研发流程与QbD简介DS.ppt

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1、原料药工艺研发流程与原料药工艺研发流程与QbDQbD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法规符合Quality by Design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 后控制法规符合法规符合Quality by Design质量源于设计质量源于设计Definition 定义定义Systematic approach to development that begins with predefined objectives and emphasizes product and process unders

2、tanding and process control,based on sound science and quality risk management.以以合合理的科学和质量风险管理的科学和质量风险管理理为依据的，起为依据的，起始于始于预定预定的质量的质量目标目标，注重，注重对对产品和工艺的理产品和工艺的理解以及对生解以及对生产工艺过程控产工艺过程控制制的的系系统的研发方法统的研发方法Reference:ICH Q8(R)(2)Pharmaceutical Development,20094法规符合法规符合What is Quality by Design?什么是质什么是质量源于设量源于

3、设计计(Reference:ICH Q8(R2),2009)Systematic approach to developmentBegins with predefined objectivesEmphasizes product and process understanding and process controlBased on sound science and quality risk management(ICH Q9)法规符合法规符合Goals of Implementing QbD应用质量源于设应用质量源于设计的目的计的目的qAchieve meaningful produc

4、t specifications that are based on clinical performance.根根据临床需求建立有意义的产品质量标准据临床需求建立有意义的产品质量标准qReduce product variability and detects by increasing product and process understanding通过对产品和其工艺的理解，减少产品通过对产品和其工艺的理解，减少产品质量质量的变异和瑕疵的变异和瑕疵qEnhance product development and manufacturing efficiencies 提高产品开发和生产效率

5、提高产品开发和生产效率qImprove post-approval change management改改善和方便批准后更改的管理善和方便批准后更改的管理7QbD Terminology nQuality Target Product Profile 目目标产品质量概况标产品质量概况nCritical Quality Attributes 关关键质键质量属性量属性nCritical Material Attributes 关键物料属性关键物料属性nCritical Process Parameters 关关键工艺参键工艺参数数nRisk Assessment 风险评风险评估估nDesign S

6、pace 设计空设计空间间nControl Strategy 控控制策制策略略nContinual Improvement 继续改进继续改进Systematic Approach by QbDPredefinedObjective预定的目标预定的目标DefinedQualityTargetProductProfile(QTPP)IdentifyCriticalQualityAttributes(CQA)ProductandProcessUnderstanding对产品和工艺的理解对产品和工艺的理解DefineCriticalMaterialAttributes(CMA)IdentifyCrit

7、icalProcessparameters(CPP)UnderstandingtherelationshipbetweenCMA,CPPandCQAProcessControl生产工艺过程控制生产工艺过程控制EstablishappropriatecontrolstrategyDefineProvenAcceptableRange(PAR)andOperationalRange(OR)SoundScience合理的科学合理的科学LiteraturePriorknowledgeDevelopmentstudyQualityRiskManagement质量风险管理质量风险管理Riskbasedap

8、proachthroughdevelopmenttocommercialmanufacturing,aswellascontinualimprovementOverview of QbD质质量源于量源于设设计计的概括的概括Quality Target Product Profile(QTPP)产品品质量概括量概括Critical Quality Attributes(CQA)关关键质量属性量属性Product Design and Process Understanding(CMA,CPP)Control Strategy(PAR,OR.Etc.)Continual Improvement法规

9、符合法规符合 Process Comparison 工艺工艺比较比较1QbD Concept ApproachTraditional Approach QTPP/CQA2Process Route IdentificationProcess Route Identification3Piloting Scale-up and Process OptimizationPiloting Scale-up and Process Optimization4Process Characterization and Process Understanding vCPP,CMA,PAR(OR)5Contr

10、ol strategy(Design Space,etc.)6Process Qualification(Validation)Process Qualification(Validation)1011ProcessDevelopmentProcedure-产品开发流程产品开发流程路线评估路线评估工艺开发工艺开发/路线确定路线确定工艺工艺优化优化工艺确认工艺确认放大研究放大研究工艺验证工艺验证明确目标明确目标商业化商业化生产生产QTPP/CQAQTPP/CQA（杂质、晶型、粒度等）（杂质、晶型、粒度等）文献文献综述综述 路线可行性分析（成本、绿色、设备、质路线可行性分析（成本、绿色、设备、质量

11、原料）合理的量、原料）合理的科学和技术科学和技术积累积累 创新创新起始物料确认，每步考察，最终工艺确定起始物料确认，每步考察，最终工艺确定 确定确定潜在产品质量属性及潜在产品质量属性及初步质量风险评估初步质量风险评估每步工艺优化每步工艺优化 CPPCPP确认确认/优化工艺优化工艺 质量风险控制质量风险控制 DoE DoE Design Space(Design Space(允许允许/操作范围操作范围)实验室三批确认实验室三批确认放大工艺放大工艺/步骤合理性说明步骤合理性说明/评估评估验证方案验证方案/验证报告验证报告ContinuousProcessImprovementExample Id

