Lyophilization of Pharmaceutical and Biological Products

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Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]1999[/DP]End of Citation

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DRUGS AND THE PHARMACEUTICAL SCIENCES Executive Editor James Swarbrick AAl, Inc. Wilmington, North Carolina Advisory Board Larry L. Augsburger University of Maryland Baltimore, Maryland Douwe D. Breimer Gorlaeus Laboratories Leiden, The Netherlands Trevor M. Jones The Association of the British Pharmaceutical Industry London, United Kingdom Hans E. Junginger Leiden/Amsterdam Center for Drug Research Leiden, The Netherlands Vincent H. L. Lee University of Southern California Los Angeles, California David E. Nichols Purdue University West Lafayette, Indiana Stephen G. Schulman University of Florida Gainesville, Florida Jerome P. Skelly Copley Pharmaceutical, Inc. Canton, Massachusetts Felix Theeuwes Alza Corporation Palo Alto, California Geoffrey T. Tucker University of Sheffield Royal Hallamshire Hospital Sheffield, United Kingdom

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Peter G. Welling Institut de Recherche Jouveinal Fresnes, France

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DRUGS AND THE PHARMACEUTICAL SCIENCES A Series of Textbooks and Monographs 1. Pharmacokinetics, Milo Gibaldi and Donald Perrier 2. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control, Sidney H. Willig, Murray M. Tuckerman, and William S. Hitchings IV 3. Microencapsulation, edited by J. R. Nixon 4. Drug Metabolism: Chemical and Biochemical Aspects, Bernard Testa and Peter Jenner 5. New Drugs: Discovery and Development, edited by Alan A. Rubin 6. Sustained and Controlled Release Drug Delivery Systems, edited by Joseph R. Robinson 7. Modern Pharmaceutics, edited by Gilbert S. Banker and Christopher T. Rhodes 8. Prescription Drugs in Short Supply: Case Histories, Michael A. Schwartz 9. Activated Charcoal: Antidotal and Other Medical Uses, David O. Cooney 10. Concepts in Drug Metabolism (in two parts), edited by Peter Jenner and Bernard Testa 11. Pharmaceutical Analysis: Modern Methods (in two parts), edited by James W. Munson 12. Techniques of Solubilization of Drugs, edited by Samuel H. Yalkowsky 13. Orphan Drugs, edited by Fred E. Karch 14. Novel Drug Delivery Systems: Fundamentals, Developmental Concepts, Biomedical Assessments, Yie W. Chien 15. Pharmacokinetics: Second Edition, Revised and Expanded, Milo Gibaldi and Donald Perrier 16. 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 17. Formulation of Veterinary Dosage Forms, edited by Jack Blodinger 18. Dermatological Formulations: Percutaneous Absorption, Brian W. Barry 19. The Clinical Research Process in the Pharmaceutical Industry, edited by Gary M. Matoren 20. Microencapsulation and Related Drug Processes, Patrick B. Deasy 21. Drugs and Nutrients: The Interactive Effects, edited by Daphne A. Roe and T. Colin Campbell

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22. Biotechnology of Industrial Antibiotics, Erick J. Vandamme 23. Pharmaceutical Process Validation, edited by Bernard T. Loftus and Robert A. Nash 24. Anticancer and Antiferon Agents: Synthesis and Properties, edited by Raphael M. Ottenbrite and George B. Butler 25. Pharmaceutical Statistics: Practical and Clinical Applications, Sanford Bolton 26. Drug Dynamics for Analytical, Clinical, and Biological Chemists, Benjamin J. Gudzinowicz, Burrows T. Younkin, Jr., and Michael J. Gudzinowicz 27. Modern Analysis of Antibiotics, edited by Adjoran Aszalos 28. Soulbility 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 31. Transdermal Controlled Systemic Medications, edited by Yie W. Chien 32. Drug Delivery Devices: Fundamentals and Applications, edited by Praveen Tyle 33. Pharmacokinetics: Regulatory • Industrial • Academic Perspectives, edited by Peter G. Welling and Francis L.S. Tse 34. Clinical Drug Trials and Tribulations, edited by Allen E. Cato 35. Transdermal Drug Delivery: Developmental Issues and Research Initiatives, edited by Joonathan 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 Shyi-Feu Chang 40. Modern Pharmaceutics: Second Edition, Revised and Expanded, edited by Gilbert S. Banker and and Christopher T. Rhodes 41. 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. Cartensen 44. Pharmaceutical Statistics: Practical and Clinical Applications, Second Edition, Revised and Expanded, Sanford Bolton

