada )> Oliver Curtis and Michael Hable of Directorate of Laboratory Sciences, US Army CHPPM 17

  5. LC-MS systems for quantitative bioanalysis. (United States)

    van Dongen, William D; Niessen, Wilfried M A


    LC-MS has become the method-of-choice in small-molecule drug bioanalysis (molecular mass Triple quadrupole MS is the established bioanalytical technique due to its unpreceded selectivity and sensitivity, but high-resolution accurate-mass MS is recently gaining ground due to its ability to provide simultaneous quantitative and qualitative analysis of drugs and their metabolites. This article discusses current trends in the field of bioanalytical LC-MS (until September 2012), and provides an overview of currently available commercial triple quadrupole MS and high-resolution LC-MS instruments as applied for the bioanalysis of small-molecule and biopharmaceutical drugs.


    Directory of Open Access Journals (Sweden)

    Gabriela Popa


    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.

  7. One year monitoring by FTIR of γ-irradiated multilayer film PE/EVOH/PE (United States)

    Gaston, Fanny; Dupuy, Nathalie; Marque, Sylvain R. A.; Barbaroux, Magali; Dorey, Samuel


    The multilayer films made of polyethylene/polyethylene-co-vinyl alcohol/polyethylene are γ-irradiated for biopharmaceutical and biotechnological applications. The radiations generate changes in the polymer films. In this study, we focused on the modifications produced on the surface of materials by Fourier transformed infrared (FTIR) spectroscopy combined with chemometric treatments. Principal component analysis (PCA) allows the ordering of the surface modifications according to absorbed doses and the natural ageing. Results show the rising of the acid band and the variation of unsaturated compounds.

  8. Liposomal chemotherapeutics. (United States)

    Gentile, Emanuela; Cilurzo, Felisa; Di Marzio, Luisa; Carafa, Maria; Ventura, Cinzia Anna; Wolfram, Joy; Paolino, Donatella; Celia, Christian


    Currently, six liposomal chemotherapeutics have received clinical approval and many more are in clinical trials or undergoing preclinical evaluation. Liposomes exhibit low toxicity and improve the biopharmaceutical features and therapeutic index of drugs, thereby increasing efficacy and reducing side effects. In this review we discuss the advantages of using liposomes for the delivery of chemotherapeutics. Gemcitabine and paclitaxel have been chosen as examples to illustrate how the performance of a metabolically unstable or poorly water-soluble drug can be greatly improved by liposomal incorporation. We look at the beneficial effects of liposomes in a variety of solid and blood-borne tumors, including thyroid cancer, pancreatic cancer, breast cancer and multiple myeloma.

  9. [Problems and prospects of gene therapeutics and DNA vaccines development and application]. (United States)

    Kibirev, Ia A; Drobkov, B I; Marakulin, I V


    The review is summarized foreign publications devoted to different aspects of DNA vaccines and gene therapeutics' biological safety. In spite of incomprehension in their action, numerous prototype DNA-based biopharmaceuticals are in advanced stages of human clinical trials. This review is focused on some safety concerns of gene formulations vaccines relate to toxic effects, vertical transmission possibility, genome integration complications, immunologic and immunopathologic effects and environmental spread. It is noted that necessity of national regulatory documents development related to gene therapy medicinal products is significant condition of their application to medical practice.

  10. Recombinant protein production in bacterial hosts. (United States)

    Overton, Tim W


    The production of recombinant proteins is crucial for both the development of new protein drugs and the structural determination of drug targets. As such, recombinant protein production has a major role in drug development. Bacterial hosts are commonly used for the production of recombinant proteins, accounting for approximately 30% of current biopharmaceuticals on the market. In this review, I introduce fundamental concepts in recombinant protein production in bacteria, from drug development to production scales. Recombinant protein production processes can often fail, but how can this failure be minimised to rapidly deliver maximum yields of high-quality protein and so accelerate drug discovery?

  11. Biotechnology: employing organism as bioreactors

    Directory of Open Access Journals (Sweden)

    Maryam Baniasad


    Full Text Available Biological products, especially proteins, have numerous applications including prevention, diagnosis, and treating diseases. Advances in biotechnology in recent years have opened up many ways to manufacture these products in large scales. To engineer biopharmaceuticals, often pro and/or eukaryotic sustainable resources are used. Selection of the cellular factory depends on the type and application of protein needed. In this review, we explore current resources used to produce biologics, examine these resources critically for their biological output, and finally highlight impact of using sustainable resources in modern medicine.

  12. Optimal design for nonlinear response models

    CERN Document Server

    Fedorov, Valerii V


    Optimal Design for Nonlinear Response Models discusses the theory and applications of model-based experimental design with a strong emphasis on biopharmaceutical studies. The book draws on the authors' many years of experience in academia and the pharmaceutical industry. While the focus is on nonlinear models, the book begins with an explanation of the key ideas, using linear models as examples. Applying the linearization in the parameter space, it then covers nonlinear models and locally optimal designs as well as minimax, optimal on average, and Bayesian designs. The authors also discuss ada

  13. Characterization of Chinese Hamster Ovary Cells Producing Coagulation Factor VIII Using Multi-omics Tools

    DEFF Research Database (Denmark)

    Kaas, Christian Schrøder

    ,000 fold over the last couple of years due to the revolution of next-generation sequencing (NGS), has dramatically accelerated CHO-omics from virtually non-existent to a vibrant growing field. The aim of this thesis was to investigate the impact of coagulation factor VIII (FVIII) production in CHO cells...... for analysis and engineering of industrially relevant CHO cells. Full implementation of such tools for generating specifically engineered CHO production cell lines may allow significant cost-reductions in production of complex biopharmaceuticals such as FVIII....

  14. 评《生物制药工业中生产规模的生物分离》

    Institute of Scientific and Technical Information of China (English)


    由山东省药学科学院院长凌沛学博士主译的专著《生物制药工业中生产规模的生物分离》是《Process Scale Bioseparations for the Biopharmaceutical Industry》(Taylor&Francis Group出版)的中文译本。该书分为20章,约63万字,由中国轻工业出版社于2011年3月出版。

  15. 评《生物制药工业中生产规模的生物分离》

    Institute of Scientific and Technical Information of China (English)


    《生物制药工业中生产规模的生物分离》是《Process Scale Bioseparations for the BiopharmaceuticalIndustry》的中文译本,凌沛学教授主译,2011年3月由中国轻工业出版社出版。本书原英文版的主编为Abhinav A.Shukla,Mark R.Etzel和Shishir Gadam,由美国Taylor&Francis出版集团旗下的CRC出版公司出版。

  16. FDA Approves Immunotherapy for a Cancer that Affects Infants and Children | Poster (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.

  17. 6th Annual European Antibody Congress 2010: November 29–December 1, 2010, Geneva, Switzerland


    Beck, Alain; Wurch, Thierry


    The 6th European Antibody Congress (EAC), organized by Terrapinn Ltd., was held in Geneva, Switzerland, which was also the location of the 4th and 5th EAC.1,2 As was the case in 2008 and 2009, the EAC was again the largest antibody congress held in Europe, drawing nearly 250 delegates in 2010. Numerous pharmaceutical and biopharmaceutical companies active in the field of therapeutic antibody development were represented, as were start-up and academic organizations and representatives from the...

  18. Monomeric CH3: A Small, Stable Antibody Domain with Therapeutic Promise | Poster (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, Ph.D., and their colleagues in the Protein Interactions Group, Cancer and Inflammation Program, Center for Cancer Research, reported their design of a novel antibody domain, monomeric CH3 (mCH3).

  19. Radiation-induced and sonochemical degradation of chitosan as a way to increase its fat-binding capacity (United States)

    Czechowska-Biskup, R.; Rokita, B.; Ulanski, P.; Rosiak, J. M.


    Three physical methods of chitosan degradation: irradiation in dry state, irradiation in aqueous solution and sonication in aqueous solution were tested and compared in the terms of yields and side effects. The influence of average molecular weight of chitosan in its fat-binding ability in vitro has been studied by using a biopharmaceutical model of digestive tract. It was found that reduction in molecular weight leads to a significant increase in the amount of fat bound by 1 g of chitosan. Thus, radiation- or sonochemical treatment may be useful in improving fat-binding properties of chitosan as an active component of dietary food additives.

  20. The Innovative Medicines Initiative moves translational immunology forward. (United States)

    Goldman, Michel; Wittelsberger, Angela; De Magistris, Maria-Teresa


    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.

  1. Galactomannan: a versatile biodegradable seed polysaccharide. (United States)

    Prajapati, Vipul D; Jani, Girish K; Moradiya, Naresh G; Randeria, Narayan P; Nagar, Bhanu J; Naikwadi, Nikhil N; Variya, Bhavesh C


    Polysaccharides have been finding, in the last decades, very interesting and useful applications in the biomedical and, specifically, in the biopharmaceutical field. Galactomannans are a group of storage polysaccharides from various plant seeds that reserve energy for germination in the endosperm. There are four major sources of seed galactomannans: locust bean (Ceratonia siliqua), guar (Cyamopsis tetragonoloba), tara (Caesalpinia spinosa Kuntze), and fenugreek (Trigonella foenum-graecum L.). Through keen references of reported literature on galactomannans, in this review, we have described occurrence of various galactomannans, its physicochemical properties, characterization, applications, and overview of some major galactomannans.

  2. Strategies for adaptation of mAb-producing CHO cells to serum-free medium


    Costa A; Rodrigues M.; Henriques Mariana; Oliveira Rosário; Azeredo Joana


    Large-scale production of biopharmaceuticals commonly requires the use of serum-free medium, for safety and cost reasons. However, serum is essential to most mammalian cells growth, and its removal implies a very time-consuming process for cell adaptation. Thus, the aim of the study was to evaluate different strategies for cell adaptation to serum-free medium. Three cell types were used to assess the impact of transfection on adaptation: one common CHO-K1 cell line and two CHO-K1 cells tr...

  3. Research in the Division of Pharmaceutical Technology. (United States)

    Junginger, H E


    Within the Center for Bio-Pharmaceutical Sciences the release characteristics of drugs form the major research object of the Division of Pharmaceutical Technology. Transdermal systems are being developed that can supply a drug during several days. Irritation of the skin may be avoided by using hydrogels. To enable long-term transdermal application also the colloidal structure of creams and ointments is investigated. As most drugs are to be taken orally, however, a research project was also started to make cheap and easy to produce controlled release tablets. The results with a microporous polypropylene polymer are promising.

  4. 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


    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.

  5. Caracterização físico-química do fármaco antichagásico benznidazol Physicochemical characterization of antichagasic benznidazole

    Directory of Open Access Journals (Sweden)

    Flávia Pires Maximiano


    Full Text Available Currently, benznidazole (BNZ is a unique therapeutic alternative available in Brazil to treat Chagas disease. Despite its traditional medical use, little is known about the chemical nature of this drug. A detailed study of the physicochemical properties of BNZ was performed using multiple assays. Thermal, diffractometric, morphological and reological drug profiles were obtained. The partition coefficient and solubility results allowed this drug to be classified as a class IV drug according to the biopharmaceutical classification system. This information will be useful for the development of more effective BNZ formulations and for establishing the quality profile of BNZ.

  6. Dissolution properties of co-amorphous drug-amino acid formulations in buffer and biorelevant media

    DEFF Research Database (Denmark)

    Heikkinen, A. T.; DeClerck, L.; Löbmann, Korbinian;


    -amorphous formulations have been tested only in buffers and their supersaturation ability remain unexplored. Consequently, dissolution studies in simulated intestinal fluids need to be conducted in order to better evaluate the potential of these systems in increasing the oral bioavailability of biopharmaceutics...... classification system class II drugs. In this study, solubility and dissolution properties of the co-amorphous simvastatin-lysine, gibenclamideserine, glibenclamide-threonine and glibenclamide-serine-threonine were studied in phosphate buffer pH 7.2 and biorelevant media (fasted and fed state simulated...

