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1、国际上不同分析方法验证准则概述Stillwatersrundeep.流流静静水深水深,人人静静心深心深Wherethereislife,thereishope。有生命必有希望。有生命必有希望分分析析方方法法验验证证是是论论证证某某一一分分析析方方法法适适用用于于其其用用途途的过程。的过程。 Analyticalmethodvalidationistheprocesstoconfirmthattheanalyticalprocedureemployedforaspecifictestissuitableforitsintendeduse. 分析方法验证分析方法验证Method Validatio
2、n 7/8/20107/8/2010Slide 3Criteria for Method ValidationLimit of detectionLimit of quantitation Precision (Intermediate precision)Accuracy Linearity/RangeSelectivity/SpecificityRuggednessRobustnessActual validation effort depends on the analysis problemProof suitability for intended useDefinition Met
3、hod ScopeDefine Validation CriteriaTestDefine Routine TestsValidation of Analytical MethodslSample matrixlCompoundslEquipment, LocationlOptimize method parameterslDefine performance characteristicslAcceptance criterialDevelop test caseslPreliminary testslFinal testslSOPslSystem Suitability testslAna
4、lytical quality controlSlide 5Scope of the MethodCompounds,SamplematrixQualitative/quantitativeinformationOperatingrange(concentration)PerformancecharacteristicsInstrument(specific brand, product e.g., Agilent 1200 Series)Location(specific lab, specific site, global)Specificregulatory/standardsrequi
5、rements(e.g., part 21 CFR Part 11, ISO17025)International regulatory bodies and their guidelines on different aspects of MVBodyFull nameGuidance onEurachemFocus for Analytical Chemistry in EuropeMethod validationCITACCooperation of International Traceability in Analytical ChemistryProficiency testin
6、gQuality AssuranceEAEuropean Cooperation for AccreditationAccreditationCENEuropean Committee for NormalizationStandardizationIUPACInternational Union of Pure & Applied Chem. Method validationISOInternational Standardization OrganisationStandardisationAOACILACAssociation of Official Analytical Chemis
7、tsInternational Laboratory Accreditation Cooperat.Internal qual. ControlProficiency testingAccreditation FDAUS Food and Drug AdministrationMethod validationUSPUnited States PharmacopoeiaMethod validationICHInternational Conference on HarmonizationMethod validationExamples of Methods That Require Val
8、idation DocumentationChromatographicMethods-HPLC,GC,TLC,GC/MS,etc.PharmaceuticalAnalysis-InsupportofCMC.BioanalyticalAnalysis-InsupportofPK/PD/ClinicalStudies.SpectrophotometricMethodsUV/VIS,IR,NIR,AA,NMR,XRD,MSCapillaryElectrophoresisMethods-Zone,IsoelectricFocusingParticleSizeAnalysisMethods-Laser
9、,Microscopic,Sieving,SEC,etc.AutomatedAnalyticalMethods-Robots,AutomatedAnalysis.7 77/8/20107/8/2010Considerations Prior to Method ValidationSuitabilityofInstrumentvStatusofQualificationandCalibrationSuitabilityofMaterialsvStatusofReferenceStandards,Reagents,PlaceboLotsSuitabilityofAnalystvStatusofT
10、rainingandQualificationRecordsSuitabilityofDocumentationvWrittenanalyticalprocedureandproperapprovedprotocolwithpre-establishedacceptancecriteria8 87/8/20107/8/2010Validation Step Definetheapplication,purposeandscopeofthemethod.Analytes?Concentration?Samplematrices?Developaanalyticalmethod.Developav
11、alidationprotocol.Qualificationofinstrument.Qualify/trainoperatorQualificationofmaterial.Performpre-validationexperiments.Adjustmethodparametersand/oracceptancecriteriaifnecessary.Performfullvalidationexperiments.DevelopSOPforexecutingthemethodinroutineanalysis.Documentvalidationexperimentsandresult
12、sinthevalidationreport.9 97/8/20107/8/2010Purpose of Method ValidationIdentificationofSourcesandQuantitationofPotentialerrorsDeterminationifMethodisAcceptableforIntendedUseEstablishProofthataMethodCanbeUsedforDecisionMakingSatisfyRegulatoryRequirementsValidation Reporttypeofcompoundsandmatrixdetaile
13、dchemicals,reagents,referencestandardsandcontrolsamplepreparationsproceduresforqualitychecksofstandardsandchemicalsusedsafetyconsiderationsmethodparameterscriticalparametersindicatedfromrobustnesstestinglistingofequipmentanditsfunctionalandperformancerequirements,e.g.celldimensions,baselinenoise,col
14、umntemperaturerangedetailedconditionsonhowtheexperimentswereconducted,includingsamplepreparationstatisticalproceduresandrepresentativecalculationsproceduresforqualitycontrolintheroutine(e.g.,systemsuitabilitytests)representativeplots,e.g.chromatograms,spectraandcalibrationcurvesmethodacceptancelimit
