Process scale bioseparations for the biopharmaceutical industry PDF
Preview Process scale bioseparations for the biopharmaceutical industry
DK3347_half-title 6/2/06 11:31 AM Page 2 PROCESS SCALE BIOSEPARATIONS FOR THE BIOPHARMACEUTICAL INDUSTRY edited by Abhinav A. Shukla Amgen Inc. Seattle,Washington, U.S.A. Mark R. Etzel University of Wisconsin-Madison Madison,Wisconsin, U.S.A. Shishir Gadam Merck & Co., Inc. West Point, Pennsylvania, U.S.A. © 2007 by Taylor & Francis Group, LLC DK3347_Discl.fm Page 1 Thursday, February 2, 2006 11:12 AM Published in 2007 by CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2007 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 1-57444-517-0 (Hardcover) International Standard Book Number-13: 978-1-57444-517-6 (Hardcover) Library of Congress Card Number 2006002480 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 information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the consequences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www.copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. 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 Process scale bioseparations for the biopharmaceutical industry / Abhinav Shukla, Mark Etzel, and Shishir Gadam, editors. p. ; cm. -- (Biotechnology and bioprocessing series ; 31) Includes bibliographical references and index. ISBN-13: 978-1-57444-517-6 (alk. paper) ISBN-10: 1-57444-517-0 (alk. paper) 1. Proteins--Purification. 2. Cell culture. 3. Pharmaceutical biotechnology. 4. Chromatographic analysis. 5. Fermentation. [DNLM: 1. Proteins--isolation & purification. 2. Cell Culture Techniques. 3. Chromatography--methods. 4. Fermentation. QU 55 P96406 2006] I. Shukla, Abhinav. II. Etzel, Mark. III. Gadam, Shishir. IV. Series. QP551.P693 2006 612.3'98--dc22 2006002480 Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com Taylor & Francis Group and the CRC Press Web site at is the Academic Division of Informa plc. http://www.crcpress.com © 2007 by Taylor & Francis Group, LLC BIOTECHNOLOGY AND BIOPROCESSING SERIES 1. Membrane Separations in Biotechnology, edited by W. Courtney McGregor 2. Commercial Production of Monoclonal Antibodies: A Guide for Scale-Up, edited by Sally S. Seaver 3. Handbook on Anaerobic Fermentations, edited by Larry E. Erickson and Daniel Yee-Chak Fung 4. Fermentation Process Development of Industrial Organisms, edited by Justin O. Neway 5. Yeast: Biotechnology and Biocatalysis, edited by Hubert Verachtert and René De Mot 6. Sensors in Bioprocess Control, edited by John V. Twork and Alexander M. Yacynych 7. Fundamentals of Protein Biotechnology, edited by Stanley Stein 8. Yeast Strain Selection, edited by Chandra J. Panchal 9. Separation Processes in Biotechnology, edited by Juan A. Asenjo 10. Large-Scale Mammalian Cell Culture Technology, edited by Anthony S. Lubiniecki 11. Extractive Bioconversions, edited by Bo Mattiasson and Olle Holst 12. Purification and Analysis of Recombinant Proteins, edited by Ramnath Seetharam and Satish K. Sharma 13. Drug Biotechnology Regulation: Scientific Basis and Practices, edited by Yuan-yuan H. Chiu and John L. Gueriguian 14. Protein Immobilization: Fundamentals and Applications, edited by Richard F. Taylor 15. Biosensor Principles and Applications, edited by Loï'efc J. Blum and Pierre R. Coulet 16. Industrial Application of Immobilized Biocatalysts, edited by Atsuo Tanaka, Tetsuya Tosa, and Takeshi Kobayashi 17. Insect Cell Culture Engineering, edited by Mattheus F. A. Goosen, Andrew J. Daugulis, and Peter Faulkner 18. Protein Purification Process Engineering, edited by Roger G. Harrison 19. Recombinant Microbes for Industrial and Agricultural Applications, edited by Yoshikatsu Murooka and Tadayuki Imanaka 20. Cell Adhesion: Fundamentals and Biotechnological Applications, edited by Martin A. Hjortso and Joseph W. Roos 21. Bioreactor System Design, edited by Juan A. Asenjo