  7. Solid Dispersion as a Strategy to Enhance Solubility: A Review Article

    Directory of Open Access Journals (Sweden)

    Bhut Vibha Z


    Full Text Available Improving oral bioavailability of drugs remains most challenging aspects in formulation development due to solubility problems of poorly water soluble drugs. Most of the new chemical entities (NCEs are poorly water soluble as well as not well-absorbed after oral administration. Solid dispersion technologies are promising task for improving solubility and hence oral bioavailability of Biopharmaceutical Classification System (BCS class II drugs. Solid dispersion techniques have attracted due to improvingthe dissolution rate of highly lipophilic drugs and hence their bioavailability. This article reviews on classification, various preparation methods, advantages and disadvantages of solid dispersion.

  8. Quality Evaluation of Pharmaceutical Formulations Containing Hydrochlorothiazide

    Directory of Open Access Journals (Sweden)

    Marcelo Antonio de Oliveira


    Full Text Available Hydrochlorothiazide is a diuretic used to treat hypertension that belongs to class IV of the Biopharmaceutics Classification System. The drug was evaluated by quality control, thermal characterization tests, and pharmaceutical formulation compatibility studies. It was concluded that the generic drug, Lab 2, was not a pharmaceutical equivalent. The compounded drugs, Lab 5 and Lab 6, produced unsatisfactory but expected results, since there is no requirement for dissolution and dissolution profile testing for the commercialization of these products. In a compatibility study, lactose and mannitol were shown to be incompatible with HCTZ, which may explain the lack of equivalence of the generic pharmaceutical product, associated with other situations.

  9. 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.;


    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...

  10. Biowaiver monographs for immediate release solid oral dosage forms: ranitidine hydrochloride. (United States)

    Kortejärvi, H; Yliperttula, M; Dressman, J B; Junginger, H E; Midha, K K; Shah, V P; Barends, D M


    Literature and experimental data relevant to the decision to allow a waiver of in vivo bioequivalence testing for the approval of immediate release (IR) solid oral dosage forms containing ranitidine hydrochloride are reviewed. According to the current Biopharmaceutics Classification System (BCS), ranitidine hydrochloride should be assigned to Class III. However, based on its therapeutic and therapeutic index, pharmacokinetic properties and data related to the possibility of excipient interactions, a biowaiver can be recommended for IR solid oral dosage forms that are rapidly dissolving and contain only those excipients as reported in this study.

  11. Scorpion venoms in gastric cancer (United States)

    Zhang, Xiao-Ying; Zhang, Pei-Ying


    Venom secretions from snakes, scorpions, spiders and bees, have been widely applied in traditional medicine and current biopharmaceutical research. Possession of anticancer potential is another novel discovery for animal venoms and toxins. An increasing number of studies have shown the anticancer effects of venoms and toxins of snakes, and scorpions in vitro and in vivo, which were achieved mainly through the inhibition of cancer growth, arrest of cell cycle, induction of apoptosis and suppression of cancer metastasis. However, more evidence is needed to support this concept and the mechanisms of anticancer actions are not clearly understood. The present review is focused on the recant updates on anticancer venom research. PMID:27900054

  12. In vitro–In Vivo Correlations: Tricks and Traps



    In vitro–in vivo correlation (IVIVC) is a biopharmaceutical tool recommended to be used in development of formulation. When validated, it can speed up development of formulation, be used to fix dissolution limits and also as surrogate of in vivo study. However, as do all tools, it presents limitations and traps. The aim of the present paper is to investigate five common traps which could limit either the setting or use of IVIVC (1) using mean or individual values; (2) correction of absolute b...

  13. Extraction and purification methods in downstream processing of plant-based recombinant proteins. (United States)

    Łojewska, Ewelina; Kowalczyk, Tomasz; Olejniczak, Szymon; Sakowicz, Tomasz


    During the last two decades, the production of recombinant proteins in plant systems has been receiving increased attention. Currently, proteins are considered as the most important biopharmaceuticals. However, high costs and problems with scaling up the purification and isolation processes make the production of plant-based recombinant proteins a challenging task. This paper presents a summary of the information regarding the downstream processing in plant systems and provides a comprehensible overview of its key steps, such as extraction and purification. To highlight the recent progress, mainly new developments in the downstream technology have been chosen. Furthermore, besides most popular techniques, alternative methods have been described.

  14. Patents & the progress of personalized medicine: biomarkers research as lens. (United States)

    Herder, Matthew


    This article addresses the barriers to personalized medicine, focusing on the burgeoning field of biomarkers research. The author begins by framing intellectual property issues as more than a product of industry incentives and suggests that these issues are deeply entangled with other barriers facing personalized medicine such as regulatory framework deficiencies. The author proposes a set of future research questions to more fully define the barriers to biomarkers research and to uncover which corrective measures may be effective. The author concludes by recommending an integration of regulatory and patent reforms, with a call to action by scholars, scientists, representatives of the biopharmaceutical industry, and policy-makers.

  15. Viral leads for chemokine-modulatory drugs

    DEFF Research Database (Denmark)

    Lindow, Morten; Lüttichau, Hans Rudolf; Schwartz, Thue W


    of years of experience in manipulating this system. For example, virally encoded "biopharmaceuticals"--chemokines and chemokine binding proteins--demonstrate the effectiveness of blocking a carefully selected group of chemokine receptors and how the local immune response can be changed from one dominated...... by Th1 cells to one dominated by Th2 cells by targeting specific chemokine receptors. The crucial importance of the binding of chemokines to glycosaminoglycans to produce their effects is also highlighted by viruses that produce binding proteins to disrupt the gradient of chemokines, which guides...

  16. [Biological treatment of multiple sclerosis

    DEFF Research Database (Denmark)

    Sorensen, P.S.; Sellebjerg, F.


    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...... alemtuzumab, daclizumab and rituximab, which have all shown promising results. However, the monoclonal antibodies generally have a less favourable safety profile and are more expensive than the currently used first-line therapies, IFNb and glatiramer acetate Udgivelsesdato: 2008/6/9...

  17. 3-Amido pyrrolopyrazine JAK kinase inhibitors: development of a JAK3 vs JAK1 selective inhibitor and evaluation in cellular and in vivo models. (United States)

    Soth, Michael; Hermann, Johannes C; Yee, Calvin; Alam, Muzaffar; Barnett, Jim W; Berry, Pamela; Browner, Michelle F; Frank, Karl; Frauchiger, Sandra; Harris, Seth; He, Yang; Hekmat-Nejad, Mohammad; Hendricks, Than; Henningsen, Robert; Hilgenkamp, Ramona; Ho, Hoangdung; Hoffman, Ann; Hsu, Pei-Yuan; Hu, Dong-Qing; Itano, Andrea; Jaime-Figueroa, Saul; Jahangir, Alam; Jin, Sue; Kuglstatter, Andreas; Kutach, Alan K; Liao, Cheng; Lynch, Stephen; Menke, John; Niu, Linghao; Patel, Vaishali; Railkar, Aruna; Roy, Douglas; Shao, Ada; Shaw, David; Steiner, Sandra; Sun, Yongliang; Tan, Seng-Lai; Wang, Sandra; Vu, Minh Diem


    The Janus kinases (JAKs) are involved in multiple signaling networks relevant to inflammatory diseases, and inhibition of one or more members of this class may modulate disease activity or progression. We optimized a new inhibitor scaffold, 3-amido-5-cyclopropylpyrrolopyrazines, to a potent example with reasonable kinome selectivity, including selectivity for JAK3 versus JAK1, and good biopharmaceutical properties. Evaluation of this analogue in cellular and in vivo models confirmed functional selectivity for modulation of a JAK3/JAK1-dependent IL-2 stimulated pathway over a JAK1/JAK2/Tyk2-dependent IL-6 stimulated pathway.

  18. Optimizing clinical drug product performance

    DEFF Research Database (Denmark)

    Dickinson, Paul A.; Kesisoglou, Filippos; Flanagan, Talia


    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...

  19. Heterologous stable expression of terpenoid biosynthetic genes using the moss Physcomitrella patens

    DEFF Research Database (Denmark)

    Bach, Søren Spanner; King, Brian Christopher; Zhan, Xin


    characterization of terpenoid biosynthetic genes, engineered Physcomitrella can be a green biotechnological platform for production of terpenoids. Here, we describe two complementary and simple procedures for stable nuclear transformation of Physcomitrella with terpenoid biosynthetic genes, selection......Heterologous and stable expression of genes encoding terpenoid biosynthetic enzymes in planta is an important tool for functional characterization and is an attractive alternative to expression in microbial hosts for biotechnological production. Despite improvements to the procedure...... already been widely recognized as a viable alternative for industrial-scale production of biopharmaceuticals. For expression of terpenoid biosynthetic genes, and reconstruction of heterologous pathways, Physcomitrella has unique attributes that makes it a very promising biotechnological host...

  20. Large-scale biophysical evaluation of protein PEGylation effects

    DEFF Research Database (Denmark)

    Vernet, Erik; Popa, Gina; Pozdnyakova, Irina


    PEGylation is the most widely used method to chemically modify protein biopharmaceuticals, but surprisingly limited public data is available on the biophysical effects of protein PEGylation. Here we report the first large-scale study, with site-specific mono-PEGylation of 15 different proteins...... and characterization of 61 entities in total using a common set of analytical methods. Predictions of molecular size were typically accurate in comparison with actual size determined by size-exclusion chromatography (SEC) or dynamic light scattering (DLS). In contrast, there was no universal trend regarding the effect...

  1. International Conference on Harmonisation; addendum to International Conference on Harmonisation Guidance on S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals; availability. Notice. (United States)


    The Food and Drug Administration (FDA) is announcing the availability of a guidance entitled "S6 Addendum to Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals'' (S6 addendum). The S6 addendum was prepared under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). The S6 addendum is intended to incorporate new knowledge and experience gained since the implementation of the ICH guidance entitled "S6 Preclinical Safety Evaluation of Biotechnology-Derived Pharmaceuticals'' (ICH S6) and to clarify and provide greater detail to enable the development of safe and effective biopharmaceuticals.

  2. [Bioavailability of drugs--concepts and problems]. (United States)

    Bekemeier, H; Hirschelmann, R


    The development of the concept of bioavailability is dealt with on the basis of definitions published in the literature. In this connexion, the often extent divergency between the definition and the determination of bioavailability in practice is indicated. Furthermore, the bioavailability is differentiated from the amount of absorption. With regard to the inclusion of the levels of in vitro liberation, liberation in the body and absorption achieved, the frequently stated use of one and the same term for different contents gives rise to a disentanglement of the terms. Perspectively, the inclusion of animal experimentation in pharmacokinetic-biopharmaceutical investigations is insisted on.

  3. Engineering antibodies for cancer therapy. (United States)

    Boder, Eric T; Jiang, Wei


    The advent of modern antibody engineering has led to numerous successes in the application of these proteins for cancer therapy in the 13 years since the first Food and Drug Administration approval, which has stimulated active interest in developing more and better drugs based on these molecules. A wide range of tools for discovering and engineering antibodies has been brought to bear on this challenge in the past two decades. Here, we summarize mechanisms of monoclonal antibody therapeutic activity, challenges to effective antibody-based treatment, existing technologies for antibody engineering, and current concepts for engineering new antibody formats and antibody alternatives as next generation biopharmaceuticals for cancer treatment.

  4. A palmitoyl conjugate of insect pentapeptide Yamamarin arrests cell proliferation and respiration. (United States)

    Sato, Yosinori; Yang, Ping; An, Ying; Matsukawa, Kazushige; Ito, Kikukatsu; Imanishi, Shigeo; Matsuda, Hirokazu; Uchiyama, Yusuke; Imai, Kunio; Ito, Shigeki; Ishida, Yoji; Suzuki, Koichi


    A palmitoyl conjugate of an insect pentapeptide that occurs in diapausing insects causes a reversible cell-cycle arrest and suppresses mitochondrial respiration. This peptide compound also causes growth arrest in murine leukemic cell line expressing human gene Bcr/Abl and a farnesoyl peptide induces embryonic diapause in Bombyx mori. These results demonstrate that the insect peptide compounds can lead to the understanding of a common pathway in developmental arrest in animals and may provide a new peptidominetic analog in the development of biopharmaceuticals and pest management.

