Quality by Design for Biopharmaceutical Drug Product Development-Sp.pdf

Quality by Design for Biopharmaceutical Drug Product Development-Sp.pdf

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AAPSAdvancesinthePharmaceuticalSciencesSeriesVolume18SeriesEditorsDaanJ.A.CrommelinUtrecht,Utrecht,TheNetherlandsRobertA.LipperBackCovePharma,LLC,Waldoboro,Maine,USATheAAPSAdvancesinthePharmaceuticalSciencesSeries,publishedinpartner-shipwiththeAmericanAssociationofPharmaceuticalScientists,isdesignedtode-liverwellwrittenvolumesauthoredbyopinionleadersandauthoritiesfromaroundtheglobe,addressinginnovationsindrugresearchanddevelopment,andbestprac-ticeforscientistsandindustryprofessionalsinthepharmaandbiotechindustries.Moreinformationaboutthisseriesathttp:

/JameelSusanHershensonMansoorA.KhanSherylMartin-MoeEditorsQualitybyDesignforBiopharmaceuticalDrugProductDevelopment13ISSN2210-7371ISSN2210-738X（electronic）AAPSAdvancesinthePharmaceuticalSciencesSeriesISBN978-1-4939-2315-1ISBN978-1-4939-2316-8（eBook）DOI10.1007/978-1-4939-2316-8LibraryofCongressControlNumber:

2015934451SpringerNewYorkHeidelbergDordrechtLondonSpringerScience+BusinessMedia,LLC2015Thisworkissubjecttocopyright.AllrightsarereservedbythePublisher,whetherthewholeorpartofthematerialisconcerned,specificallytherightsoftranslation,reprinting,reuseofillustrations,recitation,broadcasting,reproductiononmicrofilmsorinanyotherphysicalway,andtransmissionorinformationstorageandretrieval,electronicadaptation,computersoftware,orbysimilarordissimilarmethodologynowknownorhereafterdeveloped.Theuseofgeneraldescriptivenames,registerednames,trademarks,servicemarks,etc.inthispublicationdoesnotimply,evenintheabsenceofaspecificstatement,thatsuchnamesareexemptfromtherelevantprotectivelawsandregulationsandthereforefreeforgeneraluse.Thepublisher,theauthorsandtheeditorsaresafetoassumethattheadviceandinformationinthisbookarebelievedtobetrueandaccurateatthedateofpublication.Neitherthepublishernortheauthorsortheeditorsgiveawarranty,expressorimplied,withrespecttothematerialcontainedhereinorforanyerrorsoromissionsthatmayhavebeenmade.Printedonacid-freepaperSpringerispartofSpringerScience+BusinessMedia（）EditorsFerozJameelParenteralProductandProcessDevelopmentAmgenInc.ThousandOaksCaliforniaUSASusanHershensonBillandMelindaGatesFoundation,Chemistry,ManufacturingandControlsSeattleWashingtonUSAMansoorA.KhanDivisionofProductQualityResearchFoodandDrugAdministration,CenterforDrugEvaluationandResearch,OfficeofTestingandResearchandOfficeofPharmaceuticalSciencesSilverSpringMarylandUSASherylMartin-MoeEnterpriseCatalystGroupInc.PaloAltoCaliforniaUSAvThisworkisdedicatedtothememoryofourfriendandcolleagueRonaldTaticekasatributetotheimaginationthatledhimtoundertakeaprojectofthismagnitudeandmadehimapioneerinthisfield.ItisalsoatributetothededicationthatinspiredRontocarrythiseffortsofartocompletionbeforehepassedawayonApril23,2014.Ronwillbegreatlymissed.viiPrefaceOccasionallyinonesprofessionalcareeryoubecomeawarethatthehandofhistoryisrestingonyourshoulder.SoitwasinJuly2003,inBrussels,whenthemembersoftheInternationalConferenceonHarmonisation（ICH）ExpertWorkingGroups（EWG）forqualityagreedonanewvisionandstrategyforICH.Summarizedinthestatement,“Aharmonizedpharmaceuticalqualitysystemapplicableacrossthelifecycleoftheproductemphasizinganintegratedapproachtoqualityriskmanage-mentandscience,”ICHagreedtoprogressthreeparadigm-changingguidelines.ThesewereQ8（pharmaceuticaldevelopment）,Q9（qualityriskmanagement）,andQ10（pharmaceuticalqualitysystem）.WhenIcalledtoorderthefirstQ8EWG,weallthoughtthatwemightbeabletotaketheexistingEuropeanNoteforGuidanceonDevelopmentPharmaceuticsandconvertitintoanappropriateICHformatandthatwouldbeit:

asimpletask.Ittookusalittlewhiletoappreciatethefutilityofthisapproach,especiallygiventhegrowinginterestintheapplicationofprocessanalyticaltechnology（PAT）andthegrowingappreciationthatthegoalofpharma-ceuticaldevelopmentistodesignaqualityproductanditsmanufacturingprocesstodeliverconsistentlytheintendedperformanceoftheproduct.Theonlywaytoachievethatconsistencywouldbebydesigningaproductfromtheoutsetthatwouldmeetpatientsneeds,acquiringcomprehensiveproductandprocessunderstanding,andestablishingaproperlycontrolledmanufacturingprocess.Weneededtotelltheworldthatqualitycannotbetestedintoaproduct;ithastobedesignedintoaproduct.But,ofcourse,everyonealreadyknewthis,sotherewasnothingnewhere,buthowcouldwehelpmovetheindustryfromitstraditional3-sigmaprocessestoward6-sigma?