and José C. Merchuk 22. Gene Expression in Recombinant Microorganisms, edited by Alan Smith 23. Interfacial Phenomena and Bioproducts, edited by John L. Brash and Peter W. Wojciechowski 24. Metabolic Engineering, edited by Sang Yup Lee and Eleftherios T. Papoutsakis 25. Biopharmaceutical Process Validation, edited by Gail Sofer and Dane W. Zabriskie 26. Membrane Separations in Biotechnology: Second Edition, Revised and Expanded, edited by William K. Wang © 2007 by Taylor & Francis Group, LLC 27. Isolation and Purification of Proteins, edited by Rajni Hatti-Kaul and Bo Mattiasson 28. Biotransformation and Bioprocesses, Mukesh Doble, Anil Kumar Kruthiventi, and Vilas Gajanan Gaikar 29. Process Validation in Manufacturing of Biopharmaceuticals: Guidelines, Current Practices, and Industrial Case Studies, edited by Anurag Singh Rathore and Gail Sofer 30. Cell Culture Technology for Pharmaceutical and Cell-Based Therapies, edited by Sadettin S. Ozturk and Wei-Shou Hu 31. Process Scale Bioseparations for the Biopharmaceutical Industry, edited by Abhinav A. Shukla, Mark R. Etzel, and Shishir Gadam © 2007 by Taylor & Francis Group, LLC Preface Rapidgrowthinthebiopharmaceuticalindustryinrecentyears––bothinthe valueandvarietyofnovelproducts—-hasturnedthisoncefledglingindustry intoanimportantplayerintheglobaleconomy.Commercialsuccessofthese productshingesonthesuccessfuldevelopmentandimplementationofrobust, reliable, and economical production processes. Increasingly within the bio- pharmaceutical industry, bioprocess development is seen as a key source of competitiveadvantage.Thistrendwillcontinueastheindustryfurthermatures. Bioseparations (also often called downstream processing) refers to the wide varietyandcombinationsofproductionprocessesthatareemployedtorecover and purify biomolecules from biological sources. Given the diversity of bio- moleculesandthecomplexnatureoftheirbiochemicalpropertiesitisnowonder thatthefieldofbioseparationshasevolvedintoarichandvariedone. However, mostofthedevelopmentsinthebioseparationsfieldarechron- icled in a rather vast range of scientific papers, patents, and conference presentations that can pose a bewildering array for a newcomer to process development or for established scientists and engineers who are seeking to learnanunfamiliartechnique.Biologicalsystemsareinherentlycomplexand veryoftencannotbedefinedpreciselybymathematicalmodels. Duetothese reasons,bioprocessdevelopmentisoftensimultaneouslyanartandascience. Additionally, biopharmaceutical manufacturing is a highly regulated activity andhenceseveralregulatoryconsiderationsoftenenterintochoicesmadedur- ing process development. This book first lays a foundation of basic concepts andfundamentalprinciplesthatareessentialforunderstandingeachtopic,and then provides a set of rules of thumb that are based on hands-on industrial experiencewithactuallarge-scaleprocesses,hindsightlearningfromscale-up problems, and regulatory issues that arise during development and licensure. Thebookfollowsaconciseandpracticalapproachandisrepletewithtables, flowcharts, andschematicsthatprovideaperspectiveonhowprocessdevel- opment is carried out in the biopharmaceutical industry. In each chapter, the authorsattempttobringtogetherscientificprinciples,practicalconsiderations, and empirical approaches that are closely intertwined in this field to give the readeraperspectiveonhowpurificationprocessdevelopmentisactuallycarried outinthebiopharmaceuticalindustry.Inthissense,thebookisadeparturefrom previoustextsinthisareathatprovideeitheralargelytheoreticalperspective © 2007 by Taylor & Francis Group, LLC SHUKLA: “dk3347_c000” — 2006/6/2 — 09:38 — page vii — #7 intothefieldorareacompilationofreviewpapersofscientificdevelopments inanygiventopic. Thebookcontainsthreebroadareasoffocus.Firstisafocusondownstream unit operations, their fundamental principles, and considerations for