  5. Quality evaluation of pharmaceutical formulations containing hydrochlorothiazide. (United States)

    de Oliveira, Marcelo Antonio; Yoshida, Maria Irene; Silva, Daphne Carina Gonçalves Monteiro da


    Hydrochlorothiazide is a diuretic used to treat hypertension that belongs to class IV of the Biopharmaceutics Classification System. The drug was evaluated by quality control, thermal characterization tests, and pharmaceutical formulation compatibility studies. It was concluded that the generic drug, Lab 2, was not a pharmaceutical equivalent. The compounded drugs, Lab 5 and Lab 6, produced unsatisfactory but expected results, since there is no requirement for dissolution and dissolution profile testing for the commercialization of these products. In a compatibility study, lactose and mannitol were shown to be incompatible with HCTZ, which may explain the lack of equivalence of the generic pharmaceutical product, associated with other situations.

  6. Biophysical characterization of Met-G-CSF: effects of different site-specific mono-pegylations on protein stability and aggregation.

    Directory of Open Access Journals (Sweden)

    Antonino Natalello

    Full Text Available The limited stability of proteins in vitro and in vivo reduces their conversion into effective biopharmaceuticals. To overcome this problem several strategies can be exploited, as the conjugation of the protein of interest with polyethylene glycol, in most cases, improves its stability and pharmacokinetics. In this work, we report a biophysical characterization of the non-pegylated and of two different site-specific mono-pegylated forms of recombinant human methionyl-granulocyte colony stimulating factor (Met-G-CSF, a protein used in chemotherapy and bone marrow transplantation. In particular, we found that the two mono-pegylations of Met-G-CSF at the N-terminal methionine and at glutamine 135 increase the protein thermal stability, reduce the aggregation propensity, preventing also protein precipitation, as revealed by circular dichroism (CD, Fourier transform infrared (FTIR, intrinsic fluorescence spectroscopies and dynamic light scattering (DLS. Interestingly, the two pegylation strategies were found to drastically reduce the polydispersity of Met-G-CSF, when incubated under conditions favouring protein aggregation, as indicated by DLS measurements. Our in vitro results are in agreement with preclinical studies, underlining that preliminary biophysical analyses, performed in the early stages of the development of new biopharmaceutical variants, might offer a useful tool for the identification of protein variants with improved therapeutic values.

  7. Biosimilars: lights and shadows in rheumatology

    Directory of Open Access Journals (Sweden)

    Monica Todoerti


    Full Text Available In the last 10 years, the growing approval and marketing of biological agents has significantly ameliorated the outcomes of rheumatoid arthritis and spondyloarthritis patients suffering from active and refractory disease despite conventional treatments. As patent protection of many biopharmaceuticals will expire in the next years, biosimilars could be proximally introduced. Such agents could be marked only when they will be proven, through in vitro and in vivo studies, to be similar enough to the original comparator in term of quality, efficacy and safety. As biosimilars are less expensive than corresponding originators, a wider use of these drugs may substantially cut off the expenditure of biopharmaceuticals. Nevertheless, ongoing debate exists in scientific community: the intrinsic complex and large structure of biologic molecules besides the natural variability in the manufacturing processes might lead to a slightly different product respect to the original one, so that relevant implications for efficacy and safety concerns might arise, especially in the long-term period. Immunogenicity and extended indications of biosimilars represent further matter of discussion, too. Thus, before their approval and marketing, specific guidelines and steps imposed by national and/or international regulatory agencies should be followed along with the respect of scientific societies position in each specific contest.

  8. Glycosylation: impact, control and improvement during therapeutic protein production. (United States)

    Costa, Ana Rita; Rodrigues, Maria Elisa; Henriques, Mariana; Oliveira, Rosário; Azeredo, Joana


    The emergence of the biopharmaceutical industry represented a major revolution for modern medicine, through the development of recombinant therapeutic proteins that brought new hope for many patients with previously untreatable diseases. There is a ever-growing demand for these therapeutics that forces a constant technological evolution to increase product yields while simultaneously reducing costs. However, the process changes made for this purpose may also affect the quality of the product, a factor that was initially overlooked but which is now a major focus of concern. Of the many properties determining product quality, glycosylation is regarded as one of the most important, influencing, for example, the biological activity, serum half-life and immunogenicity of the protein. Consequently, monitoring and control of glycosylation is now critical in biopharmaceutical manufacturing and a requirement of regulatory agencies. A rapid evolution is being observed in this context, concerning the influence of glycosylation in the efficacy of different therapeutic proteins, the impact on glycosylation of a diversity of parameters/processes involved in therapeutic protein production, the analytical methodologies employed for glycosylation monitoring and control, as well as strategies that are being explored to use this property to improve therapeutic protein efficacy (glycoengineering). This work reviews the main findings on these subjects, providing an up-to-date source of information to support further studies.

  9. Therapeutically important proteins from in vitro plant tissue culture systems. (United States)

    Doran, Pauline M


    Plant cells cultured in liquid medium in bioreactors are now being used commercially to produce biopharmaceutical proteins. The emergence of in vitro plant cell culture as a production vehicle reflects the importance of key biosafety and biocontainment concerns affecting the competitiveness of alternative systems such as mammalian cell culture and agriculture. Food plant species are particularly attractive as hosts for in vitro protein production: the risk of transgene escape and food chain contamination is eliminated using containment facilities, while regulatory approval for oral delivery of drugs may be easier than if non-edible species were used. As in whole plants, proteolysis in cultured plant cells can lead to significant degradation of foreign proteins after synthesis; however, substantial progress has been made to counter the destructive effects of proteases in plant systems. Although protein secretion into the culture medium is advantageous for product recovery and purification, measures are often required to minimise extracellular protease activity and product losses due to irreversible surface adsorption. Disposable plastic bioreactors, which are being used increasingly in mammalian cell bioprocessing, are also being adopted for plant cell culture to allow rapid scale-up and generation of saleable product. This review examines a range of technical and regulatory issues affecting the choice of industrial production platform for foreign proteins, and assesses progress in the development of in vitro plant systems for biopharmaceutical production.

  10. Dynamic Single-Use Bioreactors Used in Modern Liter- and m(3)- Scale Biotechnological Processes: Engineering Characteristics and Scaling Up. (United States)

    Löffelholz, Christian; Kaiser, Stephan C; Kraume, Matthias; Eibl, Regine; Eibl, Dieter


    During the past 10 years, single-use bioreactors have been well accepted in modern biopharmaceutical production processes targeting high-value products. Up to now, such processes have mainly been small- or medium-scale mammalian cell culture-based seed inoculum, vaccine or antibody productions. However, recently first attempts have been made to modify existing single-use bioreactors for the cultivation of plant cells and tissue cultures, and microorganisms. This has even led to the development of new single-use bioreactor types. Moreover, due to safety issues it has become clear that single-use bioreactors are the "must have" for expanding human stem cells delivering cell therapeutics, the biopharmaceuticals of the next generation. So it comes as no surprise that numerous different dynamic single-use bioreactor types, which are suitable for a wide range of applications, already dominate the market today. Bioreactor working principles, main applications, and bioengineering data are presented in this review, based on a current overview of greater than milliliter-scale, commercially available, dynamic single-use bioreactors. The focus is on stirred versions, which are omnipresent in R&D and manufacturing, and in particular Sartorius Stedim's BIOSTAT family. Finally, we examine development trends for single-use bioreactors, after discussing proven approaches for fast scaling-up processes.

  11. Virus separation using membranes. (United States)

    Grein, Tanja A; Michalsky, Ronald; Czermak, Peter


    Industrial manufacturing of cell culture-derived viruses or virus-like particles for gene therapy or vaccine production are complex multistep processes. In addition to the bioreactor, such processes require a multitude of downstream unit operations for product separation, concentration, or purification. Similarly, before a biopharmaceutical product can enter the market, removal or inactivation of potential viral contamination has to be demonstrated. Given the complexity of biological solutions and the high standards on composition and purity of biopharmaceuticals, downstream processing is the bottleneck in many biotechnological production trains. Membrane-based filtration can be an economically attractive and efficient technology for virus separation. Viral clearance, for instance, of up to seven orders of magnitude has been reported for state of the art polymeric membranes under best conditions.This chapter summarizes the fundamentals of virus ultrafiltration, diafiltration, or purification with adsorptive membranes. In lieu of an impractical universally applicable protocol for virus filtration, application of these principles is demonstrated with two examples. The chapter provides detailed methods for production, concentration, purification, and removal of a rod-shaped baculovirus (Autographa californica M nucleopolyhedrovirus, about 40 × 300 nm in size, a potential vector for gene therapy, and an industrially important protein expression system) or a spherical parvovirus (minute virus of mice, 22-26 nm in size, a model virus for virus clearance validation studies).

  12. Automated Gravimetric Calibration to Optimize the Accuracy and Precision of TECAN Freedom EVO Liquid Handler. (United States)

    Bessemans, Laurent; Jully, Vanessa; de Raikem, Caroline; Albanese, Mathieu; Moniotte, Nicolas; Silversmet, Pascal; Lemoine, Dominique


    High-throughput screening technologies are increasingly integrated into the formulation development process of biopharmaceuticals. The performance of liquid handling systems is dependent on the ability to deliver accurate and precise volumes of specific reagents to ensure process quality. We have developed an automated gravimetric calibration procedure to adjust the accuracy and evaluate the precision of the TECAN Freedom EVO liquid handling system. Volumes from 3 to 900 µL using calibrated syringes and fixed tips were evaluated with various solutions, including aluminum hydroxide and phosphate adjuvants, β-casein, sucrose, sodium chloride, and phosphate-buffered saline. The methodology to set up liquid class pipetting parameters for each solution was to split the process in three steps: (1) screening of predefined liquid class, including different pipetting parameters; (2) adjustment of accuracy parameters based on a calibration curve; and (3) confirmation of the adjustment. The run of appropriate pipetting scripts, data acquisition, and reports until the creation of a new liquid class in EVOware was fully automated. The calibration and confirmation of the robotic system was simple, efficient, and precise and could accelerate data acquisition for a wide range of biopharmaceutical applications.

  13. Scope of claim coverage in patents of fufang Chinese herbal drugs: Substitution of ingredients

    Directory of Open Access Journals (Sweden)

    Tian Jiaher


    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.

  14. A Systematic Approach to Time-series Metabolite Profiling and RNA-seq Analysis of Chinese Hamster Ovary Cell Culture (United States)

    Hsu, Han-Hsiu; Araki, Michihiro; Mochizuki, Masao; Hori, Yoshimi; Murata, Masahiro; Kahar, Prihardi; Yoshida, Takanobu; Hasunuma, Tomohisa; Kondo, Akihiko


    Chinese hamster ovary (CHO) cells are the primary host used for biopharmaceutical protein production. The engineering of CHO cells to produce higher amounts of biopharmaceuticals has been highly dependent on empirical approaches, but recent high-throughput “omics” methods are changing the situation in a rational manner. Omics data analyses using gene expression or metabolite profiling make it possible to identify key genes and metabolites in antibody production. Systematic omics approaches using different types of time-series data are expected to further enhance understanding of cellular behaviours and molecular networks for rational design of CHO cells. This study developed a systematic method for obtaining and analysing time-dependent intracellular and extracellular metabolite profiles, RNA-seq data (enzymatic mRNA levels) and cell counts from CHO cell cultures to capture an overall view of the CHO central metabolic pathway (CMP). We then calculated correlation coefficients among all the profiles and visualised the whole CMP by heatmap analysis and metabolic pathway mapping, to classify genes and metabolites together. This approach provides an efficient platform to identify key genes and metabolites in CHO cell culture. PMID:28252038

  15. Improving the extraction and purification of immunoglobulin G by the use of ionic liquids as adjuvants in aqueous biphasic systems. (United States)

    Ferreira, Ana M; Faustino, Vânia F M; Mondal, Dibyendu; Coutinho, João A P; Freire, Mara G


    Immunoglobulins G (IgG) could become widespread biopharmaceuticals if cost-efficient processes for their extraction and purification are available. In this work, aqueous biphasic systems (ABS) composed of polyethylene glycols and a buffered salt, and with ionic liquids (ILs) as adjuvants, have been studied as alternative extraction and purification platforms of IgG from a rabbit serum source. Eleven ILs were investigated to provide insights on the chemical features which maximize the IgG partitioning. It is shown that in polymer-salt systems pure IgG preferentially partitions to the polymer-rich phase; yet, the complete extraction was never attained. Remarkably, after the addition of 5wt% of adequate ILs to polymer-salt ABS, the complete extraction of pure IgG in a single-step was accomplished. The best systems and conditions were then applied to the extraction and purification of IgG directly from rabbit serum samples. The complete extraction of IgG in a single-step was maintained while its purity in the polymer-rich phase was enhanced by ca. 37% as compared to the IL-free ABS. The antibody stability was also evaluated revealing that appropriate ILs are able to maintain the IgG stability and can be used as phase-forming components of ABS when envisaging the purification of high-cost biopharmaceuticals.

