WorldWideScience

Sample records for biopharmaceuticals

  1. Assessing the Immunogenicity of Biopharmaceuticals.

    Science.gov (United States)

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

    2016-06-01

    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. PMID:27097915

  2. Risk Management in Biopharmaceutical Supply Chains

    OpenAIRE

    Ma, Yao

    2011-01-01

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

  3. Biopharmaceuticals as Challenges to the Regulatory System

    OpenAIRE

    Ebbers, H.C.

    2012-01-01

    Biopharmaceuticals differ from small molecules in terms of structure and pharmacology. Furthermore, they are also prescribed for different patient populations. The protein nature of biopharmaceuticals makes them especially prone for immunological reactions and their safety profile may be affected by seemingly minor changes in the production process. This unpredictability of safety concerns of biopharmaceuticals has triggered increased regulatory interest in the safety of biopharmaceuticals, w...

  4. Production planning of biopharmaceutical manufacture.

    OpenAIRE

    Lakhdar, K.

    2006-01-01

    Multiproduct manufacturing facilities running on a campaign basis are increasingly becoming the norm for biopharmaceuticals, owing to high risks of clinical failure, regulatory pressures and the increasing number of therapeutics in clinical evaluation. The need for such flexible plants and cost-effective manufacture pose significant challenges for planning and scheduling, which are compounded by long production lead times, intermediate product stability issues and the high cost - low volume n...

  5. Production of biopharmaceutical proteins by yeast

    OpenAIRE

    Nielsen, Jens

    2012-01-01

    Production of recombinant proteins for use as pharmaceuticals, so-called biopharmaceuticals, is a multi-billion dollar industry. Many different cell factories are used for the production of biopharmaceuticals, but the yeast Saccharomyces cerevisiae is an important cell factory as it is used for 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 ...

  6. Traceability of biopharmaceuticals in spontaneous reporting systems

    DEFF Research Database (Denmark)

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

    2013-01-01

    , including spontaneous reporting systems (SRSs), in which reports of ADRs are collected. OBJECTIVE: The aim of this study was to explore the current status of traceability of biopharmaceuticals in the US and the EU up to patient level in SRSs. DESIGN AND SETTING: A cross-sectional study was conducted over....... CONCLUSION: This study underlines the need for improving traceability of biopharmaceuticals, in particular with respect to individual batches, allowing better identification and monitoring of postmarketing safety issues related to biopharmaceuticals....

  7. Bioethical issues in the development of biopharmaceuticals

    OpenAIRE

    Todorović Zoran; Protić Dragana

    2012-01-01

    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 immuno...

  8. Bioethical issues in the development of biopharmaceuticals

    Directory of Open Access Journals (Sweden)

    Todorović Zoran

    2012-01-01

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

  9. Process analytical technology (PAT) for biopharmaceuticals

    DEFF Research Database (Denmark)

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

    2011-01-01

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

  10. Pharmaceutical technology, biopharmaceutics and drug delivery.

    Science.gov (United States)

    Youn, Yu Seok; Lee, Beom-Jin

    2011-03-01

    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. PMID:22833999

  11. [Biopharmaceuticals in the treatment of rheumatoid arthritis

    DEFF Research Database (Denmark)

    Baslund, B.; Bendtzen, K.

    2008-01-01

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

  12. Freezing mammalian cells for production of biopharmaceuticals.

    Science.gov (United States)

    Seth, Gargi

    2012-03-01

    Cryopreservation techniques utilize very low temperatures to preserve the structure and function of living cells. Various strategies have been developed for freezing mammalian cells of biological and medical significance. This paper highlights the importance and application of cryopreservation for recombinant mammalian cells used in the biopharmaceutical industry to produce high-value protein therapeutics. It is a primer that aims to give insight into the basic principles of cell freezing for the benefit of biopharmaceutical researchers with limited or no prior experience in cryobiology. For the more familiar researchers, key cell banking parameters such as the cell density and hold conditions have been reviewed to possibly help optimize their specific cell freezing protocols. It is important to understand the mechanisms underlying the freezing of complex and sensitive cellular entities as we implement best practices around the techniques and strategies used for cryopreservation. PMID:22226818

  13. BIOPHARMACEUTICAL CLASSIFICATION SYSTEM AND BIOWAVER: AN OVERVIEW

    OpenAIRE

    Puranik Prashant K; Kasar Sagar Ashok; Gadade Deepak Dilip; Mali Prabha R

    2011-01-01

    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 absorptio...

  14. Current status of biopharmaceuticals in Iran’s pharmaceutical market

    OpenAIRE

    Professor Abdol Majid Cheraghali, PharmD, PhD

    2013-01-01

    The clinical importance of biopharmaceuticals for the management of life threatening diseases is increasing but costs have become a major obstacle to the administration of these medicines, especially in resource limited healthcare systems. Introduction of biosimilars as a cost-effective alternative to innovator biopharmaceuticals has attracted the attention of both industry and policymakers. However, due to the complex structures of biopharmaceuticals, the regulation of biosimilars has become...

  15. Biopharmaceuticals. Official position of Russian Association of Endocrinologists

    Directory of Open Access Journals (Sweden)

    . Russian Association of Endocrinologists

    2013-11-01

    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 

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

    DEFF Research Database (Denmark)

    Nielsen, Jens

    2013-01-01

    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...

  17. Transgenic plants in the biopharmaceutical market.

    Science.gov (United States)

    Twyman, Richard M; Schillberg, Stefan; Fischer, Rainer

    2005-02-01

    Many of our 'small-molecule-drugs' are natural products from plants, or are synthetic compounds based on molecules found naturally in plants. However, the vast majority of the protein therapeutics (or biopharmaceuticals) we use are from animal or human sources, and are produced commercially in microbial or mammalian bioreactor systems. Over the last few years, it has become clear that plants have great potential for the production of human proteins and other protein-based therapeutic entities. Plants offer the prospect of inexpensive biopharmaceutical production without sacrificing product quality or safety, and following the success of several plant-derived technical proteins, the first therapeutic products are now approaching the market. In this review, the different plant-based production systems are discussed and the merits of transgenic plants are evaluated compared with other platforms. A detailed discussion is provided of the development issues that remain to be addressed before plants become an acceptable mainstream production technology. The many different proteins that have already been produced using plants are described, and a sketch of the current market and the activities of the key players is provided. Despite the currently unclear regulatory framework and general industry inertia, the benefits of plant-derived pharmaceuticals are now bringing the prospect of inexpensive veterinary and human medicines closer than ever before. PMID:15757412

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

    OpenAIRE

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

    2012-01-01

    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...

  19. New opportunities by synthetic biology for biopharmaceutical production in Pichia pastoris

    OpenAIRE

    Vogl, Thomas; Franz S. Hartner; Glieder, Anton

    2013-01-01

    Biopharmaceuticals are an integral part of modern medicine and pharmacy. Both, the development and the biotechnological production of biopharmaceuticals are highly cost-intensive and require suitable expression systems. In this review we discuss established and emerging tools for reengineering the methylotrophic yeast Pichia pastoris for biopharmaceutical production. Recent advancements of this industrial expression system through synthetic biology include synthetic promoters to avoid methano...

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

    NARCIS (Netherlands)

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

    2014-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Hao Hu

    2015-12-01

    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.

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

    Science.gov (United States)

    Mercier, Sarah M; Diepenbroek, Bas; Wijffels, Rene H; Streefland, Mathieu

    2014-06-01

    Increasingly elaborate and voluminous datasets are generated by the (bio)pharmaceutical industry and are a major challenge for application of PAT and QbD principles. Multivariate data analysis (MVDA) is required to delineate relevant process information from large multi-factorial and multi-collinear datasets. Here the key role of MVDA for industrial (bio)process data is discussed, with a focus on progress and limitations of MVDA as a PAT solution for biopharmaceutical cultivation processes. MVDA based models were proven useful and should be routinely implemented for bioprocesses. It is concluded that although the highest level of PAT with process control within its design space in real-time during manufacturing is not reached yet, MVDA will be central to reach this ultimate objective for cell cultivations. PMID:24732022

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

    CERN Document Server

    Macheras, Panos

    2016-01-01

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

  4. Glyco-engineering for biopharmaceutical production in moss bioreactors

    OpenAIRE

    Decker, Eva L.; Parsons, Juliana; Reski, Ralf

    2014-01-01

    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 Chinese hamster ovary 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 ...

  5. Fusion protein technologies for biopharmaceuticals: Applications and challenges

    OpenAIRE

    Berger, Sven; Lowe, Peter; Tesar, Michael

    2015-01-01

    Stefan R. Schmidt consolidates the hugely diverse field of fusion proteins and their application in the creation of biopharmaceuticals. The text is replete with case studies and clinical data that inform and intrigue the reader as to the myriad possibilities available when considering the creation of a fusion protein. This valuable text will serve the novice as a broad introduction or the seasoned professional as a thorough review of the state of the art. The first marketed therapeutic recomb...

  6. [New role for tobacco--production of biopharmaceuticals].

    Science.gov (United States)

    Budzianowski, Jaromir

    2009-01-01

    Over one hundred of biopharmaceuticals present on the pharmaceutical market--among them mainly therapeutically peptides and proteins such as hormones, enzymes, interferons, blood factors, monoclonal antibodies, vaccines, growth factors and fusion proteins, are manufactured through recombinant DNA technology in cultures of transgenic bacterial (Escherichia coli), yeast (Saccharomyces cerevisiae) and mammalian cells (CHO, BHK) and rarely insect cells or insects (Bombyx mori). High costs of their manufacturing with simultaneous increased demand for existing and new biopharmaceuticals prompt for the search of cheaper methods of production by using transgenic domestic animals and, in particular, in transgenic crop plants. Among many plant species investigated for ability to produce biopharmaceuticals, such like cereals, legumes, oil plants, vegetables and fruit plants, aquatic plants and mosses, the outstanding features posses two tobacco species--Nicotiana tabacum and Nicotiana benthamiana. Foreign proteins can be expressed in those plants not only in nuclear genome, but also easily in chloroplast genome, through transient transformation and propagation of transgenic plant virus--e.g. tobacco mosaic virus (TMV). Tobacco was shown to be useful to produce various therapeutical proteins, even such complex ones as antibodies including secretory immunoglobulin A (sIgA), with partial humanization of N-glycans. Especially important is possibility of rapid preparation, even within a week, vaccines and monoclonal antibodies for clinical tests or personalized anticancer therapy through transient transformation or infection with transgenic virus. Tobacco with foreign gene may be employed for manufacture in two ways--either in field or green-house cultivation or in the form of in vitro suspension cell culture. Among many biopharmaceuticals expressed in tobacco, several vaccines and antibodies are in advanced stages of development, in clinical evaluations and probably close to

  7. NOVEL PROCESSES AND PRODUCTS FOR RECOMBINANT PRODUCTION OF BIOPHARMACEUTICALS

    OpenAIRE

    Giuliani, Maria

    2009-01-01

    The monoclonal antibody market represents the fastest-growing segment within the biopharmaceutical industry (Evans and Das 2005). Indeed, recombinant antibodies and antibody fragments are widespread tools for research, diagnostics and therapy (Joosten et al., 2003). Large-scale production of recombinant antibodies and antibody fragments requires a suitable expression system which has to be cheap, accessible for genetic modifications, easily scaled up for greater demands and safe for use in co...

  8. Carrier peptide-mediated transepithelial permeation of biopharmaceuticals

    DEFF Research Database (Denmark)

    Kristensen, Mie; Nielsen, Hanne Mørck

    2015-01-01

    -penetrating peptides (CPPs). Two approaches for the carrier peptide-mediated transepithelial permeation of biopharmaceuticals are generally explored: Co-administration1 or covalent conjugation2. Co-administration is often the method of choice due to e.g. ease in sample preparation and flexibility in adjustment of the......-34)) and the widely studied CPP penetratin were employed as therapeutic cargo and carrier peptide, respectively....

  9. Hairy roots culture as a source of valuable biopharmaceuticals

    OpenAIRE

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

    2016-01-01

    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...

  10. Commercialization of biopharmaceutical knowledge in Iran; challenges and solutions

    OpenAIRE

    Nassiri-Koopaei, Nasser; Majdzadeh, Reza; Kebriaeezadeh, Abbas; Rashidian, Arash; Yazdi, Mojtaba Tabatabai; Nedjat, Saharnaz; Nikfar, Shekoufeh

    2014-01-01

    Background The objective of this study was to investigate the application of the university research findings or commercialization of the biopharmaceutical knowledge in Iran and determine the challenges and propose some solutions. Results A qualitative study including 19 in-depth interviews with experts was performed in 2011 and early 2012. National Innovation System (NIS) model was employed as the study design. Thematic method was applied for the analysis. The results demonstrate that policy...

  11. Methods of high throughput biophysical characterization in biopharmaceutical development.

    Science.gov (United States)

    Razinkov, Vladimir I; Treuheit, Michael J; Becker, Gerald W

    2013-03-01

    Discovery and successful development of biopharmaceutical products depend on a thorough characterization of the molecule both before and after formulation. Characterization of a formulated biotherapeutic, typically a protein or large peptide, requires a rigorous assessment of the molecule's physical stability. Stability of a biotherapeutic includes not only chemical stability, i.e., degradation of the molecule to form undesired modifications, but also structural stability, including the formation of aggregates. In this review, high throughput biophysical characterization techniques are described according to their specific applications during biopharmaceutical discovery, development and manufacturing. The methods presented here are classified according to these attributes, and include spectroscopic assays based on absorbance, polarization, intrinsic and extrinsic fluorescence, surface plasmon resonance instrumentation, calorimetric methods, dynamic and static light scattering techniques, several visible particle counting and sizing methods, new viscosity assay, based on light scattering and mass spectrometry. Several techniques presented here are already implemented in industry; but, many high throughput biophysical methods are still in the initial stages of implementation or even in the prototype stage. Each technique in this report is judged by the specific application of the method through the biopharmaceutical development process. PMID:22725690

  12. Multiobjective long-term planning of biopharmaceutical manufacturing facilities.

    Science.gov (United States)

    Lakhdar, K; Savery, J; Papageorgiou, L G; Farid, S S

    2007-01-01

    Biopharmaceutical companies with large portfolios of clinical and commercial products typically need to allocate production across several multiproduct facilities, including third party contract manufacturers. This poses several capacity planning challenges which are further complicated by the need to satisfy different stakeholders often with conflicting objectives. This work addresses the question of how a biopharmaceutical manufacturer can make better long-term capacity planning decisions given multiple strategic criteria such as cost, risk, customer service level, and capacity utilization targets. A long-term planning model that allows for multiple facilities and accounts for multiple objectives via goal programming is developed. An industrial case study based on a large scale biopharmaceutical manufacturer is used to illustrate the functionality of the model. A single objective model is used to identify how best to use existing capacity so as to maximize profits for different demand scenarios. Mitigating risk due to unforeseen circumstances by including a dual facility constraint is shown to be a reasonable strategy at base case demand levels but unacceptable if demands are 150% higher than expected. The capacity analysis identifies where existing capacity fails to meet demands given the constraints. A multiobjective model is used to demonstrate how key performance measures change given different decision making policies where different weights are assigned to cost, customer service level, and utilization targets. The analysis demonstrates that a high profit can still be achieved while meeting key targets more closely. The sensitivity of the optimal solution to different limits on the targets is illustrated. PMID:17924645

  13. Characteristics of product recalls of biopharmaceuticals and small-molecule drugs in the USA.

    Science.gov (United States)

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

    2016-04-01

    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. PMID:26552336

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

    DEFF Research Database (Denmark)

    Cun, Dongmei; Wan, Feng; Yang, Mingshi

    2015-01-01

    Biopharmaceuticals including recombinant proteins, monoclonal antibody and nucleic acid based therapeutics have become more and more important to improve the quality of life of patients. However, the administration of biopharmaceuticals was mainly limited to parenteral routes and their delivery....... 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....

  15. Biopharmaceutical innovation system and the influence of policies:the case of taiwan (2000-2008).

    Science.gov (United States)

    Chung, Chao Chen

    2013-08-01

    This article discusses the influence of policies on the development of biopharmaceuticals. We choose the experiences of Taiwan for our empirical study and focus on the evolution between 2000 and 2008; in the period of time the country provides an interesting example for further exploration of biopharmaceutical policies. Among all the policies, the two National Programs (National Research Program for Genetic Medicine and National Science and Technology Program for Biotechnology and Pharmaceuticals) and the Law of Pharmaceutical Affairs showed the contrasting effects on the innovation system of biopharmaceuticals. As a result, the government generated very limited positive influence on the innovation of biopharmaceuticals. PMID:24596851

  16. Glyco-engineering for biopharmaceutical production in moss bioreactors

    Directory of Open Access Journals (Sweden)

    Eva L. Decker

    2014-07-01

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

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

    Science.gov (United States)

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

    2015-03-01

    Carrot (Daucus carota L.) is of importance in the molecular farming field as it constitutes the first plant species approved to produce biopharmaceuticals for human use. In this review, features that make carrot an advantageous species in the molecular farming field are analyzed and a description of the developments achieved with this crop thus far is presented. A guide for genetic transformation procedures is also included. The state of the art comprises ten vaccine prototypes against Measles virus, Hepatitis B virus, Human immunodeficiency virus, Yersinia pestis, Chlamydia trachomatis, Mycobacterium tuberculosis, enterotoxigenic Escherichia coli, Corynebacterium diphtheria/Clostridium tetani/Bordetella pertussis, and Helicobacter pylori; as well as the case of the glucocerebrosidase, an enzyme used for replacement therapy, and other therapeutics. Perspectives for these developments are envisioned and innovations are proposed such as the use of transplastomic technologies-, hairy roots-, and viral expression-based systems to improve yields and develop new products derived from this advantageous plant species. PMID:25572939

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

    CERN Document Server

    Macheras, Panos

    2006-01-01

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

  19. Analysis of illegal peptide biopharmaceuticals frequently encountered by controlling agencies.

    Science.gov (United States)

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

    2015-09-01

    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

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

    NARCIS (Netherlands)

    Haselberg, R.

    2010-01-01

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

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

    Directory of Open Access Journals (Sweden)

    Lukasz Puslecki

    2016-03-01

    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.

  2. Patent production is a prerequisite for successful exit of a biopharmaceutical company.

    Science.gov (United States)

    Saotome, Chikako; Nakaya, Yurie; Abe, Seiji

    2016-03-01

    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. PMID:26721189

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

    Science.gov (United States)

    Kinch, Michael S; Moore, Ryan

    2016-06-23

    The way new medicines are discovered and brought to market has fundamentally changed over the last 30 years. Our previous analysis showed that biotechnology companies had contributed significantly to the US Food and Drug Administration approval of new molecular entities up to the mid-1980s, when the trends started to decline. Although intriguing, the focus on biotechnology necessarily precluded the wider question of how the biopharmaceutical industry has been delivering on its goals to develop new drugs. Here, we present a comprehensive analysis of all biopharmaceutical innovators and uncover unexpected findings. The present biopharmaceutical industry grew steadily from 1800 to 1950 and then stagnated for two decades, before a burst of growth attributable to the biotechnology revolution took place; but consolidation has reduced the number of active and independent innovators to a level not experienced since 1945. The trajectories and trends we observe raise fundamental questions about biopharmaceutical innovators and the sustainability of the drug-development enterprise. PMID:27341432

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

    Science.gov (United States)

    Yan, Gujun

    2014-07-01

    Known as the "sunrise industry" of the 21st century, bio-pharmaceutical industry has been a fast-growing global industry, and many countries have been developing this industry as the focus of their national economies. In China, there exists a huge market demand for the development of bio-pharmaceutical industry, but at the present stage the industry is faced with some problems, such as low level of R & D for innovative drugs, and inappropriate capital investment in the industrialization. In order to accelerate the development of China's bio-pharmaceutical industry, it is necessary to take strategic initiatives of improving the technology transfer system, developing the bio-pharmaceutical outsourcing, and building a diversified industrial financing system. PMID:25016263

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

    DEFF Research Database (Denmark)

    Cun, Dongmei; Wan, Feng; Yang, Mingshi

    2015-01-01

    . In this review we discussed the formulation strategies and particle engineering technologies to improve the efficiency of pulmonary delivery of biopharmaceutical, with a focus on systemic therapy of pharmaceutical proteins/peptides and local delivery of siRNA via the lung administration. - See more......Biopharmaceuticals including recombinant proteins, monoclonal antibody and nucleic acid based therapeutics have become more and more important to improve the quality of life of patients. However, the administration of biopharmaceuticals was mainly limited to parenteral routes and their delivery...... 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...

  6. The Global Location of Biopharmaceutical Knowledge Activity: New Findings, New Questions

    OpenAIRE

    Iain M. Cockburn; Matthew J. Slaughter

    2010-01-01

    Location possibilities for biopharmaceutical firms are expanding, driven by factors such as falling natural and political barriers to trade and communication, extension and strengthening of patent protection through institutions including the World Trade Organization, and growing supplies of skilled labor and related infrastructure in large, relatively low-cost countries. This paper examines the causes and consequences of this global expansion of knowledge discovery by biopharmaceutical firms...

  7. Challenges of developing decision-support LCA tools in the biopharmaceutical industry

    OpenAIRE

    S. Ramasamy; Titchener-Hooker, N.; Lettieri, P.

    2013-01-01

    The biopharmaceutical industry has been slow in carrying out LCA analyses. However, as the industry matures, the level of scrutiny placed on this industry by international governments will increase and hence, there is an urgent need for the industry to implement decision-support tools for the decision-making processes. Decision-support tools based on life cycle assessment (LCA) can be potentially used for application in the biopharmaceutical industry as an aid to decision making. This paper s...

  8. A History of Biopharmaceutics in the Food and Drug Administration 1968–1993

    OpenAIRE

    Skelly, Jerome Philip

    2009-01-01

    The history of biopharmaceutics is reviewed, beginning with its origin out of the Division of Clinical Research in The Bureau of Medicine. The reason for the creation of the Division of Biopharmaceutics, the certification of Food and Drug Administration authority over the functions it was to have, and the implementation of that authority are described. The determination of bioequivalence, the bioavailability decision rules, pharmacokinetics, and drug metabolism are explained. The reason for t...

  9. Conformation and dynamics of biopharmaceuticals: transition of mass spectrometry-based tools from academe to industry

    OpenAIRE

    Kaltashov, Igor A.; Bobst, Cedric E.; Abzalimov, Rinat R.; Berkowitz, Steven A; Houde, Damian

    2009-01-01

    Mass spectrometry plays a very visible role in biopharmaceutical industry, although its use in development, characterization and quality control of protein drugs is mostly limited to the analysis of covalent structure (amino acid sequence and post-translational modifications). Despite the centrality of protein conformation to biological activity, stability and safety of biopharmaceutical products, the expanding arsenal of mass spectrometry-based methods that are currently available to probe h...

  10. The role of Periodic Safety Update Reports in the safety management of biopharmaceuticals

    OpenAIRE

    2012-01-01

    Purpose To describe and assess the outcomes of Periodic Safety Update Report (PSUR) evaluations of biopharmaceuticals. Methods A cross-sectional analysis was performed of follow-up requirements of PSURs submitted for centrally approved biopharmaceuticals in the European Union between 1 July 2008 and 30 June 2010. A follow-up analysis on a subset of products that submitted multiple PSURs within the study period was also performed. Results The cross-sectional analysis included 70 PSURs. Potenti...

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

    Directory of Open Access Journals (Sweden)

    Budhwaar Vikaas

    2012-09-01

    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.

  12. MODELING AND BIOPHARMACEUTICAL EVALUATION OF SEMISOLID SYSTEMS WITH ROSEMARY EXTRACT.

    Science.gov (United States)

    Ramanauskiene, Kristina; Zilius, Modestas; Kancauskas, Marius; Juskaite, Vaida; Cizinauskas, Vytis; Inkeniene, Asta; Petrikaite, Vilma; Rimdeika, Rytis; Briedis, Vitalis

    2016-01-01

    Scientific literature provides a great deal of studies supporting antioxidant effects of rosemary, protecting the body's cells against reactive oxygen species and their negative impact. Ethanol rosemary extracts were produced by maceration method. To assess biological activity of rosemary extracts, antioxidant and antimicrobial activity tests were performed. Antimicrobial activity tests revealed that G+ microorganisms are most sensitive to liquid rosemary extract, while G-microorganisms are most resistant to it. For the purposes of experimenting, five types of semisolid systems were modeled: hydrogel, oleogel, absorption-hydrophobic ointment, oil-in-water-type cream and water-in-oil-type cream, which contained rosemary extract as an active ingredient. Study results show that liquid rosemary extract was distributed evenly in the aqueous phase of water-in-oil-type system, forming the stable emulsion systems. The following research aim was chosen to evaluate the semisolid systems with rosemary exctract: to model semisolid preparations with liquid rosemary extract and determine the influence of excipients on their quality, and perform in vitro study of the release of active ingredients and antimicrobial activity. It was found that oil-in-water type gel-cream has antimicrobial activity against Staphylococcus epidermidis bacteria and Candida albicans fungus, while hydrogel affected only Candida albicans. According to the results of biopharmaceutical study, modeled semisolid systems with rosemary extract can be arranged in an ascending order of the release of phenolic compounds from the forms: water-in-oil-type cream rosemary extract used as an active ingredient. PMID:27008810

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

    Directory of Open Access Journals (Sweden)

    Lorena Barbosa Arrunátegui

    2015-03-01

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

  14. Hairy roots culture as a source of valuable biopharmaceuticals.

    Science.gov (United States)

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

    2016-01-01

    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. PMID:26864059

  15. Hairy roots culture as a source of valuable biopharmaceuticals

    Directory of Open Access Journals (Sweden)

    Tomasz Kowalczyk

    2016-01-01

    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.

  16. With the help of a foreign ally: biopharmaceutical innovation in India after TRIPS.

    Science.gov (United States)

    Angeli, Federica

    2014-05-01

    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

  17. Mayo, Myriad, America Invents Act and BPCIA: how has the United States biopharmaceutical market been affected?

    Science.gov (United States)

    Finston, Susan K; Davey, Neil S; Davé, Elina; Ravichandran, Varsha; Davey, Sonya R; Davé, Raj S

    2016-05-01

    This paper discusses how the United States biopharmaceutical market has been affected by recent changes in patent law resulting from United States legislations (Biologics Price Competition and Innovation Act and the Leahy-Smith America Invents Act) and Supreme Court precedents (Mayo Collaborative Services v. Prometheus Laboratories, Inc. and Molecular Pathology v. Myriad Genetics). The authors interviewed eight key opinion leaders from the United States knowledgeable in biopharmaceuticals, including industry veterans, patent counsel, senior scientists and jurists. This paper summarizes the opinions of the key opinion leaders. This paper explains the impact of these Supreme Court decisions - i.e., broadening the exceptions to patent eligibility for law of nature and natural phenomenon - on biopharmaceutical innovations and provides future perspectives. PMID:27087460

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

    Science.gov (United States)

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

    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.

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

    DEFF Research Database (Denmark)

    Huang, Mingtao; Bao, Jichen; Nielsen, Jens

    2014-01-01

    In the past few decades there has been an increasing demand of biopharmaceutical proteins in the market. Several types of cell factories are applied to produce different pharmaceutical proteins. However, manufacturers prefer to use a few favorable biological platforms to undertake the production...

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

    Science.gov (United States)

    Hsieh, Chee-Ruey; Löfgren, Hans

    2009-05-01

    South Korea, Singapore and Taiwan are well known as export-oriented developmental states which for decades employed industrial policy to target particular industries for government support. In the past fifteen years, these three countries all identified the biopharmaceutical industry as a strategic sector. This article explores, through economic analysis, the rationale for this decision and the strategies chosen for linking into the global bio-economy with the objective of catching up in biopharmaceuticals. The paper identifies three comparative advantages enjoyed by these countries in the biopharma sector: (1) public investments in basic research; (2) private investments in phase 1 clinical trials; and (3) a potentially significant contract research industry managing latter-stage clinical trials. Governments employ a range of industrial policies, consistent with these comparative advantages, to promote the biopharmaceutical industry, including public investment in biomedical hubs, research funding and research and development (R&D) tax credits. We argue that the most important feature of the biopharmaceutical industry in these countries is the dominant role of the public sector. That these countries have made progress in innovative capabilities is illustrated by input measures such as R&D expenditure as share of gross domestic product, number of patents granted and clinical trials, and volume of foreign direct investment. In contrast, output indicators such as approval of new chemical entities suggest that the process of catching up has only just commenced. Pharmaceutical innovation is at the stage of mainly generating inputs to integrated processes controlled by the globally incumbent firms. PMID:19563313

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

    International Nuclear Information System (INIS)

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

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

    OpenAIRE

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

    2014-01-01

    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 nee...

  3. A novel in vitro method to model the fate of subcutaneously administered biopharmaceuticals and associated formulation components.

    OpenAIRE

    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.

    2015-01-01

    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 Sit...

  4. Bioequivalence of Oral Products and the Biopharmaceutics Classification System: Science, Regulation, and Public Policy

    OpenAIRE

    Amidon, KS; Langguth, P; Lennernäs, H; Yu, L; Amidon, GL

    2011-01-01

    The demonstration of bioequivalence (BE) is an essential requirement for ensuring that patients receive a product that performs as indicated by the label. The BE standard for a particular product is set by its innovator, and this standard must subsequently be matched by generic drug products. The Biopharmaceutics Classification System (BCS) sets a scientific basis for an improved BE standard for immediate-release solid oral dosage forms. In this paper, we discuss BE and the BCS, as well as th...

  5. The Utility of Hydrogen/Deuterium Exchange Mass Spectrometry in Biopharmaceutical Comparability Studies

    OpenAIRE

    Houde, Damian; Berkowitz, Steven A; Engen, John R.

    2010-01-01

    The function, efficacy, and safety of protein biopharmaceuticals are tied to their three-dimensional structure. The analysis and verification of this higher-order structure are critical in demonstrating manufacturing consistency and in establishing the absence of structural changes in response to changes in production. It is, therefore, essential to have reliable, high-resolution and high sensitivity biophysical tools capable of interrogating protein structure and conformation. Here, we demon...

  6. Physicochemical and Biopharmaceutical Characterisation of Small Drug Molecules by Capillary Electrophoresis

    OpenAIRE

    Örnskov, Eivor

    2004-01-01

    Capillary Electrophoresis (CE) was explored as a means for physicochemical and biopharmaceutical characterisation of small drug molecules. Special attention was paid to the characterisation of acid-base and lipophilic properties of drug compounds by analysing their migration behaviour in different CE systems. The thesis comprises an overview of the field together with separate studies on the different topics. The utility of CE for the determination of pKa of labile drug compounds was investig...

  7. A decision-support tool for strategic decision-making in biopharmaceutical manufacture.

    OpenAIRE

    Lim, A.C.

    2005-01-01

    The need for software tools to support decision-making relating to biomanufacture is becoming increasingly critical in order to accelerate the time-to-market and reduce costs. The main objective of this thesis is the design and implementation of a decision-support tool that integrates both the business and process perspectives of biopharmaceutical manufacture to aid the evaluation of manufacturing alternatives. The tool, designated BioPharmKit, was built on the platform of the simulation pack...

  8. Regulation of biopharmaceuticals, tissue engineering and biogenerics : key issues for the developer

    OpenAIRE

    Oila, Outi

    2005-01-01

    The objective of the present study is to examine the effect of regulation on development of new biopharmaceuticals, tissue engineering and biogenerics. This includes defining key issues, which may influence the outcome of receiving marketing authorization. Most of the results are based on interviews conducted with experts with different backgrounds: regulators, representatives of biocompanies, investors, researchers and representatives of trade associations. Product information retrievable fr...

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

    Science.gov (United States)

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

    2015-01-01

    Biopharmaceuticals are a generation of drugs that include peptides, proteins, nucleic acids and cell products. According to their particular molecular characteristics (e.g. high molecular size, susceptibility to enzymatic activity), these products present some limitations for administration and usually parenteral routes are the only option. To avoid these limitations, different colloidal carriers (e.g. liposomes, micelles, microemulsions and dendrimers) have been proposed to improve biopharmaceuticals delivery. Liposomes are promising drug delivery systems, despite some limitations have been reported (e.g. in vivo failure, poor long-term stability and low transfection efficiency), and only a limited number of formulations have reached the market. Micelles and microemulsions require more studies to exclude some of the observed drawbacks and guarantee their potential for use in clinic. According to their peculiar structures, dendrimers have been showing good results for nucleic acids delivery and a great development of these systems during next years is expected. This is the Part II of two review articles, which provides the state of the art of biopharmaceuticals delivery systems. Part II deals with liposomes, micelles, microemulsions and dendrimers. PMID:26278524

  10. Nonclinical safety testing of biopharmaceuticals--Addressing current challenges of these novel and emerging therapies.

    Science.gov (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

    2015-10-01

    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. PMID:26219199

  11. The roles of patents and research and development incentives in biopharmaceutical innovation.

    Science.gov (United States)

    Grabowski, Henry G; DiMasi, Joseph A; Long, Genia

    2015-02-01

    Patents and other forms of intellectual property protection play essential roles in encouraging innovation in biopharmaceuticals. As part of the "21st Century Cures" initiative, Congress is reviewing the policy mechanisms designed to accelerate the discovery, development, and delivery of new treatments. Debate continues about how best to balance patent and intellectual property incentives to encourage innovation, on the one hand, and generic utilization and price competition, on the other hand. We review the current framework for accomplishing these dual objectives and the important role of patents and regulatory exclusivity (together, the patent-based system), given the lengthy, costly, and risky biopharmaceutical research and development process. We summarize existing targeted incentives, such as for orphan drugs and neglected diseases, and we consider the pros and cons of proposed voluntary or mandatory alternatives to the patent-based system, such as prizes and government research and development contracting. We conclude that patents and regulatory exclusivity provisions are likely to remain the core approach to providing incentives for biopharmaceutical research and development. However, prizes and other voluntary supplements could play a useful role in addressing unmet needs and gaps in specific circumstances. PMID:25646111

  12. A novel in vitro method to model the fate of subcutaneously administered biopharmaceuticals and associated formulation components.

    Science.gov (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

    2015-09-28

    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

  13. Physiologically Based Absorption Modeling to Impact Biopharmaceutics and Formulation Strategies in Drug Development-Industry Case Studies.

    Science.gov (United States)

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

    2016-09-01

    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. PMID:26886317

  14. Provisional biopharmaceutical classification of some common herbs used in Western medicine.

    Science.gov (United States)

    Waldmann, Sarah; Almukainzi, May; Bou-Chacra, Nadia Araci; Amidon, Gordon L; Lee, Beom-Jin; Feng, Jianfang; Kanfer, Isadore; Zuo, Joan Zhong; Wei, Hai; Bolger, Michael B; Löbenberg, Raimar

    2012-04-01

    The aim of this study was to classify some markers of common herbs used in Western medicine according to the Biopharmaceutical Classification System (BCS). The BCS is a scientific approach to classify drug substances based upon their intestinal permeability and their solubility, at the highest single dose used, within the physiologically relevant pH ranges. Known marker components of twelve herbs were chosen from the USP Dietary Supplement Compendium Monographs. Different BCS parameters such as intestinal permeability (P(eff)) and solubility (C(s)) were predicted using the ADMET Predictor, which is a software program to estimate biopharmaceutical relevant molecular descriptors. The dose number (D₀) was calculated when information from the literature was available to identify an upper dose for individual markers. In these cases the herbs were classified according to the traditional BCS parameters using P(eff) and D₀. When no upper dose could be determined, then the amount of a marker that is just soluble in 250 mL of water was calculated. This value, M(x), defines when a marker is changing from highly soluble to poorly soluble according to BCS criteria. This biopharmaceutically relevant value can be a useful tool for marker selection. The present study showed that a provisional BCS classification of herbs is possible but some special considerations need to be included into the classification strategy. The BCS classification can be used to choose appropriate quality control tests for products containing these markers. A provisional BCS classification of twelve common herbs and their 35 marker compounds is presented. PMID:22352942

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

    DEFF Research Database (Denmark)

    Rup, B; Pallardy, M; Sikkema, D;

    2015-01-01

    is made difficult due to lack of agreement on concepts, practices and standardized terms and definitions related to immunogenicity. The Innovative Medicines Initiative (IMI; www.imi-europe.org), ABIRISK consortium [Anti-Biopharmaceutical (BP) Immunization Prediction and Clinical Relevance to Reduce...... 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...

  16. Quality control and assurance from the development to the production of biopharmaceuticals.

    Science.gov (United States)

    Doblhoff-Dier, O; Bliem, R

    1999-07-01

    Consumer and patient safety have become the prerequisites for (bio)pharmaceutical product development, production and marketing. The ability to provide an effective, pure, safe product is the primary factor determining the product's success. However, with an ever-increasing number of national and international regulations, 'quality assurance' has acquired a threatening ring for many project managers. Many think that ensuring and improving quality is expensive, but regulations aid public acceptance. Good manufacturing practice can be developed into a business asset and need not be seen as merely a regulatory hurdle. PMID:10370232

  17. Current Developments and Future Prospects for Plant-Made Biopharmaceuticals Against Rabies.

    Science.gov (United States)

    Rosales-Mendoza, Sergio

    2015-10-01

    Rabies is a prevalent health problem in developing countries. Although vaccines and immunoglobulin treatments are available, their cost and multiple-dose treatments restrict availability. During the last two decades, plants have served as a low-cost platform for biopharmaceuticals production and have been applied to fight against rabies during the last two decades. Herein, I provide a description of the state of the art in the development of plant-made pharmaceuticals against rabies and identify key prospects for the field in terms of novel strategies, immunogen design, and therapeutic antibodies production. PMID:26163274

  18. The identification of factors linked to the potential acceptance of transgenic biopharmaceuticals: an exploratory study.

    Science.gov (United States)

    Duguay, Francois; Katsanis, Lea Prevel; Thakor, Mrugank V

    2003-01-01

    In this exploratory study, Rogers' diffusion of innovation theory was used to identify which factors are likely to contribute to the potential acceptance of transgenic biopharmaceuticals (TG-Bs). These products are not yet available to the general public. A scale was designed to assess three of five core attributes related to the potential adoption rate of innovations (Rogers 1995), as well as to measure potential acceptance characteristics for biotechnology products. These attributes were relative advantage, compatibility with existing values, and complexity. In addition, two other characteristics were included: knowledge (Gartrell and Gartrell 1979) and perceived risks (Bauer 1960). The survey was completed by 74 consumers (78% response rate) using convenience sampling. The research findings show that Rogers' three core attributes are supported, but that knowledge andperceived risks were excluded from the model. The model for transgenic biopharmaceuticals consists of: 1. Consumer-related benefits (positively correlated to potential adoption). 2. New types of animals (negatively correlated to potential 3. Perceived complexity (negatively correlated to potential adoption). All the scaled items developed for this study were highly significant, which indicates that they can be used successfully by other researchers working in this field. As TG-Bs are a discontinuous innovation, biotechnology companies may need to present the benefits of these products, as well as the ease of their use prior to their launch, in order to increase their potential acceptance by consumers. PMID:15271632

  19. Potential of hydrophilic interaction chromatography for the analytical characterization of protein biopharmaceuticals.

