Advances in Large-Scale Biopharmaceutical Manufacturing and Scale-Up Production

Transcription

1 Advances in Large-Scale Biopharmaceutical Manufacturing and Scale-Up Production October 2004 Volume 1: Emerging Technologies and Scientific Advancements ASM Press & Institute for Science and Technology Management Foreword by Thomas Monath, M.D., Chief Scientific Officer, Acambis, Inc. Editor: Eric S. Langer ASM Press: Washington, DC ISTM: Rockville, MD

2 American Society for Microbiology Press and Institute for Science and Technology Management A division of BioPlan Associates, Inc Shady Grove Road, Suite 202 Rockville MD Copyright 2004 by BioPlan Associates, Inc. All rights reserved, including the right of reproduction in whole or in part in any form. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the written permission of the publisher. For information on special discounts or permissions contact ISTM at , or [email protected] Managing Editor: Eric S. Langer Project Director: Marjory Spraycar Production Manager: Genilee Swope Parente Cover Design: David Sullivan, Admedia Communications Volume 1: ISBN

3 Acknowledgement This project would not have been possible without the exceptional efforts of the many people involved. In particular, we would like to thank Marjory Spraycar, Project Director, Genilee Swope Parente, Production Manager, Benjamin J. Kemp, Data Management and Acquisition, and Carlos Carbo, cover graphics. We would also especially like to thank our reviewers: Milton J. Axley, Ph.D. Associate Director, Process Biochemistry, MedImmune; Ed Branson, Ph.D., Vice President Operations, Biolex; Robert L. Campbell, Ph.D., Vice President Operations, BD Technologies; Vincent Narbut, Engineering, Biogen IDEC; Eric Tsao, PhD, Vice President, Cell Culture Operations, Medimmune; Robert Schwartz, PhD, Fermentation Operations, Abbott. Thank you for your tireless efforts, and your recognition of the importance of this study. Eric S. Langer Managing Editor

4 Preface This study was undertaken, managed and coordinated by BioPlan Associates, Inc., a biopharmaceutical management and marketing research consulting firm in Rockville, MD, based on its 15 years of experience and knowledge of the market segment. BioPlan surveyed the industry to identify required content, and then selected subject matter experts to author relevant chapters to this study. The American Society for Microbiology, in recognizing the importance of applied sciences in biotechnology processes, has lent its name to this endeavor. ASM s mission is to promote research and research training in the microbiological sciences and to assist communication between scientists, policy makers, and the public to improve health, protect the environment, and foster economic well-being. This study provides a platform from which both basic and applied research scientists can share findings and novel technologies associated with biopharmaceutical manufacturing. The findings of this report may also support public, health, and economic policy. Each chapter provides a unique, unbiased view of the current state of the science and technology associated with biopharmaceutical manufacturing and scale-up production. While no single body of work can encompass all the advances being made in the field, this work offers the most comprehensive information to date on technologies and processes that will be leading the next decade. Included are sections on biopharmaceutical manufacturing technologies for human therapeutics, including mammalian, microbial, and yeast systems, and other novel technologies. We have evaluated the entire production process, from early scale-up through purification and downstream production. Each chapter includes extensive technical information and quantifiable data, as well as real-world situations and relevant case studies that provide context for the discussions. The intended audiences are decision-makers at biopharmaceutical organizations, contract manufacturing organizations, suppliers to the industry, and international entities evaluating this market. As the industry progresses, we plan to keep this study current by providing regular updates as technologies progress. American Society for Microbiology Press

