Pharmaceutical Biotechnology E-Book

• Herausgeber: Wiley-VCH
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 1279

Veröffentlichungsjahr: 2012

Beschreibung

This second edition of a very successful book is thoroughly updated with existing chapters completely rewritten while the content has more than doubled from 16 to 36 chapters. As with the first edition, the focus is on industrial pharmaceutical research, written by a team of industry experts from around the world, while quality and safety management, drug approval and regulation, patenting issues, and biotechnology fundamentals are also covered. In addition, this new edition now not only includes biotech drug development but also the use of biopharmaceuticals in diagnostics and vaccinations.
With a foreword by Robert Langer, Kenneth J Germeshausen Professor of Chemical and Biomedical Engineering at MIT and member of the National Academy of Engineering and the National Academy of Sciences.

Leseprobe

Table of Contents

Cover

Related Titles

Title page

Copyright page

Preface to the 2nd Edition

List of Contributors

Part One: Concepts and Methods for Recombinant Drug Production

1 Pharmaceutical Biotechnology and Industrial Applications – Learning Lessons from Molecular Biology

1.1 Introduction

1.2 Research Developments

1.3 Production Hosts and Upstream/Downstream Processing

1.4 Future Outlook

2 Prokaryotic Cells in Biotech Production

2.1 Introduction

2.2 Production of Natural Products by Microorganisms

2.3 Prokaryotes as Producers of Recombinant Therapeutic Proteins

3 Mammalian Cells in Biotech Production

3.1 Introduction

3.2 Process Concepts and Cells

3.3 CHO-Derived Production Cell Lines

3.4 Rapid Generation of High-Producing Cell Lines

3.5 Silencing – Stability of Expression

3.6 High-Throughput Bioprocess Development

3.7 Disposable Bioreactors

3.8 Transient Gene Expression (TGE)

3.9 Conclusions

4 Biopharmaceuticals from Plants

4.1 Introduction

4.2 Basics in Plant Biotechnology

4.3 Plant Cell Cultures as Production System for Human Glucocerebrosidase

4.4 Insulin from Safflower – A Unique Purification Scheme

4.5 Fast and Scalable Transient Tobacco-Based Expression Systems

4.6 Conclusion

5 Production of Biopharmaceuticals in Transgenic Animals

5.1 Introduction

5.2 Sites of Production

5.3 Transgenic Constructs

5.4 Methods for the Production of Transgenic Animals

5.5 Analysis of Transgenic Animals

5.6 Quality and Safety of the Product

5.7 Conclusions and Outlook

6 Translation of New Technologies in Biomedicines: Shaping the Road from Basic Research to Drug Development and Clinical Application – and Back Again