    Science.gov (United States)

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

    2016-05-27

    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. PMID:27131959

  20. PEGylation of Biopharmaceuticals: A Review of Chemistry and Nonclinical Safety Information of Approved Drugs.

    Science.gov (United States)

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

    2016-02-01

    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. PMID:26869412

  1. Applications of imaged capillary isoelectric focussing technique in development of biopharmaceutical glycoprotein-based products.

    Science.gov (United States)

    Anderson, Carrie L; Wang, Yang; Rustandi, Richard R

    2012-06-01

    CE-based methods have increasingly been applied to the analysis of a variety of different type proteins. One of those techniques is imaged capillary isoelectric focusing (icIEF), a method that has been used extensively in the field of protein-based drug development as a tool for product identification, stability monitoring, and characterization. It offers many advantages over the traditional labor-intensive IEF slab gel method and even standard cIEF with on-line detection technologies with regard to method development, reproducibility, robustness, and speed. Here, specific examples are provided for biopharmaceutical glycoprotein products such as mAbs, erythropoietin (EPO), and recombinant Fc-fusion proteins, though the technique can be adapted for many other therapeutic proteins. Applications of iCIEF using a Convergent Bioscience instrument (Toronto, Canada) with whole-field imaging technology are presented and discussed. These include a quick method to establish an identity test for many protein-based products, product release, and stability evaluation of glycoproteins with respect to charge heterogeneity under accelerated temperature stress, different pH conditions, and in different formulations. Finally, characterization of glycoproteins using this iCIEF technology is discussed with respect to biosimilar development, clone selection, and antigen binding. The data presented provide a "taste'' of what icIEF method can do to support the development of biopharmaceutical glycoprotein products from early clone screening for better product candidates to characterization of the final commercial products. PMID:22736354

  2. Use of physiologically relevant biopharmaceutics tools within the pharmaceutical industry and in regulatory sciences: Where are we now and what are the gaps?

    Science.gov (United States)

    Flanagan, Talia; Van Peer, Achiel; Lindahl, Anders

    2016-08-25

    Regulatory interactions are an important part of the drug development and licensing process. A survey on the use of biopharmaceutical tools for regulatory purposes has been carried out within the industry community of the EU project OrBiTo within Innovative Medicines Initiative (IMI). The aim was to capture current practice and experience in using in vitro and in silico biopharmaceutics tools at various stages of development, what barriers exist or are perceived, and to understand the current gaps in regulatory biopharmaceutics. The survey indicated that biorelevant dissolution testing and physiologically based modelling and simulation are widely applied throughout development to address a number of biopharmaceutics issues. However, data from these in vitro and in silico predictive biopharmaceutics tools are submitted to regulatory authorities far less often than they are used for internal risk assessment and decision making. This may prevent regulators from becoming familiar with these tools and how they are applied in industry, and limits the opportunities for biopharmaceutics scientists working in industry to understand the acceptability of these tools in the regulatory environment. It is anticipated that the advanced biopharmaceutics tools and understanding delivered in the next years by OrBiTo and other initiatives in the area of predictive tools will also be of value in the regulatory setting, and provide a basis for more informed and confident biopharmaceutics risk assessment and regulatory decision making. To enable the regulatory potential of predictive biopharmaceutics tools to be realized, further scientific dialogue is needed between industry, regulators and scientists in academia, and more examples need to be published to demonstrate the applicability of these tools. PMID:27283487

  3. [Overregulation and unnecessary animal testing: requirements for market approval of biopharmaceuticals too rigid].

    Science.gov (United States)

    Schellekens, Huub

    2012-01-01

    The first biopharmaceutical was introduced more than 30 years ago. From the beginning, experts have doubted the scientific basis for preclinical safety testing of these products on animals, including non-human primates. Long clinical experience confirms that this has no scientific basis. The many guidelines introduced over the years, including the recent revision of ICH S6, are still based on the principles of the classical safety evaluation of small molecules. The reasons for this conservatism include the risk-averse attitude of regulators in general and, at the European level, the low influx of new scientific insights due to the way the marketing authorisation is organised. The members of the scientific committees of the EMA are almost exclusively selected from within the regulatory systems and there is no limit in the time they can serve in these committees. PMID:23231875

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

    International Nuclear Information System (INIS)

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

  5. GLIMPSE ON PROTEIN DRUG DELIVERY: AN UTMOST RESEARCH AREA FOR BIOPHARMACEUTICALS

    Directory of Open Access Journals (Sweden)

    YAGNESH A BHATT

    2010-06-01

    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.

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

    International Nuclear Information System (INIS)

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

  7. The importance of patents to innovation: updated cross-industry comparisons with biopharmaceuticals.

    Science.gov (United States)

    Cockburn, Iain; Long, Genia

    2015-07-01

    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. PMID:25927945

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

    Science.gov (United States)

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

    2014-01-01

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

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

    Science.gov (United States)

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

    2011-09-01

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

  10. Formulation of Controlled-Release Capsules of Biopharmaceutical Classification System I Drugs Using Niacin as a Model

    OpenAIRE

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

    2010-01-01

    Vitamin B3 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 for...

  11. Oral biopharmaceutics tools - time for a new initiative - an introduction to the IMI project OrBiTo.

    Science.gov (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

    2014-06-16

    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. PMID:24189462

  12. Biopharmaceutics classification system-based biowaivers for generic oncology drug products: case studies.

    Science.gov (United States)

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

    2015-02-01

    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. PMID:25245330

  13. Industry view on the relative importance of "clonality" of biopharmaceutical-producing cell lines.

    Science.gov (United States)

    Frye, Christopher; Deshpande, Rohini; Estes, Scott; Francissen, Kathy; Joly, John; Lubiniecki, Anthony; Munro, Trent; Russell, Reb; Wang, Tongtong; Anderson, Karin

    2016-03-01

    Recently, several health authorities have requested substantial detail from sponsor firms regarding the practices employed to generate the production cell line for recombinant DNA-(rDNA) derived biopharmaceuticals. Two possible inferences from these regulatory agency questions are that (1) assurance of "clonality" of the production cell line is of major importance to assessing the safety and efficacy of the product and (2), without adequate proof of "clonality", additional studies of the cell line and product are often required to further ensure the product's purity and homogeneity. Here we address the topic of "clonality" in the broader context of product quality assurance by current technologies and practices, as well as discuss some of the relevant science and historical perspective. We agree that the clonal derivation of a production cell line is one factor with potential impact, but it is only one of many factors. Further, we believe that regulatory emphasis should be primarily placed on ensuring product quality of the material actually administered to patients, and on ensuring process consistency and implementing appropriate control strategies through the life cycle of the products. PMID:26852257

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

    Science.gov (United States)

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

    2016-01-01

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

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

    Science.gov (United States)

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

    2016-09-01

    The economic advantages of continuous processing of biopharmaceuticals, which include smaller equipment and faster, efficient processes, have increased interest in this technology over the past decade. Continuous processes can also improve quality assurance and enable greater controllability, consistent with the quality initiatives of the FDA. Here, we discuss different continuous multi-column chromatography processes. Differences in the capture and polishing steps result in two different types of continuous processes that employ counter-current column movement. Continuous-capture processes are associated with increased productivity per cycle and decreased buffer consumption, whereas the typical purity-yield trade-off of classical batch chromatography can be surmounted by continuous processes for polishing applications. In the context of continuous manufacturing, different but complementary chromatographic columns or devices are typically combined to improve overall process performance and avoid unnecessary product storage. In the following, these various processes, their performances compared with batch processing and resulting product quality are discussed based on a review of the literature. Based on various examples of applications, primarily monoclonal antibody production processes, conclusions are drawn about the future of these continuous-manufacturing technologies. PMID:27376629

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

    Directory of Open Access Journals (Sweden)

    Ya-Shan Chen

    2015-02-01

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

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

    Science.gov (United States)

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

    2012-02-01

    The entry of biosimilar forms of biopharmaceutical therapies for the treatment of psoriasis and other immune-mediated disorders has provoked considerable interest. Although dermatologists are accustomed to the use of a wide range of generic topical agents, recognition of key differences between original agent (ie, the name brand) and the generic or biosimilar agent is necessary to support optimal therapy management and patient care. In this review we have summarized the current state of the art related to the impending introduction of biosimilars into dermatology. Biosimilars represent important interventions that are less expensive and hence offer the potential to deliver benefit to large numbers of patients who may not currently be able to access these therapies. But the development of biosimilars is not equivalent to that of small molecule generic therapies because of differences in molecular structure and processes of manufacture. The planned regulatory guidelines and path to approval may not encompass all of these potentially important differences and this may have clinical relevance to the prescriber and patient. Consequently, we have identified a series of key issues that should be considered to support the full potential of biosimilars for the treatment of psoriasis; ie, that of increased access to appropriate therapy for the psoriasis population worldwide. PMID:22243723

  18. Biopharmaceutical profile of pranoprofen-loaded PLGA nanoparticles containing hydrogels for ocular administration.

    Science.gov (United States)

    Abrego, Guadalupe; Alvarado, Helen; Souto, Eliana B; Guevara, Bessy; Bellowa, Lyda Halbaut; Parra, Alexander; Calpena, Ana; Garcia, María Luisa

    2015-09-01

    Two optimized pranoprofen-loaded poly-l-lactic-co glycolic acid (PLGA) nanoparticles (PF-F1NPs; PF-F2NPs) have been developed and further dispersed into hydrogels for the production of semi-solid formulations intended for ocular administration. The optimized PF-NP suspensions were dispersed in freshly prepared carbomer hydrogels (HG_PF-F1NPs and HG_PF-F2NPs) or in hydrogels containing 1% azone (HG_PF-F1NPs-Azone and HG_PF-F2NPs-Azone) in order to improve the ocular biopharmaceutical profile of the selected non-steroidal anti-inflammatory drug (NSAID), by prolonging the contact of the pranoprofen with the eye, increasing the drug retention in the organ and enhancing its anti-inflammatory and analgesic efficiency. Carbomer 934 has been selected as gel-forming polymer. The hydrogel formulations with or without azone showed a non-Newtonian behavior and adequate physicochemical properties for ocular instillation. The release study of pranoprofen from the semi-solid formulations exhibited a sustained release behavior. The results obtained from ex vivo corneal permeation and in vivo anti-inflammatory efficacy studies suggest that the ocular application of the hydrogels containing azone was more effective over the azone-free formulations in the treatment of edema on the ocular surface. No signs of ocular irritancy have been detected for the produced hydrogels. PMID:25681744

  19. Prospects of pharmaceuticals and biopharmaceuticals loaded microparticles prepared by double emulsion technique for controlled delivery.

    Science.gov (United States)

    Giri, Tapan Kumar; Choudhary, Chhatrapal; Ajazuddin; Alexander, Amit; Badwaik, Hemant; Tripathi, Dulal Krishna

    2013-04-01

    Several methods and techniques are potentially useful for the preparation of microparticles in the field of controlled drug delivery. The type and the size of the microparticles, the entrapment, release characteristics and stability of drug in microparticles in the formulations are dependent on the method used. One of the most common methods of preparing microparticles is the single emulsion technique. Poorly soluble, lipophilic drugs are successfully retained within the microparticles prepared by this method. However, the encapsulation of highly water soluble compounds including protein and peptides presents formidable challenges to the researchers. The successful encapsulation of such compounds requires high drug loading in the microparticles, prevention of protein and peptide degradation by the encapsulation method involved and predictable release, both rate and extent, of the drug compound from the microparticles. The above mentioned problems can be overcome by using the double emulsion technique, alternatively called as multiple emulsion technique. Aiming to achieve this various techniques have been examined to prepare stable formulations utilizing w/o/w, s/o/w, w/o/o, and s/o/o type double emulsion methods. This article reviews the current state of the art in double emulsion based technologies for the preparation of microparticles including the investigation of various classes of substances that are pharmaceutically and biopharmaceutically active. PMID:23960828

  20. Immunochromatographic removal of albumin in erythropoietin biopharmaceutical formulations for its analysis by capillary electrophoresis.

    Science.gov (United States)

    Lara-Quintanar, Pilar; Lacunza, Izaskun; Sanz, Jesus; Diez-Masa, Jose Carlos; de Frutos, Mercedes

    2007-06-15

    Human serum albumin (HSA) is added to some pharmaceutical preparations as an excipient. This is the case for some of the commercial preparations of recombinant erythropoietin (rEPO). Differences in the number of the sialic acid moieties in the different rEPO glycoforms confer to these forms different net charges and different bioactivity. Knowledge of the isoforms present in each pharmaceutical product is then of interest. Differences in net charge of the rEPO forms make possible their separation by electrophoretical methods. However it has been observed in our laboratory that the amount of HSA usually present in these drug formulations interferes or even precludes separation of rEPO bands by capillary zone electrophoresis (CZE). In this work, an immunochromatographic method to remove HSA from rEPO biopharmaceutical formulations and a procedure to concentrate the sample that is needed to be performed prior to the analysis by CZE are developed. A home-made computer program to compare the percentage of correct assignments of electrophoretical bands provided by different migration parameters is used to study the effect of HSA remaining in samples on the accuracy of assignment of rEPO bands. When there exists a residual concentration of HSA in the sample (studies and for the quality control laboratories of the manufacturers. PMID:16919660

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

    Science.gov (United States)

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

    2011-01-01

    The advent of advanced therapies in the pharmaceutical industry has moved the spotlight into virus-like particles and viral vectors produced in cell culture holding great promise in a myriad of clinical targets, including cancer prophylaxis and treatment. Even though a couple of cases have reached the clinic, these products have yet to overcome a number of biological and technological challenges before broad utilization. Concerning the manufacturing processes, there is significant research focusing on the optimization of current cell culture systems and, more recently, on developing scalable downstream processes to generate material for pre-clinical and clinical trials. We review the current options for downstream processing of these complex biopharmaceuticals and underline current advances on knowledge-based toolboxes proposed for rational optimization of their processing. Rational tools developed to increase the yet scarce knowledge on the purification processes of complex biologicals are discussed as alternative to empirical, "black-boxed" based strategies classically used for process development. Innovative methodologies based on surface plasmon resonance, dynamic light scattering, scale-down high-throughput screening and mathematical modeling for supporting ion-exchange chromatography show great potential for a more efficient and cost-effective process design, optimization and equipment prototyping. PMID:21784144

  2. Mass Spectrometry Based Mechanistic Insights into Formation of Tris Conjugates: Implications on Protein Biopharmaceutics

    Science.gov (United States)

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

    2016-08-01

    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.

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

    Science.gov (United States)

    Kristensen, Mie; Nielsen, Hanne Mørck

    2016-02-01

    Oral delivery of biopharmaceuticals, for example peptides and proteins, constitutes a great challenge in drug delivery due to their low chemical stability and poor permeation across the intestinal mucosa, to a large extent limiting the mode of administration to injections, which is not favouring patient compliance. Nevertheless, cell-penetrating peptides (CPPs) have shown promising potential as carriers to overcome the epithelium, and this minireview highlights recent knowledge gained within the field of CPP-mediated transepithelial delivery of therapeutic peptides and proteins from the intestine. Two approaches may be pursued: co-administration of the carrier and therapeutic peptide in the form of complexes obtained by simple bulk mixing, or administration of covalent conjugates demanding more advanced production methodologies. These formulation approaches have their pros and cons, and which is to be preferred depends on the physicochemical properties of both the specific CPP and the specific cargo. In addition to the physical epithelial barrier, a metabolic barrier must be overcome in order to obtain CPP-mediated delivery of a cargo drug from the intestine, and a number of strategies have been employed to delay enzymatic degradation of the CPP. The mechanisms by which CPPs translocate across membranes are not fully understood, but possibly involve endocytosis as well as direct translocation, and the CPP-mediated transepithelial delivery of cargo drugs thus likely involves similar mechanisms for the initial membrane interaction and translocation. However, the mechanisms responsible for transcytosis of the cargo drug, if taken up by an endocytic mechanism, or direct translocation across the epithelium are so far not known. PMID:26525297

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

    Science.gov (United States)

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

    2014-06-16

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

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

    Science.gov (United States)

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

    2014-01-01

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

  6. Optimizing novel implant formulations for the prolonged release of biopharmaceuticals using in vitro and in vivo imaging techniques.

    Science.gov (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

    2016-08-10

    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. PMID:27288876

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

    Science.gov (United States)

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

    2015-07-15

    The purpose of this work was to study the challenges and prospects of regional-dependent absorption in a controlled-release scenario, through the oral biopharmaceutics of the sulfonylurea antidiabetic drug glipizide. The BCS solubility class of glipizide was determined, and its physicochemical properties and intestinal permeability were thoroughly investigated, both in-vitro (PAMPA and Caco-2) and in-vivo in rats. Metoprolol was used as the low/high permeability class boundary marker. Glipizide was found to be a low-solubility compound. All intestinal permeability experimental methods revealed similar trend; a mirror image small intestinal permeability with opposite regional/pH-dependency was obtained, a downward trend for glipizide, and an upward trend for metoprolol. Yet the lowest permeability of glipizide (terminal Ileum) was comparable to the lowest permeability of metoprolol (proximal jejunum). At the colon, similar permeability was evident for glipizide and metoprolol, that was higher than metoprolol's jejunal permeability. We present an analysis that identifies metoprolol's jejunal permeability as the low/high permeability class benchmark anywhere throughout the intestinal tract; we show that the permeability of both glipizide and metoprolol matches/exceeds this threshold throughout the entire intestinal tract, accounting for their success as controlled-release dosage form. This represents a key biopharmaceutical characteristic for a successful controlled-release dosage form. PMID:25957705

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

    Science.gov (United States)

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

    2012-01-01

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

  9. Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: Recommendations of the innovative medicines initiative ABIRISK consortium

    OpenAIRE

    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.; Holland, M.C.

    2015-01-01

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

  10. In situ near-infrared (NIR) versus high-throughput mid-infrared (MIR) spectroscopy to monitor biopharmaceutical production.

    Science.gov (United States)

    Sales, Kevin C; Rosa, Filipa; Sampaio, Pedro N; Fonseca, Luís P; Lopes, Marta B; Calado, Cecília R C

    2015-06-01

    The development of biopharmaceutical manufacturing processes presents critical constraints, with the major constraint being that living cells synthesize these molecules, presenting inherent behavior variability due to their high sensitivity to small fluctuations in the cultivation environment. To speed up the development process and to control this critical manufacturing step, it is relevant to develop high-throughput and in situ monitoring techniques, respectively. Here, high-throughput mid-infrared (MIR) spectral analysis of dehydrated cell pellets and in situ near-infrared (NIR) spectral analysis of the whole culture broth were compared to monitor plasmid production in recombinant Escherichia coli cultures. Good partial least squares (PLS) regression models were built, either based on MIR or NIR spectral data, yielding high coefficients of determination (R(2)) and low predictive errors (root mean square error, or RMSE) to estimate host cell growth, plasmid production, carbon source consumption (glucose and glycerol), and by-product acetate production and consumption. The predictive errors for biomass, plasmid, glucose, glycerol, and acetate based on MIR data were 0.7 g/L, 9 mg/L, 0.3 g/L, 0.4 g/L, and 0.4 g/L, respectively, whereas for NIR data the predictive errors obtained were 0.4 g/L, 8 mg/L, 0.3 g/L, 0.2 g/L, and 0.4 g/L, respectively. The models obtained are robust as they are valid for cultivations conducted with different media compositions and with different cultivation strategies (batch and fed-batch). Besides being conducted in situ with a sterilized fiber optic probe, NIR spectroscopy allows building PLS models for estimating plasmid, glucose, and acetate that are as accurate as those obtained from the high-throughput MIR setup, and better models for estimating biomass and glycerol, yielding a decrease in 57 and 50% of the RMSE, respectively, compared to the MIR setup. However, MIR spectroscopy could be a valid alternative in the case of optimization

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

    Science.gov (United States)

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

    2015-01-01

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

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

    Science.gov (United States)

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

    2012-11-01

    A methodology based on on-line coupling of size exclusion chromatography (SEC) with mixed-mode liquid chromatography (LC) has been developed. The method allows for simultaneous measurement of a wide range of components in biopharmaceutical drug products. These components include the active pharmaceutical ingredient (protein) and various kinds of excipients such as cations, anions, nonionic hydrophobic surfactant and hydrophilic sugars. Dual short SEC columns are used to separate small molecule excipients from large protein molecules. The separated protein is quantified using a UV detector at 280 nm. The isolated excipients are switched, online, to the Trinity P1 mixed-mode column for separation, and detected by an evaporative light scattering detector (ELSD). Using a stationary phase with 1.7 μm particles in SEC allows for the use of volatile buffers for both SEC and mix-mode separation. This facilitates the detection of different excipients by ELSD and provides potential for online characterization of the protein with mass spectrometry (MS). The method has been applied to quantitate protein and excipients in different biopharmaceutical drug products including monoclonal antibodies (mAb), antibody drug conjugates (ADC) and vaccines. PMID:22999205

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

    Science.gov (United States)

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

    2016-05-10

    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. PMID:26918895

  14. 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

    2009-01-01

    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.

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

    International Nuclear Information System (INIS)

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

  16. 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.

    Science.gov (United States)

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

    2015-12-01

    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. PMID:26747917

  17. In vitro-in vivo correlation strategy applied to an immediate-release solid oral dosage form with a biopharmaceutical classification system IV compound case study.

    Science.gov (United States)

    Bredael, Gerard M; Bowers, Niya; Boulineau, Fabien; Hahn, David

    2014-07-01

    The ability to predict in vivo response of an oral dosage form based on an in vitro technique has been a sought after goal of the pharmaceutical scientist. Dissolution testing that demonstrates discrimination to various critical formulations or process attributes provides a sensitive quality check that may be representative or may be overpredictive of potential in vivo changes. Dissolution methodology with an established in vitro-in vivo relationship or correlation may provide the desired in vivo predictability. To establish this in vitro-in vivo link, a clinical study must be performed. In this article, recommendations are given in the selection of batches for the clinical study followed by potential outcome scenarios. The investigation of a Level C in vitro-in vivo correlation (IVIVC), which is the most common correlation for immediate-release oral dosage forms, is presented. Lastly, an IVIVC case study involving a biopharmaceutical classification system class IV compound is presented encompassing this strategy and techniques. PMID:24890761

  18. 生物药剂学与药物动力学实验教学模式的改革与创新%The innovation of the experimental teaching model of bio-pharmaceutics and pharmacokinetics

    Institute of Scientific and Technical Information of China (English)

    汤玥; 刘建平; 朱家壁

    2009-01-01

    In terms of objectives for the training of pharmaceutical talents and teaching characteris- tics of the experiments of biopharmaceutics and pharmacokinetics, this paper reviews the new method in the experimental teaching of biopharmaceutics and pharmacokinetics from several aspects, namely, teaching content, teaching approaches and evaluation method.%本文根据药学本科专业培养目标和生物药剂学与药物动力学实验教学特点,从实验教学内容、教学方法、考核方法等方面探讨了生物药剂学与药物动力学的实验教学新模式.

  19. Biopharmaceutical profile of hydrogels containing pranoprofen-loaded PLGA nanoparticles for skin administration: In vitro, ex vivo and in vivo characterization.

    Science.gov (United States)

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

    2016-03-30

    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. PMID:26844786

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

    Science.gov (United States)

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

    2016-09-01

    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. PMID:26886314

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

    Directory of Open Access Journals (Sweden)

    NU Rahman

    2011-05-01

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

  2. Discussion on Bio-pharmaceutical Technology Characteristic Specialty Construction%生物制药技术特色专业建设的探索

    Institute of Scientific and Technical Information of China (English)

    蔡晶晶; 王雅洁; 王蔷; 宋小平

    2015-01-01

    It aims to discuss issues concerning distinguishing specialty construction and personnel cultivation mode. Take bio-pharmaceutical technology specialty in a univeristy, a provincial characteristic specialty construction site, as an example, this paper summarized the teaching practice and proposed the construction of characteristic speciality in terms of personnel cultivation mode reform, enriching specialty connotation, speciality construction criteria, strengthening social service function and refining specialty features, maintaining that adherence to innovative construction and elevation of personnel cultivation quality are crucial to the sustainable development of speciality courses.%探讨特色专业建设及其人才培养模式问题。以某校省级特色专业建设点———生物制药技术专业为例,总结教学实践,并从改革人才培养模式、充实专业内涵、建设专业标准、增强社会服务功能、凝练专业特色等方面提出建设特色专业的工作构想,认为坚持创新性特色建设和提高人才培养质量是专业可持续发展的根本保障。

  3. 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.

    Science.gov (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

    2011-08-01

    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. PMID:21630662

  4. Development of serum-free media for the cultivation and recovery of Acholeplasma laidlawii used for challenge testing sterilizing-grade filters in biopharmaceutical applications.

    Science.gov (United States)

    Bates, Shawn; Nguyen, Nhung; Lentine, Kerry Roche

    2008-01-01

    A serum-free cultivation broth and recovery agar for use in 0.1 micron-rated filter characterization and validation studies for biopharmaceutical applications were developed using Acholeplasma laidlawii as the test microorganism. Selection criteria were (A) a single-stage, serum-free broth medium to support high-titer cell growth and yield a cellular morphology suitable for bacterial challenge testing within 24 h and (B) a serum-free agar growth medium that can recover cells using conventional enumeration techniques. Different formulation components at various concentrations were screened for their effects on growth, cell size, and recovery on membrane filters. An optimized broth, Glucose Hydrolysate Broth, containing glucose, polypeptone, bovine serum albumin, 2-Amino-2-(hydroxymethyl)-1,3-propanediol (Tris base), oleic acid, and palmitic acid produced small 370 X 406 nanometer monodisperse cells at titers in excess of 1 x 10(9) colony-forming units per milliliter (cfu mL(-1)) within 20-24 h of incubation. Glucose Mycoplasma Agar, containing glucose, mycoplasma broth base, bovine serum albumin, Tris base, oleic acid, and palmitic acid, produced colonies approximately 1 mm in size and facilitated recovery on 0.2-microm polyvinylidene fluoride membrane filters. A comparison of recovery of A. laidlawii on Glucose Mycoplasma Agar pour-plate versus membrane filters resulted in an 89 +/- 4% recovery. Linearity across the target recovery range was 0.9992 (r2). Presence/absence tests of filtrate from each 0.2-microm assay membrane resulted in absence of growth as compared to controls, thus demonstrating the suitability of using 0.2-microm membrane filters for recovery of A. laidlawii. PMID:19634344

  5. 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)

    黄锦华

    2013-01-01

      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。

  6. Analytical Framework Research on Competitive Intelligence of Biopharmaceutical Industry Based on Industrial Chain%产业链范式下的生物制药产业竞争情报分析框架

    Institute of Scientific and Technical Information of China (English)

    丁宁; 吴跃伟

    2012-01-01

      在生物制药产业发展现状的基础上提出了基于产业链进行产业竞争情报分析的重要意义。解析了生物制药产业链的特征,重点关注产业链各主体技术创新活动、技术授权交易、并购以及联盟的影响因素。以此为基础,提出生物制药产业竞争情报分析框架,重点研究了产业链内产业层面,企业层面,产业技术层面以及市场层面情报要素,为生物制药产业竞争情报开展提供参考。%  By describing the development of biopharmaceutical industry, the paper analyzed the importance of competitive intelligence based on industrial chain. Focusing on impact factors of technology innovation as well as technology licensing,acquisition and alliances,the characteristics of biopharmaceutical industry chain was illustrated,followed by the competitive intelligence analytical framework consisting of intelligence factors from company, industry, industrial technology and market levels.

  7. The evolution of biopharmaceutical innovation network -A case study on Zhangjiang%生物医药创新网络演化机理研究——以上海张江为例

    Institute of Scientific and Technical Information of China (English)

    王飞

    2012-01-01

    在资源和知识流动性日益增强的背景下,全球生物医药产业实现了从企业内部独立研发向合作创新的阶段性跨越,创新网络成为新药研发的主要组织形式。但生物医药创新网络的形成与演化机理尚待研究。本文以上海张江生物医药为典型案例,从合作创新和集体学习两个维度,解析我国生物医药创新网络的生成机制。研究表明,合作创新是生物医药创新网络形成的内在驱动力;集体学习则通过知识、资源的流动与扩散,加速了创新网络结构的拓展。随着地理空间开放度和合作扁平度的变动,生物医药创新网络呈现出从企业内部创新网络、本地化创新网络向全球化创新网络过渡的阶段性变化特征。%With the increasingly enhancing the fluidity of resources and knowledge, a staged breakthrough from inside enterprises independent R&D to cooperative innovation is stridden over in the global biopharmaeeutical industry, and innovative network becomes the main organization form in R&D for the new medicine. However, the generation and evolution law of biopharmaceutical innovative network still need to the further researched. By taking Zhangjiang in Shanghai as an example, the evolution law of biopharmaceutical innovative network has been analyzed from two dimensions of cooperative innovation and collaborative learning. The result shows that cooperative innovation is the inner drive for the development of biopharmaceutical innovative network ; col- laborative learning accelerates the structural expansion of innovative network. With the change in geographical spatial openness and cooperative flatness, biopharmaeeutical innovation network goes through the evolution of inner - enterprise innovation network, local innovation network, and global innovation networks.

  8. G.L. Amidon, H. Lennernas, V.P. Shah, and J.R. Crison. A Theoretical Basis for a Biopharmaceutic Drug Classification: The Correlation of In Vitro Drug Product Dissolution and In Vivo Bioavailability, Pharm Res 12, 413–420, 1995—Backstory of BCS

    OpenAIRE

    Shah, Vinod P.; Amidon, Gordon L.

    2014-01-01

    The Biopharmaceutics Classification System (BCS) has become widely accepted today in the academic, industrial, and regulatory world. While the initial application of the BCS was to regulatory science bioequivalence (BE) issues and related implications, it has come to be utilized widely by the pharmaceutical industry in drug discovery and development as well. This brief manuscript will relate the story of the BCS development. While much of the ground work for the BCS goes back to the pharmacok...

  9. 透明质酸衍生物在生物药品传递方面的研究进展%Advances of hyaluronic acid derivatives in biopharmaceuticals delivery

    Institute of Scientific and Technical Information of China (English)

    袁玉姣; 蒋革; 董爽

    2013-01-01

    Objective To summarize the preparation of hyaluronic acid derivatives and progress of its applications in biopharmaceuticals delivery recent years. Methods According to thirty-two recent relevant literatures,the preparation of hyaluronic acid derivatives and its development in genes and proteins delivery were summarized. Results The preparation methods of various derivatives by the chemical modification of hyaluronic acid and the applications of hyaluronic acid derivatives in drug delivery were reviewed. Conclusions Hyaluronic acid derivatives in drug delivery field is promising.%目的 综述透明质酸衍生物的制备及近年来在生物药品传递方面的研究进展.方法 参考国内外相关文献32篇,进行相关信息的分析、归纳和总结.结果 阐述通过化学修饰透明质酸制备衍生物的方法和在传递基因和蛋白质等生物药品方面的应用.结论 透明质酸衍生物在药物传递方面将会有广阔的发展的前景.

  10. Pollution Features of Bio-pharmaceutical Wastewater and Analysis of Control Strategy%生物制药废水污染特征及其控制策略分析

    Institute of Scientific and Technical Information of China (English)

    鲍锦磊; 刘道伟; 刘碧波

    2016-01-01

    针对量大面广、成分复杂、有毒、难降解的制药工业废水,指出了制药废水治理的紧迫性,论述了其污水产生环节及废水的主要特征,介绍了生物制药废水的一般处理方法。从技术与经济角度分析了制药废水的控制策略,重点分析了物化处理与生化处理、好氧与厌氧、普通处理与深度处理的关系。指出高级氧化技术与膜集成技术是今后制药废水处理的发展方向与重点。%In view of the features of large quantity, complicated compositions, toxicity and difficult degradation existed in pharmaceutical wastewater, it is imminent to carry out the treatment of pharmaceutical wastewater. In this article, the stages producing wastewater were stated and general methods of treating biopharmaceutical wastewater were introduced. The strategy of control producing wastewater was analyzed from the view points of technology and economy, the several relations, such as physiochemical and biochemical, aerobic and anaerobic, and normal treatment and advanced treatment, were emphatically analyzed. It was pointed out that the technologies of advanced oxidation and integrated membrane will be developing direction for pharmaceutical wastewater treatment.

  11. Industrial Cluster Development Status and Countermeasures of Bio-pharmaceutical Industry in Nantong City%南通市生物医药产业集群发展现状及对策

    Institute of Scientific and Technical Information of China (English)

    王慧

    2012-01-01

      Bio-pharmaceutical industry with high technology and high input requirement , urgently need to cluster development to reduce the cost pressure , improve the brand influence.Bio-pharmaceutical industry is fa-cing the favorable opportunity of the government supporting and the industry development .Nantong bio -pharma-ceutical industry has certain advantages , such as the foundation of the industry development , the initial formation of industry cluster and R&D capability.While it has obvious weakness, such as small industrial scale, the weak in-novation capability, the lower industry cluster degree , and weak brand influence .To promote the cluster develop-ment of the bio-pharmaceutical industry, the government should formulate industry planning , guide characteristic industry zone development, accelerate industrial cluster, and provide platforms for innovation and business startup .%  生物医药产业具有高技术性和高投入的要求,迫切需要集群发展以减少成本压力,提高品牌影响力。生物医药产业正面临政府支持、行业发展的有利时机。南通市生物医药产业具有一定的发展基础,已初步形成产业集群,具有一定的研发能力,但是产业规模小,创新能力弱,产业集群度低,品牌影响力小。为推动南通市生物医药产业集群发展,政府应尽快明确行业规划,引导特色园区定位发展,加快生物医药产业集群,并深化服务,为生物医药园区提供创新创业平台。

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

    Science.gov (United States)

    Shah, Vinod P; Amidon, Gordon L

    2014-09-01

    The Biopharmaceutics Classification System (BCS) has become widely accepted today in the academic, industrial, and regulatory world. While the initial application of the BCS was to regulatory science bioequivalence (BE) issues and related implications, it has come to be utilized widely by the pharmaceutical industry in drug discovery and development as well. This brief manuscript will relate the story of the BCS development. While much of the ground work for the BCS goes back to the pharmacokinetic and drug absorption research by Gordon Amidon (GLA) in the 1970s and 1980s, the realization of the need for a classification or categorization of drug and drug products for setting dissolution standards became apparent to GLA during his 1990-1991 sabbatical year at the FDA. Initiated at the invitation of the then CEDR director, Dr. Carl Peck, to become a visiting scientist at the FDA, the goal was to promote regulatory research at the FDA, in my case, in biopharmaceutics, and to develop a science-based system to simplify regulatory requirements. PMID:24961917

  13. 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

    2015-01-01

    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

  14. Pharmaceutical excipients - quality, regulatory and biopharmaceutical considerations.

    Science.gov (United States)

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

    2016-05-25

    Practically all medications contain excipients, which are added for the purpose of production enhancement, patient acceptability, improving stability, controlling release etc. Typically excipients are the major components of a drug product, with the active molecule only present in relatively small amounts. Historically, excipients were termed inactive components. However, as highlighted in the present paper; excipients can have an impact on the absorption, distribution, metabolism and elimination (ADME) processes of the co-administered drug, which is important information when selecting excipients for any new formulation. Further, this review also provides a description of the regulatory processes to get new excipients approved in different regions and a discussion of the recent regulatory initiatives, e.g. excipients for paediatric formulations, thereby providing points to consider for the pharmaceutical scientist when selecting excipients for a new drug formulation. PMID:26699228

  15. Glycan characterization of biopharmaceuticals: Updates and perspectives.

    Science.gov (United States)

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

    2016-05-19

    Therapeutic proteins are rapidly becoming the most promising class of pharmaceuticals on the market due to their successful treatment of a vast array of serious diseases, such as cancers and immune disorders. Therapeutic proteins are produced using recombinant DNA technology. More than 60% of therapeutic proteins are posttranslationally modified following biosynthesis by the addition of N- or O-linked glycans. Glycosylation is the most common posttranslational modifications of proteins. However, it is also the most demanding and complex posttranslational modification from the analytical point of view. Moreover, research has shown that glycosylation significantly impacts stability, half-life, mechanism of action and safety of a therapeutic protein. Considering the exponential growth of biotherapeutics, this present review of the literature (2009-2015) focuses on the characterization of protein glycosylation, which has witnessed an improvement in methodology. Furthermore, it discusses current issues in the fields of production and characterization of therapeutic proteins. This review also highlights the problem of non-standard requirements for the approval of biosimilars with regard to their glycosylation and discusses recent developments and perspectives for improved glycan characterization. PMID:27126786

  16. The transgenic animal platform for biopharmaceutical production.

    Science.gov (United States)

    Bertolini, L R; Meade, H; Lazzarotto, C R; Martins, L T; Tavares, K C; Bertolini, M; Murray, J D

    2016-06-01

    The recombinant production of therapeutic proteins for human diseases is currently the largest source of innovation in the pharmaceutical industry. The market growth has been the driving force on efforts for the development of new therapeutic proteins, in which transgenesis emerges as key component. The use of the transgenic animal platform offers attractive possibilities, residing on the low production costs allied to high productivity and quality of the recombinant proteins. Although many strategies have evolved over the past decades for the generation of transgenic founders, transgenesis in livestock animals generally faces some challenges, mainly due to random transgene integration and control over transgene copy number. But new developments in gene editing with CRISPR/Cas system promises to revolutionize the field for its simplicity and high efficiency. In addition, for the final approval of any given recombinant protein for animal or human use, the production and characterization of bioreactor founders and expression patterns and functionality of the proteins are technical part of the process, which also requires regulatory and administrative decisions, with a large emphasis on biosafety. The approval of two mammary gland-derived recombinant proteins for commercial and clinical use has boosted the interest for more efficient, safer and economic ways to generate transgenic founders to meet the increasing demand for biomedical proteins worldwide. PMID:26820414

  17. Biopharmaceutical aspects of oral drug delivery

    NARCIS (Netherlands)

    Faassen, Werenfriedus Adrianus

    2004-01-01

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

  18. Biopharmaceutical aspects of oral drug delivery

    OpenAIRE

    Faassen, Werenfriedus Adrianus

    2004-01-01

    Most drugs display their therapeutic activity on specific places in the human body and should reach the systemic circulation in order to be transported towards the site of action. Irrespective of the route of administration the same sequence of steps are of relevance for the exposure to a drug: release from the dosage form (dissolution), absorption into the blood (permeation through a biological membrane) and finally removal from the body (metabolism and elimination). The first part of this t...

