ICH M7(step4)：诱变性杂质评估和控制-2016

20140623ICHM7（step4)：诱变性杂质评估和控制（中英文1/3）ASSESSMENTANDCONTROLOFDNAREACTIVE(MUTAGENIC)IMPURITIESINPHARMACEUTICALSTOLIMITPOTENTIALCARCINOGENICRISK为限制潜在致癌风险而对药物中DNA活性（诱变性）杂质进行的评估和控制M7CurrentStep4versiondated23June2014ThisGuidelinehasbeendevelopedbytheappropriateICHExpertWorkingGroupandhasbeensubjecttoconsultationbytheregulatoryparties,inaccordancewiththeICHProcess.AtStep4oftheProcessthefinaldraftisrecommendedforadoptiontotheregulatorybodiesoftheEuropeanUnion,JapanandUSA.M7DocumentHistory文件历史Code文件代码History历史Date日期M7ApprovalbytheSteeringCommitteeunderStep2andreleaseforpublicconsultation.第2阶段由筹委会批准，公开征求意见6February2013M7ApprovalbytheSteeringCommitteeunderStep4andrecommendationforadoptiontothethreeICHregulatorybodies.第4阶段由筹委会批准，推荐ICH三方药监局采用5June2014CurrentStep4version现行版本第4阶段M7Corrigendumtofixtypographicalerrorsandreplaceword“degradants”with“degradationproducts”throughoutthedocument.修正输入错误，将全文中“degradants”替换成“degradationproducts”.23June2014LegalNotice:Thisdocumentisprotectedbycopyrightandmaybeused,reproduced,incorporatedintootherworks,adapted,modified,translatedordistributedunderapubliclicenseprovidedthatICH'scopyrightinthedocumentisacknowledgedatalltimes.Incaseofanyadaption,modificationortranslationofthedocument,reasonablestepsmustbetakentoclearlylabel,demarcateorotherwiseidentifythatchangesweremadetoorbasedontheoriginaldocument.Anyimpressionthattheadaption,modificationortranslationoftheoriginaldocumentisendorsedorsponsoredbytheICHmustbeavoided.Thedocumentisprovidedasiswithoutwarrantyofanykind.InnoeventshalltheICHortheauthorsoftheoriginaldocumentbeliableforanyclaim,damagesorotherliabilityarisingfromtheuseofthedocument.Theabove-mentionedpermissionsdonotapplytocontentsuppliedbythirdparties.Therefore,fordocumentswherethecopyrightvestsinathirdparty,permissionforreproductionmustbeobtainedfromthiscopyrightholder.ASSESSMENTANDCONTROLOFDNAREACTIVE(MUTAGENIC)IMPURITIESINPHARMACEUTICALSTOLIMITPOTENTIALCARCINOGENICRISK为限制潜在致癌风险而对药物中DNA活性（诱变性）杂质进行的评估和控制ICHHarmonisedTripartiteGuidelineICH三方协调指南HavingreachedStep4oftheICHProcessattheICHSteeringCommitteemeetingon5June2014,thisGuidelineisrecommendedforadoptiontothethreeregulatorypartiestoICHTABLEOFCONTENTS目录1.INTRODUCTION概述2.SCOPEOFGUIDELINE指南范围3.GENERALPRINCIPLES通用原则4.CONSIDERATIONSFORMARKETEDPRODUCTS上市产品应考虑的问题4.1Post-ApprovalChangestotheDrugSubstanceChemistry,Manufacturing,andControls批准后原料药化学、生产和质量变更4.2Post-ApprovalChangestotheDrugProductChemistry,Manufacturing,andControls批准后制剂的化学、生产和质量变更4.3ChangestotheClinicalUseofMarketedProducts上市产品临床使用变更4.4OtherConsiderationsforMarketedProducts上市产品其它应考虑问题5.DRUGSUBSTANCEANDDRUGPRODUCTIMPURITYASSESSMENT原料药和制剂杂质评估5.1SyntheticImpurities合成杂质5.2DegradationProducts降解产物5.3ConsiderationsforClinicalDevelopment临床研发要考虑的问题6.HAZARDASSESSMENTELEMENTS危害性评估要素7.RISKCHARACTERIZATION风险特征7.1TTC-basedAcceptableIntakes根据TTC制订可接受摄入量7.2AcceptableIntakesBasedonCompound-SpecificRiskAssessments根据化合物特定风险评估制订的可接受摄入量7.2.1MutagenicImpuritieswithPositiveCarcinogenicityData(Class1inTable1)致癌数据有利的诱变性杂质（表1中的第1类）7.2.2MutagenicImpuritieswithEvidenceforaPracticalThreshold具有实用阈值证据的诱变性杂质7.3AcceptableIntakesinRelationtoLTLExposure与LTL暴露相关的可接受摄入量7.3.1ClinicalDevelopment临床研发7.3.2MarketedProducts已上市产品7.4AcceptableIntakesforMultipleMutagenicImpurities多个诱变性杂质的可接受摄入量7.5ExceptionsandFlexibilityinApproaches方法例外情况和弹性8.CONTROL控制8.1ControlofProcessRelatedImpurities工艺相关杂质的控制8.2ConsiderationsforControlApproaches控制方法要考虑的问题8.3ConsiderationsforPeriodicTesting定期检查要考虑的问题8.4ControlofDegradationProducts降解产物的控制8.5LifecycleManagement生命周期管理8.6ConsiderationsforClinicalDevelopment临床研发要考虑的问题9.DOCUMENTATION文件记录9.1ClinicalTrialApplications临床试验应用9.2CommonTechnicalDocument(MarketingApplication)通用技术文件（上市申报）NOTES注解GLOSSARY术语REFERENCES参考文献APPENDICES附录ASSESSMENTANDCONTROLOFDNAREACTIVE(MUTAGENIC)IMPURITIESINPHARMACEUTICALSTOLIMITPOTENTIALCARCINOGENICRISK为限制潜在致癌风险而对药物中DNA活性（诱变性）杂质进行的评估和控制1.INTRODUCTION概述Thesynthesisofdrugsubstancesinvolvestheuseofreactivechemicals,reagents,solvents,catalysts,andotherprocessingaids.Asaresultofchemicalsynthesisorsubsequentdegradation,impuritiesresideinalldrugsubstancesandassociateddrugproducts.WhileICHQ3A(R2):ImpuritiesinNewDrugSubstancesandQ3B(R2):ImpuritiesinNewDrugProducts(Ref.1,2)providesguidanceforqualificationandcontrolforthemajorityoftheimpurities,limitedguidanceisprovidedforthoseimpuritiesthatareDNAreactive.Thepurposeofthisguidelineistoprovideapracticalframeworkthatisapplicabletotheidentification,categorization,qualification,andcontrolofthesemutagenicimpuritiestolimitpotentialcarcinogenicrisk.ThisguidelineisintendedtocomplementICHQ3A(R2),Q3B(R2)(Note1),andICHM3(R2):NonclinicalSafetyStudiesfortheConductofHumanClinicalTrialsandMarketingAuthorizationsforPharmaceuticals(Ref.3).原料药合成牵涉到使用活性化学物质、试剂、溶剂、催化剂和其它工艺助剂，导致在所有原料药及其制剂中会残留有化学合成或其降解产物、杂质。在ICHQ3A(R2)新原料药中的杂质和Q3B(R2)新制剂中的杂质（参考文献1、2）中提供了关于主要杂质定性和控制的指南，对DNA活性杂质给出了有限的指南。本指南的目的是提供实用框架，以应用于这些诱变杂质的鉴别、分类、定性和控制，对潜在致癌风险进行控制。本指南意在补充ICHQ3A(R2)、Q3B(R2)（注解1）和ICHM3(R2)药物人用临床试验和上市许可中的非临床安全性研究（参考文献3）。Thisguidelineemphasizesconsiderationsofbothsafet