ICH指导建议原则稳定性培训课件

ICH指导建议原则稳定性主要内容ICH简介ICH指导原则Q1A(R2)

ICH指导原则Q1B2ICH指导建议原则稳定性ICH简介3ICH指导建议原则稳定性说明ICH的论题主要分为四类，因此ICH根据论题的类别不同而进行相应的编码分类：“Q”类论题：Q代表QUALITY，指那些与化工和医药，质量保证方面的相关的论题。“S”类论题：S代表SAFETY，指那些与实验室和动物实验，临床前研究方面的相关的论题。3.“E”类论题：E代表EFFICACY，指那些与人类临床研究相关的课题。4.“M”类论题：M代表MULTIDISCIPLINARY,指那些不可单独划入以上三个分类的交叉涉及的论题。同时M又细分为5个小类

M1:常用医学名词（MedDRA）

M2:药政信息传递之电子标准

M3:与临床试验相关的临床前研究时间的安排

M4:常规技术文件(CTD)

M5:药物词典的数据要素和标准4ICH指导建议原则稳定性Q1A-Q1FStability稳定性Q1A(R2)StabilityTestingofNewDrugSubstancesandProducts

新原料药和制剂的稳定性试验Q1BStabilityTesting:PhotostabilityTestingofNewDrugSubstancesandProducts

新原料药和制剂的光稳定性试验Q1CStabilityTestingforNewDosageForms新剂型的稳定性试验Q1DBracketingandMatrixingDesignsforStabilityTestingofNewDrugSubstancesandProducts

原料药和制剂稳定性试验的交叉和矩阵设计Q1EEvaluationofStabilityData稳定性数据的评估Q1FStabilityDataPackageforRegistrationApplicationsinClimaticZonesIIIandIV

在气候带III和IV，药物注册申请所提供的稳定性数据5ICH指导建议原则稳定性Q1A(R2)StabilityTestingofNewDrugSubstancesandProducts1、DrugSubstance2、DrugProducts6ICH指导建议原则稳定性StressTesting强力破坏试验是通过建立降解途径，鉴定可能的降解产物，以确定分子的内在稳定性，并论证所使用的分析方法是否能反映产品的稳定性。DrugSubstance7ICH指导建议原则稳定性StressTesting可以是单批原料药，包括温度（一般比加速试验温度高10℃）、湿度（75%或者更高）、氧化、光照。DrugSubstance8ICH指导建议原则稳定性SelectionofBatches批的选择三批以上样品的数据试产规模生产的批次，应与在最终规模生产时的合成路线和生产工艺相同。用于稳定性研究的各批次原料药的总体质量应既能代表临床前研究的质量，又能代表临床研究以及规模生产时的质量。

DrugSubstance9ICH指导建议原则稳定性ContainerClosureSystem包装与储存和运输的包装相同或相似DrugSubstance10ICH指导建议原则稳定性Specification稳定性研究应检验在储存期间容易变化的原料药的属性，并且可能影响原料药的质量，安全性和/或功效。检验应适当地涵盖物理，化学，生物和微生物方面。应采用经验证的分析方法。DrugSubstance11ICH指导建议原则稳定性TestingFrequencyForlongtermstudies,frequencyoftestingshouldbesufficienttoestablishthestabilityprofileofthedrugsubstance.Fordrugsubstanceswithaproposedre-testperiodofatleast12months,thefrequencyoftestingatthelongtermstorageconditionshouldnormallybeevery3monthsoverthefirstyear,every6monthsoverthesecondyear,andannually

