美国 FDA 分析方法验证指南 （中英对照）

（中英对照）FDA（中英对照）FDA导言 背景 分析方法的类型 法定分析方法 可选择分析方法 稳定性指示分析 对照品 对照品的类型 分析报告单 对照品的界定 IND中的分析方法验证 NDA,ANDA,BLA和PLA中分析方法验证的内容和格式 原则 取样 仪器和仪器参数 试剂 系统适应性实验 对照品的制备 样品的制备 分析方法 计算 结果报告 NDA，ANDA,BLA和PLA中的分析方法验证 非法定分析方法 验证项目 其它分析方法验证信息 耐用性 强降解实验 仪器输出/原始资料 各类检测的建议验证项目 高效液相色谱(HPLC) 气相色谱(GC) A：NDA，ANDA，BLAPLAB：I.I.Thisguidanceprovidesrecommendationstoapplicantsonsubmittingprocedures,validationdata,andsamplestosupportthedocumentationoftheidentity,strength,quality,purity,andpotencyofdrugsubstancesanddrugproducts.Thisguidanceisintendedtoassistapplicantsinassemblinginformation,submittingsamples,andpresentingdatatosupportanalyticalmethodologies.Therecommendationsapplytodrugsubstancesanddrugproductscoveredinnewdrugapplications(NDAs),abbreviatednewdrugapplications(ANDAs),biologicslicenseapplications(BLAs),productlicenseapplications(PLAs),andsupplementstotheseTheprinciplesalsoapplytodrugsubstancesanddrugproductscoveredinIIdrugmasterfiles(DMFs).Ifadifferentapproachischosen,theapplicantisencouragedtodiscussthematterinadvancewiththecenterwithproductjurisdictiontopreventtheexpenditureofresourcesonpreparingasubmissionthatmaylaterbedeterminedtobeunacceptable.Theprinciplesofmethodsvalidationdescribedinthisguidanceapplytoalltypesofanalyticalprocedures.However,thespecificrecommendationsinthisguidancemaynotbeapplicabletocertainuniqueanalyticalproceduresforproductssuchasbiological,biotechnological,botanical,orradiopharmaceuticaldrugs.Forexample,manybioassaysarebasedonanimalchallengemodels,39immunogenicityassessments,orotherimmunoassaysthathaveuniquefeaturesshouldbeconsideredwhensubmittinganalyticalprocedureandmethodsvalidationFurthermore,specificrecommendationsforbiologicalandimmunochemicalteststhatmaybenecessaryforcharacterizationandqualitycontrolofmanydrugsubstancesanddrugproductsarebeyondthescopeofthisguidancedocument.Althoughthisguidancedoesnotspecificallyaddressthesubmissionofanalyticalproceduresandvalidationdataforrawmaterials,intermediates,excipients,containerclosurecomponents,andothermaterialsusedintheproductionofdrugsubstancesanddrugproducts,validatedanalyticalproceduresshouldbeusedtoanalyzethesematerials.withtheappropriatechemistryreviewstaffatFDA.Thisguidance,whenfinalized,willreplacetheFDAguidanceforindustryonSubmittingSamplesandAnalyticalDataforMethodsValidation(February1987).II.II.EachNDAandANDAmustincludetheanalyticalproceduresnecessarytoensuretheidentity,strength,quality,purity,andpotencyofthedrugsubstanceanddrugproduct,includingbioavailabilityofthedrugproduct(21CFR314.50(d)(1)and度和效力，还包括制剂的生物利用度(21CFR314.50(d)(1)和314.94(a)(9)(i))。Datamustbeavailabletoestablishthattheanalyticalproceduresusedintestingmeetproperstandardsofaccuracyandreliability(21CFR211.165(e)andMethodsvalidationistheprocessofdemonstratingthatanalyticalproceduresaresuitablefortheirintendeduse.Themethodsvalidationprocessforanalyticalproceduresbeginswiththeplannedandsystematiccollectionbytheapplicantofthevalidationdatatosupporttheanalyticalprocedures. reviewchemistevaluatestheanalyticalproceduresandvalidationdatasubmittedintheNDAorANDA.