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Freeze-Drying/lyophilization of Pharmaceutical and Biological Products Second Edition, Revised and Expanded edited by Louis Rey Cabinet d 'Etudes Lausanne, Switzerland Joan C. May Center for Biologics Evaluation and Research Food and Drug Administration Rockville, Maryland, U.S.A. Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

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Page 1: Lyophilization of Pharmaceutical and Biological Products, Rey (2004)

Freeze-Drying/lyophilization of Pharmaceutical

and Biological Products Second Edition, Revised and Expanded

edited by Louis Rey

Cabinet d 'Etudes Lausanne, Switzerland

Joan C. May Center for Biologics Evaluation and Research

Food and Drug Administration Rockville, Maryland, U.S.A.

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Page 2: Lyophilization of Pharmaceutical and Biological Products, Rey (2004)

Although great care has been taken to provide accurate and current information,

neither the author(s) nor the publisher, nor anyone else associated with this publi-

cation, shall be liable for any loss, damage, or liability directly or indirectly caused or

alleged to be caused by this book. The material contained herein is not intended to

provide specific advice or recommendations for any specific situation.

Trademark notice: Product or corporate names may be trademarks or registered

trademarks and are used only for identification and explanation without intent to

infringe.

Library of Congress Cataloging-in-Publication Data

A catalog record for this book is available from the Library of Congress.

ISBN: 0-8247-4868-9

This book is printed on acid-free paper.

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Copyright � 2004 by Marcel Dekker, Inc. All Rights Reserved.

Neither this book nor any part may be reproduced or transmitted in any form or by

any means, electronic or mechanical, including photocopying, microfilming, and

recording, or by any information storage and retrieval system, without permission in

writing from the publisher.

Current printing (last digit):

10 9 8 7 6 5 4 3 2 1

PRINTED IN THE UNITED STATES OF AMERICA

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Page 3: Lyophilization of Pharmaceutical and Biological Products, Rey (2004)

DRUGS AND THE PHARMACEUTICAL SCIENCES

Executive Editor

James Swarbrick PharmaceuTech, Inc.

Pinehurst, North Carolina

Advisory Board

Larry L. Augsburger University of Maryland

Baltimore, Maryland

Jennifer B. Dressman Johann Wolfgang Goethe-University

Frankfurt, Germany

Jeffrey A. Hughes University of Florida College of Pharmacy

Gainesville, Florida

Trevor M. Jones The Association of the

British Pharmaceutical Industry London, United Kingdom

Vincent H. L. Lee University of Southern California

Los Angeles, California

Jerome P. Skelly Alexandria, Virginia

Geoffrey T. Tucker University of Sheffield

Royal Hallamshire Hospital Sheffield, United Kingdom

Harry G. Brittain Center for Pharmaceutical Physics Milford, New Jersey

Anthony J. Hickey University of North Carolina School of Pharmacy Chapel Hill, North Carolina

Ajaz Hussain U.S. Food and Drug Administration Frederick, Maryland

Hans E. Junginger LeidedAmsterdam Center for Drug Research Leiden, The Netherlands

Stephen G. Schulman University of Florida Gainesville, Florida

Elizabeth M. Topp University of Kansas School of Pharmacy Lawrence, Kansas

Peter York University of Bradford School of Pharmacy Bradford, United Kingdom

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Page 4: Lyophilization of Pharmaceutical and Biological Products, Rey (2004)

DRUGS AND THE PHARMACEUTICAL SCIENCES

1. 2.

3. 4.

5. 6.

7.

8.

9.

10.

11.

12.

13. 14.

15.

16.

17. 18.

19.

20. 21.

22.

A Series of Textbooks and Monographs

Pharmacokinetics, Milo Gibaldi and Donald Perrier Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control, Sidney H. Willig, Murray M. Tuckerman, and William S. Hitchings IV Microencapsulation, edited by J. R. Nixon Drug Metabolism: Chemical and Biochemical Aspects, Bernard Testa and Peter Jenner New Drugs: Discovery and Development, edited by Alan A. Rubin Sustained and Controlled Release Drug Delivery Systems, edited by Joseph R. Robinson Modern Pharmaceutics, edited by Gilbert S. Banker and Chris topher T. Rhodes Prescription Drugs in Short Supply: Case Histories, Michael A. Sch wartz Activated Charcoal: Antidotal and Other Medical Uses, David 0. Cooney Concepts in Drug Metabolism (in t w o parts), edited by Peter Jenner and Bernard Testa Pharmaceutical Analysis: Modern Methods (in t w o parts), edited by James W. Munson Techniques of Solubilization of Drugs, edited by Samuel H. Yalko wsky Orphan Drugs, edited by Fred €. Karch Novel Drug Delivery Systems: Fundamentals, Developmental Con- cepts, Biomedical Assessments, Yie W. Chien P h a r m a co k i net i c s : Second Ed it i o n , Revised and Expanded , Milo Gibaldi and Donald Perrier Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control, Second Edition, Revised and Expanded, Sidney H. Willig, Murray M. Tuckerman, and William S. Hitchings IV Formulation of Veterinary Dosage Forms, edited by Jack Blodinger De r m at o I og i c a I Form u I at i o n s : Per cu t a neou s Absorption , Brian W. Barry The Clinical Research Process in the Pharmaceutical Industry, edited by Gary M. Matoren Microencapsulation and Related Drug Processes, Patrick B. Deasy Drugs and Nutrients: The Interactive Effects, edited by Daphne A. Roe and T. Colin Campbell Biotechnology of Industrial Antibiotics, €rick J. Vandamme

