ICH-Q11问答-中英对照

红色代表问题涉及到的ICHQ11章节号及相关指南#QuestionsAnswers5.1ICHQ11statesthat“Astartingmaterialisincorporatedasasignificantstructuralfragmentintothestructureofthedrugsubstance.”Whythenareintermediatesusedlateinthesynthesis,whichclearlycontainsignificantstructuralfragments,oftennotacceptableasstartingmaterials?Theselectionprincipleabout“significantstructuralfragment”hasfrequentlybeenmisinterpretedasmeaningthattheproposedstartingmaterialshouldbestructurallysimilartothedrugsubstance.However,asstatedinICHQ11,theprincipleisintendedtohelpdistinguishbetweenreagents,catalysts,solvents,orotherrawmaterials(whichdonotcontributea“significantstructuralfragment”tothemolecularstructureofthedrugsubstance)frommaterialsthatdo.Itisnotintendedtodictatetheselectionofeitheraveryearlyoraverylateintermediateasthestartingmaterial.Aproposedstartingmaterialmaybeseveralstepsfromcommerciallyavailablematerials,provideditisnotasmallnumberofchemicaltransformationstepsfromthedrugsubstance,andprovidedthejustificationacceptablyaddressestheICHQ11generalprinciples.Thepresenceofa“significantstructuralfragment”shouldnotbethesolebasisforofstartingmaterialselection.Startingmaterialsjustifiedsolelyonthebasisthattheyarea“significantstructuralfragment”probablywillnotbeacceptedasstartingmaterialsbyregulatoryauthorities,astheotherprinciplesfortheappropriateselectionofaproposedstartingmaterialalsorequireconsideration.5.1.1ICHQ11指出“起始物料是原料药结构的重要结构片断。”那么为什么最后合成步骤中用到的中间体，明确含有重要结构片断，却不能作为起始物料呢？“重要结构片断”这个选择依据经常被曲解为起始物料应该和原料药结构相似。但是，正如ICHQ11所说，该原则旨在将试剂、溶剂及其他原料这些没有原料药“重要结构片断”的物料与起始物料区分开来。并非让选择较前或较后的中间体作为起始物料。所选择的起始物料可以是市售物料通过几个步骤合成，只要不是很少几步化学转换得到原料药即可。“重要结构片断”不应单独作为起始物料选择的依据，只将这个作为论证起始物料的选择依据可能不会被药政官方所接受，因为其他的合理的起始物料选择依据也要考虑在内。5.2ICHQ11recommendsthat“manufacturingstepsthatimpacttheimpurityprofileofthedrugsubstanceshouldnormallybeincludedinthemanufacturingprocessdescribedinSection3.2.S.2.2oftheapplication.”AtwhatlevelwouldarelatedFornon-mutagenicrelatedsubstances,animpuritythatislikelytobepresentinthedrugsubstanceatalevelabovetheICHQ3AIdentificationThresholdisconsideredtohaveanimpactontheimpurityprofileofthedrugsubstance.Amutagenicimpuritythatislikelytobepresentinthedrugsubstanceabove30%oftheICHM7acceptableintakeisusuallyconsideredtoimpacttheimpurityprofileofthedrugsubstance.AnyoftheapproachesdescribedinICHM7canbeusedtodeterminewhichimpuritiesarelikelytobepresentabovethe30%threshold.The30%thresholdservesananalogousfunctioninICHM7totheIdentificationThresholdinICHQ3A.InlinewithICHM7andICHS9,therearesituations(e.g.,whenthedrugsubstanceisitselfgenotoxic,and#QuestionsAnswerssubstanceormutagenicimpuritybeconsideredtoimpacttheimpurityprofileofthedrugsubstance?othercircumstancesasdescribedintheseguidelines)whentheselectionofthestartingmaterialforadrugsubstancedoesnotneedtospecificallyconsiderthemutagenicimpurityprofileatthelevelsdescribedabove.Insuchcases,mutagenicimpuritiesarenotconsideredtoimpacttheimpurityprofileofthedrugsubstanceunlesstheyareabovetheICHQ3AIdentificationThreshold.ImpuritiesthatpersistthroughmultiplestepsofmanufactureshouldbeconsideredinconjunctionwithQ&A5.3.5.1.1M7Q3AS9ICHQ11建议“影响原料药杂质概况的生产步骤通常在申请文件3.2.S.2.2章节生产工艺部分描述”，什么水平的杂质或致畸杂质会被认为影响到原料药的杂质概况？对于非致畸杂质，该杂质水平高于ICHQ3A鉴定阈值时则被认为对原料药的杂质概况有影响。原料药中可能出现的致畸杂质高于ICHM7可接受限度的30%则被认为对原料药的杂质概况有影响。ICHM7中提到的方法均可用来测定哪些杂质可能高于30%阈值。ICHM7中30%阈值作用类似于ICHQ3A的鉴定阈值。与ICHM7和ICHS9一致，一些特殊情况如当原料药本身就是基因毒性时，及指南中提及的其他情况时，原料药起始物料的选择依据不需要特别考虑上述情况。这种情况下，致畸杂质不作为影响原料药杂质概况考虑在内，除非其水平高于ICHQ3A的鉴定阈值。经过多步生产仍然存在的杂质应结合问答5.3进行考虑。5.3Whatismeantbyimpuritiesthat“persist”inICHQ11Example4?ICHQ11recommendsthat“manufacturingstepsthatimpacttheimpurityprofileofthedrugsubstanceshouldnormallybeincludedinthemanufacturingprocessdescribedinSection3.2.S.2.2oftheapplication.”However,asdescribedinICHQ11Example4,thisprincipledoesnotnecessarilyapplywhenimpuritiesoriginateearlyinthemanufacturingprocessand“persist”acrossmultiplesteps,providedthatthestepspriortotheproposedstartingmaterialoverwhichtheimpuritiespersistdonotthemselvesimpactthedrugsubstanceimpurityprofile.InExample4therearemultiplesteps(fromCompoundBtoCompoundD)thatdonotimpactthedrugsubstanceimpurityprofile.Withoutthisexception,thesestepswouldhavetobeincludedinSection3.2.S.2.2oftheapplication.Impuritiesthatpersistmayormaynotreactinsubsequentsteps,butarenotremovedtotheextentthattheywouldnolongerbeconsideredtoimpactthedrugsubstanceimpurityprofile[For“impact”seeQ&A5.2].Forexample,animpuritythatpersistsmighthavephysico-chemicalproperties(e.g.,solubility)similartootherintermediatesorthedrugsubstance,liketheenantiomerinExample4,whichcouldmakeitsremovalintrinsicallydifficult.ICHQ11Example4illustratesthatwhenthesyntheticroutecontainsanimpuritythatpersists,itcanbe#QuestionsAnswersacceptabletocontroltheimpurityinthestartingmaterialspecificationeventhoughitimpactstheimpurityprofileofthedrugsubstance.Therefore,itisnotalwaysnecessarytoincludestepsthatformsuchanimpurityinSection3.2.S.2.2,providedthattheotherICHQ11generalprinciplesareaddressed[ICHQ11Section5.1.1].Example4isnotexclusivetostereoisomersandcanbeappliedtoothertypesofimpuri