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CONSIDERATIONS FOR ENSURING SAFETY AND EFFICACY OF VACCINES AND THERAPEUTIC PROTEINS MANUFACTURED BY USING PLATFORM APPROACHES SUMMARY OF A WORKSHOP Jeffrey Fox, Marilee Shelton-Davenport, and India Hook-Barnard, Rapporteurs Board on Life Sciences Division on Earth and Life Studies NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, DC www.nap.edu

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THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW, Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by Contract W911NF-07-C-0081between the National Academy of Sciences and Department of the Army. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the views of the organizations or agencies that provided support for the project. International Standard Book Number - 13: 978-0-309-15321-8 International Standard Book Number - 10: 0-309-15321-2 Additional copies of this report are available from: The National Academies Press 500 Fifth Street, NW Lockbox 285 Washington, DC 20055 (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area) http://www.nap.edu Copyright 2010 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal government. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. Charles M. Vest is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. Charles M. Vest are chair and vice chair, respectively, of the National Research Council. www.national-academies.org iii

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NATIONAL RESEARCH COUNCIL STANDING COMMITTEE ON BIODEFENSE AT THE US DEPARTMENT OF DEFENSE JENNIE HUNTER-CEVERA (Chair), RTI International, Research Triangle Park, NC L. GARRY ADAMS, Texas A&M University, College Station, TX JOHN F. ALDERETE, Washington State University, Pullman, WA EDWARD J. ARCURI, Novartis Vaccines and Diagnostics, Inc., Cambridge, MA MICHAEL ASCHER, University of California, Davis, CA LESLIE BENET, University of California, San Francisco, CA PHILIP E. COYLE III, Science Strategies, Sacramento, CA STEPHEN W. DREW, Drew Solutions and Science Partners, LLC, Summit, NJ DENISE FAUSTMAN, Harvard Medical School, Massachusetts General Hospital, Charlestown, MA HARRY GREENBERG, Stanford University, Stanford, CA CHARLES HOBBS, Lovelace Respiratory Research Institute, Albuquerque, NM THOMAS INGLESBY, University of Pittsburgh Medical Center, Baltimore, MD JAMES A. MARKS, University of California, San Francisco, CA TIMOTHY MOSHIER, Syracuse Research Corporation, North Syracuse, NY FRED MURPHY, University of Texas Medical Branch, Galveston, TX KAREN NELSON, J. Craig Venter Institute, Rockville, MD PETER A. PATRIARCA, Biologics Consulting Group, Inc., Bethesda, MD JOHN A. SMITH, University of Alabama, Birmingham, AL JIM SWEARENGEN, National Biodefense Analysis and Countermeasures Center, Frederick, MD GRIFFIN TROTTER, Saint Louis University Center for Health Care Ethics, St. Louis, MO DAVID H. WALKER, University of Texas Medical Branch, Galveston, TX Staff MARILEE K. SHELTON-DAVENPORT, Study Director INDIA HOOK-BARNARD, Program Officer REBECCA L. WALTER, Senior Program Assistant NORMAN GROSSBLATT, Senior Editor AMANDA L. MAZZAWI, Program Assistant Sponsor DEPARTMENT OF DEFENSE TRANSFORMATIONAL MEDICAL TECHNOLOGIES INITIATIVE iv

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PLANNING GROUP FOR THE WORKSHOP ON CONSIDERATIONS FOR ENSURING SAFETY AND EFFICACY OF VACCINES AND THERAPEUTIC PROTEINS MANUFACTURED BY USING PLATFORM APPROACHES JENNIE HUNTER-CEVERA (Chair), RTI International, Research Triangle Park, NC EDWARD J. ARCURI, Novartis Vaccines and Diagnostics, Inc., Cambridge, MA STEPHEN W. DREW, Drew Solutions and Science Partners, LLC, Summit, NJ PETER A. PATRIARCA, Biologics Consulting Group, Inc., Bethesda, MD Staff MARILEE K. SHELTON-DAVENPORT, Study Director INDIA HOOK-BARNARD, Program Officer REBECCA L. WALTER, Senior Program Assistant v

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BOARD ON LIFE SCIENCES Members KEITH R. YAMAMOTO (Chair), University of California, San Francisco, CA ANN M. ARVIN, Stanford University School of Medicine, Stanford, CA BONNIE L. BASSLER, Princeton University, Princeton, NJ VICKI L. CHANDLER, Gordon and Betty Moore Foundation, Palo Alto, CA SEAN EDDY, HHMI Janelia Farm Research Campus, Ashburn, VA MARK D. FITZSIMMONS, John D. and Catherine T. MacArthur Foundation, Chicago, IL DAVID R. FRANZ, Midwest Research Institute, Frederick, MD LOUIS J. GROSS, University of Tennessee, Knoxville, TN JO HANDELSMAN, Yale University, New Haven, CT CATO T. LAURENCIN, University of Connecticut Health Center, Farmington, CT JONATHAN D. MORENO, University of Pennsylvania, Philadelphia, PA ROBERT M. NEREM, Georgia Institute of Technology, Atlanta, GA CAMILLE PARMESAN, University of Texas, Austin, TX MURIEL E. POSTON, Skidmore College, Saratoga Springs, NY ALLISON G. POWER, Cornell University, Ithaca, NY BRUCE W. STILLMAN, Cold Spring Harbor Laboratory, Cold Spring Harbor, NY CYNTHIA WOLBERGER, Johns Hopkins University School of Medicine, Baltimore, MD MARY WOOLLEY, Research!America, Alexandria, VA Staff FRANCES E. SHARPLES, Director JO L. HUSBANDS, Scholar/Senior Project Director ADAM P. FAGEN, Senior Program Officer MARILEE K. SHELTON-DAVENPORT, Senior Program Officer INDIA HOOK-BARNARD, Program Officer ANNA FARRAR, Financial Associate CARL-GUSTAV ANDERSON, Senior Program Assistant AMANDA P. CLINE, Senior Program Assistant REBECCA L. WALTER, Senior Program Assistant AMANDA L. MAZZAWI, Program Assistant vi

