2023年07fda行业指南：分析方法验证(中英文)(下)

7A行业指南：分析方法验证〔中英文〔下〕VIISTATISTICALANALYSISANDMODELS统计学分析AStatistics统计学Statisticalanalysisofvalidationdatacanbeusedtoevaluatevalidationcharacteristicsagainstpredeterminedacceptancecriteria.Allstatisticalproceduresandparametersusedintheanalysisofthedatashouldbebasedonsoundprinciplesandappropriatefortheintendedevaluation.Severalstatisticalmethodsareusefulforassessingvalidationcharacteristics,forexample,ananalysisofvariance(ANOVA)toassessregressionanalysisR(correlationcoefficient)andRsquared(coefficientofdetermination)orlinearregressiontomeasurelinearity.Manystatisticalmethodsusedforassessingvalidationcharacteristicsrelyonpopulationnormality,anditisimportanttodeterminewhetherornottorejectthisassumptionTherearemanytechniquessuchashistograms,normalitytests,andprobabilityplotsthatcanbeusedtoevaluatetheobserveddistribution.Itmaybeappropriatetotransformthedatatobetterfitthenormaldistributionorapplydistribution-free(nonparametric)approacheswhentheobserveddataarenotnormallydistributedAppropriateliteratureortextshouldbeconsultedforinformationonstatisticalprocedurestousewhendevelopingnewtestmethods,evaluatingexistingtestmethodsorevaluatingmeasurementsystemperformance,aswellasothergeneralinformationontheinterpretationandtreatmentofanalyticaldata[18].Thedataanalysisshouldbeassuredeitherbyusingappropriatelyvalidatedsoftwareorindependentverificationforcorrectness.验证数据的统计学分析可以用于评估验证的属性是否符合预定的可承受标准。全部用于数据分析的统计学程序和参数均应是基于合理的原则，并适合于既定评估。有几个统计学方法用于评估验证属性颇为有用，例如，变量分析〔ANOVA〕用于评估相关性分析R〔相关因子〕和R平方〔判定系数或拟合优度〕或线性回归用于测量线性。很多用于评估验证属性的统计学方法依靠于样本的正态性，打算是否拒绝该假设很重要。有很多技术，如柱状图、正态分布和概率图，可以用于评估所观看到的分布状况。假设观看到的数据是非正态分布的，则将数据转换成为更为正态分布或应用非正态分布〔无参数〕方法会更为恰当。在研发的分析方法、评估现有分析方法、或评估测量系统性能时，应参考适当的文献或文件来猎取关于统计学程序的信息，以及关于分析数据诠释和处理的其它通用信息。数据分析应承受经过适当验证的软件，否则应单独确认其正确性。B.Models模型Someanalyticalmethodsmightusechemometricand/ormultivariatemodels.Whendevelopingthesemodels,thenumberofsamplestoprovideadequatestatisticalpowerandrangeformodeldevelopmentandvalidationshouldbeconsidered.Suitablesoftwareshouldbeusedfordataanalysis.Modelparametersshouldbedeliberatelyvariedtotestmodelrobustness.有些分析方法可能会使用化学计量学和/或多变量模型。假设研发的这些模型、样品数据可以供给足够的统计成效和范围用于建模，则应考虑进展验证。可以使用适当的软件进展数据分析。应当设计变化模型参数来测试模型的耐用性。VIII.LIFECYCLEMANAGEMENTOFANALYTICALPROCEDURES分析方法的生命周期治理Onceananalyticalprocedure(includingcompendialmethods)issuccessfullyvalidated(orverified)andimplementedtheprocedureshouldbefollowedduringtheassurethatitremainsfitforitsintendedpurpose.Trendanalysisonmethodperformanceshouldbeperformedatregularintervalstotooptimizetheanalyticalprocedureortorevalidateallorapartoftheanalyticalprocedure.Ifananalyticalprocedurecanonlymeettheestablishedsystemwithrepeatedadjustmentstotheoperatingconditionsstatedintheanalyticalprocedure,theanalyticalprocedureshouldbereevaluated,revalidated,oramended,asappropriate.