process development.Thisincludeschaptersonunitoperationsthatarewidelyaccepted inthebioprocessingworldaswellasonmethodologiesthatcouldfindwider acceptanceintheyearstocome.Nextcomesafocusonsomehighlyessential ancillaryaspectsofdownstreamprocessdevelopmentincludingviralvalidation and in-process analytical methods. The final chapters in the book deal with downstreamprocessdevelopmentforvariousclassesofbiomoleculesandthe strategiesadoptedfortheirprocess. Chapter 1 presents a broad review of the principles of harvest clarifica- tiontechnologies(centrifugation,depthfiltration,andtangentialflowfiltration) alongwithacasestudyofharvestingatherapeuticproteinproductfromhigh cell density fermentation broth. The comprehensive literature review within this chapter should prove to be a valuable road-map for practitioners to nav- igate this vastly studied area of downstream processing. Chapter 2 presents theoretical and experimental frameworks and a real-life case study for devel- opmentofexpandedbedadsorptionasanalternativetothemoreconventional techniquespresentedinChapter1. Giventheincreasinginterestinthisinteg- rativetechnologyinthelastdecadeanditspotentialtoreduceoverallcostof goods, we believe this chapter will be a valuable resource for many readers. Chapter 3 presents another novel technology (High Gradient Magnetic Fish- ing) that can allow integration of harvest-clarification with chromatographic captureandpurification.Magneticadsorbentshaveaverypowerfulandunique “hook”thatpermitsoneto“fish”themfromcrudecellcultureandfermenta- tionbrothssimplythroughtheapplicationofamagneticfield. Becauseofits potentialforrapidprocessingoflargevolumesofcellharvest,thefutureindus- trialprospectsforHighGradientMagneticFishinglookbright.Andthat’sno fishstory. Chapter 4 spells out the fundamental principles of protein refolding and provides the reader with experimental strategies to develop and optimize a refoldingprocess.Avarietyofusefulpointstoconsiderduringdevelopmentof large-scaleproteinrefoldingoperationsareprovidedthroughoutthechapter. Chapter 5 is on bulk protein crystallization –– a technique that is gener- atingincreasinginterestfor(1)earlystagerecovery,(2)generatingultra-high purity product in the polishing stages of a downstream process, (3) improv- ingproductstabilityandshelflife, and(4)providingnewdosageformatsfor proteintherapeutics.Thechaptersetsthestagefornewresearchersbydescrib- ing the basic principles and key equations needed for design of experiments, illustrating methods of data analysis, and providing case studies of industrial practice. © 2007 by Taylor & Francis Group, LLC SHUKLA: “dk3347_c000” — 2006/6/2 — 09:38 — page viii — #8 Chromatographicseparationsareubiquitousinthemanufactureofbiophar- maceuticals. For this reason, the next three chapters provide a tutorial, some hands-onadvice,andagazeintothecrystalballforprocesschromatography. Chapter 6 focuses on the different modes of chromatography. All the major modesofprocesschromatographyarediscussed:affinity,ionexchange,hydro- phobicinteraction,reversedphase,hydroxyapatite,immobilizedmetalaffinity, thiophilic interaction, mixed mode, and size exclusion. Rules of thumb and heuristicsbasedonlarge-scaleexperienceareprovidedineachsectiontoserve asapracticalguideforthereader. Chapter7presentspracticalconsiderationsandmethodologiesforscreen- ing and selecting chromatographic resins for industrial separation processes. Ofspecialmentionaretoolssuchashighthroughputscreening,retentatechro- matography,andcumulativeyield–impurityplotsthatgreatlyfacilitatethetask ofstationaryphaseselection. Chapter8onaprioripredictionofchromatographicseparationsfrompro- tein structure data describes a technique that might radically alter the current paradigmofprocessdevelopment. Whiletheprecedingtwochaptersconcen- trated on currently applied empirical methods for defining chromatographic unit operations, this