Navigating the Manufacturing
Process and Ensuring the
Quality of Regenerative
Medicine Therapies
PROCEEDINGS OF A WORKSHOP
Ariel Markowitz-Shulman, Siobhan Addie, Meredith Hackmann,
Joe Alper, and Sarah H. Beachy, Rapporteurs
Forum on Regenerative Medicine
Board on Health Sciences Policy
Health and Medicine Division
THE NATIONAL ACADEMIES PRESS
Washington, DC
www.nap.edu
THE NATIONAL ACADEMIES PRESS 500 Fifth Street, NW Washington, DC 20001
This project was supported by contracts between the National Academy of Sciences and Akron Biotech (unnumbered contract); Alliance for Regenerative Medicine (unnumbered contract); The ALS Association (unnumbered contract); American Society of Gene & Cell Therapy (unnumbered contract); Burroughs Wellcome Fund (Grant #1015949); California Institute for Regenerative Medicine (unnumbered contract); Centre for Commercialization of Regenerative Medicine (unnumbered contract); Christopher & Dana Reeve Foundation (unnumbered contract); Department of Veterans Affairs (Contract No. VA268-16-C-0051); Foundation Fighting Blindness (unnumbered contract); GE Healthcare (unnumbered contract); GlaxoSmithKline (Grant ID: 015948); International Society for Stem Cell Research (unnumbered contract); Johnson & Johnson (unnumbered contract); Juno Therapeutics, Inc. (unnumbered contract); The Michael J. Fox Foundation for Parkinson’s Research (unnumbered contract); National Institute of Standards and Technology (unnumbered contract); National Institutes of Health (Contract No. HHSN263201200074I, Order No. HHSN23600075: National Heart, Lung, and Blood Institute; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Biomedical Imaging and Bioengineering; National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; and National Institute of Neurological Disorders and Stroke); The New York Stem Cell Foundation (unnumbered contract); Parkinson’s Disease Foundation (unnumbered contract); Pfizer Inc. (unnumbered contract); Takeda Pharmaceuticals U.S.A., Inc. (Contract #65317); United Therapeutics Corporation (unnumbered contract); and U.S. Food and Drug Administration (Grant #1R13FD005355-01). Any opinions, conclusions, or recommendations expressed in this publication do not necessarily reflect the views of any organization or agency that provided support for the project.
International Standard Book Number-13: 978-0-309-46647-9
International Standard Book Number-10: 0-309-46647-4
Digital Object Identifier: https://doi.org/10.17226/24913
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Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2017. Navigating the manufacturing process and ensuring the quality of regenerative medicine therapies: Proceedings of a workshop. Washington, DC: The National Academies Press. doi: https://doi.org/10.17226/24913.
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PLANNING COMMITTEE ON NAVIGATING THE MANUFACTURING PROCESS AND ENSURING THE QUALITY OF REGENERATIVE MEDICINE THERAPIES1,2
STEVEN OH (Co-Chair), Acting Deputy Director, Division of Cellular and Gene Therapies, Office of Tissues and Advanced Therapies, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration
CLAUDIA ZYLBERBERG (Co-Chair), Founder and Chief Executive Officer, Akron Biotech
JAMES BECK, Vice President, Scientific Affairs, Parkinson’s Disease Foundation
RACHEL HADDOCK, Vice President, GMP Operations, Cell and Gene Therapy, GlaxoSmithKline
CATO T. LAURENCIN, Director, Institute for Regenerative Engineering; Chief Executive Officer, Connecticut Institute for Clinical and Translational Science; Distinguished Professor of Orthopedic Surgery and Chemical, Material and Biomolecular Engineering, University of Connecticut Health Center
THOMAS PETERSEN, Vice President, Regenerative Medicine, United Therapeutics Corporation
ANNE PLANT, Chief of the Biosystems and Materials Division, National Institute of Standards and Technology
JAMES RICHARDSON, Deputy Chief, Preclinical Translational Research Programs, Foundation Fighting Blindness
KRISHNENDU ROY, Robert A. Milton Chair and Professor Technical Lead, National Cell Manufacturing Consortium, Georgia Institute of Technology
KRISHANU SAHA, Assistant Professor, Department of Biomedical Engineering, Wisconsin Institute for Discovery, University of Wisconsin–Madison
MARTHA SOMERMAN, Director, National Institute of Dental and Craniofacial Research, National Institutes of Health
JIWEN ZHANG, Senior Director, Regulatory Affairs, Cell Therapy and Regenerative Medicine, GE Healthcare
___________________
1 The National Academies of Sciences, Engineering, and Medicine’s planning committees are solely responsible for organizing the workshop, identifying topics, and choosing speakers. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution.