审评化学家会对NDA或ANDAOnrequestfromFDA,anNDAorANDAapplicantmustsubmitsamplesofdrugproduct,drugsubstance,noncompendialreferencestandards,andblankssothattheapplicant'sdrugsubstanceanddrugproductanalyticalprocedurescanbeevaluatedbyFDAlaboratories(21CFR314.50(e)and314.94(a)(10)).使FDA实验室能对申请者所用分析方法进行评审(21CFR314.50(e)and314.94(a)(10))。TheFDAlaboratoryanalysisdemonstratesthattheanalyticalproceduresarereproduciblebylaboratorytesting.Thereviewchemistsandlaboratoryanalystsdeterminethesuitabilityoftheanalyticalproceduresforregulatorypurposes.(21CFRpart58),asappropriate.GMP（21CFRpart211)和GLP(21CFRpart58)。EachBLAandPLAmustincludeafulldescriptionofthemanufacturingmethods,includinganalyticalprocedures,thatdemonstratethatthemanufacturedproductmeetsprescribedstandardsofsafety,purity,andpotency(21CFR601.2(a)and符合规定睥安全，纯充和效力标准的(21CFR601.2(a)and601.2(c)(1)(iv))。Datamustbeavailabletoestablishthattheanalyticalproceduresusedintestingmeetproperstandardsofaccuracyandreliability(21CFR81theirvalidationaresubmittedaspartofthelicenseapplicationorsupplementandareevaluatedbythereviewcommittee.必须要有资料证明所用的分析方法是符合一定的准确度和可靠性要求的(21CFR81Representativesamplesoftheproductmustbesubmittedandsummariesofresultsofandverifythetestresults.需提供代表性样品及该样品所代表批号的检测结果总结(21CFR601.2(a)andAllanalyticalproceduresareofequalimportancefromavalidationperspective.Inareforin-process,release,acceptance,orstabilitytesting.EachquantitativeanalyticalprocedureshouldbedesignedtominimizeassayAnalyticalproceduresandvalidationdataaresubmittedinthesectionsoftheapplicationonanalyticalproceduresandcontrols.RecommendationsoninformationtobesubmittedareincludedinsectionsIIIthroughIXandXIofthisguidance.InformationonsubmissionofthemethodsvalidationpackagetotheNDAorANDAandsamplestotheFDAlaboratoriesisprovidedinsectionX.III.III.TYPESOFANALYTICALA.RegulatoryAnalyticalProcedureAregulatoryanalyticalprocedureistheordrugproduct.TheanalyticalproceduresintheU.S.Pharmacopeia/NationalFormulary(USP/NF)arethoselegallyrecognizedundersection501(b)oftheFood,Drug,andCosmeticAct(theAct)astheregulatoryanalyticalproceduresforcompendialitems.ForpurposesofdeterminingcompliancewiththeAct,theregulatoryanalyticalprocedureisused. A.B.AlternativeAnalyticalAnalternativeanalyticalprocedureisananalyticalprocedureproposedbytheapplicantforuseinsteadoftheregulatoryanalyticalprocedure.Avalidatedalternativeanalyticalprocedureshouldbesubmittedonlyifitisshowntoperformequaltoorbetterthantheregulatoryanalyticalprocedure.B.Ifanalternativeanalyticalprocedureissubmitted,theapplicantshouldprovidevalidationdata,andcomparativedatatotheregulatoryanalyticalprocedure.C.Stability-IndicatingAstability-indicatingassayisavalidatedquantitativeanalyticalprocedurethatcandetectthechangeswithtimeinthepertinentpropertiesofthedrugsubstanceanddrugproduct.C.interferencefromdegradationproducts,processimpurities,excipients,orotherpotentialimpurities。