  16. Establishment and verification of scale-down model of lifetime of chromatography medium%层析介质使用寿命缩小模型的建立和确认

    Institute of Scientific and Technical Information of China (English)

    杨红艳; 隋礼丽


    Chromatography is one of the most popular techniques in modern biopharmaceutical manufacturing.To improve the safety and efficacy of the biopharmaceuticals,the usage of chromatography medium shall be inspected by regulatory authority.The lifetime of medium shall be determined by study and checked and approved by the regulatory authority.Prospective study on scale-down model has been widely accepted to lifetime of chromatography medium.This paper reviews the establishment and verification of scale-down model of life time of chromatography.%在现代生物制药工艺路线中,层析是最常用的一种技术手段.层析技术所需要的层析介质是药品监管的重点项目之一,其中层析介质的使用寿命(使用次数)必须经研究确认,并经药品监管部门审核和批准.在缩小模型上进行前瞻性研究是被广泛接受的层析介质使用寿命的研究方法.本文就层析介质使用寿命缩小模型的建立和确认作一简要综述.

  17. Affitins as robust tailored reagents for affinity chromatography purification of antibodies and non-immunoglobulin proteins. (United States)

    Béhar, Ghislaine; Renodon-Cornière, Axelle; Mouratou, Barbara; Pecorari, Frédéric


    Affinity chromatography is a convenient way of purifying proteins, as a high degree of purity can be reached in one step. The use of tags has greatly contributed to the popularity of this technique. However, the addition of tags may not be desirable or possible for the production of biopharmaceuticals. There is thus a need for tailored artificial affinity ligands. We have developed the use of archaeal extremophilic proteins as scaffolds to generate affinity proteins (Affitins). Here, we explored the potential of Affitins as ligand to design affinity columns. Affitins specific for human immunoglobulin G (hIgG), bacterial PulD protein, and chicken egg lysozyme were immobilized on an agarose matrix. The columns obtained were functional and highly selective for their cognate target, even in the presence of exogenous proteins as found in cell culture media, ascites and bacterial lysates, which result in a high degree of purity (∼95%) and recovery (∼100%) in a single step. Anti-hIgG Affitin columns withstand repetitive cycles of purification and cleaning-in-place treatments with 0.25 M NaOH as well as Protein A does. High levels of Affitin productions in Escherichia coli makes it possible to produce these affinity columns at low cost. Our results validate Affitins as a new class of tailored ligands for the affinity chromatography purification of potentially any proteins of interest including biopharmaceuticals.

  18. 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.;


    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...... soluble drugs and critically assess those experimental modifications and solutions employed thus far in terms of their capacity to generate results with improved accuracy and precision. (C) 2011 Elsevier B.V. All rights reserved.......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...... a more bio-relevant model system which offers good compatibility with poorly soluble compounds. Moreover, in many instances poorly soluble drugs necessitate the inclusion of excipients to facilitate efficient delivery and to enhance their bioavailability. Thus, there exists an increasing demand...

  19. Advanced technologies for improved expression of recombinant proteins in bacteria: perspectives and applications. (United States)

    Gupta, Sanjeev K; Shukla, Pratyoosh


    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.

  20. Deciphering the Biophysical Effects of Oxidizing Sulfur-Containing Amino Acids in Interferon-beta-1a using MS and HDX-MS (United States)

    Houde, Damian J.; Bou-Assaf, George M.; Berkowitz, Steven A.


    Introduction of a chemical change to one or more amino acids in a protein's polypeptide chain can result in various effects on its higher-order structure (HOS) and biophysical behavior (or properties). These effects range from no detectable change to significant structural or conformational alteration that can greatly affect the protein's biophysical properties and its resulting biological function. The ability to reliably detect the absence or presence of such changes is essential to understanding the structure-function relationship in a protein and in the successful commercial development of protein-based drugs (biopharmaceuticals). In this paper, we focus our attention on the latter by specifically elucidating the impact of oxidation on the HOS, structural dynamics, and biophysical properties of interferon beta-1a (IFNβ-1a). Oxidation is a common biochemical modification that occurs in many biopharmaceuticals, specifically in two naturally-occurring sulfur-containing amino acids, methionine and cysteine. To carry out this work, we used combinations of hydrogen peroxide and pH to differentially oxidize IFNβ-1a (to focus on only methionine oxidation versus methionine and cysteine oxidation). We then employed several analytical and biophysical techniques to acquire information about the differential impact of these two oxidation scenarios on IFNβ-1a. In particular, the use of MS-based techniques, especially HDX-MS, play a dominant role in revealing the differential effects.

  1. Strategies for the plant-based expression of dengue subunit vaccines. (United States)

    Yap, Yun-Kiam; Smith, Duncan R


    Despite significant efforts in many countries, there is still no commercially viable dengue vaccine. Currently, attention is focused on the development of either live attenuated vaccines or live attenuated chimaeric vaccines using a variety of backbones. Alternate vaccine approaches, such as whole inactivated virus and subunit vaccines are in the early stages of development, and are each associated with different problems. Subunit vaccines offer the advantage of providing a uniform antigen of well-defined nature, without the added risk of introducing any genetic material into the person being inoculated. Preliminary trials of subunit vaccines (using dengue E protein) in rhesus monkeys have shown promising results. However, the primary disadvantages of dengue subunit vaccines are the low levels of expression of dengue proteins in mammalian or insect cells, as well as the added unknown risks of antigens produced from mammalian cells containing other potential sources of contamination. In the past two decades, plants have emerged as an alternative platform for expression of biopharmaceutical products, including antigens of bacterial, fungal or viral origin. In the present minireview, we highlight the current plant expression technologies used for expression of biopharmaceutical products, with an emphasis on plants as a production system for dengue subunit vaccines.

  2. Computer-aided process analysis and economic evaluation for biosynthetic human insulin production-A case study. (United States)

    Petrides, D; Sapidou, E; Calandranis, J


    Human insulin was the first mammalian protein produced in bacteria using recombinant DNA technology. Two technologies were developed; the first based on the separate expression of precursors of chains A and B of insulin, and the second based on the expression of a precursor of proinsulin as a Trp-E fusion protein. Both technologies utilized Escherichia coli as an expression system. Later, a third technology was developed based on a strain of yeast that can secrete a precursor of insulin. The second E. coli process, a variation of which has been commercialized by Eli Lilly and Co., is analyzed in this article from a process design and economic evaluation viewpoint. The objective of this work is to elucidate the technical complexity and high cost associated with the manufacturing of biopharmaceuticals. Human insulin is a good example of a protein-based biopharmaceutical produced in large quantities (a fex tons per year) that requires large scale equipment and presents a multitude of scale-up challenges. Based onthe analysis, a number of conclusions are drawn regarding the cost breakdown and cost dependency on process parameters. Recommendations are made for cost reduction and environmental impact minimization. This analysis was performed using a software tool for computer-aided bioprocess design. (c) 1995 John Wiley & Sons, Inc.

  3. In vitro-in vivo Pharmacokinetic correlation model for quality assurance of antiretroviral drugs

    Directory of Open Access Journals (Sweden)

    Ricardo Rojas Gómez


    Full Text Available Introduction: The in vitro-in vivo pharmacokinetic correlation models (IVIVC are a fundamental part of the drug discovery and development process. The ability to accurately predict the in vivo pharmacokinetic profile of a drug based on in vitro observations can have several applications during a successful development process. Objective: To develop a comprehensive model to predict the in vivo absorption of antiretroviral drugs based on permeability studies, in vitro and in vivo solubility and demonstrate its correlation with the pharmacokinetic profile in humans. Methods: Analytical tools to test the biopharmaceutical properties of stavudine, lamivudine y zidovudine were developed. The kinetics of dissolution, permeability in caco-2 cells and pharmacokinetics of absorption in rabbits and healthy volunteers were evaluated. Results: The cumulative areas under the curve (AUC obtained in the permeability study with Caco-2 cells, the dissolution study and the pharmacokinetics in rabbits correlated with the cumulative AUC values in humans. These results demonstrated a direct relation between in vitro data and absorption, both in humans and in the in vivo model. Conclusions: The analytical methods and procedures applied to the development of an IVIVC model showed a strong correlation among themselves. These IVIVC models are proposed as alternative and cost/effective methods to evaluate the biopharmaceutical properties that determine the bioavailability of a drug and their application includes the development process, quality assurance, bioequivalence studies and pharmacosurveillance. 

  4. Biosimilars: potential implications for clinicians

    Directory of Open Access Journals (Sweden)

    Eleryan MG


    Full Text Available Misty G Eleryan,1 Sophia Akhiyat,2 Monica Rengifo-Pardo,1 Alison Ehrlich,1,2 1Department of Dermatology, The George Washington Medical Faculty Associates, 2George Washington University School of Medicine & Health Sciences, Washington, DC, USA Abstract: With the expiration of patent protection for several biologics looming, the production of highly similar therapeutic agents has begun to emerge on the pharmaceutical market. These alternative drugs are referred to as biosimilars. Many anticipate that the introduction of these agents will result in a reduction in health care costs, which may create a more affordable biopharmaceutical market and also improve patient access. In contrast to generics, which are exact copies of their original products, biosimilars are not identical to their reference products. Due to concern about the safety and efficacy of biosimilars, separate regulatory approval pathways have been developed and implemented by several countries, including the US and Europe. Europe has led the way in acceptance of biosimilars into mainstream clinical practice. Biosimilars are not generic products and require extensive clinical and nonclinical bioequivalence studies before receiving marketing approval. Not only is there a lengthy developmental process, but also they will likely be required to have postmarketing surveillance and ongoing safety monitoring to keep track of issues that may arise, such as immunogenicity. Although US Food and Drug Administration approved the first biosimilar product in March 2015, physicians remain unfamiliar about their indications. Keywords: biologics, biopharmaceuticals, biomimics, biocopies, interchangeability, immunogenicity 

  5. Production and analysis of a biosimilar erythropoietin in Egypt

    Directory of Open Access Journals (Sweden)

    Ebied WM


    Full Text Available Wael M Ebied,1 Hytham M Ahmed,2 Fawzy A Elbarbry31SEDICO Pharmaceuticals, Merck & Co External Partner, 6th of October City, Cairo, 2Pharmaceutical Analysis Department, Faculty of Pharmacy, Damanhour University, Damanhour, Egypt; 3Pharmaceutical Sciences, School of Pharmacy, Pacific University Oregon, Hillsboro, OR, USAAbstract: Although management of chronic diseases has been a major challenge for health care systems in developed and developing countries, biopharmaceuticals have been successful in treating many life-threatening conditions. However, the high cost of these agents restricts their availability to countries where patients and/or health care systems are able to afford them. Licensing these biopharmaceuticals as biosimilars after expiration of their patents might increase access to such medicines at an affordable price in developing countries. South Egypt Drug Industries Company (SEDICO is an Egyptian pharmaceutical company that has had the opportunity to manufacture some of these drugs. SEDICO biotechnology products, such as insulin, erythropoietin, streptokinase, angiokinase, follicle-stimulating hormone, aprotinin, filgrastim, and somatropin, have been available on the Egyptian market for more than 6 years. For this paper, erythropoietin, which has been investigated over a number of years, was chosen as a representative example of SEDICO biotechnology products. Our findings confirm that SEDICO erythropoietin can compete with the originator epoetins on the Egyptian market with high quality and at a lower cost.Keywords: biosimilars, developing countries, insulin, human growth hormone, erythropoietin, epoetin, Egypt

  6. Personalized medicine: theranostics (therapeutics diagnostics) essential for rational use of tumor necrosis factor-alpha antagonists. (United States)

    Bendtzen, Klaus


    With the discovery of the central pathogenic role of tumor necrosis factor (TNF)-alpha in many immunoinflammatory diseases, specific inhibition of this pleiotropic cytokine has revolutionized the treatment of patients with several non-infectious inflammatory disorders. As a result, genetically engineered anti-TNF-alpha antibody constructs now constitute one of the heaviest medicinal expenditures in many countries. All currently used TNF antagonists may dramatically lower disease activity and, in some patients, induce remission. Unfortunately, however, not all patients respond favorably, and safety can be severely impaired by immunogenicity, i.e., the ability of a drug to induce anti-drug antibodies (ADA). Assessment of ADA is therefore an important component of the evaluation of drug safety in both pre-clinical and clinical studies and in the process of developing less immunogenic and safer biopharmaceuticals. Therapeutics diagnostics, also called theranostics, i.e., monitoring functional drug levels and neutralizing ADA in the circulation, is central to more effective use of biopharmaceuticals. Hence, testing-based strategies rather than empirical dose-escalation may provide more cost-effective use of TNF antagonists as this allows therapies tailored according to individual requirements rather than the current universal approach to diagnosis. The objective of the present review is to discuss the reasons for recommending theranostics to implement an individualized use of TNF antagonists and to highlight some of the methodological obstacles that have obscured cost-effective ways of using these therapies.

