研發(fā)流程與簡介

研發(fā)流程與簡介

技術(shù)轉(zhuǎn)化為價(jià)值

GMP–醫(yī)藥化工法規(guī)約束

穩(wěn)定的工藝–實(shí)施GMP的基礎(chǔ)

QbD(質(zhì)量源于設(shè)計(jì)）-工藝開發(fā)指導(dǎo)

法規(guī)符合QualitybyDesign

質(zhì)量源于設(shè)計(jì)–前控制

質(zhì)量源于生產(chǎn)–過程控制

質(zhì)量源于檢測–后控制

法規(guī)符合QualitybyDesign

質(zhì)量源于設(shè)計(jì)Definition定義Systematicapproachtodevelopmentthatbeginswithpredefinedobjectivesandemphasizesproductandprocessunderstandingandprocesscontrol,basedonsoundscienceandqualityriskmanagement.以合理的科學(xué)和質(zhì)量風(fēng)險(xiǎn)管理為依據(jù)的，起始于預(yù)定的質(zhì)量目標(biāo)，注重對(duì)產(chǎn)品和工藝的理解以及對(duì)生產(chǎn)工藝過程控制的系統(tǒng)的研發(fā)方法

Reference:ICHQ8(R)(2)PharmaceuticalDevelopment,20094法規(guī)符合WhatisQualitybyDesign?

什么是質(zhì)量源于設(shè)計(jì)

(Reference:ICHQ8(R2),2009)SystematicapproachtodevelopmentBeginswithpredefinedobjectivesEmphasizesproductandprocessunderstandingandprocesscontrolBasedonsoundscienceandqualityriskmanagement(ICHQ9)法規(guī)符合GoalsofImplementingQbD

應(yīng)用質(zhì)量源于設(shè)計(jì)的目的Achievemeaningfulproductspecificationsthatarebasedonclinicalperformance.

根據(jù)臨床需求建立有意義的產(chǎn)品質(zhì)量標(biāo)準(zhǔn)Reduceproductvariabilityanddetectsbyincreasingproductandprocessunderstanding通過對(duì)產(chǎn)品和其工藝的理解，減少產(chǎn)品質(zhì)量的變異和瑕疵Enhanceproductdevelopmentandmanufacturingefficiencies提高產(chǎn)品開發(fā)和生產(chǎn)效率Improvepost-approvalchangemanagement改善和方便批準(zhǔn)后更改的管理7QbDTerminologyQualityTargetProductProfile目標(biāo)產(chǎn)品質(zhì)量概況CriticalQualityAttributes

關(guān)鍵質(zhì)量屬性CriticalMaterialAttributes關(guān)鍵物料屬性CriticalProcessParameters關(guān)鍵工藝參數(shù)RiskAssessment風(fēng)險(xiǎn)評(píng)估DesignSpace

設(shè)計(jì)空間ControlStrategy控制策略ContinualImprovement

繼續(xù)改進(jìn)SystematicApproachbyQbDPredefinedObjective預(yù)定的目標(biāo)DefinedQualityTargetProductProfile(QTPP)IdentifyCriticalQualityAttributes(CQA)ProductandProcessUnderstanding對(duì)產(chǎn)品和工藝的理解DefineCriticalMaterialAttributes(CMA)IdentifyCriticalProcessparameters(CPP)UnderstandingtherelationshipbetweenCMA,CPPandCQAProcessControl生產(chǎn)工藝過程控制EstablishappropriatecontrolstrategyDefineProvenAcceptableRange(PAR)andOperationalRange(OR)SoundScience合理的科學(xué)LiteraturePriorknowledgeDevelopmentstudyQualityRiskManagement質(zhì)量風(fēng)險(xiǎn)管理Riskbasedapproachthroughdevelopmenttocommercialmanufacturing,aswellascontinualimprovementOverviewofQbD

質(zhì)量源于設(shè)計(jì)的概括QualityTargetProductProfile(QTPP)產(chǎn)品質(zhì)量概括CriticalQualityAttributes(CQA)關(guān)鍵質(zhì)量屬性ProductDesignandProcessUnderstanding(CMA,CPP)ControlStrategy(PAR,OR.Etc.)ContinualImprovement法規(guī)符合ProcessComparison工藝比較1QbDConceptApproachTraditionalApproach

QTPP/CQA2ProcessRouteIdentificationProcessRouteIdentification3PilotingScale-upandProcessOptimizationPilotingScale-upandProcessOptimization4ProcessCharacterizationandProcessUnderstandingCPP,CMA,PAR(OR)5Controlstrategy(DesignSpace,etc.)6ProcessQualification(Validation)ProcessQualification(Validation)1011ProcessDevelopmentProcedure-產(chǎn)品開發(fā)流程路線評(píng)估工藝開發(fā)/路線確定工藝優(yōu)化工藝確認(rèn)放大研究工藝驗(yàn)證明確目標(biāo)商業(yè)化生產(chǎn)QTPP/CQA（雜質(zhì)、晶型、粒度等）文獻(xiàn)綜述路線可行性分析（成本、綠色、設(shè)備、質(zhì)量、原料）合理的科學(xué)和技術(shù)積累創(chuàng)新起始物料確認(rèn)，每步考察，最終工藝確定確定潛在產(chǎn)品質(zhì)量屬性及初步質(zhì)量風(fēng)險(xiǎn)評(píng)估每步工藝優(yōu)化

