DPS_6x9_Edwards_Template.indd Pharmaceutical Science 195 DRUGS AND THE PHARMACEUTICAL SCIENCES VOLUME 195 about the book… This revised and expanded Second Edition summarizes fundamental engineering principles, operations, and development considerations that are critical to converting S E C O N D ED i t i O N bulk pharmaceutical products into patient-ready and appropriate drug delivery dosage SECOND forms. Pharmaceutical Process Engineering facilitates a comprehensive understanding EDitiON of the practical aspects of drug production and current development philosophy in an accessible, step-by-step format. Improving communication among diverse professionals in the field—including pharmaceutical researchers, and chemical, industrial, and process engineers—the P Pharmaceutical Second Edition of Pharmaceutical Process Engineering considers: h • the relation of global concepts in pharmaceutical development, exemplified by a r Quality by Design Principles, to the application of fundamental principles and major m unit operations in pharmaceutical engineering a • heat transfer, mass transfer, and fluid flow c Process Engineering e • control of manufacturing environments u • preparation of sterile materials t i c • drying, evaporation, and crystallization processes a • techniques of filtration and centrifugation l P • particle size reduction, mixing, granulation, and drying methods r • the manufacture of biological materials o • and more, with references to statistical experimental design and process analytical c e technology as they support a philosophy of Quality by Design s s about the authors... E ANTHONY J. HICKEY is Professor of Molecular Pharmaceutics and Biomedical Engineering, n g University of North Carolina at Chapel Hill, Chapel Hill, and President and CEO of Cirrus i Pharmaceuticals, Inc., Durham, North Carolina, USA; Founder and former Chief Scientific n e Officer of Oriel Therapeutics, Inc.; and Chair of the Aerosols Expert Committee of the e United States Pharmacopeia. The author, coauthor, and coeditor of numerous journal r articles, book chapters, and books, including Pharmaceutical Inhalation Aerosol Technology, i n Inhalation Aerosols, and A Guide to Pharmaceutical Particulate Science (all Informa g Healthcare titles), he is Fellow of the Institute of Biology, the American Association of Pharmaceutical Scientists, and the American Association for the Advancement of Science. He received his B.Sc. degree (1977) from Portsmouth Polytechnic, UK; M.Sc. degree (1980) from the University of Birmingham, UK; and Ph.D. (1985) and D.Sc. (2003) H degrees from Aston University, Birmingham, UK. ic k e DAVID GANDERTON was formerly Director, Vectura Limited, Bath, UK. Dr. Ganderton •y received his B. Pharm. and Ph.D. degrees from the University of London, London, UK. G a He is the author or coauthor of numerous journal articles, book chapters, and books. n d Dr. Ganderton is also Fellow of the Royal Pharmaceutical Society of Great Britain. e r to Cover illustration by Jeff Priester n H8475 Printed in the United States of America Anthony J. Hickey David Ganderton PANTONE 202 C Pharmaceutical Process Engineering DRUGS AND THE PHARMACEUTICAL SCIENCES A Series of Textbooks and Monographs Executive Editor James Swarbrick PharmaceuTech, Inc. Pinehurst,NorthCarolina Advisory Board Larry L. Augsburger Harry G. Brittain Universityof Maryland Centerfor PharmaceuticalPhysics Baltimore, Maryland Milford, NewJersey Jennifer B. Dressman Robert Gurny University ofFrankfurt Institute Universitede Geneve of PharmaceuticalTechnology Geneve,Switzerland Frankfurt,Germany Jeffrey A. Hughes Anthony J. Hickey Universityof FloridaCollege University ofNorthCarolina ofPharmacy Schoolof