15、performancedatatheexpecteduncertaintyofmeasurementresultscriteriaforrevalidationpersonwhodevelopedandinitiallyvalidatedthemethodsummaryandconclusionsUS FDA Validation GuidelinesFDA Guidance for Industry: Analytical Procedures and Methods Validation(DRAFT),August2000FDAPolicyguide:RequestingMethodsVa
16、lidationforAbbreviatedNewDrugApplications(ANDAs),May1998FDAGuidanceforIndustry:BioanalyticalMethodValidation,May2001FDAGuidance:Mass,SpectrometryforConfirmationoftheIdentityofAnimalDrugResidues(Draft),FDAGuidance:GuidelineforSubmittingSamplesandAnalyticalDataforMethodsValidationFDAGuidance:Protocolf
17、ortheConductofMethodTransferforTypeCMedicatedFeedAssayMethods,May2007US FDA Validation GuidelinesFDA Guidance for Industry: Analytical Procedures and Methods Validation(DRAFT),August2000FDAPolicyguide:RequestingMethodsValidationforAbbreviatedNewDrugApplications(ANDAs),May1998FDAGuidanceforIndustry:B
18、ioanalyticalMethodValidation,May2001FDAGuidance:Mass,SpectrometryforConfirmationoftheIdentityofAnimalDrugResidues(Draft),FDAGuidance:GuidelineforSubmittingSamplesandAnalyticalDataforMethodsValidationFDAGuidance:ProtocolfortheConductofMethodTransferforTypeCMedicatedFeedAssayMethods,May2007ICH Validat
19、ion GuidelinesICH-GuidanceforIndustry:Q2A-TextonValidationofAnalyticalProceduresICH-GuidanceforIndustry:Q2B-ValidationofAnalyticalProcedures-MethodologyEU Validation GuidelinesEURACHEM The Fitness for Purpose of Analytical Methods Probablythemostdetailedofficialdocumentformethodvalidation,1998EMEA G
20、uide Residues: Guidance for generating and reportingmethodsofanalysisinsupportofpre-registrationdatarequirementsforAnnexII(partA,Section4)andAnnexIII(partA,Section5)ofDirective91/414,Nov.2000Australian Validation GuidelinesTGAGuide(Australia)-StartingMaterialAnalyticalProcedureValidation for Complim
21、entary Medicines,March2006NATATechnicalNote#17-GuidelinesfortheValidationandVerificationofChemicalTestMethods,April2009US EPA Validation GuidelinesUSEPAGuidetoMethodFlexibilityandApprovalofEPAWaterMethods40CFRPart136GuidelinesEstablishingTestProceduresfortheAnalysisofPollutants;AnalyticalMethodsforB
22、iologicalPollutantsinAmbientWater;FinalRule,Jan.31,200340CFRParts136and503GuidelinesEstablishingTestProceduresfortheAnalysis of Pollutants; Analytical Methods for Biological Pollutants inWastewaterandSewageSludge:March26,2007USEPA,GuidanceformethodsdevelopmentandmethodsvalidationfortheResource Conse
23、rvation and Recovery Act (RCRA) Program, Washington,1995Validation GuidelinesIUPACTechnicalReport:HarmonizedGuidelinesforSingleLaboratoryValidationofMethodsofAnalysisPureAppl.Chem.,Vol.74,No.5,pp.835-855,2002AOACHowtoMeetISO17025RequirementsforMethodVerification.PreparedbyAOACINTERNATIONAL481N.Frede
24、rickAve,Suite500,2007UnitedStatesPharmacopeia,ValidationofCompendialMethods,e.g.,XXVI,Rockville,MD,20022149/2152(Chapter1225),1999Regulatory and Compliance Requirements ReviewnFDA FDA regulations regulations such such as as GMP, GMP, GLP GLP and and GCP GCP and and quality quality standards standard
25、s such such as as ISO17025 ISO17025 require require analytical analytical methods to be validated before and during routine use. methods to be validated before and during routine use. nThere There are are no no specific specific regulations regulations on on method method validations validations but
26、 but the the FDA, FDA, other other agencies agencies and and industry industry task task forces forces have developed guidelines for method validation. have developed guidelines for method validation. Validation Requirements & Parameters ICH/USP Validation Requirements & Parameters SpecificityLinear
27、ityRangeAccuracyPrecisionRepeatabilityIntermediatePrecisionReproducibilityLimitofDetectionLimitofQuantitationICHICHn nSpecificitySpecificitySpecificitySpecificityn nLinearity and RangeLinearity and RangeLinearity and RangeLinearity and Rangen nAccuracyAccuracyAccuracyAccuracyn nPrecision Precision P
28、recision Precision n nLimit of DetectionLimit of DetectionLimit of DetectionLimit of Detectionn nLimit of QuantitationLimit of QuantitationLimit of QuantitationLimit of Quantitationn nRuggednessRuggednessRuggednessRuggednessn nRobustnessRobustnessRobustnessRobustnessUSPUSPUSP CategoriesCategory1:Qua
