2023年07FDA行業(yè)指南：分析方法驗證（中英文）（上）

202307FDA〔中英文〕〔上〕AnalyticalProceduresandMethodsValidationforDrugsandBiologics藥品和生物制品分析方法驗證GuidanceforIndustry行業(yè)指南U.S.DepartmentofHealthandHumanServicesFoodandDrugAdministrationCenterforDrugEvaluationandResearch(CDER)CenterforBiologicsEvaluationandResearch(CBER)July2023PharmaceuticalQuality/CMCAnalyticalProceduresandMethodsValidationforDrugsandBiologicsGuidanceforIndustryAdditionalcopiesareavailablefrom:OfficeofCommunications,DivisionofDrugInformationCenterforDrugEvaluationandResearchFoodandDrugAdministration10001NewHampshireAve.,HillandaleBldg.,4thFloorSilverSpring,MD20993Phone:855-543-3784or301-796-3400;Fax:301-431-6353Email:.govces/default.htmand/orOfficeofCommunication,OutreachandDevelopmentCenterforBiologicsEvaluationandResearchFoodandDrugAdministration10903NewHampshireAve.,Bldg.71,Room3128SilverSpring,MD20993Phone:800-835-4709or240-402-7800Email:.govormation/Guidances/default.htmU.S.DepartmentofHealthandHumanServicesFoodandDrugAdministrationCenterforDrugEvaluationandResearch(CDER)CenterforBiologicsEvaluationandResearch(CBER)July2023PharmaceuticalQuality/CMCAnalyticalProceduresandMethodsValidationforDrugsandBiologics藥物和生物制品分析方法驗證GuidanceforIndustry[1]行業(yè)指南ThisguidancerepresentsthecurrentthinkingoftheFoodandDrugAdministration(FDAorAgency)onthistopic.ItdoesnotcreateanyrightsforanypersonandisnotbindingonFDAorthepublic.Youcanuseanalternativeapproachifitsatisfiestherequirementsoftheapplicablestatutesandregulations.Todiscuss an alternative approach, contact the FDA staffresponsibleforthisguidanceaslistedonthetitle.本指南代表了FDA對本專題的當前想法。它并不賜予任何人以任何權利，也并不對FDA或公眾形成強制效力。假設有方法可以滿足適用的法規(guī)要求，你可使用該方法來替代。要爭論替代性方法，請聯(lián)系FDAINTRODUCTIONThisguidancesupersedesthedraftofthesamenamethatpublishedonFebruary19,2023(79FR169467)andreplacesthe2023draftguidanceforindustryonAnalyticalProceduresandsde7srsdlars.trecommendations on how you, the applicant, can submitanalytical procedures[4]and methods validation[5]data tosupportthedocumentationoftheidentity,strength,quality,purity,andpotencyofdrugsubstancesanddrugproducts[6].Itwillhelpyouassembleinformationandpresentdatatosupportyouranalyticalmethodologies.Therecommendationsapplytodrug substancesand drug productscoveredin new drugapplications(NDAs),abbreviatednewdrugapplications(ANDAs),biologicslicenseapplications(BLAs),andsupplementstotheseapplications.TheprinciplesinthisguidancealsoapplytodrugsubstancesanddrugproductscoveredinTypeIIdrugmasterfiles(DMFs).本指南取代2023年2月19〔79FR169467〕，替代2023年的行業(yè)指南“分析方法驗證”和1987年的“提交方法驗證的樣品和分析數(shù)據(jù)指南”。它指導你、申報人如何提交分析方法驗證數(shù)據(jù)來支持原料藥和制劑鑒別、劑量、質量、純度和效價文件。它會幫助你組織資料，呈現(xiàn)數(shù)據(jù)來支持你的分析方法學。建議適用于藥申報〔NDA〕、簡單藥申報〔 ANDA〕、生物藥品許可申報〔BLA〕以及對這些申報的補充資料中的原料藥和制劑。本指南中的原則也適用于二類藥物主文件〔DMF〕所包括的原料藥和制劑。ThisguidancecomplementstheInternationalConferenceonHarmonisation(ICH)guidanceQ2(R1)ValidationofAnalyticalandMethodolog(yQ2(R1))fordevelopingandvalidatinganalyticalmethods.本指南補充ICH的指南Q2(R1)分析方法驗證：正文和方法學〔Q2(R1)〕，該指南用于分析方法的研發(fā)和驗證。