6.1 Drug Discovery and Development

6.2 The Nature of Models and the Need for Them

6.3 New Technologies Toolbox

6.4 Strategic Use of the New Technology Tools

6.5 Translation as a Two-Way Process

6.6 Concluding Comment

Part Two: Bringing the Drug into Action – From Downstreaming to Approval

7 Overview and Classification of Approved Recombinant Drugs

7.1 Introduction

7.2 Classification of Recombinant Drugs from a Technical Point of View

7.3 Expression Systems

7.4 Proteins Derived from Modified Genes

7.5 Artificial Proteins

7.6 Post-expression Modifications of Recombinant Proteins

7.7 Biosimilars

8 Downstream Processing

8.1 Introduction

8.2 General Principles of DSP

8.3 Clarification

8.4 Chromatography

8.5 Ultrafiltration/Diafiltration, and Virus Filtration

8.6 Crystallization

8.7 Recent Developments in Downstream Processing

9 Characterization of Recombinant Proteins

9.1 Introduction

9.2 Physical Chemical Characterization

9.3 Biological Characterization of Biopharmaceuticals In Vitro

Acknowledgments

Legals

10 Formulation Strategies for Recombinant Protein and Related Biotech Drugs

10.1 Introduction

10.2 Formulation and Stability of Protein Solutions

10.3 Formulation of Vaccines

11 Drug Approval in the European Union and United States

11.1 Introduction

11.2 Regulation within the European Union

11.3 Regulation in the United States of America

11.4 International Regulatory Harmonization

11.5 Regulation of Biosimilars

12 Patents in the Pharmaceutical Biotechnology Industry: Legal and Ethical Issues

12.1 Introduction

12.2 Patent Law

12.3 Ethical and Policy Issues in Biotechnology Patents

12.4 Conclusion

13 Biosimilar Drugs

13.1 Introduction

13.2 Recombinant Therapeutic Proteins

13.3 Definition of Biosimilars

13.4 Regulatory Situation

13.5 Patent Situation

13.6 First Wave of Biosimilars in the EU

13.7 Biosimilar Targets: Second Wave of Future Biosimilars

13.8 Biosimilar Developments and Requirements

13.9 Conclusions

14 Pharmacokinetics and Pharmacodynamics of Therapeutic Peptides and Proteins

14.1 Introduction

14.2 Pharmacokinetics of Peptides and Proteins

14.3 Immunogenicity and Protein Pharmacokinetics

14.4 Exposure–Response Correlations for Protein Therapeutics

14.5 Summary and Conclusions

Part Three: Vaccines

15 Scientific, Technical, and Economic Aspects of Vaccine Research and Development

15.1 Introduction

15.2 From the Research Concept to a Development Candidate

15.3 Vaccine Research Projects

15.4 Scientific Challenges of Vaccine R&D

15.5 Technical Aspects of Vaccine Development

15.6 Economic Aspects of Vaccine Development

15.7 Conclusions

16 New Nanobiotechnological Strategies for the Development of Vectors for Cancer Vaccines

16.1 Introduction

16.2 Biodegradable Nanoparticles

16.3 Liposomal Nanovectors

16.4 Gelatin Nanoparticles

16.5 Sub-micron Emulsions

16.6 Amphiphilic Block-Graft Copolymers

16.7 Iron Oxide Nanoparticles

16.8 Viruses–Virus-Like Particles–Virosomes

16.9 Conclusion

Acknowledgments

17 Recombinant Vaccines: Development, Production, and Application

17.1 Introduction

17.2 Range of Recombinant Vaccines on the Market and in Development Today

17.3 Vaccine Dialectic

17.4 Comparing Vaccine Efficacy

17.5 Vaccines: A Brief Overview

17.6 Recombinant Vaccine Development

17.7 Delivery Systems

17.8 At the Vanguard

17.9 Novel, Recombinant DNA Approach to Identifying Attenuated Vaccine Strains

17.10 Clinical Trials

17.11 Conclusion

Part Four: Recent Applications in Pharmaceutical Biotechnology

18 In Silico and Ultrahigh-Throughput Screenings (uHTS) in Drug Discovery: an Overview

18.1 Introduction

18.2 In Silico Pharmacology and Virtual Ligand Screening for Drug Discovery

18.3 Lead Discovery Using Integrative Virtual Screening

18.4 Application of Microarray Technology in HTS and Drug Discovery

18.5 Chemical Proteomics for Drug Discovery and Development

18.6 Target and Drug Discovery Using Lipomic Profiling

18.7 Drug Discovery Using Integrative Genomics

18.8 Toxicogenomics in Drug Discovery and Development

18.9 HTP RNAi Screening for Targeted Drug Discovery

18.10 High-Throughput Screening with Stem Cells

18.11 Systems Biology in Drug Discovery

18.12 Conclusion

19 Metabolic Engineering of Medicinal Plants and Microorganisms for the Production of Natural Products

19.1 Introduction

19.2 The Plant as a Source of Natural Products

19.3 Optimizing Biochemical Pathways