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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

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47. HPLC in the Pharmaceutical Industry, edited by Godwin W. Fong and Stanley K. Lam 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. Cochetto and Ronald V. Nardi 52. Good Manufacturing Processes 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. Opthalmic 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 61. 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. Mulitparticulate Oral Drug Delivery, edited by Isaac Ghebre-Sellasie 66. Colloidal Drug Delivery Systems, edited by Jörg 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 J. Brittain 71. Pharmaceutical Powder Compaction Technology, edited by Göran Alderborn and Christer Nyström http://emedia.netlibrary.com/nlreader/nlreader.dll?bookid=11507&filename=cover-4.html PDF 文件使用 "FinePrint pdfFactory Pro" 试用版本创建 www.fineprint.com.cn

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72. Modern Pharmaceutics: Third Edition, Revised and Expanded, edited by Gilbert S. Banker and Christopher T. Rhodes 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 Bleidt and Michael Montagne 76. The Drug Development Process: Increasing Efficiency and Cost Effectiveness, edited by Peter G. Welling, Louis Lasagna, and Umesh V. Banakar 77. Microparticulate Systems for the Delivery of Proteins and Vaccines, edited by Smadar Cohen and Howard Bernstein 78. Good Manufacturing Practices for Pharmaceuticals: A Plan for Total Quality Control, Fourth Edition, Revised and Expanded, Sidney H. Willig and James R. Stoker 79. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms: Second Edition, Revised and Expanded, edited by James W. McGinity 80. Pharmaceutical Statistics: Practical and Clinical Applications, Third Edition, Sanford Bolton 81. Handbook of Pharmaceutical Granulation Technology, edited by Dilip M. Parikh 82. Biotechnology of Antibiotics: Second Edition, Revised and Expanded, edited by William R. Strohl 83. Mechanisms of Transdermal Drug Delivery, edited by Russell O. Potts and Richard H. Guy 84. Pharmaceutical Enzymes, edited by Albert Lauwers and Simon Scharpé 85. Development of Biopharmaceutical Parenteral Dosage Forms, edited by John A. Bontempo 86. Pharmaceutical Project Management, edited by Tony Kennedy 87. Drug Products for Clinical Trials: An International Guide to Formulation • Production • Quality Control, edited by Donald C. Monkhouse and Christopher T. Rhodes 88. Development and Formulation of Veterinary Dosage Forms: Second Edition, Revised and Expanded, edited by Gregory E. Hardee and J. Desmond Baggot 89. Receptor-Based Drug Design, edited by Paul Leff 90. Automation and Validation of Information in Pharmaceutical Processing, edited by Joseph F. deSpautz 91. Dermal Absorption and Toxicity Assessment, edited by Michael S. Roberts and Kenneth A. Walters 92. Pharmaceutical Experimental Design, Gareth A. Lewis, Didier Mathieu, and Roger PhanTan-Luu 93. Preparing for FDA Pre-Approval Inspections, edited by Martin D. Hynes III

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94. Pharmaceutical Excipients: Characterization by IR, Raman, and NMR Spectroscopy, David E. Bugay and W. Paul Findlay 95. Polymorphism in Pharmaceutical Solids, edited by Harry G. Brittain 96. Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products, edited by Louis Rey and Joan C. May 97. Percutaneous Absorption: Drugs— Cosmetics— Mechanisms— Methodology, Third Edition, Revised and Expanded, edited by Robert L. Bronaugh and Howard l. Maibach ADDITIONAL VOLUMES IN PREPARATION Transport Processes in Pharmaceutical Systems, edited by Gordon Amidon, Ping L Lee, and Elizabeth M. Topp Bioadhesive Drug Delivery Systems: Fundamentals, Novel Approaches, and Development, edited by Edith Mathiowitz, Donald E. Chickering, and Claus-Michael Lehr Peptide and Protein Drug Analysis, edited by Ronald E. Reid Protein Formulation and Stability, edited by Eugene McNally New Drug Approval Process: Third Edition, Revised and Expanded, edited by Richard A. Guarino Excipient Toxicity and Safety, edited by Myra Weiner and Lois Kotkoskie

