EMA关于 API 中基因毒性、金属杂质和残留溶剂的标准(中英文对照)

1.Whatisareasonablepolicyforsettingspecificationsforpotentiallygenotoxicimpuritieswhicharetheoreticaloractualimpuritiesinadrugsubstancemanufacturingprocess?HJune2012

1.什么是设定潜在基因毒性杂质（原料药生产工艺中理论或实际的杂质）标准的基本原则？人用药品，2012年6月

Differentpossiblescenarioscanbeidentifiedandtheapplicablepoliciestobeappliedforeachofthemaredescribedbelow:

不同的可能情况可被划分，并且不同的适用原则对应于下面描述的各个情况：Example1–Apotentialgenotoxicimpurity举例1—潜在基因毒性杂质

Thedefinitionforapotentialgenotoxicimpurityisderivedfromthedefinitionfor'potentialimpurity':animpuritythattheoreticallycanariseduringmanufactureorstorage.Itmayormaynotactuallyappearinthe(new)drugsubstance(ICHQ3A,glossary).

潜在基因毒性杂质的定义起源于“潜在杂质”的定义：理论上可能在生产中或贮藏中出现的杂质，它可能会或不会实际存在于（新）原料药中（ICHQ3A，术语）。

Ifapotentialgenotoxicimpurityisjustatheoreticalimpurityi.e.basedontheoreticalconsiderationsbutnotfoundinpracticeatanykeystageinthemanufacturingprocessasdemonstratedbystudiesduringdevelopmentofthemanufacture,theimpuritydoesnotneedtobeincludedinthedrugsubstancespecificationoraspecificationofanintermediate.

如果潜在基因毒性杂质仅是理论杂质，即：基于理论考虑但在生产开发研究中证明生产工艺的任何关键阶段均不会发现，则该杂质不需要包含在原料药的标准或中间体的标准中。

Example2–A(potentially)genotoxicimpurityactuallyformedorintroducedpriortothefinalstepofthesynthesis

举例2—在合成最后一步前形成或引入（潜在）基因毒性杂质

基因毒性杂质资料汇总下载：http://www.yaoqun.net/thread-16503-1-1.htmlIfa(potentially)genotoxicimpurityisformedorintroducedinastepbeforethefinalsynthesisstep,itisconsideredpossibletonotincludethisimpurityinthedrugsubstancespecificationifitiscontrolledbyasuitablelimitinasynthesisintermediateandifitisunambiguouslydemonstratedbyanalysisresults(useofspikingexperimentsareencouraged)thatpresenceofthisimpuritydoesnotexceed30%ofthelimit,derivedeitherfromthresholdoftoxicologicalconcern(TTC)orotherwisedefinedacceptablelimitetc.,inthedrugsubstance.如果在最后合成步骤前产生或引入了（潜在）基因毒性杂质，假如在合成中间体中控制在适当的限度并且通过分析结果（鼓励使用加样试验）明确地证明该杂质在原料药中不超过限度（由毒理学关注阈值（TTC）或明确的可接受限度推导出）的30%，则认为原料药标准中可以不包含该杂质。Itisconsideredpossibletoapplyskiptestingiftheleveloftheimpurityinasynthesisintermediatedoesnotexceed30%ofthelimit,derivedfromeitherTTCorotherwisedefinedacceptablelimitetc,intheintermediate.Datashouldbepresentedforatleast6consecutivepilotscaleor3consecutiveproductionscalebatches.Ifthisconditionisnotfulfilled,aroutinetestintheintermediateisneeded.Iftheimpurityexceeds30%ofthelimit,derivedeitherfromTTCorotherwisedefinedacceptablelimitetc.,inthedrugsubstancetheimpurityhastobeincludedinthedrugsubstancespecificationandthetesthastobecarriedoutonaroutinebasis.如果合成中间体中的杂质水平不超过限度（由毒理学关注阈值（TTC）或确定的可接受限度等推导出）的30%，则认为可以使用跳跃检测，至少具有6个连续中试批或3个连续生产批的数据，如果不满足这些条件，则需要对中间体进行例行检测。如果原料药中该杂质超过限度（由毒理学关注阈值（TTC）或明确的可接受限度等推导出）的30%，则原料药标准中必须包含该杂质，并且应进行例行检测。Shouldagenotoxicimpuritynotbecontrolledattheintermediatestage,thenthescenarioofexample3applies.