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Page 5: Lyophilization of Pharmaceutical and Biological Products, Rey (2004)

23. Pharmaceutical Process Validation, edited by Bernard T. Loftus and Robert A. Nash

24. Anticancer and Interferon Agents: Synthesis and Properties, edited by Raphael M. Ottenbrite and George B. Butler

25. Pharmaceutical Statistics: Practical and Clinical Applications, San- ford Bolton

26. Drug Dynamics for Analytical, Clinical, and Biological Chemists, Benjamin J. Gudzino wicz, Burrows T. Younkin, Jr., and Michael J. Gudzino wicz

27. Modern Analysis of Antibiotics, edited by Adjoran Aszalos 28. Solubility and Related Properties, Kenneth C. James 29. Controlled Drug Delivery: Fundamentals and Applications, Second

Edition, Revised and Expanded, edited by Joseph R. Robinson and Vincent H. Lee

30. New Drug Approval Process: Clinical and Regulatory Management, edited by Richard A. Guarino

3 1 . Transdermal Controlled Systemic Medications, edited by Yie W. Chien 32. Drug Delivery Devices: Fundamentals and Applications, edited by

Praveen Tyle 33. Pharmacokinetics: Regulatory 0 Industrial 0 Academic Perspectives,

edited by Peter G. Welling and Francis L. S. Tse 34. Clinical Drug Trials and Tribulations, edited by Allen E. Cat0 35. Transdermal Drug Delivery: Developmental Issues and Research

Initiatives, edited by Jonathan Hadgraft and Richard H. Guy 36. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms,

edited by James W. McGinity 37. Pharmaceutical Pelletization Technology, edited by Isaac Ghebre-

Sellassie 38. Good Laboratory Practice Regulations, edited by Allen F. Hirsch 39. Nasal Systemic Drug Delivery, Yie W. Chien, Kenneth S. E. Su,

and Sh yi-Feu Chang 40. Modern Pharmaceutics: Second Edition, Revised and Expanded,

edited by Gilbert S. Banker and Christopher T. Rhodes 4 1 . Specialized Drug Delivery Systems: Manufacturing and Production

Technology, edited by Praveen Tyle 42. Topical Drug Delivery Formulations, edited by David W. Osborne

and Anton H. Amann 43. Drug Stability: Principles and Practices, Jens T. Carstensen 44. Pharmaceutical Statistics: Practical and Clinical Applications, Sec-

ond Edition, Revised and Expanded, Sanford Bolton 45. Biodegradable Polymers as Drug Delivery Systems, edited by Mark

Chasin and Robert Langer 46. Preclinical Drug Disposition: A Laboratory Handbook, Francis L. S.

Tse and James J. Jaffe 47. HPLC in the Pharmaceutical Industry, edited by Godwin W. Fong

and Stanley K. Lam

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Page 6: Lyophilization of Pharmaceutical and Biological Products, Rey (2004)

48. Pharmaceutical Bioequivalence, edited by Peter G. Welling, Francis L. S. Tse, and Shrikant V. Dinghe

49. Pharmaceutical Dissolution Testing, Umesh V. Banakar 50. Novel Drug Delivery Systems: Second Edition, Revised and

Expanded, Yie W. Chien 51. Managing the Clinical Drug Development Process, David M. Coc-

chetto and Ronald V. Nardi 52. Good Manufacturing Practices for Pharmaceuticals: A Plan for

Total Quality Control, Third Edition, edited by Sidney H. Willig and James R. Stoker

53. Prodrugs: Topical and Ocular Drug Delivery, edited by Kenneth B. Sloan 54. Pharmaceutical Inhalation Aerosol Technology, edited by Anthony

J. Hickey 55. Radiopharmaceuticals: Chemistry and Pharmacology, edited by

Adrian D. Nunn 56. New Drug Approval Process: Second Edition, Revised and

Expanded, edited by Richard A. Guarino 57. Pharmaceutical Process Validation: Second Edition, Revised and