Thisguidancedoesnotaddressinvestigationalnewdrugapplication(IND)methodsvalidation,butsponsorspreparingINDsshouldconsidertherecommendationsinthisguidance.ForINDs,sufficientinformationisrequiredateachphaseofaninvestigationtoensureproperidentity,quality,purity,strength,and/or potency.The amount of information on analyticalproceduresandmethodssuitabilitywillvary withthephaseofthe investigation[7].For general guidance on analyticalproceduresandmethodsvalidationinformationtobesubmittedforphaseonestudies,sponsorsshouldrefertotheFDAguidanceforindustryonContentandFormatofInvestigationalNewDrugApplications(INDs)forPhase1StudiesofDrugs,IncludingWell-Characterized,Therapeutic,Biotechnology-DerivedProducts.GeneralconsiderationsforanalyticalproceduresandmethodsvalidationbeforeconductofphasetwoandthreestudiesarediscussedintheFDAguidancesforindustryonINDsforPhase2and3StudiesofDrugs,IncludingSpecifiedTherapeuticBiotechnology-DerivedProducts(February1999)andINDMeetingsforHumanDrugsandBiologics,Chemistry,,ds.本指南并不爭論INDIND時應考慮本指南中的建議。對于IND，要求一個臨床的各階段都有充分的資料來確保適當?shù)蔫b別、質量、純度、劑量和/或效價。分析方法適用性的資料數(shù)量會因臨床階段不同而不同。一般來說，在一期臨床提交的分析方法驗證資料，需要參考FDA行業(yè)指南“藥品一期臨床爭論IND申報資料內(nèi)容和格式，包括特性明確、治療用生物技術衍生產(chǎn)品”。在二期和三期臨床爭論之前的分析方法驗證的一般考慮要點在FDA行業(yè)指南“藥品的二期和三期臨床爭論IND”和“人用藥和生物制品、CMCINDThisguidancedoesnotaddressspecificmethodvalidationrecommendationsforbiologicalandimmunochemicalassaysforcharacterizationandqualitycontrolofmanydrugsubstancesanddrugproducts.Forexample,somebioassaysarebasedonanimalchallengemodels,andimmunogenicityassessmentsorother immunoassayshave unique features that should beconsideredduringdevelopmentandvalidation.本指南并不爭論很多原料藥和藥品的質量掌握和生物和免疫化學測定的定性中特定的方法驗證建議。例如，有些生物含量是基于動物挑戰(zhàn)模式，免疫基因評估或其它免疫測試具有獨特的性質，在研發(fā)和驗證時需要考慮。Analyticalmethodsrequiredduringproductandprocessdevelopment activities are discussed in FDA guidance forindustryonProcessValidationGeneralPrinciplesandPractices .在藥品和工藝研發(fā)期間所需的分析方法已在FDA行業(yè)指南“工藝驗證：一般原則和標準”中進展了爭論。In addition, a risk-based approach on the need forrevalidationofexistinganalyticalmethodsmayneedtobeconsideredwhenthemanufacturingprocesschangesduringtheproduct’slifecycle.Forquestionsonappropriatevalidationapproaches for analytical procedures or submission ofinformationnotaddressedinthisguidance,youshouldconsultwiththeappropriateFDAqualityassessmentstaff.此外，在產(chǎn)品的生命周期中當生產(chǎn)工藝變更時，可能需要承受基于風險的方法考慮是否需要對現(xiàn)有分析方法進展再驗證。對于本指南中未爭論的關于分析方法適當?shù)尿炞C方法或資料提交的問題，你應當FDAIfyouchooseadifferentapproachthanthoserecommendedinthisguidance,weencourageyoutodiscussthematterwiththeappropriateFDAqualityassessmentstaffbeforeyousubmityourapplication.假設你選擇了一個不同于本指南中的方法，我們鼓舞你在提交申FDAIngeneral,FDA’sguidancedocumentsdonotestablishlegallyenforceableresponsibilities.Instead,guidancesdescribetheAgency’scurrentthinkingonatopicandshouldbeviewedonlyasrecommendations,unlessspecificregulatoryorstatutoryrequirementsarecited.Theuseofthewordshould inAgencyguidancesmeansthatsomethingissuggestedorrecommended,butnotrequired.一般來說，F(xiàn)DA的指南文件沒有法律強制性。指南只是描述了當局目前對某個專題的考慮，除了其中引用的特定的法規(guī)或法律條款要求外，應當僅作為是建議來對待。在官方指南中用詞“應”表示建議或推舉某事，但并不是強制要求。BACKGROUNDEachNDAandANDAmustincludetheanalyticalproceduresnecessarytoensuretheidentity,strength,quality,purity,andpotencyofthedrugsubstanceanddrugproduct[8].EachBLAmustincludeafulldescriptionofthemanufacturingprocess,including analytical procedures that demonstrate themanufacturedproductmeetsprescribedstandardsofidentity,quality,safety,purity,andpotency[9].Datamustbeavailabletoestablishthattheanalyticalproceduresusedintestingmeetproper standards of accuracy, sensitivity, specificity, andreproducibilityandaresuitablefortheirintendedpurpose[10].