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Page i

Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products edited by Louis Rey Cabinet d É tudes Lausanne, Switzerland Joan C. May Food and Drug Administration Rockville, Maryland

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Page ii

ISBN: 0-8247-1983-2 This book is printed on acid-free paper. Headquarters Marcel Dekker, Inc. 270 Madison Avenue, New York, NY 10016 tel: 212-696-9000; fax: 212-685-4540 Eastern Hemisphere Distribution Marcel Dekker AG Hutgasse 4, Postfach 812, CH-4001 Basel, Switzerland tel: 41-61-261-8482; fax: 41-61-261-8896 World Wide Web http://www.dekker.com The publisher offers discounts on this book when ordered in bulk quantities. For more information, write to Special Sales/Professional Marketing at the headquarters address above. Copyright © 1999 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

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Page iii

Preface Since its discovery by Altman at the turn of the century and its subsequent development by Gersh, freeze-drying has been used for the preservation of delicate biologicals and biochemicals that present a high instability at room temperature because of their important water content. More or less considered a laboratory curiosity until the end of the 1930s, drying from the frozen state underwent striking development during the last world war. Under the impetus of Earl Flosdorf in the United States, Ronald Greaves in the United Kingdom, and François Henaff in France, it became a routine technology for the preparation of blood plasma and plasma fractions, which were of massive use on most battlefields and saved millions of lives throughout the world. The process was then named lyophilization since it helped to prepare dry products with a great affinity for their hydrated solvants. Later, the late Sir Ernst Boris Chain, Nobel Laureate, applied freeze-drying for the first time for the preservation of the newly discovered penicillin, and less than a decade later it became commonly used for the stabilization of vaccines, thanks to Charles Merieux and his associates. At the same time, on a purely engineering basis, extensive work was conducted in all major developed countries to design and build large-scale reliable freeze-drying plants that were able to handle batches of several tens— sometimes hundreds-of thousands of vials or ampoules in wellcontrolled sterile conditions. In parallel, an important amount of basic research was conducted in several laboratories to understand and monitor the freeze-drying process. Our own work in the field started in 1954 and has been pursued ever since. During that time, the scope of application of freeze-drying was opened to the food and chemical industries, and new semicontinuous and even purely continuous processes developed for the operations of large multitons/day plants.

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Page iv

However, as biological research evolved into the more sophisticated approach of physiological biochemistry, and with the rocketing advance of genetical engineering, freeze-drying appeared in most cases as a unique technique for the long-term perservation of very small amounts of highly refined biological products. This, in turn, compelled most researchers to increase their knowledge on the role and performances of bulking agents, additives, cryoprotectants, antioxidants, and free radical scavengers, which were discovered to play a leading role in the protection of the integrity of the active substances, during both freezing and drying as well as in the course of storage. In that field, a better understanding of the behavior of complex molecules, such as proteins, during lyophilization was acquired, as well as more and more information gathered on the leading role of water in the whole process. The basic properties and the different ''states" of this critical component of all living matter were studied with cutting-edge technologies such as X-ray and neutron diffraction, nuclear paramagnetic resonance, or Debye dipolar absorption in addition to the already classical tools of conventional physical chemistry. Concomitantly, the structure and ultrastructure of freeze-dried products were investigated with direct or indirect technologies ranging from classical to electron scanning microscopy, to more advanced methods such as thermoluminescence. The purpose of Freeze-Drying/Lyophilization of Pharmaceutical and Biological Products is not to present an exhaustive view of the process, but essentially to shed light on some focal areas of the field in which pioneering research has been achieved and assess its impact on current manufacturing practices. This book also provides a critical review of such wide issues as the design and construction of equipment to identify the main trends and sometimes locate the specific sectors where our technological know-how is still incomplete. To the end, the editors have selected a group of knowledgeable experts who share a long experience in the field and have a large understanding of the adjacent and complementary disciplines. The contributors range from pure theoreticians to confirmed technicians with a wide in-depth field practice. They agreed to present their views in a clear and comprehensive way, avoiding unnecessary semantics and specialized mathematical treatments, in order to remain readily accessible to the diversified group of potential users of freeze-drying in the pharmaceutical industry. Special emphasis has been given to some grass-roots approaches to the process, which are of basic importance for operators and can also incline theoreticians to take a closer look into the actual unfolding of lyophilization. The editors hope that this somewhat unconventional approach to freeze-drying will be of interest and help not only for those who plan to enter this area, but also to the great majority of the experienced operators who wish to better understand the odds and ends of a challenging process. LOUIS REY