Expanded, edited by Ira R. Berry and Robert A. Nash 58. Ophthalmic Drug Delivery Systems, edited by Ashim K. Mitra 59. Pharmaceutical Skin Penetration Enhancement, edited by Kenneth

A. Walters and Jonathan Hadgraft 60. Colonic Drug Absorption and Metabolism, edited by Peter R. Bieck 6 1 . Pharmaceutical Particulate Carriers: Therapeutic Applications,

edited by Alain Rolland 62. Drug Permeation Enhancement: Theory and Applications, edited by

Dean S. Hsieh 63. Glycopeptide Antibiotics, edited by Ramakrishnan Nagarajan 64. Achieving Sterility in Medical and Pharmaceutical Products, Nigel

A. Halls 65. Multiparticulate Oral Drug Delivery, edited by Isaac Ghebre-

Sellassie 66. Colloidal Drug Delivery Systems, edited by Jlirg Kreuter 67. Pharmacokinetics: Regulatory Industrial Academic Perspectives,

Second Edition, edited by Peter G. Welling and Francis L. S. Tse 68. Drug Stability: Principles and Practices, Second Edition, Revised

and Expanded, Jens T. Carstensen 69. Good Laboratory Practice Regulations: Second Edition, Revised and

Expanded, edited by Sandy Weinberg 70. Physical Characterization of Pharmaceutical Solids, edited by Harry

G. Brittain 7 1 . Pharmaceutical Powder Compaction Technology, edited by Goran

Alderborn and Christer Nystrom 72. Modern Pharmaceutics: Third Edition, Revised and Expanded,

edited by Gilbert S. Banker and Christopher T. Rhodes

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Page 7: Lyophilization of Pharmaceutical and Biological Products, Rey (2004)

73. Microencapsulation: Methods and Industrial Applications, edited by Simon Benita

74. Oral Mucosal Drug Delivery, edited by Michael J, Rathbone 75. Clinical Research in Pharmaceutical Development, edited by Barry

76

77

78

79

80

81

82

83

84.

85.

86. 87.

88.

89. 90.

91.

92.

93.

94.

95.

Bleidt and Michael Montagne The Drug Development Process: Increasing Efficiency and Cost Ef- fectiveness, edited by Peter G. Welling, Louis Lasagna, and Umesh V. Banakar Microparticulate Systems for the Delivery of Proteins and Vaccines, edited by Smadar Cohen and Howard Bernstein Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control, Fourth Edition, Revised and Expanded, Sid- ney H. Willg and James R. Stoker Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms: Second Edition, Revised and Expanded, edited by James W. McGinity Pharmaceutical Statistics: Practical and Clinical Applications, Third Edition, Sanford Bolton Handbook of Pharmaceutical Granulation Technology, edited by Dilip M. Parikh Biotechnology of Antibiotics: Second Edition, Revised and Ex- panded, edited by William R. Strohl Mechanisms of Transdermal Drug Delivery, edited by Russell 0. Potts and Richard H. Guy Pharmaceutical Enzymes, edited by Albert Lauwers and Simon Scharpe Development of Biopharmaceutical Parenteral Dosage Forms, edited by John A. Bontempo Pharmaceutical Project Management, edited by Tony Kennedy Drug Products for Clinical Trials: A n International Guide t o Formu- lation 0 Production 0 Quality Control, edited by Donald C. Monk- house and Christopher T. Rhodes Development and Formulation of Veterinary Dosage Forms: Second Edition, Revised and Expanded, edited by Gregory E. Hardee and J. Desmond Baggot Receptor-Based Drug Design, edited by Paul Leff Automation and Validation of Information in Pharmaceutical Pro- cessing, edited by Joseph F. deSpautz Dermal Absorption and Toxicity Assessment, edited by Michael S. Roberts and Kenneth A. Walters Pharmaceutical Experimental Design, Gareth A. Lewis, Didier Mathieu, and Roger Phan-Tan-Luu Preparing for FDA Pre-Approval Inspections, edited by Martin D. Hynes Ill Pharmaceutical Excipients: Characterization by IR, Raman, and NMR Spectroscopy, David E. Bugay and W. Paul Findlay Polymorphism in Pharmaceutical Solids, edited by Harry G. Brittain

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Page 8: Lyophilization of Pharmaceutical and Biological Products, Rey (2004)

96.

97.

98.

99. 100.

101. 102.

103.

104.

105.

106.

107.

108. 109.

110. 111.

112.

113.

114.

115.

116. 117.

118. 119.