CPP確認(rèn)/優(yōu)化工藝質(zhì)量風(fēng)險(xiǎn)控制

DoE

DesignSpace(允許/操作范圍)實(shí)驗(yàn)室三批確認(rèn)放大工藝/步驟合理性說明/評(píng)估驗(yàn)證方案/驗(yàn)證報(bào)告ContinuousProcessImprovementExample

IdentifyCQAinDrugSubstanceQualityAttributesTargetCriticalJustificationSolidStateFormIIYesDirectlylinktosolubility&stabilityPSDDefinedrangeYes/NoFormulationandprocessdodependentAssay(purity)100%oflabelclaimYesAssayvaluewillaffectsafetyandefficacySolubilityInformationNoNotcontrolbyprocessDegradationProductsXXX:NMT0.5%AnyunknownNMT0.2%Total:NMT1.0%YesTheymayimpactsafetyWaterContentNMT4.0%NoUnlikelytoimpactsafety13QualityRiskManagementProcessProcessDevelopmentControlStrategyDevelopmentContinualImprovementRiskAssessmentTools

風(fēng)險(xiǎn)評(píng)估的工具ToolsforparameterscreeningExamples:Ishikawa(Fishbone)diagrams,What-ifAnalysis,HAZOPanalysisToolsforriskrankingExamples:FMEA/FMECA,Paretoanalysis,

RelativerankingExperimentaltoolsforprocessunderstandingExamples:Statisticallydesignedexperiments(DOE),mechanisticmodels14SelectedToolsUsedintheRiskAssessment

用于風(fēng)險(xiǎn)評(píng)估的工具舉例Ishikawa(Fishbone)Diagramtoidentifyallpotentialvariables,suchasrawmaterials,compressionparameters,andenvironmentalfactors,whichcanhaveanimpactonaparticularCQA,suchastablethardness. FailureModeEffectAnalysis(FMEA)torankthevariablesbasedonrisk(i.e.,acombinationofprobability,severity,anddetectability)andtoselecttheprocessparameterswithhigherrisksforfurtherstudiestogaingreaterunderstandingoftheireffectsonCQAs.1516Ishikawa(Fishbone)DiagramsAlsoknownasCause&EffectDiagramIncludesallthepotentialinputsthataffectadesiredoutput(CQA)EffectiveforinitialbrainstormingofpotentialdesignspaceparametersQualityAttribute(Effect)MaterialAttributesProcessParametersOperationalFactors(Causes)17FailureModeEffectsAnalysis(FMEA)Cross-functionalteamevaluationProductandprocessunderstandingappliedPotentialfailuremodesidentifiedandrelatedtoproductqualityandperformanceProductandprocessrisksprioritizedOutput/resultscanbeusedasabasisfordesignofexperimentorfurtheranalysisRiskquantitativelyassessedRisk=SeverityXLikelihoodXDetectability

嚴(yán)重性X

可能性

X可測試性18CriticalQualityAttribute(right)

AppearanceChemicalIdentityPhysicalIdentityResidualPrecursorsS.M.RelatedImpuritiesProcessRelatedImpuritiesEnantiomericPurityPhthalimideProductsEDC.HCl+ureaby-productDMAPmethylamineInorganicSaltsDMFDichloromethaneIsopropanolEthanolAceticAcidAcetoneAssayParticleSizeStability/StorageProcessStage(below)StartingMaterialRIA10

StartingMaterialRIA20

RIA30Reaction

Isolation

Drying

RIA35Reaction

Isolation

Drying

RIA46Reaction

Work-up

StartingMaterialRIA60

RIA56Reaction

Work-up

RIAReaction

Isolation

Purification

Drying/Milling

Overall

PreliminaryProcessRiskAssessmentMap19DesignSpace

設(shè)計(jì)空間Definition

定義Themultidimensionalcombinationandinteractionofinputvariables(e.g.,materialattributesandprocessparameters)thathavebeendemonstratedtoprovideassuranceofquality

輸入變數(shù)(物料屬性和工藝參數(shù))的多維結(jié)合和相互作用已證明能提

供產(chǎn)品質(zhì)量的保障Workingwithinthedesignspaceisnotconsideredasachange.MovementoutofthedesignspaceisconsideredtobeachangeDesignspaceisproposedbythedrugapplicantandissubjecttoregulatoryassessmentandapprovalDesignSpace