如果在中间体阶段没有基因毒性杂质需要控制，则适应举例3的情况。

Example3-A(potentially)genotoxicimpurityisformedorintroducedinthelastsynthesisstep举例3—在合成最后一步形成或引入（潜在）基因毒性杂质

Ifa(potentially)genotoxicimpurityisformedorintroducedinthefinalsynthesisstep,itshouldbeincludedinthespecifications.However,itisconsideredpossibletoapplyskiptestingiftheleveloftheimpuritydoesnotexceed30%ofthelimit,derivedfromeitherTTCorotherwisedefinedacceptablelimitetc.,inthedrugsubstance.Datashouldbepresentedforatleast6consecutivepilotscaleor3consecutiveproductionscalebatches.Ifthisconditionisnotfulfilled,aroutinetestinthedrugsubstancespecificationisneeded.

如果在最后合成步骤形成或引入（潜在）基因毒性杂质，则应包含于质量标准中。然而，如果原料药中该杂质不超过限度（由毒理学关注阈值（TTC）或明确的可接受限度等推导出）的30%，则认为可以使用跳跃检测，至少具有6个连续中试批或3个连续生产批的数据，如果不满足这些条件，则原料药标准中需要包含例行检测。

Definitions:定义：

Forthepurposeofthesequestionsandanswers,thefollowingdefinitionsapply:下列定义适用于这些问答：

·Genotoxicimpurity:animpuritythathasbeendemonstratedtobegenotoxicinanappropriategenotoxicitytestmodel,e.g.bacterialgenemutation(Ames)test.

·基因毒性：在适宜的基因毒性检测模型（如：细菌基因突变（Ames）检测）中证明是基因毒性的杂质。

·Potentiallygenotoxicimpurity:animpuritythatshows(a)structuralalert(s)forgenotoxicitybutthathasnotbeentestedinanexperimentaltestmodel.Herepotentiallyrelatestogenotoxicity,nottothepresenceorabsenceofthisimpurity.

·潜在基因毒性杂质：显示有基因毒性结构性警示但未经过实验检测模型检测的杂质，此处的“潜在”与基因毒性相关，与该杂质的存在与否无关。

2.Inordertoharmonisethepoliciestobeappliedforsettingspecificationsforgenotoxicimpuritiesandheavy-metal-catalystresidues,whatarereasonablepoliciestobeappliedwhensettingspecificationsforheavy-metal-catalystresidues?HJune2012

2.为了协调应用于设定基因毒性杂质和重金属催化剂残留标准的原则，在为重金属催化剂残留设定标准时应用什么原则是合理的？人用药品，2012年6月

Inordertoharmonisethepolicyforsettingspecificationsformetalresidueswiththatforsettingspecificationsforgenotoxicimpurities,someclarificationsoftheinterpretationofsections4.5and4.6oftheheavy-metal-catalystguideline(EMEA/CHMP/SWP/4446/2000)aregivenbelow.

为了将金属残留设定标准与基因毒性杂质的设定标准的原则相互协调，对重金属催化剂指南(EMEA/CHMP/SWP/4446/2000)中第4.5和4.6项的解释进行阐明如下：

Sinceitistheclass-1metalsthatarethemosttoxicmetalswithpermitteddailyexposures(PDEs)thatapproachthelevelofthethresholdoftoxicologicalconcern(TTC)appliedforgenotoxicimpurities,itseemsreasonablethatclass-1metalsaretheprimefocusforharmonisationwiththepolicyforgenotoxicimpuritieswhileclass-2and3metalscouldbetreatedsimilarlybutsomewhatlessstrictly.更多资料请登录药群论坛

www.yaoqun.net

因为1类金属是最毒的金属，其允许日暴露量（PDE）接近于基因毒性杂质的毒理学关注阈值（TTC）的水平，所以协调1类金属与基因毒性杂质的原则是合理的，而2类和3类金属用与其相似的方式但要相对宽松对待。

Example1–Aclass-1metalisnotusedorsuspectedtobepresentinasynthesisprocess举例1—1类金属未使用或不怀疑存在于合成工艺中