Freeze-Drying/Lyophilization of Pharmaceutical and Biological Prod- ucts, edited by Louis Rey and Joan C. May Percutaneous Absorption: Drugs-Cosmetics-Mechanisms-Metho- dology, Third Edition, Revised and Expanded, edited by Robert L. Bronaugh and Howard I. Maibach Bioadhesive Drug Delivery Systems: Fundamentals, Novel Ap- proaches, and Development, edited by Edith Mathiowitz, Donald E. Chickering Ill, and Claus-Michael Lehr Protein Formulation and Delivery, edited by Eugene J. McNally New Drug Approval Process: Third Edition, The Global Challenge, edited by Richard A. Guarino Peptide and Protein Drug Analysis, edited by Ronald E. Reid Transport Processes in Pharmaceutical Systems, edited by Gordon 1. Amidon, Ping I. lee, and Elizabeth M. Topp Excipient Toxicity and Safety, edited by Myra L. Weiner and Lois A. Kotkoskie The Clinical Audit in Pharmaceutical Development, edited by Mich- ael R. Hamrell Pharmaceutical Emulsions and Suspensions, edited by Francoise Nielloud and Gilberte Marti-Mestres Oral Drug Absorption: Prediction and Assessment, edited by Jennifer B. Dressman and Hans Lennernas Drug Stability: Principles and Practices, Third Edition, Revised and Expanded, edited by Jens T. Carstensen and C. T. Rhodes Containment in the Pharmaceutical Industry, edited by James P. Wood Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control from Manufacturer to Consumer, Fifth Edition, Revised and Expanded, Sidney H. Willig Advanced Pharmaceutical Solids, Jens T. Carstensen Endotoxins: Pyrogens, LAL Testing, and Depyrogenation, Second Edition, Revised and Expanded, Kevin L. Williams Pharmaceutical Process Engineering, Anthony J. Hickey and David Ganderton Pharmacogenomics, edited by Werner Kalow, Urs A. Meyer, and Rachel F. Tyndale Handbook of Drug Screening, edited by Ramakrishna Seethala and Prabhava thi B. Fernandes Drug Targeting Technology: Physical Chemical Biological Meth- ods, edited by Hans Schreier Drug-Drug Interactions, edited by A. David Rodrigues Handbook of Pharmaceutical Analysis, edited by Lena Ohannesian and Anthony J. Streeter Pharmaceutical Process Scale-Up, edited by Michael Levin Dermatological and Transdermal Formulations, edited by Kenneth A. Walters

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Page 9: Lyophilization of Pharmaceutical and Biological Products, Rey (2004)

120. Clinical Drug Trials and Tribulations: Second Edition, Revised and Expanded, edited by Allen Cato, Lynda Sutton, and Allen Cat0 Ill

121. Modern Pharmaceutics: Fourth Edition, Revised and Expanded, edi- ted by Gilbert S. Banker and Christopher T. Rhodes

122. Surfactants and Polymers in Drug Delivery, Martin Malmsten 1 23. Transdermal Drug Delivery: Second Edition, Revised and Expanded,

edited by Richard H. Guy and Jonathan Hadgraft 1 24. Good Laboratory Practice Regulations: Second Edition, Revised and

Expanded, edited by Sandy Weinberg 1 25. Parenteral Quality Control: Sterility, Pyrogen, Particulate, and

Package Integrity Testing: Third Edition, Revised and Expanded, Michael J. Akers, Daniel S. Larrimore, and Dana Morton Guazzo

1 26. Modified-Release Drug Delivery Technology, edited by Michael J. Rathbone, Jonathan Hadgraft, and Michael S. Roberts

1 27. Simulation for Designing Clinical Trials: A Pharmacokinetic-Pharma- codynamic Modeling Perspective, edited by Hui C. Kimko and Ste- phen B. Duffull

1 28. Affinity Capillary Electrophoresis in Pharmaceutics and Biopharma- ceutics, edited by Reinhard H. H. Neubert and Hans-Hermann Rii ttinger

1 29. Pharmaceutical Process Validation: An International Third Edition, Re- vised and Expanded, edited by Robert A, Nash and Alfred H. Wachter

130. Ophthalmic Drug Delivery Systems: Second Edition, Revised and Expanded, edited by Ashim K. Mitra

1 3 1 . Pharmaceutical Gene Delivery Systems, edited by Alain Rolland and Sean M. Sullivan

132. Biomarkers in Clinical Drug Development, edited by John C. Bloom and Robert A. Dean

1 33. Pharmaceutical Extrusion Technology, edited by Isaac Ghebre- Sellassie and Charles Martin

1 34. Pharmaceutical Inhalation Aerosol Technology: Second Edition, Re- vised and Expanded, edited by Anthony J. Hickey

