Copyright © 2003 Marcel Dekker, Inc.

1 Copyright 2003 Marcel dekker , :PharmaceuticalProcessValidation:SecondE dition,RevisedandEx-panded( , ,eds.), , ,NewYork,NY10016tel:212-696-9000;fax:212 -685-4540 EasternHemisphereDistributionMarcelDekke rAGHutgasse4,Postfach812,CH-4001 Basel,Switzerlandtel:41-61-260-6300;fax: 41-61-260-6333 publisher offers discounts on this book when ordered in bulk quantities. For moreinformation, write to Special Sales/Professional Marketing at the headquarters 2003 by Marcel dekker , Inc. All Rights this book nor any part may be reproduced or transmitted in any form or by anymeans, electronic or mechanical, including photocopying, microfilming, and recording,or by any information storage and retrieval system, without permission in writing fromthe printing (last digit):10987654321 PRINTED IN THE UNITED STATES OF AMERICAC opyright 2003 Marcel dekker , AND THE pharmaceutical SCIENCESE xecutive EditorJames SwarbrickPharmaceuTech, IncPinehurst, North CarolinaAdvisory BoardLarry L.

2 Augsburger David E. NicholsUniversity of Maryland Purdue UniversityBaltimore, Maryland West Lafayette, IndianaDouwe D. Breimer Stephen G. SchulmanGorlaeus Laboratories University of FloridaLeiden, The Netherlands Gamesville, FloridaTrevor M Jones Jerome P. SkellyThe Association of the Alexandria, VirginiaBritish pharmaceutical IndustryLondon, United KingdomHans E. Junginger Felix TheeuwesLeiden/Amsterdam Center Alza Corporationfor Drug Research Palo Alto, CaliforniaLeiden, The NetherlandsVincent H. L. Lee Geoffrey T TuckerUniversity of Southern California University of SheffieldLos Angeles, California Royal Hallamshire HospitalSheffield, United KingdomPeter G. WellingInstitut de Recherche JouvemalFresnes, FranceCopyright 2003 Marcel dekker , AND THE pharmaceutical SCIENCESA Series of Textbooks and Monographs1. Pharmacokmetics, Milo Gibaldi and Donald Perrier2. Good Manufacturing Practices for Pharmaceuticals: A Plan for TotalQuality Control, Sidney H.

3 Willig, Murray M. Tuckerman, and WilliamS. Hitchings IV3. Microencapsulation, edited by J. R Nixon4. Drug Metabolism. Chemical and Biochemical Aspects, Bernard Testaand Peter Jenner5. New Drugs: Discovery and Development, edited by Alan A. Rubin6. Sustained and Controlled Release Drug Delivery Systems, edited byJoseph R. Robinson7. Modern Pharmaceutics, edited by Gilbert S. Banker and ChristopherT. Rhodes8. Prescription Drugs in Short Supply Case Histories, Michael Activated Charcoal' Antidotal and Other Medical Uses, David Concepts in Drug Metabolism (in two parts), edited by Peter Jennerand Bernard Testa11. pharmaceutical Analysis: Modern Methods (in two parts), edited byJames W, Munson12. Techniques of Solubilization of Drugs, edited by Samuel H Yalkow-sky13. Orphan Drugs, edited by Fred E. Karch14. Novel Drug Delivery Systems: Fundamentals, Developmental Con-cepts, Biomedical Assessments, Yie W.

4 Chien15. Pharmacokmetics: Second Edition, Revised and Expanded, MiloGibaldi and Donald Perrier16 Good Manufacturing Practices for Pharmaceuticals' A Plan for TotalQuality Control, Second Edition, Revised and Expanded, Sidney HWillig, Murray M Tuckerman, and William S. Hitchings IV17 Formulation of Veterinary Dosage Forms, edited by Jack Blodinger18 Dermatological Formulations. Percutaneous Absorption, Brian WBarry19. The Clinical Research Process in the pharmaceutical Industry, editedby Gary M. Matoren20. Microencapsulation and Related Drug Processes, Patrick B. Deasy21. Drugs and Nutrients The Interactive Effects, edited by Daphne and T. Colin Campbell22. Biotechnology of Industrial Antibiotics, Enck J. VandammeCopyright 2003 Marcel dekker , pharmaceutical Process Validation, edited by Bernard T Loftus andRobert A Nash24 Anticancer and Interferon Agents Synthesis and Properties, edited byRaphael M Ottenbrtte and George B Butler25 pharmaceutical Statistics Practical and Clinical Applications, SanfordBolton26 Drug Dynamics for Analytical, Clinical, and Biological Chemists,Benjamin J Gudzmowicz, Burrows T Younkm, Jr, and Michael JGudzmowicz27 Modern Analysis of Antibiotics, edited by Adjoran Aszalos28 Solubility and Related Properties, Kenneth C James29 Controlled Drug Delivery Fundamentals and Applications, SecondEdition, Revised and Expanded, edited by Joseph R Robinson andVincent H Lee30 New Drug Approval Process Clinical and Regulatory Management,edited by Richard A Guarino31 Transdermal Controlled Systemic Medications.

5 Edited by Yie W Chien32 Drug Delivery Devices Fundamentals and Applications, edited byPraveen Tyle33 Pharmacokinetics Regulatory Industrial Academic Perspectives,edited by Peter G Welling and Francis L S Tse34 Clinical Drug Trials and Tribulations, edited by Alien E Cato35 Transdermal Drug Delivery Developmental Issues and Research Ini-tiatives, edited by Jonathan Hadgraft and Richard H Guy36 Aqueous Polymeric Coatings for pharmaceutical Dosage Forms,edited by James W McGmity37 pharmaceutical Pelletization Technology, edited by Isaac Ghebre-Sellassie38 Good Laboratory Practice Regulations, edited by Alien F Hirsch39 Nasal Systemic Drug Delivery, Yie W Chien, Kenneth S E Su, andShyi-Feu Chang40 Modern Pharmaceutics Second Edition, Revised and Expanded,edited by Gilbert S Banker and Chnstopher T Rhodes41 Specialized Drug Delivery Systems Manufacturing and ProductionTechnology, edited by Praveen Tyle42 Topical Drug Delivery Formulations, edited by David W Osborne andAnton H Amann43 Drug Stability Principles and Practices, Jens T Carstensen44 pharmaceutical Statistics Practical and Clinical Applications, SecondEdition, Revised and Expanded, Sanford Bolton45 Biodegradable Polymers as Drug Delivery Systems, edited by MarkChasm and Robert Langer46 Preclmical Drug Disposition A Laboratory Handbook, Francis L STse and James J Jaffe47 HPLC in the pharmaceutical Industry, edited by Godwin W Fong andStanley K Lam48 pharmaceutical Bioequivalence, edited by Peter G Welling, Francis LS Tse, and Shrikant V DingheCopyright 2003 Marcel dekker , pharmaceutical Dissolution Testing, Umesh V.

6 Sana/car50. Novel Drug Delivery Systems: Second Edition, Revised andExpanded, Yie W. Chien51. Managing the Clinical Drug Development Process, David M. Coc-chetto and Ronald V. Nardi52. Good Manufacturing Practices for Pharmaceuticals: A Plan for TotalQuality Control, Third Edition, edited by Sidney H. Willig and JamesR. Stoker53. Prodrugs: Topical and Ocular Drug Delivery, edited by Kenneth pharmaceutical Inhalation Aerosol Technology, edited by Anthony Radiopharmaceuticals: Chemistry and Pharmacology, edited byAdrian D. Nunn56. New Drug Approval Process: Second Edition, Revised and Expanded,edited by Richard A. Guarino57. pharmaceutical Process Validation: Second Edition, Revised and Ex-panded, edited by Ira R. Berry and Robert A. Nash58. Ophthalmic Drug Delivery Systems, edited byAshim K. Mitra59. pharmaceutical Skin Penetration Enhancement, edited by Kenneth and Jonathan Hadgraft60.

7 Colonic Drug Absorption and Metabolism, edited by Peter R. Bieck61. pharmaceutical Particulate Carriers1 Therapeutic Applications, editedby Alain Rolland62. Drug Permeation Enhancement: Theory and Applications, edited byDean S. Hsieh63. Glycopeptide Antibiotics, edited by Ramakrishnan Nagarajan64. Achieving Sterility in Medical and pharmaceutical Products, Nigel Multiparticulate Oral Drug Delivery, edited by Isaac Ghebre-Sellassie66. Colloidal Drug Delivery Systems, edited byJorg Kreuter67 Pharmacokinetics: Regulatory Industrial Academic Perspectives,Second Edition, edited by Peter G. Welling and Francis L. S. Tse68. Drug Stability: Principles and Practices, Second Edition, Revised andExpanded, Jens T. Carstensen69. Good Laboratory Practice Regulations: Second Edition, Revised andExpanded, edited by Sandy Weinberg70. Physical Characterization of pharmaceutical Solids, edited by HarryG. Bnttain71. pharmaceutical Powder Compaction Technology, edited by Goran Al-derborn and Christer Nystrom72.