  19. Polybasic research on the biopharmaceutical characteristics of 20 (S)-protopanaxadiol%20(S)-原人参二醇生物药剂学性质的多元化研究

    Institute of Scientific and Technical Information of China (English)

    金鑫; 张振海; 孙娥; 谭晓斌; 夏海建; 刘其媛; 贾晓斌

    2013-01-01

    本研究旨在对20(S)-原人参二醇(PPD)的生物药剂学性质进行多元化研究.首先测定PPD的平衡溶解度和表观油水分配系数,预测其在体内的吸收行为;其次结合Caco-2细胞模型与在体单向肠灌流模型,探讨PPD的膜渗透性和吸收窗;最后将生物利用度与体内代谢相结合,多元化研究分析PPD在体内的吸收和代谢特性,为PPD的剂型设计提供理论和实践基础.结果表明:PPD的水溶性较差,在水中的平衡溶解度仅为35.24mg·L-1,油水分配系数(P)为46.21 (logP=1.66).Caco-2细胞模型显示PPD吸收一般,有一定的外排现象.在体肠灌流模型结果表明,PPD在各肠段吸收良好,且各段的有效渗透系数按大小依次为十二指肠、空肠、回肠和结肠.PPD的口服生物利用度较低,为29.39%.代谢研究表明PPD在体内存在广泛的代谢.因此PPD的溶解性差和首过作用是影响其口服生物利用度的主要因素.%In this study, the biopharmaceutical properties of 20 (S)-protopanaxadiol (PPD) were studied. Firstly, the equilibrium solubility and apparent oil / water partition coefficient of PPD were used to predict the absorption in vivo. Meanwhile the membrane permeability and absorption window were studied by Caco-2 cell model and single-pass intestinal perfusion model. Furthermore, the bioavailability and metabolism were combined to study the absorption properties and metabolic properties in vivo. All of them were used to provide theoretical and practical foundation for designing PPD preparation. The results showed that PPD is poorly water-soluble, and the equilibrium solubility in water is only 35.24 mg·L-1. The oil-water partition coefficient is 46.21 (logP = 1.66). By Caco-2 cell model, the results showed PPD uptake in general, and it also has efflux. By in situ intestinal perfusion model, the results showed that the absorption of PPD in the intestine is good, and the effective permeability coefficient were duodenum

  20. 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

    2005-12-01

    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

  1. 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

    2010-01-01

    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 www.clinicaltrials.gov on February 2nd 2009. Proportions of sites in each country were compared among emerging countries. Multiple logistic regressions were performed to evaluate whether trial placement in Brazil could be predicted by trial location in other countries and/or by trial features. 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 (www.clinicaltrials.gov 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

  2. 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

    2011-01-01

    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.

  3. Aggregation of biopharmaceuticals in human plasma and human serum

    OpenAIRE

    Arvinte, Tudor; Palais, Caroline; Green-Trexler, Erin; Gregory, Sonia; Mach, Henryk; Narasimhan, Chakravarthy; Shameem, Mohammed

    2013-01-01

    Analytical methods based on light microscopy, 90° light-scattering and surface plasmon resonance (SPR) allowed the characterization of aggregation that can occur when antibodies are mixed with human plasma. Light microscopy showed that aggregates formed when human plasma was mixed with 5% dextrose solutions of Herceptin® (trastuzumab) or Avastin® (bevacizumab) but not Remicade® (infliximab). The aggregates in the plasma-Herceptin®-5% dextrose solution were globular, size range 0.5–9 μm, with ...

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

    DEFF Research Database (Denmark)

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

    2008-01-01

    Process modeling can be a useful tool to aid in process development, process optimization, and process scale-up. When modeling a chromatography process, one must first select the appropriate models that describe the mass transfer and adsorption that occurs within the porous adsorbent. The theoret...... theoretical understanding of chromatographic behavior can augment available experimental data and aid in the design of specific experiments to develop a more complete understanding of the behavior of a unit operation....

  5. Risk Management Plan and Pharmacovigilance System. Biopharmaceuticals: Biosimilars

    OpenAIRE

    Calvo, Begoña; Zuñiga, Leyre

    2011-01-01

    Editor literario del libro, Giancarlo Nota - All chapters are Open Access articles distributed under the Creative Commons Non Commercial-Share Alike-Attribution 3.0 license, which permits to copy, distribute, transmit, and adapt the work in any medium, so long as the original work is properly cited.

  6. Delivery of large biopharmaceuticals from cardiovascular stents: a review

    OpenAIRE

    Takahashi, Hironobu; Letourneur, Didier; Grainger, David W.

    2007-01-01

    This review focuses on the new and emerging large-molecule bioactive agents delivered from stent surfaces in drug-eluting stents (DES) to inhibit vascular restenosis in the context of interventional cardiology. New therapeutic agents representing proteins, nucleic acids (small interfering RNAs and large DNA plasmids), viral delivery vectors and even engineered cell therapies require specific delivery designs distinct from traditional smaller molecule approaches on DES. While small molecules a...

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

    Directory of Open Access Journals (Sweden)

    Aníbal Domínguez Odio

    2016-01-01

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

  8. Passivation and quality practices in the biopharmaceuticals industry

    International Nuclear Information System (INIS)

    The successful production of a pharmaceutical product requires a permanent supply of sterile high purity water. In order to warrant the former it is necessary to assure that the roughness of inner surfaces of these facilities will not promote growth of bacteria colonies. At the same time they must show an optimal corrosion resistance. This condition should be fulfilled by the welded joints and the general design of the system. Passivity of austenitic stainless steels has been studied in different environments have been solutions as much mineral as organic acids. The organization of a Quality Assurance Systems implies an initial organized technical work. It requires previous definition of the flow of activities which are related to the control, inspection welding and cleaning and passivation of inner surfaces system. At the same time, elaboration of specific and technical procedures is required. Design and organization of records of results of all involved operations, inspections, controls and test is also concerned. This activity is an important element of concern for Validation. In this paper main features of a Quality Assurance System, applied to mineral acid Cleaning and Passivation of WFI and CIP facilities

  9. Production of biopharmaceutical compounds in plants: Potential and applications

    International Nuclear Information System (INIS)

    Full text: Plants are gaining widespread acceptance as a suitable system for the large-scale production of recombinant proteins. As molecular farming has come of age, there have been technological developments on many levels, including transfection methods, control of gene expression, protein targeting, the use of different crops as production platforms, and modifications to alter the structural and functional properties of the recombinant product. The skepticism that received this technology when first envisaged has turned into a cautious optimism. A wide variety of proteins can be produced in plants and they are almost indistinguishable from their native counterparts. Over the last few years, there has been a continuing commercial development of novel plant-based expression platforms accompanied by success in tackling some of the limitations of plants as bioreactors, such as low yields and inconsistent product quality that have limited the approval of plant-derived pharmaceuticals. Indeed, one of the most important driving factors has been yield improvement, as product yield has a significant impact on economic feasibility. Strategies to improve the recombinant protein yield in plants include the development of novel promoters, the improvement of protein stability and accumulation, and the improvement of downstream processing technologies. Attention is now shifting from basic research towards commercial exploitation, and molecular farming is reaching the stage at which it may challenge established production technologies based on bacteria, yeast, and cultured mammalian cells. There are already several plant-produced proteins on the market including one at a large scale. Several plant-derived recombinant pharmaceutical proteins are reaching the final stages of clinical evaluation, and more are in the development pipeline. The low cost of plant-based vaccines make them ideal for large-scale programs in poor countries. It is hoped that the issue of IP does not represent an insurmountable obstacle to this end. During the talk, the potential of plant based vaccines for veterinary use as well as current research and experimental trials, problems associated with antigen expression and immune response and the potential risks of the technology will be reviewed. The potential impact of the technology in developing countries will also be reviewed. (author)

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

    OpenAIRE

    Chebolu, S.; Daniell, H

    2009-01-01

    Chloroplast genetic engineering offers several advantages, including high levels of transgene expression, transgene containment via maternal inheritance, and multi-gene expression in a single transformation event. Oral delivery is facilitated by hyperexpression of vaccine antigens against cholera, tetanus, anthrax, plague, or canine parvovirus (4%–31% of total soluble protein, TSP) in transgenic chloroplasts (leaves) or non-green plastids (carrots, tomato) as well as the availability of antib...

  11. Purification of complex biopharmaceuticals with new processes, advanced analytics and computer-aided process design tools

    OpenAIRE

    Martins, Duarte Lima

    2013-01-01

    Viruses are highly efficient vectors that have been used for vaccination and gene therapy applications. However, their complexity renders downstream process particularly challenging since devices and strategies especially designed for virus purification are still lacking or need further optimization. After an introduction to the challenges of virus purification and the current strategies being employed, this dissertation presents the study of three different stages of the downstream proces...

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

    Directory of Open Access Journals (Sweden)

    Jhoany Acosta

    2016-04-01

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

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

    Directory of Open Access Journals (Sweden)

    Víctor Pérez Medina Martínez

    2014-01-01

    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.

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

    OpenAIRE

    Víctor Pérez Medina Martínez; Mario E. Abad-Javier; Alexis J. Romero-Díaz; Francisco Villaseñor-Ortega; Néstor O. Pérez; Flores-Ortiz, Luis F.; Emilio Medina-Rivero

    2014-01-01

    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....

  15. The Impact of the Dutch Biopharmaceutical Industry on Regional Economic Development in the Randstad

    OpenAIRE

    Sable, Michael

    2005-01-01

    The nature of economic development in advanced and developing economies alike has changed dramatically during the last generation as high-technology/knowledge-intensive industries have had a profound impact upon the way that people work and live. As The Economist has noted: "America gets more than half its economic growth from industries that barely existed a decade ago—such is the power of innovation, especially in the information and biotechnology industries.” The first phase of this revolu...

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

    Science.gov (United States)

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

    2016-04-01

    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. PMID:26687898

  17. Prospects of pharmaceuticals and biopharmaceuticals loaded microparticles prepared by double emulsion technique for controlled delivery

    OpenAIRE

    Giri, Tapan Kumar; Choudhary, Chhatrapal; Ajazuddin,; Alexander, Amit; Badwaik, Hemant; Tripathi, Dulal Krishna

    2012-01-01

    Several methods and techniques are potentially useful for the preparation of microparticles in the field of controlled drug delivery. The type and the size of the microparticles, the entrapment, release characteristics and stability of drug in microparticles in the formulations are dependent on the method used. One of the most common methods of preparing microparticles is the single emulsion technique. Poorly soluble, lipophilic drugs are successfully retained within the microparticles prepar...

  18. Understanding interactions of oleic acid with basic drugs in solid lipids on different biopharmaceutical levels

    Directory of Open Access Journals (Sweden)

    Zdravka Misic

    2014-06-01

    Full Text Available Recently, the impact of intestinal supersaturation on absorption of poorly water-soluble drugs has raised much interest among researchers. A focus has been mostly to study excipient effects on maintenance of drug supersaturation. The aim of the present study was to better understand the effects of drug-excipient interactions on the level of the anhydrous formulation, upon dispersion in simple buffer media and, in particular, regarding precipitation kinetics. A solid lipid-based formulation comprising PEG-32 stearate and oleic acid (OA (8:2 w/w was developed as a model. Loratadine (pKa = 4.33 and carvedilol (pKa = 8.74 were chosen as basic drugs. UV/FTIR spectroscopy and viscometry were used to characterize drug-OA molecular interactions in solution, while solid formulations were studied using x-ray diffraction, thermal analysis and van’t Hoff solubility-temperature plots. Precipitation kinetics of drug formulations was real-time monitored in phosphate buffer (pH = 6.5 by focused beam reflectance measurements. It was found that the addition of OA in the formulations resulted in substantial drug solubility increase. Although the drug-OA interactions appeared to be partially lost upon formulation dispersion, the extent of precipitation was markedly lowered compared to the formulations without OA. A Precipitation number (Pnc was introduced as a ratio of a relevant residence time of drug in the gastrointestinal tract (GIT to the induction time (the onset time of crystalline precipitation. Without OA, Pnc was already taking critical values (>1, while the anhydrous formulation was still below saturation for both model drugs. Interestingly, the addition of OA resulted in amorphous instead of crystalline precipitates, which is advantageous for drug re-dissolution and absorption. In conclusion, this study provides an improved understanding of OA and basic drug interactions on different levels of in vitro performance for more rational oral formulation development.

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

    DEFF Research Database (Denmark)

    Minssen, Timo

    appropriated scope of protection to be conferred to patents, the "obvious to try" issue and hindsight problems, but also pharmaceutical life cycle strategies and the notion of a so called “innovation gap” in the pharmaceutical sector. Recognizing that the gravity of potential and actual problems associated....../non-obviousness requirement in order to achieve well defined “high quality” patents that may either forestall problems or at least provide a sound basis for more comprehensive solution models.”...

  20. Reversed-phase liquid-chromatographic mass spectrometric N-glycan analysis of biopharmaceuticals

    OpenAIRE

    Higel, Fabian; Demelbauer, Uwe; Seidl, Andreas; Friess, Wolfgang; Sörgel, Fritz

    2013-01-01

    N-Glycosylation is a common post-translational modification of monoclonal antibodies with a potential effect on the efficacy and safety of the drugs; detailed knowledge about this glycosylation is therefore crucial. We have developed a reversed-phase liquid chromatographic–mass spectrometric method, with different fluorescent labels, for analysis of N-glycosylation, and compared the sensitivity and selectivity of the methods. Our work demonstrates that anthranilic acid as fluorescent label in...

  1. From the bench to clinical practice: understanding the challenges and uncertainties in immunogenicity testing for biopharmaceuticals.

    Science.gov (United States)

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

    2016-05-01

    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. PMID:26597698

  2. Evaluation of Exogenous siRNA Addition as a Metabolic Engineering Tool for Modifying Biopharmaceuticals

    OpenAIRE

    Tummala, Seshu; Titus, Michael; Wilson, Lee; Wang, Chunhua; Ciatto, Carlo; Foster, Donald; Szabo, Zoltan; Guttman, Andras; Li, Chen; Bettencourt, Brian; Jayaraman, Muthuswamy; Deroot, Jack; Thill, Greg; Kocisko, David; Pollard, Stuart

    2013-01-01

    Traditional metabolic engineering approaches, including homologous recombination, zinc finger nucleases, and short hairpin RNA (shRNA), have previously been employed to generate biologics with specific characteristics that improve efficacy, potency, and safety. An alternative approach is to exogenously add soluble small interfering RNA (siRNA) duplexes, formulated with a cationic lipid, directly to cells grown in shake flasks or bioreactors, This approach has the following potential advantage...

  3. Mechanistic investigation of biopharmaceutic and pharmacokinetic characteristics of surface engineering of satranidazole nanocrystals.

    Science.gov (United States)

    Dhat, Shalaka; Pund, Swati; Kokare, Chandrakant; Sharma, Pankaj; Shrivastava, Birendra

    2016-03-01

    The designing of surface engineered nanocrystals for improved stability and bioavailability is a multivariate process depending on several critical formulation and process variables. The present investigation deals with formulation of stable nanocrystals of poorly soluble satranidazole (SAT) for improving dissolution rate and pharmacokinetic profiling. SAT has low polar surface area, high dose and dosing frequency. Based on goniometric and stability studies of formulations prepared with various stabilizers, a unique combination of Span 20 and HPMC E-5 was selected for detailed investigation. Lyophilization of SAT nanosuspension was explored with nine different cryoprotectants in varying amounts to obtain easily redispersible nanocrystals (SAT-NC). The mean particle size and zeta potential of SAT-NC were found to be 208.8nm and -41.3mV respectively. DSC and XRPD confirmed the crystalline state of SAT. In vitro release studies of SAT-NC showed almost complete dissolution within 20min in water. Extravascular, one compartment pharmacokinetic modeling of in vivo plasma concentration versus time studies in male Wistar rats revealed twofold increase in Cmax, and AUC0-∞. Method of residuals was employed to calculate rate of absorption Ka and lag time. Nanosizing with appropriate stabilizers and programmed processing conditions successfully produced SAT-NC with improved pharmaceutic and pharmacokinetic characteristics. PMID:26748382

  4. Technological knowledge base, R&D organization structure and alliance formation: Evidence from the biopharmaceutical industry

    OpenAIRE

    Zhang, J.; Baden-Fuller, C.; Mangematin, V.

    2007-01-01

    We explore how an incumbent firm's internal knowledge and organization structure influences its strategic alliance formation. We propose that the firm's knowledge breadth and the centrality of its R&D organization structure positively influence its absorptive capacity, and consequently, its propensity to form strategic alliances. We also argue that the centrality of the R&D organization structure may be a substitute for the breadth of the knowledge base. We validate our ideas using data on 26...

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

    Science.gov (United States)

    Wan, Feng; Yang, Mingshi

    2016-02-10

    Currently, most of the approved protein and peptide-based medicines are delivered via conventional parenteral injection (intramuscular, subcutaneous or intravenous). A frequent dosing regimen is often necessary because of their short plasma half-lives, causing poor patient compliance (e.g. pain, abscess, etc.), side effects owing to typical peak-valley plasma concentration time profiles, and increased costs. Among many sustained-release formulations poly lactic-co-glycolic acid (PLGA)-based depot microparticle systems may represent one of the most promising approaches to provide protein and peptide drugs with a steady pharmacokinetic/pharmacodynamic profile maintained for a long period. However, the development of PLGA-based microparticle systems is still impeded by lack of easy, fast, effective manufacturing technologies. The aim of this paper is to review recent advances in spray drying, a one-step, continuous microencapsulation process, for manufacturing of PLGA-based depot microparticle systems with a focus on the recent efforts on understanding of the role of nozzle design in the microencapsulation of proteins/peptides, and the effect of critical solvent properties and process parameters on the critical quality attributes of the spray-dried microparticles. PMID:26688034

  6. Functionalized Nanocarriers for Enhanced Bioactive Delivery to Squamous Cell Carcinomas: Targeting Approaches and Related Biopharmaceutical Aspects.

    Science.gov (United States)

    Adebowale, Adeyemi S; Choonara, Yahya E; Kumar, Pradeep; du Toit, Lisa C; Pillay, Viness

    2015-01-01

    Cancer has been described as one of the major and leading causes of death worldwide. By the year 2030, it has been postulated that over 21.4 million new cases of cancer could be expected, 17 million cancer deaths yearly and a total of 75 million people will be living with cancer within five years of diagnosis. Chemotherapy is the main therapeutic intervention for treating people living with SCC. However, drug resistance has rendered it inefficient and ineffective in combating the disease even after combination chemotherapy. Many peptides and proteins have been investigated to possess biological activities that mark them as potential anti-cancer agents. Targeting peptides are conjugated with other functional peptides or nanoparticles to augment drug delivery both in vitro and in vivo assays. The current identification of tumor-homing peptides through phage display technology has opened a new strategy for targeted therapy in SCC diseases. Despite the advances in cancer nanomedicine, targeted approaches in the delivery of therapeutics for the treatment of squamous cell carcinoma related tumours have not been well established. In this review, current drugs employed in cancer nanomedicine are highlighted, possible rate limiting factors for the application of polymeric materials in cancer nanomedicine are elucidated and functionalized nano-constructs using receptor ligands and homing peptides as targeted moieties are discussed. The combinatorial strategy of attaching both homing peptides and receptor ligands as dual moieties on nano-cargos should further strengthen the advantages of each technology in cancer targeted therapy. PMID:26027569

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

    OpenAIRE

    Rybalkin М. V; Strilets O.P; Strelnikov L.S.; Kalyuzhna O. S

    2014-01-01

    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 fung...

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

    Science.gov (United States)

    Landowski, Christopher P; Huuskonen, Anne; Wahl, Ramon; Westerholm-Parvinen, Ann; Kanerva, Anne; Hänninen, Anna-Liisa; Salovuori, Noora; Penttilä, Merja; Natunen, Jari; Ostermeier, Christian; Helk, Bernhard; Saarinen, Juhani; Saloheimo, Markku

    2015-01-01

    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. PMID:26309247

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

    Directory of Open Access Journals (Sweden)

    Rybalkin М. V

    2014-10-01

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

  10. Proteomic Profiling of Recombinant Escherichia coli in High-Cell- Density Fermentations for Improved Production of an Antibody Fragment Biopharmaceutical

    OpenAIRE

    Aldor, Ilana S.; Krawitz, Denise C.; Forrest, William; Chen, Christina; Nishihara, Julie C.; Joly, John C.; Champion, Kathleen M.

    2005-01-01

    By using two-dimensional polyacrylamide gel electrophoresis, a proteomic analysis over time was conducted with high-cell-density, industrial, phosphate-limited Escherichia coli fermentations at the 10-liter scale. During production, a recombinant, humanized antibody fragment was secreted and assembled in a soluble form in the periplasm. E. coli protein changes associated with culture conditions were distinguished from protein changes associated with heterologous protein expression. Protein sp...

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

    Science.gov (United States)

    Landowski, Christopher P.; Huuskonen, Anne; Wahl, Ramon; Westerholm-Parvinen, Ann; Kanerva, Anne; Hänninen, Anna-Liisa; Salovuori, Noora; Penttilä, Merja; Natunen, Jari; Ostermeier, Christian; Helk, Bernhard; Saarinen, Juhani; Saloheimo, Markku

    2015-01-01

    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. PMID:26309247

  12. Accelerated tryptic digestion for the analysis of biopharmaceutical monoclonal antibodies in plasma by liquid chromatography with tandem mass spectrometric detection.

    Science.gov (United States)

    Lesur, Antoine; Varesio, Emmanuel; Hopfgartner, Gérard

    2010-01-01

    Accelerated tryptic digestion of a therapeutic protein including microwave irradiation and thermal transfer by convection at 60 degrees C and 37 degrees C was investigated. An analytical setup was devised to follow the protein digestion rate using 1D gel electrophoresis and liquid chromatography coupled a triple quadrupole linear ion trap mass spectrometer. The formation kinetic of its tryptic peptides was monitored in the selected monitoring mode (LC-SRM/MS). Different digestion end points (e.g. 2, 5, 10, 15, 30 and 60min) as well as an overnight digestion were tested using a therapeutic human monoclonal antibody (mAb) with the goal of its LC-SRM/MS quantification in human plasma. The peptides from the human mAb were generated at different rates and were classified into three categories: (1) the fast forming peptides, (2) the slow forming peptides and (3) the peptides degrading over time. For many monitored peptides, a heating temperature of 37 degrees C with a 750rpm mixing applied for at least 30min provided equivalent results to microwave-assisted digestion and generally allowed the achievement of an equivalent peptide concentration as an overnight digestion carried out at 37 degrees C. The disappearance of the protein of the heavy and light chains can be monitored by 1D gel electrophoresis but was found not to be representative of the final tryptic peptide concentrations. For quantitative purposes a stable isotope labeled version ((13)C(4), (15)N(1)) of the therapeutic protein was used. The labeled protein as internal standard was found to be very efficient to compensate for incomplete digestion or losses during sample preparation. PMID:19939394

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

    Science.gov (United States)

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

    2015-04-10

    Human glycoproteins, expressed in hamster cell lines, show similar glycosylation patterns to naturally occurring human molecules except for a minute difference in the linkage of terminal sialic acid: both cell types lack α2,6-galactosyl-sialyltransferase, abundantly expressed in human hepatocytes and responsible for the α2,6-sialylation of circulating glycoproteins. This minute difference, which is currently not known to have any physiological relevance, was the basis for the selective measurement of recombinant glycoproteins in the presence of their endogenous counterparts. The assay is based on using the lectin Sambucus nigra agglutinin (SNA), selectively binding to α2,6-sialylated N-glycans. Using von Willebrand factor (VWF), factor IX (FIX), and factor VIIa (FVIIa), it was demonstrated that (i) the plasma-derived proteins, but not the corresponding recombinant proteins, specifically bind to SNA and (ii) this binding can be used to deplete the plasma-derived proteins. The feasibility of this approach was confirmed in spike-recovery studies for all three recombinant coagulation proteins in human plasma and for recombinant VWF (rVWF) in macaque plasma. Analysis of plasma samples from macaques after administration of recombinant and a plasma-derived VWF demonstrated the suitability and robustness of this approach. Data showed that rVWF could be selectively measured without changing the ELISAs and furthermore revealed the limitations of baseline adjustment using a single measurement of the predose concentration only. The SNA gel-based depletion procedure can easily be integrated in existing procedures as a specific sample pre-treatment step. While ELISA-based methods were used to measure the recombinant coagulation proteins in the supernatants obtained by depletion, this procedure is applicable for all biochemical analyses. PMID:25703236

  14. 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

    2012-01-01

    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.

  15. Effects of Uremic Toxins on Transport and Metabolism of Different Biopharmaceutics Drug Disposition Classification System (BDDCS) Xenobiotics

    OpenAIRE

    Reyes, Maribel; Benet, Leslie Z.

    2011-01-01

    Chronic kidney disease (CKD) is recognized to cause pharmacokinetic changes in renally excreted drugs; however, pharmacokinetic changes are also reported for drugs that are non-renally eliminated. Few studies have investigated how uremic toxins may affect drug transporters and metabolizing enzymes and how these may result in pharmacokinetic/metabolic changes in CKD. Here, we investigated the effects of uremic toxins and human uremic serum on the transport of the prototypical transporter subst...

  16. 中国生物医药产业SCP分析%SCP analysis of bio-pharmaceutical industry in China

    Institute of Scientific and Technical Information of China (English)

    曹阳; 洪亮; 宋文; 茅宁莹

    2013-01-01

    运用现代产业组织理论中的市场结构-企业行为-行业绩效分析法(SCP)对我国生物医药产业的市场结构、企业行为和行业绩效进行详细分析,提出加快产业重组、优化产业结构,鼓励开展模仿创新,优化生物仿制药的审批程序等建议和措施.%With the analysis paradigm of "structure-conduct-performance ( SCP)" described in modern industrial organization theory, this paper detailedly analyzed the market structure, enterprise conduct and performance of biological pharmaceutical industry in China. It suggest the government to speed up the industrial restructuring , to optimize the industrial structure, to encourage the imitation innovation , to optimize approval procedures of biological generics, etc.

  17. Biophysical signatures of noncovalent aggregates formed by a glucagonlike peptide-1 analog: a prototypical example of biopharmaceutical aggregation.

    Science.gov (United States)

    Doyle, Brandon L; Pollo, Mark J; Pekar, Allen H; Roy, Michael L; Thomas, Beth Ann; Brader, Mark L

    2005-12-01

    LY307161 is a 31 amino acid analog of glucagonlike peptide-1(7-37)OH susceptible to physical instability associated with pharmaceutical processing. Orthogonal biophysical studies were conducted to explore the origins of this physical instability and to distinguish pharmaceutically desirable states of this aggregating peptide from undesirable ones. Equilibrium sedimentation analysis established that LY307161 exists as a monomer at pH 3, and reversibly self-associates in the pH range 7.5-10.5. Causative factors for physical instability related to lyophilization conditions were investigated. Solution pH, acetonitrile content, and concentration of the peptide prior to lyophilization each impacted physicochemical properties of the resultant powders. A comparative study of two powder samples exhibiting physicochemically disparate properties established that LY307161 forms soluble noncovalent aggregates. FT-IR analyses in the solid and solution states identified a prominent band at 1657-1659 cm(-1) attributed to alpha-helix structure. Noncovalent soluble aggregate exhibited characteristic bands at 1615 and 1698 cm(-1) indicative of intermolecular beta-sheet structure. An agitation-induced, precipitated solid form of LY307161 exhibited a different FT-IR signature indicative of a conformationally distinct species. Circular dichroism and fluorescence spectroscopy, together with dynamic light scattering measurements and dye-aggregate complexation, provided additional insights into the distinctions between aggregated and native LY307161. PMID:16258989

  18. Chemometrics and in-line near infrared spectroscopic monitoring of a biopharmaceutical Chinese hamster ovary cell culture: prediction of multiple cultivation variables.

    Science.gov (United States)

    Clavaud, Matthieu; Roggo, Yves; Von Daeniken, Ralph; Liebler, André; Schwabe, Jan-Oliver

    2013-07-15

    In the present study near infrared (NIR) spectroscopy was used to monitor the cultivation of mammalian Chinese hamster ovary (CHO) cells producing a monoclonal antibody in a fed-batch cell culture process. A temperature shift was applied during the cultivation. The cells were incubated at 37 °C and 33 °C. The Fourier transform near infrared (FT-NIR) multiplex process analyzer spectroscopy was investigated to monitor cultivation variables of the CHO cell culture from 10 independent batches using two channels of the FT-NIR. The measurements were performed on production scale bioreactors of 12,500 L. The cell cultures were analyzed with the spectrometer coupled to a transflection sterilizable fiber optic probe inserted into the bioreactors. Multivariate data analysis (MVDA) employing unsupervised principal component analysis (PCA) and partial least squares regression methods (PLS) were applied. PCA demonstrated that 96% of the observed variability was explained by the process trajectory and the inter-batch variability. PCA was found to be a significant tool in identifying batch homogeneity between lots and in detecting abnormal fermentation runs. Seven different cell culture parameters such as osmolality, glucose concentration, product titer, packed cell volume (PCV), integrated viable packed cell volume (ivPCV), viable cell density (VCD), and integrated viable cell count (iVCC) were monitored inline and predicted by NIR. NIR spectra and reference analytics data were computed using control charts to evaluate the monitoring abilities. Control charts of each media component were under control by NIR spectroscopy. The PLS calibration plots offered accurate predictive capabilities for each media. This paper underlines the capability for inline prediction of multiple cultivation variables during bioprocess monitoring. PMID:23622522

  19. 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

    2008-01-01

    生物药剂分类系统是根据药物的溶解性和渗透性对药物进行分类的一种科学框架,目前FDA、WHO和EMEA都接受了这种分类概念.文中比较了不同管理当局对于生物药剂分类系统(BCS)的定义以及BCS在药品注册申报中支持生物等效免除的应用情况,综述了不同管理当局对于BCS的认识并提出了展望.

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

    OpenAIRE

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

    2014-01-01

    Ciprofloxacin bioavailability may be reduced when ciprofloxacin is co-administered with metallic ion containing preparations. In our previous study, physicochemical interaction between ciprofloxacin and ferrous sulphate was successfully simulated in vitro. In the present work, comparative in vitro ciprofloxacin solubility and dissolution studies were performed in the reactive media containing aluminium hydroxide, calcium carbonate or zinc sulphate. Solid phases collected from the dissolution ...

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

    Science.gov (United States)

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

    2014-03-01

    Ciprofloxacin bioavailability may be reduced when ciprofloxacin is co-administered with metallic ion containing preparations. In our previous study, physicochemical interaction between ciprofloxacin and ferrous sulphate was successfully simulated in vitro. In the present work, comparative in vitro ciprofloxacin solubility and dissolution studies were performed in the reactive media containing aluminium hydroxide, calcium carbonate or zinc sulphate. Solid phases collected from the dissolution vessel with aluminium hydroxide, calcium carbonate and zinc sulphate were investigated for their properties. The results obtained indicate that different types of adducts may form and retard ciprofloxacin solubility and dissolution. In the case of aluminium, no phase changes were observed. The solid phase generated in the presence of calcium carbonate was identified as hydrated ciprofloxacin base. Similarly to iron, a new complex consistent with Zn(SO4)2(Cl)2(ciprofloxacin)2 × nH2O stoichiometry was generated in the presence of relatively high concentrations of ciprofloxacin hydrochloride and zinc sulphate, indicating that small volume dissolution experiments can be useful for biorelevant dissolution tests. PMID:24670353

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

    Directory of Open Access Journals (Sweden)

    Stojković Aleksandra

    2014-03-01

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

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

    Science.gov (United States)

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

    2013-12-01

    The diversity of lipid excipients available commercially has enabled versatile formulation design of lipid-based drug delivery systems for enhancing the oral absorption of poorly water-soluble drugs, such as emulsions, microemulsions, micelles, liposomes, niosomes and various self-emulsifying systems. The transformation of liquid lipid-based systems into solid dosage forms has been investigated for several decades, and has recently become a core subject of pharmaceutical research as solidification is regarded as viable means for stabilising lipid colloidal systems while eliminating stringent processing requirements associated with liquid systems. This review describes the types of pharmaceutical grade excipients (silica nanoparticle/microparticle, polysaccharide, polymer and protein-based materials) used as solid carriers and the current state of knowledge on the liquid-to-solid conversion approaches. Details are primarily focused on the solid-state physicochemical properties and redispersion capacity of various dry lipid-based formulations, and how these relate to the in vitro drug release and solubilisation, lipid carrier digestion and cell permeation performances. Numerous in vivo proof-of-concept studies are presented to highlight the viability of these dry lipid-based formulations. This review is significant in directing future research work in fostering translation of dry lipid-based formulations into clinical applications. PMID:23775443

  4. Industrial perspective on validation of tangential flow filtration in biopharmaceutical applications. Technical Report No. 15. Parenteral Drug Association. Biotechnology Task Force on Purification and Scale-up.

    Science.gov (United States)

    1992-01-01

    Validation of tangential flow filtration is required to ensure the process delivers a product of consistent quality, safety, and efficacy. A thorough and sound validation program not only satisfies regulatory requirements, but also provides a valuable source of information which facilitates development of future processes, training of production personnel, and trouble shooting for the validated process. Validation of TFF shares many common elements with validation of other traditional operations and equipment. Existing personnel and procedures should be readily adapted to execute the TFF validation protocols. IQ's and OQ's will most likely follow familiar formats. In performance qualification, key areas needing attention include: assessment of compatibles, testing of parameters affecting membrane retention and selectivity, cleaning, sanitization, and membrane lifetime. Finally, the hallmark of a sound validation program is the quality of its scientific approach and its congruence with the definition of validation contained in the 1987 guidelines (6). PMID:1432457

  5. Biopharmaceutical evaluation of epigallocatechin gallate-loaded cationic lipid nanoparticles (EGCG-LNs): In vivo, in vitro and ex vivo studies.

    Science.gov (United States)

    Fangueiro, Joana F; Calpena, Ana C; Clares, Beatriz; Andreani, Tatiana; Egea, Maria A; Veiga, Francisco J; Garcia, Maria L; Silva, Amélia M; Souto, Eliana B

    2016-04-11

    Cationic lipid nanoparticles (LNs) have been tested for sustained release and site-specific targeting of epigallocatechin gallate (EGCG), a potential polyphenol with improved pharmacological profile for the treatment of ocular pathologies, such as age-related macular edema, diabetic retinopathy, and inflammatory disorders. Cationic EGCG-LNs were produced by double-emulsion technique; the in vitro release study was performed in a dialysis bag, followed by the drug assay using a previously validated RP-HPLC method. In vitro HET-CAM study was carried out using chicken embryos to determine the potential risk of irritation of the developed formulations. Ex vivo permeation profile was assessed using rabbit cornea and sclera isolated and mounted in Franz diffusion cells. The results show that the use of cationic LNs provides a prolonged EGCG release, following a Boltzmann sigmoidal profile. In addition, EGCG was successfully quantified in both tested ocular tissues, demonstrating the ability of these formulations to reach both anterior and posterior segment of the eye. The pharmacokinetic study of the corneal permeation showed a first order kinetics for both cationic formulations, while EGCG-cetyltrimethylammonium bromide (CTAB) LNs followed a Boltzmann sigmoidal profile and EGCG-dimethyldioctadecylammonium bromide (DDAB) LNs a first order profile. Our studies also proved the safety and non-irritant nature of the developed LNs. Thus, loading EGCG in cationic LNs is recognised as a promising strategy for the treatment of ocular diseases related to anti-oxidant and anti-inflammatory pathways. PMID:26921515

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

    Institute of Scientific and Technical Information of China (English)

    吴菲菲; 张广安; 张辉; 黄鲁成

    2014-01-01

    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.%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。

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

    OpenAIRE

    Geysa Aguiar; Luciane Gomes Faria; Humberto Gomes Ferraz; Cristina Helena do Reis Serra; Valentina Porta

    2005-01-01

    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 dissolu...

  8. 生物医药产业基地公共创新服务平台的构建%Research on the Construction of Public Innovative Platform in Bio-pharmaceutical Industry Bases

    Institute of Scientific and Technical Information of China (English)

    陈一鸣; 廖芝; 贺正楚

    2015-01-01

    文章分析了生物医药产业基地内公共创新服务平台的主要功能,给出了生物医药产业基地内公共创新服务平台的通用架构及其网络服务平台的基本框架.该架构包括公共研发平台、产业化平台、公共服务平台、基础条件平台等四个平台.生物医药产业基地内网络服务平台为“四横两纵”结构:“四横”自底向上依次为基础设施层、数据资源库层、应用支撑技术层、应用服务层;“两纵”分别为安全保障体系扣标准规范体系.

  9. 生物制药专业综合性大试验的教学改革与创新%Reformation and innovation of comprehensive experimental teaching in bio-pharmaceuticals

    Institute of Scientific and Technical Information of China (English)

    黄秀梅

    2009-01-01

    从实验教学内容、实验理论教学方法、学生实验技术能力培养手段、实验室管理方法等多方位积极开展生物制药综合性大试验的实验教学改革与创新,促使学生从学习的被动型转为学习的主动型,努力培养学生的动手能力、分析问题和解决问题的能力.

  10. EMERGING TRENDS IN REGULATORY DEVELOPMENTS FOR BIOSIMILARS: RECENT ADVANCES IN GLOBAL AND INDIAN REGULATIONS

    OpenAIRE

    Shah Kalpesh; Kumar Sokindra

    2012-01-01

    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 co...

  11. Biosimilars: Current perspectives and future implications

    OpenAIRE

    Monika Misra

    2012-01-01

    Biosimilars are biological products that are the replicas of their innovator biopharmaceuticals. These are developed after patent expiration of innovator biopharmaceuticals and are submitted for separate marketing approval. In view of the structural and manufacturing complexities of biopharmaceuticals, biosimilars should not be considered as "biological generics". These are rather unique molecules with limited data at time of approval, so there are concerns about the safety and efficacy of bi...

  12. 75 FR 10487 - International Conference on Harmonisation; Guidance on S9 Nonclinical Evaluation for Anticancer...