12、entify CQA in Drug SubstanceQualityAttributesTargetCriticalJustificationSolidStateFormIIYesDirectlylinktosolubility&stabilityPSDDefinedrangeYes/NoFormulationandprocessdodependentAssay(purity)100%oflabelclaimYesAssayvaluewillaffectsafetyandefficacySolubilityInformationNoNotcontrolbyprocessDegradation

13、ProductsXXX:NMT0.5%AnyunknownNMT0.2%Total:NMT1.0%YesTheymayimpactsafetyWaterContentNMT4.0%NoUnlikelytoimpactsafety13Quality Risk Management ProcessProcessDevelopmentControlStrategyDevelopmentContinualImprovementRisk Assessment Tools风险评估的工具估的工具pTools for parameter screeningExamples:Ishikawa(Fishbone)

14、diagrams,What-if Analysis,HAZOP analysispTools for risk rankingExamples:FMEA/FMECA,Pareto analysis,Relative rankingpExperimental tools for process understandingExamples:Statistically designed experiments(DOE),mechanistic models14Selected Tools Used in the Risk Assessment 用于用于风险评估的工估的工具具举例例pIshikawa(

15、Fishbone)Diagramto identify all potential variables,such as raw materials,compression parameters,and environmental factors,which can have an impact on a particular CQA,such as tablet hardness.pFailure Mode Effect Analysis(FMEA)to rank the variables based on risk(i.e.,a combination of probability,sev

16、erity,and detectability)and to select the process parameters with higher risks for further studies to gain greater understanding of their effects on CQAs.1516Ishikawa(Fishbone)DiagramsAlso known as Cause&Effect DiagramIncludes all the potential inputs that affect a desired output(CQA)Effective for i

17、nitial brainstorming of potential design space parametersQualityAttribute(Effect)MaterialAttributesProcessParametersOperationalFactors(Causes)17Failure Mode Effects Analysis(FMEA)Cross-functional team evaluation Product and process understanding appliedPotential failure modes identified and related

18、to product quality and performanceProduct and process risks prioritized Output/results can be used as a basis for design of experiment or further analysisRisk quantitatively assessednRisk=Severity X Likelihood X Detectability严重性严重性 X 可能性可能性 X 可可测试性测试性 18CriticalQualityAttribute(right)AppearanceChemi

19、calIdentityPhysicalIdentityResidualPrecursorsS.M.RelatedImpuritiesProcessRelatedImpuritiesEnantiomericPurityPhthalimideProductsEDC.HCl+ureaby-productDMAPmethylamineInorganicSaltsDMFDichloromethaneIsopropanolEthanolAceticAcidAcetoneAssayParticleSizeStability/StorageProcessStage(below)StartingMaterial

20、RIA10StartingMaterialRIA20RIA30ReactionIsolationDryingRIA35ReactionIsolationDryingRIA46ReactionWork-upStartingMaterialRIA60RIA56ReactionWork-upRIAReactionIsolationPurificationDrying/MillingOverallPreliminaryProcessRiskAssessmentMap19Design Space 设计空空间Definition 定义定义The multidimensional combination a

21、nd interaction of input variables(e.g.,material attributes and process parameters)that have been demonstrated to provide assurance of quality输入变数输入变数(物料属性和工艺参物料属性和工艺参数数)的多维结的多维结合和相互作用已证明能提合和相互作用已证明能提供产品质量的保障供产品质量的保障vWorking within the design space is not considered as a change.Movement out of the de

22、sign space is considered to be a change vDesign space is proposed by the drug applicant and is subject to regulatory assessment and approvalDesign Space 设计空空间 Design space is potentially scale-and equipment-dependent 设计空设计空间与批量和设备有关间与批量和设备有关Design space determined at the laboratory scale may not be

23、relevant to the process at the commercial scale 实验或小试中取实验或小试中取得的设计空得的设计空间也许与商业间也许与商业生产工艺没有直接的关联生产工艺没有直接的关联 Therefore,design-space verification at the commercial scale becomes essential unless it is demonstrated that the design space is scale-independent.与生产批量有与生产批量有关的设计空关的设计空间参数间参数应在商应在商业批生产过程中证实业批生

24、产过程中证实20Important NoteFor generic drug/API applications:pDesign space is optionalpQbD can be implemented without a design space because product and process understanding can be established without a formal design space.pImplementation of QbD is strongly encouraged by FDA.For some complex drug substa

25、nces or drug products,implementation of QbD is considered a required component of the application.21Control Strategy控制策控制策略略ICH Q8 defines Control Strategy as:qA planned set of controls,derived from current product and process understanding that ensures process performance and product quality.基于在对产品

26、和工艺的理解基础上制定的控制要点以确保工艺稳定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和产品质量The controls can include parameters and attributes related to drug substance and drug-product materials and components,facility and equipment operating conditions,in-process controls,finished-product specifications,and the associated meth