Ifanapplicantsubmitsanon-stability-indicatinganalyticalprocedureforreleasetesting,thenananalyticalprocedurecapableofqualitativelyandquantitativelymonitoringtheimpurities,includingdegradationproducts,shouldcomplementit.Assayanalyticalproceduresforstabilitystudiesshouldbestability-indicating,unlessscientificallyjustified.IV.IV.REFERENCEA.TypesofAreferencestandard(i.e.,primarystandard)maybeobtainedfromtheUSP/NForotherofficialsources(e.g.,CBER,21CFR610.20).IftherearequestionsonwhetherasourceofastandardwouldbeconsideredbyFDAtobeanofficialsource,applicantsshouldcontacttheappropriatechemistryreviewstaff.Whenthereisnoofficialsource,areferencestandardshouldbeofthehighestpossiblepurityandbefullycharacterized.IVA．可以从USP/NF处或其它官方(比如说，CBER，21CFR610.20)获得标准品(也就是一级对照品)。如果不能确定一标准品的来源是否会被FDA认为是官方来源，申请者应当要向适当的并得到充分界定。Aworkingstandard(i.e.,in-houseorsecondarystandard)isastandardthatisqualifiedagainstandusedinsteadofthereferencestandard.B.Certificateofshouldbesubmittedinthesectionoftheapplicationonanalyticalproceduresandofthereferencestandard.Thestandardshouldbestoredcorrectlyandusedwithintheestablisheduseinterval.B．对于从官方获得的标准品，用户应当要确保标准品的适用性。应当正确储存标准品并在已确定的时间段内使用该标准品。C.CharacterizationofaReferencecharacterization.Areferencestandardthatisnotobtainedfromanofficialsourceshouldbeofthehighestpuritythatcanbeobtainedbyreasonableeffort,anditandpotency.C．Thequalitativeandquantitativeanalyticalproceduresusedtocharacterizeareferencestandardareexpectedtobedifferentfrom,andmoreextensivethan,thoseusedtocontroltheidentity,strength,quality,purity,andpotencyofthedrugsubstanceorthedrugproduct.AnalyticalproceduresusedtoDraft—NotforImplementationcharacterizeareferencestandardshouldnotrelysolelyoncomparisontestingtoapreviouslydesignatedreferencestandard.Generally,thischaracterizationinformationshouldAbriefdescriptionofthemanufactureofthereferencestandard,ifthemanufacturingprocessdiffersfromthatofthedrugsubstance.AnyadditionalpurificationproceduresusedinthepreparationofthereferencestandardshouldbeLegiblereproductionsoftherelevantspectra,chromatograms,thin-layerchromatogram(TLC)photographsorreproductions,andotherappropriateinstrumental Dataestablishingpurity.Thedatashouldbeobtainedbyusingappropriatetests,suchasTLC,gaschromatography(GC),high-pressureliquidchromatography(HPLC),phasesolubilityanalysis,appropriatethermometricanalyticalprocedures,andothersasnecessary.相关光谱图，色谱图，TLCAppropriatechemicalattributeinformation,suchasstructuralformula,empiricalformula,andmolecularweight.Informationtosubstantiatetheproofofstructureshouldincludeappropriateanalyticaltests,suchaselementalanalysis,infraredspectrophotometry(IR),ultravioletspectrophotometry(UV),nuclearmagneticresonancespectroscopy(NMR),andmassspectrometry(MS),aswellasapplicablefunctionalgroupanalysis.Detailedinterpretationofthetestdatainsupportoftheclaimedstructureshouldbeprovided.Aphysicaldescriptionofthematerial,includingitscolorandphysicalform.Appropriatephysicalconstantssuchasmeltingrange,boilingrange,refractiveindex,dissociationconstants(pKvalues),andopticalrotation.Adetaileddescriptionoftheanalyticalproceduresusedtocharacterizethereferencestandard.Forbiotechnological/biologicalproductreferencestandards,therecommendationsoncharacterizationinformationabovemayapplyandshouldbeconsidered.However,additionaland/ordifferenttestswouldbeimportanttoassessphysicochemicalcharacteristics,structuralcharacteristics,biologicalactivity,and/orimmunochemicalactivity.Physicochemicaldeterminationsmayincludeisoform,electrophoretic,andliquidchromatographicpatterns,aswellasspectroscopicprofiles.Structuralcharacterizationmayincludeadeterminationofaminoacidsequence,aminoacidcomposition,peptidemap,andcarbohydratestructure.Biologicaland/orimmunochemicalactivityshouldbeassessedusingthesameanalyticalproceduresusedtodetermineproductpotency.Thesecanincludeanimal-based,cellculture-based,biochemical,orligand/receptor-bindingassays.Whilethesetestsmaybeneededforcompletecharacterizationofcertainreferencestandards,specificrecommendationsforV.V.METHODSVALIDATIONFORForaninvestigationalnewdrug,sufficientinformationisrequiredineachphaseofaninvestigationtoensureproperidentification,quality,purity,strength,and/orpotency.Theamountofinformationonanalyticalproceduresandmethodsvalidationnecessarywillvarywiththephaseoftheinvestigation(21CFRCFR312.23(a)(7))。tobesubmittedforphase1studies,sponsorsshouldrefertotheFDAguidanceindustryonContentandFormatofInvestigationalNewDrugApplications(INDs)forPhase1StudiesofDrugs,IncludingWell-Characterized,Therapeutic,Biotechnology-DerivedProducts(November1995).Generalguidanceregardinganalyticalproceduresandmethodsvalidationinformationtobesubmittedforphase2orphase3studieswillbeprovidedintheFDAguidanceforindustryINDsforPhase2and3StudiesofDrugs,IncludingSpecifiedTherapeuticBiotechnology-DerivedProducts,Chemistry,Manufacturing,andControlsContentandFormat,whenfinalized(draftguidancepublishedApril1999).theNDA,ANDA,BLA,orPLAissubmitted.在递交NDA，ANDA，BLA或PLAVI.VI.CONTENTANDFORMATOFANALYTICALPROCEDURESFORNDAs,ANDAs,BLAs,ANDAnyanalyticalproceduresubmittedinanNDA,ANDA,BLA,orPLAshouldbedescribedinsufficientdetailtoallowacompetentanalysttoreproducethenecessaryconditionsandobtainresultscomparabletotheapplicant=s.Aspectsoftheanalyticalprocedurethatrequirespecialattentionshouldbedescribed.NDA，ANDA，BLA和PLA中分析方法的内容和格式NDA，ANDA，BLAIftheanalyticalprocedureusedisinthecurrentrevisionoftheUSP/NForotherFDArecognizedstandardreferences(e.g.,AOACInternationalBookOfMethods)thereferencedanalyticalprocedureisnotmodified,astatementindicatingtheanalyticalprocedureandreferencemaybeprovidedratherthanadescriptionofthemethod(21CFR211.194).的描述（21CFR211.194）。Adescriptionofanalyticalproceduresfromanyotherpublishedsourcesshouldbeprovided,becausethereferencedsourcesmaynotbereadilyaccessibletotheAstatementoftheprincipleoftheanalyticalprocedureshouldbeincluded.Forexample,separationisbasedonisocraticreversedphaseHPLCwithdetectionbySamplingThenumberofsamples(e.g.,vials,tablets)selected,howtheyareused(i.e.,asindividualorcompositesamples),andthenumberofreplicateanalysespersampleshouldbedescribed.HPLCUVD.EquipmentandEquipmentAlistingofallequipment(e.g.,instrumenttype,detector,columntype,dimensions)shouldbeincluded,aswellasalistofequipmentparameters(e.g.,flowrate,temperatures,runtime,wavelengthsettings).Adrawingrepresentingtheexperimentalconfiguration(e.g.,illustratingpositionsforaspraypatternanalyticalprocedure)shouldbeprovided,whenappropriate.