8 Modern Pharmaceutics. Third Edition, Revised and Expanded, editedby Gilbert S. Banker and Christopher J Rhodes73. Microencapsulation. Methods and Industrial Applications, edited bySimon Benita74. Oral Mucosal Drug Delivery, edited by Michael J. Rathbone75. Clinical Research in pharmaceutical Development, edited by BarryBleidt and Michael MontagneCopyright 2003 Marcel dekker , The Drug Development Process Increasing Efficiency and Cost Ef-fectiveness, edited by Peter G Welling, Louis Lasagna, and UmeshV Banakar77 Microparticulate Systems for the Delivery of Proteins and Vaccines,edited by Smadar Cohen and Howard Bernstein78 Good Manufacturing Practices for Pharmaceuticals A Plan for TotalQuality Control, Fourth Edition, Revised and Expanded, Sidney HWillig and James R Stoker79 Aqueous Polymeric Coatings for pharmaceutical Dosage FormsSecond Edition, Revised and Expanded, edited by James WMcGmity80 pharmaceutical Statistics Practical and Clinical Applications, ThirdEdition, Sanford Bolton81 Handbook of pharmaceutical Granulation Technology edited by DilipM Pankh82 Biotechnology of Antibiotics Second Edition.

9 Revised and Expanded,edited by William R Strohl83 Mechanisms of Transdermal Drug Delivery, edited by Russell O Pottsand Richard H Guy84 pharmaceutical Enzymes edited by Albert Lauwers and SimonScharpe85 Development of Biopharmaceutical Parenteral Dosage Forms, editedby John A Bontempo86 pharmaceutical Project Management, edited by Tony Kennedy87 Drug Products for Clinical Trials An International Guide to Formula-tion Production Quality Control, edited by Donald C Monkhouseand Christopher T Rhodes88 Development and Formulation of Veterinary Dosage Forms SecondEdition, Revised and Expanded, edited by Gregory E Hardee and JDesmond Baggot89 Receptor-Based Drug Design, edited by Paul Leff90 Automation and Validation of Information in pharmaceutical Pro-cessing, edited by Joseph F deSpautz91 Dermal Absorption and Toxicity Assessment, edited by Michael SRoberts and Kenneth A Walters92 pharmaceutical Experimental Design, Gareth A Lewis, DidierMathieu, and Roger Phan-Tan-Luu93 Preparing for FDA Pre-Approval Inspections, edited by Martin DHynes III94 pharmaceutical Excipients Characterization by IR, Raman, and NMRS pectroscopy, David E Bugay and W Paul Fmdlay95 Polymorphism in pharmaceutical Solids, edited by Harry G Brittam96 Freeze-Drymg/Lyophihzation of pharmaceutical and Biological Prod-ucts, edited by Louis Rey and Joan C May97 Percutaneous Absorption Drugs-Cosmetics-Mechanisms-Metho-dology, Third Edition, Revised and Expanded, edited by Robert LBronaugh and Howard I MaibachCopyright 2003 Marcel dekker , Bioadhesive Drug Delivery Systems: Fundamentals, Novel Ap-proaches, and Development, edited by Edith Mathiowitz, Donald III, and Claus-Michael Lehr99.

10 Protein Formulation and Delivery, edited by Eugene J. McNally100. New Drug Approval Process: Third Edition, The Global Challenge,edited by Richard A. Guarino101. Peptide and Protein Drug Analysis, edited by Ronald E. Reid102 Transport Processes in pharmaceutical Systems, edited by Gordon LAmidon, Ping I. Lee, and Elizabeth M. Topp103. Excipient Toxicity and Safety, edited by Myra L. Weiner and Lois The Clinical Audit in pharmaceutical Development, edited by MichaelR. Hamrell105. pharmaceutical Emulsions and Suspensions, edited by FrancoiseNielloud and Gilberte Marti-Mestres106. Oral Drug Absorption: Prediction and Assessment, edited by Jennifer and Hans Lennernas107. Drug Stability: Principles and Practices, Third Edition, Revised andExpanded, edited by Jens T. Carstensen and C. T. Rhodes108. Containment in the pharmaceutical Industry, edited by James Good Manufacturing Practices for Pharmaceuticals: A Plan for TotalQuality Control from Manufacturer to Consumer, Fifth Edition, Revisedand Expanded, Sidney H Willig110.