    Science.gov (United States)

    2010-03-08

    ... Federal Register of February 17, 2009 (74 FR 7445), FDA published a notice announcing the availability of... for biopharmaceuticals, (3) assessment of the safety of pharmaceutical combinations, and...

  13. The role of industry associations in health innovation and politics of development: the cases of South Africa and India

    OpenAIRE

    Papaioannou, Theo; Kale, Dinar; Mugwagwa, Julius; Watkins, Andrew

    2014-01-01

    The rapid growth of health innovation in developing countries and the increased importance of biopharmaceutical industry associations in influencing innovative performance require new thinking about the business and politics institutions which diffuse and govern knowledge in emerging contexts of economic and political pluralism. This paper examines the extent to which biopharmaceutical industry associations and their umbrella organisations promote the development of technological capabilities...

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

    DEFF Research Database (Denmark)

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

    2015-01-01

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

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    Biopharmaceutical products are emerging within the pharmaceutical industry. However, biopharmaceuticals are often unstable in aqueous solution. Freeze-drying (lyophilisation) is the preferred method to achieve a stable product with an increased shelf-life. During batch freeze-drying, there are only...

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

    Directory of Open Access Journals (Sweden)

    Ana Cristina Ribeiro Rama

    2005-09-01

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

  17. 生物技术企业接力创新中的知识产权运营模式研究--以生物制药为例%Study on the Operation Models of the Intellectual Property Rights of the Bio-technology Enterprises during the Relay Innovation--Taking Bio-pharmaceutical for Example

    Institute of Scientific and Technical Information of China (English)

    冯薇; 银路; 李天柱; 马佳

    2014-01-01

    现代生物技术的创新过程具有明显的“接力创新”的特质,而知识产权运营对于相关企业在“接力创新”中获利显得尤为重要。在生物技术的“接力创新”过程中,基于不同的创新阶段和时机,专家型公司和核心公司可能选择不同的接力模式。在已有研究的基础上,以生物制药企业为样本,深入探讨两类公司不同接力方式下的不同知识产权运营模式,为我国现代生物技术企业的知识产权管理和实践提供有效借鉴。%The innovation process of the modern bio-technology is characterized by “relay innovation”, meanwhile, the operation of the intellectual property rights is especially important to the relative enterprises. During the process of the relay innovation, the expert company and the core company will choose different relay modes based on the different stage and timing of the innovation. On the basis of the existing research, taking the bio-pharmaceuticalenterprises as example, it discusses thoroughly the different operation modes of the intellectual property rights of the expert company and the core company under the different ways of relay cooperation. We are looking forward to providing effective references to the modern bio-technology enterprises in China for the intellectual property rights management and practice.

  18. Biosimilars: Current perspectives and future implications

    Directory of Open Access Journals (Sweden)

    Monika Misra

    2012-01-01

    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.

  19. In-situ product removal by membrane extraction

    NARCIS (Netherlands)

    Heerema, L. D.

    2012-01-01

    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

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

    DEFF Research Database (Denmark)

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

    2014-01-01

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

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

    NARCIS (Netherlands)

    Bonarius, H.P.J.

    1998-01-01

    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

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

    Data.gov (United States)

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

  3. Preparation and evaluation of andrographolide solid dispersion vectored by silicon dioxide

    Directory of Open Access Journals (Sweden)

    Dingkun Zhang

    2016-01-01

    Abbreviation used: Andro: Andrographolide, BCS: Biopharmaceutics Classification System, SDS: Tetrahydrofuran and Sodium dodecyl sulfate, HPLC: High Performance Liquid Chromatography, SEM: Scanning Electron Microscope, BET: Brumauer–Emmett–Teller, FTIR: Fourier Transform Infrared Spectroscopy, XRD: X-ray Diffraction.

  4. Explore the Latest Progress on Medicines in Development

    Science.gov (United States)

    ... by uniting workers throughout the industry. Learn More Patent protection should always be considered by an inventor ... medicines in development. Report Medicines in Development for Diabetes 2014 Report America’s biopharmaceutical research companies currently are ...

  5. Characterisation of Chromatography Media Aimed for Purification of Biomolecules

    OpenAIRE

    Andersson, Mikael

    2014-01-01

    Chromatography media (resins) are very important for and widely used by the biopharma industry in large scale production of biopharmaceuticals, e.g. monoclonal antibodies. Today there are several hundred biopharmaceuticals released globally on the healthcare market. This thesis discusses various strategies and methods for the characterisation of chemical and functional stability of chromatography media. In addition, various analytical techniques used in these areas were evaluated and applied....

  6. 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

    OpenAIRE

    Wei Zhou; Haidan Wang; Xuanxuan Zhu; Jinjun Shan; Ailing Yin; Baochang Cai; Liuqing Di

    2013-01-01

    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 derivat...

  7. Biotechnology

    International Nuclear Information System (INIS)

    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

  8. Case Studies for Practical Food Effect Assessments across BCS/BDDCS Class Compounds using In Silico, In Vitro, and Preclinical In Vivo Data

    OpenAIRE

    Heimbach, Tycho; Xia, Binfeng; Lin, Tsu-Han; He, Handan

    2012-01-01

    Practical food effect predictions and assessments were described using in silico, in vitro, and/or in vivo preclinical data to anticipate food effects and Biopharmaceutics Classification System (BCS)/Biopharmaceutics Drug Disposition Classification System (BDDCS) class across drug development stages depending on available data: (1) limited in silico and in vitro data in early discovery; (2) preclinical in vivo pharmacokinetic, absorption, and metabolism data at candidate selection; and (3) ph...

  9. Applications of recombinant Pichia pastoris in the healthcare industry

    OpenAIRE

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

    2014-01-01

    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. Small scale affinity purification and high sensitivity reversed phase nanoLC-MS N-glycan characterization of mAbs and fusion proteins

    OpenAIRE

    Higel, Fabian; Seidl, Andreas; Demelbauer, Uwe; Sörgel, Fritz; Frieß, Wolfgang

    2014-01-01

    N-glycosylation is a complex post-translational modification with potential effects on the efficacy and safety of therapeutic proteins and known influence on the effector function of biopharmaceutical monoclonal antibodies (mAbs). Comprehensive characterization of N-glycosylation is therefore important in biopharmaceutical development. In early development, e.g. during pool or clone selection, however, only minute protein amounts of multiple samples are available for analytics. High sensitivi...

  11. The successes and limitations of preclinical studies in predicting the pharmacodynamics and safety of cell-surface-targeted biological agents in patients

    OpenAIRE

    Polson, Andrew G; Fuji, Reina N

    2012-01-01

    To improve drug development outcomes, it is important to review when preclinical pharmacodynamic and safety models have successfully predicted human responses and when they have not. In a recent issue of the BJP, Bugelski and Martin examined the concordance between preclinical and human data for biopharmaceuticals targeted to cell-surface proteins. The cases are interesting and several trends emerge. The pharmacodynamics of biopharmaceuticals in non-human primates is largely predictive; the u...

  12. Presently available biosimilars in hematology-oncology: G-CSF

    OpenAIRE

    Gascon, Pere

    2012-01-01

    Biopharmaceuticals were copies of endogenous human proteins developed in the mid-1990s that were characterized by complex three-dimensional, high-molecular weight compounds. What made them unique was that contrary to classical chemotherapeutical drugs, they were manufactured by living cells. One of these biopharmaceuticals was granulocyte-colony stimulating factor (G-CSF). Once their patent expired, generic versions appeared in pharmacies. They are now called biosimilars. There are several bi...

  13. Ocular delivery of macromolecules

    OpenAIRE

    Kim, Yoo-Chun; Chiang, Bryce; Wu, Xianggen; Prausnitz, Mark R.

    2014-01-01

    Biopharmaceuticals are making increasing impact on medicine, including treatment of indications in the eye. Macromolecular drugs are typically given by physician-administered invasive delivery methods, because non--invasive ocular delivery methods, such as eye drops, and systemic delivery, have low bioavailability and/or poor ocular targeting. There is a need to improve delivery of biopharmaceuticals to enable less-invasive delivery routes, less-frequent dosing through controlled-release drug...

  14. Biosimilar therapeutics—what do we need to consider?

    OpenAIRE

    2009-01-01

    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 critical issues surrounding the use of biosimilars to make informed treatment decisions. The complex high-molecular-weight three-dimensional structures of biopharmaceuticals, their heterogeneity an...

  15. The Emergence of Biosimilar Insulin Preparations—A Cause for Concern?

    OpenAIRE

    Owens, David R; Landgraf, Wolfgang; Schmidt, Andrea; Bretzel, Reinhard G.; Kuhlmann, Martin K.

    2012-01-01

    Several biopharmaceuticals, including insulin and insulin analogs, are, or shortly will be, off-patent, thereby providing an opportunity for companies to attempt to manufacture “copies” commonly referred to as biosimilars and also known as follow-on biologics. Reassurance that such copy biologics are equally safe and effective as the conventional products is essential. It is important for the clinician to consider what information is therefore necessary for such assurances. Biopharmaceuticals...

  16. Usefulness in Decision Making of Accounting Information under Old and New Accounting Standards——A Comparative Study Based on Statement of Case Flows of Biopharmaceuticals Listed Companies%新旧会计准则下会计信息决策有用性比较研究——基于生物制药上市公司现金流量表数据检验

    Institute of Scientific and Technical Information of China (English)

    林斌; 冯倩

    2012-01-01

    以生物制药上市公司为样本,以现金流量表补充资料为研究对象,通过多元线性回归法,统计检验新旧准则下现金流量表补充资料信息对下一年度盈利水平的解释能力,得出我国执行新会计准则后的会计信息比旧准则下的会计信息更具决策有用性的结论.

  17. 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

    2012-01-01

    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。

  18. A European perspective on the market accessibility of biosimilars

    Directory of Open Access Journals (Sweden)

    Declerck PJ

    2012-11-01

    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

  19. Protein pharmaceuticals: discovery and preclinical development.

    Science.gov (United States)

    Gill, Davinder S

    2009-01-01

    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. PMID:20047032

  20. Biotechnology

    International Nuclear Information System (INIS)

    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.

  1. Transgenic Plants as Expression Factories for Bio Pharmaceuticals

    Directory of Open Access Journals (Sweden)

    Shabir H Wani

    2015-06-01

    Full Text Available At present agriculture not only provides food, but is also used for the production of pharmaceuticals or industrial compounds such as pharmaceutical drugs, vaccines along with biodegradable plastic and industrial chemicals. Since last three decades, plant genetic engineering has played a vital role in the production of bio-pharmaceutical products from crops. Due to technological advancement of genetic engineering, biotechnologist are able to engineer plants by using living organism with the help of different transformation techniques like Agrobacterium mediated transformation, biolistic gene gun, and so on to produce biopharmaceuticals products for diagnostic purposes as well as nutritional supplements.

  2. BDDCS Applied to Over 900 Drugs

    DEFF Research Database (Denmark)

    Benet, Leslie Z.; Broccatelli, Fabio; Oprea, Tudor

    2011-01-01

    Here, we compile the Biopharmaceutics Drug Disposition Classification System (BDDCS) classification for 927 drugs, which include 30 active metabolites. Of the 897 parent drugs, 78.8% (707) are administered orally. Where the lowest measured solubility is found, this value is reported for 72.7% (513...

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

    DEFF Research Database (Denmark)

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

    2012-01-01

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

  4. Daedalus: a robust, turnkey platform for rapid production of decigram quantities of active recombinant proteins in human cell lines using novel lentiviral vectors

    OpenAIRE

    Bandaranayake, Ashok D.; Correnti, Colin; Ryu, Byoung Y.; Brault, Michelle; Strong, Roland K.; Rawlings, David J.

    2011-01-01

    A key challenge for the academic and biopharmaceutical communities is the rapid and scalable production of recombinant proteins for supporting downstream applications ranging from therapeutic trials to structural genomics efforts. Here, we describe a novel system for the production of recombinant mammalian proteins, including immune receptors, cytokines and antibodies, in a human cell line culture system, often requiring

  5. 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.; Christensen, Niels Johan; Hoeg-Jensen, Thomas; Jensen, Knud J.; Arleth, Lise

    2012-01-01

    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 studi...

  6. Correlation of cell growth and heterologous protein production by Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Liu, Zihe; Hou, Jin; Martínez, José L.;

    2013-01-01

    With the increasing demand for biopharmaceutical proteins and industrial enzymes, it is necessary to optimize the production by microbial fermentation or cell cultures. Yeasts are well established for the production of a wide range of recombinant proteins, but there are also some limitations; e.g...

  7. A Methods-Based Biotechnology Course for Undergraduates

    Science.gov (United States)

    Chakrabarti, Debopam

    2009-01-01

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

  8. 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.

    2015-01-01

    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

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

    Science.gov (United States)

    Bruyer, Tom; Jacobs, Geert; Vandendaele, Astrid

    2016-01-01

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

  10. Recombinant organisms for production of industrial products

    OpenAIRE

    Adrio, Jose-Luis; Demain, Arnold L.

    2009-01-01

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

  11. Application of biocontrol agents in forest nurseries

    Science.gov (United States)

    Bare-root conifer seedling culture consists of growing seedlings (sown or transplanted) in soil, and is the predominant method for supplying America’s need for healthy regeneration stock to produce and sustain forests, wildlife food sources, fiber, wood products, paper, bio-pharmaceuticals and now p...

  12. Irish Chemical News

    OpenAIRE

    Roche, James J.; Franklin, Margaret; Hobbs, Patrick; Hodnett, Kieran; Cantwell, Helen; Bradley, Derek; Burke, Mary

    2016-01-01

    Contents: A Message from the President p.3 -- Editorial p.5 -- Polymorphic Transformations in Pharmaceutical Compounds p.7 -- Navigating the Challenges of Method Validation –with a little help from Eurachem p.24 -- Obituary: Professor Richard Butler NUI Galway, February 10th, 2016 p.30 -- Congress 2016: Chemistry and Society, GMIT p.34 -- Characterisation of Biopharmaceuticals p.40 -- Industry & Business news p.78.

  13. 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;

    2016-01-01

    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 t...

  14. The CssRS two-component regulatory system controls a general secretion stress response in Bacillus subtilis

    NARCIS (Netherlands)

    Westers, Helga; Westers, L; Darmon, E.; van Dijl, Jan Maarten; Quax, Wim; Zanen, Geeske

    2006-01-01

    Bacillus species are valuable producers of industrial enzymes and biopharmaceuticals, because they can secrete large quantities of high-quality proteins directly into the growth medium. This requires the concerted action of quality control factors, such as folding catalysts and 'cleaning proteases'.

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

    NARCIS (Netherlands)

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

    2006-01-01

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

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

    NARCIS (Netherlands)

    Schellekens, H.

    2009-01-01

    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

  17. Proceedings of the International Symposium on Biotechnology

    International Nuclear Information System (INIS)

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

  18. 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; Kristensen, Claus; Kildegaard, Helene Faustrup; Andersen, Mikael Rørdam

    2014-01-01

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

  19. [Biological treatment of multiple sclerosis

    DEFF Research Database (Denmark)

    Sorensen, P.S.; Sellebjerg, F.

    2008-01-01

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

  20. Sparging-shear sensitivity of animal cells.

    NARCIS (Netherlands)

    Pol, van der L.A.

    1998-01-01

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

  1. Biofarmaka til behandling af reumatoid artritis

    DEFF Research Database (Denmark)

    Baslund, Bo; Bendtzen, Klaus

    2008-01-01

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

  2. Amino acid and glucose metabolism in fed-batch CHO cell culture affects antibody production and glycosylation

    DEFF Research Database (Denmark)

    Fan, Yuzhou; Jimenez Del Val, Ioscani; Müller, Christian;

    2015-01-01

    Fed-batch Chinese hamster ovary (CHO) cell culture is the most commonly used process for IgG production in the biopharmaceutical industry. Amino acid and glucose consumption, cell growth, metabolism, antibody titer, and N-glycosylation patterns are always the major concerns during upstream proces...

  3. A NOVEL METHOD FOR MICROENCAPSULATION OF PROTEIN USING HIGH-VOLTAGE ELECTROSTATIC FIELD SYSTEM

    Science.gov (United States)

    Protein and peptide-based bio-pharmaceuticals and nutraceuticals have been developed in recent years. However, since such products, unlike traditional small-molecule drugs, may not be administered orally, injection or infusion is normally required. There is a need of encapsulation of such proteins...

  4. 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

    2002-01-01

    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.

  5. Digitizing and Securing Archived Laboratory Notebooks

    Science.gov (United States)

    Caporizzo, Marilyn

    2008-01-01

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

  6. Early pharmaceutical profiling to predict oral drug absorption

    DEFF Research Database (Denmark)

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

    2014-01-01

    Preformulation measurements are used to estimate the fraction absorbed in vivo for orally administered compounds and thereby allow an early evaluation of the need for enabling formulations. As part of the Oral Biopharmaceutical Tools (OrBiTo) project, this review provides a summary of the...

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    Large molecules, such as biopharmaceuticals, are considered the key driver of growth for the pharmaceutical industry. Freeze-drying is the preferred way to stabilise these products when needed. However, it is an expensive, inefficient, time- and energy-consuming process. During freeze-drying, there...

  8. Uninformed and disinformed society and the GMO market.

    Science.gov (United States)

    Twardowski, Tomasz; Małyska, Aleksandra

    2015-01-01

    The EU has a complicated regulatory framework, and this is slowing down the approval process of new genetically modified (GM) crops. Currently, labeling of GM organisms (GMOs) is mandatory in all Member States. However, the USA, in which GMO labeling is not mandatory, continues to lead the production of biotech crops, biopharmaceuticals, biomaterials, and bioenergy. PMID:25528967

  9. Animal pharming, two decades on.

    Science.gov (United States)

    Kind, Alexander; Schnieke, Angelika

    2008-12-01

    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. PMID:18663595

  10. Applications of recombinant Pichia pastoris in the healthcare industry.

    Science.gov (United States)

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

    2013-12-01

    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. PMID:24688491

  11. Managing risks in drug discovery: reproducibility of published findings.

    Science.gov (United States)

    Kannt, Aimo; Wieland, Thomas

    2016-04-01

    In spite of tremendous advances in biopharmaceutical science and technology, the productivity of pharmaceutical research and development has been steadily declining over the last decades. The reasons for this decline are manifold and range from improved standard of care that is more and more difficult to top to inappropriate management of technical and translational risks along the R&D value chain. In this short review, major types of risks in biopharmaceutical R&D and means to address them will be described. A special focus will be on a risk, i.e., the lack of reproducibility of published information, that has so far not been fully appreciated and systematically analyzed. Measures to improve reproducibility and trust in published information will be discussed. PMID:26883784

  12. The regulatory framework for similar biotherapeutic products in Cuba.

    Science.gov (United States)

    Hechavarría Núñez, Yanet; Pérez Massipe, Rodrigo Omar; Orta Hernández, Santa Deybis; Muñoz, Lázara Martínez; Jacobo Casanueva, Olga Lidia; Pérez Rodríguez, Violeta; Domínguez Morales, Rolando Bárbaro; Pérez Cristiá, Rafael B

    2011-09-01

    Biopharmaceuticals make up a significant proportion of medicinal products used for the treatment of diseases such as cancer, arthritis, cardiac dysfunctions and AIDS. Access to therapies based on the use of these products has been limited as a result of the high marketing costs. Cuba has a biopharmaceutical industry with great potential for innovation, capable of developing new products and to produce others, like the biosimilars destined to fulfill the needs of its National Health System. The Center for State Control on the Quality of Drugs (CECMED) the Cuban NRA, is facing the challenge of regulating the approval of biosimilar products manufactured locally. Consequently, CECMED has issued a position paper establishing the basic principles for regulation of these products and a specific guideline on this was elaborated. PMID:21930393

  13. 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;

    2015-01-01

    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...... consists 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...... to reduce production costs significantly. The aim of this study was to establish a versatile target gene screening platform for improving productivity for primarily non-mAb glycoproteins with complete interchangeability of model proteins and target genes using transient expression. The platform...

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

    Directory of Open Access Journals (Sweden)

    Lukasz Puslecki

    2015-06-01

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

  15. A new approach to assess drug development performance.

    Science.gov (United States)

    Rosiello, Alessandro; Dimitri, Nicola; Fiorini, Filippo

    2013-05-01

    This article suggests that successful innovation in biopharmaceuticals is strongly related to the ability of firms to move compounds forward along the drug pipeline, relatively to other companies, within the same therapeutic area. We used this intuition to build indicators of performance at the firm-level and use them to conduct empirical analysis that relies upon a comprehensive database. We consider the effect of various factors on drug development performance, including R&D funds allocation across therapeutic areas and the proportion of biological molecules in the drug development portfolio. Subsequently, we show that a correlation exists between our performance variables and the per-capita growth of biopharmaceutical firms' revenues. PMID:23337387

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

    Science.gov (United States)

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

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

  17. Chemical materials and their regulation of the movement of molecules.

    Science.gov (United States)

    Langer, Robert

    2015-11-01

    Materials chemistry has been fundamental to the enormous field that encompasses the delivery of molecules both to desired sites and/or at desired rates and durations. The field encompasses the delivery of molecules including fertilizers, pesticides, herbicides, food ingredients, fragrances and biopharmaceuticals. A personal perspective is provided on our early work in this field that has enabled the controlled release of ionic substances and macromolecules. Also discussed are new paradigms in creating biomaterials for human use, the non-invasive delivery of molecules through the skin and lungs, the development of intelligent delivery systems and extensions to nanomedicine. With the advent of potentially newer biopharmaceutics such as siRNA, mRNA and gene editing approaches and their use being limited by delivery, future research in this field may be more critical than ever before. PMID:26537401

  18. Discovery pharmaceutics—Challenges and opportunities

    OpenAIRE

    Chen, Xue-Qing; Antman, Melissa D.; Gesenberg, Christoph; Gudmundsson, Olafur S.

    2006-01-01

    Most pharmaceutical companies are now evaluating compounds for druglike properties early in the discovery process. The data generated at these early stages allow upfront identification of potential development challenges and thus selection of the best candidates for lead nomination. Most often, lead nomination candidates are selected based on pharmacological and toxicological data. However, many drugs in development suffer from poor biopharmaceutical properties due to suboptimal physiochemica...

  19. P135-T Structural Characterization of a Recombinant Monoclonal Antibody by Electrospray Ion-Mobility Time-of-Flight Mass Spectrometry

    OpenAIRE

    Chen, W.; Olivova, P.; Chakraborty, A. B.; Gilar, M; Gebler, J. C.

    2007-01-01

    Recombinant monoclonal antibodies (MAb) comprise a significant proportion of biopharmaceuticals used in diagnostic and therapeutic applications. Although the general structural features of monoclonal antibody such as disulfide bond patterns have been known for decades, the intrinsic heterogeneity of such molecules has imposed the needs for thorough analytical characterizations so the structural details of each pharmaceutical MAb are determined, and safe, effective, and reproducible products c...

  20. A Comprehensive Review on Cyclodextrin-Based Carriers for Delivery of Chemotherapeutic Cytotoxic Anticancer Drugs

    OpenAIRE

    Bina Gidwani; Amber Vyas

    2015-01-01

    Most of the cytotoxic chemotherapeutic agents have poor aqueous solubility. These molecules are associated with poor physicochemical and biopharmaceutical properties, which makes the formulation difficult. An important approach in this regard is the use of combination of cyclodextrin and nanotechnology in delivery system. This paper provides an overview of limitations associated with anticancer drugs, their complexation with cyclodextrins, loading/encapsulating the complexed drugs into carrie...

  1. Technological progresses in monoclonal antibody production systems

    OpenAIRE

    Rodrigues, E.; Costa, A R; Henriques, Mariana; Azeredo, Joana; Oliveira, Rosário

    2009-01-01

    Monoclonal antibodies (mAbs) have become vitally important to modern medicine and are currently one of the major biopharmaceutical products in development. However, the high clinical dose requirements of mAbs demand a greater biomanufacturing capacity, leading to the development of new technologies for their large-scale production, with mammalian cell culture dominating the scenario. Although some companies have tried to meet these demands by creating bioreactors of increased capacity, the op...

  2. PASylation: a biological alternative to PEGylation for extending the plasma half-life of pharmaceutically active proteins

    OpenAIRE

    Schlapschy, Martin; Binder, Uli; Börger, Claudia; Theobald, Ina; Wachinger, Klaus; Kisling, Sigrid; Haller, Dirk; Skerra, Arne

    2013-01-01

    A major limitation of biopharmaceutical proteins is their fast clearance from circulation via kidney filtration, which strongly hampers efficacy both in animal studies and in human therapy. We have developed conformationally disordered polypeptide chains with expanded hydrodynamic volume comprising the small residues Pro, Ala and Ser (PAS). PAS sequences are hydrophilic, uncharged biological polymers with biophysical properties very similar to poly-ethylene glycol (PEG), whose chemical conjug...

  3. Development and evaluation of a self-emulsifying drug delivery system of amphotericin B

    OpenAIRE

    Arundhati Bhattacharyya; Meenakshi Bajpai

    2012-01-01

    Amphotericin B is a polyene antifungal antibiotic belonging to Class IV of Biopharmaceutics Classification System which is not absorbed from the gastrointestinal tract after oral administration. The aim of this research work was to develop a self-emulsifying drug delivery system (SEDDS) of amphotericin B and to evaluate the dissolution and permeability of amphotericin B from the formulation. The solubility of amphotericin B in various oils, surfactants and cosurfactants was determined. Variou...

  4. Formulation and development of self-microemulsifying drug delivery system of pioglitazone hydrochloride

    OpenAIRE

    Jyotsana R. Madan; Bandavane Sudarshan; Vinod S. Kadam; Dua Kamal

    2014-01-01

    Self-microemulsifying drug delivery system (SMEDDS) is a promising system for the Biopharmaceutics Classification System (BCS) class II drugs. The current research aimed to improve the dissolution of poorly water-soluble antidiabetic drug pioglitazone HCl by formulating it in SMEDDS. Liquid SMEDDS of pioglitazone HCl were formulated with Capmul MCM C8 and oleic acid as oil phase, Cremophor RH 40 and Tween 80 as surfactant phase, and Transcutol P as cosurfactant phase after screening various v...

  5. Diffusion of Pharmaceuticals: Cross-Country Evidence of Anti-TNF drugs

    OpenAIRE

    Brekke, Kurt; Dalen, Dag Morten; Holmås, Tor Helge

    2013-01-01

    This article studies the diffusion of biopharmaceuticals across European countries, focusing on anti-TNF drugs, which are used to treat autoimmune diseases (e.g., rheumatism, psoriasis). We use detailed sales information on the three brands Remicade, Enbrel and Humira for nine European countries covering the period from the first launch in 2000 until becoming blockbusters in 2009. Descriptive statistics reveal large variations across countries in per-capita consumption and price levels both o...

  6. Transgenic Plants as Expression Factories for Bio Pharmaceuticals

    OpenAIRE

    Wani, Shabir. H.; Sah, Saroj K.

    2015-01-01

    At present agriculture not only provides food, but is also used for the production of pharmaceuticals or industrial compounds such as pharmaceutical drugs, vaccines along with biodegradable plastic and industrial chemicals. Since last three decades, plant genetic engineering has played a vital role in the production of bio-pharmaceutical products from crops. Due to technological advancement of genetic engineering, biotechnologist are able to engineer plants by using living organism with the h...

  7. Milestones in chloroplast genetic engineering: an environmentally friendly era in biotechnology

    OpenAIRE

    Daniell, Henry; Khan, Muhammad S.; Allison, Lori

    2002-01-01

    Chloroplast genomes defied the laws of Mendelian inheritance at the dawn of plant genetics, and continue to defy the mainstream approach to biotechnology, leading the field in an environmentally friendly direction. Recent success in engineering the chloroplast genome for resistance to herbicides, insects, disease and drought, and for production of biopharmaceuticals, has opened the door to a new era in biotechnology. The successful engineering of tomato chromoplasts for high-level transgene e...

  8. Role of Physiological Intestinal Water in Oral Absorption

    OpenAIRE

    Sutton, Steven C.

    2009-01-01

    Water volume has impact when the compound has low aqueous solubility. For example, the absorption of compounds with a Biopharmaceutics Classification System class 2 or 4 is likely to be solubility-limited. Provided the formulation does not contribute to a dissolution-limited condition (e.g., particle size, Waterman and Sutton, J Control Release 86:293–304, 2003) and permeability is rapid, any impact on solubility factors in the gastrointestinal (GI) tract will directly impact the fraction abs...

  9. Preformulation investigation of some clopidogrel addition salts:

    OpenAIRE

    Benkič, Primož; Kristl, Albin; Plevnik, Miha; Ritlop, Gregor; Simonič, Igor; Smrkolj, Matej; Vrečer, Franc; Zupančič, Vinko

    2010-01-01

    Physico-chemical properties of active substances such as solubility, dissolution rate, chemical stability, pharmaceutical processibility, etc. can be improved by salt formation of active substances. Characterization of physical properties of such salts is important for selection of an optimal salt having required biopharmaceutical properties, stability and manufacturability. The present study deals with the preformulation study of selected clopidogrel acid addition salts, i.e. hydrogen sulfat...

  10. Membrane-less microfiltration using inertial microfluidics

    OpenAIRE

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

    2015-01-01

    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...

  11. Experimental Studies of the Ability of Pharmacopoeial Excipients to Release Pharmacologically Active Substances when Developing Dental Dressing

    OpenAIRE

    Haioshko, O. B.

    2016-01-01

    The biopharmaceutical studies have undoubtedly proven that pharmacopoeial excipients based on polyethylene oxide, sodium carboxymethyl cellulose and apple pectin can release pharmacologically active substances and produce pharmacopoeial excipients in the form of ointments and pastes. The dynamics of diffusion of biologically active substances in agar gel within 6 hours of the experiment was practically the same in all samples. The least significant changes in samples consistency and preservat...

  12. Characterising electrospun nanofibre adsorbents for bioprocessing

    OpenAIRE

    Dods, S. R.

    2016-01-01

    Biopharmaceutical manufacturing is one of largest sectors in the world and purification steps are expensive. Packed-bed resins are widely used, but are limited by diffusion mass transfer. Convective mass transfer media offer improved productivities using high flowrates. Electrospun nanofibres are a non-woven with an open structure and high surface area. Cellulose acetate was electrospun into reproducible adsorbents and activation methodologies were evaluated. Aldehyde activation caused degrad...

  13. An Overview of Current Regulatory Requirements for Approval of Biosimilar Insulins

    OpenAIRE

    Heinemann, Lutz; Khatami, Hootan; McKinnon, Ross; Home, Philip

    2015-01-01

    Abstract Insulin analog patent expiry is likely to mean that, increasingly, copies of original biopharmaceutical products will be submitted for authorization. Experience with biosimilars in other therapeutic areas suggests that careful regulation and caution are needed. Published guidelines of regulatory authorities around the world on approval of biosimilars and, where available, insulin biosimilars were reviewed. Information was sourced through Internet searching and cross-referencing guide...

  14. Proximité territoriale et innovation : une enquête sur la région de Montréal

    OpenAIRE

    Diane-Gabrielle Tremblay; Jean-Marc Fontan; Juan-Luis Klein; Serge Rousseau

    2003-01-01

    The effect of proximity on development has fostered much interest over recent years and STORPER has put forward the hypothesis of a winning configuration for the 3rd millenium, that is one based on innovation, organizations and territory. Our research was conducted with firms of three high tech sectors in Montreal (biopharmaceutical, telecommunications and aeronautics) and aimed at identifying the effects of proximity on innovation and local development; the method was based on interviews and...

  15. A gene responsible for prolyl-hydroxylation of moss-produced recombinant human erythropoietin

    OpenAIRE

    Juliana Parsons; Friedrich Altmann; Manuela Graf; Johannes Stadlmann; Ralf Reski; Decker, Eva L

    2013-01-01

    Recombinant production of pharmaceutical proteins is crucial, not only for personalized medicine. While most biopharmaceuticals are currently produced in mammalian cell culture, plant-made pharmaceuticals gain momentum. Post-translational modifications in plants are similar to those in humans, however, existing differences may affect quality, safety and efficacy of the products. A frequent modification in higher eukaryotes is prolyl-4-hydroxylase (P4H)-catalysed prolyl-hydroxylation. P4H sequ...

  16. Guidelines to cell engineering for monoclonal antibody production

    OpenAIRE

    Costa, A.; Rodrigues, E; Henriques, Mariana; Azeredo, Joana; Oliveira, Rosário

    2010-01-01

    Monoclonal antibodies (mAbs) are currently used for many diagnostic and therapeutic applications. The high demand for these biopharmaceuticals has led to the development of large-scale manufacturing processes, with productivity improvements being mainly achieved by optimization of bioreactor systems. However, more recently, the early steps of production, previous to bioreactor culture, have been presented as alternative areas where productivity enhancements can be achieved. Thus, ...

  17. A chimeric affinity tag for efficient expression and chromatographic purification of heterologous proteins from plants

    OpenAIRE

    Frank eSainsbury; Philippe V. Jutras; Juan eVorster; Marie-Claire eGoulet; Dominique eMichaud

    2016-01-01

    The use of plants as expression hosts for recombinant proteins is an increasingly attractive option for the production of complex and challenging biopharmaceuticals. Tools are needed at present to marry recent developments in high-yielding gene vectors for heterologous expression with routine protein purification techniques. In this study we designed the Cysta-tag, a new purification tag for immobilized metal affinity chromatography (IMAC) of plant-made proteins based on the protein-stabilizi...

  18. AN UPDATED REVIEW ON TECHNICAL ADVANCES TO ENHANCE DISSOLUTION RATE OF HYDROPHOBIC DRUGS

    OpenAIRE

    Anjan K. Mahapatra; P. Narasimha Murthy; E. Radha Rani; S. Pallavi Soujanya; Ruchita Kumari Patra

    2012-01-01

    The dissolution behavior of drugs continues to be one of the challenging aspects in formulation development. The advent of combinatorial chemistry and high throughput screening increased the number of hydrophobic compounds significantly. The Biopharmaceutical classification scheme (BCS) takes into account three major factors: solubility, intestinal permeability, and dissolution rate and all the three govern the rate and extent of oral absorption and hence bioavailability. Especially for BCS C...

  19. Solubility enhancement of rosiglitazone by using melt sonocrystallization technique

    OpenAIRE

    Jagtap, Vaibhavkumar A.; Vidyasagar, G.; Dvivedi, S. C.

    2014-01-01

    The poor solubility and low dissolution rate in gastro-intestinal fluid, especially for class-II drugs according to Biopharmaceutics Classification System (BCS) the bioavailability enhanced by increasing the solubility and dissolution rate. A novel melt sonocrystallization technique of particle engineering to enhance solubility as well as dissolution of hydrophobic drug and to study its effect on crystal properties of drug. The present study leads to use investigate solubility of melt sonocry...

  20. Identification of Growth Phases and Influencing Factors in Cultivations with AGE1.HN Cells Using Set-Based Methods

    OpenAIRE

    Borchers, S.; Freund, S; Rath, A.; Streif, S; Reichl, U.; Findeisen, R.

    2013-01-01

    Production of bio-pharmaceuticals in cell culture, such as mammalian cells, is challenging. Mathematical models can provide support to the analysis, optimization, and the operation of production processes. In particular, unstructured models are suited for these purposes, since they can be tailored to particular process conditions. To this end, growth phases and the most relevant factors influencing cell growth and product formation have to be identified. Due to noisy and erroneous experimenta...

  1. Expression of functionally active sialylated human erythropoietin in plants

    OpenAIRE

    Jez, Jakub; Castilho, Alexandra; Grass, Josephine; Vorauer-Uhl, Karola; Sterovsky, Thomas; Altmann, Friedrich; Steinkellner, Herta

    2013-01-01

    Recombinant human erythropoietin (rhEPO), a glycohormone, is one of the leading biopharmaceutical products. The production of rhEPO is currently restricted to mammalian cell expression systems because of rhEPO's highly complex glycosylation pattern, which is a major determinant for drug-efficacy. Here we evaluate the ability of plants to produce different glycoforms of rhEPO. cDNA constructs were delivered to Nicotiana benthamiana (N. benthamiana) and transiently expressed by a viral based ex...

  2. Progress on RNAi-based molecular medicines

    OpenAIRE

    Chen J; Xie JP

    2012-01-01

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

  3. One-step non-chromatography purification of a low abundant fucosylated protein from complex plant crude extract

    OpenAIRE

    Lindsay Arnold; Rachel Chen

    2015-01-01

    Effective methods for isolation and purification of glycoproteins and other glycoconjugates are important to biopharmaceutical industry and diagnostic industry. They are also critical to an emerging field of glycoproteomics. In this work, we applied the newly-developed affinity ligand, a fusion protein of elastic like polymer (ELP) and a bacterial lectin, in an affinity precipitation process to purify soybean peroxidase (SBP) based on the presence of fucoseon the protein surface. We addressed...

  4. Engineering the rational design and optimisation of lyophilization processes for biological materials

    OpenAIRE

    Grant, Y. G.

    2011-01-01

    Lyophilization is a common method used for long term stability of pharmaceutical and biopharmaceutical products that are unstable in the liquid state for a substantial period of time. Currently, formulation and cycle development are often determined empirically. Although this approach is gradually changing as scientific publications reveal more about the nature of protein stability, nevertheless the lack of material during early stage development prevents large screening inv...

  5. A probability approach to pharmaceutical demand and price setting: Does the identity of the third-party payer matters for prescribing doctors?

    OpenAIRE

    Dalen, Dag Morten; Locatelli, Marilena; Sorisio, Enrico; Strøm, Steinar

    2011-01-01

    TNF-alpha inhibitors represent one of the most important areas of biopharmaceuticals by sales, with three blockbusters accounting for 8 per cent of total pharmaceutical sale in Norway. Novelty of the paper is to examine, with the use of a unique natural policy experiment in Norway, to what extent the price responsiveness of prescription choices is affected when the identity of the third-party payer changes. The three dominating drugs in this market, Enbrel, Remicade, and Humira, are substitut...

  6. Choosing among competing blockbusters: Does the identity of the third-party payer matter for prescribing doctors?

    OpenAIRE

    Dalen, Dag Morten; Sorisio, Enrico; Strøm, Steinar

    2010-01-01

    TNF-alpha inhibitors represent one of the most important areas of biopharmaceuticals by sales, with three blockbusters accounting for 8 % of total pharmaceutical sale in Norway. With use of a unique natural policy experiment in Norway, this paper examines to what extent the identity of the third-party payer affects doctors’ choice between the three available drugs. We are able to investigate to what extent the price responsiveness of prescription choices is affected when the identity of the t...

