Biological Drug Products E-Book

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 1491

Veröffentlichungsjahr: 2013

Beschreibung

Tested and proven solutions to the challenges of biological drug product development Biological drug products play a central role in combating human diseases; however, developing new successful biological drugs presents many challenges, including labor intensive production processes, tighter regulatory controls, and increased market competition. This book reviews the current state of the science, offering readers a single resource that sets forth the fundamentals as well as tested and proven development strategies for biological drugs. Moreover, the book prepares readers for the challenges that typically arise during drug development, offering straightforward solutions to improve their ability to pass through all the regulatory hurdles and deliver new drug products to the market. Biological Drug Products begins with general considerations for the development of any biological drug product and then explores the strategies and challenges involved in the development of specific types of biologics. Divided into five parts, the book examines: * Part 1: General Aspects * Part 2: Proteins and Peptides * Part 3: Vaccines * Part 4: Novel Biologics * Part 5: Product Administration/Delivery Each chapter has been prepared by one or more leading experts in biological drug development. Contributions are based on a comprehensive review and analysis of the current literature as well as the authors' first-hand experience developing and testing new drugs. References at the end of each chapter serve as a gateway to original research papers and reviews in the field. By incorporating lessons learned and future directions for research, Biological Drug Products enables pharmaceutical scientists and students to improve their success rate in developing new biologics to treat a broad range of human diseases.

Leseprobe

Contents

Cover

Title Page

Copyright

Dedication

Preface

Contributors

Part 1: General Aspects

Chapter 1: An Overview of the Discovery and Development Process for Biologics

1.1 Introduction

1.2 The Discovery Process for Monoclonal Antibodies

1.3 Manufacturing Process Development for Biologics

1.4 Regulatory Review and Approval for Biologics

1.5 Biologics: The Past, the Present, And the Future

1.6 Conclusion

References

Chapter 2: Nonclinical Safety Assessment of Biologics, Including Vaccines

2.1 Introduction

2.2 Considerations in the Selection of the Animal Species

2.3 Considerations for the Nonclinical Safety Evaluation

2.4 Pharmacokinetics

2.5 Selection of the Initial Clinical Dose

2.6 Future Directions

References

Chapter 3: Clinical Assessment of Biologic Agents

3.1 Introduction

3.2 Clinical Trial Structure

3.3 Incorporating Patients into the Structure of a Trial

3.4 Efficacy

3.5 Pharmacovigilance

3.6 Diseases Treated with Biologics

3.7 Future Perspectives

References

Chapter 4: Key Regulatory Guidelines for the Development of Biologics in the United States and Europe

4.1 Introduction

4.2 General United States Regulatory Scheme

4.3 European Union Guidelines

4.4 Regulatory Strategies for Worldwide Marketing of Biological Products

4.5 Preventive Vaccine Development: Special Considerations

4.6 Conclusion

Chapter 5: Landscape and Consideration of Intellectual Property for Development of Biosimilars

5.1 Introduction

5.2 Legislative History

5.3 Approval Guidelines for a Generic Biological Product

5.4 Intellectual Property Protection Under the Bpci Act

5.5 Legal Issues

5.6 Future Perspectives

Chapter 6: Scientific Aspects of Sterility Assurance, Sterility, Asepsis, and Sterilization

6.1 Introduction

6.2 Contamination Control

6.3 Fundamental Concepts in “Sterile” Product Manufacturing

6.4 The Evolution of Aseptic Processing Technology

6.5 Sterility and Asepsis: Toward a Common Scientific Understanding

6.6 Sterility, Viability, and Virulence

6.7 Regulations and Aseptic Contamination Rates

6.8 Considerations Regarding Environmental Monitoring

6.9 Practical Considerations in Current Good Manufacturing Processes–Compliant Aseptic Processing: Achieving Sterility by Design [17]