分析方法〔包括药典方法〕被成功验证〔或确认〕和实施后，在其产品的生命周期中应遵守该方法，以持续保证方法保持适合其既定用途。应定期对方法表现进展趋势分析，评估是否需要对分析方法进展优化，或对全面或局部分析方法进展再验证。假设一个分析方法只能通过不断调整分析方法里载明的运行参数来符合所建立的系统适用性要求，则应对该分析方法进展再评估、再验证，适当时进展修正。Overthelifecycleofaproduct,newinformationandriskassessments(e.g.,aofproductCQAsorawarenessofaofaneworalternativeanalyticalmethod.Newtechnologiesmayallowforgreaterunderstandingand/orconfidencewhenensuringproductquality.Applicantsshouldperiodicallyevaluatetheappropriatenessofaproduct’sanalyticalmethodsandconsiderneworalternativemethods.在一个产品的整个生命周期中，的资料和风险评估〔CQA质〕可能会保证一个的或替代的分析方法的研发和验证。技术可能会带来产品质量保证方面更多的了解和/或可信度。申报者应定期评估产品分析方法的适当性，考虑的或可替代的方法。Inanticipationoflifecyclechangesofretentionsamplesshouldbemaintainedtoallowforcomparativestudies.Thenumbershouldbebasedonscientificprinciplesandanassessmentofrisk.Forcomplexproductsthataresensitivetomanufacturingchanges,reservesamplescanbeanimportanttooltomakethesecomparisons中会对分析方法进展变更，因此要保存适当数据量留样进展比照争论。样品数量应基于科学原理，以及风险评估。对生产工艺较为敏感的简单产品，其留样可能是做比照争论的重要工具。Theretentionsamplesusedincomparativestudiesshouldincludesamplesthatrepresentmarketedproductand,whenpossible,pivotalclinicaltrialmaterial于比照争论的留样应包括代表上市药品的样品，如可能，还应包括关键的临床试验物料。Ifarisk-basedevaluationorotherdriversleadtochangesinananalyticalprocedureorreplacementwithanewmethodoriftheprocedureistransferredtoanewtestingsite;revalidation,anewvalidationexercise,ananalyticalmethodcomparabilitystudyoracombinationoftheseexercisesshouldbeconsidered.Insomecases,changestothedrugsubstanceordrugproductmanufacturingprocessmayalsowarrantanalyticalprocedurerevalidation.Theseadditionalstudiesarediscussedbelow.假设基于风险的评估或其它缘由导致对分析方法进展变更，或实行的方法取代旧的方法，或分析方法转移至一个的检测场所，则要考虑进展再验证、的验证、分析方法比照争论或联合进展这些工作。在有些情形下，对原料药或药品生产工艺的变更也会导致分析方法再验证。这些额外的争论争论如下：A.Revalidation再验证Principlesdescribedinthevalidationsection(sectionVI)applytorevalidation.Whenachangeismadetoananalyticalprocedure(e.g.,achangeinapieceofequipmentorreagentorbecauseofachangeinmanufacturingprocessorformulation),revalidationofallorpartoftheanalyticalprocedureshouldbeconsidered.Analyticalmethodrevalidationmayalsobewarrantedbecauseofmanufacturingprocesschanges,suchasanalterationintheprocessthatcouldimpactmethodperformance(e.g.,routeofsynthesis,fermentation)formulation〔VI〕所述原则适用于再验证。假设对一个分析方法进展了变更〔例如，对设备有变更，或试剂的变更，或由于生产工艺或配方有变更，则可能要考虑对分析方法进展全部或局部再验证。在和平工艺变更时可能也需要对分析方法进展再验证，例如可能影响分析方法性能的原料药生产工艺变更〔例如，合成路线、发酵〕或引入的制剂配方。Youshouldrevalidatetoensurethattheanalyticalproceduremaintainsitscriticalperformancecharacteristics(e.g.,specificity,precision,accuracy).Thedegreeofrevalidationdependsonthenatureofthechange再验证以保证分析方法维持其关键性能指标〔例如，专属性、周密度、准确性。再验证的程度取决于变更的性质。