5 Advances in Large-Scale Biopharmaceutical Manufacturing and Scale-Up Production Table of Contents Emerging Technologies and Scientific Advancements, Volume 1 FOREW OREWORD: ORD: Thomas Monath, M.D.. Chief Scientific Officer, Acambis, Inc.... i INTRODUCTION: Large Scale Biopharmaceutical Manufacturing: Implications of Reducing Costs and Optimizing Production Efficiency... 1 Eric S. Langer, Nigel Grinter, Ph.D., BioPlan Associates, Inc. SCIENCE: Emerging Tec echnologies New Frontiers in Bioprocessing K. John Morrow, Ph.D., Preston Dorsett, Ph.D., Meridian Bioscience Emerging and Novel Technologies in Biopharmaceutical Manufacturing: Technologies most affecting operations over the next 5 years Robert L. Campbell, BD Technologies, Advanced Drug Delivery Tec echnology Processes Maximizing Productivity in Biopharmaceutical Manufacturing Matthew D. Hilton, Ph.D., Lilly Research Laboratories Challenges in Biopharmaceutical Scale-up to Production Beth Junker, Ph.D., Merck Research Laboratories Advances in Improved Expression of Recombinant Proteins in Microbial Systems Daniel Rudolph, Ph.D., Sriram Srinivasan, Ph.D., Don R. Durham, Ph.D., Aaron Heifetz, Ph.D., Cambrex Bio Science Baltimore, Inc. Design of Large-Scale Cell Culture Process - A Process Engineering Point of View Chun-Ko Jin, Ph.D. Tony Cope, Megan Jakobsen, Jennifer Foelske, Kelly Kivett, Teresa Cheung, Greg Francis, Fluor Daniel Inc. ASM Press October 2004

6 Table of Contents (Cont d) Emerging Technologies and Scientific Advancements, Volume 1 Launching New Biologics: A Process and Facility Design Approach Trent Carrier, Ph.D., Abraham Shamir, Ph.D., Joye L. Bramble, Ph.D., Marshall Gayton, Merck & Co. Inc. Impact of Prolonging Cell Culture Lifetimes on Scale-up Production Thomas Primiano, Ph.D., and Todd Bucciarelli, Clonex Development, Inc. Initial Protein Recovery Process: Purification Methods for Pilot and Mid-Scale Processes, The Advantages and Disadvantages Joseph Shiloach, Ph.D., Jeanne B. Kaufman, Loc B. Trinh, National Institutes of Health, Biotechnology Unit, NIDDK Purification of Monoclonal and Genetically Engineered Antibodies Robert M. Kennedy, Ph.D., Amersham Biosciences, Inc Protein Stability, Solubility and Solute Interactions for Manufacturing Process Development Brent S. Kendrick, Ph.D., Amgen, Inc. ASM Press October 2004

7 Advances in Large-Scale Biopharmaceutical Manufacturing and Scale-Up Production Regulat egulator ory Issues Regulatory and Business, Volume 2 FDA and Regulatory Issues in Biopharmaceutical Manufacturing Andrea Chamblee, Esq., RAC, Johns Hopkins University, MD Good Automation Manufacturing Practice (GAMP) in Large Scale Biopharmaceutical Production Beth Junker, Ph.D., Paul Kardos, W. Smizaski, and T. Brix, Merck Research Laboratories Post-Approval Changes for Large Scale Biopharmaceutical Manufacturing: Global Regulatory Issues John J. Dougherty, James W. Precup, Ph.D., Josephine Secnik, & John K. Towns, Ph.D., Eli Lilly and Company Business Practices Table of Contents Commercial Dynamics of BioTherapeutics: Defining Characteristics of Biologics Markets Craig C. Parker, Lehman Brothers San Francisco, CA Forecasting Industry-wide Biopharmaceutical Manufacturing Capacity Requirements Thomas C. Ransohoff, Robert E. Mittendoff II, and Howard L. Levine, Ph.D., BioProcess Technology Consultants Inc. Worldwide Therapeutic Protein Production Capacity Andrew Sinclair, BioPharm Services, Cambridge, UK Biomanufacturing Capacity: When is the Next Bottleneck? Barry Middleton, Ph.D., Charles Craig, Ernst & Young Strategic Issues: Capital Investment Jeffery N. Odum, Clark Richardson & Biskup Consulting Engineers, Inc. Pricing Issues for Biopharmaceutical Products E.M. Kolassa, Ph.D., William Lobb, R.Ph., Brian Reisetter, Ph.D., Kevin Patterson, CPA, Douglas Paul, Pharm.D, Medical Marketing Economics, LLC Intellectual Property Considerations in Scale-Up of Biomanufacturing Processes Janal Kalis, Schwegman Lundberg Woessner & Kluth ASM Press October 2004

