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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
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Page viii Cite
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
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Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
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Page R9
Suggested Citation:"Front Matter." National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. doi: 10.17226/26009.
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Committee to Identify Innovative Technologies to Advance Pharmaceutical Manufacturing Board on Chemical Sciences and Technology Division on Earth and Life Studies A Consensus Study Report of

THE NATIONAL ACADEMIES PRESS   500 Fifth Street, NW   Washington, DC 20001 This project was supported by Contract 75F40119C10045 between the National Academies of Sciences, Engineering, and Medicine and the Department of Health and Human Services. Any opinions, findings, conclusions, or recommendations expressed in this publication are those of the authors and do not necessarily reflect the view of the organizations or agencies that provided support for this project. International Standard Book Number-13: 978-0-309-08867-1 International Standard Book Number-10: 0-309-08867-4 Digital Object Identifier: https://doi.org/10.17226/26009 Additional copies of this publication are available from the National Academies Press, 500 Fifth Street, NW, Keck 360, Washington, DC 20001; (800) 624-6242 or (202) 334-3313; http://www.nap.edu. Copyright 2021 by the National Academy of Sciences. All rights reserved. Printed in the United States of America Suggested citation: National Academies of Sciences, Engineering, and Medicine. 2021. Innovations in Pharmaceutical Manufacturing on the Horizon: Technical Challenges, Regulatory Issues, and Recommendations. Washington, DC: The National Academies Press. https://doi.org/10.17226/26009.

The National Academy of Sciences was established in 1863 by an Act of Congress, signed by President Lincoln, as a private, nongovernmental institution to advise the nation on issues related to science and technology. Members are elected by their peers for outstanding contributions to research. Dr. Marcia McNutt is president. The National Academy of Engineering was established in 1964 under the charter of the National Academy of Sciences to bring the practices of engineering to advising the nation. Members are elected by their peers for extraordinary contributions to engineering. Dr. John L. Anderson is president. The National Academy of Medicine (formerly the Institute of Medicine) was established in 1970 under the charter of the National Academy of Sciences to advise the nation on medical and health issues. Members are elected by their peers for distinguished contributions to medicine and health. Dr. Victor J. Dzau is president. The three Academies work together as the National Academies of Sciences, Engineering, and Medicine to provide independent, objective analysis and advice to the nation and conduct other activities to solve complex problems and inform public policy decisions. The National Academies also encourage education and research, recognize outstanding contributions to knowledge, and increase public understanding in matters of science, engineering, and medicine. Learn more about the National Academies of Sciences, Engineering, and Medicine at www.nationalacademies. org.

Consensus Study Reports published by the National Academies of Sciences, Engineering, and Medicine document the evidence-based consensus on the study’s statement of task by an authoring committee of ex- perts. Reports typically include findings, conclusions, and recommendations based on information gathered by the committee and the committee’s deliberations. Each report has been subjected to a rigorous and independent peer-review process and it represents the position of the National Academies on the statement of task. Proceedings published by the National Academies of Sciences, Engineering, and Medicine chronicle the pre- sentations and discussions at a workshop, symposium, or other event convened by the National Academies. The statements and opinions contained in proceedings are those of the participants and are not endorsed by other participants, the planning committee, or the National Academies. For information about other products and activities of the National Academies, please visit www.nation- alacademies.org/about/whatwedo.

COMMITTEE TO IDENTIFY INNOVATIVE TECHNOLOGIES TO ADVANCE PHARMACEUTICAL MANUFACTURING1 Members GINTARAS REKLAITIS (NAE) (Chair), Purdue University, IN TIMOTHY CHARLEBOIS, Pfizer Inc, MA MATTHEW DELISA, Cornell University, NY CHRISTOPHER EARNHART, U.S. Army, Department of Defense, MD STEPHEN W. HADLEY, Bill & Melinda Gates Foundation, WA ARLENE JOYNER, U.S. Department of Health and Human Services, Washington, DC KATHERINE LEWIS, Lawrence Livermore National Laboratory, CA PAUL MORT, Purdue University, IN TODD PRZYBYCIEN, Rensselaer Polytechnic Institute, NY KELLEY ROGERS, National Institute of Standards and Technology, MD SALY ROMERO-TORRES, Thermo Fisher Scientific, NC GREGORY STEPHANOPOULOS (NAE), Massachusetts Institute of Technology, MA SEONGKYU YOON, University of Massachusetts Lowell, MA Staff ELLEN K. MANTUS, Project Director MARILEE SHELTON-DAVENPORT, Senior Program Officer RADIAH ROSE-CRAWFORD, Manager, Editorial Projects KESIAH CLEMENT, Senior Program Assistant Sponsor FOOD AND DRUG ADMINISTRATION 1 See Appendix B, Disclosure of Conflict(s) of Interest. v