B.AnalyticalMethodComparabilityStudies分析方法比照争论aretypicallygeneratedwhenyouproposetosubstituteanFDA-approvedanalyticalprocedurewithanalternativeanalyticalprocedureorwhenananalyticalmethodistransferredfromonelaboratorytotheother.Forinformationonstatisticalprocedurestousefordeterminingequivalenceoftwotestmethods,appropriateliteratureortextshouldbeconsulted[19].Thesescenariosarediscussedbelow比照争论要求一般是在你提议承受一个替代分析方法取代一个FDA批准的分析方法时，或将一个分析方法从一个试验室转移至另一个试验室时产生的。用于打算两个分析方法的等同性的统计学方法信息，需要引用适当的文献或文件。这些状况争论如下：1.AlternativeAnalytical可替代的分析方法procedureisananalyticalprocedurethatyouuseinplaceoftheFDAapprovedanalyticalprocedure.ForanNDAorANDA,youshouldincludeanyproposedalternateanalyticalproceduresintheapplication.YoumustincludeaforanNDAorANDA,orforaprocedureapprovedinaBLAbutnotincludedinanFDAregulation,theaddition,revision,ordeletionofanalternativeanalyticalprocedurethatprovidesthesameorincreasedassuranceoftheidentity,strength,qualitypurityorpotencyofthematerialbeingtestedastheanalyticalproceduredescribedintheapprovedapplication,mustbedocumentedinthenextannualreport[21]析方法是你用来代替FDA已经批准的分析方法的一种分析方法。对于一个NDA或ANDA，你要将全部拟定的替代分析方法包括在申报资料中。你必需包括方法描述。在批准后，对于一个NDA或ANDA，或在BLA里批准但未包括在FDA法规里的分析方法，凡增加、修改或删除替代分析方法均要在下一次年报中记载。Forbiologicalproducts,inrarecasesananalyticalproceduremaybeincludedinanFDAregulation.Iftheanalyticalmethodrequiredisdescribedbyaregulation,however,andyouwanttouseanalternatemethodyoumustsubmitthealternatemethodforreviewandapprovalaccordingto21CFR610.9(a).Youmustpresentevidence“…demonstratingthatthemodificationwillprovideassurancesofthesafety,purity,potency,andeffectivenessofthebiologicalproductequaltoorgreaterthantheassurancesprovidedbythemethodorprocessspecifiedinthegeneralstandardsoradditionalstandardsforthebiologicalproduct.ModificationofsuchproceduresrequiresFDAapprovalduringapplicationrevieworinapostapprovalsupplement[22].对于生物制品，FDA法规里可能很少包括分析方法。假设所需的分析方法在法规里进展了描述，但你想使用一个方法来替代，你必需依据21CFR610.9(a)提交替代方法供审核和批准。你必需提交证据“……证明方法修订能确保生物制品的安全、纯度、效价和有效性等同或优于生物制品通用标准或附加标准中给出的方法或程序”。对这样程序的修订需要在申报资料评估过程中或FDAYoushouldidentifytheuseofthealternativeanalyticalprocedure(e.g.,release,stabilitytesting)andprovidearationaleforitsinclusion,validationdata,andcomparativedatatotheFDA-approvedanalyticalprocedure.Youshouldperformananalyticalmethodcomparabilitystudythatdemonstratesataminimumthat:你要区分可替代性分析方法的使用〔例如，放行检测、稳定性测试，供给其内容的合理性论证、验证数据和与FDA批准的分析方法的比照数据。你要进展分析方法比照争论，至少证明： Thenewmethodcoupledwithanyadditionalcontrolmeasuresisequivalentorsuperiortotheoriginalmethodfortheintendedpurpose.的方法配备了另外的掌握手段，在其既定用途上等同或超过原始方法 Thenewanalyticalprocedureisnotmoresusceptibletomatrixeffectsthantheoriginalprocedure.的分析方法比原始方法更不易受到基质的影响Ifnewprocess-relatedorproduct-relatedvariantsoranynewtestingonretentionsamplesfromhistoricalbatchesshouldbeperformedtodemonstratethatthevariants/impuritiesdetectedbythenewmethodarearesultofanincreaseinthesensitivityorselectivityofthenewprocedureandnotaresultofachangetoprocess-relatedimpurities的检验方法能发同的与工艺杂质或产品变化产生的杂质或全部的杂质，则应对历史批准的留样进展检查，证明方法检出的变化/杂质是由于的方法灵敏度或选择性增加的结果，而不是工艺杂质变化的结果。