chapter describes some major strides toward the “holy grail”ofresearchersinbeingabletopredictchromatographicperformanceby simulationalone.Thechapterdescribesmethodologiesforpredictingchroma- tographicparametersofproteinsandpresentsanoverviewofrecentadvances madeinextendingthesepredictivetechniquesbeyondthesmallmoleculerealm forwhichtheyhavebeenemployedsofar. Thenextthreechaptersdealwithmembrane-basedunitoperations.Chapter 9presentssimplemathematicalmodelsforpredictingbreakthroughcurvesin membrane chromatography systems, and explains how to use these models to analyze laboratory and large-scale data. This analysis is extended to the predictionofviralclearanceinmembranechromatographicsystems. Chapter 10 focuses on the design and implementation of an ultrafiltration step in an industrial scale process. Ultrafiltration/diafiltration is ubiquitous in down- stream processing for concentration, buffer exchange, and final formulation. Special attention is paid to addressing engineering constraints faced during scale-up of ultrafiltration systems. Chapter 11 —- on virus filtration process design and implementation –– provides an overview of viral filter selection, process design and optimization (in both normal and tangential flow mode), and a detailed overview of the actual operating procedures for-full scale implementation. Recognizingtheeconomicpotentialoftransgenicsourcesforbiopharma- ceuticalproduction,thebookincludesachapteronrecoveryofproteinsfrom emergingtransgenicsources.Chapter12providesacomprehensiveeducational overviewofthefieldofproteinproductionandrecoveryfromtransgenicsources © 2007 by Taylor & Francis Group, LLC SHUKLA: “dk3347_c000” — 2006/6/2 — 09:38 — page ix — #9 and also discusses the challenges that need to be addressed for transgenic sourcedproductstobecomearealityinthefuture. The next several chapters in the book deal with additional efforts aimed at ensuring purity, efficacy, and safety in the development of downstream processes for biopharmaceutical manufacturing. Key amongst these are in- processanalyticalmethods,thatformtheeyesandearsofdownstreamprocess developers.Chapter13dealswithvariousqualityandefficacyattributesofbio- pharmaceuticalsandprovidespracticalguidanceonanalyticalmethodsthatcan beemployedtoassessthem. Chapter14providesanexcellenttutorialonthe elementsthatneedtobeinplaceinadownstreamprocesstoensuresafetyfrom viralcontamination.Thechapterprovidesanoverviewofthevariouspotential meansofviralintroductionintotheprocessstream,designofappropriatevirus clearance studies, considerations in selecting appropriate model viruses, and design of scale-down models. Chapter 15 describes the latest trends in viral clearance,aregulatoryperspectiveofthisarea,andanin-depthcomparisonof thevariousestablishedandupcomingmethodsofachievingviralclearance. The final set of chapters in the book focus on various classes of bio- moleculesandprovideinsightintotheirprocessscalepurification.Monoclonal antibodies have emerged as one of the most important classes of biopharma- ceuticals today and their downstream processing aspects are covered in three chapters. Chapter 16 provides a comprehensive introduction to this class of therapeuticsandprovidesdetailedpracticalguidancefordevelopingProteinA chromatographyasthekeypurificationstepinantibodydownstreamprocessing. Chapter17describesthedevelopmentofpolishingchromatographicstepsfor monoclonalantibodydownstreamprocessing. Inadditiontoprovidinguseful practical advice, the chapter also provides several useful process templates. Purificationoflargebiomoleculessuchasgenetherapyvectorspresentsigni- ficant challenges during scale-up when conventional chromatographic resins areusedduetotheirlowbindingcapacities.Chapter18providesanindustrial case-studyforanapprovedbiopharmaceutical(Remicade®)dealingwithpost licensureprocesschangesandstrategiesemployedfortheirregulatoryapproval. Chapter19describesthepurificationofabacterialpolysaccharidevaccine. Investigation