1 35. Pharmaceutical Statistics: Practical and Clinical Applications, Fourth Edition, Sanford Bolton and Charles Bon

1 36. Compliance Handbook for Pharmaceuticals, Medical Devices, and Biologics, edited by Carmen Medina

1 37. Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products: Second Edition, Revised and Expanded, edited by Louis Rey and Joan C. May

ADDITIONAL VOLUMES IN PREPARATION

New Drug Approval Process: Fourth Edition, Accelerating Global Registrations, edited by Richard A. Guarino

Microbial Contamination Control in Parenteral Manufacturing, edited by Kevin L. Williams

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Page 10: Lyophilization of Pharmaceutical and Biological Products, Rey (2004)

Foreword

Like most of today’s technological success stories, the history of freeze-

drying has been pretty much limited to the 20th century. Whereas Altmann

(1), in 1890, reported drying frozen tissues to make histological sections, it

was not until 1909 that an application to biologicals was first reported (2).

Although the first patent was filed in 1927 (3), there appears to have been

little interest in commercial uses until 1935 with a publication by Flosdorf

and Mudd (4) that introduced the concept of the cold trap. In the early

1940s Flosdorf et al. (5) in the United States and Greaves (6), working quite

independently in England, constructed plants for the large-scale production

of dried plasma for wartime use, establishing both the principles and the

commercial potential of a new industry.During the subsequent half-century, the potential of freeze-drying

captured the imagination of both scientists and industrial engineers, often

without full appreciation of the economic limitations imposed by the

immutable thermodynamic costs of freezing and the subsequent sublimation

of the frozen water. The food industry in particular was attracted by the

potential of prolonged room-temperature storage at a time when home

freezers were not yet a staple in every kitchen. It is surprising how long

it took to recognize the inappropriateness of this demanding technology for

use with a low-cost, high-volume product.It is the biological and pharmaceutical industries that have been

best able to capitalize on the unique virtues of lyophilization and that

have stimulated continuing research into the biophysics of both freezing

and freeze-drying, some of which is displayed in the initial chapters of

this volume. These are the studies that are progressively converting the

pioneering and somewhat ‘‘brute force’’ demonstrations by Flosdorf

and Greaves into modern, more finely tuned procedures, the importance

of which cannot be underestimated. At present it is the pharmaceutical

industry with its high-cost product that drives the development of this

demanding technology that is increasingly delivering great benefits to our

society.

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Page 11: Lyophilization of Pharmaceutical and Biological Products, Rey (2004)

This volume provides clear evidence of the mature state offreeze-drying technology, from the mundane to the sophisticated, allof which are essential to a quality product. And, paradoxically, it isthe potential for a high-quality product that will stimulate efforts for stillhigher quality. The more faithfully the lyophilized product resembles thestarting material, the more the focus will fall on the quality of the startingmaterial.

The ability to maintain the complex and delicate structural rela-tionships of biologically active compounds during storage at ambienttemperatures has been a boon to manufacturers but with an impact wellbeyond the manufacturing process itself. Analyses of the freeze-dryingprocess are beginning to shift from the physical aspects of freezing andsublimation to a more sophisticated examination of the effects of the processon the chemical structures and the biological properties of the productsthemselves.

It is here that the technology of freeze-drying may ultimately makeits greatest contribution. Protein function and protein conformationare inexorably linked, and the forces that maintain functional conforma-tions can be substantially and often irreversibly altered by cold and bydehydration (7,8). As those in the pharmaceutical industry look moreclosely at how these forces may be altering the structure and jeopardizingthe function of biologicals during lyophilization, they will inevitably findthat many of these alterations, particularly those induced by cold, are notlimited only to the freeze-drying process but are inherent in many of theisolation and purification procedures conducted well before final processingbegins.

An active site on a protein may be a very small proportion of thetotal molecule. Is maintaining the function of the active site good enough?Why is the rest of the molecule there? Does it make an unrecognizedcontribution and should we worry about its integrity? The human bodyis exquisitely designed to reject malformed and altered proteins. Willdenaturation of ‘‘inactive’’ portions of a protein alter its physiologicalfunction? Can such denaturation be responsible for unrelated side effects?The resolution of technical concerns such as freezing rates, drying tem-peratures, and product solubility will permit a more critical reassessment ofproduct quality.

As the technology of lyophilization is perfected, it is creating anenvironment in which attention will be increasingly focused on the stabilityof product at the molecular level, not just after or even during lyophilizationbut throughout the entire manufacturing process. The benefits to society ofsafe and more effective pharmaceuticals are indisputable and for those of us

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Page 12: Lyophilization of Pharmaceutical and Biological Products, Rey (2004)

who have participated in the development of freeze-drying technology, it isa privilege to have been part of that history.