27、ods and frequency of monitoring and control.22Control Strategy控制策略控制策略Control strategy may include:Control of input material attributes(CMAs)Controls for unit operations(CPPs and process endpoints)In-process or real-time release testing Product specifications(CQAs)2324CriticalQualityAttribute(right)

28、AppearanceChemicalIdentityPhysicalIdentityResidualPrecursorsS.M.RelatedImpuritiesProcessRelatedImpuritiesEnantiomericPurityPhthalimideProductsEDC.HCl+ureaby-productDMAPmethylamineInorganicSaltsDMFDichloromethaneIsopropanolEthanolAceticAcidAcetoneAssayParticleSizeStability/StorageProcessStage(below)S

29、tartingMaterialRIA10StartingMaterialRIA20RIA30ReactionIsolationDryingRIA35ReactionIsolationDryingRIA46ReactionWork-upStartingMaterialRIA60RIA56ReactionWork-upRIAReactionIsolationPurificationDrying/MillingOverallOptimizedProcessRiskAssessmentMap25CriticalQualityControlStrategyofDrugSubstanceCriticalQ

30、ualityAttribute(TestMethod)DSConfirmationTestAcceptanceCriteriaProductQualityControlTypeDescriptionofControlsAppearance(Visual)Whitetooff-whitepowderStartingMaterials(RIA10,RIA60)&RIAProcess:RIA35Isolation&RIACrystallizationRIA10 Appearance Specification(white to light brownsolid);Filtered&washed,RI

31、A35AppearanceSpecification(whitetooff-whitesolid);RIA60 Appearance Specification(white to dark beigesolid);FiltercakewashofcrudeRIAandcrystallizedRIAensurescolourremoval.ChemicalIdentification(IR)The IR absorption spectrum of thesampleexhibitsthemaximaonlyatthesame wavelengths as that of thecorrespo

32、ndingstandard.StartingMaterials(RIA10,RIA20,RIA60)&GeneralCGMPRIA10,RIA20&RIA60IdentificationSpecification;ChemicalIdentification(HPLC)The retention time of the principlepeak in the chromatogram of thesample preparation conforms to thatofthereferencestandardpreparationobtained as directed in the Ass

33、aymethod.StartingMaterial(RIA10,RIA60,phthalimidepotassium,)&GeneralCGMPRIA10,phthalimide potassium&RIA60 IdentificationSpecification.Process Development Report工艺工艺硏发报吿硏发报吿 qAll written documents should follow Good Document PracticeDocument numbersAuthor and approver signaturesData traceability(note

34、book numbers)Individual report can reference other reports26ProcessDevelopmentReport工艺工艺硏发报吿硏发报吿 qNot a written regulatory requirementqAbsence of the report is not a reason for a FDA-483 observationHowever,vCompanies must produce documented data to justify critical process parameters,controls ranges

35、 and specifications,etc.vNo documented supportive data will result in 483 observation(GMP deficiency).27ProcessDevelopmentReport工艺工艺硏发报吿硏发报吿 qObjectiveSummarize development history to support proposed commercial processSupport qualification/validation protocolDemonstrate knowledge and control strate

36、gy over the commercial process Prepare for Pre-Approval Inspection(PAI)Reference for future optimization and investigation activities,such as OOS and deviationsSupport CMC/DMF filing(Section 3.2.S.2.6)28291.Introduction:DrugSubstanceIdentityandAttributes2.SyntheticRouteDevelopmentEvaluation3.Potenti

37、alQualityAttributesoftheDrugSubstance4.PreliminaryRiskAssessmentforCriticalQualityAttributes5.StartingMaterialDiscussion6.OptimizationofManufacturingProcess7.Manufacturing7.1.BriefDescription7.2.SyntheticScheme7.3.DetailedDescriptionoftheProcessControl8.CriticalQualityControlStrategyofDrugSubstance9

38、HistoryofManufacturingProcessProcessDevelopmentReport-产品开发报告产品开发报告30Attachments:SupplierSpecificationsforStartingMaterialSpecificationsforStartingMaterialandIntermediatesProcessControlMapDetailedRiskAssessmentCofASummaryofManufacturedBatchesGlossaryofAbbreviationsProcessDevelopmentReport-产品开发报告产品开发报告31QbD-产品开发流程产品开发流程工艺开发报告工艺开发报告比较比较QbD工艺开发工艺开发产品产品开发开发报告报告QTPP/CQA目标产品质量标准引言-产品介绍及要求工艺设计与风险评估工艺路线评估/路线选择与确定路线选择与开发潜在质量属性确定初步风险评估起始物料确定风险控制策略工艺优化/确认/放大/验证生产工艺优化生产工艺控制产品质量控制策略持续改进商业化生产生产批次历史/年报分析Quality by Design质量源于设计目标：设计和开发的工艺能够在可控风险的情况下生产出符合质量标准的产品满足产品质量要求的工艺开发是执行GMP全过程的基础-全程可控全程可控法规符合法规符合