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Page v

Contents Preface

iii

Contributors

vii

1. Glimpses into the Realm of Freeze-Drying: Classical Issues and New Ventures Louis Rey

1

2. Potential Energy Surfaces, Computer Simulations, and the Structure of Water Robert O. Watts

31

3. Structural and Dynamic Properties of Bulk and Confined Water Marie-Claire Bellissent-Funel And José Teixeira

53

4. Experimental Freeze-Drying: Procedures and Equipment Hanna Willemer

79

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

123

6. Mechanisms of Protein Stabilization During Freeze-Drying and Storage: The Relative Importance of Thermodynamic Stabilization and Glassy State Relaxation Dynamics Michael J. Pikal

161

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Page vi

7. Regulatory Control of Freeze-Dried Products: Importance and Evaluation of Residual Moisture

199

Joan C. May 8. Basic Aspects and Industrial Strategies for the Preservation of Microorganisms by Freezing and Drying Hiroshi Souzu

231

9. Industrial Freeze-Drying for Pharmaceutical Applications Georg-Wilhelm Oetjen

267

10. Industrial Freeze-Drying of Vaccines Destined for Veterinary Purposes: An Overview Pierre Precausta, Noel Genin, Gérard Bénet, And Nicolas Tourneur

337

11. Manufacturing Principles of Freeze-Dried Collagen Sponges: Characteristics and Applications Petra Tewes-Schwarzer

359

12. Lyophilization Process Validation Christian Bindschaedler

373

13. Critical Steps in the Preparation of Elastomeric Closures for Biopharmaceutical Freeze-Dried Products Maninder S. Hora And Sidney N. Wolfe

409

14. Technical Procedures for Operation of Cleaning-in-Place and Sterilization-in-Place Process for Production Freeze-Drying Equipment

423

Gilles A. Beurel 15. Studies on Development of Manufacturing Processes for Pharmaceutical Freeze-Dried Products Yusuke Suzuki, Yutaka Sumi, And Taiichi Mizuta

433

16. Potential Prospects in Freeze-Drying Louis Rey

465

Index

473

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Page vii

Contributors Marie-Claire Bellissent-Funel, Ph.D. Director of Research, Léon-Brillouin Laboratory, CNRS, Gif-sur-Yvette, France Gérard Bénet, Ph.D. Associate Director, Pilot Department, Merial SAS, Lyon, France Gilles A. Beurel General Manager, S.G.D. Serail, Argenteuil, France Christian Bindschaedler, Ph.D. Project Manager, Process Support, Serono Laboratories S.A., Aubonne, Switzerland John F. Carpenter, Ph.D. Associate Professor, Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado Noël Genin, Ph.D. Associate Manager, Pilot Department, Merial SAS, Lyon, France Maninder S. Hora, Ph.D. Senior Director, Department of Formulation Development, Chiron Corporation, Emeryville, California Ken-ichi Izutsu, Ph.D. Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado

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Page viii

Joan C. May, Ph.D. Director, Laboratory of Analytical Chemistry, Center for Biologics Evaluation and Research, Food and Drug Administration, Rockville, Maryland Taiichi Mizuta, Ph.D. Director and Senior General Manager, Manufacturing Division, Shionogi & Co. Ltd., Hyogo, Japan Georg-Wilhelm Oetjen, Ph.D. Chemical Engineering Consultant, Lübeck, Germany Michael J. Pikal, Ph.D. Professor of Pharmaceutics, Department of Pharmaceutical Science, School of Pharmacy, University of Connecticut, Storrs, Connecticut Pierre Precausta, D.V.M. Merial SAS, Lyon, France Theodore W. Randolph, Ph.D. Associate Professor, Department of Chemical Engineering, University of Colorado, Boulder, Colorado Louis Rey, Ph.D. Professor Emeritus, Scientific Advisor, Cabinet d'É tudes, Lausanne, Switzerland Hiroshi Souzu, Ph.D. Professor, Institute of Low Temperature Science, Hokkaido University, Sapporo, Japan Yutaka Sumi General Manager, Formulation and Packaging Technical Services Department, Shionogi & Co. Ltd., Hyogo, Japan Yusuke Suzuki, Ph.D. Senior Researcher and Deputy General Manager, Formulation Research and Development Laboratories, Shionogi & Co. Ltd., Hyogo, Japan José Teixeira, Ph.D. Director of Research, Léon-Brillouin Laboratory, CNRS, Gif-sur-Yvette, France Petra Tewes-Schwarzer Department of Research and Development, Dr. Suwelack Skin and Health Care AG, Billerbeck, Germany Nicolas Tourneur Associate Director, Manufacturing Department, Merial SAS, Lyon, France