6.10 The Need for Scientifically Valid Standards and Regulations

6.11 An Overview of Sterilization and Decontamination

6.12 Microbial Death Curves

6.13 Toward a Measure of Real Product Safety

6.14 A Few Scientifically Modest Proposals

References

Part 2: Proteins and Peptides

Chapter 7: Cell Culture Processes in Monoclonal Antibody Production

7.1 Introduction

7.2 Mammalian Expression System and Cell Line Engineering

7.3 Cell Line and Cell Bank Tests

7.4 Process Development, Scale UP, and Tech Transfer

7.5 Process Advances and Future Perspectives

7.6 Acknowledgments

References

Chapter 8: Protein and Peptide Purification

8.1 Introduction

8.2 Overview of Downstream Processing

8.3 Protein Refolding Methods

8.4 Challenges in Purification

8.5 Purification Strategies

8.6 Future Directions

References

Chapter 9: Chemical and Genetic Modification

9.1 Introduction

9.2 Protein Modification to Increase Circulation Half-Life

9.3 Structure-Based Engineering to Modify Protein and Peptide Therapeutics

9.4 Protein Modification to Add a Therapeutic Effect

9.5 Protein Modification Used for Diagnostics

9.6 Future Directions

Acknowledgments

References

Chapter 10: Analytical Characterization of Proteins and Peptides

10.1 Introduction

10.2 Structural Characterization and Confirmation

10.3 Physicochemical Properties

10.4 Biophysical Properties (Higher Order Structure and Stability)

10.5 Other Posttranslational Modifications and Product-Related Impurities

10.6 Aggregates and Particulates

10.7 Summary

Acknowledgments

References

Chapter 11: Protein and Peptide Formulation Development

11.1 Introduction

11.2 General Formulation Development Strategies

11.3 Key Challenges in Drug Product Formulation and Fill-Finish

11.4 Summary

References

Chapter 12: Regulatory Strategies and Lessons in the Development of Biosimilars

12.1 Background and Objective

12.2 History

12.3 Market

12.4 Why are Biopharmaceuticals Different from Small Molecules?

12.5 Typical Biopharmaceutical Manufacturing Steps and Analytical Techniques for Characterization

12.6 Generics versus Biosimilars

12.7 Current Regulatory Status and Pathways to Biosimilar Products

12.8 Conclusion

References

Part 3: Vaccines

Chapter 13: Vaccine Development: History, Current Status, and Future Trends

13.1 Introduction

13.2 Current Vaccine Development (Product and Process)

13.3 Specific Relevant Trends

13.4 Future Trends for Vaccine Development

Acknowledgments

References

Chapter 14: Role and Application of Adjuvants and Delivery Systems in Vaccines

14.1 Introduction

14.2 Challenges in Developing Vaccine Adjuvants

14.3 Vaccine Adjuvants, Adjuvant Effect, and Toxicity

14.4 Characteristics of an “Optimal” Adjuvant

14.5 Regulatory Aspects for Adjuvants Used in Human Vaccines

14.6 Adjuvants Used in Licensed Vaccines

14.7 Future Directions and Prospects

Addendum

Acknowledgments

References

Chapter 15: Methods for Characterizing Proteins in Aluminum Adjuvant Formulations