19.4 Metabolic Engineering Strategies and Techniques in Medicinal Plant Biotechnology

19.5 Challenges in Plant Metabolic Engineering

19.6 Metabolic Engineering Applications in Medicinal Plant Biotechnology

19.7 Crossing Borders – Heterologous Production of Plant Compounds in Microorganisms

19.8 Conclusion and Future Prospects

20 Metabolomics as a Bioanalytical Tool for Characterization of Medicinal Plants and Their Phytomedical Preparations

20.1 Introduction

20.2 Bioanalytical Tools

20.3 Metabolomics Applications in Medicinal Plants

20.4 Conclusions

Acknowledgment

21 Integration of Biotechnologies for the Development of Personalized Medicine

21.1 Introduction

21.2 Genetic Variations in the Human Genome

21.3 Role of Biomarkers in the Development of Personalized Medicine

21.4 Technologies Used for the Development of Personalized Medicine

21.5 Molecular Diagnosis as a Basis for Personalized Medicine

21.6 Sequencing and Personalized Medicine

21.7 Role of Biochips/Microarrays in the Development of Personalized Medicine

21.8 Role of Cytogenetics in the Development of Personalized Medicine

21.9 Role of “Omics” in Personalized Medicine

21.10 Role of Nanobiotechnology for the Development of Personalized Medicine

21.11 Systems Biology and Personalized Medicine

21.12 Personalized Biological Therapies

21.13 Personalized Vaccines

21.14 Concluding Remarks and Future Prospects of Personalized Medicine

22 Xenotransplantation in Pharmaceutical Biotechnology

22.1 Introduction

22.2 Biological Barriers to Xenotransplantation

22.3 Physiological and Infectious Hurdles to Xenotransplantation

22.4 Scenario for the Clinical Application of Xenotransplantation

23 Nutraceuticals–Functional Foods for Improving Health and Preventing Disease

23.1 Introduction

23.2 Plant Food, Pharmaceuticals, Nutraceuticals, and Human Health

23.3 Concepts of Functional Foods, Nutraceuticals, and Other Related Terms

23.4 FFN Principles and Their Potential Health Benefits

23.5 Herbal Nutraceuticals and Multiple Herbal Component Formulations

23.6 FFNs and Metabolic Syndrome, Facial Aging, and Cosmetic Surgery

23.7 Absorption and Metabolism of FFNs and Interaction with Drugs

23.8 Epidermiological Study and Clinical Trials on FFNs

23.9 Biotechnology for Improved Nutritional Value and Creation of Medical Foods

23.10 Future Developments

Index

Related Titles

Behme, S.

Manufacturing of Pharmaceutical Proteins

From Technology to Economy

2009

ISBN: 978-3-527-32444-6

Walsh, G. (ed.)

Post-translational Modification of Protein Biopharmaceuticals

2009

ISBN: 978-3-527-32074-5

Tobin, J. J., Walsh, G.

Medical Product Regulatory Affairs

Pharmaceuticals, Diagnostics, Medical Devices

2008

ISBN: 978-3-527-31877-3

Walsh, G.

Pharmaceutical Biotechnology

Concepts and Applications

2007

ISBN: 978-0-470-01245-1

Gad, S. C. (ed.)

Handbook of Pharmaceutical Biotechnology

2007

ISBN: 978-0-471-21386-4

The Editors

Prof. Dr. Oliver Kayser

Technical University Dortmund

Laboratory of Technical Biochemistry

Emil-Figge-Straße 68

44227 Dortmund

Germany

Prof. Dr. Heribert Warzecha

TU Darmstadt

Biological Science

Schnittspahnstraße 3

64287 Darmstadt

Germany

Cover

250 L Setup, © Rentschler Biotechnologie GmbH

DNA molecule

© mauritius images/Science Photos Library

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A catalogue record for this book is available from the British Library.

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The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at <http://dnb.d-nb.de>.

© 2012 Wiley-VCH Verlag & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany

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Print ISBN: 978-3-527-32994-6

ePDF ISBN: 978-3-527-65126-9

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Preface to the 2nd Edition

Pharmaceutical biotechnology has emerged as one of the major disciplines for drug discovery and development. In the past, the pharmaceutical branch of biotechnology – the former red biotechnology – was limited to fermentation and production of recombinant therapeutic proteins. Today, the shape and vision of pharmaceutical aspects and challenges have completely changed, and the prefix “pharma” can also be accepted as a synonym for integrated life science approaches, ranging from genetics to molecular biology to diagnostics, with the common goal of delivering the best drug to the patient by biotechnological techniques.