Metalsarenotexpectedtobeformedinsynthesisprocesses.Onlyifdeliberatelyintroducedorsuspectedtobepresentforotherreasons,residuesofmetalscanbeexpected.Ifnotusedorsuspectedtobepresent,themetaldoesnotneedtobeincludedinthedrugsubstancespecificationoraspecificationofanintermediate.合成工艺中不会形成金属，除非故意引入或其他原因怀疑存在，则可能有金属残留。如果未使用或不怀疑存在，原料药标准或中间体标准中不需要包含金属检测。

Example2–Aclass-1metalisformedorintroducedpriortothefinalstepofthesynthesis举例2—在合成最后一步前形成或引入1类金属

Ifaclass-1metalisintroducedinastepbeforethefinalsynthesisstep,itisconsideredpossibletonotincludethismetalinthedrugsubstancespecificationifitiscontrolledbyasuitablelimitinasynthesisintermediateandifitisunambiguouslydemonstratedbyanalysisresultsthatthepresenceofthismetaldoesnotexceed30%oftheguidelinelimitinthedrugsubstance.

如果在最后合成步骤前产生或引入了1类金属，如果在合成中间体中控制在适当的限度并且通过分析结果明确地证明该杂质在原料药中不超过指南限度的30%，则认为原料药标准中可以不包含该金属。Itisconsideredpossibletoapplyskiptestingiftheleveloftheclass-1metalinasynthesisintermediatedoesnotexceed30%oftheguidelinelimitintheintermediate.Datashouldbepresentedforatleast6consecutivepilotscaleor3consecutiveproductionscalebatches.Ifthisconditionisnotfulfilled,aroutinetestintheintermediateisneeded.Iftheclass-1metalexceeds30%oftheguidelinelimitinthedrugsubstancetheimpurityhastobeincludedinthedrugsubstancespecificationandthetesthastobecarriedoutonaroutinebasis.如果合成中间体中的1类金属水平不超过指南限度的30%，则认为可以使用跳跃检测，至少具有6个连续中试批或3个连续生产批的数据，如果不满足这些条件，则需要对中间体进行例行检测，如果原料药中该1类金属超过指南限度的30%，则原料药标准中必须包含该杂质，并且应进行例行检测。Shouldaclass-1metalnotbecontrolledattheintermediatestage,thenthescenarioofexample3applies.如果在中间体阶段没有1类金属需要控制，则适应举例3的情况。

Example3–Aclass-1metalisintroducedinthelastsynthesisstep举例3—在合成最后一步形成或引入1类金属

Ifaclass-1metalisintroducedinthefinalsynthesisstep,itshouldbeincludedinthespecifications.However,itisconsideredpossibletoapplyskiptestingifthelevelofthemetaldoesnotexceed30%oftheguidelinelimitinthedrugsubstance.Datashouldbepresentedforatleast6consecutivepilotscaleor3consecutiveproductionscalebatches.Ifthisconditionisnotfulfilled,aroutinetestinthedrugsubstancespecificationisneeded.

如果在最后合成步骤形成或引入1类金属，则应包含于质量标准中。然而，如果原料药中金属不超过指南限度的30%，则认为可以使用跳跃检测，至少具有6个连续中试批或3个连续生产批的数据，如果不满足这些条件，则原料药标准中需要包含例行检测。

3.Inordertoharmonisethepoliciestobeappliedforsettingspecificationsforgenotoxicimpuritiesandclass-1solventresidues,whatarereasonablepoliciestobeappliedwhensettingspecificationsforclass-1solventresidues?HJune2012

3.为了协调应用于设定基因毒性杂质和1类残留溶剂标准的原则，在为1类溶剂残留设定标准时应用什么原则是合理的？人用药品，2012年6月

Inordertoharmonisethepolicyforsettingspecificationsforclass-1solventswiththatforsettingspecificationsforgenotoxicimpurities,someclarificationsoftheinterpretationofannexItotheresidualsolventsguideline(CPMP/ICH/283/96/CVMP/VICH/502/99):Specificationsforclass1andclass2residualsolventsinactivesubstances(CPMP/QWP/450/03/EMEA/CVMP/511/03)aregivenbelow.