需要叙述的有：仪器列表（比如，仪器类型，检测器，柱子类型，尺寸等）Alistofreagentsandtheirgrades(e.g.,USP/NF,AmericanChemicalSociety(ACS)AnalyticalReagent)shouldbeincluded.Ifin-houseormodifiedcommercialreagentsareused,directionsfortheirpreparationshouldbeincluded.Unstableorpotentiallyhazardousreagentsshouldbeidentified,andstorageconditions,directionsforsafeuse,andusableshelflifeforthesereagentsshouldbespecified.（USP/NF（ACS分析试剂如果使用的是自制试剂或更改过的商业试剂，则应当要有其制备方法。对于不稳定的或有潜在危险的试剂，应标明其储存条件，安全使用说明和使用周期。E.SystemSuitabilitySystemsuitabilitytestparametersandacceptancecriteriaarebasedontheconceptthattheequipment,electronics,analyticaloperations,andsamplestobeanalyzedconstituteanintegratedsystem.Systemsuitabilitytestingensuresthatthesystemisworkingproperlyatthetimeofanalysis.Appropriatesystemsuitabilitycriteriashouldbedefinedandincludedintheanalyticalprocedure.Allchromatographicanalyticalproceduresshouldincludesystemsuitabilitytestingandcriteria.ParameterstypicallyusedinsystemsuitabilityevaluationsaredefinedanddiscussedintheCDERreviewerguidanceonValidationofChromatographicMethods(November1994).色谱分析方法的验证>>（199411）对用于评估系统适应性的典型参数进行了定义和讨Systemsuitabilitytestingisrecommendedasacomponentofanyanalyticalfunctioncorrectlyindependentoftheenvironmentalconditions.Forexample,titrationanalyticalproceduresshouldalwaysincludetheevaluationofablank(commonlyreferredtoasablanktitration).F.PreparationofProceduresforthepreparationofallstandardsolutions(e.g.,stock,workingstandardsolutions,internalstandards)shouldbeincluded.FG.PreparationofSamplepreparationforindividualtestsshouldbeclearlydescribed.Specificdetailsshouldbeprovidedforunusualsamplepreparations(e.g.,solid-phaseextraction,derivatization).I.factors,andspecificinstructionsforthecalculationofdegradationproductsandimpuritiesshouldbeincluded.Anymathematicaltransformationsorformulastransformationsusedtoobtainalinearrelationshipfromexponentialdata,ortheuseofmultipleorderregressionanalyses.JReportingofResults1.Theformatusedtoreportresults(e.g.,percentlabelclaim,weight/weight,figurestobereportedshouldbeprovided.应该规定关键计算步骤中的数字单位（，W/W，W/L，ppmThenameandlocation/identifier(e.g.,retentiontime(RT),relativeretentiontime(RRT))ofimpuritiesandthetypeofimpurity(e.g.,process,(QL)shouldbestated,asappropriate.TheDLorQLcanbesetusingthedrugsubstance'sdetectionresponse.RRTDLQLDLQL。byname,(2)specifiedunidentifiedimpuritiesbylocation/identifier,(3)anyunspecifiedimpurities,and(4)totalimpurities.ThetotalorganicimpuritiesforthedrugproductordrugsubstanceisthesumofallimpuritiesequaltoorgreaterthantheirindividualQL.SeerecommendationsregardingappropriateQLsinFDAimpuritiesguidances(seereferences).InorganicimpuritiesandresidualsolventsshouldalsobeForthedrugproduct,drugsubstanceprocessimpuritiesmaybeexcludedfromreportingifanacceptablerationaleisprovidedinthesectionsonanalyticalprocess,packaging,andlabelingshouldbeaddressed.Theabovereportinginformationmaynotbestrictlyapplicabletoallproductssignificantprocessandproduct-relatedimpuritiesshouldbedeterminedandVII.VII.METHODSVALIDATIONFORNDAs,ANDAs,BLAs,ANDNoncompendialAnalyticalInanNDA,ANDA,BLA,orPLA,datamustbesubmittedtoestablishthattheanalyticalproceduresusedintestingmeetproperstandardsofaccuracyandreliability(21CFR211.194(a)(2)).Methodsvalidationistheprocessoftimeofsubmission,theNDA,ANDA,BLA,orPLAshouldcontainmethodsvalidationinformationtosupporttheadequacyoftheanalyticalprocedures.