29、ntitationofmajorcomponentsoractiveingredientsCategory2:DeterminationofimpuritiesordegradationproductsCategory3:DeterminationofperformancecharacteristicsUSP Data Elements Required For Assay ValidationAnalytical Analytical PerformancePerformanceParameterParameterAssay Assay Category 1Category 1Assay C
30、ategory 2Assay Category 2Assay Assay Category 3Category 3QuantitativeQuantitativeLimit TestsLimit TestsAccuracyAccuracyYesYesYesYes* * *PrecisionPrecisionYesYesYesYesNoNoYesYesSpecificitySpecificityYesYesYesYesYesYes* *LODLODNoNoNoNoYesYes* *LOQLOQNoNoYesYesNoNo* *LinearityLinearityYesYesYesYesNoNo*
31、 *RangeRangeYesYesYesYes* * *RuggednessRuggednessYesYesYesYesYesYesYesYes* May be required, depending on the nature of the specific test.* May be required, depending on the nature of the specific test.ICH Validation Characteristics vs. Type of Analytical ProcedureType of Type of Analytical Analytica
32、l ProcedureProcedureIdentificationIdentificationImpurity testingImpurity testingAssayAssayQuantitativeQuantitativeLimit TestsLimit TestsAccuracyAccuracyNoNoYesYesNoNoYesYesPrecisionPrecision Repeatability RepeatabilityNoNoYesYesNoNoYesYes Interm. Prec. Interm. Prec.NoNoYesYesNoNoYesYesSpecificitySpe
33、cificityYesYesYesYesYesYesYesYesLODLODNoNoNoNoYesYesNoNoLOQLOQNoNoYesYesNoNoNoNoLinearityLinearityNoNoYesYesNoNoYesYesRangeRangeNoNoYesYesNoNoYesYesAOAC Categories of Chemical MethodsCategory1:ConfirmationofIdentityCategory2:QuantifyingananalyteatalowconcentrationCategory 3: Determining if an analyt
34、e is present above or below aspecified, low concentration (often called a Limit Test). The specifiedconcentrationisclosetotheLOQ.Category4:QuantifyingananalyteatahighconcentrationCategory 5: Determining if an analyte is present above or below aspecified, high concentration (often called a Limit Test
35、). The specifiedconcentrationissubstantiallyabovetheLOQ.Category6:Qualitativetest.AOAC Validation Characteristics vs. Type of Analytical ProcedureType of Type of Analytical Analytical ProcedureProcedurePerformance Characteristics Included in a ValidationPerformance Characteristics Included in a Vali
36、dationCategory Category 1 1CategoryCategory 2 2CategoryCategory 3 3CategoryCategory 4 4CategoryCategory 5 5CategoryCategory 6 6AccuracyAccuracyNoNoYesYesNoNoYesYesYesYesNoNoPrecisionPrecisionNoNoYesYesNoNoYesYesYesYesNoNoSpecificitySpecificityYesYesYesYesYesYesYesYesYesYesYesYesLODLODNoNoYesYesYesYe
37、sYesYes/ /NoNoNoNoNoNoLOQLOQNoNoYesYesNoNoYesYes/ /NoNoNoNoNoNoRuggednessRuggednessNoNoYesYesNoNoYesYesNoNoNoNoLinearity/RangeLinearity/RangeNoNoYesYesNoNoYesYesNoNoNoNoAOAC Validation Characteristics -Analyte concentration versus precision within orbetween daysAOAC Validation Characteristics -Analy
38、te recovery at different concentrationsHow do we Know the expectations of the FDA?FDAForm483FDAWarningLettersPersonalExperiences483 Observations There was inadequate method validation specificitydatatodemonstratethateachmethodwascapableofdistinguishingtheactiveingredientfromitsimpuritiesanddegradati
39、onproducts.Specificitystudiesdidnotincludetheminimumstressconditions of acid and base hydrolysis, oxidation,thermal degradation and photolysis, degradationschematic for the active ingredient that identifies themajordegradationproductswasnotincludedforeachproduct.30302009FDA Waning LetterOnadditionto
40、theexampleofmodifyingbothcompendialmethodsandcustomersuppliedmethods,wealsoobservedtheuseofunvalidatedin-housemethodsaswellasunvalidatedmodificationstoin-housemethods.Astatementindicatingthatthemethodhasnotbeenvalidatedintheparticularformulationwasincludedinthecertificateofanalysisforuseofthisstatem
41、entdoesnotabsolve fromusingvalid,accurate,andreproduciblemethods.(June2000)31312009FDA Systems Based Inspection:Laboratory System3232Method Method ValidationValidation13%13%Training/Qual.Training/Qual.4%4%Stability Program Stability Program 21%21%InadequateInadequateRecordsRecords27%27%Controls. Gen
42、eralControls. General35%35%Feb Feb July 2002: 212 Inspections (US) July 2002: 212 Inspections (US)* Reference: Albinus D* Reference: Albinus D Sa, FDA, CDER Office of Compliance, from AAPS, Nov. 2002 presentation. Sa, FDA, CDER Office of Compliance, from AAPS, Nov. 2002 presentation.2009Related Sitewww.fda.govwww.fda.gov/cder/