15.1 Introduction

15.2 Analytical Methods

15.3 Conclusion

Acknowledgments

References

Part 4: Novel Biologics

Chapter 16: The State of the Art and Future of Gene Medicines

16.1 Introduction and Historic Perspective

16.2 Gene Therapy in the Clinic

16.3 Adeno-Associated Viral Vectors as a Technological Platform for Clinical Translation

16.4 Challenges in Hepatocyte-Directed Gene Therapy

16.5 Regulatory Aspects of Gene Therapy

16.6 General Conclusions and Perspectives

References

Chapter 17: Nucleic Acid Vaccines

17.1 Introduction

17.2 History of Nucleic Acid Vaccines

17.3 DNA Plasmids as a New Group of Biological Drug Products

17.4 Optimization of DNA Vaccines

17.5 Unproven Safety Concerns

17.6 Manufacturing Process

17.7 Regulatory Considerations

17.8 Summary

References

Chapter 18: Multifunctional Polymeric Nanosystems for RNA Interference Therapy

18.1 Introduction

18.2 RNA Interference Therapy

18.3 Delivery Systems for RNA-Interference

18.4 Multifunctional Nanosystems for Delivery of RNA-Interference Therapeutics

18.5 Illustrative Examples of Nanoparticle-Mediated Small Interfering RNA Delivery

18.6 Illustrative Examples of Nanoparticle-Mediated Micro RNA Delivery

18.7 Conclusions

References

Chapter 19: Advent and Maturation of Regenerative Medicine

19.1 Introduction

19.2 Regenerative Medicine: Looking Back

19.3 Transplantation Medicine: Historical Perspectives

19.4 Bone Marrow Transplantation and Hematopoietic Cell Transplantation

19.5 Emergence of Stem Cell Therapy

19.6 Emergence of Tissue Engineering and Scaffolds

19.7 Regenerative Medicine: Looking Forward

19.8 Cell Therapy, Tissue Engineering, and the Global Landscape of Regenerative Medicine

19.9 Global Regenerative Medicine and Medical Tourism

19.10 Regulatory Hurdles

19.11 The Future and Challenges

References

Part 5: Product Administration/Delivery

Chapter 20: Conventional and Novel Container Closure and Delivery Systems

20.1 Introduction

20.2 General Development Approach of a Combination Product (Drug or Biologic with Device)

20.3 Containers and Product Quality

20.4 Recently Marketed and Emerging Container Platforms

20.5 Blow-Fill-Seal Plastic Ampoule

20.6 Nonparenteral Delivery

20.7 Device Functionality Testing

20.8 Recommendations

References

Chapter 21: Controlled-Release Systems for Biologics

21.1 Introduction

21.2 Choice of a Suitable Delivery System

21.3 Feasible Systems for Biologics

21.4 Future Directions

References

Chapter 22: Routes of Delivery for Biological Drug Products

22.1 Introduction

22.2 Conventional Administration of Biological Drug Products

22.3 Alternative Routes of Administration

22.4 Summary and Outlook

Acknowledgments

References

Index

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Published simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data:

Biological drug products : development and strategies / edited by Wei Wang, Manmohan Singh.

p. ; cm.

Includes bibliographical references and index.

ISBN 978-1-118-14889-1 (cloth)

I. Wang, Wei, 1957 March 10-II. Manmohan Singh, 1964 November 8-

[DNLM: 1. Biological Agents–pharmacology. 2. Biological Agents–therapeutic use. 3. Drug Delivery Systems. 4. Drug Discovery. QV 241]

RM301.25

615.1’9–dc23

2013016301

To my wife, Linlin Wang, for her unconditional support and love.

—Wei Wang

I dedicate this work to my family for their lifetime of support.

—Manmohan Singh

Preface

Biological drug products have been playing a key role in combating human diseases. The growth of biologics has clearly outpaced that for small molecule drugs in the past decade, and the trend is expected to continue for the next one. However, successful development of biological drug products has not been straightforward because of both the labor-extensive production processes and the rather limited process and storage stabilities of biologics. On top of these are additional challenges, including stringent requirements of good manufacturing process (GMP) compliances, ever-increasing regulatory scrutiny, and intense market competition (e.g., biosimilars).

This book is intended to summarize the recent progress in the development of different types of biologics, to describe the development challenges and more importantly, to discuss the development strategies. It is divided into five parts, covering general aspects in the development of biologics (Part 1) and challenges and strategies in the development of specific types of biologics (Parts 2 to 5). The general topics include overall product development process (Chapter 1), preclinical and clinical assessment (Chapter 2 and 3), key regulatory guidelines (Chapter 4), intellectual property considerations (Chapter 5), and GMP issues (Chapter 6). Development of specific types of biologics are discussed, covering proteins and peptides (Chapters 7 to 11), biosimilars (Chapter 12), vaccines (Chapters 13 to 15), gene medicines (Chapter 16), nucleic acid vaccines (Chapter 17), oligonucleotides (Chapter 18), and regenerative medicines (Chapter 19) along with product administration and delivery-related issues (Chapters 20 to 22).