  7. 多成分药物肠吸收代谢数学算法的设计与分析%Design and analyze mathematical algorithms of intestinal absorption and metabolism of multicomponent drug

    Institute of Scientific and Technical Information of China (English)

    董玲; 项佳媚; 王耘; 邬瑞光; 唐明敏; 孙墨涵


    生物药剂学分类系统(biopharmaceutics classification system,BCS)中的渗透性评价主要指向肠吸收问题,相对于单一成分药物,在中药生物药剂学分类系统(biopharmaceutics classification system of Chinese materia medica,CMMBCS)构建中,多成分环境下的某单一成分吸收代谢受到多成分体系的影响而更为复杂,亟需适当的数学模型进行描述.作者团队在借鉴已有单成分肠吸收代谢数学算法的基础上,设计了多成分药物肠吸收代谢数学算法,提出参数P影响(多成分环境下某一单成分的吸收代谢相对于其单成分环境下的吸收代谢相对变化率)来反映多成分体系对其中某一单成分的吸收代谢影响,突出了多成分环境下药物肠吸收代谢的特点,为中药生物药剂学分类系统的构建奠定基础.

  8. High-throughput miniaturized bioreactors for cell culture process development: reproducibility, scalability, and control. (United States)

    Rameez, Shahid; Mostafa, Sigma S; Miller, Christopher; Shukla, Abhinav A


    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.

  9. Comparative in vitro dissolution of two commercially available Er-Zhi-Wan herbal medicinal products

    Directory of Open Access Journals (Sweden)

    M Wang


    Full Text Available In vitro dissolution test is an essential tool to assess the quality of herbal medicinal products in the solid dosage forms for oral use. Our work aimed to evaluate the dissolution behavior of Er-Zhi-Wan, in the formulations of water-honeyed pill and formula granule. Different media (water, 30% EtOH, 0.1 M HCl, acetate buffer, pH 4.5 and phosphate buffer, pH 6.8 were used following United States Pharmacopoeia and Chinese Pharmacopeia. An ultra-high performance liquid chromatography method was developed and validated to detect simultaneously six active ingredients for quantification and dissolution study (salidroside, specnuezhenide, nuezhenoside, luteolin, apigenin, oleanolic acid. As we observed, contents of main active ingredients were close in the two formulations for daily dose. In each medium, more ingredients dissolved from formula granule with higher Ymax and Ka. The mean dissolution time of the most ingredients in granule was significantly shorter than that in pill in acetate buffer, pH 4.5 and phosphate buffer, pH 6.8. Furthermore, salidroside, specnuezhenide and luteolin dissolved more than 80% in 30 min from formula granule, which indicated higher solubility along the intestinal tract according to biopharmaceutics classification system. The dissolution test developed and validated was adequate for its purposes and could be applied for quality control of herbal medicine. This work also can be used to provide necessary information on absorption for its biopharmaceutical properties.

  10. Biowaiver Monographs for Immediate Release Solid Oral Dosage Forms: Ribavirin. (United States)

    Goodarzi, Navid; Barazesh Morgani, Ahmadreza; Abrahamsson, Bertil; Cristofoletti, Rodrigo; Groot, D W; Langguth, Peter; Mehta, Mehul U; Polli, James E; Shah, Vinod P; Dressman, Jennifer B


    Literature data relevant to the decision to allow a waiver of in vivo bioequivalence (BE) testing for the approval of immediate release solid oral dosage forms containing ribavirin are reviewed. Ribavirin is highly soluble, but its permeability characteristics are not well defined. Therefore according to the Biopharmaceutical Classification System, and taking a "worst case" approach, ribavirin should be assigned to class III. As ribavirin is transported across the brush border membrane of the human jejunum by hCNT2, it shows saturable uptake in the intestine. However, no common excipients have been shown to compete for ribavirin absorption, nor have problems with BE of immediate release ribavirin formulations containing different excipients and produced by different manufacturing methods been reported in the open literature. So the risk of bioinequivalence caused by these factors appears to be low. Ribavirin is considered a narrow therapeutic index drug, as judged by comparing the minimum effective concentration and minimum toxic concentrations in blood. Although ribavirin would not be eligible for approval via a Biopharmaceutical Classification System-based biowaiver procedure according to today's guidances due to its narrow therapeutic index, the risks of biowaiving should be weighed against the considerable risks associated with studying BE of ribavirin products in healthy subjects.

  11. The evolution of down-scale virus filtration equipment for virus clearance studies. (United States)

    Wieser, Andreas; Berting, Andreas; Medek, Christian; Poelsler, Gerhard; Kreil, Thomas R


    The role of virus filtration in assuring the safety of biopharmaceutical products has gained importance in recent years. This is due to the fundamental advantages of virus filtration, which conceptually can remove all pathogens as long as their size is larger than the biomolecule of commercial interest, while at the same time being neutral to the biological activity of biopharmaceutical compound(s). Major progress has been made in the development of adequate filtration membranes that can remove even smaller viruses, or possibly even all. Establishing down-scaled models for virus clearance studies that are fully equivalent with respect to operating parameters at manufacturing scale is a continuing challenge. This is especially true for virus filtration procedures where virus clearance studies at small-scale determine the operating parameters, which can be used at manufacturing scale. This has limited volume-to-filter-area-ratios, with significant impact on process economics. An advanced small-scale model of virus filtration, which allows the investigation of the full complexity of these processes, is described here. It includes the automated monitoring and control of all process parameters, as well as an electronic data acquisition system, which is fully compliant with current regulatory requirements for electronic records in a pharmaceutical environment.

  12. Pharmacokinetic aspects and in vitro–in vivo correlation potential for lipid-based formulations

    Directory of Open Access Journals (Sweden)

    Sivacharan Kollipara


    Full Text Available Lipid-based formulations have been an attractive choice among novel drug delivery systems for enhancing the solubility and bioavailability of poorly soluble drugs due to their ability to keep the drug in solubilized state in the gastrointestinal tract. These formulations offer multiple advantages such as reduction in food effect and inter-individual variability, ease of preparation, and the possibility of manufacturing using common excipients available in the market. Despite these advantages, very few products are available in the present market, perhaps due to limited knowledge in the in vitro tests (for prediction of in vivo fate and lack of understanding of the mechanisms behind pharmacokinetic and biopharmaceutical aspects of lipid formulations after oral administration. The current review aims to provide a detailed understanding of the in vivo processing steps involved after oral administration of lipid formulations, their pharmacokinetic aspects and in vitro in vivo correlation (IVIVC perspectives. Various pharmacokinetic and biopharmaceutical aspects such as formulation dispersion and lipid digestion, bioavailability enhancement mechanisms, impact of excipients on efflux transporters, and lymphatic transport are discussed with examples. In addition, various IVIVC approaches towards predicting in vivo data from in vitro dispersion/precipitation, in vitro lipolysis and ex vivo permeation studies are also discussed in detail with help of case studies.

  13. Biosimilars in rheumatology: current perspectives and lessons learnt. (United States)

    Dörner, Thomas; Kay, Jonathan


    Biosimilars, based on biopharmaceuticals approved by regulatory agencies that are no longer under patent protection, have efficacy and safety comparable to their reference products, and are a new therapeutic option to treat inflammatory diseases. Biosimilars must be distinguished from 'biomimics' or 'biocopies', which are marketed in some countries but have not been evaluated according to the stringent regulatory pathway used for biosimilars. CT-P13, based on infliximab, was the first biosimilar approved for the treatment of inflammatory diseases; however, some countries did not allow extrapolation of indications to all eight diseases for which the reference drug infliximab is approved. Antidrug antibodies can reduce drug levels and affect clinical efficacy, but although available data suggest that biosimilars and their reference products have comparable immunogenicity, this important property might differ between individual biopharmaceuticals. This Review discusses biosimilars already approved within the past 3 years to treat rheumatic diseases, as well as others that are currently under development. The main challenges posed by biosimilars are also addressed, such as the extrapolation of indications to diseases only studied for the reference drug, and the definition of strategies for adequate pharmacovigilance to monitor biosimilars after marketing approval.

  14. Self-emulsifying excipient platform for improving technological properties of alginate-hydroxypropylcellulose pellets. (United States)

    Mannina, Paolo; Segale, Lorena; Giovannelli, Lorella; Bonda, Andrea Foglio; Pattarino, Franco


    In this work, alginate, alginate-pectin and alginate-hydroxypropylcellulose pellets were produced by ionotropic gelation and characterized. Ibuprofen was selected as model drug; it was suspended in the polymeric solution in crystalline form or dissolved in a self-emulsifying phase and then dispersed into the polymeric solution. The self-emulsifying excipient platform composed of Labrasol (PEG-8 caprylic/capric glycerides) and d-α-tocopherol polyethylene glycol 1000 succinate (TPGS), able to solubilize the drug was used to improve the technological and biopharmaceutical properties of the alginate pellets. The pellets had diameters between 1317 and 2026 μm and a high drug content (>51%). DSC analysis showed the amorphous state of drug in the pellets containing the self-emulsifying phase. All the systems restricted drug release in conditions simulating the gastric environment and made the drug completely available at a pH value typical for the intestine. Only alginate-HPC systems containing the drug solubilized into the self-emulsifying phase showed the ability to partially control the release of ibuprofen at neutral pH. The self-emulsifying excipient platform is a useful tool to improve technological and biopharmaceutical properties of alginate-HPC pellets.

  15. Retrospective Evaluation of Low-pH Viral Inactivation and Viral Filtration Data from a Multiple Company Collaboration. (United States)

    Mattila, John; Clark, Mike; Liu, Shengjiang; Pieracci, John; Gervais, Thomas R; Wilson, Eileen; Galperina, Olga; Li, Xinfang; Roush, David; Zoeller, Konstantin; Brough, Helene; Simpson-Platre, Christelle


    Considerable resources are spent within the biopharmaceutical industry to perform viral clearance studies, which are conducted for widely used unit operations that are known to have robust and effective retrovirus clearance capability. The collaborative analysis from the members of the BioPhorum Development Group Viral Clearance Working Team considers two common virus reduction steps in biopharmaceutical processes: low-pH viral inactivation and viral filtration. Analysis included eight parameters for viral inactivation and nine for viral filtration. The extensive data set presented in this paper provides the industry with a reference point for establishing robust processes in addition to other protocols available in the literature (e.g., ASTM Std. E2888-12 for low-pH inactivation). In addition, it identifies points of weakness in the existing data set and instructs the design and interpretation of future studies. Included is an abundance of data that would have been difficult to generate individually but collectively will help support modular viral clearance claims.