2 Affiliation listed at the time of the workshop.
Health and Medicine Division Staff
SARAH H. BEACHY, Project Director
ARIEL MARKOWITZ-SHULMAN, Associate Program Officer
SIOBHAN ADDIE, Program Officer
MEREDITH HACKMANN, Research Associate
HILARY BRAGG, Program Coordinator (until August 2017)
ANDREW M. POPE, Director, Board on Health Sciences Policy
FORUM ON REGENERATIVE MEDICINE1,2
R. ALTA CHARO (Co-Chair), Warren P. Knowles Professor of Law and Bioethics, School of Law and School of Medicine and Public Health, University of Wisconsin–Madison
JAY P. SIEGEL (Co-Chair), Chief Biotechnology Officer and Head, Scientific Strategy and Policy, Johnson & Johnson
JAMES C. BECK, Vice President, Scientific Affairs, Parkinson’s Disease Foundation
SANGEETA BHATIA, John J. and Dorothy Wilson Professor, Institute for Medical Engineering and Science, Electrical Engineering and Computer Science, Massachusetts Institute of Technology
LUCIE BRUIJN, Chief Scientist, The ALS Association
GEORGE Q. DALEY, Director, Stem Cell Transplantation Program, Boston Children’s Hospital and Dana-Farber Cancer Institute; Dean, Harvard Medical School
CYNTHIA DUNBAR, President, American Society of Gene & Cell Therapy
BRIAN FISKE, Senior Vice President, Research Programs, The Michael J. Fox Foundation for Parkinson’s Research
LAWRENCE GOLDSTEIN, Distinguished Professor, Department of Cellular and Molecular Medicine, Department of Neurosciences; Director, University of California, San Diego, Stem Cell Program; Scientific Director, Sanford Consortium for Regenerative Medicine; Director, Sanford Stem Cell Clinical Center, University of California, San Diego, School of Medicine
SUSAN HOWLEY, Executive Vice President, Research, Christopher & Dana Reeve Foundation
ROSEMARIE HUNZIKER, Director of Tissue Engineering and Regenerative Medicine, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health
SEIGO IZUMO, Global Head, Regenerative Medicine, Takeda Pharmaceuticals International, Inc.
RUSSELL KELLEY, Program Officer, Interfaces in Science and Regulatory Science, Burroughs Wellcome Fund
AUDREY KUSIAK, Scientific Program Manager, Rehabilitation Research and Development Service, Office of Research and Development, Department of Veterans Affairs
___________________
1 The National Academies of Sciences, Engineering, and Medicine’s forums and roundtables do not issue, review, or approve individual documents. The responsibility for the published Proceedings of a Workshop rests with the workshop rapporteurs and the institution.
2 Affiliation listed at the time of the workshop.
ROBERT S. LANGER, David H. Koch Institute Professor, Massachusetts Institute of Technology
CATO T. LAURENCIN, Director, Institute for Regenerative Engineering; Chief Executive Officer, Connecticut Institute for Clinical and Translational Science; Distinguished Professor of Orthopedic Surgery and Chemical, Material and Biomolecular Engineering, University of Connecticut Health Center
JOHN LEPORE, Senior Vice President, Research and Development Pipeline, GlaxoSmithKline
MARTHA LUNDBERG, Program Director, Division of Cardiovascular Sciences, Advanced Technologies and Surgery Branch, National Heart, Lung, and Blood Institute, National Institutes of Health
TERRY MAGNUSON, Sarah Graham Kenan Professor, Vice Chancellor for Research, University of North Carolina at Chapel Hill
MICHAEL MAY, President and Chief Executive Officer, Centre for Commercialization of Regenerative Medicine
DAVID OWENS, Acting Deputy Director, Division of Extramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health
DIANA PANEKVICH, Director, Science Policy and Advocacy, Pfizer Inc.
