Table Of ContentLyophilized 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
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Preface
Lyophilization has become a popular approach for stabilization of the biologics.
In the recent years, advances in biotechnology have resulted in various modali-
ties 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 be-
havior and instrumental analysis of lyophilized biologics or vaccines is described.
Special focus is given on recent advances in controlled ice nucleation with a spe-
cific discussion on VERISEQ® nucleation technology.
Part II—Lyophilized Biologics and Vaccines—Modality Considerations are dis-
cussed in five chapters. First an overview of the challenges and developments in ly-
ophilized 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 lyophili-
zation 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 understand-
ing 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 pack-
aging. 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