thereafterthroughtheproposedre-testperiod.Attheacceleratedstoragecondition,aminimumofthreetimepoints,includingtheinitialandfinaltimepoints(e.g.,0,3,and6months),froma6-monthstudyisrecommended.Whereanexpectation(basedondevelopmentexperience)existsthatresultsfromacceleratedstudiesarelikelytoapproachsignificantchangecriteria,increasedtestingshouldbeconductedeitherbyaddingsamplesatthefinaltimepointorbyincludingafourthtimepointinthestudydesign.DrugSubstance12ICH指导建议原则稳定性TestingFrequencyWhentestingattheintermediatestorageconditioniscalledforasaresultofsignificantchangeattheacceleratedstoragecondition,aminimumoffourtimepoints,includingtheinitialandfinaltimepoints(e.g.,0,6,9,12months),froma12-monthstudyisrecommended.DrugSubstance13ICH指导建议原则稳定性StorageConditions1、Generalcase*有显著变化时，增加中间条件DrugSubstanceStudyStoragecondition Minimumtimeperiodcoveredbydataatsubmission Longterm 25°C±2°C/60%RH±5%RHor30°C±2°C/65%RH±5%RH 12months Intermediate 30°C±2°C/65%RH±5%RH 6months Accelerated 40°C±2°C/75%RH±5%RH 6months 14ICH指导建议原则稳定性StorageConditions2、DrugsubstancesintendedforstorageinarefrigeratorIfsignificantchangeoccurswithinthefirst3months’testingattheacceleratedstoragecondition,adiscussionshouldbeprovidedtoaddresstheeffectofshorttermexcursionsoutsidethelabelstoragecondition,e.g.,duringshippingorhandling.可以进一步考察单批原料药在少于3个月内的稳定性，提高检样频率。DrugSubstanceStudyStoragecondition Minimumtimeperiodcoveredbydataatsubmission Longterm 5°C±3°C 12months Accelerated30°C±2°C/65%RH±5%RH 6months 15ICH指导建议原则稳定性StorageConditions3、DrugsubstancesintendedforstorageinafreezerIntheabsenceofanacceleratedstorageconditionfordrugsubstancesintendedtobestoredinafreezer,testingonasinglebatchatanelevatedtemperature(e.g.,5°C±3°Cor25°C±2°C)foranappropriatetimeperiodshouldbeconductedtoaddresstheeffectofshorttermexcursionsoutsidetheproposedlabelstoragecondition,e.g.,duringshippingorhandling.DrugSubstanceStudyStoragecondition Minimumtimeperiodcoveredbydataatsubmission Longterm -20°C±5°C 12months 16ICH指导建议原则稳定性GeneralThedesignoftheformalstabilitystudiesforthedrugproductshouldbebasedonknowledgeofthebehaviorandpropertiesofthedrugsubstanceandfromstabilitystudiesonthedrugsubstanceandonexperiencegainedfromclinicalformulationstudies.Thelikelychangesonstorageandtherationalefortheselectionofattributestobetestedintheformalstabilitystudiesshouldbestated.成品稳定性试验设计应以原料药的性质以及从临床处方研究和原料药稳定性研究中得到的经验为基础，应阐述贮存中可能发生的变化以及将产品可变因素选入试验方案的理由。DrugProduct18ICH指导建议原则稳定性SelectionofBatchesDatafromstabilitystudiesshouldbeprovidedonatleastthreeprimarybatchesofthedrugproduct.Theprimarybatchesshouldbeofthesameformulationandpackagedinthesamecontainerclosuresystemasproposedformarketing.Themanufacturingprocessusedforprimarybatchesshouldsimulatethattobeappliedtoproductionbatchesandshouldprovideproductofthesamequalityandmeetingthesamespecificationasthatintendedformarketing.Twoofthethreebatchesshouldbeatleastpilotscalebatchesandthethirdonecanbesmaller,ifjustified.Wherepossible,batchesofthedrugproductshouldbemanufacturedbyusingdifferentbatchesofthedrugsubstance.DrugProduct19ICH指导建议原则稳定性SelectionofBatches加速和长期试验的稳定性资料至少应包括与上市产品具有相同处方、剂型和容器及闭塞物的三批样品的数据，三批中至少有两批样品应是试生产规模生产的，第三批可以少一些(如：固体口服剂型可以25000~50000片剂或胶囊)。长期试验至申报时至少应进行12个月。所用生产工艺应尽可能模拟用于上市药品大规模生产的工艺，该生产工艺应能提供与上市质量相同的药品，同时也要符合与出厂产品相同的质量要求。若可能，应该用不同批号的原料药生产几批成品。DrugProduct20ICH指导建议原则稳定性ContainerClosureSystemStabilitytestingshouldbeconductedonthedosageformpackagedinthecontainerclosuresystemproposedformarketing(including,asappropriate,anysecondarypackagingandcontainerlabel).DrugProduct21ICH指导建议原则稳定性SpecificationStabilitystudiesshouldincludetestingofthoseattributesofthedrugproductthataresusceptibletochangeduringstorageandarelikelytoinfluencequality,safety,and/orefficacy.Thetestingshouldcover,asappropriate,thephysical,chemical,biological,andmicrobiologicalattributes,preservativecontent(e.g.,antioxidant,antimicrobialpreservative),andfunctionalitytests(e.g.,foradosedeliverysystem).Analyticalproceduresshouldbefullyvalidatedandstabilityindicating.Whetherandtowhatextentreplicationshouldbeperformedwilldependontheresultsofvalidationstudies.试验项目应该包括在贮存期内易于改变和可能影响质量、安全性和(或)药效的那些因素。试验范围应包括物理、化学、生物以及微生物稳定性，还应包括防腐剂含量（抗氧剂，抗菌防腐剂）。分析方法应经过充分论证。DrugProduct22ICH指导建议原则稳定性TestingFrequency（同DrugSubstance原料药）Forlongtermstudies,frequencyoftestingshouldbesufficienttoestablishthestabilityprofileofthedrugsubstance.Fordrugsubstanceswithaproposedre-testperiodofatleast12months,thefrequencyoftestingatthelongtermstorageconditionshouldnormallybeevery3monthsoverthefirstyear,every6monthsoverthesecondyear,andannually

