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Lyophilized Biologics and Vaccines Dushyant Varshney • Manmohan Singh Editors Lyophilized Biologics and Vaccines Modality-Based Approaches Editors Dushyant Varshney Manmohan Singh Novartis Vaccines and Diagnostics Novartis Vaccines and Diagnostics Holly Springs Holly Springs North Carolina North Carolina USA USA AND Director, Manufacturing Assessment, MS&T Hospira Lake Forest Illinois USA ISBN 978-1-4939-2382-3 ISBN 978-1-4939-2383-0 (eBook) DOI 10.1007/978-1-4939-2383-0 Library of Congress Control Number: 2015938701 Springer New York Heidelberg Dordrecht London © Springer Science+Business Media New York 2015 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recita- tion, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com) Preface Lyophilization has become a popular approach for stabilization of the biologics. In the recent years, advances in biotechnology have resulted in various modalities of antibodies, antigens, and cancer drugs being explored in the development of therapeutic proteins, effective drugs, and vaccines. Diverse forms of antibodies (e.g., monoclonal, domain, fused), complex biologics (e.g., antibody drug conju- gate, PEGylated proteins), peptides (e.g., cyclic peptides), and vaccines (e.g., com- bination type, inactivated virus, recombinant protein based) are being stabilized in the lyophilized form. Recent advances in lyophilization equipment, formulation, analytical instrumentation, delivery devices (e.g., cartridges), and manufacturing processes are being explored to overcome challenges posed by differences in the biophysical and chemical stability of each modality. The book “Lyophilized Biolog- ics and Vaccines—Modality-Based Approaches” covers advances in lyophilization theories, product and process development approaches, and delivery approaches based on new modalities of biologics and vaccines. Recent advances in alternate drying methods and bulk lyophilization are also discussed in depth. The book is composed of four major sections having a total of 17 chapters, presented by expert and world renowned authors from academia, industry, and regulatory agencies. Part I—Lyophilization History and Fundamentals is covered in five chapters. First a detail account of the historical development of lyophilization is discussed followed by recent advances in the understanding of heterogeneity of protein envi- ronment in the frozen or dried state, new developments in understanding buffer behavior and instrumental analysis of lyophilized biologics or vaccines is described. Special focus is given on recent advances in controlled ice nucleation with a specific discussion on VERISEQ® nucleation technology. Part II—Lyophilized Biologics and Vaccines—Modality Considerations are discussed in five chapters. First an overview of the challenges and developments in lyophilized formulations for different modalities of biologics or vaccines is presented. Next, recent advances in quality by design (QbD) and process analytical technology (PAT) approaches for process scale-up of therapeutic protein are discussed in depth. The chapter on lyophilized vaccine provides a complete and detailed overview of a typical vaccine product and process development, from scale-up to optimization. v vi Preface A special highlight on advances in stabilization of plasmid DNA and lipid-based therapeutics as dehydrated formulations is covered. Part III—Advances in Alternate Drying methods is covered in four chapters. A detailed account of alternate drying methods compared to traditional vial lyophilization is discussed. Some of these include sterile spray drying, sterile powder fill- ing, vacuum drying and drying on a fiber matrix. Chapters on recent advances in the spray drying, bulk freeze drying and crystallization provide an in-depth understanding of technology, challenges, and advantages, with nicely illustrated case studies. Part IV—Regulatory, Packaging, and Technology Transfer Considerations is discussed in three important chapters, providing the latest regulatory perspective on lyophilized biologics, recent trends in lyophilized delivery devices, and packaging. The chapter on lyophilization technology transfer process provides critical considerations with case studies in detail for successful process scale-up to process validation and launch of lyophilized biologics and vaccines. Dushyant Varshney Manmohan Singh Contents Part I Lyophilization History and Fundamentals History of Lyophilization ................................................................................. 3 Dushyant Varshney and Manmohan Singh Heterogeneity of Protein Environments in Frozen Solutions and in the Dried State ............................................................................................. 11 Maya Salnikova, Dushyant Varshney and Evgenyi Shalaev Advance Understanding of Buffer Behavior during Lyophilization ........... 25 Cindy Wu, Sheri Shamblin, Dushyant Varshney and Evgenyi Shalaev Advances in Instrumental Analysis Applied to the Development of Lyophilization Cycles .................................................................................. 