Harold T. Meryman, M.D.Founding Member and Past-President

The Society of CryobiologyRockville, Maryland, U.S.A.

REFERENCES

1. R Altmann. ‘‘Die Elementarorganismen und ihre Beziehungen zu den Lellen.’’

Veit and Co., Leipzig, 1890.

2. L Shackell. Amer. J. Physiol. 24:325, 1909.

3. HL Tival. U.S. Patent No. 1,630,985, 1927 (and 1932, No. RE 18,364).

4. EW Flosdorf and S Mudd. J. Immunol. 29:389, 1935.

5. EW Flosdorf, F Stokes, and S Mudd. J. Amer. Med. Ass. 115:1095, 1940.

6. RIN Greaves. ‘‘The Preservation of Proteins by Drying,’’ H.M.S.O., London,

1946.

7. JF Carpenter, BS Chang. Lyophilization of protein pharmaceuticals. Bio-

technology and Biopharmaceutical Manufacturing, Processing and Preservation.

Edited by KE Avis and VL Wu, Volume 2, 199–264, 1996.

8. LI Tsonev and AG Hirsh. Fluorescence ratio intrinsic basic states analysis:

a novel approach to monitor and analyze protein unfolding by fluorescence.

J. of Biochemical and Biophysical Methods 45, Issue 1, 1–21.

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Page 13: Lyophilization of Pharmaceutical and Biological Products, Rey (2004)

Foreword

When I first became aware of the freezing process, some 30 years ago, theprocess appeared to me to be rather simple and straightforward. Atthat time I was employed by a major manufacturer of freeze-dryers butworking in the field of microelectronics. Given my background in physicalchemistry, I found myself becoming increasingly involved in the field offreeze-drying. I must admit I was surprised and somewhat puzzled to learnthat some of those using this process were experiencing difficulties. Manyformulations of lyophilized products were made isotonic and containeda host of other recipients such as bulking compounds, cryoprotectants,surfactants, and pH modifiers. It was then that I started to read publicationsconcerning the freeze-drying process, particularly those that offered anyexplanation regarding why some freeze-drying processes were not success-ful. It was at that time that I realized that the freeze-drying process wasmore complex than my first impression. That viewpoint has not been alteredand perhaps has only been reinforced as the years have passed. However,a great deal of research has been and continues to be done in this field toenhance our understanding.

The actual number of factors we should take into account with afreeze-drying or lyophilization process I simply never stopped to count. ButI am certain that they will exceed the 10 fingers on our hands. While notwishing to examine every possible aspect of this process, let me just sharewith the reader just three areas that I feel to be of major concern.

The first and foremost is the thermal properties of the formulation,without which one is reduced to process development by trial and error.With knowledge of the thermal properties, one is able to quickly developand validate a lyophilization process. Without such knowledge one has noreference point on which to rely should a change occur in the properties ofthe formulation. Knowledge of the thermal properties is paramount to thedevelopment of a lyophilization process.

The stability of a lyophilized product will be dependent on the residualmoisture content. The industry is certainly very much in need of a means

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Page 14: Lyophilization of Pharmaceutical and Biological Products, Rey (2004)

of determining the residual moisture in a product that is both nondestruc-tive and noninvasive. The method should determine the moisture withoutdestroying the dried product, nor should the measurement cause anychanges in the product properties such as a loss in activity.

Finally, although the equipment should only provide a safe environ-ment for the product and the necessary operating parameters for thelyophilization process, differences in freeze-drying equipment can affectthe process. One should be aware of such differences, especially whentransferring a process from one dryer to another. So in any discussionof the lyophilization process, the freeze-drying equipment should not beoverlooked.

It is the intent of this Foreword to provide the reader with anappreciation that considerable efforts are being made to enhance ourknowledge of the lyophilization process and its associated instrumentationand equipment. While admittedly we will need more information tocomplete our knowledge of this process, the advances described in this bookwill take us closer to achieving this final objective.

Thomas A. Jennings, Ph.D.President

The International Society for Lyophilization–Freeze-Drying, Inc.Bala Cynwyd, Pennsylvania, U.S.A.

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Page 15: Lyophilization of Pharmaceutical and Biological Products, Rey (2004)

Preface

In the middle of the 1950s, when I was actively engaged in low-temperaturepreservation of living tissues and organs, and tissue banking, I discoveredwith surprise that in 1902, in St. Petersburg, the participants of theInternational Congress on Paleontology were given mammoth meat at thebanquet. That curiosity actually came from Iakoutia, where a whole frozenmammoth suddenly appeared in the collapsed bank of a Siberian river.Apparently this body had been stored there in the permafrost for 15,000years and the wolves still found it palatable, as did the conferenceparticipants.