的准确度和可靠性要求(21CFR211.194(a)92))。分析方法验证是个论述分析方法是适用于TheInternationalConferenceonHarmonisation(ICH)guidanceQ2ATextonValidationofAnalyticalProcedures(March1995)andQ2BValidationofAnalyticalProcedures:Methodology(November1996)providerecommendationsonvalidationofshouldstillbevalidated.ValidationApplicantsshouldsubmitinformationonthevalidationcharacteristicsoftheirproposedanalyticalprocedures(seeICHQ2AandICHQ2B).Althoughnotallofthevalidationcharacteristicsareneededforalltypesoftests(seesectionVII.A.3),typicalvalidationcharacteristicsare:申请者应当要送交其所拟定分析方法的验证项目方面的信息（见ICH Q2B尽管不是对于所有类型的分析方法都需要进行所有的验证项目（见第VII.A.3章但还是有Precision(repeatabilityandintermediateprecision)DetectionQuantitationlimit精密度（重复性和中间精密度OtherMethodsValidationMethodsvalidationinformationshouldalsothetimerequiredtocompletetheanalysis.bLegiblereproductionsofrepresentativeinstrumentoutputorrecordings(e.g.,chromatograms)andrawdataoutput(e.g.,integratedareas),asappropriate.Instrumentoutputforplacebo,standard,andsampleshouldalsobeprovided(seesectionVII.A.2.c).剂，对照品和样品的仪器输出也都是需要提供的（VII.A.2.c。indrugsubstancearecalculated.Informationfromstressstudies(seesectionforchromatographicdata)fortheimpurityanalyticalprocedure.强降解实验资料（VII.A.2.bRRTFordrugAdiscussionofthepossibleformationandcontrolofpolymorphicandenantiomericIdentificationandcharacterizationofeachorganicimpurity,asappropriate.Thisinformationmaynotbeneededforallproducts(e.g.,botanicals).Otherimpurities(e.g.,inorganics,residualsolvents)shouldbeaddressedandquantitated.RecommendationsonsubmittinginformationonimpuritiesisprovidedinvariousAlistofknownimpurities,withstructureifavailable,includingprocessimpurities,degradants,andpossibleisomers.质（1996年1。Fordrugproducts:Adegradationpathwayforthedrugsubstanceinthedosageform,wherepossible.Datademonstratingrecoveryfromthesamplematrixasillustratedbytheaccuracystudies.Datademonstratingthatneitherthefreshlypreparednorthedegradedplacebointerfereswiththequantitationoftheactiveingredient.ICHQ2AandQ2Baddressalmostallofthevalidationparameters.Areasthatshouldbeprovidedinmoredetailaredescribedbelow.-对于制剂： Q2A和ICH a.Robustness,ameasureoftheanalyticalprocedure'scapabilitytoremaintestingshouldbeperformedduringdevelopmentoftheanalyticalprocedureandthedatadiscussedand/orsubmitted.Incaseswhereaneffectisobserved,representativeinstrumentoutput(e.g.,chromatograms)shouldbesubmitted. Q2A和ICH Q2B对耐用性是有论述的，它衡量的是分析方法在细微的变化下不受Stressandfortheactiveingredientinthedrugproductshouldbeprovidedtodemonstratethespecificityoftheassayandanalyticalproceduresforimpurities.Thestressanddrugproductexcipientsdonotinterferewiththequantitationoftheactiveingredient.StressstudiesaredescribedinvariousFDAguidancesrelatingtothestabilityofdrugproducts(seereferences).Thedesignofthestressstudiesandtheresultsshouldbesubmittedtothestabilitysectionoftheapplication.thesectionsonanalyticalproceduresandcontrols.a.对活性成分的定量分析产生干扰。FDA很多关于药品稳定性的指导原则都对强降解实验进行法和控制一章中。