設(shè)計(jì)空間

Designspaceispotentiallyscale-andequipment-dependent設(shè)計(jì)空間與批量和設(shè)備有關(guān)Designspacedeterminedatthelaboratoryscalemaynotberelevanttotheprocessatthecommercialscale實(shí)驗(yàn)或小試中取得的設(shè)計(jì)空間也許與商業(yè)生產(chǎn)工藝沒有直接的關(guān)聯(lián)Therefore,design-spaceverificationatthecommercialscalebecomesessentialunlessitisdemonstratedthatthedesignspaceisscale-independent.與生產(chǎn)批量有關(guān)的設(shè)計(jì)空間參數(shù)應(yīng)在商業(yè)批生產(chǎn)過程中證實(shí)20ImportantNoteForgenericdrug/APIapplications:DesignspaceisoptionalQbDcanbeimplementedwithoutadesignspacebecauseproductandprocessunderstandingcanbeestablishedwithoutaformaldesignspace.ImplementationofQbDisstronglyencouragedbyFDA.Forsomecomplexdrugsubstancesordrugproducts,implementationofQbDisconsideredarequiredcomponentoftheapplication.21ControlStrategy

控制策略ICHQ8definesControlStrategyas:Aplannedsetofcontrols,derivedfromcurrentproductandprocessunderstandingthatensuresprocessperformanceandproductquality.

基于在對(duì)產(chǎn)品和工藝的理解基礎(chǔ)上制定的控制要點(diǎn)以確保工藝穩(wěn)定和產(chǎn)品質(zhì)量Thecontrolscanincludeparametersandattributesrelatedtodrugsubstanceanddrug-productmaterialsandcomponents,facilityandequipmentoperatingconditions,in-processcontrols,finished-productspecifications,andtheassociatedmethodsandfrequencyofmonitoringandcontrol.22ControlStrategy

控制策略Controlstrategymayinclude:Controlofinputmaterialattributes(CMAs)Controlsforunitoperations(CPPsandprocessendpoints)In-processorreal-timereleasetestingProductspecifications(CQAs)2324CriticalQualityAttribute(right)

AppearanceChemicalIdentityPhysicalIdentityResidualPrecursorsS.M.RelatedImpuritiesProcessRelatedImpuritiesEnantiomericPurityPhthalimideProductsEDC.HCl+ureaby-productDMAPmethylamineInorganicSaltsDMFDichloromethaneIsopropanolEthanolAceticAcidAcetoneAssayParticleSizeStability/StorageProcessStage(below)StartingMaterialRIA10

StartingMaterialRIA20

RIA30Reaction

Isolation

Drying

RIA35Reaction

Isolation

Drying

RIA46Reaction

Work-up

StartingMaterialRIA60

RIA56Reaction

Work-up

RIAReaction

Isolation

Purification

Drying/Milling

Overall

Optimized

ProcessRiskAssessmentMap25CriticalQualityControlStrategyofDrugSubstanceCriticalQualityAttribute(TestMethod)DSConfirmationTestAcceptanceCriteriaProductQualityControlTypeDescriptionofControlsAppearance(Visual)Whitetooff-whitepowderStartingMaterials(RIA10,RIA60)&RIAProcess:RIA35Isolation&RIACrystallizationRIA10AppearanceSpecification(whitetolightbrownsolid);Filtered&washed,RIA35AppearanceSpecification(whitetooff-whitesolid);RIA60AppearanceSpecification(whitetodarkbeigesolid);FiltercakewashofcrudeRIAandcrystallizedRIAensurescolourremoval.ChemicalIdentification(IR)TheIRabsorptionspectrumofthesampleexhibitsthemaximaonlyatthesamewavelengthsasthatofthecorrespondingstandard.StartingMaterials(RIA10,RIA20,RIA60)&GeneralCGMPRIA10,RIA20&RIA60IdentificationSpecification;ChemicalIdentification(HPLC)TheretentiontimeoftheprinciplepeakinthechromatogramofthesamplepreparationconformstothatofthereferencestandardpreparationobtainedasdirectedintheAssaymethod.StartingMaterial(RIA10,RIA60,phthalimidepotassium,)&GeneralCGMPRIA10,phthalimidepotassium&RIA60IdentificationSpecification.

ProcessDevelopmentReport

工藝硏發(fā)報(bào)吿AllwrittendocumentsshouldfollowGoodDocumentPracticeDocumentnumbersAuthorandapproversignaturesDatatraceability(notebooknumbers)Individualreportcanreferenceotherreports26ProcessDevelopmentReport

工藝硏發(fā)報(bào)吿N(yùn)otawrittenregulatoryrequirementAbsenceofthereportisnotareasonforaFDA-483observationHowever,Companiesmustproducedocumenteddatatojustifycriticalprocessparameters,controlsrangesandspecifications,etc.Nodocumentedsupportivedatawillresultin483observation(GMPdeficiency).27ProcessDevelopmentReport

工藝硏發(fā)報(bào)吿ObjectiveSummarizedevelopmenthistorytosuppo