  7. Does the Identity of the Third-Party Payer Matter for Prescribing Doctors?

    OpenAIRE

    2014-01-01

    TNF-alpha inhibitors represent one of the most important areas of biopharmaceuticals by sales, with three blockbusters accounting for 8 per cent of total pharmaceutical sale in Norway. Novelty of the paper is to examine, with the use of a unique natural policy experiment in Norway, to what extent the price responsiveness of prescription choices is affected when the identity of the third-party payer changes. The three dominating drugs in this market, Enbrel, Remicade, and Humira, are substitut...

  8. Biosimilar Drugs

    OpenAIRE

    Muradiye Nacak; Zafer Sezer; Aydın Erenmemisoglu

    2012-01-01

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

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

    OpenAIRE

    Lukasz Puslecki; Michal Staszkow

    2015-01-01

    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 ...

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

    OpenAIRE

    Lukasz Puslecki; Michal Staszkow

    2015-01-01

    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...

  11. How to achieve high-level expression of microbial enzymes: Strategies and perspectives

    OpenAIRE

    Liu, Long; Yang, Haiquan; Shin, Hyun-dong; Chen, Rachel R.; Li, Jianghua; Du, Guocheng; Chen, Jian

    2013-01-01

    Microbial enzymes have been used in a large number of fields, such as chemical, agricultural and biopharmaceutical industries. The enzyme production rate and yield are the main factors to consider when choosing the appropriate expression system for the production of recombinant proteins. Recombinant enzymes have been expressed in bacteria (e.g., Escherichia coli, Bacillus and lactic acid bacteria), filamentous fungi (e.g., Aspergillus) and yeasts (e.g., Pichia pastoris). The favorable and ver...

  12. Establishment of reference standards in biosimilar studies

    OpenAIRE

    2013-01-01

    When an innovative biological product goes off-patent, biopharmaceutical or biotechnological companies may file an application for regulatory approval of biosimilar products. In practice, however, important information on the innovative (reference) product may not be available for assessment. Thus, it is important to first establish a reference standard while assessing biosimilarity between a biosimilar product and the reference product. In this paper, reference standard is established throug...

  13. Biosimilar medicines – their use in the treatment of inflammatory bowel diseases. Position statement of the Working Group of the Polish National Consultant in Gastroenterology

    OpenAIRE

    Mularczyk, Aldona; Gonciarz, Maciej; Bartnik, Witold; Durlik, Marek; Eder, Piotr; GĄSIOROWSKA, ANITA; Linke, Krzysztof; Łodyga, Michał; Łykowska-Szuber, Liliana; Małecka-Panas, Ewa; Pawlik, Magdalena; Radwan, Piotr; Rydzewska, Grażyna

    2014-01-01

    Biological medical products are drugs whose active components are produced only by living, genetically modified organisms or live cell cultures. Patents and exclusivity for most biopharmaceuticals has either expired or will expire soon, which enables biotechnological companies to introduce similar biological products. The problem of replacing a biological medicine with a biosimilar in the course of therapy remains open. In this statement, the Working Group of the Polish National Consultant in...

  14. Study and ICH validation of a reverse-phase liquid chromatographic method for the quantification of the intact monoclonal antibody cetuximab

    OpenAIRE

    Antonio Martínez-Ortega; Agustín Herrera; Antonio Salmerón-García; José Cabeza; Luis Cuadros-Rodríguez; Natalia Navas

    2016-01-01

    Cetuximab (CTX) is a potent chimeric mouse/human monoclonal antibody (mAb) approved worldwide for treatment of metastatic colorectal cancer. Among the various biological and physical analyses performed for full study on this biopharmaceutic, the determination of the concentration preparations throughout manufacturing and subsequent handling in hospital is particularly relevant. In the present work, the study and validation of a method for quantifying intact CTX by reverse-phase high-performan...

  15. State-Level R&D Tax Credits: A Firm-Level Analysis

    OpenAIRE

    Paff Lolita A

    2005-01-01

    California’s changes in R&D tax credit rates on biopharmaceutical and software firms’ research investment during 1994-1996 and 1997-1999 is compared using two approaches. Consistent with the federal research tax credit literature, the difference-in-differences analysis provides some evidence of increased R&D expenditure in response to research tax credit rate increases. In contrast, the estimated tax price elasticities obtained by computing and testing the tax prices for in-house research are...

  16. CURRENT STATUS AND FUTURE DIRECTIONS OF NEW DRUG DELIVERY TECHNOLOGIES

    OpenAIRE

    Garg Tarun; Bilandi Ajay; Kapoor Bhawna; Kumar Sunil; Chanana Arsh

    2011-01-01

    New drug delivery systems based products have significantly increased in the past few years, and this growth is expected to continue in the near future. Today a large number of companies are busy developing protein- and peptide-based drugs. Large molecules that degrade rapidly in the blood stream so these biopharmaceuticals (proteins, peptides, carbohydrates, oligo-nucleotides, and nucleic acids in the form of DNA) present drug delivery challenges. Moreover, they have a limited ability to cro...

  17. What innovative business models can be triggered by precision medicine? Analogical reasoning from the magazine industry

    OpenAIRE

    Sabatier, Valérie

    2015-01-01

    Neva Bojovic,1 Valérie Sabatier,1 Stephane Rouault2 1Grenoble Ecole de Management, Grenoble, France; 2Innovation Hub, Strategic Innovation, F Hoffmann-La Roche Ltd, Basel, Switzerland Abstract: Presently, the health care industry is facing many technological and organizational challenges, and the emergence of precision medicine is bringing innovation and potentially a complete redefinition of the industry. This study suggests several paths for incumbent biopharmaceutical companies...

  18. Determination of IGF-1-Producing CHO-K1 Growth Phases Using GCMS-Based Global Metabolite Analysis

    OpenAIRE

    S. E. M. SABERI; Y.Z.H-Y Hashim; V. Packeer Mohamad; M. Mel; R. Ahmad-Raus; and A. Amid

    2011-01-01

    Mammalian cell lines, in particular CHO-K1 is vital for the multibillion dollar biotechnology industry. The majority of large scale bioprocessing of commercially valuable protein biopharmaceuticals is produced using this type of cell. An ideal mammalian cell system as host for biologics production should retain efficient use of energy sources in order to boost productivity at minimum cost. Various analyses such as cell counting and monitoring of specific biochemical responses are used to prov...

  19. A laminated polymer film formulation for enteric delivery of live vaccine and probiotic bacteria

    OpenAIRE

    de Barros, João M. S.; Scherer, Timothy; Charalampopoulos, Dimitris; Khutoryanskiy, Vitaliy V.; Edwards, Alexander D.

    2014-01-01

    Live bacterial cells (LBC) are administered orally as attenuated vaccines, to deliver biopharmaceutical agents, and as probiotics to improve gastrointestinal health. However, LBC present unique formulation challenges and must survive gastrointestinal antimicrobial defenses including gastric acid after administration. We present a simple new formulation concept, termed Polymer Film Laminate (PFL). LBC are ambient dried onto cast acid-resistant enteric polymer films that are then laminated toge...

  20. Comparative pharmacokinetic study of dosage forms with morpholinium 2-[5-(pyridin-4-yl)-1,2,4-triazol-3-ylthio] acetate

    OpenAIRE

    Bushueva, I. V.; Gladyshev, V. V.; Panasenko, О. I.; Knish, E. G.

    2014-01-01

    Using mathematical models of income distribution and excretion of drugs greatly enhances the interpretation of the results of biopharmaceutical research. Pharmacokinetic modeling makes it possible to quantify the biological assessment of pharmaceutical factors, opens the possibility of a science-based regulation of the kinetics of substances introduced through targeted changesof pharmaceutical factors. Results of the study of kinetic models are used to solve some practical problems associated...

  1. Klucel™ EF and ELF polymers for immediate-release oral dosage forms prepared by melt extrusion technology

    OpenAIRE

    Mohammed, Noorullah Naqvi; Majumdar, Soumyajit; Singh, Abhilasha; Deng, Weibin; Murthy, Narasimha S.; Pinto, Elanor; Tewari, Divya; Durig, Thomas; Repka, Michael A.

    2012-01-01

    The objective of this research work was to evaluate Klucel™ hydroxypropylcellulose (HPC) EF and ELF polymers, for solubility enhancement as well as to address some of the disadvantages associated with solid dispersions. Ketoprofen (KPR), a Biopharmaceutics Classification System class II drug with poor solubility, was utilized as a model compound. Preliminary thermal studies were performed to confirm formation of a solid solution/dispersion of KPR in HPC matrix and also to establish processing...

  2. Cloning, Transformation and Expression of Proinsulin Gene in Tomato (Lycopersicum esculentum Mill.)

    OpenAIRE

    Soltanmohammadi, Behnoush; Jalali-Javaran, Mokhtar; Rajabi-Memari, Hamid; Mehdi MOHEBODINI

    2014-01-01

    Background: Plants are among promising and suitable platform systems for production of recombinant biopharmaceutical proteins due to several features such as safety, no need for fermentation, inexpensive investment, and fast and easy scale-up. Human insulin is one of the most widely used medicines in the world. Up to now different expression systems including Escherichia coli, yeast and CHO have been exploited for producing recombinant human insulin and a variety of different recombinant insu...

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

    Directory of Open Access Journals (Sweden)

    Juan Leonardo Martínez-Hurtado

    2012-12-01

    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.

  4. EMERGING TRENDS IN REGULATORY DEVELOPMENTS FOR BIOSIMILARS: RECENT ADVANCES IN GLOBAL AND INDIAN REGULATIONS

    Directory of Open Access Journals (Sweden)

    Shah Kalpesh

    2012-08-01

    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.

  5. Chitosan Nanoplexes For Target siRNA Delivery

    OpenAIRE

    Gutoaia, Andra

    2016-01-01

    In recent years biopharmaceutical companies have started to turn their attention towards small interfering RNA (siRNA) therapeutics, as they offer a strategy to address therapeutically interesting targets that are not “druggable” with classic small molecule inhibitors. siRNAs can be easily adapted to any target of interest; they operate upstream of the protein production by silencing the messenger RNA (mRNA) before it is translated into pathogenic or disease-related proteins. However, the ...

  6. Does the Identity of the Third-Party Payer Matters for Prescribing Doctors?

    OpenAIRE

    Morten Dalen Dag; Locatelli Marilena; Sorisio Enrico; Strom Steinar

    2012-01-01

    TNF-alpha inhibitors represent one of the most important areas of biopharmaceuticals by sales, with three blockbusters accounting for 8 per cent of total pharmaceutical sale in Norway. Novelty of the paper is to examine, with the use of a unique natural policy experiment in Norway, to what extent the price responsiveness of prescription choices is affected when the identity of the third-party payer changes. The three dominating drugs in this market, Enbrel, Remicade, and Humira, are substitut...

  7. Diffusion of Pharmaceuticals: Cross-Country Evidence of Anti-TNF drugs

    OpenAIRE

    2013-01-01

    This paper studies the diffusion of biopharmaceuticals across European countries, focusing on anti-TNF drugs, which are used to treat autoimmune diseases (e.g., rheumatism, psoriasis). We use detailed sales information on the three brands Remicade, Enbrel and Humira for nine European countries covering the period from the fi…rst launch in 2000 until becoming blockbusters in 2009. Descriptive statistics reveal largevariations across countries in per-capita consumption and price levels both ove...

  8. Does the identity of the third-party payer matter for prescribing doctors?

    OpenAIRE

    Dalen, Dag Morten; Locatelli, Marilena; Sorisio, Enrico; Strøm, Steinar

    2014-01-01

    TNF-alpha inhibitors represent one of the most important areas of biopharmaceuticals by sales, with threeblockbusters accounting for 8 per cent of total pharmaceutical sale in Norway. Novelty of the paper is to examine, with the use of a unique natural policy experiment in Norway, to what extent the price responsiveness of prescription choices is affected when the identity of the third-party payer changes. The three dominating drugs in this market, Enbrel, Remicade, and Humira, are substitute...

  9. Diffusion of pharmaceuticals : cross-country evidence of anti-TNF drugs

    OpenAIRE

    Brekke, Kurt Richard; Dalen, Dag Morten; Holmås, Tor Helge

    2013-01-01

    This paper studies the diffusion of biopharmaceuticals across European countries, focusing on anti-TNF drugs, which are used to treat autoimmune diseases (e.g., rheumatism, psoriasis). We use detailed sales information on the three brands Remi-cade, Enbrel and Humira for nine European countries covering the period from the first launch in 2000 until becoming blockbusters in 2009. Descriptive statistics reveal large variations across countries in per-capita consumption and price levels both ov...

  10. Diffusion of pharmaceuticals: cross-country evidence of anti-TNF drugs

    OpenAIRE

    Brekke, Kurt; Dalen, Dag Morten; Holmås, Tor Helge

    2014-01-01

    This article studies the diffusion of biopharmaceuticals across European countries, focusing on anti-TNF drugs, which are used to treat autoimmune diseases (e.g., rheumatism, psoriasis). We use detailed sales information on the three brands Remicade, Enbrel and Humira for nine European countries covering the period from the first launch in 2000 until becoming blockbusters in 2009. Descriptive statistics reveal large variations across countries in per-capita consumption and price levels both o...

  11. Simple and Precise UV Spectrophotometric Method Development for Estimation of Albendazole for Dissolution Study

    OpenAIRE

    Vipin Kumar Agrawal; Shashank Chaturvedi; Amresh Gupta

    2015-01-01

    Albendazole is a class II drug in biopharmaceutical classification system, so its dissolution study is very difficult because of its low solubility and difficulty during estimation of drug in bulk. The present study deals with UV spectrophotometric method development and validation for estimation of albendazole in bulk form. Albendazole is a benzimidazole derivative with an oral broad spectrum of activity against human and animal helminthes parasites. The drug obeyed the Beer’s law and showed...

  12. THE SOCIAL RESPONSIBILITY OF BUSINESS ORGANIZATIONS: THE CASE OF PFIZER

    OpenAIRE

    TOMA Sorin-George; MARINESCU Paul

    2012-01-01

    The complex relationships between business and society have constituted the subject of many researchers from different disciplines in the last century. The aims of our paper are to render in brief the theoretical framework related to the concept of social responsibility of business organizations, and to highlight the implementation of the concept in the case of the largest biopharmaceutical corporation in the world. The methodological approach was based on the literature review. Our paper con...

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

    OpenAIRE

    Bonarius, H.P.J.

    1998-01-01

    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 correctly, and therefore the only possible production system for many (recombinant) therapeutics.Cultivated mammalian cells are similar to tumor cells: in contrast to normal cells in mammalian tissue they...

  14. POLYMERS IN DRUG DELIVERY SYSTEMS

    OpenAIRE

    Patel, P. K.

    2012-01-01

    The future of pharmaceutical industry is now shifting from new drug research to novel drug delivery systems. Biopharmaceuticals present challenges because of their unique nature and difficulty in delivery through conventional routes. These challenges inspire for the invention of new medical grade polymers for novel drug delivery systems. Polymeric drug delivery systems bring a true benefit over glass. Polymer provide improved robustness against breakability and better ergonomy, while deliveri...

  15. Synthetic polymers are more effective than natural flocculants for the clarification of tobacco leaf extracts

    OpenAIRE

    Buyel, J.F.; Fischer, R.

    2015-01-01

    The use of synthetic polymers as flocculants can increase filter capacity and thus reduce the costs of downstream processing during the production of plant-derived biopharmaceutical proteins, but this may also attract regulatory scrutiny due to the potential toxicity of such compounds. Therefore, we investigated the efficacy of three non-toxic natural flocculants (chitosan, kaolin and polyphosphate) alone and in combination with each other or with a synthetic polymer (Polymin P) during the cl...

  16. Formulation, optimization and characterization of gemfibrozil nanocrystals prepared by wet milling technique

    OpenAIRE

    Zahra Bastami; Azade Taheri; Shahla Soltanpour

    2015-01-01

    Today, nanotechnology has a variety of application areas. Pharmacy is one of the most important application fields of nanotechnology. Preparation of nanoparticular drug delivery systems such as nanocrystals could improve the solubility and bioavailability of poorly water soluble drugs. Gemfibrozil (GEM) is a low water soluble drug biopharmaceutical classification system II and used as a lipid regulating agent. In this study, a rapid and simple wet milling method was used for preparation of GE...

  17. Affinity capillary electrophoresis applied to quantitative evaluation of non-covalent peptide interactions with metal ions and cyclodextrins

    Czech Academy of Sciences Publication Activity Database

    Kašička, Václav; Ehala, Sille; Šolínová, Veronika; Schimperková, Tereza; Sázelová, Petra; Makrlík, E.

    Sevilla : CSIC, 2009. s. 35-35. [Latin American Symposium on Biotechnology, Biomedical, Biopharmaceutical and Industrial Applications of Capillary Electrophoresis and Microchip Technology /15./. 02.10.2009-06.10.2009, Sevilla] R&D Projects: GA ČR(CZ) GA203/08/1428 Grant ostatní: GA ČR(CZ) GA203/09/0675 Institutional research plan: CEZ:AV0Z40550506 Keywords : affinity capillary electrophoresis * peptide interactions * cyclodextrin s Subject RIV: CB - Analytical Chemistry, Separation

  18. Production of therapeutic proteins in algae, analysis of expression of seven human proteins in the chloroplast of Chlamydomonas reinhardtii

    OpenAIRE

    Rasala, Beth A.; Muto, Machiko; Lee, Philip A.; Jager, Michal; Cardoso, Rosa MF; Behnke, Craig A; Kirk, Peter; Hokanson, Craig A.; Crea, Roberto; Mendez, Michael; Mayfield, Stephen P

    2010-01-01

    Recombinant proteins are widely used today in many industries, including the biopharmaceutical industry, and can be expressed in bacteria, yeasts, mammalian and insect cell cultures, or in transgenic plants and animals. In addition, transgenic algae have also been shown to support recombinant protein expression, both from the nuclear and chloroplast genomes. However, to date, there are only a few reports on recombinant proteins expressed in the algal chloroplast. It is unclear if this is due ...

  19. PELLETIZATION TECHNIQUES: A LITERATURE REVIEW

    OpenAIRE

    Punia Supriya; Bala Rajni; Rana A. C.

    2012-01-01

    In present times, the pelletization technologies are gaining much attention as they represent an efficient pathway for manufacture of oral drug delivery systems. This is due to the reason that pellets offer many therapeutic, technological as well as biopharmaceutical advantages over the conventional oral dosage forms. Pelletization technique enables the formation of spherical beads or pellets with a mean diameter usually ranging from 0.5-2.0 mm which can be eventually coated for preparation o...

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

    CERN Document Server

    Chen, Ding-Geng

    2012-01-01

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

  1. 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

    OpenAIRE

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

    2013-01-01

    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....

  2. Electrophoretic preconcentration and separation of cationic labeled saccharides

    Czech Academy of Sciences Publication Activity Database

    Partyka, Jan; Foret, František

    Grupo VLS Print Solution, 2014 - (Guzman, N.; Taveres, M.). s. 97-97 [International Symposium on Electro- and Liquid Phase-Separation Techniques /21./ and Latin-American Symposium on Biotechnology, Biomedical, Biopharmaceutical, and Industrial Applications of Capillary Electrophoresis and Microchip Technology /21./. 04.10.2014-08.10.2014, Natal] R&D Projects: GA ČR(CZ) GAP301/11/2055 Institutional support: RVO:68081715 Keywords : saccharide * AETMA * electrophoresis Subject RIV: CB - Analytical Chemistry, Separation

  3. A Chemogenomic Analysis of Ionization Constants - Implications for Drug Discovery

    OpenAIRE

    David T. Manallack; Prankerd, Richard J.; Nassta, Gemma C.; Ursu, Oleg; Oprea, Tudor I.; Chalmers, David K.

    2013-01-01

    Chemogenomics methods seek to characterize the interaction between drugs and biological systems and are an important guide for the selection of screening compounds. The acid/base character of drugs has a profound influence on their affinity for the receptor, on their absorption, distribution, metabolism, excretion and toxicity (ADMET) profile and the way the drug can be formulated. In particular, the charge state of a molecule greatly influences its lipophilicity and biopharmaceutical charact...

  4. Improved Stability of a Model IgG3 by DoE-Based Evaluation of Buffer Formulations

    OpenAIRE

    Chavez, Brittany K.; Cyrus D. Agarabi; Read, Erik K.; Boyne II, Michael T.; Khan, Mansoor A.; Brorson, Kurt A

    2016-01-01

    Formulating appropriate storage conditions for biopharmaceutical proteins is essential for ensuring their stability and thereby their purity, potency, and safety over their shelf-life. Using a model murine IgG3 produced in a bioreactor system, multiple formulation compositions were systematically explored in a DoE design to optimize the stability of a challenging antibody formulation worst case. The stability of the antibody in each buffer formulation was assessed by UV/VIS absorbance at 280 ...

  5. Sparging-shear sensitivity of animal cells.

    OpenAIRE

    Pol, van der, P.

    1998-01-01

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

  6. Genibet : a bioharmaceutical contract manufacturing start-up

    OpenAIRE

    Alves, Sara Brites

    2015-01-01

    The thesis that is by this means present under the form of a case study intends to emphasize the challenges faced by a Portuguese start-up, Genibet, upon its initial years of operations and the need to grow internationally. The case study may also be used as a learning tool, once it enables instructors and students to apply strategic knowledge and frameworks on a real life situation of a company. Genibet is a biopharmaceutical contract manufacturing organization that provides c...

  7. Comprehensive structural annotation of Pichia pastoris transcriptome and the response to various carbon sources using deep paired-end RNA sequencing

    OpenAIRE

    Liang Shuli; Wang Bin; Pan Li; Ye Yanrui; He Minghui; Han Shuangyan; Zheng Suiping; Wang Xiaoning; Lin Ying

    2012-01-01

    Abstract Background The methylotrophic yeast Pichia pastoris is widely used as a bioengineering platform for producing industrial and biopharmaceutical proteins, studying protein expression and secretion mechanisms, and analyzing metabolite synthesis and peroxisome biogenesis. With the development of DNA microarray and mRNA sequence technology, the P. pastoris transcriptome has become a research hotspot due to its powerful capability to identify the transcript structures and gain insights int...

  8. THE APPLICATION OF KNOWLEDGE MANAGEMENT PRACTICES IN THE PROCUREMENT AND CONSTRUCTION OF CLEANROOM PROJECTS

    OpenAIRE

    Graham, Brian; Gahan, Declan; Thomas, Ken

    2007-01-01

    Many of the world’s largest biotechnology, pharmaceutical and medical device companies have established production facilities in Ireland in recent years. The country’s leading contracting firm, Sisk have developed an expertise in constructing these facilities through the management contracting procurement route. Identifying the sector as a major growth driver, the company has established a bio-pharmaceutical division as part of their corporate strategy within the past year. The procurement...

  9. Predicting Pharmacokinetics of Drugs Using Physiologically Based Modeling—Application to Food Effects

    OpenAIRE

    Parrott, N.; Lukacova, V.; Fraczkiewicz, G.; Bolger, M. B.

    2009-01-01

    Our knowledge of the major mechanisms underlying the effect of food on drug absorption allows reliable qualitative prediction based on biopharmaceutical properties, which can be assessed during the pre-clinical phase of drug discovery. Furthermore, several recent examples have shown that physiologically based absorption models incorporating biorelevant drug solubility measurements can provide quite accurate quantitative prediction of food effect. However, many molecules currently in developme...

  10. A Self-microemulsifying Drug Delivery System (SMEDDS) for a Novel Medicative Compound Against Depression: a Preparation and Bioavailability Study in Rats

    OpenAIRE

    Wu, Lan; Qiao, Yanli; Wang, Lina; Guo, Jiahua; Wang, Guocheng; He, Wei; Yin, Lifang; Zhao, Jinhua

    2015-01-01

    AJS is the code name of an untitled novel medicative compound synthesized by the Tasly Holding Group Company (Tianjin, China) based on the structure of cinnamamide, which is one of the Biopharmaceutics Classification System (BCS) class II drugs. The drug has better antidepressant effect, achieved by acting on the 5-hydroxytryptamine receptor. However, the therapeutic effects of the drug are compromised due to its poor water solubility and lower bioavailability. Herein, a self-microemulsifying...

  11. Molecular buckets: cyclodextrins for oral cancer therapy

    OpenAIRE

    Calleja, P.; Huarte, J; Agüeros, M.; Ruiz-Gaton, L. (Luisa); Espuelas, S.; J.M. Irache

    2012-01-01

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

  12. Hybrid modeling as a QbD/PAT tool in process development: an industrial E. coli case study

    OpenAIRE

    von Stosch, Moritz; Hamelink, Jan-Martijn; de Oliveira, Rui

    2016-01-01

    Process understanding is emphasized in the process analytical technology initiative and the quality by design paradigm to be essential for manufacturing of biopharmaceutical products with consistent high quality. A typical approach to developing a process understanding is applying a combination of design of experiments with statistical data analysis. Hybrid semi-parametric modeling is investigated as an alternative method to pure statistical data analysis. The hybrid model framework provides ...

  13. HOW DISSIMILARLY SIMILAR ARE BIOSIMILARS?

    OpenAIRE

    Ramshankar Vijayalakshmi; Kesavan Sabitha; Krishnamurthy Arvind

    2012-01-01

    Recently Biopharmaceuticals are the new chemotherapeutical agents that are called as “Biosimilars” or “follow on protein products” by the European Medicines Agency (EMA) and the American regulatory agencies (Food and Drug Administration) respectively. Biosimilars are extremely similar to the reference molecule but not identical, however close their similarities may be. A regulatory framework is therefore in place to assess the application for marketing authorisation of biosimilars. When a bi...

  14. Advances and challenges in analytical characterization of biotechnology products: mass spectrometry-based approaches to study properties and behavior of protein therapeutics

    OpenAIRE

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

    2011-01-01

    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 protei...

  15. Sustained biochemical control in patients with acromegaly treated with lanreotide depot 120 mg administered every 4 weeks, or an extended dosing interval of 6 or 8 weeks: a pharmacokinetic approach

    OpenAIRE

    Gomez-Panzani E; Chang S; Ramis J; Landolfi MM; Bakker B

    2012-01-01

    Edda Gomez-Panzani,1 Stephen Chang,1 Joaquim Ramis,2 Michelle M Landolfi,1 Bert Bakker11Ipsen Biopharmaceuticals, Inc, Basking Ridge, New Jersey, USA; 2Ipsen Innovation SAS, Pharmacokinetic and Drug Metabolism, Les Ulis, FranceObjective: Lanreotide depot is a long-acting somatostatin receptor ligand injected deep subcutaneously every 4 weeks for the treatment of acromegaly. The aim of the presented studies was to establish whether lanreotide depot, administered to patients with acromegaly at ...

  16. An innovative approach for the characterization of the isoforms of a monoclonal antibody product

    OpenAIRE

    Sundaram, Shanmuuga; Matathia, Alice; Qian, Jun; Zhang, Jingming; Hsieh, Ming-Ching; Liu, Tun; Crowley, Richard; Parekh, Babita; Zhou, Qinwei

    2011-01-01

    Protein biopharmaceuticals, such as monoclonal antibodies (mAbs) are widely used for the prevention and treatment of various diseases. The complex and lengthy upstream and downstream production methods of the antibodies make them susceptible to physical and chemical modifications. Several IgG1 immunoglobulins are used as medical agents for the treatment of colon, breast and head and neck cancers, and at least four to eight isoforms exist in the products. The regulatory agencies understand the...

  17. Quality Control of Widely Used Therapeutic Recombinant Proteins by a Novel Real-Time PCR Approach

    OpenAIRE

    Mamnoon, Babak; Naserpour Farivar, Taghi; Kamyab, Ahmad Reza; Ilghari, Dariush; Khamesipour, Ali; Karimi Arzenani, Mohsen

    2016-01-01

    Background: Existence of bacterial host-cell DNA contamination in biopharmaceutical products is a potential risk factor for patients receiving these drugs. Hence, the quantity of contamination must be controlled under the regulatory standards. Although different methods such as hybridization assays have been employed to determine DNA impurities, these methods are labor intensive and rather expensive. In this study, a rapid real-time PCR test was served as a method of choice to quantify the E....

  18. Identification of cross-contaminated animal cells by PCR and isoenzyme analysis

    OpenAIRE

    Ramya, R.; T. Nagarajan; Sivakumar, V.; Senthilkumar, R. L.; Bala Obulapathi, B.; Thiagarajan, D; Srinivasan, V.A.

    2009-01-01

    Animal cell lines have become very popular substrates for the production of vaccines and biopharmaceuticals. Characterization of candidate production cell lines is central to ensure product safety and maintenance of consistency in the manufacture of biologicals. Nested PCR and isoenzyme analysis have been used widely to prove the identity and purity of various cell lines and primary cells individually and also after deliberate cross-contamination. The nested PCR based on the Cytochrome b (Cyt...

  19. Computational detection of allergenic proteins attains a new level of accuracy with in silico variable-length peptide extraction and machine learning

    OpenAIRE

    Soeria-Atmadja, D.; Lundell, T.; Gustafsson, M. G.; Hammerling, U.

    2006-01-01

    The placing of novel or new-in-the-context proteins on the market, appearing in genetically modified foods, certain bio-pharmaceuticals and some household products leads to human exposure to proteins that may elicit allergic responses. Accurate methods to detect allergens are therefore necessary to ensure consumer/patient safety. We demonstrate that it is possible to reach a new level of accuracy in computational detection of allergenic proteins by presenting a novel detector, Detection based...

  20. Genetically Modified T Cells for the Treatment of Malignant Disease

    OpenAIRE

    Wieczorek, Agnieszka; Uharek, Lutz

    2013-01-01

    The broaden application of adoptive T-cell transfer has been constrained by the technical abilities to isolate and expand antigen-specific T cells potent to selectively kill tumor cells. With the recent progress in the design and manufacturing of cellular products, T cells used in the treatment of malignant diseases may be regarded as anticancer biopharmaceuticals. Genetical manipulation of T cells has given T cells desired specificity but also enable to tailor their activation and proliferat...

  1. Dissolving Microneedle Patch for Transdermal Delivery of Human Growth Hormone

    OpenAIRE

    Lee, Jeong Woo; Choi, Seong-O; Felner, Eric I.; Prausnitz, Mark R.

    2011-01-01

    Clinical impact of biotechnology has been constrained by the limitations of traditional hypodermic injection of biopharmaceuticals. Microneedle patches have been proposed as a minimally invasive alternative. In this study, we assess the translation of a dissolving microneedle patch designed for simple, painless self-administration of biopharmacetucials that generates no sharp biohazardous waste. To study pharmacokinetics and safety of this approach, human growth hormone (hGH) w...

  2. Targeting MDR1-P-glycoprotein (MDR1-Pgp) in immunochemotherapy of acute myeloid leukemia (AML)

    OpenAIRE

    Maurizio Cianfriglia

    2013-01-01

    BACKGROUND: Monoclonal antibodies represent the fastest growing sector of pharmaceutical biotechnology and a number of antibody-based biopharmaceuticals have been approved for cancer treatment. However, in many cases the antibodies used for the treatment of tumors offer only a modest survival benefit to cancer patients. AIMS: In the present review-article we intend to analyze: i) the curative regimen gemtuzumab ozogamicin (GO) -mediate characterized by the absence of cytotoxic drugs MDR1-Pgp ...

  3. Evaluating the Immunogenicity of Protein Drugs by Applying In Vitro MHC Binding Data and the Immune Epitope Database and Analysis Resource

    OpenAIRE

    Sinu Paul; Kolla, Ravi V.; John Sidney; Daniela Weiskopf; Ward Fleri; Yohan Kim; Bjoern Peters; Alessandro Sette

    2013-01-01

    The immune system has evolved to become highly specialized in recognizing and responding to pathogens and foreign molecules. Specifically, the function of HLA class II is to ensure that a sufficient sample of peptides derived from foreign molecules is presented to T cells. This leads to an important concern in human drug development as the possible immunogenicity of biopharmaceuticals, especially those intended for chronic administration, can lead to reduced efficacy and an undesired safety p...

  4. Establishing a new marketplace for biologic therapy with biosimilar agents: importance of extrapolation of data

    OpenAIRE

    Bressler B; Dingermann T

    2015-01-01

    Brian Bressler,1 Theo Dingermann2 1St Paul’s Hospital, University of British Columbia, Vancouver, BC, Canada; 2Institute of Pharmaceutical Biology, Frankfurt, Germany Abstract: Despite their enormous value for our health care system, biopharmaceuticals have become a serious threat to the system itself due to their high cost. Costs may be warranted if the medicine is new and innovative; however, it is no longer an innovation when its patent protection expires. As patents and exclusiviti...

  5. Population pharmacokinetics of pegaptanib sodium (Macugen®) in patients with diabetic macular edema

    OpenAIRE

    Basile AS; Hutmacher MM; Kowalski KG; Gandelman KY; Nickens DJ

    2015-01-01

    Anthony S Basile,1 Matthew M Hutmacher,2 Kenneth G Kowalski,2 Kuan Y Gandelman,3 Dana J Nickens1 1Clinical Pharmacology, Specialty Care Business Unit, Pfizer Inc, San Diego, CA, USA; 2Ann Arbor Pharmacometrics Group, Ann Arbor, MI, USA; 3Clinical Pharmacology, World Wide Biopharmaceuticals, Pfizer Inc, New York, NY, USA Objective: Population pharmacokinetic modeling of pegaptanib was undertaken to determine influence of renal function on apparent clearance. Methods: In a randomized, double-...

  6. Low Level Sequence Variant Analysis of Recombinant Proteins: An Optimized Approach

    OpenAIRE

    Zeck, Anne; Regula, Jörg Thomas; Larraillet, Vincent; Mautz, Björn; Popp, Oliver; Göpfert, Ulrich; Wiegeshoff, Frank; Vollertsen, Ulrike E. E.; Gorr, Ingo H.; Koll, Hans; Papadimitriou, Apollon

    2012-01-01

    Sequence variants in recombinant biopharmaceuticals may have a relevant and unpredictable impact on clinical safety and efficacy. Hence, their sensitive analysis is important throughout bioprocess development. The two stage analytical approach presented here provides a quick multi clone comparison of candidate production cell lines as a first stage, followed by an in-depth analysis including identification and quantitation of aberrant sequence variants of selected clones as a second stage. We...

  7. Follow-on biologics in oncology – the need for global and local regulations

    OpenAIRE

    Hus, Iwona

    2013-01-01

    The patent expiration for first-generation biological drugs has prompted the development of a new group of biopharmaceuticals – follow-on biologics. The extent of studies needed in the process of follow-on biologics approval is incomparably greater than in the case of generics but reduced in comparison to innovative biologics. The basis for the approval is to show the similarity sufficient to ensure the same quality, safety and efficacy as the reference medicine. In oncology, the most widely ...

  8. Prediction of allergenic proteins and mapping of IgE epitopes in allergens

    OpenAIRE

    sprotocols

    2015-01-01

    In present era use of genetically modified proteins in foods, therapeutics and biopharmaceuticals is increasing with exponential rate. Thus it is important to predict whether a modified protein allergenic or not. In 2003, the Codex Alimentarius Commission (Codex) conveyed a panel of international food safety regulators to review the FAO/ WHO 2001 recommendations and recognized the uncertainties associated with the bioinformatics part of the guidelines. They recommended various tests for exami...

  9. Biosimilar epoetins and other “follow-on” biologics: Update on the European experiences

    OpenAIRE

    Jelkmann, Wolfgang

    2010-01-01

    Abstract Summary After the patents of biopharmaceuticals have expired, based on specific regulatory approval pathways copied products (?biosimilars? or ?follow-on biologics?) have been launched in the EU. The present article summarizes experiences with hematopoietic medicines, namely the epoetins (two biosimilars traded under five different brand names) and the filgrastims (two biosimilars, six brand names). Physicians and pharmacists should be familiar with the legal and pharma...

  10. Characterization of complex systems using the design of experiments approach: Transient protein expression in tobacco as a case study

    OpenAIRE

    Buyel, Johannes Felix; Fischer, Rainer

    2014-01-01

    Plants provide multiple benefits for the production of biopharmaceuticals including low costs, scalability, and safety. Transient expression offers the additional advantage of short development and production times, but expression levels can vary significantly between batches thus giving rise to regulatory concerns in the context of good manufacturing practice. We used a design of experiments (DoE) approach to determine the impact of major factors such as regulatory elements in the expression...

  11. Current Status of Biosimilar Growth Hormone

    OpenAIRE

    Paul Saenger

    2009-01-01

    As the first wave of biopharmaceuticals is set to expire, biosimilars or follow-on protein products (FOPPs) have emerged. The regulatory foundation for these products is more advanced and better codified in Europe than in the US. Recent approval of biosimilar Somatropin (growth hormone) in Europe and the US prompted this paper. The scientific viability of biosimilar growth hormone is reviewed. Efficacy and safety data (growth rates, IGF-1 generation) for up to 7 years for pediatric indication...

  12. Current Status of Biosimilar Growth Hormone

    OpenAIRE

    Saenger Paul

    2009-01-01

    As the first wave of biopharmaceuticals is set to expire, biosimilars or follow-on protein products (FOPPs) have emerged. The regulatory foundation for these products is more advanced and better codified in Europe than in the US. Recent approval of biosimilar Somatropin (growth hormone) in Europe and the US prompted this paper. The scientific viability of biosimilar growth hormone is reviewed. Efficacy and safety data (growth rates, IGF-1 generation) for up to 7 years for pediatric indicatio...

  13. Biosimilars: lights and shadows in rheumatology

    OpenAIRE

    Monica Todoerti; Roberto Caporali; Francesca De Nard; Nicola Boffini; Garifallia Sakellariou; Maria Eva Romano; Lorenzo Cavagna

    2014-01-01

    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...

  14. In-situ product removal by membrane extraction

    OpenAIRE

    Heerema, L. D.

    2012-01-01

    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 downstream processing are caused by the fact that the products are often produced in a dilute environment. Since high product concentrations can cause inhibition of biological growth and productio...

  15. Stability-enhanced Hot-melt Extruded Amorphous Solid Dispersions via Combinations of Soluplus® and HPMCAS-HF

    OpenAIRE

    Alshahrani, Saad M.; Lu, Wenli; Park, Jun-Bom; Morott, Joseph T.; Alsulays, Bader B.; Majumdar, Soumyajit; Langley, Nigel; Kolter, Karl; Gryczke, Andreas; Repka, Michael A.

    2015-01-01

    The aim of this study was to evaluate a novel combination of Soluplus® and hypromellose acetate succinate (HPMCAS-HF) polymers for solubility enhancement as well as enhanced physicochemical stability of the produced amorphous solid dispersions. This was accomplished by converting the poorly water-soluble crystalline form of carbamazepine into a more soluble amorphous form within the polymeric blends. Carbamazepine (CBZ), a Biopharmaceutics Classification System class II active pharmaceutical ...