c.InstrumentOutput/RawOrganicRepresentativedatashouldbesubmittedtosupportanassessmentoftheorganicimpurities.Representativedataforresidualsolventsaregenerallynotneeded.Instrumentoutputandtherawnumericalvalues(e.g.,peakarea)withappropriateidentificationandlabeling(e.g.,RTforchromatographicpeaks,chemicalshift(d)andcouplingconstant(J)forNMR)shouldbeprovided.Theimpurityprofileshouldbeassessedatthequantitationlimitandtheinstrumentoutputprovided.Additionalinformationshouldbeprovidedtoconfirmthattheimpurityprofileisadequatelycharacterized.Forexample,arepresentativechromatogramusingdetectionatalowwavelength,suchas205nm,anddoubletheproposedtotalruntimecouldbesubmittedtosupportthespecificityoftheanalyticalprocedure.205nm，则可以将拟定的运行时间延长至两倍以支持分Forquantitationpurposes,theresponsefactorofthedrugsubstancemaybeusedforimpuritieswithoutareferencestandard.Incaseswheretheresponsefactorsarenotclose,thispracticemaystillbeacceptable,providedacorrectionfactorisappliedortheimpuritiesare,infact,beingoverestimated.Acceptancecriteriaandanalyticalproceduresusedtoestimateidentifiedorunidentifiedimpuritiesoftenarebasedonanalyticalassumptions(e.g.,equivalentdetectorresponse).Assumptionsshouldbediscussedandjustified.DrugDatashouldbesubmittedshowingtheseparationanddetectionofimpuritiesusingspikedorstresssamples.Completeimpurityprofilesasgraphicoutput(e.g.,chromatograms)andrawdata(e.g,integratedpeakareas)ofrepresentativebatchesshouldbesubmittedinthesectionsonanalyticalproceduresandcontrolsforthedrugsubstance.ForANDAsandrelatedsubmissions,appropriateinformationforthebatchesusedinthebiobatchorsubmissionbatchshouldbeprovided.Allresponses(e.g.,peaks)shouldlabeled.Theanalyticalprocedureusedshouldbecapableofdifferentiatingchanges,ifany,betweenpastandpresentbatches.Thequantitationlimitandthetypeprocedurenumber,batchnumber,manufacturingdateandsite,anddateofanalysisshouldbeprovided.的批次（biobatch）或者提交批次（submissionbatch）的相关资料应当要提供。所有的响Drugintegratedpeakareas)fromrepresentativebatchesunderlong-termandacceleratedstabilityconditions,andstressedsamplesshouldbesubmittedinthesectionsonanalyticalproceduresandcontrolsofthedrugproduct.ForANDAsandrelatedstabilitysectionoftheapplication.Ataminimum,thesubmissionshouldincludeinstrumentoutputandrawdatareleasetestingandatthelatestavailabletimepointforthesamebatch.Allresponses(e.g.,peaks)shouldbelabeledandidentified.Inaddition,theanalyticalprocedurenumber,batchnumberofthedrugproduct,manufacturingdate,dateofanalysis,sourceandbatchnumberofdrugsubstance,manufacturingsite,andcontainer/closureinformationshouldbeprovided.Theanalyticalproceduresusedshouldbecapableofdifferentiatingchanges,ifany,betweenpastandpresentbatches.Thequantitationlimitandthetype(e.g.,degradant,leachablesfrompackaging)shouldbereported.Multiplemethodologiescanbeused.至少，递交材料中应当要包括放行检测(Releasetesting)的仪器输出和原始资料.需标2.RecommendedValidationCharacteristicsforTypesofTable1isasummaryofthevalidationcharacteristicsthatshouldbeaddressedcanbeusedforseveralpurposes.Thevalidationinformationshouldsupporttheintendedpurposeofthetest.Forexample,ifRamanspectroscopyisthemethodologyselectedtoquantitatepolymorphicformsasimpurities,orchiralHPLCforquantitativetestingforimpuritieswouldapply.However,ifRamanspectroscopyorchiralHPLCareusedforthepurposeofidentificationorasspecifictests,therecommendedvalidationcharacteristicslistedforthosetypesoftestswoulda1验证资料需要能支持该分析方法的拟定用途。