I learned then that this discovery was not uncommon and that, fromtime to time, well-preserved mammoth were found in Northern Siberia.Quite excited by this news I started to investigate whether I could get asample of that unique material. Numerous requests made at all levels of theadministration were fruitless and I had almost forgotten the issue when, inthe late 1960s, I received in Switzerland a big box from the USSR Academyof Sciences and—what a surprise—inside there was a big mammoth steakwith its fur still attached to the skin. Instead of being frozen it was perfectlyfreeze-dried and, of course, naturally so. Apparently the big animal hadbroken its backbone falling into a crevasse and was buried under snow,almost immediately and relatively close to the surface, where it sublimedfor millennia, which kept its anatomical features almost intact. We mademany scientific investigations of this sample and obtained excellent electronmicrographs of the dried muscles. Less successful, by far, was the ‘‘stew’’that the Nestle cooks managed to prepare with it : it definitely was nodelicacy!

Much more recently, when opening a microbiological conference inMorocco, I came across in my preparation work, on several interestingpapers dealing with lithopanspermia, the fantastic ride of living cells insuspended animation, dashing throughout outer space on a rock’s back.Quite certainly freeze-dried, they traveled there for maybe millions of yearsbefore being captured by the earth’s gravity field and falling into the depths

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Page 16: Lyophilization of Pharmaceutical and Biological Products, Rey (2004)

of the ocean, where—it is claimed by some scientists—they ‘‘seeded’’ life onour planet. Freeze-drying, as a natural phenomenon, was again in thelimelight.

A scientific curiosity for almost 40 years after the publication ofBordas and d’Arsonval in 1906, freeze-drying, later called lyophilization byEarl Flosdorf at the time of World War II, has bloomed again within thepast 20 years to become an almost unavoidable technology to preserve rareand sensitive biochemicals and drugs. Concomitantly, new challengesappeared in basic and applied engineering fields and required more andmore sophisticated approaches.

This is the reason that Joan May and I found it useful, if notcompulsory, to prepare a second edition of our 1999 book Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products. Indeed, ourunderstanding of the fundamentals of freeze-drying has been continuouslyimproving in such areas as confined water, annealing, NMR assessment ofmobility in dried products, formulation, protein stabilization, and the roleof additives. We witness rising interest in some fields which have been longconsidered as collateral but which are of prime importance today:properties and behavior of glass and elastomeres in the always presentcontainer-closer system. In parallel, industrial operations are becomingmore diversified and offer numerous different problems: scaling up towardsproduction from the laboratory bench throughout the pilot plant, cleaningand environmental concerns, and sterile handling of bulk material with theassociated qualification and validation strategies. Moreover, new technol-ogies are starting to develop: the use of co-solvents and irradiation.However, in all cases, an absolute duty of care still remains for the operatorsto provide both security and quality and keep their outgoing products in linewith the international standards, a field which is quickly expanding.

Thus, year after year, lyophilization is becoming a vast, diversifiedfield for research and development, engineering, and production, still underthe close eye of the administration and of the compliance officers.

Therefore, it comes as no surprise that the publisher and the editorsdecided to prepare this revised and expanded second edition. In so doing, itis a privilege and pleasure for Joan May and I to extend our warmappreciation to all our devoted, competent contributors and acknowledgeonce more the generous support and professional skill of the staff atMarcel Dekker, Inc.

Louis Rey, Ph.D.

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Page 17: Lyophilization of Pharmaceutical and Biological Products, Rey (2004)

Contents

Foreword Harold T. Meryman

Foreword Thomas A. Jennings

Preface Louis Rey

Contributors

1 Glimpses into the Realm of Freeze-Drying: Fundamental Issues

Louis Rey

2 Structural and Dynamic Properties of Bulk and Confined Water

M.-C. Bellissent-Funel and J. Teixeira

3 Mechanisms of Protein Stabilization During Freeze-Drying

and Storage: The Relative Importance of Thermodynamic

Stabilization and Glassy State Relaxation Dynamics

Michael J. Pikal

4 Freezing and Annealing Phenomena in Lyophilization

James A. Searles

5 Freezing- and Drying-Induced Perturbations of

Protein Structure and Mechanisms of Protein

Protection by Stabilizing Additives

John F. Carpenter, Ken-ichi Izutsu, and Theodore W. Randolph

6 Molecular Mobility of Freeze-Dried Formulations as Determined

by NMR Relaxation, and its Effect on Storage Stability

Sumie Yoshioka

7 Formulation Characterization

D. Q. Wang

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Page 18: Lyophilization of Pharmaceutical and Biological Products, Rey (2004)