43 William J. Kessler, Puneet Sharma and Mircea Mujat New Developments in Controlled Nucleation: Commercializing VERISEQ® Nucleation Technology ................................................................ 73 Joseph Brower, Ron Lee, Eugene Wexler, Steven Finley, Monica Caldwell and Peter Studer Part II Lyophilized Biologics and Vaccines – Modality Considerations Lyophilized Biologics ....................................................................................... 93 Byeong S. Chang, Michael Reilly, and Hana Chang Lyophilization of Therapeutic Proteins in Vials: Process Scale-Up and Advances in Quality by Design................................................ 121 Bingquan (Stuart) Wang, Timothy R. McCoy, Michael J. Pikal and Dushyant Varshney vii viii Contents Advances in Process Analytical Technology in Freeze-Drying .................. 157 Bingquan (Stuart) Wang and Timothy R. McCoy Process Scale-Up and Optimization of Lyophilized Vaccine Products ...... 179 Jeffrey T. Blue, Jessica R. Sinacola and Akhilesh Bhambhani Stabilization of Plasmid DNA and Lipid-Based Therapeutics as Dehydrated Formulations ............................................................................. 211 Marion dC. Molina, Nicole M. Payton and Thomas J. Anchordoquy Part III Advances in Alternate Drying Alternatives to Vial Lyophilization ............................................................... 257 Jim Searles and Mathew Cherian Spray-Drying of Biopharmaceuticals ........................................................... 273 Grace A. Ledet, Richard A. Graves, Levon A. Bostanian and Tarun K. Mandal Current Trends and Advances in Bulk Crystallization and Freeze-Drying of Biopharmaceuticals .......................................................... 299 Hiten Gutka and Krishna Prasad Case Studies and Examples of Biopharmaceutical Modalities Processed by Bulk Crystallization or Bulk Freeze-Drying ........................ 319 Hiten Gutka and Krishna Prasad Part IV Regulatory, Packaging and Technology Transfer Considerations Lyophilization of Biologics: An FDA Perspective ....................................... 341 David Awotwe-Otoo and Mansoor A. Khan Recent Trends in Lyophilized Delivery Devices and Packaging ................ 361 Renaud Janssen Lyophilization Process Technology Transfer Towards Product Launch .... 381 Madhav Kamat and Dushyant Varshney Index ................................................................................................................ 399 Contributors Thomas J. Anchordoquy School of Pharmacy, University of Colorado Denver, Aurora, CO, USA David Awotwe-Otoo Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA Akhilesh Bhambhani Greater Philadelphia Area, USA Jeffrey T. Blue Telford, USA Levon A. Bostanian College of Pharmacy, Center for Nanomedicine and Drug Delivery, Xavier University of Louisiana, New Orleans, LA, USA Joseph Brower IMA Life, Tonawanda, NY, USA Monica Caldwell Linde Gases, Murray Hill, NJ, USA Byeong S. Chang Integrity Bio, Inc., Camarillo, CA, USA Hana Chang Integrity Bio, Inc., Camarillo, CA, USA Mathew Cherian Hospira, Inc. One 2 One® Research and Development, Lake Forest, IL, USA Steven Finley Linde Gases, Murray Hill, NJ, USA Richard A. Graves College of Pharmacy, Center for Nanomedicine and Drug Delivery, Xavier University of Louisiana, New Orleans, LA, USA Hiten Gutka Thermalin Diabetes LLC, Cleveland, OH, USA Renaud Janssen Datwyler Pharma Packaging International NV, Alken, Belgium Madhav Kamat Kamat Pharmatech LLC, North Brunswick, NJ, USA ix x Contributors William J. Kessler Physical Sciences Inc., Andover, MA, USA Mansoor A. Khan Division of Product Quality Research, Office of Testing and Research, Office of Pharmaceutical Sciences, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD, USA Grace A. Ledet College of Pharmacy, Center for Nanomedicine and Drug Delivery, Xavier University of Louisiana, New Orleans, LA, USA Ron Lee Linde Gases, Murray Hill, NJ, USA Tarun K. Mandal College of Pharmacy, Center for Nanomedicine and Drug Delivery, Xavier University of Louisiana, New Orleans, LA, USA Timothy R. McCoy Technical Development, Genzyme Ireland Ltd. IDA Industrial Park, Waterford, Ireland Marion dC. Molina Independent Pharmaceutical Consultant, Ashland, MA, USA Mircea Mujat Physical Sciences Inc., Andover, MA, USA Nicole M. Payton School of Pharmacy, University of Colorado Denver, Aurora, CO, USA Michael J. Pikal Department of Pharmaceutical Sciences, University of Connecticut, Storrs, CT, USA Krishna Prasad Julphar Pharmaceuticals, Ras Al Khaimah, United Arab Emirates Michael Reilly Integrity Bio, Inc., Camarillo, CA, USA Maya Salnikova Novartis Vaccines and Diagnostics, Holly Springs, NC, USA Jim Searles Hospira, Inc. One 2 One® Research and Development, McPherson, KS, USA Evgenyi Shalaev Allergan, Irvine, CA, USA Sheri Shamblin Pfizer, Groton, CT, USA Puneet Sharma Genentech Inc., South San Francisco, CA, USA Jessica R. Sinacola Collegeville, USA Manmohan Singh Novartis Vaccines and Diagnostics, Holly Springs, NC, USA Peter Studer Linde Gases, Murray Hill, NJ, USA Dushyant Varshney Novartis Vaccines and Diagnostics, Holly Springs, NC, USA MS & T Hospira, Inc., Lake Forest, IL, USA