为了将1类溶剂的设定标准与基因毒性杂质设定标准的原则相互协调，对残留溶剂指南(CPMP/ICH/283/96/CVMP/VICH/502/99)附件I：原料药中1类和2类溶剂标准(CPMP/QWP/450/03/EMEA/CVMP/511/03)中的解释进行阐明如下：

Sinceitistheclass-1solventsthataremosttoxicsolventsandhavepermitteddailyexposures(PDEs)thatapproachthelevelofthethresholdoftoxicologicalconcern(TTC)appliedforgenotoxicimpurities,itseemsreasonablethatclas-1solventsarethefocusforharmonisationwiththepolicyforgenotoxicimpurities.因为1类溶剂是最毒的溶剂，其允许日暴露量（PDE）接近于基因杂质的毒理学关注阈值（TTC）的水平，所以协调1类溶剂与基因毒性杂质的原则是合理的。

Example1–Aclass-1solventisnotusedorsuspectedtobepresentinasynthesisprocess举例1—1类溶剂未使用或不怀疑存在于合成工艺中

Ifaclass-1solventisjustapotentialimpurity,notuseddirectlyorfoundinpracticeasdemonstratedbystudiesduringdevelopmentofthemanufacture,theclass-1solventdoesnotneedtobeincludedinthedrugsubstancespecificationoraspecificationofanintermediate.

如果1类溶剂仅是潜在的杂质，未直接使用或通过生产开发过程的研究明确实际不存在则原料药标准或中间体标准中不需要包含该1类溶剂。

Example2–Aclass-1solventisformedorintroducedpriortothefinalstepofthesynthesis举例2—在合成最后一步前形成或引入1类溶剂

Ifaclass-1solventisformedorintroducedinastepbeforethefinalsynthesisstep,itisconsideredpossibletonotincludethissolventinthedrugsubstancespecificationifitiscontrolledbyasuitablelimitinastartingmaterialorsynthesisintermediateandifitisunambiguouslydemonstratedbyanalysisresultsthatthepresenceofthissolventdoesnotexceed30%oftheguidelinelimitinthedrugsubstance.

如果在最后合成步骤前产生或引入了1类溶剂，如果在合成中间体控制在适当的限度并且通过分析结果明确地证明该杂质在原料药中含量不超过指南限度的30%，则认为原料药标准中可以不包含该溶剂。

Itisconsideredpossibletoapplyskiptestingifthelevelofthesolventinasynthesisintermediatedoesnotexceed30%oftheguidelinelimitintheintermediate.Datashouldbepresentedforatleast6consecutivepilotscaleor3consecutiveproductionscalebatches.Ifthisconditionisnotfulfilled,aroutinetestintheintermediateisneeded.Ifthesolventexceeds30%oftheguidelinelimitinthedrugsubstancethesolventhastobeincludedinthedrugsubstancespecificationandthetesthastobecarriedoutonaroutinebasis.

如果合成中间体中的1类溶剂水平不超过指南限度的30%，则认为可以使用跳跃检测，至少具有6个连续中试批或3个连续生产批的数据，如果不满足这些条件，则需要对中间体进行例行检测。如果原料药中该1类溶剂超过指南限度的30%，则原料药标准中必须包含该溶剂，并且应进行例行检测。Shouldaclass-1solventnotbecontrolledatthestartingmaterialorintermediatestage,thenthescenarioofexample3applies.

如果在中间体阶段没有1类溶剂需要控制，则适应举例3的情况。Example3–Aclass-1solventisformedorintroducedinthelastsynthesisstep举例3—在合成最后一步有1类溶剂形成或引入

一致性评价资料汇总下载地址：http://www.yaoqun.net/thread-15475-1-1.htmlIfaclass-1solventisformedorintroducedinthefinalsynthesisstep,itshouldbeincludedinthespecifications.However,itisconsideredpossibletoapplyskiptestingifthelevelofthesolventdoesnotexceed30%oftheguidelinelimitinthedrugsubstance.Datashouldbepresentedforatleast6consecutivepilotscaleor3consecutiveproductionscalebatches.

如果在最后合成步骤形成或引入1类溶剂，则应包含于质量标准中。然而，如果原料药中溶剂不超过指南限度的30%，则认为可以使用跳跃检测，但至少具有6个连续中试批或3个连续生产批的数据。