8 Practical Aspects of Freeze-Drying of Pharmaceutical and

Biological Products Using Non-Aqueous Co-Solvent Systems

Dirk L. Teagarden and David S. Baker

9 Closure and Container Considerations in Lyophilization

Frances L. DeGrazio

10 Advanced Glassware for Freeze-Drying

Jurgen Thurk and Peter Knaus

11 Critical Steps in the Preparation of Elastomeric Closures for

Biopharmaceutical Freeze-Dried Products

Maninder S. Hora and Sidney N. Wolfe

12 Development of a New Concept for Bulk Freeze-Drying:

LYOGUARD� Freeze-Dry Packaging

Meagan Gassler and Louis Rey

13 Regulatory Control of Freeze-Dried Products: Importance and

Evaluation of Residual Moisture

Joan C. May

14 Freeze-Drying of Biological Standards

Paul Matejtschuk, Michelle Andersen, and Peter Phillips

15 Industrial Freeze-Drying for Pharmaceutical Applications

Georg-Wilhelm Oetjen

16 Development of Process Data in a Pilot Plant Transferable

to Production

Hanna Willemer

17 Technical Procedures for Operation of

Cleaning-in-Place/Sterilization-in-Place Process for Production

Freeze-Drying Equipment

Gilles A. Beurel

18 Global Validation of Freeze-Drying Cycle Parameters

by Using Integral HFT Systems

Gilles A. Beurel

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Page 19: Lyophilization of Pharmaceutical and Biological Products, Rey (2004)

19 Lyophilizer Qualification: Some Practical Advice

Thorsten Fischer

20 Lyophilization Process Validation

Christian Bindschaedler

21 A New Development: Irradiation of Freeze-DriedVaccine and Other Select Biological Products

Louis Rey and Joan C. May

22 Some Leading Edge Prospects in Lyophilization

Louis Rey

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Page 20: Lyophilization of Pharmaceutical and Biological Products, Rey (2004)

Contributors

Michelle Andersen Standards Division, National Institute for BiologicalStandards & Control (NIBSC), Hertfordshire, England

David S. Baker Pfizer Corporation, Kalamazoo, Michigan, U.S.A.

M.-C. Bellissent-Funel Laboratoire Leon-Brillouin (CEA-CNRS), CEASaclay, Gif-sur-Yvette, France

Gilles A. Beurel S.G.D. Serail, Argenteuil, France

Christian Bindschaedler Serono Laboratories S.A., Aubonne, Switzerland

John F. Carpenter University of Colorado Health Sciences Center,Denver, Colorado, U.S.A.

Frances L. DeGrazio West Pharmaceutical Services, Inc., Lionville,Pennsylvania, U.S.A.

Thorsten Fischer Aventis Behring GmbH, Marburg, Germany

Meagan Gassler W. L. Gore & Associates, Inc., Elkton, Maryland,U.S.A.

Maninder S. Hora Chiron Corporation, Emeryville, California, U.S.A.

Ken-ichi Izutsu University of Colorado Health Sciences Center, Denver,Colorado, U.S.A.

Peter Knaus Forma Vitrum, Schott Pharmaceutical Packaging, St. Gallen,Switzerland

Paul Matejtschuk Standards Division, National Institute for BiologicalStandards & Control (NIBSC), Hertfordshire, England

Joan C. May Center for Biologics Evaluation and Research, Food andDrug Administration, Rockville, Maryland, U.S.A.

Georg-Wilhelm Oetjen Lubeck, Germany

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.

Page 21: Lyophilization of Pharmaceutical and Biological Products, Rey (2004)

Peter Phillips Standards Division, National Institute for BiologicalStandards & Control (NIBSC), Hertfordshire, England

Michael J. Pikal School of Pharmacy, University of Connecticut, Storrs,Connecticut, U.S.A.

TheodoreW. Randolph University of Colorado, Boulder, Colorado, U.S.A.

Louis Rey Cabinet d’Etudes, Lausanne, Switzerland

James A. Searles Global Parenteral Products, Manufacturing Scienceand Technology, Eli Lilly and Company, Indianapolis, Indiana, U.S.A.

Dirk L. Teagarden Pfizer Corporation, Kalamazoo, Michigan, U.S.A.

J. Teixeira Laboratoire Leon-Brillouin (CEA-CNRS), CEA Saclay,Gif-sur-Yvette, France

Jurgen Thurk Forma Vitrum, Schott Pharmaceutical Packaging, St.Gallen, Switzerland

D. Q. Wang Bayer Corporation, Berkeley, California, U.S.A.

Hanna Willemer Koln, Germany

Sidney N. Wolfe Chiron Corporation, Emeryville, California, U.S.A.

Sumie Yoshioka National Institute of Health Sciences, Tokyo, Japan

Copyright 2004 by Marcel Dekker, Inc. All Rights Reserved.