DUANQING PEI, Director General, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences
THOMAS PETERSEN, Vice President, Regenerative Medicine, United Therapeutics Corporation
ANNE PLANT, Chief of the Biosystems and Materials Division, National Institute of Standards and Technology
HEATHER ROOKE, Scientific Director, International Society for Stem Cell Research
STEPHEN ROSE, Chief Research Officer, Foundation Fighting Blindness
KRISHNENDU ROY, Robert A. Milton Chair in Biomedical Engineering; Technical Lead, National Cell Manufacturing Consortium; Director, Marcus Center for Therapeutic Cell Characterization and Manufacturing, Georgia Institute of Technology
KRISHANU SAHA, Assistant Professor, Department of Biomedical Engineering, Wisconsin Institute for Discovery, University of Wisconsin–Madison
ELIZABETH SMITH, Senior Vice President of Regulatory and Quality Assurance, Juno Therapeutics, Inc.
MARTHA SOMERMAN, Director, National Institute of Dental and Craniofacial Research, National Institutes of Health
SOHEL TALIB, Scientific Program Officer, California Institute for Regenerative Medicine
SHARON TERRY, President and Chief Executive Officer, Genetic Alliance
MICHAEL WERNER, Executive Director, Alliance for Regenerative Medicine
CELIA WITTEN, Deputy Director, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration
MICHAEL YAFFE, Vice President, Scientific Programs, The New York Stem Cell Foundation
JIWEN ZHANG, Senior Director, Regulatory Affairs, Cell Therapy and Regenerative Medicine, GE Healthcare
CLAUDIA ZYLBERBERG, Founder and Chief Executive Officer, Akron Biotech
Forum on Regenerative Medicine Staff
SARAH H. BEACHY, Project Director
ARIEL MARKOWITZ-SHULMAN, Associate Program Officer
SIOBHAN ADDIE, Program Officer
MEREDITH HACKMANN, Research Associate
REBECCA RAY, Senior Program Assistant (from August 2017)
HILARY BRAGG, Program Coordinator (until August 2017)
ANDREW M. POPE, Director, Board on Health Sciences Policy
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Reviewers
This Proceedings of a Workshop was reviewed in draft form by individuals chosen for their diverse perspectives and technical expertise. The purpose of this independent review is to provide candid and critical comments that will assist the National Academies of Sciences, Engineering, and Medicine in making each published proceedings as sound as possible and to ensure that it meets the institutional standards for quality, objectivity, evidence, and responsiveness to the charge. The review comments and draft manuscript remain confidential to protect the integrity of the process.
We thank the following individuals for their review of this proceedings:
STEWART ABBOT, Fate Therapeutics
THOMAS BOLLENBACH, Advanced Regenerative Manufacturing Institute
JOSEPH GOLD, City of Hope
JAMES RICHARDSON, Foundation Fighting Blindness
Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the content of the proceedings nor did they see the final draft before its release. The review of this proceedings was overseen by HAROLD J. FALLON, Medical University of South Carolina. He was responsible for making certain that an independent examination of this proceedings was carried out in accordance with standards of the National Academies and that all review comments were carefully considered. Responsibility for the final content rests entirely with the rapporteurs and the National Academies.