Iftheprocedurehasstability-indicatingproperties:假设分析方法具有稳定性指示特性： Appropriatesamplesshouldbeincludedthatallowacomparisonoftheabilityofthenewandoriginalrelevantproductvariantsanddegradationspecies. 应包括适当的样品，比较的方法和原始方法检出相关产品变化和降解物的力量 Thenumberofbatchesanalyzedforcomparisonshouldprovidesufficientstatisticalpower. 比照时所分析的批次数应能供给足够的统计成效Equivalence,non-inferiority,orsuperioritystudiesshouldbeperformedwithappropriatestatisticalmethodstodemonstratethattheneworrevisedmethodsperformanceiscomparableorbetterthantheoriginalmethod[23]. 要承受适当的统计学方法来实施等同性、不低于或优越性争论，来证明方法或修订过的方法的性能等同或优于原始方法 Thestatisticalanalysesperformedtocompareproducttestingshouldbeidentified. 要识别出用于比较产品检测结果的统计学分析方法 Allbiasordifferencesbetweenanalyticalproceduresseenwithcomparativeresultsshouldbediscussedwithanexplanation,asappropriate. 适当时，分析方法间全部观看到的偏差或差异以及比照结果均应进展争论，并提出解释2.AnalyticalMethodsTransferStudies分析方法转移争论Analyticalmethodtransferistypicallymanagedunderatransferprotocolthatdetailstheparameterstobeevaluatedinadditiontothepredeterminedacceptancecriteriathatwillbeappliedtotheresults.Transferstudiesusuallyinvolvetwoormorelaboratoriesorsites(originatinglabandreceivinglabs)executingthepreapprovedtransferprotocol.Asufficientnumberofrepresentativetestarticles(e.g.,samelot(s)ofdrugsubstanceordrugproduct)areusedbytheoriginatingandreceivinglaboratories.Thecomparativestudiesareperformedtoevaluateaccuracyandprecision,especiallywithregardtoassessmentofinterlaboratoryvariability.Incaseswherethetransferredanalyticalprocedureisalsoastability-indicatingmethod,forceddegradationsamplesorsamplescontainingpertinentproduct-relatedimpuritiesshouldbeanalyzedatbothsites.TheUSPGeneralChapterTransferofAnalyticalProceduresprovidesadditionalguidanceonthistopic般要使用转移方案进展治理，在方案中具体写明要评估的参数，以及适用于结果的预定可承受标准。转移争论通常包括两个或更多化验室或场所〔转出化验室和接收化验室，由其实施预先批准的转移方案。转出化验室和接收化验室使用具有代表性的足够数量的测试物〔例如，一样批号的原料药或制剂。实施比照争论是为了评估准确度和周密度，特别是试验室之间的差异。假设所转移的分析方法也是稳定性指示性方法，则应在两个化验室均对强降解样品或含有所要检测的相关杂质的样品进展检测。USP通论“分析方法转移”供给了关于此问题的更多指南。C.ReportingPostmarketingChangestoanApprovedNDA,ANDA,orBLA已批准的NDA、ANDA或BLA的上市后变更报告PostmarketingchangestoanalyticalproceduresmustbereportedtotheFDAincompliancewith21CFR314.70or21CFR601.12[24].AdditionalinformationontheappropriatereportingcategoryforvariouskindsofpostapprovalchangesforNDAsandANDAsisprovidedintheFDAguidanceforindustryonChangestoanApprovedNDAorANDAandChangestoanApprovedNDAorANDA;Specifications–UseofEnforcementDiscretionforCompendialChanges.SimilarinformationonpostapprovalchangestoBLAsregulatedbyCDERandCBERisprovidedintheFDAguidanceChangestoanApprovedApplicationforSpecifiedBiotechnologyandSpecifiedSyntheticBiologicalProducts.上市后对分析方法的变更必需依据21CFR314.70或21CFR601.12向FDAFDAANDANDAANDA准---药典变更自行裁定实施”中给出了NDAANDA各种批准后变更的报告分类信息。由CDERCBERBLA上市后变更的类似信息已在FDA指南“特定生物技术和特定合成