  16. Pharmacokinetic aspects and in vitro-in vivo correlation potential for lipid-based formulations. (United States)

    Kollipara, Sivacharan; Gandhi, Rajesh Kumar


    Lipid-based formulations have been an attractive choice among novel drug delivery systems for enhancing the solubility and bioavailability of poorly soluble drugs due to their ability to keep the drug in solubilized state in the gastrointestinal tract. These formulations offer multiple advantages such as reduction in food effect and inter-individual variability, ease of preparation, and the possibility of manufacturing using common excipients available in the market. Despite these advantages, very few products are available in the present market, perhaps due to limited knowledge in the in vitro tests (for prediction of in vivo fate) and lack of understanding of the mechanisms behind pharmacokinetic and biopharmaceutical aspects of lipid formulations after oral administration. The current review aims to provide a detailed understanding of the in vivo processing steps involved after oral administration of lipid formulations, their pharmacokinetic aspects and in vitro in vivo correlation (IVIVC) perspectives. Various pharmacokinetic and biopharmaceutical aspects such as formulation dispersion and lipid digestion, bioavailability enhancement mechanisms, impact of excipients on efflux transporters, and lymphatic transport are discussed with examples. In addition, various IVIVC approaches towards predicting in vivo data from in vitro dispersion/precipitation, in vitro lipolysis and ex vivo permeation studies are also discussed in detail with help of case studies.

  17. [Preclinical in vitro and in vivo models for the assessment of biological activity in biosimilarity studies]. (United States)

    Escobedo-Moratilla, Abraham; Barba de la Rosa, Ana Paulina; Pérez-Urizar, José Trinidad


    A drug that contains a recombinant protein as an active principle is called a biotechnological drug or biopharmaceutical.There are currently over 300 biopharmaceuticals worldwide. Many of these contains a similar active principle (biosimilar drug) as other previously registered (innovator drug). It has suggested that due to the complex implications in a formulation containing a protein, the manufacturing process is a key factor for efficacy and safety requirements. In fact, certain variability has been detected of the protein properties in different lots (or batches) of the same manufacturer, which produce changes at a clinical level. For this reason, the evaluation of biosimilar drugs has acquired great relevance, being the preclinical level of one of the more important stages of the development due to its lower cost (with respect to the clinical level) and its high capacity to detect formulation-manufacture problems. However, the demonstration of comparability at physicochemical, preclinical, and clinical levels is required in order to achieve market registration. In this review the in vitro and in vivo models used for the assessment of proposed biosimilars will be discussed.

  18. Moss-made pharmaceuticals: from bench to bedside. (United States)

    Reski, Ralf; Parsons, Juliana; Decker, Eva L


    Over the past two decades, the moss Physcomitrella patens has been developed from scratch to a model species in basic research and in biotechnology. A fully sequenced genome, outstanding possibilities for precise genome-engineering via homologous recombination (knockout moss), a certified GMP production in moss bioreactors, successful upscaling to 500 L wave reactors, excellent homogeneity of protein glycosylation, remarkable batch-to-batch stability and a safe cryopreservation for master cell banking are some of the key features of the moss system. Several human proteins are being produced in this system as potential biopharmaceuticals. Among the products are tumour-directed monoclonal antibodies with enhanced antibody-dependent cytotoxicity (ADCC), vascular endothelial growth factor (VEGF), complement factor H (FH), keratinocyte growth factor (FGF7/KGF), epidermal growth factor (EGF), hepatocyte growth factor (HGF), asialo-erythropoietin (asialo-EPO, AEPO), alpha-galactosidase (aGal) and beta-glucocerebrosidase (GBA). Further, an Env-derived multi-epitope HIV protein as a candidate vaccine was produced, and first steps for a metabolic engineering of P. patens have been made. Some of the recombinant biopharmaceuticals from moss bioreactors are not only similar to those produced in mammalian systems such as CHO cells, but are of superior quality (biobetters). The first moss-made pharmaceutical, aGal to treat Morbus Fabry, is in clinical trials.

  19. Animal-derived pharmaceutical proteins. (United States)

    Redwan, el-Rashdy M


    Livestock animals have made a significant contribution to human health and well-being throughout humankind's history. A significant contribution of farm animals to human health are the longstanding use of bovine and porcine for production of insulin (for treatment of diabetes), gelatin (for pharmaceutical and other purposes), as well as horse and sheep antibody against natural venoms, toxins, drugs and microbial peptides. Gelatin being the biggest animal protein consumed in human health, follows with antibodies fragments. The chronic problem of animal-derived therapeutics, especially those of high molecular weight, is the immunogenicity induction in addition to their biosafety. However, the invertebrates and lower vertebrates donate the human being a several crucial emergency saving life small-peptides or their analogs such as Refludan, Prialt, Exendin. Not only, but the farm animals are enormously using as models for novel surgical strategies, testing of biodegradable implants and sources of tissue replacements, such as skin and heart valves. Recently, they are being harnessing as bioreactor for production of biopharmaceutical related products through gene farming with efficiency far greater than any conventional microbial or cell-culture production systems. Only 16 transgenic cows would be covering the worldwide needs from human growth hormone. The transgenic, especially animal, technology would be solving a several biopharmaceutical products disadvantages, such as cost, biosafety, immunogenicity and the availability dimensions.

  20. Efficient and reproducible generation of high-expressing, stable human cell lines without need for antibiotic selection

    Directory of Open Access Journals (Sweden)

    Kewes Helmut


    Full Text Available Abstract Background Human cell lines are the most innovative choice of host cell for production of biopharmaceuticals since they allow for authentic posttranslational modification of therapeutic proteins. We present a new method for generating high and stable protein expressing cell lines based on human amniocytes without the requirement of antibiotic selection. Results Primary amniocytes from routine amniocentesis samples can be efficiently transformed with adenoviral functions resulting in stable human cell lines. Cotransfection of the primary human amniocytes with a plasmid expressing adenoviral E1 functions plus a second plasmid containing a gene of interest resulted in permanent cell lines expressing up to 30 pg/cell/day of a fully glycosylated and sialylated protein. Expression of the gene of interest is very stable for more than 90 passages and, importantly, was achieved in the absence of any antibiotic selection. Conclusion We describe an improved method for developing high protein expressing stable human cell lines. These cell lines are of non-tumor origin, they are immortalized by a function not oncogenic in human and they are from an ethically accepted and easily accessible cell source. Since the cell can be easily adapted to growth in serum-free and chemically defined medium they fulfill the requirements of biopharmaceutical production processes.

  1. Regulatory guidelines for biosimilars in Malaysia. (United States)

    Abas, Arpah


    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.

  2. 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 (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

  3. Human granulocyte colony stimulating factor (hG-CSF: cloning, overexpression, purification and characterization

    Directory of Open Access Journals (Sweden)

    Vanz Ana LS


    Full Text Available Abstract Background Biopharmaceutical drugs are mainly recombinant proteins produced by biotechnological tools. The patents of many biopharmaceuticals have expired, and biosimilars are thus currently being developed. Human granulocyte colony stimulating factor (hG-CSF is a hematopoietic cytokine that acts on cells of the neutrophil lineage causing proliferation and differentiation of committed precursor cells and activation of mature neutrophils. Recombinant hG-CSF has been produced in genetically engineered Escherichia coli (Filgrastim and successfully used to treat cancer patients suffering from chemotherapy-induced neutropenia. Filgrastim is a 175 amino acid protein, containing an extra N-terminal methionine, which is needed for expression in E. coli. Here we describe a simple and low-cost process that is amenable to scaling-up for the production and purification of homogeneous and active recombinant hG-CSF expressed in E. coli cells. Results Here we describe cloning of the human granulocyte colony-stimulating factor coding DNA sequence, protein expression in E. coli BL21(DE3 host cells in the absence of isopropyl-β-D-thiogalactopyranoside (IPTG induction, efficient isolation and solubilization of inclusion bodies by a multi-step washing procedure, and a purification protocol using a single cationic exchange column. Characterization of homogeneous rhG-CSF by size exclusion and reverse phase chromatography showed similar yields to the standard. The immunoassay and N-terminal sequencing confirmed the identity of rhG-CSF. The biological activity assay, in vivo, showed an equivalent biological effect (109.4% to the standard reference rhG-CSF. The homogeneous rhG-CSF protein yield was 3.2 mg of bioactive protein per liter of cell culture. Conclusion The recombinant protein expression in the absence of IPTG induction is advantageous since cost is reduced, and the protein purification protocol using a single chromatographic step should reduce cost

  4. Clinical data management: Current status, challenges, and future directions from industry perspectives

    Directory of Open Access Journals (Sweden)

    Zhengwu Lu


    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

  5. Polymeric microdevices for transdermal and subcutaneous drug delivery. (United States)

    Ochoa, Manuel; Mousoulis, Charilaos; Ziaie, Babak


    Low cost manufacturing of polymeric microdevices for transdermal and subcutaneous drug delivery is slated to have a major impact on next generation devices for administration of biopharmaceuticals and other emerging new formulations. These devices range in complexity from simple microneedle arrays to more complicated systems incorporating micropumps, micro-reservoirs, on-board sensors, and electronic intelligence. In this paper, we review devices currently in the market and those in the earlier stages of research and development. We also present two examples of the research in our laboratory towards using phase change liquids in polymeric structures to create disposable micropumps and the development of an elastomeric reservoir for MEMS-based transdermal drug delivery systems.

  6. Immunocytokines

    Directory of Open Access Journals (Sweden)

    Katrin L. Gutbrodt


    Full Text Available A number of cytokines have shown beneficial effects in preclinical animal models of cancer and chronic inflammatory diseases. However, cytokine treatment is often associated with severe side effects, which prevent the administration of clinically relevant doses in humans. Immunocytokines are a novel class of biopharmaceuticals, consisting of a cytokine moiety fused to monoclonal antibodies or to an antibody fragment, which selectively accumulate at the disease site and thereby enhance the therapeutic effects of cytokines. This review surveys the recent preclinical and clinical advances in the field, with a special focus on the impact of antibody formats, target antigen and cytokine moieties on the therapeutic performance in vivo. We also discuss emerging data about the possibility to combine immunocytokines with other pharmacological agents.

  7. Uncertainty in measurement of protein circular dichroism spectra (United States)

    Cox, Maurice G.; Ravi, Jascindra; Rakowska, Paulina D.; Knight, Alex E.


    Circular dichroism (CD) spectroscopy of proteins is widely used to measure protein secondary structure, and to detect changes in secondary and higher orders of structure, for applications in research and in the quality control of protein products such as biopharmaceuticals. However, objective comparison of spectra is challenging because of a limited quantitative understanding of the sources of error in the measurement. Statistical methods can be used for comparisons, but do not provide a mechanism for dealing with systematic, as well as random, errors. Here we present a measurement model for CD spectroscopy of proteins, incorporating the principal sources of uncertainty, and use the model in conjunction with experimental data to derive an uncertainty budget. We show how this approach could be used in practice for the objective comparison of spectra, and discuss the benefits and limitations of this strategy.

  8. Marine Sponge Lectins: Actual Status on Properties and Biological Activities

    Directory of Open Access Journals (Sweden)

    Sandro Mascena Gomes Filho


    Full Text Available Marine sponges are primitive metazoans that produce a wide variety of molecules that protect them against predators. In studies that search for bioactive molecules, these marine invertebrates stand out as promising sources of new biologically-active molecules, many of which are still unknown or little studied; thus being an unexplored biotechnological resource of high added value. Among these molecules, lectins are proteins that reversibly bind to carbohydrates without modifying them. In this review, various structural features and biological activities of lectins derived from marine sponges so far described in the scientific literature are discussed. From the results found in the literature, it could be concluded that lectins derived from marine sponges are structurally diverse proteins with great potential for application in the production of biopharmaceuticals, especially as antibacterial and antitumor agents.