  16. Techniques for Monitoring Protein Misfolding and Aggregation in Vitro and in Living Cells

    OpenAIRE

    Gregoire, Simpson; Irwin, Jacob; Kwon, Inchan

    2012-01-01

    Protein misfolding and aggregation have been considered important in understanding many neurodegenerative diseases and recombinant biopharmaceutical production. Therefore, various traditional and modern techniques have been utilized to monitor protein aggregation in vitro and in living cells. Fibril formation, morphology and secondary structure content of amyloidogenic proteins in vitro have been monitored by molecular probes, TEM/AFM, and CD/FTIR analyses, respectively. Protein aggregation i...

  17. Expression in CHO Cells and Pharmacokinetics and Brain Uptake in the Rhesus Monkey of an IgG-Iduronate-2-Sulfatase Fusion Protein

    OpenAIRE

    Lu, Jeff Zhiqiang; Boado, Ruben J.; Hui, Eric K.-W.; Zhou, Qing-Hui; Pardridge, William M.

    2011-01-01

    Sulfatases are potential therapeutic biopharmaceuticals, as mutations in sulfatase genes leads to inherited disease. Mucopolysaccharidosis (MPS) Type II is caused by mutations in the lysosomal enzyme, iduronate 2-sulfatase (IDS). MPS-II affects the brain and enzyme replacement therapy is ineffective for the brain, because IDS does not cross the blood-brain barrier (BBB). To deliver IDS across the human BBB, the sulfatase has been re-engineered as an IgG-sulfatase fusion protein with a genetic...

  18. Nanotechnology: an effective tool for enhancing bioavailability and bioactivity of phytomedicine

    OpenAIRE

    Gunasekaran, Thirumurugan; Haile, Tedesse; Nigusse, Tedele; Dhanaraju, Magharla Dasaratha

    2014-01-01

    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 pharmacop...

  19. Dissolution Profile of Mefenamic Acid Solid Dosage Forms in Two Compendial and Biorelevant (FaSSIF) Media

    OpenAIRE

    Nurhikmah, Wilda; Sumirtapura, Yeyet Cahyati; Pamudji, Jessie Sofia

    2016-01-01

    Mefenamic acid is a non-steroidal anti-inflammatory drug (NSAID) that is widely used for the treatment of mild-to-moderate pain. Mefenamic acid belongs to the Biopharmaceutical Classification System (BCS) class II drug which has lower water solubility but high permeability. There are two different compendial methods available for dissolution tests of mefenamic acid solid dosage forms, i.e. methods of United States Pharmacopeia 37 (USP) and Pharmacopoeia of the People’s Republic of China 2010 ...

  20. Using quality risk management in the plantibody HB-01 manufacturing by transgenic tobacco Plants for vaccine production

    OpenAIRE

    Mila C., Loreley; Valdes, Rodolfo; Padilla, Sigifredo; Mendoza, Otto; Gomez, Leonardo; García A., Cristina; Geada, Déborah; Ferro, Williams; Pujol, Merardo; Tamayo, Andrés de; Enriquez, Gil; Álvarez, Tatiana; Sanchez, Rafael; Brito, José de

    2010-01-01

    The production of biopharmaceuticals by transgenic plants is a promising choice to achieve the multi-kilogram amount of products needed to treat many human diseases. However, this scientific field is still lacking of approved specific guidelines regarding points to consider for manufacturing and application of these products. In such sense, the implementation of new manufacturing processes and quality systems using the quality risks management is recognized as something of prime importance in...

  1. Teaching biomedical technology innovation as a discipline.

    Science.gov (United States)

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

    2011-07-20

    Recently, universities in the United States and abroad have developed dedicated educational programs in life science technology innovation. Here, we discuss the two major streams of educational theory and practice that have informed these programs: design thinking and entrepreneurship education. We make the case that the process of innovation for new medical technologies (medtech) is different from that for biopharmaceuticals and outline the challenges and opportunities associated with developing a discipline of medtech innovation. PMID:21775665

  2. Excipient selection can significantly affect solid-state phase transformation in formulation during wet granulation

    OpenAIRE

    Airaksinen, Sari; Karjalainen, Milja; Kivikero, Niina; Westermarck, Sari; Shevchenko, Anna; Rantanen, Jukka; Yliruusi, Jouko

    2005-01-01

    Phase transformations in formulations can lead to instability in physicochemical, biopharmaceutical, and processing properties of products. The influences of formulation design on the optimal dosage forms should be specified. The aim here was to investigate whether excipients with different water sorption behavior affect hydrate formation of nitrofurantoin in wet masses. Nitrofurantoin anhydrate was used as a hydrate-forming model drug, and 4 excipients with different water-absorbing potentia...

  3. Clinical trials for vaccine development in registry of Korea Food and Drug Administration

    OpenAIRE

    Kang, Seog-Youn

    2013-01-01

    Based on the action plan "Ensuring a stable supply of National Immunization Program vaccines and sovereignty of biopharmaceutical products," Korea Food and Drug Administration (KFDA) has made efforts to develop vaccines in the context of self reliance and to protect public health. Along with the recognized infrastructures for clinical trials, clinical trials for vaccines have also gradually been conducted at multinational sites as well as at local sites. KFDA will support to expand six to ele...

  4. 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.

  5. Science-Technology-Industry Network The Competitiveness of Swiss Biotechnology: A Case Study of Innovation

    OpenAIRE

    J. Bart Carrin; Yuko Harayama; J. Alexander K. Mack; Milad Zarin-Nejadan

    2004-01-01

    This study proposes to analyse in an exploratory way the state of innovation and production systems in Swiss biotechnology and especially its innovative capacity and related factors. As biotechnology as such cannot be considered as an industrial sector but rather as a set of technologies developed in the field of life sciences, the direct link with science makes innovative capacity a major determinant of competitiveness. While large multinationals, such as biopharmaceuticals, may not need loc...

  6. Clinical data management: Current status, challenges, and future directions from industry perspectives

    OpenAIRE

    Lu, Zhengwu

    2010-01-01

    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...

  7. ПОЛИКОМПЛЕКСНАЯ МАТРИЧНАЯ СИСТЕМА ДОСТАВКИ В ТОЛСТЫЙ ОТДЕЛ КИШЕЧНИКА НА ОСНОВЕ CARBOMER 940/EUDRAGIT ® ЕРО

    OpenAIRE

    Кабанова, Т.; Буховец, А.; Гарипова, В.; Мустафин, Р.; Сёмина, И.; Шиловская, Е.; Насибуллин, Ш.; Ситенков, А.

    2010-01-01

    Biopharmaceutical study of a new carrier based on interpolyelectrolyte complex (IPEC) between Carbomer 940 and Eudragit ® ЕРО composed of polycomplex matrix system (PMS) in order to design the potential carriers for oral drug delivery systems. Release profiles of diclofenac sodium from the developed PMS and "Voltaren ® retard" in simulating the gastrointestinal tract medium refer to the "intestinal" and "sustained" type, respectively.

  8. A scale-down mimic for mapping the process performance of centrifugation, depth and sterile filtration

    OpenAIRE

    Joseph, A; Kenty, B.; Mollet, M.; Hwang, K.; S Rose; Goldrick, S.; Bender, J; Farid, S. S.; Titchener-Hooker, N.

    2016-01-01

    In the production of biopharmaceuticals disk-stack centrifugation is widely used as a harvest step for the removal of cells and cellular debris. Depth filters followed by sterile filters are often then employed to remove residual solids remaining in the centrate. Process development of centrifugation is usually conducted at pilot-scale so as to mimic the commercial scale equipment but this method requires large quantities of cell culture and significant levels of effort for successful charact...

  9. The Protein and Nucleic Acid (PAN) Facility at Stanford University

    OpenAIRE

    Eckart, M.; Kosovilka, N.; Sanchez, A; Tran, Y; Walker, P; Winant, R.; Zuo, E.; Patel, S.

    2010-01-01

    The Protein and Nucleic Acid (PAN) Facility (http://pan.stanford.edu) at Stanford University's Beckman Center is a multifaceted biotechnology fee-for-service laboratory providing services to the Stanford scientific community, other non-profit and biopharmaceutical organizations. The Facility's mission is to be adaptable and responsive to the changing needs of biomedical research by providing basic science investigators continued access to key tools and applications in an efficient and cost ef...

  10. Biocompatibility of Chitosan Carriers with Application in Drug Delivery

    OpenAIRE

    Ana Grenha; Susana Rodrigues; Carmen Remuñán López; Marita Dionísio

    2012-01-01

    Chitosan is one of the most used polysaccharides in the design of drug delivery strategies for administration of either biomacromolecules or low molecular weight drugs. For these purposes, it is frequently used as matrix forming material in both nano and micron-sized particles. In addition to its interesting physicochemical and biopharmaceutical properties, which include high mucoadhesion and a great capacity to produce drug delivery systems, ensuring the biocompatibility of the drug delivery...

  11. Automation of cell line development

    OpenAIRE

    Lindgren, Kristina; Salmén, Andréa; Lundgren, Mats; Bylund, Lovisa; Ebler, Åsa; Fäldt, Eric; Sörvik, Lina; Fenge, Christel; Skoging-Nyberg, Ulrica

    2009-01-01

    An automated platform for development of high producing cell lines for biopharmaceutical production has been established in order to increase throughput and reduce development costs. The concept is based on the Cello robotic system (The Automation Partnership) and covers screening for colonies and expansion of static cultures. In this study, the glutamine synthetase expression system (Lonza Biologics) for production of therapeutic monoclonal antibodies in Chinese hamster ovary cells was used ...

  12. Macroscopic modelling of hybridoma cell fed-batch cultures with overflow metabolism: model-based optimization and state estimation

    OpenAIRE

    Amribt, Zakaria

    2014-01-01

    Monoclonal antibodies (MAbs) have an expanding market for use in diagnostic and therapeutic applications. Industrial production of these biopharmaceuticals is usually achieved based on fed-batch cultures of mammalian cells in bioreactors (Chinese hamster ovary (CHO) and Hybridoma cells), which can express different kinds of recombinant proteins. In order to reach high cell densities in these bioreactors, it is necessary to carry out an optimization of their production processes. Hence, macros...

  13. Stabilité colloïdale et repliement d'anticorps en présence de dérivés de l'acide poly(acrylique) : rôle des interactions hydrophobes et électrostatiques

    OpenAIRE

    MARTIN, Nicolas

    2014-01-01

    Antibodies constitute the fastest growing class of human biopharmaceuticals. The development of these engineered proteins is yet hampered by their natural propensity towards irreversible aggregation particularly critical during refolding steps. Reversible (non-covalent) association of proteins with water-soluble polymers could circumvent this issue. In the present study, we investigated the interactions between model proteins and hydrophobically-modified poly(sodium acrylate) (PAA) chains wit...

  14. Nose-to-Brain delivery of insulin for Alzheimer’s disease

    OpenAIRE

    Stützle, Martina; Flamm, Johannes; Carle, Stefan; Schindowski, Katharina

    2015-01-01

    The transport of small molecules, peptides and proteins via the olfactory epithelium and along olfactory and trigeminal nerve pathways from the nasal cavity to the brain is very well known and clinically established for central nervous system (CNS) active drugs like oxytocin, sumatriptan or insulin. Insulin is a clinically well-established biopharmaceutical with a validated function in cognition. Central supply with insulin via intranasal administration improves cognition in animal models and...

  15. Inhalation drug delivery devices: technology update

    OpenAIRE

    Ibrahim M.; Verma R; Garcia-Contreras L

    2015-01-01

    Mariam Ibrahim, Rahul Verma, Lucila Garcia-ContrerasDepartment of Pharmaceutical Sciences, College of Pharmacy, The University of Oklahoma Health Sciences Center, Oklahoma City, OK, USAAbstract: The pulmonary route of administration has proven to be effective in local and systemic delivery of miscellaneous drugs and biopharmaceuticals to treat pulmonary and non-pulmonary diseases. A successful pulmonary administration requires a harmonic interaction between the drug formulation, the inhaler d...

  16. Strategic aspects of higher education reform to cultivate specialists in diagnostic and biopharma industry as applicable to Predictive, Preventive and Personalized Medicine as the Medicine of the Future

    OpenAIRE

    Studneva, М.; Mandrik, M.; Song, Sh.; Tretyak, E.; Krasnyuk, I.; Yamada, Y.; Tukavin, A.; Ansari, A; Kozlov, I.; Reading, C; Ma, Y.; Krapfenbauer, K.; Svistunov, A; Suchkov, S.

    2015-01-01

    Predictive, Preventive and Personalized Medicine as the Medicine of the Future represents an innovative model for advanced healthcare and robust platform for relevant industrial branches for diagnostics and pharmaceutics. However, rapid market penetration of new medicines and technologies demands the implementation of reforms not only in the spheres of biopharmaceutical industries and healthcare, but also in education. Therefore, the problem of the fundamental, modern preparation of specialis...

  17. REFORMING DRUG APPROVAL IN THE UNITED STATES: MEASURES NECESSARY TO ALLEVIATE THE CASH CRUNCH FACED BY SMALL BIOTECHNOLOGY COMPANIES

    OpenAIRE

    McWilliams, Douglas E.

    1995-01-01

    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...

  18. Human Health Biotechnologies to 2015

    OpenAIRE

    Anthony Arundel; David Sawaya; Ioana Valeanu

    2009-01-01

    This article provides an overview of the current use of biotechnology to produce human health products and short-term estimates of the number and types of these products that are likely to reach the market by 2015. Relevant health products include biopharmaceuticals, experimental therapies (e.g. cell/tissue engineering and gene therapy), small molecule therapeutics, diagnostics, bioinformatics (including DNA sequencing and pharmacogenetics), functional food and nutraceuticals, and medical dev...

  19. Intracellular Protein Delivery and Gene Transfection by Electroporation Using a Microneedle Electrode Array

    OpenAIRE

    Choi, Seong-O; Kim, Yeu-Chun; Lee, Jeong Woo; Park, Jung-Hwan; Mark R Prausnitz; Allen, Mark G.

    2012-01-01

    The impact of many biopharmaceuticals, including protein- and gene-based therapies, has been limited by the need for better methods of delivery into cells within tissues. Here, we present intracellular delivery of molecules and transfection with plasmid DNA by electroporation using a novel microneedle electrode array designed for targeted treatment of skin and other tissue surfaces. The microneedle array is molded out of polylactic acid. Electrodes and circuitry required for electroporation a...

  20. Biocompatible medical implant materials with binding sites for a biodegradable drug-delivery system

    OpenAIRE

    Al-Dubai H; Pittner G; Pittner F; Gabor F

    2011-01-01

    Haifa Al-Dubai1, Gisela Pittner1, Fritz Pittner1, Franz Gabor21Max F Perutz Laboratories, Department of Biochemistry, University of Vienna, Vienna, Austria; 2Department of Pharmaceutical Technology and Biopharmaceutics, Faculty of Life Sciences, University of Vienna, Vienna, AustriaAbstract: Feasibility studies have been carried out for development of a biocompatible coating of medical implant materials allowing the binding of biodegradable drug-delivery systems in a way that their reloading ...

  1. Determination of 5-methyltetrahydrofolate in serum by isotachophoresis combined with zone electrophoresis using UV and MS detectors

    Czech Academy of Sciences Publication Activity Database

    Pantůčková, Pavla; Tomáš, Roman; Foret, František; Křivánková, Ludmila

    Sevilla : Casa de la Ciencia CSIC, 2009. LM-A-01. [Latin American Symposium on Biotechnology, Biomedical, Biopharmaceutical and Industrial Applications of Capillary Electrophoresis and Microchip Technology /15./. 02.10.2009-06.10.2009, Sevilla] R&D Projects: GA ČR GA203/08/1536; GA AV ČR IAA400310703 Institutional research plan: CEZ:AV0Z40310501 Keywords : 5-methyltetrahydrofolate * CITP * serum Subject RIV: CB - Analytical Chemistry, Separation

  2. Prediction of solubility and permeability class membership: provisional BCS classification of the world's top oral drugs.

    Science.gov (United States)

    Dahan, Arik; Miller, Jonathan M; Amidon, Gordon L

    2009-12-01

    The Biopharmaceutics Classification System (BCS) categorizes drugs into one of four biopharmaceutical classes according to their water solubility and membrane permeability characteristics and broadly allows the prediction of the rate-limiting step in the intestinal absorption process following oral administration. Since its introduction in 1995, the BCS has generated remarkable impact on the global pharmaceutical sciences arena, in drug discovery, development, and regulation, and extensive validation/discussion/extension of the BCS is continuously published in the literature. The BCS has been effectively implanted by drug regulatory agencies around the world in setting bioavailability/bioequivalence standards for immediate-release (IR) oral drug product approval. In this review, we describe the BCS scientific framework and impact on regulatory practice of oral drug products and review the provisional BCS classification of the top drugs on the global market. The Biopharmaceutical Drug Disposition Classification System and its association with the BCS are discussed as well. One notable finding of the provisional BCS classification is that the clinical performance of the majority of approved IR oral drug products essential for human health can be assured with an in vitro dissolution test, rather than empirical in vivo human studies. PMID:19876745

  3. Applications of circular dichroism (CD) for structural analysis of proteins: qualification of near- and far-UV CD for protein higher order structural analysis.

    Science.gov (United States)

    Li, Cynthia H; Nguyen, Xichdao; Narhi, Linda; Chemmalil, Letha; Towers, Edward; Muzammil, Salman; Gabrielson, John; Jiang, Yijia

    2011-11-01

    Circular dichroism (CD) spectroscopy is routinely used in the biopharmaceutical industry to study the effects of manufacturing, formulation, and storage conditions on protein conformation and stability, and these results are often included in regulatory filings. In this context, the purpose of CD spectroscopy is often to verify that a change in the formulation or manufacturing process of a product has not produced a change in the conformation of a protein. A comparison of two or more spectra is often required to confirm that the protein's structure has been maintained. Traditionally, such comparisons have been qualitative in nature, based on visually inspecting the overlaid spectra. However, visual assessment is inherently subjective and therefore prone to error. Furthermore, recent requests from regulatory agencies to demonstrate the suitability of the CD spectroscopic method for the purpose of comparing spectra have highlighted the need to appropriately qualify CD spectroscopy for characterization of biopharmaceutical protein products. In this study, we use a numerical spectral comparison approach to establish the precision of the CD spectroscopic method and to demonstrate that it is suitable for protein structural characterization in numerous biopharmaceutical applications. PMID:21732370

  4. An approach to quality and security of supply for single-use bioreactors.

    Science.gov (United States)

    Barbaroux, Magali; Gerighausen, Susanne; Hackel, Heiko

    2014-01-01

    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. PMID:23793913

  5. An approach to engineer paracetamol crystals by antisolvent crystallization technique in presence of various additives for direct compression.

    Science.gov (United States)

    Kaialy, Waseem; Larhrib, Hassan; Chikwanha, Brian; Shojaee, Saeed; Nokhodchi, Ali

    2014-04-10

    Paracetamol is a popular over-the-counter analgesic and a challenging model drug due to its poor technological and biopharmaceutical properties such as flowability, compressibility, compactibility and wettability. This work was aimed to alter the crystal habit of paracetamol from elongated to polyhedral-angular via particle engineering whilst maintaining the stable polymorphic form (form I: monoclinic form). The engineered paracetamol crystals obtained in the present investigation showed better technological and biopharmaceutical properties in comparison to the commercial paracetamol. Engineered paracetamol crystals were obtained using antisolvent crystallization technique in the presence of various concentrations (0.1, 0.5 and 1%, w/w) of additives, namely, polyvinyl alcohol (PVA), Avicel PH 102 (microcrystalline cellulose), Brij 58, methylcellulose (MC) and polyethylene glycol having different molecular weights (PEGs 1500, 6000 and 8000). Paracetamols crystallized in the presence of Avicel (or physically mixed with Avicel), Brij 58 and PEG 6000 demonstrated the best compactibility over a range of compaction pressures. Brij-crystallized paracetamol provided the fastest dissolution rate among all the paracetamol batches. Paracetamols crystallized in the presence of PVA or Avicel, or physically mixed with Avicel demonstrated a reduced degree of crystallinity in comparison to the other paracetamols. This study showed that the type, the grade and the concentration of additives could influence the physical stability such as flow, crystallinity and polymorphic transformation of paracetamol, the technological and biopharmaceutical properties of paracetamol. Stable polymorphic form of paracetamol with optimal tableting characteristics can be achieved through particle engineering. PMID:24480534

  6. Plant-derived pharmaceuticals for the developing world.

    Science.gov (United States)

    Hefferon, Kathleen

    2013-10-01

    Plant-produced vaccines and therapeutic agents offer enormous potential for providing relief to developing countries by reducing the incidence of infant mortality caused by infectious diseases. Vaccines derived from plants have been demonstrated to effectively elicit an immune response. Biopharmaceuticals produced in plants are inexpensive to produce, require fewer expensive purification steps, and can be stored at ambient temperatures for prolonged periods of time. As a result, plant-produced biopharmaceuticals have the potential to be more accessible to the rural poor. This review describes current progress with respect to plant-produced biopharmaceuticals, with a particular emphasis on those that target developing countries. Specific emphasis is given to recent research on the production of plant-produced vaccines toward human immunodeficiency virus, malaria, tuberculosis, hepatitis B virus, Ebola virus, human papillomavirus, rabies virus and common diarrheal diseases. Production platforms used to express vaccines in plants, including nuclear and chloroplast transformation, and the use of viral expression vectors, are described in this review. The review concludes by outlining the next steps for plant-produced vaccines to achieve their goal of providing safe, efficacious and inexpensive vaccines to the developing world. PMID:23857915

  7. Multiplexed, targeted gene editing in Nicotiana benthamiana for glyco-engineering and monoclonal antibody production.

    Science.gov (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

    2016-02-01

    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. PMID:26011187

  8. Extraction and downstream processing of plant-derived recombinant proteins.

    Science.gov (United States)

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

    2015-11-01

    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

  9. 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.

  10. The Patient's Voice in Pharmacovigilance: Pragmatic Approaches to Building a Patient-Centric Drug Safety Organization.

    Science.gov (United States)

    Smith, Meredith Y; Benattia, Isma

    2016-09-01

    Patient-centeredness has become an acknowledged hallmark of not only high-quality health care but also high-quality drug development. Biopharmaceutical companies are actively seeking to be more patient-centric in drug research and development by involving patients in identifying target disease conditions, participating in the design of, and recruitment for, clinical trials, and disseminating study results. Drug safety departments within the biopharmaceutical industry are at a similar inflection point. Rising rates of per capita prescription drug use underscore the importance of having robust pharmacovigilance systems in place to detect and assess adverse drug reactions (ADRs). At the same time, the practice of pharmacovigilance is being transformed by a host of recent regulatory guidances and related initiatives which emphasize the importance of the patient's perspective in drug safety. Collectively, these initiatives impact the full range of activities that fall within the remit of pharmacovigilance, including ADR reporting, signal detection and evaluation, risk management, medication error assessment, benefit-risk assessment and risk communication. Examples include the fact that manufacturing authorization holders are now expected to monitor all digital sources under their control for potential reports of ADRs, and the emergence of new methods for collecting, analysing and reporting patient-generated ADR reports for signal detection and evaluation purposes. A drug safety department's ability to transition successfully into a more patient-centric organization will depend on three defining attributes: (1) a patient-centered culture; (2) deployment of a framework to guide patient engagement activities; and (3) demonstrated proficiency in patient-centered competencies, including patient engagement, risk communication and patient preference assessment. Whether, and to what extent, drug safety departments embrace the new patient-centric imperative, and the methods and

  11. Biosimilar medicines and cost-effectiveness

    Directory of Open Access Journals (Sweden)

    Steven Simoens

    2011-02-01

    Full Text Available Steven SimoensResearch Centre for Pharmaceutical Care and Pharmaco-economics, Faculty of Pharmaceutical Sciences, Katholieke Universiteit Leuven, Leuven, BelgiumAbstract: Given that biosimilars are agents that are similar but not identical to the reference biopharmaceutical, this study aims to introduce and describe specific issues related to the economic evaluation of biosimilars by focusing on the relative costs, relative effectiveness, and cost-effectiveness of biosimilars. Economic evaluation assesses the cost-effectiveness of a medicine by comparing the costs and outcomes of a medicine with those of a relevant comparator. The assessment of cost-effectiveness of a biosimilar is complicated by the fact that evidence needed to obtain marketing authorization from a registration authority does not always correspond to the data requirements of a reimbursement authority. In particular, this relates to the availability of adequately powered equivalence or noninferiority studies, the need for comparative data about the effectiveness in a real-world setting rather than the efficacy in a structured setting, and the use of health outcome measures instead of surrogate endpoints. As a biosimilar is likely to be less expensive than the comparator (eg, the reference biopharmaceutical, the assessment of the cost-effectiveness of a biosimilar depends on the relative effectiveness. If appropriately designed and powered clinical studies demonstrate equivalent effectiveness between a biosimilar and the comparator, then a cost-minimization analysis identifies the least expensive medicine. If there are differences in the effectiveness of a biosimilar and the comparator, other techniques of economic evaluation need to be employed, such as cost-effectiveness analysis or cost-utility analysis. Given that there may be uncertainty surrounding the long-term safety (ie, risk of immunogenicity and rare adverse events and effectiveness of a biosimilar, the cost

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

    Science.gov (United States)

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

  13. Assessment of a novel alder biorefinery concept to meet demands of economics feasibility, energy production and long term environmental sustainability

    DEFF Research Database (Denmark)

    Thomsen, Tobias; Ahrenfeldt, Jesper; Thomsen, Sune Tjalfe

    2012-01-01

    (Alnus incana), and provide the following end products: Heat and power, bio-pharmaceuticals (diaryl heptanoids), Bio-SNG, ethyl acetate, replenished soils and a carbon sink. Several system setups were examined and compared. The optimal design obtained the following production characteristics: Total...... system Energy Return on energy Invested 4.4, total system Exergy Return on exergy Invested 3.5, Net Energy Output 78 GJ/ha/year, Net Exergy Output 50 GJ/ha/year, Net carbon sequestration 0.8 ton CO2-eq/ha/year, Total product value 2030 euro/ha/year and Net Dry Matter Removal 90%....

  14. Optimal design for nonlinear response models

    CERN Document Server

    Fedorov, Valerii V

    2013-01-01

    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

  15. Validación de un método analítico empleando cromatografía líquida de alta eficiencia para la determinación de ibuprofeno en medios biorrelevantes Validation of an analytical method by liquid chromatography for determination of ibuprofen in biorelevant media

    Directory of Open Access Journals (Sweden)

    Sandra M. Gómez

    2010-01-01

    Full Text Available An analytical method by liquid chromatography has been proposed and validated to study the apparent solubility of ibuprofen in biorelevant dissolution media. The main properties of the studied media were pH values of 5.0 and 6.5 and the presence or absence of some natural surfactant agents. The parameters evaluated were specificity, linearity, precision, accuracy, and detection and quantification limits, as well as the drug stability under the analysis conditions. The developed method was useful to determine the apparent solubility of this drug as a function of temperature and surfactants concentration to demonstrate the validity of the Biopharmaceutics Classification System.

  16. Recent achievements in characterization of chiral helical molecules by capillary electrophoresis

    Czech Academy of Sciences Publication Activity Database

    Koval, Dušan; Růžička, Martin; Severa, Lukáš; Vávra, Jan; Reyes Gutierrez, Paul Eduardo; Teplý, Filip; Kašička, Václav

    Sao Bernardo do Campo: Grupo VLS Print Solution, 2015 - (Guzman, N.; Tavares, M.). s. 56 [LACE 2015. Latin-American Symposium on Biotechnology , Biomedical, Biopharmaceutical, and Industrial Applications of Capillary Electrophoresis and Microchip Technology /21./. 05.12.2015-08.12.2015, Cartagena] R&D Projects: GA ČR GA13-32974S; GA ČR(CZ) GA13-17224S; GA ČR GA13-19213S; GA ČR(CZ) GA15-01948S Institutional support: RVO:61388963 Keywords : helquats * chiral molecules * capillary electrophoresis Subject RIV: CB - Analytical Chemistry, Separation

  17. Improving the prediction of the brain disposition for orally administered drugs using BDDCS

    DEFF Research Database (Denmark)

    Broccatelli, Fabio; Larregieu, Caroline A.; Cruciani, Gabriele;

    2012-01-01

    penetration for a significant number of marketed central nervous system (CNS) agents. The Biopharmaceutics Drug Disposition Classification System (BDDCS) has proved useful in predicting drug disposition in the human body, particularly in the liver and intestine. Here we discuss the value of using BDDCS to...... improve BBB predictions of oral drugs. BDDCS class membership was integrated with in vitro Pgp efflux and in silico permeability data to create a simple 3-step classification tree that accurately predicted CNS disposition for more than 90% of 153 drugs in our data set. About 98% of BDDCS class 1 drugs...

  18. 6th Annual European Antibody Congress 2010: November 29–December 1, 2010, Geneva, Switzerland

    OpenAIRE

    Beck, Alain; Wurch, Thierry

    2011-01-01

    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...

  19. The effects of electrolysis in electromembrane extractions

    Czech Academy of Sciences Publication Activity Database

    Šlampová, Andrea; Kubáň, Pavel; Boček, Petr

    Grupo VLS Print Solution, 2014 - (Guzman, N.; Taveres, M.). s. 180-180 [ITP & LACE 2014. International Symposium on Electro- and Liquid Phase-Separation Techniques /21./ and Latin-American Symposium on Biotechnology, Biomedical, Biopharmaceutical, and Industrial Applications of Capillary Electrophoresis and Microchip Technology /20./. 04.10.2014-08.10.2014, Natal] R&D Projects: GA ČR(CZ) GA13-05762S Institutional support: RVO:68081715 Keywords : electromembrane extractions * electrolysis * extraction performance Subject RIV: CB - Analytical Chemistry, Separation

  20. Free liquid membranes - a novel progressive concept of phase interfaces for electrically enhanced microextraction techniques

    Czech Academy of Sciences Publication Activity Database

    Kubáň, Pavel; Boček, Petr

    Grupo VLS Print Solution, 2014 - (Guzman, N.; Taveres, M.). s. 64-64 [ITP & LACE 2014. International Symposium on Electro- and Liquid Phase-Separation Techniques /21./ and Latin-American Symposium on Biotechnology, Biomedical, Biopharmaceutical, and Industrial Applications of Capillary Electrophoresis and Microchip Technology /20./. 04.10.2014-08.10.2014, Natal] R&D Projects: GA ČR(CZ) GA13-05762S Institutional support: RVO:68081715 Keywords : free liquid membranes * microextractions * complex samples Subject RIV: CB - Analytical Chemistry, Separation

  1. IPRs in biobanking- risks and opportunities for translational research

    DEFF Research Database (Denmark)

    Minssen, Timo; Verlinden, Michiel; Huys, Isabelle

    2015-01-01

    The gradual shift from traditional closed innovation systems to more “open” and “transparent” innovation models, rapid technological advances and bio-pharmaceutical innovation gaps have highlighted the importance of an effective governance and use of biobanks. This raises important legal questions....... Section 2 will analyze and discuss potential strategies and options to stimulate the exchange of HBM, data and research results. It will also look into the question of how to address, govern and manage IPRs directed to biobank material and data. This will ultimately allow us to draw conclusions in section...

  2. Assessment of a novel alder biorefinery concept to meet demands of economics feasibility, energy production and long term environmental sustainability

    DEFF Research Database (Denmark)

    Thomsen, Tobias; Ahrenfeldt, Jesper; Thomsen, Sune Tjalfe

    (Alnus incana), and provide the following end products: Heat and power, bio-pharmaceuticals (diaryl heptanoids), Bio-SNG, ethyl acetate, replenished soils and a carbon sink. Several system setups were examined and compared. The optimal design obtained the following production characteristics: Total...... system Energy Return on energy Invested 4.4, total system Exergy Return on exergy Invested 3.5, Net Energy Output 78 GJ/ha/year, Net Exergy Output 50 GJ/ha/year, Net carbon sequestration 0.8 ton CO2-eq/ha/year, Total product value 2030 euro/ha/year and Net Dry Matter Removal 90%....

  3. One year monitoring by FTIR of γ-irradiated multilayer film PE/EVOH/PE

    Science.gov (United States)

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

    2016-08-01

    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.

  4. 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;

    2015-01-01

    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...... orders of magnitude lower than for antibodies. In the present study we investigated CHO DXB11 cells transfected with a plasmid encoding human coagulation factor VIII. Single cell clones were isolated from the pool of transfectants and a panel of 14 clones representing a dynamic range of FVIII...

  5. Method for assembling and expressing multiple genes in the nucleus of microalgae.

    Science.gov (United States)

    Noor-Mohammadi, Samaneh; Pourmir, Azadeh; Johannes, Tyler W

    2014-03-01

    The green alga, Chlamydomonas reinhardtii, is a model organism used in the study of photosynthesis and biotechnological research. Despite its importance, a complete set of genetic tools has yet to be developed. Here, we report the development of a new method for constructing a multi-gene pathway in Saccharomyces cerevisiae and integrating the assembled pathway into the nuclear genome of C. reinhardtii. To demonstrate the use of this method, we assembled and functionally expressed up to three reporter proteins (Ble, AphVIII, and GFP) simultaneously in the nucleus of C. reinhardtii. This new molecular tool should aid efforts to engineer microalgae for biofuel and biopharmaceutical production. PMID:24129955

  6. Current Status: Site-Specific Antibody Drug Conjugates.

    Science.gov (United States)

    Schumacher, Dominik; Hackenberger, Christian P R; Leonhardt, Heinrich; Helma, Jonas

    2016-05-01

    Antibody drug conjugates (ADCs), a promising class of cancer biopharmaceuticals, combine the specificity of therapeutic antibodies with the pharmacological potency of chemical, cytotoxic drugs. Ever since the first ADCs on the market, a plethora of novel ADC technologies has emerged, covering as diverse aspects as antibody engineering, chemical linker optimization and novel conjugation strategies, together aiming at constantly widening the therapeutic window for ADCs. This review primarily focuses on novel chemical and biotechnological strategies for the site-directed attachment of drugs that are currently validated for 2nd generation ADCs to promote conjugate homogeneity and overall stability. PMID:27003914

  7. Improved Production of a Heterologous Amylase in Saccharomyces cerevisiae by Inverse Metabolic Engineering

    DEFF Research Database (Denmark)

    Liu, Zihe; Liu, Lifang; Osterlund, Tobias;

    2014-01-01

    The increasing demand for industrial enzymes and biopharmaceutical proteins relies on robust production hosts with high protein yield and productivity. Being one of the best-studied model organisms and capable of performing posttranslational modifications, the yeast Saccharomyces cerevisiae is...... engineering to identify novel targets for improving protein secretion. Screening that combined UV-random mutagenesis and selection for growth on starch was performed to find mutant strains producing heterologous amylase 5-fold above the level produced by the reference strain. Genomic mutations that could be...

  8. Biophysical characterization of a model antibody drug conjugate.

    Science.gov (United States)

    Arakawa, Tsutomu; Kurosawa, Yasunori; Storms, Michael; Maruyama, Toshiaki; Okumura, C J; Maluf, Nasib Karl

    2016-01-01

    Antibody drug conjugates (ADC) are important next-generation biopharmaceuticals and thus require stringent structure characterization as is the case for monoclonal antibodies. We have tested several biophysical techniques, i.e., circular dichroism, analytical ultracentrifugation, differential scanning calorimetry and fluorescence spectroscopy, to characterize a fluorescein-labeled monoclonal antibody as a model ADC. These techniques indicated possible small structure and stability changes by the conjugation, while largely retaining the tertiary structure of the antibody, consistent with unaltered biological activities. Thus, the above biophysical techniques are effective at detecting changes in the structural properties of ADC. PMID:27534450

  9. Development of partial-filling affinity capillary electrophoresis method for chiral separations using helical extended diquats (helquats) as new chiral selectors

    Czech Academy of Sciences Publication Activity Database

    Růžička, Martin; Jirásek, Michael; Reyes Gutierrez, Paul Eduardo; Teplý, Filip; Koval, Dušan; Kašička, Václav

    Natal: -, 2014. s. 174. [ITP & LACE 2014. International Symposium on Electro- and Liquid Phase-Separation Techniques /21./ and Latin-American Symposium on Biotechnology, Biomedical, Biopharmaceutical, and Industrial Applications of Capillary Electrophoresis and Microchip Technology /20./. 04.10.2014-08.10.2014, Natal] R&D Projects: GA ČR(CZ) GA13-17224S; GA ČR GA13-32974S; GA ČR(CZ) GAP206/12/0453 Institutional support: RVO:61388963 Keywords : affinity capillary electrophoresis * helquats * chiral separation Subject RIV: CB - Analytical Chemistry, Separation

  10. Capillary electrophoresis and isotachophoresis employed for physicochemical characterization of peptides

    Czech Academy of Sciences Publication Activity Database

    Kašička, Václav; Šolínová, Veronika; Koval, Dušan; Ibrahim, A.; Cottet, H.