Wei Wang

Manmohan Singh

Contributors

James P. Agalloco, Agalloco & Associates, Belle Mead, New Jersey, USA

James E. Akers, Akers Kennedy & Associates, Kansas City, Missouri, USA

Ashraf Amanullah, Genentech, Inc., Oceanside, California, USA

Mansoor Amiji, Northeastern University, Boston, Massachusetts, USA

Jean-Pierre Amorij, Institute for Translational Vaccinology (Intravacc), Bilthoven, The Netherlands

Tudor Arvinte, University of Geneva and Therapeomic, Inc., Basel, Switzerland

Anthony Atala, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA

George O. Badescu, PolyTherics Ltd., London, UK

Steve J. Brocchini, PolyTherics Ltd., London, UK

Rachel Buglione-Corbett, University of Massachusetts Medical School, Worcester, Massachusetts, USA

Martinus A.H. Capelle, Therapeomic, Inc., Basel, Switzerland

Krista Hessler Carver, Covington & Burling LLP, Washington, DC, USA

Mahesh V. Chaubal, Baxter Healthcare Corporation, Round Lake, Illinois, USA

David W. Clarke, Pfizer, Inc., Pearl River, New York, USA

Bart de Geest, Catholic University of Leuven, Leuven, Belgium

Luis R. Espinoza, Louisiana State University, New Orleans, Louisiana, USA

Monika Farys, PolyTherics Ltd., London, UK

Esteban J. Freydell, DSM Biotechnology Center, Delft, The Netherlands

Shanthi Ganesh, Northeastern University, Boston, Massachusetts, USA

Claire L. Ginn, UCL School of Pharmacy, London, UK

Stephanie C. Gordts, Catholic University of Leuven, Leuven, Belgium

Rajesh K. Gupta, Biologics Quality & Regulatory Consultants, LLC, North Potomac, Maryland, USA

Douglas C. Harnish, Teva, Malvern, Pennsylvania, USA

Brian Hosken, Genentech—A Member of Roche Group, South San Francisco, California, USA

Liangbiao George Hu, Pfizer, Inc., Pearl River, New York, USA

Darrell J. Irvine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

Arun Iyer, Northeastern University, Boston, Massachusetts, USA

Frank Jacobs, Catholic University of Leuven, Leuven, Belgium

Hanieh Khalili, National Institute for Health Research Biomedical Research Centre, London, UK

Richard Kingham, Covington & Burling LLP, Washington, DC, USA and London, UK

Gabriela Klasa, Covington & Burling LLP, Brussels, Belgium

Brandon Kwong, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

Buddhadev Layek, North Dakota State University, Fargo, North Dakota, USA

Feng Li, Genentech, Inc., Oceanside, California, USA

Shan Lu, University of Massachusetts Medical School, Worcester, Massachusetts, USA

Rhishikesh Mandke, North Dakota State University, Fargo, North Dakota, USA

Srikumaran Melethil, University of Missouri, Kansas City, Missouri, USA

Abner M. Mhashilkar, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA

Paula Miller, Pfizer, Inc., Chesterfield, Missouri, USA

Shikha Mittoo, University of Toronto, Toronto, Ontario, Canada

Beckley K. Nfor, Delft University of Technology, Delft, The Netherlands

Mayura Oak, North Dakota State University, Fargo, North Dakota, USA

Satoshi Ohtake, Pfizer, Inc., Chesterfield, Missouri, USA

Marcel Ottens, Delft University of Technology, Delft, The Netherlands

Estera M. Pawlisz, PolyTherics Ltd., London, UK

Karolina Peciak, PolyTherics Ltd., London, UK

Emilie Poirier, Therapeomic, Inc., Basel, Switzerland

Lesley Ann Saketkoo, Louisiana State University, New Orleans, Louisiana, USA

Umang S. Shah, Novartis Vaccines and Diagnostics, Holly Springs, North Carolina, USA

Gitanjali Sharma, North Dakota State University, Fargo, North Dakota, USA

Amy Shen, Genentech, Inc., South San Francisco, California, USA

Heather H. Shih, Pfizer, Inc., Cambridge, Massachusetts, USA

Jagdish Singh, North Dakota State University, Fargo, North Dakota, USA

Xingfang Su, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA

John Suschak, University of Massachusetts Medical School, Worcester, Massachusetts, USA

Leo van der Pol, Institute for Translational Vaccinology (Intravacc), Bilthoven, The Netherlands

Shixia Wang, University of Massachusetts Medical School, Worcester, Massachusetts, USA

Wei Wang, Pfizer, Inc., Chesterfield, Missouri, USA

Yajun Jennifer Wang, Genentech—A Member of Roche Group, South San Francisco, California, USA