比如说，如果拉曼光谱用于定量分析多晶型杂HPLC1杂质定量分析1：Signifiesthatthischaracteristicisnotnormally+Signifiesthatthischaracteristicisnormally1Incaseswherereproducibilityhasbeenperformed,intermediateprecisionisnotneeded.2Lackofspecificityforananalyticalproceduremaybecompensatedforbytheadditionofasecondanalytical3Maybeneededinsome4Maynotbeneededinsome5Lackofspecificityforanassayforreleasemaybecompensatedforbyimpurities2：3：IdentificationanalyticalproceduresmayincludetestssuchasIR,scanningcalorimetry(DSC),X-raydiffraction(XRD),UV,andHPLCretentiontime.possible.Incaseswhereanonspecificidentificationanalyticalprocedureisproposedfortheactiveingredient,twoindependentanalyticalproceduresaregenerallysufficient,ifjustified.Forotheridentificationtests(e.g.,achiralHPLCretentiontimeasconfirmationforthepresenceofanenantiomer,chloridetestforacounterion)asingletestisacceptable.Thisconceptofthenumberofidentificationtestsisapplicabletoboththedrugsubstanceanddrugproduct.HPLCThevalidationcharacteristicsunderquantitativetestingforimpurities,asdescribedinTable1,apply,regardlessofwhichmethodologyisusedtoquantitatecharacteristicsunderlimittestingforimpuritieswillapply.b.1杂质定性分析项下的验证项目进行验证。c.measurementofcontentindissolutionandcontentuniformitysamples.c.d.SpecificSpecificteststocontrolthedrugsubstance,excipient,ordrugproductcanincludetestssuchasparticlesizeanalysis,dropletdistribution,spraypattern,dissolution(excludesmeasurement),opticalrotation,andmethodologiessuchasDSC,XRD,andRamanspectroscopy.Thevalidationcharacteristicsmaydifferforthevariousanalyticalprocedures.Forexample,accuracy,repeatability,intermediateprecisionandrobustnessshouldbeevaluatedformolecularsizedistributiongelpermeationchromatography(GPC).CompendialAnalyticalThesuitabilityofacompendialanalyticalproceduremustbeverifiedunderactualconditionsofuse(21CFR211.194(a)(2)).InformationtodemonstratethatUSP/NFanalyticalproceduresaresuitableforthedrugproductordrugsubstanceshouldbeincludedinthesubmission.Informationonthespecificity,intermediateprecision,andstabilityofthesamplesolutionshouldbeincluded.Compendialassayanalyticalproceduresmaynotbestability-indicating,andthisshouldbeconsideredwhendevelopingthespecification(seesectionIII.C).Forcompendialitems,additionalanalyticalprocedures,suchasimpuritiesorosmolality,mayrequestedtosupportthequalityofthedrugproductordrugsubstance.Theseadditionalanalyticalproceduresshouldbevalidated(seesectionVII.A).需根据实际使用条件确认药典分析方法的适用性(21CFR211.194(a)(2))STATISTICALMethodsvalidationincludesanassessmentoftheadequacyoftheanalyticalprocedure.Statisticalanalysis(e.g.,linearregressionanalysis,relativestandarddeviation)ofmethodsvalidationdataisoftenusedtodemonstratethevalidityofthemethod.Thestatisticalproceduresfortheanalysisofthevalidationdatashouldbedeterminedpriortothestartofanyvalidationstudy.Theprocedurefollowed,includingtheamountofdatatocollectandthecriteriausedindeterminingtheacceptabilityoftheanalyticalprocedure,shouldbespecified.Therawmethodsvalidationdataandstatisticalproceduresusedt