每個NDA和ANDA都必需包括用以確保原料藥和制劑鑒別、劑量、質量、純度和效價的分析方法。每個BLA必需包括生產(chǎn)工藝的全面描述，包括用以證明所生產(chǎn)產(chǎn)品符合所述鑒別、質量、案例、純度和效價標準的分析方法。必需有數(shù)據(jù)證明用于測試的分析方法符適宜當?shù)臏蚀_度、靈敏度、專屬性和重復性標準，并適合于其既定用途。AnalyticalproceduresverificationorvalidationdatashouldbesubmittedinthecorrespondingsectionsoftheapplicationintheICHM2eCTD:ElectronicCommonTechnicalDocumentSpecification[11].分析方法確認或驗證數(shù)據(jù)應在ICHM2eCTD“電子通用技術文件標準”申報資料中相應的局部提交。Whenananalyticalprocedureisapproved/licensedaspartoftheNDA,ANDA,orBLA,itbecomestheFDA-approvedanalyticalprocedurefortheapprovedproduct.ThisanalyticalproceduremayoriginatefromFDArecognizedsources(e.g.,acompendial procedure from theUnited Pharmacopeia/NationalFormulary(USP/NF)) or a validatedprocedureyousubmittedthatwasdeterminedtobeacceptablebyFDA.Toapplyananalyticalmethodtoadifferentdrugproduct,appropriatevalidationorverificationstudiesforcompendialprocedureswiththematrixofthenewproductshouldbeconsidered.假設分析方法作為NDA、ANDA或BLA的一局部被批準，則其成為FDA批準產(chǎn)品的批準的分析方法。該分析方法可以是來源于FDA認可的來源〔USP/NF藥典方法〕或一個你所提交的經(jīng)過驗證的方法，而被FDA認為是可以承受的。在不同藥品中應用一個分析方法時，要考慮參加藥的基底后對藥典方法進展適當?shù)尿炞C或確認研究。ANALYTICALMETHODSDEVELOPMENTAnanalyticalprocedureisdevelopedtotestadefinedcharacteristicofthedrugsubstanceordrugproductagainstestablishedacceptancecriteriaforthatcharacteristic.Earlyinthedevelopmentofanewanalyticalprocedure,thechoiceofanalyticalinstrumentationandmethodologyshouldbeselectedbasedontheintendedpurposeandscopeoftheanalyticalmethod.Parametersthatmaybeevaluatedduringmethoddevelopmentarespecificity,linearity,limitsofdetection(LOD)andlimitsofquantitation(LOQ),range,accuracy,andprecision.研發(fā)分析方法是為了測試原料藥或藥品的指定屬性，以確認其是否符合已建立的該屬性可承受標準。在分析方法的研發(fā)早期，應根據(jù)其應用目的和范圍來選擇所用的器和方法。在方法研發(fā)中需要進展評估的參數(shù)為專屬性、線性、檢測限〔LOD〕和定量限〔LOQ〕、范圍、準確度和周密度。Duringearlystagesofmethoddevelopment,therobustnessofmethodsshouldbeevaluatedbecausethischaracteristiccanhelpyoudecidewhichmethodyouwillsubmitforapproval.Analyticalproceduresintheearlystagesofdevelopmentareinitiallydevelopedbasedonacombinationofmechanisticunderstandingofthebasicmethodologyandpriorexperience.Experimentaldatafromearlyprocedurescanbeusedtoguidefurtherdevelopment.Youshouldsubmitdevelopmentdatawithin the method validation section if they support thevalidationofthemethod.在方法研發(fā)早期，應對方法的耐用性進展評估，由于該屬性可以幫助你打算提交哪個方法去批準。研發(fā)早期的分析方法最早是基于對根底方法學的了解和之前的閱歷來建立的。早期程序的試驗數(shù)據(jù)可以用于指導進一步的研發(fā)。假設這些研發(fā)數(shù)據(jù)支持方法的驗證的話，你應當在方法驗證局部提交研發(fā)數(shù)據(jù)。Tofullyunderstandtheeffectofchangesinmethodparametersonananalyticalprocedure,youshouldadoptasystematicapproachforamethodrobustnessstudy(e.g.,adesignofexperimentswithmethodparameters).Youshouldbeginwithaninitialriskassessmentandfollowwithmultivariateexperiments.Suchapproachesallowyoutounderstandfactorialparametereffectsonmethodperformance.Evaluationofamethod’s performance may include analyses of samplesobtainedfromvariousstagesofthemanufacturingprocessfromin-processtothefinishedproduct.Knowledgegainedduringthesestudiesonthesourcesofmetho