If we take a look at the first edition of Pharmaceutical Biotechnology, we see that the focus was more on molecules as potential drugs and less on the production strategies and the molecular concepts behind. The completely updated and rewritten second edition reflects the emerging trend in the pharmaceutical industry where molecular biology techniques and genetics play an increasingly important role. Today, many new biological entities can be characterized as muteins or significantly backbone-modified proteins, an exception in 2004 when we published the first edition (see insulin muteins). We are glad that we were able to attract the majority of the authors from the previous edition as experts. They reviewed the latest trends in their subjects of expertise and shared their experience and open opinion about the developments from the recent years to the near future. Pharmaceutical biotechnology and the pharmaceutical industry is a fast moving business and we all know that the future is hard to predict, but we are glad that with the selected contributors being in touch with industrial needs and challenges, we made the right choice to give answers to the readers’ questions not only about new developments in protein production, host organism selection, and future platform organisms for biosynthesis and vaccine production, but also on biological generics, drug formulation, and legal aspects of biotechnology. In this textbook you will find updated facts and figures about the pharmaceutical industry and the latest drug approvals. In the first part a detailed discussion is provided about production systems for the biosynthesis of both low molecular weight drugs and proteins in prokaryotic and eukaryotic cell cultures and organisms. In the second part the drug formulation and manufacturing process is in focus, but we also want to highlight quality control and bioanalytical aspects, which have been largely neglected before. Therefore, this second part is now updated and dedicated to the recombinant therapeutic proteins and vaccines that are already in clinical use, as well as requirements for quality control. In contrast to the first edition we recognized that drug regulation and quality assurance are becoming more important, while the legal aspects of drug patenting, and the drug approval process are again emphasized. In the third part we had a hard task of sorting and structuring the emerging diversity of research and development in this field and bring it under one single chapter. This is nearly impossible, but our aim is to guide the reader through the new upcoming lines of research impacted by genetics, synthetic biology, and nanobiotechnology. Finally we selected chapters showing exemplarily ongoing research trends that, hopefully, will find their way into clinical applications in the future or as approved drugs into the second edition of this textbook. Well-updated by authors from the previous edition, we learn about personalized medicine and xenotransplantation, and we are proud to introduce new contributors telling us about nanocarriers as future drug delivery systems, ultrahigh-throughput screening for accelerated drug discovery, and transgenic plants as future green factories.

The editors want to thank all the authors for their valuable contributions and the time they have invested in this work. We know very well that time was and is a scarce resource and that the chapters were written alongside the authors’ regular duties. Special thanks also to the families behind for their patience and understanding why time was spent in this project. Special thanks to Anne Chassin du Guerny and Gregor Cichetti of Wiley-Blackwell for their professional support in the layout, proofreading, and production of this textbook.

We know that this book is far from being complete and we are aware that by the day of publishing it could be updated again. But our intention is to provide a “primer” for the interested reader to start working and to show how exciting research is in this fast moving field of life science.

Oliver Kayser

Heribert Warzecha

Dortmund and Darmstadt, January 2012

List of Contributors

Shoaib Ahmad

Rayat and Bahra Institute of Pharmacy

Department of Pharmacology

Sahauran, Punjab 140104

India

Michael Balls

Fund for the Replacement of Animals in Medical Experiments (FRAME)

Russell & Burch House

96–98 North Sherwood Street

Nottingham NG1 4EE

UK

Debmalya Barh

Institute of Integrative Omics and Applied Biotechnology (IIOAB)