Joseph Wong, Baxter Healthcare Corporation, Round Lake, Illinois, USA

Qiong L. Zhou, Northeastern University, Boston, Massachusetts, USA

Part 1

General Aspects

1

An Overview of the Discovery and Development Process for Biologics

Heather H. Shih, Paula Miller and Douglas C. Harnish

1.1 Introduction

Biologics, also called biotherapeutics or biopharmaceuticals, are drug substances derived from living organisms or produced using biotechnology that are composed of biological entities such as proteins, peptides, nucleic acids, or cells [1]. They differ from small molecule (SM) drugs that are chemically synthesized and have low molecular weights. Some biologics, such as antibody–drug conjugates, consist of both a protein moiety and an SM component, both of which are required for the therapeutic action of the drug. Traditional biologics that have reached the market include vaccines and blood-derived factors. The advancement in modern biotechnology has brought forth new classes of biologics as exemplified by monoclonal antibodies (mAbs), Fc fusion proteins, recombinant proteins, and peptide drugs. Some early clinical success is now seen in several novel classes of biologics, which include antibody variants, novel protein scaffolds, RNA therapeutics, and cell-based therapies [2–5]. This chapter focuses on protein-based biologics, particularly mAbs because they represent the largest class of biologic drugs. By the end of 2011, the US Food and Drug Administration (FDA) had approved close to 40 mAbs and antibody variants as summarized in Table 1.1. Details on other forms of biologics such as vaccines and RNA drugs can be found in later chapters.

Table 1.1 List of Food and Drug Administration–Approved Antibody-Based Therapeutics Up to 2011 as Categorized by Types.

The first protein-based biologic drug, recombinant insulin Humulin, was approved in the United States in 1982 [6]. Since then the field of biologics grew steadily, with the biotechnology sector laying the foundation for both the drug discovery process and technology innovation. Around late 1990s, the pharmaceutical industry started to invest more in the development of biologics. This shift from a primary focus on SM drugs was largely due to patent expiration on these drugs and the concurrent fierce competition from generic SM drugs. In addition, the increasing difficulty to bring new drugs to the market because of tightened regulations and a lack of breakthroughs in the drug discovery process has also contributed to this shift. Presently, the number of biologics on the market has reached more than 200, and the sales of biologics in 2009 reached $93 billion, with approximately one third of current pharmaceutical pipelines consisting of biologics [7]. Given that almost all of the large pharmaceutical companies have acquired infrastructures and committed resources to develop biologics, we will continue to see a robust growth in this sector in the coming years.

Compared with SM drugs, protein-based biologics have unique therapeutic features. A therapeutic protein usually exhibits exquisite specificity when binding to and modulating its molecular target, which often translates into low off-target toxicity and clinical safety. For example, therapeutic mAbs bind to their target molecules with affinities in the picomolar to low nanomolar range (e.g., [8]). Furthermore, the interaction occurs over a broad interface with multiple physical and chemical bonds formed between an antibody and its cognate antigen, resulting in an extraordinary binding specificity that allows the differentiation of binding partners that differ by as few as one amino acid or subtle conformational difference. On the contrary, the small size of an SM drug makes it prone to off-target binding to proteins other than its intended target, which may result in unacceptable levels of toxicities. A potentially short development cycle is another advantage for the development of biologics, particularly mAbs and recombinant proteins. A clinical candidate for mAb or recombinant protein can be generated and selected in as short as 3 to 5 years compared with typically 7 to 8 years for SMs.

Protein-based biologics have their own limitations. Presently, almost all protein-based drugs must be administered as intravenous or subcutaneous injections because oral delivery is not yet a viable route of administration. Furthermore, protein drugs do not readily penetrate cell membrane and blood–brain barrier (BBB) and therefore are limited to the modulation of peripherally located extracellular targets. The cost of goods to manufacture protein drugs is significantly higher than for SM drugs, which translates into a high drug price that exacerbates health management cost issues [9].

Based on these pros and cons associated with the development of biologics, presently the pharmaceutical industry strives to achieve a balanced portfolio consisting of both SM and biologic drugs. This chapter provides an overview of the discovery and development process for protein therapeutics with a primary focus on mAbs (). Additionally, the chapter summarizes the current status of the protein-based biologics field and discusses several future trends.