    Natal: -, 2014. s. 41. [ITP & LACE 2014. International Symposium on Electro- and Liquid Phase-Separation Techniques /21./ and Latin-American Symposium on Biotechnology, Biomedical, Biopharmaceutical, and Industrial Applications of Capillary Electrophoresis and Microchip Technology /20./. 04.10.2014-08.10.2014, Natal] R&D Projects: GA ČR(CZ) GAP206/12/0453; GA ČR(CZ) GA13-17224S Grant ostatní: GA AV ČR(CZ) M200551207 Institutional support: RVO:61388963 Keywords : capillary electrophoresis * peptides * electrophoretic mobility Subject RIV: CB - Analytical Chemistry, Separation

  11. New adventures in chiral separation of helical molecules by capillary electrophoresis

    Czech Academy of Sciences Publication Activity Database

    Koval, Dušan; Reyes Gutierrez, Paul Eduardo; Severa, Lukáš; Jirásek, Michael; Teplý, Filip; Kašička, Václav

    Natal: -, 2014. s. 80. [ITP & LACE 2014. International Symposium on Electro- and Liquid Phase-Separation Techniques /21./ and Latin-American Symposium on Biotechnology, Biomedical, Biopharmaceutical, and Industrial Applications of Capillary Electrophoresis and Microchip Technology /20./. 04.10.2014-08.10.2014, Natal] R&D Projects: GA ČR(CZ) GA13-17224S; GA ČR GA13-32974S; GA ČR GA13-19213S Institutional support: RVO:61388963 Keywords : helquats * capillary electrophoresis * chiral separation Subject RIV: CB - Analytical Chemistry, Separation

  12. An assay for measurement of protein adsorption to glass vials.

    Science.gov (United States)

    Varmette, Elizabeth; Strony, Brianne; Haines, Daniel; Redkar, Rajendra

    2010-01-01

    Protein adsorption to primary packaging is one of the problems faced by biopharmaceutical drug companies. An assay was developed to quantify loss of proteins to glass vial surfaces. The assay involves the labeling of protein with a fluorescent dye, incubation of the labeled protein with the vial surface, elution of the adsorbed protein using a stripping buffer, and determination of fluorescence of the adsorbed protein using a fluorometer. The assay is simple to set up, accurate, sensitive, and flexible. The assay can be modified for indirect measurement of protein adsorption and offers an attractive alternative for researchers to quantify protein adsorption to glass vials and syringes. PMID:21502031

  13. Bioassay case study applying the maximin D-optimal design algorithm to the four-parameter logistic model.

    Science.gov (United States)

    Coffey, Todd

    2015-01-01

    Cell-based potency assays play an important role in the characterization of biopharmaceuticals but they can be challenging to develop in part because of greater inherent variability than other analytical methods. Our objective is to select concentrations on a dose-response curve that will enhance assay robustness. We apply the maximin D-optimal design concept to the four-parameter logistic (4 PL) model and then derive and compute the maximin D-optimal design for a challenging bioassay using curves representative of assay variation. The selected concentration points from this 'best worst case' design adequately fit a variety of 4 PL shapes and demonstrate improved robustness. PMID:26235135

  14. Immunogenicity of Anti-TNF-α Biotherapies

    DEFF Research Database (Denmark)

    Bendtzen, Klaus

    2015-01-01

    patients do not respond and about 50% of those who do loose response with time. Furthermore, safety may be compromised by immunogenicity with the induction of anti-drug-antibodies (ADA). Assessment of drug pharmacokinetics and ADA is increasingly recognized as a requirement for safe and rational use of...... article - and the accompanying article - is to discuss the reasons for recommending assessments of circulating drug and ADA levels in patients treated with anti-TNF biopharmaceuticals and to detail some of the methodological issues that obscure cost-effective and safer therapies....

  15. Immunogenicity of mAbs in non-human primates during nonclinical safety assessment

    OpenAIRE

    2013-01-01

    The immunogenicity of biopharmaceuticals used in clinical practice remains an unsolved challenge in drug development. Non-human primates (NHPs) are often the only relevant animal model for the development of monoclonal antibodies (mAbs), but the immune response of NHPs to therapeutic mAbs is not considered to be predictive of the response in humans because of species differences. In this study, we accessed the drug registration files of all mAbs registered in the European Union to establish t...

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

    OpenAIRE

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

    2011-01-01

    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...

  17. Enantiopurity analysis of anti-AIDS drugs and related acyclic nucleoside phosphonates-based antivirotics by capillary electrophoresis

    Czech Academy of Sciences Publication Activity Database

    Kašička, Václav; Šolínová, Veronika; Sázelová, Petra; Mikysková, Hana; Koval, Dušan; Holý, Antonín

    Alphaville: AlphaGraphics, 2013 - (Guzman, N.; Tavares, M.). s. 32-32 [LACE 2013. Latin-American Symposium on Biotechnology, Biomedical, Biopharmaceutical, and Industrial Applications of Capillary Electrophoresis and Microchip Technology /19./. 29.11.2013-03.12.2013, Lima] R&D Projects: GA ČR(CZ) GAP206/12/0453; GA ČR(CZ) GA13-17224S; GA MŠk(CZ) ME10040; GA MV VG20102015046 Institutional support: RVO:61388963 Keywords : acyclic nucleoside phosphonates * capillary electrophoresis * chiral analysis Subject RIV: CB - Analytical Chemistry, Separation

  18. Cytotoxic activity screening of some indigenous Thai plants.

    Science.gov (United States)

    Prayong, P; Barusrux, S; Weerapreeyakul, N

    2008-12-01

    The 50% ethanolic extracts from 14 plant species used in Thai traditional folklore were screened for cytotoxic activity against a malignant human hepatoma (HepG2) cell line and a normal African green monkey kidney (Vero) cell line. The extracts of Polyalthia evecta and Erythroxylum cuneatum showed potent anticancer activity in the HepG2 cell line with IC(50) of 70+/-3 microg/ml and 64+/-4 microg/ml, respectively. P. evecta demonstrated more selectivity to the HepG2 than the Vero cell (selectivity index>14.3) indicating its potential for biopharmaceutical use. PMID:18664377

  19. The PP-fold solution structure of human polypeptide YY and human PYY3-36 as determined by NMR

    DEFF Research Database (Denmark)

    Nygaard, Rie; Nielbo, Steen; Schwartz, Thue W;

    2006-01-01

    PYY3-36 is a biopharmaceutical antiobesity agent under development as well as an endogenous satiety hormone, which is generated by dipeptidyl peptidase-IV digestion of polypetide YY (PYY), and in contrast to the parent hormone, PYY is highly selective for the Y2 versus the Y1 receptor. NMR analysis...... revealed a highly ordered, back-folded structure for human PYY in aqueous solution similar to the classical PP-fold structure of pancreatic polypeptide. The NMR analysis of PYY3-36 also showed a folded structure resembling a PP-fold, which however was characterized by far fewer long distance NOEs than the...

  20. Single cell analysis of signaling molecules

    Czech Academy of Sciences Publication Activity Database

    Klepárník, Karel; Luksch, Jaroslav; Adamová, Eva; Potáčová, Anna; Matalová, E.; Foret, František

    Grupo VLS Print Solution, 2014 - (Guzman, N.; Taveres, M.). s. 49-49 [International Symposium on Electro- and Liquid Phase-Separation Techniques /21./ and Latin-American Symposium on Biotechnology, Biomedical, Biopharmaceutical, and Industrial Applications of Capillary Electrophoresis and Microchip Technology /21./. 04.10.2014-08.10.2014, Natal] R&D Projects: GA ČR(CZ) GA14-28254S Institutional support: RVO:68081715 ; RVO:67985904 Keywords : single cell analysis * signaling molecules * caspase Subject RIV: CB - Analytical Chemistry, Separation

  1. Application of Fӧrster resonance energy transfer (FRET) for a detection of DNA mutations

    Czech Academy of Sciences Publication Activity Database

    Datinská, Vladimíra; Klepárník, Karel; Belšánová, Barbora; Minárik, M.; Foret, František

    Grupo VLS Print Solution, 2014 - (Guzman, N.; Taveres, M.). s. 93-93 [International Symposium on Electro- and Liquid Phase-Separation Techniques /21./ and Latin-American Symposium on Biotechnology, Biomedical, Biopharmaceutical, and Industrial Applications of Capillary Electrophoresis and Microchip Technology /21./. 04.10.2014-08.10.2014, Natal] R&D Projects: GA ČR(CZ) GA14-28254S; GA TA ČR(CZ) TA02010672 Institutional support: RVO:68081715 Keywords : quantum dots * Förster resonance energy transfer * CE-LIF Subject RIV: CB - Analytical Chemistry, Separation

  2. Microbial biotechnology.

    Science.gov (United States)

    Demain, A L

    2000-01-01

    For thousands of years, microorganisms have been used to supply products such as bread, beer and wine. A second phase of traditional microbial biotechnology began during World War I and resulted in the development of the acetone-butanol and glycerol fermentations, followed by processes yielding, for example, citric acid, vitamins and antibiotics. In the early 1970s, traditional industrial microbiology was merged with molecular biology to yield more than 40 biopharmaceutical products, such as erythropoietin, human growth hormone and interferons. Today, microbiology is a major participant in global industry, especially in the pharmaceutical, food and chemical industries. PMID:10631778

  3. Technological progresses in monoclonal antibody production systems.

    Science.gov (United States)

    Rodrigues, Maria Elisa; Costa, Ana Rita; Henriques, Mariana; Azeredo, Joana; Oliveira, Rosário

    2010-01-01

    Monoclonal antibodies (mAbs) have become vitally important to modern medicine and are currently one of the major biopharmaceutical products in development. However, the high clinical dose requirements of mAbs demand a greater biomanufacturing capacity, leading to the development of new technologies for their large-scale production, with mammalian cell culture dominating the scenario. Although some companies have tried to meet these demands by creating bioreactors of increased capacity, the optimization of cell culture productivity in normal bioreactors appears as a better strategy. This review describes the main technological progresses made with this intent, presenting the advantages and limitations of each production system, as well as suggestions for improvements. New and upgraded bioreactors have emerged both for adherent and suspension cell culture, with disposable reactors attracting increased interest in the last years. Furthermore, the strategies and technologies used to control culture parameters are in constant evolution, aiming at the on-line multiparameter monitoring and considering now parameters not seen as relevant for process optimization in the past. All progresses being made have as primary goal the development of highly productive and economic mAb manufacturing processes that will allow the rapid introduction of the product in the biopharmaceutical market at more accessible prices. PMID:20043321

  4. Development and evaluation of a self-emulsifying drug delivery system of amphotericin B

    Directory of Open Access Journals (Sweden)

    Arundhati Bhattacharyya

    2012-01-01

    Full Text Available Amphotericin B is a polyene antifungal antibiotic belonging to Class IV of Biopharmaceutics Classification System which is not absorbed from the gastrointestinal tract after oral administration. The aim of this research work was to develop a self-emulsifying drug delivery system (SEDDS of amphotericin B and to evaluate the dissolution and permeability of amphotericin B from the formulation. The solubility of amphotericin B in various oils, surfactants and cosurfactants was determined. Various SEDDS formulations were prepared with varying amounts of oil, surfactant and co-surfactant. Evaluation parameters for formulation optimization were drug content, self-emulsification, droplet size analysis, and precipitation studies. In vitro dissolution was studied in comparison to the pure drug. Permeability was studied using non-everted intestinal sac method. The optimized formulation consisted of glycerol mono-oleate (10%, w/w, tween 80 (36%, w/w, polyethylene glycol 400 (27%, w/w, and propylene glycol (27%, w/w with a drug content of about 8 mg per ml. The self-emulsifying formulation showed 100% dissolution within 30 minutes whereas the pure drug exhibited a very poor rate of dissolution. In vitro intestinal permeability was studied by noneverted intestinal sac method using rat intestine. The self-emulsifying formulation showed 100% drug permeation within 30 minutes compared to negligible permeation from the drug suspension. The study demonstrates that SEDDS approach may be useful for enhancement of dissolution and intestinal permeation of amphotericin B belonging to class IV of Biopharmaceutic Classification System.

  5. A self-microemulsifying drug delivery system to overcome intestinal resveratrol toxicity and presystemic metabolism.

    Science.gov (United States)

    Seljak, Katarina Bolko; Berginc, Katja; Trontelj, Jurij; Zvonar, Alenka; Kristl, Albin; Gašperlin, Mirjana

    2014-11-01

    A mixed lipid-mixed surfactant self-microemulsifying drug delivery system (SMEDDS) was developed to exploit the health benefits of resveratrol, a Biopharmaceutical Classification System Class 2 natural polyphenol, subject to extensive intestinal presystemic metabolism. SMEDDS with a mixed lipid phase (castor oil/Capmul MCM 1:1) and a mixed surfactant phase (Kolliphor EL/Kolliphor RH 40 1:1) was developed and evaluated for its self-emulsifying properties and in vitro dispersion. The impact of SMEDDS on the permeability properties of resveratrol and its metabolite fluxes through the rat intestine and Caco-2 cells was monitored. The inhibitory effect of selected SMEDDS components on the efflux transporters multidrug resistance-associated protein and P-gp as well as cytotoxicity was assessed on Caco-2 cells. The formulation allowed for high resveratrol loading (122.5 mg/g SMEDDS), excellent self-emulsifying properties, and very rapid release. When formulated in SMEDDS, resveratrol metabolite efflux significantly declined. The formulation (SMEDDS without incorporated resveratrol) and its individual components did not compromise in vitro cell vitality and integrity. Mixed lipid-mixed surfactant SMEDDS is a prospective formulation to improve resveratrol biopharmaceutical, pharmacokinetic, and toxicological properties, leading the way to resveratrol use not only as a supplement but also as a pharmacological drug. PMID:25103361

  6. Moss-made pharmaceuticals: from bench to bedside.

    Science.gov (United States)

    Reski, Ralf; Parsons, Juliana; Decker, Eva L

    2015-10-01

    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. PMID:26011014

  7. 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

    2013-01-01

    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.

  8. Towards dynamic metabolic flux analysis in CHO cell cultures.

    Science.gov (United States)

    Ahn, Woo Suk; Antoniewicz, Maciek R

    2012-01-01

    Chinese hamster ovary (CHO) cells are the most widely used mammalian cell line for biopharmaceutical production, with a total global market approaching $100 billion per year. In the pharmaceutical industry CHO cells are grown in fed-batch culture, where cellular metabolism is characterized by high glucose and glutamine uptake rates combined with high rates of ammonium and lactate secretion. The metabolism of CHO cells changes dramatically during a fed-batch culture as the cells adapt to a changing environment and transition from exponential growth phase to stationary phase. Thus far, it has been challenging to study metabolic flux dynamics in CHO cell cultures using conventional metabolic flux analysis techniques that were developed for systems at metabolic steady state. In this paper we review progress on flux analysis in CHO cells and techniques for dynamic metabolic flux analysis. Application of these new tools may allow identification of intracellular metabolic bottlenecks at specific stages in CHO cell cultures and eventually lead to novel strategies for improving CHO cell metabolism and optimizing biopharmaceutical process performance. PMID:22102428

  9. Production and analysis of a biosimilar erythropoietin in Egypt

    Directory of Open Access Journals (Sweden)

    Ebied WM

    2014-05-01

    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

  10. Water Proton NMR for In Situ Detection of Insulin Aggregates.

    Science.gov (United States)

    Taraban, Marc B; Truong, Huy C; Feng, Yue; Jouravleva, Elena V; Anisimov, Mikhail A; Yu, Yihua Bruce

    2015-12-01

    The need for quality control during the manufacturing and distribution of biopharmaceuticals is becoming increasingly necessary. At present, detecting drug degradation through the monitoring of active factor aggregation is accomplished through "invasive" techniques, such as size-exclusion chromatography (SEC), analytical ultracentrifugation (AUC), and so on. Unfortunately, these analytical methods require sampling the drug by opening the drug container that renders the remaining drug unusable regardless of the outcome of the test. Visual inspection, the current non-invasive quality control method is qualitative and can only detect visible particulates. Thus, it will miss sub-visible protein aggregates. In this paper, human insulin preparations were used to demonstrate that the transverse relaxation rate of water protons R2 ((1) H2 O) can serve as a sensitive and reliable indicator to detect and quantify both visible and sub-visible protein aggregates. R2 ((1) H2 O) is measured using a wide-bore low-field bench-top NMR instrument with permanent magnets. Such analysis could be carried out without opening the drug container, thus saving a drug for further use. The results suggest a novel, economical, non-destructive in situ analytical technique that allows for on-the-site quantification of protein aggregation in biopharmaceutical products. PMID:26344698

  11. Self-emulsifying excipient platform for improving technological properties of alginate-hydroxypropylcellulose pellets.

    Science.gov (United States)

    Mannina, Paolo; Segale, Lorena; Giovannelli, Lorella; Bonda, Andrea Foglio; Pattarino, Franco

    2016-02-29

    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. PMID:26721727

  12. Positively charged self-nanoemulsifying oily formulations of olmesartan medoxomil: Systematic development, in vitro, ex vivo and in vivo evaluation.

    Science.gov (United States)

    Beg, Sarwar; Sharma, Gajanand; Thanki, Kaushik; Jain, Sanyog; Katare, O P; Singh, Bhupinder

    2015-09-30

    The current research work explores the potential applications of cationic self-nanoemulsifying oily formulations (CSNEOFs) for enhancing the oral bioavailability of olmesartan medoxomil. Initial preformulation studies, risk assessment and factor screening studies revealed selection of oleic acid, Tween 40 and Transcutol HP as the critical factors. Systematic optimization of SNEOFs was carried out employing D-optimal mixture design and evaluating them for responses viz. emulsification efficiency, globule size and in vitro drug release. The CSNEOFs were prepared from the optimized SNEOFs by adding oleylamine as cationic charge inducer. In vitro cell line studies revealed markedly better drug uptake along with safer and biocompatible nature of CSNEOFs than free drug suspension. In situ perfusion, and in vivo pharmacokinetic and pharmacodynamic studies in Wistar rats revealed significant improvement in the biopharmaceutical performance of the drug from CSNEOFs and SNEOFs vis-à-vis the marketed formulation. Successful establishment of various levels of in vitro/in vivo correlations (IVIVC) substantiated high degree of prognostic ability of in vitro dissolution conditions in predicting the in vivo performance. In a nutshell, the present studies report successful development of CSNEOFs of olmesartan medoxomil with distinctly improved biopharmaceutical performance. PMID:26211900

  13. Capillary electrophoresis for automated on-line monitoring of suspension cultures: Correlating cell density, nutrients and metabolites in near real-time.

    Science.gov (United States)

    Alhusban, Ala A; Breadmore, Michael C; Gueven, Nuri; Guijt, Rosanne M

    2016-05-12

    Increasingly stringent demands on the production of biopharmaceuticals demand monitoring of process parameters that impact on their quality. We developed an automated platform for on-line, near real-time monitoring of suspension cultures by integrating microfluidic components for cell counting and filtration with a high-resolution separation technique. This enabled the correlation of the growth of a human lymphocyte cell line with changes in the essential metabolic markers, glucose, glutamine, leucine/isoleucine and lactate, determined by Sequential Injection-Capillary Electrophoresis (SI-CE). Using 8.1 mL of media (41 μL per run), the metabolic status and cell density were recorded every 30 min over 4 days. The presented platform is flexible, simple and automated and allows for fast, robust and sensitive analysis with low sample consumption and high sample throughput. It is compatible with up- and out-scaling, and as such provides a promising new solution to meet the future demands in process monitoring in the biopharmaceutical industry. PMID:27114228

  14. Biosimilars in rheumatology: current perspectives and lessons learnt.

    Science.gov (United States)

    Dörner, Thomas; Kay, Jonathan

    2015-12-01

    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. PMID:26282080

  15. Biosimilars: lights and shadows in rheumatology

    Directory of Open Access Journals (Sweden)

    Monica Todoerti

    2014-11-01

    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.

  16. Multi-primer qPCR assay capable of highly efficient and specific detection of the vast majority of all known Mycoplasma.

    Science.gov (United States)

    Salling, H K; Bang-Christensen, S R

    2016-05-01

    Mycoplasma bacteria are able to pass through sterilizing grade filters due to their small size and lack of a cell wall, making them a common contaminant of biopharmaceutical productions. The classical method for detecting Mycoplasma is described in the European Pharmacopeia (Ph.Eur) 2.6.7. The method takes 28 days to perform, due to the slow growing nature of some Mycoplasma species. The Ph.Eur has described Nucleic Acid Testing (NAT) as a rapid alternative to the classical method. Here we present the development of a quantitative polymerase chain reaction (qPCR) assay capable of unambiguous detection of Mycoplasma with high sensitivity and specificity. The broadness of detection and the specificity towards Mycoplasma has been investigated by in silico analysis of the primer sequences followed by testing on purified Mycoplasma DNA as well as DNA from closely related genera. The assay will in all probability detect at least 356 species and strains of Mycoplasma, Spiroplasma and Acholeplasma with high sensitivity. To our knowledge this assay has the most uniform amplification efficiency over the broadest range of species and it is extremely specific towards Mycoplasma. With appropriate validation, the assay can be applied as a powerful tool for rapid Mycoplasma detection in the biopharmaceutical industry. PMID:27067447

  17. Comparative in vitro dissolution of two commercially available Er-Zhi-Wan herbal medicinal products

    Directory of Open Access Journals (Sweden)

    M Wang

    2015-01-01

    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.

  18. Transient protein expression in three Pisum sativum (green pea) varieties.

    Science.gov (United States)

    Green, Brian J; Fujiki, Masaaki; Mett, Valentina; Kaczmarczyk, Jon; Shamloul, Moneim; Musiychuk, Konstantin; Underkoffler, Susan; Yusibov, Vidadi; Mett, Vadim

    2009-02-01

    The expression of proteins in plants both transiently and via permanently transformed lines has been demonstrated by a number of groups. Transient plant expression systems, due to high expression levels and speed of production, show greater promise for the manufacturing of biopharmaceuticals when compared to permanent transformants. Expression vectors based on a tobacco mosaic virus (TMV) are the most commonly utilized and the primary plant used, Nicotiana benthamiana, has demonstrated the ability to express a wide range of proteins at levels amenable to purification. N. benthamiana has two limitations for its use; one is its relatively slow growth, and the other is its low biomass. To address these limitations we screened a number of legumes for transient protein expression. Using the alfalfa mosaic virus (AMV) and the cucumber mosaic virus (CMV) vectors, delivered via Agrobacterium, we were able to identify three Pisum sativum varieties that demonstrated protein expression transiently. Expression levels of 420 +/- 26.24 mg GFP/kgFW in the green pea variety speckled pea were achieved. We were also able to express three therapeutic proteins indicating promise for this system in the production of biopharmaceuticals. PMID:19156736

  19. Establishing the pharmaceutical quality of Chinese herbal medicine: a provisional BCS classification.

    Science.gov (United States)

    Fong, Sophia Y K; Liu, Mary; Wei, Hai; Löbenberg, Raimar; Kanfer, Isadore; Lee, Vincent H L; Amidon, Gordon L; Zuo, Zhong

    2013-05-01

    The Biopharmaceutical Classification System (BCS), which is a scientific approach to categorize active drug ingredient based on its solubility and intestinal permeability into one of the four classes, has been used to set the pharmaceutical quality standards for drug products in western society. However, it has received little attention in the area of Chinese herbal medicine (CHM). This is likely, in part, due to the presence of multiple active components as well as lack of standardization of CHM. In this report, we apply BCS classification to CHMs provisionally as a basis for establishing improved in vitro quality standards. Based on a top-200 drugs selling list in China, a total of 31 CHM products comprising 50 official active marker compounds (AMCs) were provisionally classified according to BCS. Information on AMC content and doses of these CHM products were retrieved from the Chinese Pharmacopoeia. BCS parameters including solubility and permeability of the AMCs were predicted in silico (ACD/Laboratories). A BCS classification of CHMs according to biopharmaceutical properties of their AMCs is demonstrated to be feasible in the current study and can be used to provide a minimum set of quality standards. Our provisional results showed that 44% of the included AMCs were classified as Class III (high solubility, low permeability), followed by Class II (26%), Class I (18%), and Class IV (12%). A similar trend was observed when CHMs were classified in accordance with the BCS class of AMCs. Most (45%) of the included CHMs were classified as Class III, followed by Class II (16%), Class I (10%), and Class IV (6%); whereas 23% of the CHMs were of mixed class due to the presence of multiple individual AMCs with different BCS classifications. Moreover, about 60% of the AMCs were classified as high-solubility compounds (Class I and Class III), suggesting an important role for an in vitro dissolution test in setting quality control standards ensuring consistent

  20. Human granulocyte colony stimulating factor (hG-CSF: cloning, overexpression, purification and characterization

    Directory of Open Access Journals (Sweden)

    Vanz Ana LS

    2008-04-01

    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

  1. Fragments of the V1/V2 domain of HIV-1 glycoprotein 120 engineered for improved binding to the broadly neutralizing PG9 antibody.

    Science.gov (United States)

    Morales, Javier F; Yu, Bin; Perez, Gerardo; Mesa, Kathryn A; Alexander, David L; Berman, Phillip W

    2016-09-01

    The V1/V2 domain of the HIV-1 envelope protein gp120 possesses two important epitopes: a glycan-dependent epitope recognized by the prototypic broadly neutralizing monoclonal antibody (bN-mAb), PG9, as well as an epitope recognized by non-neutralizing antibodies that has been associated with protection from HIV infection in the RV144 HIV vaccine trial. Because both of these epitopes are poorly immunogenic in the context of full length envelope proteins, immunization with properly folded and glycosylated fragments (scaffolds) represents a potential way to enhance the immune response to these specific epitopes. Previous studies showed that V1/V2 domain scaffolds could be produced from a few selected isolates, but not from many of the isolates that would be advantageous in a multivalent vaccine. In this paper, we used a protein engineering approach to improve the conformational stability and antibody binding activity of V1/V2 domain scaffolds from multiple diverse isolates, including several that were initially unable to bind the prototypic PG9 bN-mAb. Significantly, this effort required replicating both the correct glycan structure as well as the β-sheet structure required for PG9 binding. Although scaffolds incorporating the glycans required for PG9 binding (e.g., mannose-5) can be produced using glycosylation inhibitors (e.g., swainsonine), or mutant cell lines (e.g. GnTI(-) 293 HEK), these are not practical for biopharmaceutical production of proteins intended for clinical trials. In this report, we describe engineered glycopeptide scaffolds from three different clades of HIV-1 that bind PG9 with high affinity when expressed in a wildtype cell line suitable for biopharmaceutical production. The mutations that improved PG9 binding to scaffolds produced in normal cells included amino acid positions outside of the antibody contact region designed to stabilize the β-sheet and turn structures. The scaffolds produced address three major problems in HIV vaccine

  2. Clinical data management: Current status, challenges, and future directions from industry perspectives

    Directory of Open Access Journals (Sweden)

    Zhengwu Lu

    2010-06-01

    Full Text Available Zhengwu Lu1, Jing Su21Smith Hanley Consulting, Houston, Texas; 2Department of Chemical Engineering, University of Massachusetts, Amherst, MA, USAAbstract: To maintain a competitive position, the biopharmaceutical industry has been facing the challenge of increasing productivity both internally and externally. As the product of the clinical development process, clinical data are recognized to be the key corporate asset and provide critical evidence of a medicine’s efficacy and safety and of its potential economic value to the market. It is also well recognized that using effective technology-enabled methods to manage clinical data can enhance the speed with which the drug is developed and commercialized, hence enhancing the competitive advantage. The effective use of data-capture tools may ensure that high-quality data are available for early review and rapid decision-making. A well-designed, protocol-driven, standardized, site workflow-oriented and documented database, populated via efficient data feed mechanisms, will ensure regulatory and commercial questions receive rapid responses. When information from a sponsor’s clinical database or data warehouse develops into corporate knowledge, the value of the medicine can be realized. Moreover, regulators, payer groups, patients, activist groups, patient advocacy groups, and employers are becoming more educated consumers of medicine, requiring monetary value and quality, and seeking out up-todate medical information supplied by biopharmaceutical companies. All these developments in the current biopharmaceutical arena demand that clinical data management (CDM is at the forefront, leading change, influencing direction, and providing objective evidence. Sustaining an integrated database or data repository for initial product registration and subsequent postmarketing uses is a long-term process to maximize return on investment for organizations. CDM should be the owner of driving clinical data

  3. Essays on measurement and evaluation of demand side management programs in the electricity industry, and impacts of firm strategy on stock price in the biotechnology industry

    Science.gov (United States)

    Bandres Motola, Miguel A.

    Essay one estimates changes in small business customer energy consumption (kWh) patterns resulting from a seasonally differentiated pricing structure. Econometric analysis leverages cross-sectional time series data across the entire population of affected customers, from 2007 through the present. Observations include: monthly energy usage (kWh), relevant customer segmentations, local daily temperature, energy price, and region-specific economic conditions, among other variables. The study identifies the determinants of responsiveness to seasonal price differentiation. In addition, estimated energy consumption changes occurring during the 2010 summer season are reported for the average customer and in aggregate grouped by relevant customer segments, climate zone, and total customer base. Essay two develops an econometric modeling methodology to evaluate load impacts for short duration demand response events. The study analyzes time series data from a season of direct load control program tests aimed at integrating demand response into the wholesale electricity market. I have combined "fuzzy logic" with binary variables to create "fuzzy indicator variables" that allow for measurement of short duration events while using industry standard model specifications. Typically, binary variables for every hour are applied in load impact analysis of programs dispatched in hourly intervals. As programs evolve towards integration with the wholesale market, event durations become irregular and often occur for periods of only a few minutes. This methodology is innovative in that it conserves the degrees of freedom in the model while allowing for analysis of high frequency data using fixed effects. Essay three examines the effects of strategies, intangibles, and FDA news on the stocks of young biopharmaceutical firms. An event study methodology is used to explore those effects. This study investigates 20,839 announcements from 1990 to 2005. Announcements on drug development

  4. Empirical investigation of the ethical reasoning of physicians and molecular biologists – the importance of the four principles of biomedical ethics

    Directory of Open Access Journals (Sweden)

    Ebbesen Mette

    2007-10-01

    Full Text Available Abstract Background This study presents an empirical investigation of the ethical reasoning and ethical issues at stake in the daily work of physicians and molecular biologists in Denmark. The aim of this study was to test empirically whether there is a difference in ethical considerations and principles between Danish physicians and Danish molecular biologists, and whether the bioethical principles of the American bioethicists Tom L. Beauchamp and James F. Childress are applicable to these groups. Method This study is based on 12 semi-structured interviews with three groups of respondents: a group of oncology physicians working in a clinic at a public hospital and two groups of molecular biologists conducting basic research, one group employed at a public university and the other in a private biopharmaceutical company. Results In this sample, the authors found that oncology physicians and molecular biologists employed in a private biopharmaceutical company have the specific principle of beneficence in mind in their daily work. Both groups are motivated to help sick patients. According to the study, molecular biologists explicitly consider nonmaleficence in relation to the environment, the researchers' own health, and animal models; and only implicitly in relation to patients or human subjects. In contrast, considerations of nonmaleficence by oncology physicians relate to patients or human subjects. Physicians and molecular biologists both consider the principle of respect for autonomy as a negative obligation in the sense that informed consent of patients should be respected. However, in contrast to molecular biologists, physicians experience the principle of respect for autonomy as a positive obligation as the physician, in dialogue with the patient, offers a medical prognosis based upon the patients wishes and ideas, mutual understanding, and respect. Finally, this study discloses utilitarian characteristics in the overall conception of

  5. Use of a charge reducing agent to enable intact mass analysis of cysteine-linked antibody-drug-conjugates by native mass spectrometry

    Directory of Open Access Journals (Sweden)

    Kamila J. Pacholarz

    2016-06-01

    Full Text Available Antibody-drug-conjugates (ADC are a growing class of anticancer biopharmaceuticals. Conjugation of cysteine linked ADCs, requires initial reduction of mAb inter-chain disulfide bonds, as the drugs are attached via thiol chemistry. This results in the active mAb moiety being transformed from a covalently linked tetramer to non-covalently linked complexes, which hinders precise determination of drug load with LC–MS. Here, we show how the addition of the charge reducing agent triethylammonium acetate (TEAA preserves the intact mAb structure, is well suited to the study of cysteine linked conjugates and facilitates easy drug load determination by direct infusion native MS.

  6. Equation to Line the Borders of the Folding-Unfolding Transition Diagram of Lysozyme.

    Science.gov (United States)

    Mohammad, Mohammad Amin; Grimsey, Ian M; Forbes, Robert T

    2016-07-21

    It is important for the formulators of biopharmaceuticals to predict the folding-unfolding transition of proteins. This enables them to process proteins under predetermined conditions, without denaturation. Depending on the apparent denaturation temperature (Tm) of lysozyme, we have derived an equation describing its folding-unfolding transition diagram. According to the water content and temperature, this diagram was divided into three different areas, namely, the area of the water-folded lysozyme phase, the area of the water-folded lysozyme phase and the bulk water phase, and the area of the denatured lysozyme phase. The water content controlled the appearance and intensity of the Raman band at ∼1787 cm(-1) when lysozyme powders were thermally denatured at temperatures higher than Tm. PMID:27341101

  7. Exploring two plant hosts for expression of diterpenoid pathway genes

    DEFF Research Database (Denmark)

    Bach, Søren Spanner

    Plants produce more than 10.000 diterpenoid compounds of which the large majority is involved in specialized metabolism, while a few are involved in general metabolism. Specialized metabolism diterpenoids have functions in interactions of plants with other organisms and selected ones are utilized...... by humanity in biopharmaceuticals or as industrial bioproducts. Yields and purity of diterpenoids purified from natural sources or made by chemical synthesis are generally insufficient for large-volume or high-end applications, thus alternative sources are needed. Synthetic biology, where heterologous pathways...... is compatible with native codon usage, and through the conserved mechanisms of protein targeting and posttranslational odifications, has the capacity to produce functional enzymes. To further explore plant based expression and characterization of diterpenoid pathway genes, two different plant expression hosts...

  8. Commonality between BCS and TCS.

    Science.gov (United States)

    Shah, Vinod P; Rădulescu, Flavian Ştefan; Miron, Dalia Simona; Yacobi, Avraham

    2016-07-25

    Both biopharmaceutics classification system (BCS) and topical drug classification system (TCS) are based on sound scientific principles with the aim of providing biowaiver and reducing regulatory burden without lowering the quality requirements and standards of approval for the drug products. BCS is based on the solubility and permeability properties of the active pharmaceutical ingredient (API, or drug substance) whereas the TCS is based on the qualitative and quantitative composition of the dosage form and the in vitro release rate of the active ingredient as key decision tools. Both BCS and TCS take drug release and dissolution as their guiding principle for providing biowaiver, increasing the availability and affordability of safe and effective medicines to the consumers and at the same time maintaining the drug product quality. PMID:27208656

  9. Venture Capital Investment in the Life Sciences in Switzerland.

    Science.gov (United States)

    Hosang, Markus

    2014-12-01

    Innovation is one of the main driving factors for continuous and healthy economic growth and welfare. Switzerland as a resource-poor country is particularly dependent on innovation, and the life sciences, which comprise biotechnologies, (bio)pharmaceuticals, medical technologies and diagnostics, are one of the key areas of innovative strength of Switzerland. Venture capital financing and venture capitalists (frequently called 'VCs') and investors in public equities have played and still play a pivotal role in financing the Swiss biotechnology industry. In the following some general features of venture capital investment in life sciences as well as some opportunities and challenges which venture capital investors in Switzerland are facing are highlighted. In addition certain means to counteract these challenges including the 'Zukunftsfonds Schweiz' are discussed. PMID:26508600

  10. Determination of Disulfide Bond Connectivity of Cysteine-rich Peptide IpTx{sub a}

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Chul Won; Kim, Jim Il [Chonnam National Univ., Gwangju (Korea, Republic of); Sato, Kazuki [Fukuoka Women' s Univ., Fukuoka (Japan)

    2013-06-15

    Cysteine-rich peptides stabilized by intramolecular disulfide bonds have often been isolated from venoms of microbes, animals and plants. These peptides typically have much higher stability and improved biopharmaceutical properties compared to their linear counterparts. Therefore the correct disulfide bond formation of small proteins and peptides has been extensively studied for a better understanding of their folding mechanism and achieving efficient generation of the naturally occurring biologically active product. Imperatoxin A (IpTx{sub a}), a peptide toxin containing 6 cysteine residues, was isolated from the venom of scorpion Pandinus imperator, selectively binds the ryanodine receptors and activates Ca{sup 2+} release from sarcoplasmic reticulum (SR). IpTx{sub a} increases the binding of ryanodine to ryanodine receptors (RyRs) and encourages reconstituted single channel to induce subconductance states.

  11. Determination of Disulfide Bond Connectivity of Cysteine-rich Peptide IpTxa

    International Nuclear Information System (INIS)

    Cysteine-rich peptides stabilized by intramolecular disulfide bonds have often been isolated from venoms of microbes, animals and plants. These peptides typically have much higher stability and improved biopharmaceutical properties compared to their linear counterparts. Therefore the correct disulfide bond formation of small proteins and peptides has been extensively studied for a better understanding of their folding mechanism and achieving efficient generation of the naturally occurring biologically active product. Imperatoxin A (IpTxa), a peptide toxin containing 6 cysteine residues, was isolated from the venom of scorpion Pandinus imperator, selectively binds the ryanodine receptors and activates Ca2+ release from sarcoplasmic reticulum (SR). IpTxa increases the binding of ryanodine to ryanodine receptors (RyRs) and encourages reconstituted single channel to induce subconductance states

  12. Imiglucerase in the treatment of Gaucher disease: a history and perspective

    Directory of Open Access Journals (Sweden)

    Deegan PB

    2012-04-01

    Full Text Available Patrick B Deegan, Timothy M CoxDepartment of Medicine, University of Cambridge, Lysosomal Disorders Unit, Addenbrooke's NHS Foundation Hospitals Trust, Cambridge, UKAbstract: The scientific and therapeutic development of imiglucerase (Cerezyme® by the Genzyme Corporation is a paradigm case for a critical examination of current trends in biotechnology. In this article the authors argue that contemporary interest in treatments for rare diseases by major pharmaceutical companies stems in large part from an exception among rarities: the astonishing commercial success of Cerezyme. The fortunes of the Genzyme Corporation, latterly acquired by global giant Sanofi SA, were founded on the evolution of a blockbuster therapy for a single but, as it turns out, propitious ultra-orphan disorder: Gaucher disease.Keywords: enzyme therapy, ultra-orphan, macrophage targeting, lysosomal disease, mannose lectin, biopharmaceutical

  13. Nanoemulsion: A new concept of delivery system

    Directory of Open Access Journals (Sweden)

    Nitin Sharma

    2010-01-01

    Full Text Available Nanoemulsion has been identified as a promising delivery system for various drugs including biopharmaceuticals. Nanoemulsion is a heterogeneous system composed of one immiscible liquid dispersed as droplets within another liquid. The droplets size of nano emulsion is between 20 to 500 nm. Diameter and surface properties of droplets of nanoemulsion plays an important role in the biological behavior of the formulation. Small droplet sizes lead to transparent emulsions so that product appearance is not altered by the addition of an oil phase. In this paper various aspects of nanoemulsion have been discussed including advantages, disadvantages and methods of preparation. Furthermore new approaches of stability of formulation, effect of types and concentration of surfactant, process variables and method are also discussed to improve the stability of nanoemulsion formulation

  14. The synthesis and characterization of a novel biodegradable and electroactive polyphosphazene for nerve regeneration

    International Nuclear Information System (INIS)

    Conductive polymers have been of great interest to the biopharmaceutical industry because of their cell adhesion and proliferation. In this paper, a novel electrically-conductive and biodegradable polyphosphazene polymer containing parent aniline pentamer (PAP) and glycine ethyl ester (GEE) as side chains was synthesized through a nucleophilic substitution reaction for its potential application in nerve regeneration. The electrical conductivity of the polymer was ∼ 2 x 10-5 S/cm in the semiconducting region upon preliminarily protonic-doped experiment. Degradation studies carried out in phosphate-buffered saline at 37 deg. C showed a mass loss of ∼ 50% after 70 days. In vitro cytotoxicity to the RSC96 Schwann cells was evaluated using the cell viability assay. The polymer exhibited no cytotoxicity, indicating that such a polyphosphazene polymer has potential as scaffold material in tissue engineering for peripheral nerve regeneration or other biomedical devices that require electroactivity.