PB Barh Centre for Bioprocess, Biotechnology, and Renewable Energy

Nonakuri, Purba Medinipur

West Bengal 721172

India

Ross T. Barnard

The University of Queensland, St Lucia

Australian Infectious Diseases Research Centre

School of Chemistry and Molecular Biosciences

Brisbane, Queensland 4072

Australia

Andreas Bechthold

Albert Ludwigs University of Freiburg

Department of Pharmaceutical Biology and Biotechnology

Institute for Pharmaceutical Sciences

79104 Freiburg

Germany

Andrew Bennett

University of Nottingham Medical School

School of Biomedical Sciences

FRAME Alternatives Laboratory

Queen’s Medical Centre

Nottingham NG7 2UH

UK

Atanu Bhattacharjee

North Eastern Hill University

Department of Biotechnology and Bioinformatics

Shillong 22

India

Gregory J. Brunn

Mayo Clinic

Department of Molecular Pharmacology and Experimental Therapeutics

Rochester, MN 55905

USA

Maria J. De Jesus

ExcellGene SA

Route de l′ile-au-bois 1A

1870 Monthey

Switzerland

Theo Dingermann

Goethe University Frankfurt

Institute of Pharmaceutical Biology

Max-von-Laue-Straße 9

60438 Frankfurt/Main

Germany

Sean M. Geary

University of Iowa

Department of Pharmaceutical Sciences and Experimental Therapeutics

College of Pharmacy

M5S. Grand Avenue

Iowa City, IA 52242

USA

Christoph Giese

ProBioGen AG

Goethestraße 54

13086 Berlin

Germany

Uwe Gottschalk

Sartorius-Stedim Biotech

Purification Technologies

August-Spindler-Straße 11

37079 Göttingen

Germany

Jens-Peter Gregersen

Novartis Vaccines and Diagnostics GmbH

Emil-von-Behring Straße 76

35041 Marburg

Germany

Nizar Happyana

Technical University of Dortmund

Laboratory of Technical Biochemistry

Emil-Figge Straße 66

44227 Dortmund

Germany

and

Bandung Institute of Technology

Department of Chemistry

Jl. Ganesha 10

Bandung 40132

Indonesia

Oktavia Hendrawati

University of Groningen

Pharmaceutical Biology Department

Antonius Deusinglaan 1

9713 AV Groningen

The Netherlands

Jacques Hille

University of Groningen

Molecular Biology of Plants Department

Kerklaan 30

9751 NN Haren

The Netherlands

Walter Hinderer

Gedeon Richter Pharma GmbH

Robert-Bosch-Straße 11B

63225 Langen

Germany

Henning von Horsten

ProBioGen AG

Goethestraße 54

13086 Berlin

Germany

Kewal K. Jain

Jain PharmaBiotech

Blaesiring 7

4057 Basel

Switzerland

Oliver Kayser

Technical University Dortmund

Laboratory of Technical Biochemistry

Emil-Figge Straße 66

44227 Dortmund

Germany

David Kendall

University of Nottingham Medical School

School of Biomedical Sciences

FRAME Alternatives Laboratory

Queen’s Medical Centre

Nottingham NG7 2UH

UK

Alexander Kind

Technical University Munich

Department of Livestock Biotechnology

Liesel-Beckmann Straße 1

85354 Freising-Weihenstephan

Germany

Yogita Krishnamachari

University of Iowa

Department of Pharmaceutical Sciences and Experimental Therapeutics

College of Pharmacy

M5S. Grand Avenue

Iowa City, IA 52242

USA

Luke R. Le Grand

The University of Queensland, St. Lucia

School of Chemistry and Molecular Biosciences

Brisbane, Queensland 4072

Australia

Caitlin D. Lemke

University of Iowa

Department of Pharmaceutical Sciences and Experimental Therapeutics

College of Pharmacy

M5S. Grand Avenue

Iowa City, IA 52242

USA

Andriy Luzhetskyy

Albert Ludwigs University of Freiburg

Department of Pharmaceutical Biology and Biotechnology

Institute for Pharmaceutical Sciences

79104 Freiburg

Germany

Bernd Meibohm

University of Tennessee Health Science Center

College of Pharmacy

Department of Pharmaceutical Sciences

Memphis, TN 38163

USA

Remco Muntendam

University of Groningen

Department of Pharmaceutical Biology

Antonius Deusinglaan 1

9713 AV Groningen

The Netherlands

Julia Myschik

Ludwig-Maximilians-University Munich

Department of Pharmacy

Pharmaceutical Technology and Biopharmaceutics

Butenandtstraße 5

81377 Munich

Germany

Heiner Niemann

Friedrich Loeffler Institute (FLI)

Institute of Farm Animal Genetics

Mariensee

31535 Neustadt

Germany

Jeffrey L. Platt

University of Michigan

Departments of Surgery and Microbiology & Immunology

Ann Arbor, MI 48109

USA

David B. Resnik

East Carolina University

The Brody School of Medicine

Greenville, NC 27858

USA

Aliasger K. Salem

University of Iowa

Department of Pharmaceutical Sciences and Experimental Therapeutics

College of Pharmacy

M5S. Grand Avenue

Iowa City, IA 52242

USA

Angelika Schnieke

Technical University Munich

Department of Livestock Biotechnology

Liesel-Beckmann Straße 1

85354 Freising-Weihenstephan

Germany

Evan B. Siegel

Ground Zero Pharmaceuticals

2600 Michelson Drive

Irvine, CA 92612

USA

Gary Walsh

University of Limerick

Industrial Biochemistry Program and the Materials and Surface Science Institute

Limerick City

Ireland

Heribert Warzecha

Technische Universität Darmstadt

Biology

Schnittspahnstraße 3-5

64267 Darmstadt

Germany

Gabriele Weitnauer

Albert Ludwigs University of Freiburg

Department of Pharmaceutical Biology and Biotechnology

Institute for Pharmaceutical Sciences

79104 Freiburg

Germany

Michaela White

Thomson Reuters

Life Sciences

Asia Pacific

Melbourne, Victoria 3001

Australia

Gerhard Winter

Ludwig-Maximilians-University Munich

Department of Pharmacy

Pharmaceutical Technology and Biopharmaceutics

Butenandtstraße 5

81377 Munich

Germany

Herman J. Woerdenbag

University of Groningen

Pharmaceutical Technology and Biopharmacy Department

Antonius Deusinglaan 1

9713 AV Groningen

The Netherlands

Florian M. Wurm

Ecole Polytechnique Fédérale de Lausanne (EPFL)