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PREFACE The US Department of Defense (DOD) is developing new efforts to protect warfighters from disease and biologic-warfare agents. The DOD Transformational Medical Technologies Initiative (TMTI) seeks to shorten the timeline for development of medical measures to counter emerging biologic-warfare threats: genetically engineered and other nontraditional toxins, virulence factors, and microorganisms. One goal of the TMTI is development of platforms for identifying unknown agents and developing countermeasures so that within five years an infrastructure will be in place for reacting quickly to a variety of threats, including agents that have been genetically engineered. In response to a request from the Office of the Secretary of Defense, the National Academies formed the Standing Committee on Biodefense at the US Department of Defense. One purpose of the standing committee is to convene periodic meetings to discuss potential avenues for research, development, demonstration, and practical operational implementation of DOD's biologic-defense programs. Another purpose is to develop and coordinate studies and other activities in this field at the National Academies. On September 15, 2008, the National Academies held the workshop “Considerations for Ensuring Safety and Efficacy of Vaccines and Therapeutic Proteins Manufactured by Using Platform Approaches”. The workshop was planned and organized by an ad hoc planning committee made up of members of the standing committee. The charge to the planning committee (see Appendix A) was to bring together scientists from academe, government, and the biotechnology industry to identify and discuss challenges and ideas related to the TMTI’s vision of developing countermeasures within a few months after an agent is identified. The workshop focused (see Appendix B for agenda) on manufacturing processes and specifically on the development of "manufacturing platforms"— repeatable components of manufacturing that reduce both development time and risk. An underlying assumption was that demonstrating that integrated platforms can reliably produce safe and efficacious countermeasures might shorten the regulatory approval process. Participants discussed manufacturing-related characteristics of monoclonal antibodies and vaccines. Although the planning committee understood that the TMTI efforts are broader than biologics and that TMTI platform approaches for biologics extend beyond monoclonal antibodies and vaccines, the planning committee believed that focusing on monoclonal antibodies and vaccines could illustrate some of the promise and challenges of platform approaches. This summary is based on a transcript of the workshop, and statements are attributed to specific participants according to the transcript. It is presented as a narrative rather than a strict chronology to highlight the major themes that emerged from the meeting. Views expressed in the summary are those of the individual participants and are not necessarily those of the planning committee, the National Academies, or the project sponsor. Jennie Hunter-Cevera, Chair Planning Group for the Workshop on Considerations for Ensuring Safety and Efficacy of Vaccines and Therapeutic Proteins Manufactured by Using Platform Approaches vii

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ACKNOWLEDGMENTS The committee thanks those who made this workshop possible through their participation—speakers and panelists (their names and biographies are available in Appendix C) and the other workshop attendees. The workshop was successful in large part owing to the advance work conducted by the workshop planning group: Jennie Hunter-Cevera, Edward J. Arcuri, Stephen W. Drew, and Peter A. Patriarca. In accordance with National Research Council policies, the workshop planners were not involved in the preparation of this summary. James A. Marks, a member of the standing committee, provided insightful comments on early drafts of the summary. This report has been reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise, in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making its published workshop summary as sound as possible and to ensure that it meets institutional standards of objectivity, evidence, and responsiveness to the charge. The review comments and the draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of this summary: L. Garry Adams, Texas A&M University Jonathan Coffman, Wyeth BioPharma Peter A. Patriarca, Biologics Consulting Group, Inc. Although the reviewers and Dr. Marks have provided many constructive comments and suggestions, they were not asked to endorse the content nor did they see a final draft of the summary before its release. The review of this summary was overseen by P. Frederick Sparling, University of North Carolina. Appointed by the National Research Council, he was responsible for making certain that an independent examination of this summary was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this summary rests entirely with the institution. ix

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CONTENTS INTRODUCTION 1 TMTI Case for Versatile Production Platforms, 2 Discussion of TMTI Efforts, 3 PLATFORMS FOR LARGE-SCALE MONOCLONAL ANTIBODY PRODUCTION 4 Presentation by Brian Kelley, 4 Presentation by Dane Zabriskie, 6 Discussion, 8 Suitability of Platforms and Supply Needed Reducing Timeline Manufacturing Production Capacity Regulatory Issues PLATFORMS FOR VACCINE PRODUCTION 11 Presentation by David Robinson, 11 Discussion, 12 Various Platforms Manufacturing Facilities Regulatory Issues SUMMARY OF KEY POINTS 15 APPENDIXES 16 A. Statement of Task, 16 B. Agenda, 17 C. Biographies, 19 xi

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