8 Table of Contents (cont d) Regulatory and Business, Volume 2 Biopharmaceutical Manufacturing Training and Education A Survey Report of Curriculum Recommendations Arvind Chhatbar, Vitesse Re-Skilling Canada Inc. A Visionary Perspective on the Future of Biopharmaceutical Manufacturing G. Steven Burrill, Burrill & Company APPENDIX: Company Listings Organizations Supplying or Involved in Large-Scale Biopharmaceutical Manufacturing ASM Press October 2004

9 For orewor ord The industrial goal for any biopharmaceutical manufacturer in today s competitive environment is to build a safe, efficient, consistent and cost-effective biopharmaceutical process. The humanitarian and public sector goal is to make the new biopharmaceutical products widely available at minimized cost. It is clear that bioengineering advances and scale-up are the keys to the reduction of manufacturing costs. The availability of biopharmaceutical products must ultimately be broad enough to encompass the treatment of diseases in both industrialized and developing nations. Since very large numbers of patients can benefit from these new biopharmaceutical products, industry faces many challenges in manufacturing proteins at large scale. This may require multiple reactors and the annual production of hundreds or even thousands of kilograms of product. The technical challenges include the development of optimized and regulated transgene expression to produce sufficient yields at industrial scale, the stability of both the amino acid and carbohydrate side chains of the molecule in question, the downstream (purification) process that must be tailored to the specific product, and the sensitive bioassay systems that may need to detect different protein isoforms generated by the manufacturing process. These technical requirements must be met within an increasingly challenging regulatory environment, in which the safety and quality of biopharmaceutical products is ensured by standardizing, controlling, and validating the production methods. We live in an era of rapidly expanding knowledge about the genetic basis and pathophysiology of disease states affecting humans and domesticated animals. As a consequence, many new products have been developed with diagnostic, therapeutic, and prophylactic activities. The most dramatic new biopharmaceutical products have been monoclonal antibodies which now make up approximately 20% of all such products and recombinant proteins, such as Factor VIII, Factor VIIa, tpa, soluble CD4, erythropoietin, interferons, TNF-α, GM-CSF, human bone morphogenetic protein, and others. Literally hundreds of novel protein drugs are in various stages of development. Many new protein products must be made in cell cultures because of the system s ability to produce appropriately folded or glycosylated active forms, relative to bacteria and yeast fermentation systems. However, industry is faced with the difficulty of manufacturing different recombinant proteins in different host systems (mammalian cells, yeast, bacteria, insect cells) in an increasingly complex, multi-product environment. i

10 For orewor ord This book, Advances in Large-Scale Biopharmaceutical Manufacturing and Scale-up Production, was conceived to define and analyze the many challenges described above. The first part of the book is devoted to newly emerging and current processes for growing cells, regulating protein expression, achieving efficient target protein recovery, and other technical requirements for commercial production. Chapters are written by experts from the biopharmaceutical industry who have responsibility for scale-up and for managing manufacturing costs, and who must search for process improvements while recognizing that change may be constrained by practical and regulatory concerns. Specific case studies provide clear demonstrations of the issues faced in large-scale manufacturing. The second part of the book deals with regulatory issues and business practices. Biopharmaceutical production must be performed in full compliance with current Good Manufacturing Practices in an era of increasing regulatory scrutiny. The complexity of the production and downstream processes and of the manufacturing environment (facilities, equipment, and computer controls) increases the scope of validation and control. The book examines the regulatory environment from the perspective of industry. Other chapters deal extensively with critical business strategic decision-making and commitments by industry to protection of intellectual property, predicting market dynamics, and determining pricing and reimbursement. Large-scale manufacturing of biopharmaceutical products has required significant capital and infrastructure investments, and much progress has been made in the last decade. Scale-up and improvements in efficiency are the obvious keys to reduction in costs and to the wider availability of life-saving products, but the investments required may also compete with resources available for discovery research and new product development. The book contains a wealth of information that will be of wide interest to those engaged in managing biopharmaceutical organizations, research institutes engaged in bioengineering and technical improvements, government agencies in health policy and product regulation, and those interested in modeling strategic manufacturing options. Thomas P. Monath, M.D. Chief Scientific Officer Acambis, Inc. Cambridge, MA i i