  9. Carboranyl oligonucleotides. 3. Biochemical properties of oligonucleotides containing 5-(o-carboranyl-l-yl)-2{prime}-deoxyuridine

    Energy Technology Data Exchange (ETDEWEB)

    Lesnikowski, Z.J.; Fulcrand, G.; Lloyd, R.M. Jr. [Veterans Affairs Medical Center and Georgia Research Center for AIDS and HIV Infections, Decatur, GA (United States)]|[Emory Univ. School of Medicine, Atlanta, GA (United States)


    Boronated oligonucleotides are potential candidates for boron neutron capture therapy, antisense technology, and as tools in molecular biology. The biological properties of dodecathymidylic acids containing one or more 5-(o-carboran-l-yl)-2{prime}-deoxyuridine residues at different locations within the oligonucleotide chain were studied. 5-(o-carboran-l-yl)-2{prime}-deoxyuridine containing oligonucleotides manifested marked increased lipophilicity and resistance to 3{prime}- or 5{prime}-phosphodiesterases compared to the corresponding unmodified oligomer. They were substrates for T4 polynucleotide kinase and primers for Escherichia coli polymerase I and human immunodeficiency virus type 1 reverse transcriptase but not for human DNA polymerase {alpha} and {beta}. They also formed heteroduplexes that were substrates for E. coli RNase H, an essential property for antisense technology. These studies indicate that the carboranyl-containing oligonucleotides have desirable properties that need to be exploited further in the design of novel biopharmaceuticals. 33 refs., 2 figs., 1 tab.

  10. Systematic single-cell analysis of Pichia pastoris reveals secretory capacity limits productivity.

    Directory of Open Access Journals (Sweden)

    Kerry Routenberg Love

    Full Text Available Biopharmaceuticals represent the fastest growing sector of the global pharmaceutical industry. Cost-efficient production of these biologic drugs requires a robust host organism for generating high titers of protein during fermentation. Understanding key cellular processes that limit protein production and secretion is, therefore, essential for rational strain engineering. Here, with single-cell resolution, we systematically analysed the productivity of a series of Pichia pastoris strains that produce different proteins both constitutively and inducibly. We characterized each strain by qPCR, RT-qPCR, microengraving, and imaging cytometry. We then developed a simple mathematical model describing the flux of folded protein through the ER. This combination of single-cell measurements and computational modelling shows that protein trafficking through the secretory machinery is often the rate-limiting step in single-cell production, and strategies to enhance the overall capacity of protein secretion within hosts for the production of heterologous proteins may improve productivity.

  11. The action of red scorpion (Mesobuthus tamulus coconsis, pocock venom and its isolated protein fractions on blood sodium levels

    Directory of Open Access Journals (Sweden)

    R. V. Badhe


    Full Text Available Red scorpion (Mesobuthus tamulus or Buthus tamulus venom samples were collected at different regions of India: western (Chiplun and Ahmednagar from Maharashtra State and southern (Ratnagiri and Chennai from Tamil Nadu State. The action of whole venoms on the blood sodium levels of mice was assessed using flame photometry. Seven peptides were common to all venom samples. They were separated using the native polyacrylamide gel electrophoresis (PAGE technique and their activities were also studied using flame photometry. There was a decrease in the concentration of sodium ions in the serum, which suggested the blockage of such ions by scorpion venom toxins. Among the 10 protein bands isolated, the band at 79.6 kDa presented maximum activity in decreasing serum sodium ions concentration. Whole venom from Chiplun region also showed maximum activity. The western blotting technique demonstrated that the anti-scorpion venom sera produced by Haffkine Biopharmaceuticals Corporation Ltd., India, neutralized all four venom samples.

  12. Nanoemulsion: A new concept of delivery system

    Directory of Open Access Journals (Sweden)

    Nitin Sharma


    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

  13. Use of Orbital Shaken Disposable Bioreactors for Mammalian Cell Cultures from the Milliliter-Scale to the 1,000-Liter Scale (United States)

    Zhang, Xiaowei; Stettler, Matthieu; de Sanctis, Dario; Perrone, Marco; Parolini, Nicola; Discacciati, Marco; de Jesus, Maria; Hacker, David; Quarteroni, Alfio; Wurm, Florian

    Driven by the commercial success of recombinant biopharmaceuticals, there is an increasing demand for novel mammalian cell culture bioreactor systems for the rapid production of biologicals that require mammalian protein processing. Recently, orbitally shaken bioreactors at scales from 50 mL to 1,000 L have been explored for the cultivation of mammalian cells and are considered to be attractive alternatives to conventional stirred-tank bioreactors because of increased flexibility and reduced costs. Adequate oxygen transfer capacity was maintained during the scale-up, and strategies to increase further oxygen transfer rates (OTR) were explored, while maintaining favorable mixing parameters and low-stress conditions for sensitive lipid membrane-enclosed cells. Investigations from process development to the engineering properties of shaken bioreactors are underway, but the feasibility of establishing a robust, standardized, and transferable technical platform for mammalian cell culture based on orbital shaking and disposable materials has been established with further optimizations and studies ongoing.

  14. Monoconjugation of Human Amylin with Methylpolyethyleneglycol.

    Directory of Open Access Journals (Sweden)

    Tháyna Sisnande

    Full Text Available Amylin is a pancreatic hormone cosecreted with insulin that exerts unique roles in metabolism and glucose homeostasis. The therapeutic restoration of postprandial and basal amylin levels is highly desirable in diabetes mellitus. Protein conjugation with the biocompatible polymer polyethylene glycol (PEG has been shown to extend the biological effects of biopharmaceuticals. We have designed a PEGylated human amylin by using the aminoreactive compound methoxylpolyethylene glycol succinimidyl carbonate (mPEGsc. The synthesis in organic solvent resulted in high yields of monoPEGylated human amylin, which showed large stability against aggregation, an 8 times increase in half-life in vivo compared to the non-conjugated amylin, and pharmacological activity as shown by modulation of cAMP production in MCF-7 cell line, decrease in glucagon and modulation of glycemia following subcutaneous administration in mice. Altogether these data reveal the potential use of PEGylated human amylin for the restoration of fasting amylin levels.

  15. Analysis of carbohydrates and glycoconjugates by matrix-assisted laser desorption/ionization mass spectrometry: an update for 2009-2010. (United States)

    Harvey, David J


    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.

  16. Quantitative systems pharmacology: a promising approach for translational pharmacology. (United States)

    Gadkar, K; Kirouac, D; Parrott, N; Ramanujan, S

    Biopharmaceutical companies have increasingly been exploring Quantitative Systems Pharmacology (QSP) as a potential avenue to address current challenges in drug development. In this paper, we discuss the application of QSP modeling approaches to address challenges in the translational of preclinical findings to the clinic, a high risk area of drug development. Three cases have been highlighted with QSP models utilized to inform different questions in translational pharmacology. In the first, a mechanism based asthma model is used to evaluate efficacy and inform biomarker strategy for a novel bispecific antibody. In the second case study, a mitogen-activated protein kinase (MAPK) pathway signaling model is used to make translational predictions on clinical response and evaluate novel combination therapies. In the third case study, a physiologically based pharmacokinetic (PBPK) model it used to guide administration of oseltamivir in pediatric patients.

  17. Metabolic engineering of chloroplasts for artemisinic acid biosynthesis and impact on plant growth

    Indian Academy of Sciences (India)

    Bhawna Saxena; Mayavan Subramaniyan; Karan Malhotra; Neel Sarovar Bhavesh; Shobha Devi Potlakayala; Shashi Kumar


    Chloroplasts offer high-level transgene expression and transgene containment due to maternal inheritance, and are ideal hosts for biopharmaceutical biosynthesis via multigene engineering. To exploit these advantages, we have expressed 12 enzymes in chloroplasts for the biosynthesis of artemisinic acid (precursor of artemisinin, antimalarial drug) in an alternative plant system. Integration of transgenes into the tobacco chloroplast genome via homologous recombination was confirmed by molecular analysis, and biosynthesis of artemisinic acid in plant leaf tissues was detected with the help of 13C NMR and ESI-mass spectrometry. The excess metabolic flux of isopentenyl pyrophosphate generated by an engineered mevalonate pathway was diverted for the biosynthesis of artemisinic acid. However, expression of megatransgenes impacted the growth of the transplastomic plantlets. By combining two exogenous pathways, artemisinic acid was produced in transplastomic plants, which can be improved further using better metabolic engineering strategies for commercially viable yield of desirable isoprenoid products.

  18. 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


    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.

  19. Analysis of submicron-sized niflumic acid crystals prepared by electrospray crystallization. (United States)

    Ambrus, Rita; Radacsi, Norbert; Szunyogh, Tímea; van der Heijden, Antoine E D M; Ter Horst, Joop H; Szabó-Révész, Piroska


    Interest in submicron-sized drug particles has emerged from both laboratory and industrial perspectives in the last decade. Production of crystals in the nano size scale offers a novel way to particles for drug formulation solving formulation problems of drugs with low solubility in class II of the Biopharmaceutical Classification System. In this work niflumic acid nanoparticles with a size range of 200-800nm were produced by the novel crystallization method, electrospray crystallization. Their properties were compared to those from evaporative and anti-solvent crystallizations, using the same organic solvent, acetone. There is a remarkable difference in the product crystal size depending on the applied methods. The size and morphology were analyzed by scanning electron microscopy and laser diffraction. The structure of the samples was investigated using differential scanning calorimetry, Fourier-transformed infrared spectroscopy and X-ray powder diffraction. The particles produced using electrospray crystallization process were probably changing from amorphous to crystalline state after the procedure.

  20. Industrial systems biology and its impact on synthetic biology of yeast cell factories

    DEFF Research Database (Denmark)

    Fletcher, Eugene; Krivoruchko, Anastasia; Nielsen, Jens


    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...

  1. Delivery strategies for antiparasitics. (United States)

    Kayser, Oliver; Kiderlen, Albrecht F


    Optimisation of drug carrier systems and drug delivery strategies that take into account the peculiarities of individual infectious agents and diseases are key elements of modern drug development. In the following, different aspects of a rational design for antiparasitic drug formulation will be reviewed, covering delivery systems such as nano- and microparticles, liposomes, emulsions and microemulsions, cochleates and bioadhesive macromolecules. Functional properties for each carrier system will be discussed as well as their therapeutic efficacy for parasitic diseases, including leishmaniasis, human African trypanosomiasis, human cryptosporidiosis, malaria and schistosomiasis. Critical issues for the application of drug carrier systems will be discussed, focusing on biopharmaceutical and pathophysiological parameters such as routes of application, improvement of body distribution and targeting intracellularly persisting pathogens.

  2. Industrial systems biology and its impact on synthetic biology of yeast cell factories. (United States)

    Fletcher, Eugene; Krivoruchko, Anastasia; Nielsen, Jens


    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.

  3. The Nutraceutical Bioavailability Classification Scheme: Classifying Nutraceuticals According to Factors Limiting their Oral Bioavailability. (United States)

    McClements, David Julian; Li, Fang; Xiao, Hang


    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*).

  4. Nanotechnology:an effective tool for enhancing bioavailability and bioactivity of phytomedicine

    Institute of Scientific and Technical Information of China (English)

    Thirumurugan Gunasekaran; Tedesse Haile; Tedele Nigusse; Magharla Dasaratha Dhanaraju


    To achieve the desired therapeutic objective, the drug product must deliver the active drug at an optimal rate and amount. By proper biopharmaceutic design, the rate and extent of drug absorption (also called as bioavailability) or the systemic delivery of drugs to the body can be varied from rapid and complete absorption to slow and sustained absorption depending upon the desired therapeutic objective. Phytomedicine have served as the foundation for a larger fraction of the current pharmacopeia. But the delivery of phytomedicine is always problematic due to poor aqueous solubility, poor permeation, low systemic availability, instability and extensive first pass metabolism. Current review will discuss in detail about how nanotechnology can enhance the bioavilability and bioactivity of the phytomedicine.

  5. Absolute quantification of Bovine Viral Diarrhea Virus (BVDV) RNA by the digital PCR technique (United States)

    Flatschart, R. B.; Almeida, D. O.; Heinemann, M. B.; Medeiros, M. N.; Granjeiro, J. M.; Folgueras-Flatschart, A. V.