BOARD ON CHEMICAL SCIENCES AND TECHNOLOGY Co-Chairs SCOTT COLLICK, DuPont JENNIFER SINCLAIR CURTIS, University of California, Davis Members GERARD BAILLELY, Procter and Gamble RUBEN G. CARBONELL (NAE), North Carolina State University JOHN FORTNER, Yale School of Engineering and Applied Science SAMUEL H. GELLMAN (NAS), University of Wisconsin-Madison KAREN I. GOLDBERG (NAS), University of Pennsylvania TIMOTHY HALL, McNesse State University MIRIAM E. JOHN, Sandia National Laboratories (Ret.) JODIE L. LUTKENHAUS, Texas A&M University JOSEPH B. POWELL, Shell Global PETER ROSSKY (NAS), Rice University REBECCA T. RUCK, Merck Process Research & Development RICHMOND SARPONG, University of California, Berkeley VIJAY SWARUP, ExxonMobil SALY ROMERO-TORRES, Thermo Fisher Scientific Staff JEREMY T. MATHIS, Board Director ELLEN MANTUS, Scholar MARILEE SHELTON-DAVENPORT, Senior Program Officer MAGGIE WALSER, Senior Program Officer NICHOLAS ROGERS, Financial Associate JESSICA WOLFMAN, Research Associate KESIAH CLEMENT, Senior Program Assistant SARAH HARPER, Program Assistant OLIVIA TORBERT, Program Assistant BENJAMIN ULRICH, Program Assistant ELISE ZAIDI, Communications & Media Associate vi

Acknowledgments This Consensus Study Report was reviewed in draft form by persons chosen for their diverse perspectives and tech- nical 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 report as sound as possible and to ensure that it meets institutional standards of quality, objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We thank the following for their review of this report: Matthew Bio, Snapdragon Chemistry Richard D. Braatz (NAE), Massachusetts Institute of Technology Barry Coller (NAS/NAM), The Rockefeller University Margaret Hamburg (NAM), National Academy of Medicine Klavs Jensen (NAS/NAE), Massachusetts Institute of Technology Christine Moore, Merck Jean Tom (NAE), Bristol-Myers Squibb Greg Troiano, BIND Therapeutics Although the reviewers listed above provided many constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations of this report, nor did they see the final draft before its release. The review of the report was overseen by Babatunde A. Ogunnaike (NAE) and Stephen W Drew (NAE) who were responsible for making certain that an independent examination of the report was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content rests entirely with the author- ing committee and the National Academies. The completion of this study would not have been successful without the assistance of many individuals and organizations. The committee thanks especially the following for their contributions: Noubar Afeyan, Flagship Pioneering; Karin Balss, Janssen; Akilesh Bhambhani, Merck; Dan Blackwood, Pfizer; Andy Bommarius, Georgia Institute of Technology; Richard Braatz, Massachusetts Institute of Technology; Jon Coffman, AstraZeneca; Paul Collins, Lilly; Mauricio Futran, Janssen; David Gaugh, Association for Accessible Medicines; Susan Hershenson, Bill & Melinda Gates Foundation; Jun Huang, Pfizer; Günter Jagschies, GE Healthcare (Retired); Amy Jenkins, Defense Advanced Research Projects Agency; Mansoor Khan, Texas A&M University; Michael Kopcha, Food and Drug Administration (FDA); Richard Korsmeyer, Consultant; Sau (Larry) Lee, FDA; David Lechuga-Ballesteros, AstraZeneca; Kelvin Lee, University of Delaware; Brent Lieffers, Singota Solutions; Kerry Love, Sunflower Therapeutics; Gustavo Mahler, Dynamk Capital; Salvatore Mascia, Continuus; Christine Moore, Merck; Steve Nail, Baxter; Roger Nosal, Pfizer; Gregg Nyberg, Merck; Lisa Parks, Association for Accessible Medicines; Jack Prior, Sanofi; Govind Rao, University of Maryland; John Schiel, National Institute of Standards and Technology; Patricia Seymour, BDO; Jason Starkey, Pfizer; Patrick Swann, Amgen; Jim Thomas, Just – Evotec Biologics; Jorg Thommes, Bill & Melinda Gates Medical Research Institute; Jean Tom, Bristol-Myers Squibb; Katherine Tyner, FDA; Kim Wolfram, Biogen; Janet Woodcock, FDA; Jae Yoo, Aprecia; and Ping Zhao, Bill & Melinda Gates Foundation. vii