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Page ix

Robert O. Watts, Ph.D.* Professor, School of Chemistry, University of Melbourne, Parkville, Victoria, Australia Hanna Willemer Consultant, Köln, Germany Sidney N. Wolfe Principal Scientist, Department of Formulation Development, Chiron Corporation, Emeryville, California *Current affiliation: Chief Scientist, Melbourne Laboratories, The Broken Hill Proprietary Company Limited, Mulgrave, Victoria, Australia.

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Page 473

Index A Active ingredient, 338-339 Aggregation, 204 Air injection, 20 Amide I band, 130 Amorphous excipient, 127 Antibiotics, 434, 451 B Barrier, 410 Batch size commercial, 434, 453, 456 impact on freeze-drying, 386, 392, 393 Biomatrix, 361, 362, 365, 372 Biopharmaceuticals, 409, 422 Bonds (bonding) covalent, 31 hydrogen, 31, 55-59, 61, 64, 69, 70, 72, 260, hydrophic, 58, 260 Bound (unfreezable) water, 241, 245, 253, 258, 259, 260 C Cake appearance, 342 (Figs.12-14) Carbon dioxide freeze-drying, 470 Cephalotin sodium, 434, 437, 439, Chilling lability, 138 Closure(s), 409-422 Cold denaturation, 142 Collagen sponge, 359, 360, 362, 364, 366, 369, 370, 371 http://emedia.netlibrary.com/nlreader/nlreader.dll?bookid=11507&filename=Page_473.html PDF 文件使用 "FinePrint pdfFactory Pro" 试用版本创建 www.fineprint.com.cn

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Collapse, 452, 453, 455 of product, 375, 377, 379, 383, 385, 388, 389, 392, 398 structure, 302 temperature, 82, 377, 379 Computer molecular dynamics CMD, 64, 66 simulation, 32 Condensor temperature as a function of other variables, 381 impact on primary and secondary drying, 387, 388 Container closure/stoppers, 205, 409 Cooling (freezing) rate, 233, 235, 245, 256 rates, -methods, 86, 93 speed, 284, 288 sub-, -temperature, 87, 94 Coordination number, 55, 58 Cosmetic, 359, 360, 361, 370, 371 Cryomicroscope, 90, 98

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Page 473

Index A Active ingredient, 338-339 Aggregation, 204 Air injection, 20 Amide I band, 130 Amorphous excipient, 127 Antibiotics, 434, 451 B Barrier, 410 Batch size commercial, 434, 453, 456 impact on freeze-drying, 386, 392, 393 Biomatrix, 361, 362, 365, 372 Biopharmaceuticals, 409, 422 Bonds (bonding) covalent, 31 hydrogen, 31, 55-59, 61, 64, 69, 70, 72, 260, hydrophic, 58, 260 Bound (unfreezable) water, 241, 245, 253, 258, 259, 260 C Cake appearance, 342 (Figs.12-14) Carbon dioxide freeze-drying, 470 Cephalotin sodium, 434, 437, 439, Chilling lability, 138 Closure(s), 409-422 Cold denaturation, 142 Collagen sponge, 359, 360, 362, 364, 366, 369, 370, 371 http://emedia.netlibrary.com/nlreader/nlreader.dll?bookid=11507&filename=Page_473.html PDF 文件使用 "FinePrint pdfFactory Pro" 试用版本创建 www.fineprint.com.cn

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Collapse, 452, 453, 455 of product, 375, 377, 379, 383, 385, 388, 389, 392, 398 structure, 302 temperature, 82, 377, 379 Computer molecular dynamics CMD, 64, 66 simulation, 32 Condensor temperature as a function of other variables, 381 impact on primary and secondary drying, 387, 388 Container closure/stoppers, 205, 409 Cooling (freezing) rate, 233, 235, 245, 256 rates, -methods, 86, 93 speed, 284, 288 sub-, -temperature, 87, 94 Coordination number, 55, 58 Cosmetic, 359, 360, 361, 370, 371 Cryomicroscope, 90, 98

Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]1999[/DP]End of Citation

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Cryoprotectant, 143 Crystalline freeze-dried product, 434 Crystallization, 126, 434, 436, re-crystallization, of ice, 452, 453 D Dehydration, 256, 257 Desorption equation, 298 rate (DR), 298-306 rate measurement, 105, 106, 109 Devitrification, 10 Differential scanning calorimetry (DSC), 89 thermal analysis, 7, 379, 384 Disaccharides, 125 Dissociation, 139 Drug delivery, 365, 369, 370 Drying, 410, 411, 412, 416, 418, 419, 420, 421 end of main, 293-297 main, 97, 285-297 primary end point determination, 377-378 product structure after, 377 secondary, 105, 298-308, 442, 452 completion of, 386 mechanisms of, 379 E Effective potential, 55 Electric impedance, 7

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Electric resistance measurement (ER), 88 Equation Adam-Gibbs equation, 179 desorption, 298 freezing time, 279 main drying time, 289 VTF equation, 179 Eutectic crystals, 434, 438 Evacuation time, 320 Extra-cellular freezing, 235, 245, 257, 260 F Failure, categories, 330-331 Filling process, validation of, 395, 396 Filtration, filter compatibility, 395 Flomoxef sodium, 434, 453, 457, 458 Formulation, 123, 204 injectable, 434, 438 Freeze concentration, 81 -drying continuous, 468, 469 industrial freeze-drying, 337 plants, 110, 115 semi-continuous, 466, 467 individual quick, 468 -thawing, 232, 233 Freezing, 86, 144, 231, 233, 234, 263 product structure after, 374-376 rate, impact on product, 375, 376, 384, 403 G

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Gamma rays activation, 13 Gas, chromatographic method, 226 Glass(y), 8 solid, 127 state, 161 transition, 163 transition temperature, 57, 82, 163, 375, 377, 379 Gravimetric method, 206, 224 H Haze, 411, 413 Heat transfer coefficient Kto, 271, 272, 292, 296 Hemostat, 365, 369, 370 Homeopathy, 16, 18, 19 Hormone, human growth, 173 I Ice amorphous, 59, 61 cubic, 59 hexagonal, 59 Infrared (FTIR) spectroscopy, 128 In-process sampling, in-process validation, 395, 396 Internal surface-specific area (B.E.T.), 21, 23 Interstitial fluids, 6 Intra-cellular freezing, 235, 246, 248, 249, 260

Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]1999[/DP]End of Citation

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Ionization, 469 Isothermal desorption, 232, 238, 239 K Karl Fischer method, 208, 225 L Latamoxef sodium, 434, 453, 454, 456, 457, 458 Leak(s) calibrated, 381, 382, 383 leak detector, helium, 276 leak "hunting", 276 rate acceptable, 275 definition, 274 Lennard-Jones [12, 6] potential, 33 Loading (un-) system, 278 automatic in isolators, 310 Loss on drying, 206 Lyophilization -induced unfolding, 133 process, validation of, 373-408 Lyophilized protein formulations, 124 Lyoprotectant, 170 M Mannitol, 126 Mass spectrometers, 407 Measuring and control system, 328-330 Moisture, 410, 414, 416, 417, 418, 419, 420, 421 content, uniformity of, 384, 402-405 equilibrium water vapor measurement, 24

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evolution analyzer, 226 monitoring system, 458 occluded, 414, 417, 419, 421 regulations, residual moisture, 201 residual, 107, 109, 200, 342-349 residual, content, 268 (see Water, desorbable water (dW)) Molecular dynamic, 32 Monte Carlo, 32 N Near-infrared reflectance spectroscopy, 227 Nonaqueous media, 470 Nuclear magnetic resonance (NMR), 89 O Organic solvents, 79, 82 P Pair correlation function, 54-56, 60, 62, 63, 65 Particulates, 411, 412, 413, 421 Performance qualification, of the lyophilization process, 392-396 Pharmaceutical stability, 162 Phase separation, 154 split, 152 pH in the frozen state, 139 Pressure level as a function of other variables, 381 impact on primary and secondary drying, 382, 383, 385 operating pressure, 18 rise measurement, 105