of an unexpected problem during scale-up of ultrafiltration for thismoleculeledtoatroubleshootinginvestigationthatledtoabetterprocess understanding. Chapter 20 further highlights the advantages of convective transport in membrane chromatography in overcoming capacity limitations in conven- tionalbeadedchromatographicresinsforlargerbiomolecules.Thechapteralso providesacomprehensiveliteraturereviewforthepurificationofgenetherapy vectors—-anotheremergingclassofbiopharmaceuticals. WehopeProcessScaleBioseparationsfortheBiopharmaceuticalIndustry will be a valuable text for the growing numbers of scientific staff involved © 2007 by Taylor & Francis Group, LLC SHUKLA: “dk3347_c000” — 2006/6/2 — 09:38 — page x — #10 inprocessdevelopmentinthebiopharmaceuticalandbiotechnologyindustries, academia,andgovernmentlaboratories.Insomeways,thisbookwasmotivated bythesharedfeelingamongtheeditorsandauthorsthattherewasneedfora comprehensive tutorial text combining fundamental principles and empirical guidelinesoriginatingfromlarge-scaleexperienceinthebioseparationsarena. Thismakesusconfidentthatthiswillalsobeatimelybookforgraduatestudents andseniorlevelundergraduateswhoarepreparingforacareerinbioprocessing. We believe this book will find a worldwide audience in the rapidly growing biopharmaceuticalsector. AbhinavA.Shukla MarkR.Etzel ShishirGadam © 2007 by Taylor & Francis Group, LLC SHUKLA: “dk3347_c000” — 2006/6/2 — 09:38 — page xi — #11 Editors AbhinavA.ShuklaisPrincipalScientistinPurificationProcessDevelopment atAmgenInc.inSeattle,Washington.Hisgroupisresponsibleforthedevel- opment,characterization,validation,andtransferofdownstreamprocessesfor bothearly-andlate-stagebiopharmaceuticals.Dr.Shuklahasbeeninstrumental in setting up Amgen’s platform strategy for the purification of monoclonal antibody therapeutics. He has also started several technology initiatives at Amgen, and authored numerous publications and presentations in biosepara- tions.PriortojoiningAmgenin2000,Dr.Shuklaheldasimilarroleinprocess development at ICOS Corporation, Bothell, Washington dealing with down- stream processing of bacterial and mammalian cell-culture-derived products. He received his Ph.D. in chemical engineering from Rensselaer Polytechnic Institute, Troy, New York and his B.S. and M.S. in biochemical engineering andbiotechnologyfromtheIndianInstituteofTechnology. Mark R. Etzel is Professor of Chemical and Biological Engineering at the University of Wisconsin-Madison. Dr. Etzel has seventeen years of teaching, research,andconsultingexperienceinbiologicalseparationprocessesinclud- ing membrane adsorption and filtration, freeze drying and spray drying, ion exchange and affinity chromatography, and protein crystallization. Professor EtzelreceivedaB.S.atPurdueUniversity,andaPh.D.attheUniversityofCali- forniaatBerkeley, bothinthedepartmentofchemicalengineering. Dr.Etzel workedinindustryforsixyearsbeforereturningtoacademia. Shishir Gadam is part of the Bioprocess Research and Development divi- sionatMerckandCo., Inc., WestPoint, Pennsylvania, andisresponsiblefor clinicalmanufacturingofbulkvaccineandtherapeuticproteinsusingMerck’s state-of-the-artmultiproductbiologicspilotplant.Duringhislastnineyearsof stay at Merck he has contributed in various areas within biologics including process development, scale up, technology transfer to manufacturing, GMP manufacturingforclinicaluse,andprocessvalidation.PriortojoiningMerck in 1997, Dr. Gadam spent three years at Millipore Corporation, Bedford, Massachusetts, developing new and novel membrane purification technolo- gies. Dr.GadamobtainedhisPh.D.inchemicalengineeringfromRensselaer PolytechnicInstitute,Troy,NewYork. © 2007 by Taylor & Francis Group, LLC SHUKLA: “dk3347_c000” — 2006/6/2 — 09:38 — page xiii — #13
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