Laboratory of Cellular Biotechnology

1015 Lausanne

Switzerland

and

ExcellGene SA

Route de l′ile-au-bois 1A

1870 Monthey

Switzerland

Yi Zhang

University of Tennessee Health Science Center

College of Pharmacy

Department of Pharmaceutical Sciences

Memphis, TN 38163

USA

Jian Zhao

The Samuel Roberts Noble Foundation

2510 Sam Noble Parkway

Ardmore, OK 73401

USA

Stefan Zietze

ProBioGen AG

Goethestraße 54

13086 Berlin

Germany

Ilse Zündorf

Goethe University Frankfurt

Institute of Pharmaceutical Biology

Max-von-Laue-Straße 9

60438 Frankfurt/Main

Germany

Part One Concepts and Methods for Recombinant Drug Production

1

Pharmaceutical Biotechnology and Industrial Applications – Learning Lessons from Molecular Biology

Oliver Kayser and Heribert Warzecha

1.1 Introduction

To date, biotechnology has produced more than 200 new therapies and vaccines, including products to treat cancer, diabetes, HIV/AIDS, and autoimmune disorders. There are more than 400 biotech drug products and vaccines currently in clinical trials, targeting more than 200 diseases, including various cancers, Alzheimer’s disease, heart disease, diabetes, multiple sclerosis, AIDS, and arthritis. These few figures demonstrate the importance of biotechnological methods and techniques, which are increasingly dominating the process of drug research and development [1].

An average approval of 10–15 products a year indicates that pharmaceutical biotechnology is a highly active sector. Amongst these, the number of genuinely new biopharmaceuticals is around 40%, indicating the high innovative character of research; some of these products are likely to be future blockbusters (Table 1.1). Examples are monoclonal antibody-based products such as Rituximab (Rituxan®/MabThera®) for the treatment of cancer with $18 billion in sales in 2009, insulin and insulin analogues ($13.3 billion/2009), and finally erythropoietin-based products ($9.5 billion/2009). The global market is growing by 7% per year for protein-based therapeutics and among all blockbuster drugs only one is a classical low molecular drug, the other four top selling drugs (Table 1.2) are derived from the biotechnology sector [3]. In addition to new drug entities (NDE), biosimilars or follow-up-biologicals will continue to increase in market value; this is the focus of Chapter 13. This trend is supported by new or adapted approved routes from the regulatory bodies such as the EMA (European Medicines Agency) and the FDA (Food and Drug Administration) (see Chapter 11).

Table 1.1 Classification of recombinant proteins for human use

(according to [1]).

CategoryProductGenuinely new biopharmaceuticalsActemra®/Roactrema®, Arcalyst®, Arzerra®, Atryn®, Cervarix®, Cimzia®, Elaprase®, Elonva®, Gardasil®/Silgard®, Ilaris®, Kalbitor®, Lucentis®, Myozyme®, Nplate®, Preotach®, Prolia®, Provenge®, Recothrom®, Removab®, Scintimun®, Simponi®, Soliris®, Stelara®, Vectibix®, Victoza®BiosimilarsAbseamed®, Binocrit®, Biogastrim®, Epoetin-α-heaxal (Erythropoetin)®, Filgastrim hexal®, Filgrastim ratiopharm®, Nivestim®, Omnitrope®, Ratiogastrim®, Valtropin®, Zarzio®Reformulated me-too and relatedAccretropin®, Biopin®, Eporatio®, Extavia®, Exubera®a), Fertavid®, Lumizyme®, Mircera®, Novolog mix®, PEGintron/ribetol combo®, Pergoveris®, Opgenra®, Vpriv®, Xyntha®Previously approved elsewhereIncrelex®, Macugen®, Naglazyme®, Orencia®, Tysabri®

a) No longer available.

Table 1.2 The ten top selling recombinant proteins for human use in 2010

(source: LaMerie Business Intelligence, Barcelona [2]).

ProductSales value (US$ billions)CompanyEnbrel®, Etanercept6.58Amgen, Wyeth, Takeda PharmaceuticalsRemicade®, Infliximab5.93Centocor, Schering-Plow, Mitsubishi Tanabe PharmaAvastin®, Bevacizumad5.77Genentech, Roche, ChugaiRituxan®, Rituximab5.65Genentech, Biogen-IDEC, RocheHumira®, Adalimumab5.48