Pharmacy Gainesville,Florida ChapelHill,NorthCarolina Vincent H. L. Lee Ajaz Hussain USFDA Centerfor Drug Sandoz EvaluationandResearch Princeton,NewJersey LosAngeles,California Joseph W. Polli Kinam Park GlaxoSmithKline PurdueUniversity Research TrianglePark WestLafayette,Indiana NorthCarolina Jerome P. Skelly Stephen G. Schulman Alexandria,Virginia University ofFlorida Gainesville,Florida Elizabeth M. Topp Universityof Kansas Yuichi Sugiyama Lawrence,Kansas University ofTokyo,Tokyo, Japan Peter York Geoffrey T. Tucker Universityof Bradford University ofSheffield SchoolofPharmacy Royal HallamshireHospital Bradford,United Kingdom Sheffield, UnitedKingdom For information on volumes 1–149 in the Drugs and Pharmaceutical Science Series, please visit www.informahealthcare.com 150. Laboratory Auditing for Quality and Regulatory Compliance, Donald Singer, Raluca-Ioana Stefan, and Jacobus van Staden 151. Active Pharmaceutical Ingredients: Development, Manufacturing, and Regulation, edited by Stanley Nusim 152. PreclinicalDrugDevelopment,editedbyMarkC.RoggeandDavidR.Taft 153. Pharmaceutical Stress Testing: Predicting Drug Degradation, edited by Steven W. Baertschi 154. Handbook of Pharmaceutical Granulation Technology: Second Edition, edited by Dilip M. Parikh 155. Percutaneous Absorption: Drugs–Cosmetics–Mechanisms–Methodology, Fourth Edition, edited by Robert L. Bronaugh and Howard I. Maibach 156. Pharmacogenomics:SecondEdition,editedbyWernerKalow,UrsA.Meyer andRachel F.Tyndale 157. PharmaceuticalProcessScale-Up,SecondEdition,editedbyMichaelLevin 158. Microencapsulation: Methods and Industrial Applications, Second Edition, edited by Simon Benita 159. Nanoparticle Technology for Drug Delivery, edited by Ram B. Gupta and Uday B. Kompella 160. Spectroscopy of Pharmaceutical Solids, edited by Harry G. Brittain 161. Dose Optimization in Drug Development, edited by Rajesh Krishna 162. Herbal Supplements-Drug Interactions: Scientific and Regulatory Perspectives, edited by Y. W. Francis Lam, Shiew-Mei Huang, and Stephen D. Hall 163. Pharmaceutical Photostability and Stabilization Technology, edited by Joseph T. Piechocki and Karl Thoma 164. Environmental Monitoring for Cleanrooms and Controlled Environments, edited by Anne Marie Dixon 165. Pharmaceutical Product Development: In Vitro-In Vivo Correlation, edited by Dakshina Murthy Chilukuri, Gangadhar Sunkara, and David Young 166. NanoparticulateDrugDeliverySystems,editedbyDeepakThassu,Michel Deleers, and Yashwant Pathak 167. Endotoxins: Pyrogens, LAL Testing and Depyrogenation, Third Edition, edited by Kevin L. Williams 168. Good Laboratory Practice Regulations, Fourth Edition, edited by Anne Sandy Weinberg 169. Good Manufacturing Practices for Pharmaceuticals, Sixth Edition, edited by Joseph D. Nally 170. Oral-Lipid Based Formulations: Enhancing the Bioavailability of Poorly Water-soluble Drugs, edited by David J. Hauss 171. Handbook of Bioequivalence Testing, edited by Sarfaraz K. Niazi 172. Advanced Drug Formulation Design to Optimize Therapeutic Outcomes, edited by Robert O. Williams III, David R. Taft, and Jason T. McConville 173. Clean-in-PlaceforBiopharmaceuticalProcesses,editedbyDaleA.Seiberling 174. Filtration and Purification in the Biopharmaceutical Industry, Second Edition, edited by Maik W. Jornitz and Theodore H. Meltzer 175. Protein Formulation and Delivery, Second Edition, edited by Eugene J. McNally and Jayne E. Hastedt 176. Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms, Third Edition, edited by James McGinity and Linda A. Felton 177. Dermal Absorption and Toxicity Assessment, Second Edition, edited by Michael S. Roberts and Kenneth A. Walters 178. Preformulation Solid Dosage Form Development, edited by Moji C. Adeyeye and Harry G. Brittain 179. Drug-Drug Interactions, Second Edition, edited by A. David Rodrigues 180. Generic Drug Product Development: Bioequivalence Issues, edited by Isadore Kanfer and Leon Shargel 181. PharmaceuticalPre-ApprovalInspections:AGuidetoRegulatorySuccess, Second Edition, edited by Martin D. Hynes III 182. Pharmaceutical Project Management, Second Edition, edited by Anthony Kennedy 183. Modified Release Drug Delivery Technology, Second Edition, Volume 1, edited by Michael J. Rathbone, Jonathan Hadgraft, Michael S. Roberts, and Majella E. Lane 184. Modified-Release Drug Delivery Technology, Second Edition, Volume 2, edited by Michael J. Rathbone, Jonathan Hadgraft, Michael S. Roberts, and Majella E. Lane 185. The Pharmaceutical Regulatory Process, Second Edition, edited by Ira R. Berry and Robert P. Martin 186. HandbookofDrugMetabolism,SecondEdition,editedbyPaulG.Pearson and Larry C. Wienkers 187. PreclinicalDrugDevelopment,SecondEdition,editedbyMarkRoggeand David R. Taft 188. Modern Pharmaceutics, Fifth Edition, Volume 1: Basic Principles and Systems, edited by Alexander T. Florence and Juergen Siepmann 189. Modern Pharmaceutics, Fifth Edition, Volume 2: Applications and Advances, edited by Alexander T. Florence and Juergen Siepmann 190. New Drug Approval Process, Fifth Edition, edited by Richard A.Guarino 191. DrugDeliveryNanoparticulateFormulationandCharacterization,editedby Yashwant Pathak and Deepak Thassu 192. Polymorphism of Pharmaceutical Solids, Second Edition, edited by Harry G. Brittain 193. Oral Drug Absorption: Prediction and Assessment, Second Edition, edited by Jennifer J. Dressman, hans Lennernas, and Christos Reppas 194. Biodrug Delivery Systems: Fundamentals, Applications, and Clinical Development, edited by Mariko Morishita and Kinam Park 195. Pharmaceutical Process Engineering, Second Edition, Anthony J. Hickey and David Ganderton S E C O N D E D i t i O N Pharmaceutical Process Engineering Anthony J. Hickey Cirrus Pharmaceuticals, Inc. Durham, North Carolina, USA University of North Carolina Chapel Hill, North Carolina, USA David Ganderton London, UK InformaHealthcareUSA,Inc. 52VanderbiltAvenue NewYork,NY10017 #2010byInformaHealthcareUSA,Inc. InformaHealthcareisanInformabusiness NoclaimtooriginalU.S.Governmentworks PrintedintheUnitedStatesofAmericaonacid-freepaper 10987654321 InternationalStandardBookNumber-10:1-4200-8475-5(Hardcover) InternationalStandardBookNumber-13:978-1-4200-8475-7(Hardcover) This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and infor- mation, but the author and the publishercannot assume responsibility for the validity of all materialsorfortheconsequenceoftheiruse. Nopartofthisbookmaybereprinted,reproduced,transmitted,orutilizedinanyformbyany electronic, mechanical, or other means, now known or hereafter invented, including photo- copying, microfilming, and recording, or in any information storage or retrieval system, withoutwrittenpermissionfromthepublishers. Forpermissiontophotocopyorusematerialelectronicallyfromthiswork,pleaseaccesswww .copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC)222RosewoodDrive,Danvers,MA01923,978-750-8400.CCCisanot-for-profitorganization thatprovides licensesand registration for a variety of users. For organizations that have been grantedaphotocopylicensebytheCCC,aseparatesystemofpaymenthasbeenarranged. TrademarkNotice:Productorcorporatenamesmaybetrademarksorregisteredtrademarks, andareusedonlyforidentificationandexplanationwithoutintenttoinfringe. LibraryofCongressCataloging-in-PublicationData Hickey,AnthonyJ.,1955– Pharmaceuticalprocessengineering/AnthonyJ.Hickey,DavidGanderton.— 2nded. p.;cm.