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Acknowledgments
The support of the sponsors of the Forum on Regenerative Medicine was crucial to the planning and conduct of the workshop, Navigating the Manufacturing Process and Ensuring the Quality of Regenerative Medicine Therapies, and for the development of this Proceedings of a Workshop. Federal sponsors were the Department of Veterans Affairs; National Institute of Standards and Technology; National Institutes of Health: National Heart, Lung, and Blood Institute; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Biomedical Imaging and Bioengineering; National Institute of Dental and Craniofacial Research; National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Neurological Disorders and Stroke; and U.S. Food and Drug Administration. Nonfederal sponsorship was provided by Akron Biotech; Alliance for Regenerative Medicine; The ALS Association; American Society of Gene & Cell Therapy; Burroughs Wellcome Fund; California Institute for Regenerative Medicine; Centre for Commercialization of Regenerative Medicine; Christopher & Dana Reeve Foundation; Foundation Fighting Blindness; GE Healthcare; GlaxoSmithKline; International Society for Stem Cell Research; Johnson & Johnson; Juno Therapeutics, Inc.; The Michael J. Fox Foundation for Parkinson’s Research; The New York Stem Cell Foundation; Parkinson’s Disease Foundation; Pfizer Inc.; Takeda Pharmaceuticals U.S.A., Inc.; and United Therapeutics Corporation.
The Forum on Regenerative Medicine wishes to express gratitude to the expert speakers who explored the opportunities and challenges associated
with manufacturing regenerative medicine therapies and related technologies. The forum also wishes to thank the members of the planning committee for their work in developing an excellent workshop agenda. The project director would like to thank the project staff who worked diligently to develop both the workshop and the resulting Proceedings of a Workshop.
Contents
Organization of the Proceedings of a Workshop
2 TRANSITIONING FROM DISCOVERY AND DEVELOPMENT TO MANUFACTURING
Transitioning Engineered T Cells from Discovery to Manufacturing and Regulatory Approval
Learning from Past Experiences in Vascular Engineering
Getting to the Factory of the Future
3 IDENTIFYING AND MEASURING CRITICAL QUALITY ATTRIBUTES
Achieving Confidence in Measurements for Regenerative Medicine Products
4 DESIGNING TECHNOLOGIES TO MEET THE MANUFACTURING NEEDS OF NEW REGENERATIVE MEDICINE THERAPIES
Models for Manufacturing Cell Therapy Products
The Role of Automation in Manufacturing
Scaling Personalized Cell Therapy Manufacturing
5 CONSIDERATIONS FOR IMPROVING AND REGULATING REGENERATIVE MEDICINE PRODUCTS
Improving Stem Cell–Based Products: Perspectives from a Patient-Centric Research Organization
Strategies to Improve Characterization of Stem Cell–Based Products
Regulatory Implications for Development and Global Manufacturing of Regenerative Medicine Products
Fostering Innovation and Collaboration: An Interdisciplinary Approach to Regenerative Medicine
Reflections and Take-Away Messages from the Workshop
Boxes, Figures, and Table
BOXES
1-1 Objectives of the Workshop
2-1 Suggested Ways for the Field of Regenerative Medicine to Move Forward
3-1 Example of Questions Addressed in a Target Product Profile
FIGURES
2-1 Using a protocol for consistent transduced T cell product from individual patient material
3-1 Total number of academic versus industry-sponsored cell therapy trials, listed in databases
4-1 CAR T cell manufacturing flow at Memorial Sloan Kettering
Acronyms and Abbreviations
aHSCT |
autologous hematopoietic stem cell transplantation |
ALL |
acute lymphocytic leukemia |
ARMI |
Advanced Regenerative Manufacturing Institute |
BLA |
biologics license application |
CAR |
chimeric antigen receptor |
CFR |
Code of Federal Regulations |
CMC |
chemistry, manufacturing, and control |
CQA |
critical quality attribute |
FDA |
U.S. Food and Drug Administration |
FIRST |
For Inspiration and Recognition of Science and Technology |
GMP |
good manufacturing practice |
HIV |
human immunodeficiency virus |
HLA |
human leukocyte antigen |
IND |
investigational new drug |
IP |
intellectual property |
iPSC |
induced pluripotent stem cell |
ISBT |
Information Standard for Blood and Transplant |
MS |
multiple sclerosis |
MSC |
mesenchymal stem/stromal cell |
NEDA |
no evidence of disease activity |
NIIMBL |
National Institute for Innovation in Manufacturing Biopharmaceuticals |
NIST |
National Institute of Standards and Technology |
RCR |
replication competent retroviral |
STEM |
science, technology, engineering, and mathematics |
URS |
user requirement specification |
USP |
U.S. Pharmacopeia |
WHO |
World Health Organization |