    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.


    Directory of Open Access Journals (Sweden)

    Radha Bhati


    Full Text Available Oral mucosal drug delivery system is widely applicable as novel site for administration of drug for immediate and controlled release action by preventing first pass metabolism and enzymatic degradation due to GI microbial flora. Oral mucosal drug delivery system provides local and systemic action. In this review, attention is focused to give regarding physiology of oral mucosal including tissue permeability, barriers to permeation and route of permeation, biopharmaceutics of buccal and sublingual absorption, factors affecting drug absorption, detailed information of penetration enhancers, design of oral mucosal drug delivery system and role of mucoadhesion and various theories of bioadhesion. Evaluation techniques and selection of animal model for in-vivo studies are also discussed.

  7. [Establishment of a novel biotin-inducible eukaryotic gene regulation system]. (United States)

    Ye, Lingling; Hong, Liu; Li, Shichong; Wang, Qiwei; Lan, Sanchun; Chen, Zhaolie


    To establish a gene regulation system compatible with biopharmaceutical industry and gene therapy, we constructed a fusion protein of biotin ligase from Bacillus subtilis (BS-BirA) and the trans-activation domain, and used its expression vector as the regulatory vector. Meanwhile, BS-BirA-specific operators were ligated upstream of attenuated CMV promoter to obtain the response vector. In this way, a novel eukaryotic gene regulation system responsive to biotin was established and named BS-Biotin-On system. BS-Biotin-On system was further investigated with the enhancing green fluorescent protein (EGFP) as the reporter gene. The results showed that our system was superior to the current similar regulation system in its higher induction ratio, and that the expression of interest gene could be tuned in a rapid and efficient manner by changing the biotin concentrations in the cultures, Our results show that the established system may provide a new alternative for the exogenous gene modulation.

  8. On the ubiquitous presence of fractals and fractal concepts in pharmaceutical sciences: a review. (United States)

    Pippa, Natassa; Dokoumetzidis, Aristides; Demetzos, Costas; Macheras, Panos


    Fractals have been very successful in quantifying nature's geometrical complexity, and have captured the imagination of scientific community. The development of fractal dimension and its applications have produced significant results across a wide variety of biomedical applications. This review deals with the application of fractals in pharmaceutical sciences and attempts to account the most important developments in the fields of pharmaceutical technology, especially of advanced Drug Delivery nano Systems and of biopharmaceutics and pharmacokinetics. Additionally, fractal kinetics, which has been applied to enzyme kinetics, drug metabolism and absorption, pharmacokinetics and pharmacodynamics are presented. This review also considers the potential benefits of using fractal analysis along with considerations of nonlinearity, scaling, and chaos as calibration tools to obtain information and more realistic description on different parts of pharmaceutical sciences. As a conclusion, the purpose of the present work is to highlight the presence of fractal geometry in almost all fields of pharmaceutical research.

  9. Possible participation of receptor for advanced glycation end products (RAGE) in the origin of cancer stem cells in diabetic patients with colon cancer. (United States)

    Hu, Xiang; Cheng, Yong


    The association between diabetes and the associated increased risk of several solid malignancies has been the subject of investigation for many years, while potential biologic links between the two diseases are incompletely understood. The receptor for advanced glycation end-products (RAGE) signal transduction may represent a focal point in their respective contributions to malignant transformation associated diabetes. While the physiopathology of RAGE axis in promoting malignancies cannot be explained completely by the available mechanism as perpetuating inflammation at tumor microenvironment. In addition, experimental researches revealed a crucial role for upstreams of RAGE signaling pathway in maintaining the stemness properties and tumorigenicity of cancer stem cells. Hence, we hypothesized that RAGE inducing cancer stem cells may be a key determinant in the origin and progression of colon malignant tumors concomitant diabetes. Such an opinion not only bands together the seemingly disparate various complications in diabetes and colon cancers, but also has future implications for risk assessment and biopharmaceutical treatment.

  10. Pharmaceutical prospects: biopharming and the geography of technological expectations. (United States)

    Milne, Richard


    The paper explores the role of imagined geographies in the shaping of new technologies. I argue that the role of place in future-oriented visions of technoscience is a neglected topic in studies of the social shaping of technology. The paper proposes an approach that combines the sociology of expectations with the geography of science. It focuses on the interplay between envisaged and current geographies to highlight the recursive dynamics of place and imagination. To illustrate this approach, the paper discusses the example of biopharming, the production of biopharmaceuticals using genetically modified crops. I argue that expectations for biopharming bear the imprint of place, or rather of the places in which they are imagined, as well as those they imagine, and ultimately those they produce. I use this example to suggest how social studies of science and technology can usefully investigate the spaces, places and scales of technological development.

  11. Venture Capital Investment in the Life Sciences in Switzerland. (United States)

    Hosang, Markus


    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.

  12. Viral vectors for gene transfer: current status of gene therapeutics. (United States)

    Heilbronn, Regine; Weger, Stefan


    Gene therapy for the correction of inherited or acquired disease has gained increasing importance in recent years. Successful treatment of children suffering from severe combined immunodeficiency (SCID) was achieved using retrovirus vectors for gene transfer. Encouraging improvements of vision were reported in a genetic eye disorder (LCA) leading to early childhood blindness. Adeno-associated virus (AAV) vectors were used for gene transfer in these trials. This chapter gives an overview of the design and delivery of viral vectors for the transport of a therapeutic gene into a target cell or tissue. The construction and production of retrovirus, lentivirus, and AAV vectors are covered. The focus is on production methods suitable for biopharmaceutical upscaling and for downstream processing. Quality control measures and biological safety considerations for the use of vectors in clinical trials are discussed.

  13. Gene Therapy for Advanced Melanoma: Selective Targeting and Therapeutic Nucleic Acids

    Directory of Open Access Journals (Sweden)

    Joana R. Viola


    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.

  14. Cell death in mammalian cell culture: molecular mechanisms and cell line engineering strategies. (United States)

    Krampe, Britta; Al-Rubeai, Mohamed


    Cell death is a fundamentally important problem in cell lines used by the biopharmaceutical industry. Environmental stress, which can result from nutrient depletion, by-product accumulation and chemical agents, activates through signalling cascades regulators that promote death. The best known key regulators of death process are the Bcl-2 family proteins which constitute a critical intracellular checkpoint of apoptosis cell death within a common death pathway. Engineering of several members of the anti-apoptosis Bcl-2 family genes in several cell types has extended the knowledge of their molecular function and interaction with other proteins, and their regulation of cell death. In this review, we describe the various modes of cell death and their death pathways at molecular and organelle level and discuss the relevance of the growing knowledge of anti-apoptotic engineering strategies to inhibit cell death and increase productivity in mammalian cell culture.

  15. Conformational Analysis of Proteins in Highly Concentrated Solutions by Dialysis-Coupled Hydrogen/Deuterium Exchange Mass Spectrometry

    DEFF Research Database (Denmark)

    Houde, Damian; Esmail Nazari, Zeinab; Bou-Assaf, George M;


    When highly concentrated, an antibody solution can exhibit unusual behaviors, which can lead to unwanted properties, such as increased levels of protein aggregation and unusually high viscosity. Molecular modeling, along with many indirect biophysical measurements, has suggested that the cause......-MS experiments have limited utility for the direct analysis of solutions with high concentrations of protein. Here, we present a dialysis-based HDX-MS (di-HDX-MS) method as an alternative HDX-MS labeling format, which takes advantage of passive dialysis rather than the classic dilution workflow. We applied...... this approach to a highly concentrated antibody solution without dilution or significant sample manipulation, prior to analysis. Such a method could pave the way for a deeper understanding of the unusual behavior of proteins at high concentrations, which is highly relevant for development of biopharmaceuticals...

  16. Multidrug co-crystals: towards the development of effective therapeutic hybrids. (United States)

    Thipparaboina, Rajesh; Kumar, Dinesh; Chavan, Rahul B; Shastri, Nalini R


    Co-crystals have garnered the interest of the pharmaceutical industry with the introduction of regulatory guidelines by the US Food and Drug Administration (FDA) as a result of expanded patent portfolios. The Phase II clinical success of tramadol and celecoxib co-crystal for the treatment of acute pain followed by a recent reflection paper published by the European Medicines Agency (EMA) have further boosted the development of drug-drug co-crystals. Here, we shed light on the developments of drug-drug co-crystals and highlight future perspectives for exploring new therapeutic hybrids deploying drug-drug, drug-nutraceuticals and drug-inorganic salt combinations with improved pharmaceutical and biopharmaceutical performance.

  17. A Perspective on the Development of Plant-Made Vaccines in the Fight against Ebola Virus (United States)

    Rosales-Mendoza, Sergio; Nieto-Gómez, Ricardo; Angulo, Carlos


    The Ebola virus (EBOV) epidemic indicated a great need for prophylactic and therapeutic strategies. The use of plants for the production of biopharmaceuticals is a concept being adopted by the pharmaceutical industry, with an enzyme for human use currently commercialized since 2012 and some plant-based vaccines close to being commercialized. Although plant-based antibodies against EBOV are under clinical evaluation, the development of plant-based vaccines against EBOV essentially remains an unexplored area. The current technologies for the production of plant-based vaccines include stable nuclear expression, transient expression mediated by viral vectors, and chloroplast expression. Specific perspectives on how these technologies can be applied for developing anti-EBOV vaccines are provided, including possibilities for the design of immunogens as well as the potential of the distinct expression modalities to produce the most relevant EBOV antigens in plants considering yields, posttranslational modifications, production time, and downstream processing. PMID:28344580

  18. The emerging CHO systems biology era: harnessing the ‘omics revolution for biotechnology

    DEFF Research Database (Denmark)

    Kildegaard, Helene Faustrup; Baycin-Hizal, Deniz; Lewis, Nathan


    line was recently sequenced. Now, the CHO systems biology era is underway. Critical ‘omics data sets, including proteomics, transcriptomics, metabolomics, fluxomics, and glycomics, are emerging, allowing the elucidation of the molecular basis of CHO cell physiology. The incorporation of these data sets...... 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...

  19. The influence of lysozyme on mannitol polymorphism in freeze-dried and spray-dried formulations depends on the selection of the drying process

    DEFF Research Database (Denmark)

    Grohganz, Holger; Lee, Yan-Ying; Rantanen, Jukka;


    Freeze-drying and spray-drying are often applied drying techniques for biopharmaceutical formulations. The formation of different solid forms upon drying is often dependent on the complex interplay between excipient selection and process parameters. The purpose of this study was to investigate...... the influence of the chosen drying method on the solid state form. Mannitol-lysozyme solutions of 20mg/mL, with the amount of lysozyme varying between 2.5% and 50% (w/w) of total solid content, were freeze-dried and spray-dried, respectively. The resulting solid state of mannitol was analysed by near......-dried formulations an increase in protein concentration resulted in a shift from ß-mannitol to a-mannitol. An increase in final drying temperature of the freeze-drying process towards the temperature of the spray-drying process did not lead to significant changes. It can thus be concluded that it is the drying...

  20. Cequent Pharmaceuticals, Inc.: the biological pitcher for RNAi therapeutics. (United States)

    Keates, Andrew C; Fruehauf, Johannes H; Xiang, Shuanglin; Parker, Peter D; Li, Chiang J


    Cequent Pharmaceuticals, Inc. is a recently established biopharmaceutical company that aims to develop clinically compatible therapies based on RNAi, a potent gene-silencing mechanism discovered in 1998. The company's proprietary technology, transkingdom RNAi (tkRNAi), uses nonpathogenic bacteria to produce and deliver shRNA into target cells to induce RNAi. Our initial focus is on the development of a tkRNAi-based therapy for familial adenatomous polyposis, an inherited form of colon cancer. Cequent's first tkRNAi-based drug for familial adenatomous polyposis, CEQ501, is currently in advanced preclinical testing. As part of its ongoing activities, Cequent plans to develop additional tkRNAi-based products for indications within and outside the GI tract. Our overall goal is to establish tkRNAi as a platform for developing a wide range of RNAi-based therapies.