Contents SUMMARY.................................................................................................................................................................................1 1 INTRODUCTION........................................................................................................................................................7 The Pharmaceutical Industry Today and Innovation, 7 The Food and Drug Administration and Innovation, 8 Statement of Task, 8 The Committee’s Approach to Its Task, 8 Organization of This Report, 9 References, 9 2 INNOVATIONS IN MANUFACTURING DRUG SUBSTANCES........................................................................12 Unit Operations, 12 Process Intensification, 14 Process Innovations That Create New Stream Compositions, 17 Overcoming Regulatory Challenges, 20 References, 20 3 INNOVATIONS IN MANUFACTURING DRUG PRODUCTS............................................................................23 Innovations in Manufacturing Approaches for Conventional Drug Products, 23 Enabling New Forms of Drug Products, 26 Enabling New Drug-Product Formulations: Novel Excipients, 29 Overcoming Regulatory Challenges, 32 References, 33 4 NEW CONTROL APPROACHES TO ENABLE QUALITY ASSURANCE AND PROCESS CAPABILITY..............................................................................................................................................................36 Systems, 36 Sensors, 37 Data Analytics and System Modeling, 39 Overcoming Regulatory Challenges, 44 References, 45 5 INNOVATIONS IN INTEGRATED, FLEXIBLE, AND DISTRIBUTED MANUFACTURING NETWORKS...............................................................................................................................................................48 End-To-End Systems, 48 Modular Systems, 50 Highly Portable Systems, 51 Key Technical Challenges for Innovations, 52 Key Regulatory Challenges to Innovations, 55 Overcoming Regulatory Challenges, 57 References, 58 ix

x Contents 6 ADVANCING INNOVATION: OBSERVATIONS, CHALLENGES, OPPORTUNITIES, AND RECOMMENDATIONS...................................................................................................................................60 Key Manufacturing Innovations, 61 The Effect of Product Review and Approval as the Basis of Acceptance and Implementation of Manufacturing Technology, 63 The Need for Incentives to Advance Technology Innovation, 63 The Need for Global Convergence and Harmonization, 65 Post-Approval Changes: Essential for Accelerating Innovation, 66 Challenges Within the Sphere of FDA Influence in Supporting and Enabling Innovation, 66 Committee Recommendations, 68 References, 71 APPENDIXES A BIOGRAPHIC INFORMATION ON THE COMMITTEE TO IDENTIFY INNOVATIVE TECHNOLOGIES TO ADVANCE PHARMACEUTICAL MANUFACTURING..............................................72 B DISCLOSURE OF UNAVOIDABLE CONFLICTS OF INTEREST....................................................................76 C WORKSHOP AND WEBINAR AGENDAS.............................................................................................................77 D INNOVATIONS IN PHARMACUETICAL MANUFACTURING: PROCEEDING OF A WORKHSOP—IN BRIEF.........................................................................................................................................84 E BARRIERS TO INNOVATIONS IN PHARMACEUTICAL MANUFACTURING: PROCEEDINGS OF A WORKSHOP—IN BRIEF.................................................................................................97

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In 2002, the U.S. Food and Drug Administration (FDA) launched the Pharmaceutical Quality for the 21st Century Initiative to encourage adoption of innovative technologies that would lead to an agile, flexible pharmaceutical manufacturing sector. The goal was to encourage a transition to manufacturing processes and approaches that could produce high-quality drugs reliably without extensive regulatory oversight. Much progress has been made toward that goal as the industry has developed and advanced new technologies, but more progress is required as recent natural disasters and the coronavirus pandemic have revealed vulnerabilities in supply chains and highlighted the need to modernize pharmaceutical manufacturing further.

At the request of the FDA Center for Drug Evaluation and Research (CDER), Innovations in Pharmaceutical Manufacturing on the Horizon identifies emerging technologies - such as product technologies, manufacturing processes, control and testing strategies, and platform technologies - that have the potential to advance pharmaceutical quality and modernize pharmaceutical manufacturing for products regulated by CDER. This report describes many innovations to modernize the manufacture of drug substances and drug products, to advance new control approaches, and to develop integrated, flexible, and distributed manufacturing networks within 5-10 years.

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