— (Drugsandthepharmaceuticalsciences;195) Includesbibliographicalreferencesandindex. ISBN-13:978-1-4200-8475-7(hardcover:alk.paper) ISBN-10:1-4200-8475-5(hardcover:alk.paper) 1. Pharmaceutical technology.2. Productionengineering. I.Ganderton,David.II. Title.III.Series:Drugsandthepharmaceuticalsciences;v.195. [DNLM: 1. Pharmaceutical Preparations—chemistry. 2. Biomedical Engineering. W1DR893Bv.1952009/QV744H628p2009] RS192.H532009 615’.19—dc22 2009025871 ForCorporateSalesandReprintPermissionscall212-520-2700orwriteto:SalesDepartment, 52VanderbiltAvenue,7thfloor,NewYork,NY10017. VisittheInformaWebsiteat www.informa.com andtheInformaHealthcareWebsiteat www.informahealthcare.com Preface The motivation for expanding and updating Unit Processes in Pharmacy (David Ganderton, 1968) into the first edition of a book titled Pharmaceutical Process Engineeringwasadesiretomakethisvaluableintroductoryvolumeavailabletoa new generation of pharmaceutical scientists and technologists. The basic prin- cipleshavenotchangedintheinterveningyears,buttheenvironmentinwhich manufacturingisconducted,bothfromapracticalandaregulatorystandpoint, has undergone a substantial evolution. The important principles of Quality by DesignandthesubtopicofProcessAnalyticalTechnologyareroutinelyfoundon the programs of symposia devoted to pharmaceutical engineering and have a clearimpactonthefutureofpharmaceuticalmanufacturing. Thepresentvolumecoversthebasicprincipleswithupdatedexamplesof theunitoperationsinpharmacyandtheirapplication.Asinthefirstedition,the many unique drug delivery systems that extend beyond classical oral and parenteral dosage forms are not covered extensively as these are specialized topics covered in other volumes in this series. A new section has been added on quality principles and the underlying mathematical and statistical methods. Adoption of known input variables that define the relevant process space can bring about consistency of product per- formance.Thecurrentcapacitytostoreandmanipulatedatacouldnothavebeen envisaged when the original volume on unit operations was published. The evolvingtoolofcomputer-aideddesignislikelytobecomeastandardprocedure inthefutureand,therefore,deservestobeaddressedintherevisededition. This volume remains an introductory text for pharmaceutical scientists and technologists who require an understanding of engineering principles. We hope that academic, industry, and government scientists and students will find this a useful text that serves the purpose of an easily accessible reference. Anthony J. Hickey David Ganderton vii Acknowledgments We are grateful for the support and encouragement of Carolyn Honour and Sandy Beberman, of Informa Healthcare, to prepare a second edition of this book. Kathryn Fiscelli assisted in collating materials used in the manuscript. Thefirsteditionwouldnothavebeenpossiblewithoutthecontributionof Dr Vasu Sethuraman. His endeavors with respect to integration of chapters, production of figures, and copyediting were the foundation on which the text was built. There is no doubt that his activities contributed to the clarity and continuity of the book. In addition, Dr Paul Pluta was generous in sharing his thoughtsonsoliddosageformsandallowedtheiruseintherelevantsectionsof the volume. The majority of the text continues to be based on a portion of David Ganderton’sUnitProcessesinPharmacy,abookpublishedin1968byHeineman MedicalBooks,Ltd.,andnowoutofprint.Itisappropriatetoacknowledgethe contributions of that original volume. The original text was the commission of Dr D. M. Moulden. We acknowledge the considerable help given by his ideas, plans, and drafts. In addition, we thank Mr Ian Boyd and Dr John Hersey, who read and evaluated manuscripts. ix