WeneededtotalkaboutDeming,Juran,kaizen,riskassessments,experimentaldesigns,eventhevalueof“failed”experiments.Weneededtogivetheindustrypermissiontosharethefullnessoftheirscientificknowledgewithoutthefearofcreatinganever-increasinglistofregulatoryquestionsthataddedlittlevaluebutmuchtimetothereviewandapprovalprocesses.Withthesethingsinmind,theEWGdraftedtheICHQ8guideline.Recognizingthattraditionaldevelopmentprocesseswouldstillbeneeded,wereferredtothenewthinkingasan“enhancedapproach,”deliberatelyavoidingthemonikerof“qualitybydesign.”EvenasQ8wentthroughitsfinalrevisionsandadoption,itbecameclearthatoutsidetheconfinesoftheEWG,neithertheindustrynorregulatorshadaclearunderstandingofthenewparadigm.WewereaskedtousetheaddendumtoviiiPrefaceQ8todefineandexemplify“qualitybydesign,”andwedidourbest,comparingtraditionalapproacheswithanenhancedquality-by-designapproach.Butevenwiththiseffort,andwithsubsequentImplementationWorkingGroupefforts（whichhaveincludedquestionandanswerdocuments,pointstoconsider）,thereisstillmysteryandconfusionaboutwhatQbDreallymeansforthepharmaceuticalindustry.Fortunately,ourjourneyhasbeenhelpedbytheforesightandcommitmentofanumberofearlyadopters.BeforetheinkwasdryonthefirstpartofQ8,ateamwithintheEuropeanFederationofPharmaceuticalIndustriesandAssociationsde-velopedamocksectionP2（Examplain）,whichdemonstratedsomeofthekeyele-mentsofQbDincludingaqualitytargetproductprofile,riskassessments,designofexperiments,anddesignspace.Twomorecomprehensivecasestudies,intendedfordiscussionandteachingpurposes,quicklyfollowed.Thefirst,ACEtablets,wasaspirationalinmanyrespectsandexploredanumberofinnovativeconceptsthatindustrywascontemplating.Thesecond,A-Mab,discussedtheapplicationofQbDprinciplestoabiotechnologyproduct,stimulatingmuchdiscussionbetweenindus-tryandregulatorsatthesametimeastheFDAwasintroducingitspilotprograms.OthercasestudiessuchastheSakuramockP2fromJapanandA-Vax（QbDforvaccines）andtheseveralmockANDAsubmissionshavestrengthenedourunder-standingandappreciationofbothbusinessandregulatoryopportunities.ManywouldregardQbDforchemicalsubstancesasstraightforward:

ourunder-standingofkineticsandthermodynamicsenablesrapidbuildingonpriorknowledgetoprovidescalablesyntheses.Ontheotherhand,drugproductdevelopmentstillremainsacomplexblendofartandsciencewhichmaybebehindtheoftenexpe-riencedchallengesofestablishingwellcharacterized,robustmanufacturingpro-cessesthatcanbedescribedbyreliablemodels.Forbiologics,itcouldbearguedthattheoppositesituationpertains.Thedrugsubstanceistheprocess:

theprocessesareoftenexquisitelydesignedandengineeredwithfeed-forwardandfeedbackcon-trolstrategies.Whilethequalityisdesignedfromtheoutset,themanydegreesoffreedomandthecharacterizationchallengesmeanthatfullapplicationofQbDprin-ciplesisnoteasy.Thelistofcriticalqualityattributesisgenerallyextensive,ourabilitytodirectlyconnectthemthroughanalyticaltechniquesbacktothecriticalprocessparametersandforwardtothepatientisoftennotstraightforward,andtherealizationofdesignspacesbecomeschallenging,especiallywhenyouconsidertherisksassociatedwithmovementwithadesignspace.However,applicationofQbDprinciplestothefinalsteps,thedrugproduct,ismuchmorestraightforward.Intooneinsightfulvolumeiscollectedawiderangeofdiscussionsandprac-ticalexamplesoftheapplicationofQbDtobiologicaldrugproducts.Forthosestilluncertainaboutthebusinessbenefit,thisistheareatostart.Biologicaldrugproductmanufacturingprocesseslendthemselvestotheenhancedapproach.Therisks,scienceandengineeringareallmuchbetterunderstoodthanthoseinmanyotherareasofourindustry.Thedegreesoffreedomaremanageable.QbDprin-ciplesfacilitatedevelopinganeffectivecontrolstrategy,arguablythemostcriticaldeliverableofawellplannedandexecuteddevelopmentprogram,includingreal-timerelease-testingopportunities.ixPrefaceMostoftheleadingpharmacompaniesnowconsiderQbDtobe“businessasusual”forthecurrentdevelopmentportfolio.AnincreasingnumberofpublicationsattesttothebusinessbenefitsthathaveaccruedfromQbDprogramsandfilings.Experienceisgrowingwithsuccessfulregulatorysubmissionsandapprovals.Forsure,bothindustryandagencieshavebeenonasteeplearningcurvewiththenewparadigm,butintheUSA,thesmallmoleculepilotprogramfollowedbythebio-logicspilotprogramhaveprovidedvaluableinsightandlearning.Similarinitiativeshaveoccurredelsewhere.Theinternationalagencieshavemountedjointassessmentandinspectionprogramsournewparadigmisheretostay,andthepublicationofthisbookcouldnotbebettertimed.Nowisthetimetowholeheartedlygrasptheop-portunities,todothegreat