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:Fq**:€gr#EE-s+MBjwEwr.{stiFE.NDIW:dderi'J*;d#ffi1r:rPff-$l;ln$PankajShahJatinPatelDouglasBothGaryMcGeorgeTimStevensChandraVerma-VarapuStresss.eti.rffDrdldidLdk-\s,.&.dArC{]$VSBItStglDisintegralionvs,Dlssoluflon2.5{gTabletsAPrdeo(ilt)ProcessQualityICH(N=10,30r,i/lCH(N=1o,s)AlbylrizarryAmirRazaghiCarmenLopezDavidZieringElenaZourFrancesMontesGeraldDiDonatoJayawickramaDimuthuPankajShahPrakashParabScottA.MillerTimStevensTobiasMassaICHQ9QualityRiskManagementandApplicationsinpharmaceuticalDevelopmentDr.YunMaoPharmaceuticalsciences;Merck&Co.InclcH-conferenceonHarmonizationofrechnicarRequirementsforResistrationofpharmaceuiicarslbiHu;ia;Li;;l//;;iih;;''Beijing,China,27Apr2012Outline.lntroductiorrtoICHeg-DefinitionofeualityRiskManagement(ORM)-ExamplesofRiskManagement.QualityRistManagementOverview-Principles-Processes-Methodologies.ApplicationsofQRMinpharmaceuticalDevelopment-ProductDevelopment:Riskassessment-ProcessDevelopment:eualitybyDesign-Manufacture:RealTimeReleaseChallengesforPharmaceuticalIndustry.IncreasingDrugDevelopmentCosts-CosttoDevelopaDrug.$138millionUSDin1975.$318millionUSDin1987.$802millionUSDin2001.$1.3billionUSDin2005.LongResearchandDevelopmentTimelint;-10to15YearstoDevelopaProduct.GrowingComplexityandScopeofRisks-IndustryGlobalization-HigherRegulatoryExPectationQualityRiskManagementandQualitybyDesignQualityRiskManagement(oRM)isoneerementoftheQualitybyDesignapproachouflinedinICHeg,egandQ10-ICHQB:PharmaceuticalDevelopment-ICHQ9:QualityRiskManagement-ICHQ10:PharmaceuticaleualitySystemsQRMcanbeappliedinallphasesofproductlifecyclebutisverypowerfulaspartofaeualitybyDesignapproachinpharmaceuticaldevelopmentMerckFullySupportsebDMerckhasembracedebDasastrategicinitiativeonhowwedevelopandmanufactureproducts-QbDprovidesaconsistentframeworkfordeveropinghighquarityproductsthatprovidebenefitstoourpatientsanom6et6ur'customer'sneeds-QbDpromotessystematic,scientificandrisk-basedapproachestoproductandprocessdevelopmentMerckisexecutingacompany-wideebDstrategyandplaybookAllofMerck'sdevelopmentprogramsnowfollowtheQbDapproach-workprocessesareestabrishedtoreafizeMerck'sebDstrategyRiskBasedGonceptsandPrinciplesareNewRegulationParardigmFromlcHQgBriefingPackPresenUFutureIGHQ8:PharmaceuticalDevelopmentDatatransfer/VariableoutputKnowledgetransfer/Sciencebased/GonsistentoutputICHQ9:QualityRiskManagementUsed,howeverpoorlydefinedOpportunitytousestructuredprocessthinkingIGHQ1O:PharmaceuticalQualitySystemsQualitySystemsacrossproductlifecycleQualityDefinitionQuality:Degreetowhichasetofinherentpropertiesofaproduct,systemorprocessfulfillsrequirements.MedicationorDeviceErrorFromICHQgBdefingPackRiskDefinitionRrbk;definedasthecombinationoftheprobabilityofoccurrenceofharmandtheseverityofthatharmCalculatingRisk:RiskpriorityNumberseverity2ofharmFromIGHQ9BriefingPacksSeverity(future)RiskManagementDefinitionManagement:Systematicprocessfortheassessment,control,communicationandreviewofriskstothequalityofthedrug(medicinal)productacrosstheproductlifecycle.FromICHQ9BriefingPackSimpleRiskManagementExamPleProjectObjective:FlyfromUSAtoGhinatoPresentatthisConferenceCouilesyofMariaCruanesSimpleRiskManagementExamPleRiskldentificationCause...duetoProbabilityScalet-5IarrivelatetoShang-HaiMycarbreaksonthewaytoairportandImissflightRiskPriorityNumber(Reru1=ProbabiIity/OccurrenceXlmpacUSeveritycourtesyofMariacruanes12SimpfeRiskManagementExampleYellowAvoidanceMitigationTransferenceGreenAcceptancelmpactCourtesyofMariaCruanesSimpleRiskManagementExampleRiskResponseCause..,duetoProbabilitvScale1.5IarrivelatetoShang-HaiFlightdelaylmisstheConf.Avoid:BookflightdepartingthreedaysearlierAvoid:donotdrive,takeshuttleserviceMitigate:CarinspectionandmaintenanceaweekearlierAccept:Donothingofl\4ariaCruanesCourtesyMoreExamplesofRisk-BasedDecisionMakinginOurPersonalLivesWeroutinelyassessriskonadailybasis...-Driving:WhatistheriskofinjuryifIdrivefasterthanthespeedlimit?-Health:WhatistherisktomyhealthifIdon'tgotothedoctorforahighfever?-Finance:WhatistherisktomyfinancialsituationifIinvestinavolatilestockfund?...buteachpersonperceivestheacceptablelevelofriskdifferentlyandhasadifferentriskthreshold-l'veneverhadanaccident,mycarisingoodshape,andl'magooddriver.orl'lldriveatareasonablespeedbecausedrivingfasterwillonlygetmethere5minutesearlier.-l'vehadafeverlikethisbefore-l'lljusttakeaTylenolandrest.orltcouldbesomethingserious,sol'llhaveitcheckedout.-'lfIlosethemoney,IstillhaveenoughinvestedinotherfundsandIdon'tneedthismoneyuntilretirement.orl'llinvestinamorestablestockfundwithalowerootentialrateofreturn.courtesyofSocratesKyritsisExamplesofRisk-basedDecisionMakinginthePharmaceuticalIndustry.Development-Whatvariablesshouldbestudiedandhow?-Whatvariablesshouldbecontrolled?.FacilitiesandEquipment-HowinvolveddoIQ/OQ/PQactivitiesneedtobe?-Howoftenareenvironmentalandmicrobialconditionsmonitored?.Materials-HowoftendoisasupPlieraudited?-Canmultiplesuppliersofthesameingredientbeused?.Production-AretheappropriateSOPsandtrainingimplemented?14+1-Willadeviationhaveanyimpactonpatientsafetyand/oreffica