研发流程与QbD简介DSPPT课件

,原料药工艺研发流程与QbD,技术转化为价值GMP医药化工法规约束稳定的工艺实施GMP的基础QbD(质量源于设计）-工艺开发指导,法规符合,QualitybyDesign质量源于设计前控制质量源于生产过程控制质量源于检测后控制,法规符合,4,QualitybyDesign质量源于设计,Definition定义Systematicapproachtodevelopmentthatbeginswithpredefinedobjectivesandemphasizesproductandprocessunderstandingandprocesscontrol,basedonsoundscienceandqualityriskmanagement.以合理的科学和质量风险管理为依据的，起始于预定的质量目标，注重对产品和工艺的理解以及对生产工艺过程控制的系统的研发方法Reference:ICHQ8(R)(2)PharmaceuticalDevelopment,2009,法规符合,WhatisQualitybyDesign?什么是质量源于设计(Reference:ICHQ8(R2),2009),法规符合,GoalsofImplementingQbD应用质量源于设计的目的,Achievemeaningfulproductspecificationsthatarebasedonclinicalperformance.根据临床需求建立有意义的产品质量标准Reduceproductvariabilityanddetectsbyincreasingproductandprocessunderstanding通过对产品和其工艺的理解，减少产品质量的变异和瑕疵Enhanceproductdevelopmentandmanufacturingefficiencies提高产品开发和生产效率Improvepost-approvalchangemanagement改善和方便批准后更改的管理,7,QbDTerminology,QualityTargetProductProfile目标产品质量概况CriticalQualityAttributes关键质量属性CriticalMaterialAttributes关键物料属性CriticalProcessParameters关键工艺参数RiskAssessment风险评估DesignSpace设计空间ControlStrategy控制策略ContinualImprovement继续改进,SystematicApproachbyQbD,OverviewofQbD质量源于设计的概括,法规符合,10,ProcessComparison工艺比较,11,ProcessDevelopmentProcedure-产品开发流程,路线评估,工艺开发/路线确定,工艺优化,工艺确认,放大研究,工艺验证,明确目标,商业化生产,QTPP/CQA（杂质、晶型、粒度等）,文献综述路线可行性分析（成本、绿色、设备、质量、原料）合理的科学和技术积累创新,起始物料确认，每步考察，最终工艺确定确定潜在产品质量属性及初步质量风险评估,每步工艺优化CPP确认/优化工艺质量风险控制DoEDesignSpace(允许/操作范围),实验室三批确认,放大工艺/步骤合理性说明/评估,验证方案/验证报告,ContinuousProcessImprovement,ExampleIdentifyCQAinDrugSubstance,13,QualityRiskManagementProcess,14,RiskAssessmentTools风险评估的工具,ToolsforparameterscreeningExamples:Ishikawa(Fishbone)diagrams,What-ifAnalysis,HAZOPanalysisToolsforriskrankingExamples:FMEA/FMECA,Paretoanalysis,RelativerankingExperimentaltoolsforprocessunderstandingExamples:Statisticallydesignedexperiments(DOE),mechanisticmodels,15,SelectedToolsUsedintheRiskAssessment用于风险评估的工具举例,Ishikawa(Fishbone)Diagramtoidentifyallpotentialvariables,suchasrawmaterials,compressionparameters,andenvironmentalfactors,whichcanhaveanimpactonaparticularCQA,suchastablethardness.FailureModeEffectAnalysis(FMEA)torankthevariablesbasedonrisk(i.e.,acombinationofprobability,severity,anddetectability)andtoselecttheprocessparameterswithhigherrisksforfurtherstudiestogaingreaterunderstandingoftheireffectsonCQAs.,16,Ishikawa(Fishbone)Diagrams,AlsoknownasCause&EffectDiagramIncludesallthepotentialinputsthataffectadesiredoutput(CQA)Effectiveforinitialbrainstormingofpotentialdesignspaceparameters,QualityAttribute(Effect),MaterialAttributesProcessParametersOperationalFactors(Causes),17,FailureModeEffectsAnalysis(FMEA),Cross-functionalteamevaluationProductandprocessunderstandingappliedPotentialfailuremodesidentifiedandrelatedtoproductqualityandperformanceProductandprocessrisksprioritizedOutput/resultscanbeusedasabasisfordesignofexperimentorfurtheranalysisRiskquantitativelyassessedRisk=SeverityXLikelihoodXDetectability严重性X可能性X可测试性,18,PreliminaryProcessRiskAssessmentMap,19,DesignSpace设计空间,Definition定义Themultidimensionalcombinationandinteractionofinputvariables(e.g.,materialattributesandprocessparameters)thathavebeendemonstratedtoprovideassuranceofquality输入变数(物料属性和工艺参数)的多维结合和相互作用已证明能提供产品质量的保障Workingwithinthedesignspaceisnotconsideredasachange.MovementoutofthedesignspaceisconsideredtobeachangeDesignspaceisproposedbythedrugapplicantandissubjecttoregulatoryassessmentandapproval,20,DesignSpace设计空间,Designspaceispotentiallyscale-andequipment-dependent设计空间与批量和设备有关Designspacedeterminedatthelaboratoryscalemaynotberelevanttotheprocessatthecommercialscale实验或小试中取得的设计空间也许与商业生产工艺没有直接的关联Therefore,design-spaceverificationatthecommercialscalebecomesessentialunlessitisdemonstratedthatthedesignspaceisscale-independent.与生产批量有关的设计空间参数应在商业批生产过程中证实,21,ImportantNote,Forgenericdrug/APIapplications:DesignspaceisoptionalQbDcanbeimplementedwithoutadesignspacebecauseproductandprocessunderstandingcanbeestablishedwithoutaformaldesignspace.ImplementationofQbDisstronglyencouragedbyFDA.Forsomecomplexdrugsubstancesordrugproducts,implementationofQbDisconsideredarequiredcomponentoftheapplication.,22,ControlStrategy控制策略,ICHQ8definesControlStrategyas:Aplannedsetofcontrols,derivedfromcurrentproductandprocessunderstandingthatensuresprocessperformanceandproductquality.基于在对产品和工艺的理解基础上制定的控制要点以确保工艺稳定和产品质量Thecontrolscanincludeparametersandattributesrelatedtodrugsubstanceanddrug-productmaterialsandcomponents,facilityandequipmentoperatingconditions,in-processcontrols,finished-productspecifications,andtheassociatedmethodsandfrequencyofmonitoringandcontrol.,23,ControlStrategy控制策略,Controlstrategymayinclude:Controlofinputmaterialattributes(CMAs)Controlsforunitoperations(CPPsandprocessendpoints)In-processorreal-timereleasetestingProductspecifications(CQAs),24,OptimizedProcessRiskAssessmentMap,25,CriticalQualityControlStrategyofDrugSubstance,26,ProcessDevelopmentReport工艺硏发报吿,AllwrittendocumentsshouldfollowGoodDocumentPracticeDocumentnumbersAuthorandapproversignaturesDatatraceability(notebooknumbers)Individualreportcanreferenceotherreports,27,ProcessDevelopmentReport工艺硏发报吿,NotawrittenregulatoryrequirementAbsenceofthereportisnotareasonforaFDA-483observationHowever,Companiesmustproducedocumenteddatatojustifycriticalprocessparameters,controlsrangesandspecifications,etc.Nodocumentedsupportivedatawillresultin483observation(GMPdeficiency).,28,ProcessDevelopmentReport工艺硏发报吿,ObjectiveSummarizedevelopmenthistorytosupportproposedcommercialprocessSupportqualification/validationprotocolDemonstrateknowledgeandcontrolstrategyoverthecommercialprocessPrepareforPre-ApprovalInspection(PAI)Referenceforfutureoptimizationandinvestigationactivities,suchasOOSanddeviationsSupportCMC/DMFfiling(Section3.2.S.2.6),29,1.Introduction:DrugSubstanceIdentityandAttributes2.SyntheticRouteDevelopmentEvaluation3.PotentialQualityAttributesoftheDrugSubstance4.PreliminaryRiskAssessmentf