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test, 377, 386 Primary drying, 433, 435, 443, 451, 455, 456, 457 Process capability, 394 limits validation of, 388-392 Product drying time, as a function of other variables, 375, 379, 382, 383, 387 potency, 202 temperature, as a function of other variables, 376, 382-383 uniformity assessment of, 394 within the lyophilizer, 399-406 Protective substance (additive), 233, 252, 254, 259, 260, 261, 262, 263, 264 Protein(s), 61, 64, 65, 123, 409, 419, 420, 421 content, uniformity of, 400-402 denaturation, 124 stability, 161 Pumping speed, 320-321 pumping system, 320, 323

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Q Quasi elastic neutron scattering, 66, 67, 69 R Radial distribution functions, 45 Rehydration, 132 Relaxation, structural relaxation times, 183 Residence time, 64-67, 69-72, 74 Resistivity measurements, 4, 379 Rubber(s), 410, 414, 416, 417 behavior, 11 S Scale -down, 456, 458 -up, 440, 456, 458 Sealing process, validation of, 403-406 Seed crystal, 436, 437, 439, 440 Shelf, flatness, 270 Silicone oil, 411, 412, 413 Siliconization, 411, 412, 413, 421 Solid ammonia freeze-drying, 471 Solid-state conformation, 188 Specific ligands, 125 Stability, 343-344, 419, 420, 421 Stabilizers, 125 nonspecific, 125 Sterilization, 410, 414 vaporized hydrogen peroxide (VHP) cycle, 326 Stopper(s), 85, 409-422 flow resistance, 273

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water content, 308 Storage, 308-310 stability, 124 Sublimation, 232, 234, 238, 239, 240, 241, 254 front temperature, 97, 101 Substrate, 339-340 Sucrose and trehalose, 126 Supersaturation, 437, 439, 445 Surfactants, 144 Syringes, 84 T Target cycle deviations from, 390 validation of, 392-394 Technology transfers, 383, 389 Temperature barometric temperature measurement (B.T.M.), 96, 101, 103, 294 eutectic temperature, 7, 375 "fictive temperature", 180 incipient melting temperature, 377 maximum temperature of complete solidification, 7 minimum temperature of incipient melting, 7 recrystallization, 82 shelf impact on product, 384-385 impact on product temperature, 382 softening, 377 storage, 347, 350-352 Tgtemperature of devitrification, 10, 268 Tice temperature of ice at sublimation front, 285

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zero mobility temperature, 179 Thermal history, 4 of solution, 449 treatment, 10 product structure after, 376 treatment (annealing), 86, 89, 95 Thermogravimetry, 210, 226 mass spectrometry, 214 Thermoluminescence, 13-18, 27-30 Tice, function of operation pressure, 291 Timasheff mechanism, 146 Tritium isotope, 226 Tumor necrosis factor, 412, 413, 421 Tunnel (freeze-drying tunnel), 467 U Ultra-low doses (see Homoeopathy) V Vacuum gauge capacitance (CA), 277, 327 thermal conductivity (TM), 277, 327 level as a function of other variables, 381 impact on primary and secondary drying, 18, 382, 383, 385 impact on product temperature, 382

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Validation, 417, 419, 421 concurrent, 393, prospective, 388-392 retrospective, 396-399 van der Waals forces, 31 Vapor flow density, 318 flow speed, 320 pressure, 235, 239, 240 pressure of ice, 290 pressure moisture methodology, 222 Venting gas, 108, 109 Veterinary vaccines, 337 Vial(s), 83 flat bottom, 270 inspection, 308 Vitreous transformation, 10 transition temperature, 339, 352 Vitrification, 249, 259 W Water activity, 346-349 compressibility, 57 density, 57, 58 density of liquid, 31 desorbable water (dW), 303 diffusion, 64, 66, 67, 69, 70, 74 entropy, 57

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equilibrium water vapor, 24-27 interfacial, 59 replacement hypothesis, 128 solutions, 58 structure of liquid, 32 substitute, 170 traps, 28 unfreezable, 82 vibrational density of states, 66-68, 70, 73 Wound-dressing, 366, 367, 368 Wyman linkage function, 146 Start of Citation[PU]Marcel Dekker, Inc.[/PU][DP]1999[/DP]End of Citation

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