thereafterthroughtheproposedre-testperiod.Attheacceleratedstoragecondition,aminimumofthreetimepoints,includingtheinitialandfinaltimepoints(e.g.,0,3,and6months),froma6-monthstudyisrecommended.Whereanexpectation(basedondevelopmentexperience)existsthatresultsfromacceleratedstudiesarelikelytoapproachsignificantchangecriteria,increasedtestingshouldbeconductedeitherbyaddingsamplesatthefinaltimepointorbyincludingafourthtimepointinthestudydesign.DrugProduct23ICH指导建议原则稳定性TestingFrequency（同DrugSubstance原料药）Whentestingattheintermediatestorageconditioniscalledforasaresultofsignificantchangeattheacceleratedstoragecondition,aminimumoffourtimepoints,includingtheinitialandfinaltimepoints(e.g.,0,6,9,12months),froma12-monthstudyisrecommended.DrugProduct24ICH指导建议原则稳定性StorageConditions1、Generalcase*有显著变化时，增加中间条件DrugProductStudyStoragecondition Minimumtimeperiodcoveredbydataatsubmission Longterm 25°C±2°C/60%RH±5%RHor30°C±2°C/65%RH±5%RH 12months Intermediate 30°C±2°C/65%RH±5%RH 6months Accelerated 40°C±2°C/75%RH±5%RH 6months 25ICH指导建议原则稳定性Ingeneral,“significantchange”foradrugproductisdefinedas:

1.A5%changeinassayfromitsinitialvalue;orfailuretomeettheacceptancecriteriaforpotencywhenusingbiologicalorimmunologicalprocedures;2.Anydegradationproduct’sexceedingitsacceptancecriterion;3.Failuretomeettheacceptancecriteriaforappearance,physicalattributes,andfunctionalitytest(e.g.,color,phaseseparation,resuspendibility,caking,hardness,dosedeliveryperactuation);however,somechangesinphysicalattributes(e.g.,softeningofsuppositories,meltingofcreams)maybeexpectedunderacceleratedconditions;and,asappropriateforthedosageform:4.FailuretomeettheacceptancecriterionforpH;or5.Failuretomeettheacceptancecriteriafordissolutionfor12dosageunits.（12粒胶囊或片剂的溶出度超出了规定限度；）DrugProduct26ICH指导建议原则稳定性StorageConditions2、Drugproductspackagedinimpermeablecontainers