  15. The emerging CHO systems biology era: harnessing the ‘omics revolution for biotechnology

    DEFF Research Database (Denmark)

    Kildegaard, Helene Faustrup; Baycin-Hizal, Deniz; Lewis, Nathan;

    2013-01-01

    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......Chinese hamster ovary (CHO) cells are the primary factories for biopharmaceuticals because of their capacity to correctly fold and post-translationally modify recombinant proteins compatible with humans. New opportunities are arising to enhance these cell factories, especially since the CHO-K1 cell...

  16. Whom to Choose as License Partner?

    DEFF Research Database (Denmark)

    Laursen, Keld; Reichstein, Toke; Trombini, Giulia

    2013-01-01

    benefits and obviate issues related to technology transfer and knowledge recombination. At the same time, firms wish to select a partner operating in a different product market to minimize competitive downside issues and to access other product markets, skills and resources. We contend interdependence......This paper investigates the matching of firms on the market for technology. The paper forwards two dimensions along which license formation occurs: technology and product-market. Both sides of the market search for a partner representing potential for high technology synergies to maximize licensing...... between technology and market forces: if partners are market distant, the likelihood of technology license contractual partnership decreases with partners’ technological distance. Using data on the formation of license partnerships in the global biopharmaceutical industry over the period 1994-2004 the...

  17. Cyclodextrin complexes for treatment improvement in infectious diseases.

    Science.gov (United States)

    Imperiale, Julieta C; Sosnik, Alejandro D

    2015-05-01

    Infectious diseases are a heterogeneous group of maladies that represent a serious burden to healthcare systems worldwide. Most of the available antimicrobial drugs display poor biopharmaceutical properties that compromise their effectiveness. Cyclodextrins (CDs) are cyclic oligosaccharides of glucopyranose formed by a variable number of repeating units that combine a hydrophilic surface with a hydrophobic cavity. The production of drug/CD complexes has become one of the most extensively investigated technology approaches to improve the stability, solubility, dissolution rate and bioavailability of drugs. The present work overviews the applications of CDs for the formulation of anti-infective agents along with the most relevant administration routes. Finally, an update on the complexes with CDs available on the market to treat infectious diseases is presented. PMID:26008196

  18. Rate- and Extent-Limiting Factors of Oral Drug Absorption: Theory and Applications.

    Science.gov (United States)

    Sugano, Kiyohiko; Terada, Katsuhide

    2015-09-01

    The oral absorption of drugs has been represented by various concepts such as the absorption potential, the maximum absorbable dose, the biopharmaceutics classification system, and in vitro-in vivo correlation. The aim of this article is to provide an overview of the theoretical relationships between these concepts. It shows how a simple analytical solution for the fraction of a dose absorbed (Fa equation) can offer a theoretical base to tie together the various concepts, and discusses how this solution relates to the rate-limiting cases of oral drug absorption. The article introduces the Fa classification system as a framework in which all the above concepts were included, and discusses its applications for food effect prediction, active pharmaceutical ingredient form selection, formulation design, and biowaiver strategy. PMID:25712830

  19. Antibody engineering: facing new challenges in cancer therapy

    Institute of Scientific and Technical Information of China (English)

    Laura SANZ; (A)ngel M CUESTA; Marta COMPTE; Luis (A)LVAREZ-VALLINA

    2005-01-01

    Antibody-based therapeutics are beginning to realize the promise enclosed in their early denomination as "magic bullets". Initial disappointment has turned into clinical and commercial success, and engineered antibodies currently represent over 30% of biopharmaceuticals in clinical trials. Recent structural and functional data have allowed the design of a new generation of therapeutic antibodies, with strategies ranging from complement-mediated and antibody-dependant cellular cytotoxicity enhancement to improved cytotoxic payloads using toxins, drugs,radionucleids and viral delivery. This review considers the structure of different types of recombinant antibodies, their mechanism of action and how their efficacy has been increased using a broad array of approaches. We will also focus on the additional benefits offered by the use of gene therapy methods for the in vivo production of therapeutic antibodies.

  20. Sherlock Holmes and the proteome--a detective story.

    Science.gov (United States)

    Righetti, Pier Giorgio; Boschetti, Egisto

    2007-02-01

    The performance of a hexapeptide ligand library in capturing the 'hidden proteome' is illustrated and evaluated. This library, insolubilized on an organic polymer and available under the trade name 'Equalizer Bead Technology', acts by capturing all components of a given proteome, by concentrating rare and very rare proteins, and simultaneously diluting the abundant ones. This results in a proteome of 'normalized' relative abundances, amenable to analysis by MS and any other analytical tool. Examples are given of analysis of human urine and serum, as well as cell and tissue lysates, such as Escherichia coli and Saccharomyces cerevisiae extracts. Another important application is impurity tracking and polishing of recombinant DNA products, especially biopharmaceuticals meant for human consumption. PMID:17241233

  1. PASylation: a biological alternative to PEGylation for extending the plasma half-life of pharmaceutically active proteins

    Science.gov (United States)

    Schlapschy, Martin; Binder, Uli; Börger, Claudia; Theobald, Ina; Wachinger, Klaus; Kisling, Sigrid; Haller, Dirk; Skerra, Arne

    2013-01-01

    A major limitation of biopharmaceutical proteins is their fast clearance from circulation via kidney filtration, which strongly hampers efficacy both in animal studies and in human therapy. We have developed conformationally disordered polypeptide chains with expanded hydrodynamic volume comprising the small residues Pro, Ala and Ser (PAS). PAS sequences are hydrophilic, uncharged biological polymers with biophysical properties very similar to poly-ethylene glycol (PEG), whose chemical conjugation to drugs is an established method for plasma half-life extension. In contrast, PAS polypeptides offer fusion to a therapeutic protein on the genetic level, permitting Escherichia coli production of fully active proteins and obviating in vitro coupling or modification steps. Furthermore, they are biodegradable, thus avoiding organ accumulation, while showing stability in serum and lacking toxicity or immunogenicity in mice. We demonstrate that PASylation bestows typical biologics, such as interferon, growth hormone or Fab fragments, with considerably prolonged circulation and boosts bioactivity in vivo. PMID:23754528

  2. Diatom-Specific Oligosaccharide and Polysaccharide Structures Help to Unravel Biosynthetic Capabilities in Diatoms

    Directory of Open Access Journals (Sweden)

    Bruno Gügi

    2015-09-01

    Full Text Available Diatoms are marine organisms that represent one of the most important sources of biomass in the ocean, accounting for about 40% of marine primary production, and in the biosphere, contributing up to 20% of global CO2 fixation. There has been a recent surge in developing the use of diatoms as a source of bioactive compounds in the food and cosmetic industries. In addition, the potential of diatoms such as Phaeodactylum tricornutum as cell factories for the production of biopharmaceuticals is currently under evaluation. These biotechnological applications require a comprehensive understanding of the sugar biosynthesis pathways that operate in diatoms. Here, we review diatom glycan and polysaccharide structures, thus revealing their sugar biosynthesis capabilities.

  3. Diatom-Specific Oligosaccharide and Polysaccharide Structures Help to Unravel Biosynthetic Capabilities in Diatoms.

    Science.gov (United States)

    Gügi, Bruno; Le Costaouec, Tinaïg; Burel, Carole; Lerouge, Patrice; Helbert, William; Bardor, Muriel

    2015-09-01

    Diatoms are marine organisms that represent one of the most important sources of biomass in the ocean, accounting for about 40% of marine primary production, and in the biosphere, contributing up to 20% of global CO₂ fixation. There has been a recent surge in developing the use of diatoms as a source of bioactive compounds in the food and cosmetic industries. In addition, the potential of diatoms such as Phaeodactylum tricornutum as cell factories for the production of biopharmaceuticals is currently under evaluation. These biotechnological applications require a comprehensive understanding of the sugar biosynthesis pathways that operate in diatoms. Here, we review diatom glycan and polysaccharide structures, thus revealing their sugar biosynthesis capabilities. PMID:26393622

  4. Differential Mobility Spectrometry-Hydrogen Deuterium Exchange (DMS-HDX) as a Probe of Protein Conformation in Solution

    Science.gov (United States)

    Zhu, Shaolong; Campbell, J. Larry; Chernushevich, Igor; Le Blanc, J. C. Yves; Wilson, Derek J.

    2016-03-01

    Differential mobility spectrometry (DMS) is an ion mobility technique that has been adopted chiefly as a pre-filter for small- to medium-sized analytes (mobility spectroscopy (FAIMS)—the application of DMS to intact biomacromolecules remains largely unexplored. In this work, we employ DMS combined with gas-phase hydrogen deuterium exchange (DMS-HDX) to probe the gas-phase conformations generated from proteins that were initially folded, partially-folded, and unfolded in solution. Our findings indicate that proteins with distinct structural features in solution exhibit unique deuterium uptake profiles as function of their optimal transmission through the DMS. Ultimately we propose that DMS-HDX can, if properly implemented, provide rapid measurements of liquid-phase protein structural stability that could be of use in biopharmaceuticals development.

  5. Solar-powered factories for new vaccines and antibiotics.

    Science.gov (United States)

    Bock, Ralph; Warzecha, Heribert

    2010-05-01

    Chloroplasts, the green differentiation form of a group of plant cell organelles called plastids, are the sites of photosynthesis, the main energy source for life on Earth. The small circular genome of the plastid has become increasingly amenable to genetic modification, providing biotechnologists with an attractive site for the accommodation of foreign genes. In recent years, the development of optimized expression strategies has given a huge boost to the exploitation of chloroplasts in molecular farming. Exciting progress has been made with the chloroplast-based production of two particularly important classes of pharmaceuticals: vaccines and antibiotics. Extraordinarily high expression levels and the prospects of developing edible biopharmaceuticals make transgenic chloroplasts a promising platform for the production of next-generation vaccines and antimicrobials. PMID:20207435

  6. Synthetic biology and microbioreactor platforms for programmable production of biologics at the point-of-care

    Science.gov (United States)

    Perez-Pinera, Pablo; Han, Ningren; Cleto, Sara; Cao, Jicong; Purcell, Oliver; Shah, Kartik A.; Lee, Kevin; Ram, Rajeev; Lu, Timothy K.

    2016-01-01

    Current biopharmaceutical manufacturing systems are not compatible with portable or distributed production of biologics, as they typically require the development of single biologic-producing cell lines followed by their cultivation at very large scales. Therefore, it remains challenging to treat patients in short time frames, especially in remote locations with limited infrastructure. To overcome these barriers, we developed a platform using genetically engineered Pichia pastoris strains designed to secrete multiple proteins on programmable cues in an integrated, benchtop, millilitre-scale microfluidic device. We use this platform for rapid and switchable production of two biologics from a single yeast strain as specified by the operator. Our results demonstrate selectable and near-single-dose production of these biologics in system with analytical, purification and polishing technologies could lead to a small-scale, portable and fully integrated personal biomanufacturing platform that could advance disease treatment at point-of-care. PMID:27470089

  7. GLOBAL MANUFACTURING VIRTUAL NETWORK (GMVN): A REVISITING OF THE CONCEPT AFTER THREE YEARS FIELDWORK

    Institute of Scientific and Technical Information of China (English)

    Yongjiang SHI; Don FLEET; Mike GREGORY

    2003-01-01

    The idea of the global manufacturing virtual network (GMVN) was introduced in 2000 in order to highlight an emerging as well as an alternative manufacturing system which will have strong impacts on industry and implications to management theory. During the last three years, more than thirty companies - based in the electronics, bio-pharmaceuticals, garment, and home electronics appliance industries - have been studied in the UK and China. The research project addresses the emergence of the collaborative manufacturing phenomenon at three levels - sector, system and enabling technology. This paper summarises preliminary research findings from fieldwork conducted over the last three years. It seeks to clarify the characteristics and functionality of GMVN through the case studies and to contrast it to other types of business model, such as the multinational corporations (MNC) and international strategic alliances (ISAs). It also raises some new research questions and themes for further research into GMVN.

  8. The NIAID Radiation Countermeasures Program business model.

    Science.gov (United States)

    Hafer, Nathaniel; Maidment, Bert W; Hatchett, Richard J

    2010-12-01

    The National Institute of Allergy and Infectious Diseases (NIAID) Radiation/Nuclear Medical Countermeasures Development Program has developed an integrated approach to providing the resources and expertise required for the research, discovery, and development of radiation/nuclear medical countermeasures (MCMs). These resources and services lower the opportunity costs and reduce the barriers to entry for companies interested in working in this area and accelerate translational progress by providing goal-oriented stewardship of promising projects. In many ways, the radiation countermeasures program functions as a "virtual pharmaceutical firm," coordinating the early and mid-stage development of a wide array of radiation/nuclear MCMs. This commentary describes the radiation countermeasures program and discusses a novel business model that has facilitated product development partnerships between the federal government and academic investigators and biopharmaceutical companies. PMID:21142762

  9. Teaching and implementing autonomous robotic lab walkthroughs in a biotech laboratory through model-based visual tracking

    Science.gov (United States)

    Wojtczyk, Martin; Panin, Giorgio; Röder, Thorsten; Lenz, Claus; Nair, Suraj; Heidemann, Rüdiger; Goudar, Chetan; Knoll, Alois

    2010-01-01

    After utilizing robots for more than 30 years for classic industrial automation applications, service robots form a constantly increasing market, although the big breakthrough is still awaited. Our approach to service robots was driven by the idea of supporting lab personnel in a biotechnology laboratory. After initial development in Germany, a mobile robot platform extended with an industrial manipulator and the necessary sensors for indoor localization and object manipulation, has been shipped to Bayer HealthCare in Berkeley, CA, USA, a global player in the sector of biopharmaceutical products, located in the San Francisco bay area. The determined goal of the mobile manipulator is to support the off-shift staff to carry out completely autonomous or guided, remote controlled lab walkthroughs, which we implement utilizing a recent development of our computer vision group: OpenTL - an integrated framework for model-based visual tracking.

  10. Money and morals: ending clinical trials for financial reasons.

    Science.gov (United States)

    Eaton, Margaret L; Kwon, Brian K; Scott, Christopher Thomas

    2015-01-01

    Too often, biopharmaceutical companies stop their clinical trials solely for financial reasons. In this chapter, we discuss this phenomenon against the backdrop of a 2011 decision by Geron Corporation to abandon its stem cell clinical trial for spinal cord injury (SCI), the preliminary results of which were released in May 2014. We argue that the resultant harms are widespread and are different in nature from the consequences of stopping trials for scientific or medical reasons. We examine the ethical and social effects that arise from such decisions and discuss them in light of ethical frameworks, including duties of individual stakeholders and corporate sponsors. We offer ways that sponsors and clinical sites can ensure that trials are responsibly started, and once started adequately protect the interests of participants. We conclude with recommendations that industry sponsors of clinical trials should adopt in order to advance a collective and patient-centered research ethic. PMID:25062706

  11. Bioanalytical method validation: An updated review.

    Science.gov (United States)

    Tiwari, Gaurav; Tiwari, Ruchi

    2010-10-01

    The development of sound bioanalytical method(s) is of paramount importance during the process of drug discovery and development, culminating in a marketing approval. The objective of this paper is to review the sample preparation of drug in biological matrix and to provide practical approaches for determining selectivity, specificity, limit of detection, lower limit of quantitation, linearity, range, accuracy, precision, recovery, stability, ruggedness, and robustness of liquid chromatographic methods to support pharmacokinetic (PK), toxicokinetic, bioavailability, and bioequivalence studies. Bioanalysis, employed for the quantitative determination of drugs and their metabolites in biological fluids, plays a significant role in the evaluation and interpretation of bioequivalence, PK, and toxicokinetic studies. Selective and sensitive analytical methods for quantitative evaluation of drugs and their metabolites are critical for the successful conduct of pre-clinical and/or biopharmaceutics and clinical pharmacology studies. PMID:23781413

  12. A new nanospray drying method for the preparation of nicergoline pure nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Martena, Valentina; Censi, Roberta [University of Camerino, School of Pharmacy (Italy); Hoti, Ela; Malaj, Ledjan [University of Tirana, Department of Pharmacy (Albania); Di Martino, Piera, E-mail: piera.dimartino@unicam.it [University of Camerino, School of Pharmacy (Italy)

    2012-06-15

    Three different batches of pure nanoparticles (NPs) of nicergoline (NIC) were prepared by spray drying a water:ethanol solution by a new Nano Spray Dryer Buechi B-90. Spherical pure NPs were obtained, and several analytical techniques such as differential scanning calorimetry and X-ray powder diffractometry permitted to assess their amorphous character. A comparison of the solubility, intrinsic dissolution, and drug release of original particles and pure amorphous NPs were determined, revealing an interesting improvement of biopharmaceutical properties of amorphous NPs, due to both amorphous properties and nanosize dimensions. Since in a previous work, the high-thermodynamic stability of amorphous NIC was demonstrated, this study is addressed toward the formulation of NIC as pure amorphous NPs.

  13. A new nanospray drying method for the preparation of nicergoline pure nanoparticles

    International Nuclear Information System (INIS)

    Three different batches of pure nanoparticles (NPs) of nicergoline (NIC) were prepared by spray drying a water:ethanol solution by a new Nano Spray Dryer Büchi B-90. Spherical pure NPs were obtained, and several analytical techniques such as differential scanning calorimetry and X-ray powder diffractometry permitted to assess their amorphous character. A comparison of the solubility, intrinsic dissolution, and drug release of original particles and pure amorphous NPs were determined, revealing an interesting improvement of biopharmaceutical properties of amorphous NPs, due to both amorphous properties and nanosize dimensions. Since in a previous work, the high-thermodynamic stability of amorphous NIC was demonstrated, this study is addressed toward the formulation of NIC as pure amorphous NPs.

  14. Differential Mobility Spectrometry-Hydrogen Deuterium Exchange (DMS-HDX) as a Probe of Protein Conformation in Solution

    Science.gov (United States)

    Zhu, Shaolong; Campbell, J. Larry; Chernushevich, Igor; Le Blanc, J. C. Yves; Wilson, Derek J.

    2016-06-01

    Differential mobility spectrometry (DMS) is an ion mobility technique that has been adopted chiefly as a pre-filter for small- to medium-sized analytes (mobility spectroscopy (FAIMS)—the application of DMS to intact biomacromolecules remains largely unexplored. In this work, we employ DMS combined with gas-phase hydrogen deuterium exchange (DMS-HDX) to probe the gas-phase conformations generated from proteins that were initially folded, partially-folded, and unfolded in solution. Our findings indicate that proteins with distinct structural features in solution exhibit unique deuterium uptake profiles as function of their optimal transmission through the DMS. Ultimately we propose that DMS-HDX can, if properly implemented, provide rapid measurements of liquid-phase protein structural stability that could be of use in biopharmaceuticals development.

  15. Development, modelling, optimisation and scale-up of chromatographic purification of a therapeutic protein

    DEFF Research Database (Denmark)

    Mollerup, Jørgen; Hansen, Thomas Budde; Kidal, Steffen;

    2007-01-01

    Development of a chromatographic purification step proceeds through a number of stages. High-throughput screening techniques are used to identify suitable resins. This technique is also suitable for the design of a capture step and some intermediate chromatographic steps, but development and true...... by industry. The theory of residence time based scale-up is developed and applied. (c) 2007 Elsevier B.V. All rights reserved....... chromatographic separations. Application of simulation of chromatographic processes supports innovation, efficiency and thus quality by design in biopharmaceutical development, manufacturing, and quality assurance and it enhances process understanding to facilitate innovation and risk-based regulatory decisions......Development of a chromatographic purification step proceeds through a number of stages. High-throughput screening techniques are used to identify suitable resins. This technique is also suitable for the design of a capture step and some intermediate chromatographic steps, but development and true...

  16. In vitro testing of thiolated poly(aspartic acid) from ophthalmic formulation aspects.

    Science.gov (United States)

    Budai-Szű Cs, Mária; Horvát, Gabriella; Gyarmati, Benjámin; Szilágyi, Barnabás Áron; Szilágyi, András; Csihi, Tímea; Berkó, Szilvia; Szabó-Révész, Piroska; Mori, Michela; Sandri, Giuseppina; Bonferoni, Maria Cristina; Caramella, Carla; Csányi, Erzsébet

    2016-08-01

    Ocular drug delivery formulations must meet anatomical, biopharmaceutical, patient-driven and regulatory requirements. Mucoadhesive polymers can serve as a better alternative to currently available ophthalmic formulations by providing improved bioavailability. If all requirements are addressed, a polymeric formulation resembling the tear film of the eye might be the best solution. The optimum formulation must not have high osmotic activity, should provide appropriate surface tension, pH and refractive index, must be non-toxic and should be transparent and mucoadhesive. We would like to highlight the importance of in vitro polymer testing from a pharmaceutical aspect. We, therefore, carried out physical-chemical investigations to verify the suitability of certain systems for ophthalmic formulations. In this work, in situ gelling, mucoadhesive thiolated poly(aspartic acid)s were tested from ophthalmic formulation aspects. The results of preformulation measurements indicate that these polymers can be used as potential carriers in ophthalmic drug delivery. PMID:26556306

  17. Revision of the ICH guideline on detection of toxicity to reproduction for medicinal products: SWOT analysis.

    Science.gov (United States)

    Barrow, Paul

    2016-09-01

    SWOT analysis was used to gain insights and perspectives into the revision of the ICH S5(R2) guideline on detection of toxicity to reproduction for medicinal products. The current ICH guideline was rapidly adopted worldwide and has an excellent safety record for more than 20 years. The revised guideline should aim to further improve reproductive and developmental (DART) safety testing for new drugs. Alternative methods to animal experiments should be used whenever possible. Modern technology should be used to obtain high quality data from fewer animals. Additions to the guideline should include considerations on the following: limit dose setting, maternal toxicity, biopharmaceuticals, vaccines, testing strategies by indication, developmental immunotoxicity, and male-mediated developmental toxicity. Emerging issues, such as epigenetics and the microbiome, will most likely pose challenges to DART testing in the future. It is hoped that the new guideline will be adopted even outside the ICH regions. PMID:27046733

  18. The rise of biosimilars: potential benefits and drawbacks in rheumatoid arthritis.

    Science.gov (United States)

    Yoo, Dae Hyun

    2014-08-01

    Although biologic agents are effective in the treatment of rheumatoid arthritis, the high price of drugs and restricted health care budgets have restricted easy access to biologics. Eventually, the use of biologic disease-modifying antirheumatic drugs might be inversely associated with disease activity in countries with low gross domestic product. The EMA approved an infliximab biosimilar for the first time in September 2013. The first approval of a biosimilar monoclonal antibody by a major regulatory authority provided a global standard for subsequent biosimilars and for biopharmaceutical companies developing biosimilars. Biosimilars with a highly similar quality and efficacy profile at an acceptable lower cost would significantly increase affordability of biologic disease-modifying antirheumatic drugs in the treatment of rheumatoid arthritis. Here, we will review the current status of first biosimilar antibody agent and the potential discussion points raised against biosimilars. In addition, the importance of awareness on biosimilars for stakeholders is discussed. PMID:24961712

  19. Protein misfolding and aggregation research: some thoughts on improving quality and utility.

    Science.gov (United States)

    Murphy, Regina M; Roberts, Christopher J

    2013-01-01

    Once misfolded and aggregated proteins were as interesting as yesterday's trash, just a bothersome byproduct of productive activities. Today, they attract sustained interest from both basic researchers and practicing engineers. In the burgeoning biopharmaceutical industry, protein misfolding and aggregation pose significant challenges to the economic manufacture of safe and effective protein products. In the clinic, protein aggregates are believed to be pathological agents in a number of serious neurodegenerative disorders, such as Alzheimer's and Parkinson's. Over the past few years, the quantity of research into biotechnological aspects of protein misfolding and aggregation has skyrocketed. However, the quality of the published work is quite variable. In this brief opinion piece, we describe what we believe are some key features of high-quality publications in protein aggregation. We focus on experimental studies that may also have a kinetic modeling component. PMID:24124114

  20. 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

    2014-03-01

    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.

  1. Improving membrane binding as a design strategy for amphipathic peptide hormones

    DEFF Research Database (Denmark)

    Pedersen, Søren Ljungberg; Bhatia, Vikram Kjøller; Jurt, Simon;

    2012-01-01

    It has been hypothesized that amphipathic peptides might bind to membranes prior to activating their cognate receptors, but this has proven difficult to test. The peptide hormone PYY3-36 is believed to perform its appetite-suppressing actions through binding to hypothalamic Y2 receptors. It has...... by paramagnetic relaxation enhancement using a spin label, which confirmed that the hydrophobic residues bound to the membrane. Our studies further support the hypothesis that PYY3-36 associates with the membrane and indicate that this can be used in the design of novel molecules with high receptor binding...... potency. These observations are likely to be generally important for peptide hormones and biopharmaceutical drugs derived from them. This new 2-helix variant of PYY3-36 will be useful as a tool compound for studying peptide-membrane interactions....

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

    DEFF Research Database (Denmark)

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

    2016-01-01

    , the present study illustrated that the enhancement of CXB solubility was not proportionally translated into enhanced permeability; both parameters were highly dependent on the PL-to-drug ratios as well as the dispersion media (i.e., the presence of 3-mM sodium taurocholate). This study highlights......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...... in CXB solubility leads to a subsequent increase in permeability across intestinal barrier and (2) the presence of bile salts affects the solubility and permeability behavior of CXB formulations. By formulating CXB solid phospholipid (PL) dispersions with various PL-to-drug ratios using freeze drying...

  3. 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

    2014-01-01

    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.

  4. Mobile economics and pricing of health care services.

    Science.gov (United States)

    Huttin, Christine C

    2012-01-01

    This paper presents tools and concepts to analyze the business environment of the biopharmaceutical industry. It was presented at MEDETEL 2010. Emerging paradigms appear in that industry and new ways to value life science technologies are developed especially using mobile economics analysis. At a time, mobile computing technologies revolutionize the field of health care, this paper contributes to show how the value chain concept can be useful to analyze the value system in a mobile computing environment. It is also a milestone for the designs of future technology platforms and of health care infrastructure, in order to retain enough value between innovators, new and traditionnal players from life science, IT and other new comers, in a fragmented global competitive environment. PMID:23079949

  5. Mathematical Models of the Pharmacokinetic Behavior of Clindamycin in Healthy Subjects after Oral Administration of 150 mg of Clindamycin

    Directory of Open Access Journals (Sweden)

    Mária Ďurišová

    2015-12-01

    Full Text Available The goal of the current study was to provide a further example of a successful use of a non-traditional modeling method in the development of mathematical models in pharmacokinetics. The current study is a companion piece of the earlier study by Forist et al. published in February issue of Journal of Pharmacokinetics and Biopharmaceutics, therefore the data published in the study cited here were used. All mathematical models developed, successfully described the data of all healthy male volunteers enrolled in the study by Forist et al. and in the current study. The modeling method used in the current study is used to developed mathematical models of dynamic systems not only in pharmacokinetics but also in several other scientific and practical fields.

  6. Comparison of the effects of two drying methods on polymorphism of theophylline

    DEFF Research Database (Denmark)

    Airaksinen, Sari; Karjalainen, Milja; Räsänen, Eetu; Rantanen, Jukka; Yliruusi, Jouko

    Processing-induced transformations in drug formulation may induce adverse biopharmaceutical changes in the finished product. During the drying phase of wet granulation, theophylline monohydrate transforms either the stable (form I), or a polymorphic, metastable (form I(*)) form of anhydrous...... theophylline. We investigated the effect of two drying methods (multichamber microscale fluid bed dryer MMFD) or variable temperature X-ray powder diffractometer (VT-XRPD) on the relative amounts of the different theophylline forms remaining in the dried granules. Granules were analyzed using XRPD and near......-infrared spectroscopy. Form I(*) was the predominant form of theophylline after drying at 40-50 degrees C with both drying techniques. Although drying at temperatures over 50 degrees C produced mostly form I, more than 20% of form I(*) remained even at 90 degrees C when drying in MMFD. In these conditions, humidity had...

  7. Conformation Distributions in Adsorbed Proteins.

    Science.gov (United States)

    Meuse, Curtis W.; Hubbard, Joseph B.; Vrettos, John S.; Smith, Jackson R.; Cicerone, Marcus T.

    2007-03-01

    While the structural basis of protein function is well understood in the biopharmaceutical and biotechnology industries, few methods for the characterization and comparison of protein conformation distributions are available. New methods capable of measuring the stability of protein conformations and the integrity of protein-protein, protein-ligand and protein-surface interactions both in solution and on surfaces are needed to help the development of protein-based products. We are developing infrared spectroscopy methods for the characterization and comparison of molecular conformation distributions in monolayers and in solutions. We have extracted an order parameter describing the orientational and conformational variations of protein functional groups around the average molecular values from a single polarized spectrum. We will discuss the development of these methods and compare them to amide hydrogen/deuterium exchange methods for albumin in solution and on different polymer surfaces to show that our order parameter is related to protein stability.

  8. Absolute quantification of Bovine Viral Diarrhea Virus (BVDV) RNA by the digital PCR technique

    Science.gov (United States)

    Flatschart, R. B.; Almeida, D. O.; Heinemann, M. B.; Medeiros, M. N.; Granjeiro, J. M.; Folgueras-Flatschart, A. V.

    2015-01-01

    The quality control of cell lines used in research and industry is critical to ensure confidence in experimental results and to guarantee the safety of biopharmaceuticals to consumers. The BVDV is a common adventitious agent in many cell lines. We preliminarly evaluate the use of Digital Droplet PCR (ddPCR) for the detection and enumeration of genome copies of BVDV in cell culture and on FBS. The application of a commercial Real-Time PCR kit with the ddPCR technique was successful on different matrices. The technique allowed the absolute quantification of the genome without the use of calibration standards, suggesting its promising application on the development of reference materials for quantification of nucleic acids.

  9. Absolute quantification of Bovine Viral Diarrhea Virus (BVDV) RNA by the digital PCR technique

    International Nuclear Information System (INIS)

    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

  10. Toward greener analytical techniques for the absolute quantification of peptides in pharmaceutical and biological samples.

    Science.gov (United States)

    Van Eeckhaut, Ann; Mangelings, Debby

    2015-09-10

    Peptide-based biopharmaceuticals represent one of the fastest growing classes of new drug molecules. New reaction types included in the synthesis strategies to reduce the rapid metabolism of peptides, along with the availability of new formulation and delivery technologies, resulted in an increased marketing of peptide drug products. In this regard, the development of analytical methods for quantification of peptides in pharmaceutical and biological samples is of utmost importance. From the sample preparation step to their analysis by means of chromatographic or electrophoretic methods, many difficulties should be tackled to analyze them. Recent developments in analytical techniques emphasize more and more on the use of green analytical techniques. This review will discuss the progresses in and challenges observed during green analytical method development for the quantification of peptides in pharmaceutical and biological samples. PMID:25864956

  11. 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.

  12. 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;

    2013-01-01

    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...

  13. Current Status of Biosimilar Growth Hormone

    Directory of Open Access Journals (Sweden)

    Saenger Paul

    2009-08-01

    Full Text Available As the first wave of biopharmaceuticals is set to expire, biosimilars or follow-on protein products (FOPPs have emerged. The regulatory foundation for these products is more advanced and better codified in Europe than in the US. Recent approval of biosimilar Somatropin (growth hormone in Europe and the US prompted this paper. The scientific viability of biosimilar growth hormone is reviewed. Efficacy and safety data (growth rates, IGF-1 generation for up to 7 years for pediatric indications measure up favorably to previously approved growth hormones as reference comparators. While the approval in the US is currently only for treatment of growth hormone deficiency (GHD in children and adults, the commercial use of approved biosimilar growth hormones will allow in the future for in-depth estimation of their efficacy and safety in non-GH deficient states as well.

  14. Current Status of Biosimilar Growth Hormone

    Directory of Open Access Journals (Sweden)

    Paul Saenger

    2009-01-01

    Full Text Available As the first wave of biopharmaceuticals is set to expire, biosimilars or follow-on protein products (FOPPs have emerged. The regulatory foundation for these products is more advanced and better codified in Europe than in the US. Recent approval of biosimilar Somatropin (growth hormone in Europe and the US prompted this paper. The scientific viability of biosimilar growth hormone is reviewed. Efficacy and safety data (growth rates, IGF-1 generation for up to 7 years for pediatric indications measure up favorably to previously approved growth hormones as reference comparators. While the approval in the US is currently only for treatment of growth hormone deficiency (GHD in children and adults, the commercial use of approved biosimilar growth hormones will allow in the future for in-depth estimation of their efficacy and safety in non-GH deficient states as well.

  15. Comparative Application of PLS and PCR Methods to Simultaneous Quantitative Estimation and Simultaneous Dissolution Test of Zidovudine - Lamivudine Tablets.

    Science.gov (United States)

    Üstündağ, Özgür; Dinç, Erdal; Özdemir, Nurten; Tilkan, M Günseli

    2015-01-01

    In the development strategies of new drug products and generic drug products, the simultaneous in-vitro dissolution behavior of oral dosage formulations is the most important indication for the quantitative estimation of efficiency and biopharmaceutical characteristics of drug substances. This is to force the related field's scientists to improve very powerful analytical methods to get more reliable, precise and accurate results in the quantitative analysis and dissolution testing of drug formulations. In this context, two new chemometric tools, partial least squares (PLS) and principal component regression (PCR) were improved for the simultaneous quantitative estimation and dissolution testing of zidovudine (ZID) and lamivudine (LAM) in a tablet dosage form. The results obtained in this study strongly encourage us to use them for the quality control, the routine analysis and the dissolution test of the marketing tablets containing ZID and LAM drugs. PMID:26085428

  16. Soft sensors in bioprocessing: A status report and recommendations

    DEFF Research Database (Denmark)

    Luttmann, Reiner; Bracewell, Daniel G.; Cornelissen, Gesine;

    2012-01-01

    The following report with recommendations is the result of an expert panel meeting on soft sensor applications in bioprocess engineering that was organized by the Measurement, Monitoring, Modelling and Control (M3C) Working Group of the European Federation of Biotechnology - Section of Biochemical...... Engineering Science (ESBES). The aim of the panel was to provide an update on the present status of the subject and to identify critical needs and issues for the furthering of the successful development of soft sensor methods in bioprocess engineering research and for industrial applications, in particular...... with focus on biopharmaceutical applications. It concludes with a set of recommendations, which highlight current prospects for the extended use of soft sensors and those areas requiring development....

  17. Online flow cytometry for monitoring apoptosis in mammalian cell cultures as an application for process analytical technology.

    Science.gov (United States)

    Kuystermans, Darrin; Avesh, Mohd; Al-Rubeai, Mohamed

    2016-05-01

    Apoptosis is the main driver of cell death in bioreactor suspension cell cultures during the production of biopharmaceuticals from animal cell lines. It is known that apoptosis also has an effect on the quality and quantity of the expressed recombinant protein. This has raised the importance of studying apoptosis for implementing culture optimization strategies. The work here describes a novel approach to obtain near real time data on proportion of viable, early apoptotic, late apoptotic and necrotic cell populations in a suspension CHO culture using automated sample preparation in conjunction with flow cytometry. The resultant online flow cytometry data can track the progression of apoptotic events in culture, aligning with analogous manual methodologies and giving similar results. The obtained near-real time apoptosis data are a significant improvement in monitoring capabilities and can lead to improved control strategies and research data on complex biological systems in bioreactor cultures in both academic and industrial settings focused on process analytical technology applications. PMID:25352493

  18. New binary solid dispersion of Indomethacin and croscarmellose sodium: Physical characterization and in-vitro dissolution enhancement

    Directory of Open Access Journals (Sweden)

    Silvina Castro

    2012-12-01

    Full Text Available Solid dispersions (SDx containing Indomethacin (IND, a poorly water-soluble drug, and the disintegrant excipient sodium croscarmellose (SC were prepared by a co-drying method and characterized by Infrared spectroscopy (FT-IR, X-ray diffraction (XRD, differential scanning calorimetry (DSC and scanning electronmicroscopy (SEM. An FT-IR analysis performed on IND-SC solid dispersion and their physical mixtures indicated that IND does not interact with SC in the solid state. An analysis of the information produced by DSC, XRD, and SEM confirmed that the crystalline α-form of IND was homogeneously incorporated into SDx. IND release from SDx was significantly greater than that from its corresponding physical mixtures with the high homogeneous molecular dispersion and the crystalline modification of IND appearing to be the cause. This behavior may have a beneficial effect on the biopharmaceutical performance of this drug.

  19. Drug Transporters in the Intestine

    DEFF Research Database (Denmark)

    Steffansen, Bente

    2016-01-01

    that may impact drug absorption. Thus absorptive transporters may facilitate BA of APIs that are substrates/victims for the transporters and have permeability-limited absorption, i.e. those that are classified in the biopharmaceutics classification system (BCS) Class 3 and 4. On the other hand, exsorptive...... transporters may restrict BA of APIs that are victims for these efflux transporters, especially those APIs classified to have solubility-limited absorption, i.e. compounds in BCS Class 2 and 4. The aim of the present Chapter is to review drug transporters (DTs) present within the intestine and to discuss...... and exemplify their roles in drug absorption/exsorption and in drug-drug interactions (DDIs). Although focus in the present Chapter is on DTs that are mentioned in American and European regulatory guidances, the intestinal transporters for nutrients and endogens (endogenous compounds) are also briefly...

  20. Genetic engineering of the chloroplast: novel tools and new applications.

    Science.gov (United States)

    Bock, Ralph

    2014-04-01

    The plastid genome represents an attractive target of genetic engineering in crop plants. Plastid transgenes often give high expression levels, can be stacked in operons and are largely excluded from pollen transmission. Recent research has greatly expanded our toolbox for plastid genome engineering and many new proof-of-principle applications have highlighted the enormous potential of the transplastomic technology in both crop improvement and the development of plants as bioreactors for the sustainable and cost-effective production of biopharmaceuticals, enzymes and raw materials for the chemical industry. This review describes recent technological advances with plastid transformation in seed plants. It focuses on novel tools for plastid genome engineering and transgene expression and summarizes progress with harnessing the potential of plastid transformation in biotechnology. PMID:24679252