Q3C(R7)英文原文

Q3C(R7)英文原文INTERNATIONALCOUNCILFORHARMONISATIONOFTECHNICALREQUIREMENTSFORPHARMACEUTICALSFORHUMANUSEICHHARMONISEDGUIDELINEIMPURITIES:GUIDELINEFORRESIDUALSOLVENTSQ3C(R7)CurrentStep4versiondated15October2018ThisGuidelinehasbeendevelopedbytheappropriateICHExpertWorkingGroupandhasbeensubjecttoconsultationbytheregulatoryparties,inaccordancewiththeICHProcess.AtStep4oftheProcessthefinaldraftisrecommendedforadoptiontotheregulatorybodiesofICHregions.Q3C(R7)DocumentHistoryCodeHistoryDateParentGuideline:Impurities:GuidelineforResidualSolventsQ3CApprovalbytheSteeringCommitteeunderStep2andreleaseforpublicconsultation.6November1996Q3CApprovalbytheSteeringCommitteeunderStep4andrecommendationforadoptiontothethreeICHregulatorybodies.17July1997RevisionofthePDEinformationforTHFcontainedintheParentGuidelineQ3C(R1)Note:PriortoaddingtherevisiontotheparentGuidelineinNovember2005,thecodewasQ3C(M)forTHF.PermissibleDailyExposure(PDE)forTetrahydrofuran(THF):revisionofPDEbasedonnewtoxicologicaldata.ApprovalbytheSteeringCommitteeofthenewPDEforTHFunderStep2andreleaseforpublicconsultation.20July2000Q3C(R1)Note:PriortoaddingtherevisiontotheparentGuidelineinNovember2005,thecodewasQ3C(M)forTHF.ApprovalbytheSteeringCommitteeunderStep4andrecommendationforadoptiontothethreeICHregulatorybodies.12September2002RevisionofPDEinformationforNMPcontainedintheParentGuidelineQ3C(R2)Note:PriortoaddingtherevisiontotheparentGuidelineinNovember2005,thecodewasQ3C(M)forNMP.PermissibleDailyExposure(PDE)forN-Methylpyrrolidone(NMP):revisionofPDEbasedonnewtoxicologicaldata.ApprovalbytheSteeringCommitteeoftheRevisionunderStep2andreleaseforpublicconsultation.20July2000Q3C(R2)Note:PriortoaddingtherevisiontotheparentGuidelineinNovember2005,thecodewasQ3C(M)forNMP.ApprovalbytheSteeringCommitteeunderStep4andrecommendationforadoptiontothethreeICHregulatorybodies.12September2002Q3C(R3)Note:PriortoaddingthecorrigendumtotheparentGuidelineinNovember2005,thecodewasQ3C(M)forNMP.CorrigendumtocalculationformulaapprovedbytheSteeringCommittee.28October2002Q3C(R3)TheparentGuidelineisnowrenamedQ3C(R3)asthetwoupdates(PDEforN-MethylpyrrolidoneandPDEforTetrahydrofuran)andthecorrigendumoftheupdateforNMPhavebeenaddedtotheparentGuideline.November2005ParentGuideline:Impurities:GuidelineforResidualSolventsQ3C(R4)UpdateofTable2,Table3andAppendix1toreflecttherevisionofthePDEsforN-MethylpyrrolidoneandTetrahydrofuran.February2009RevisionofPDEinformationforCumenecontainedintheParentGuidelineQ3C(R5)PermissibleDailyExposure(PDE)forCumene:revisionofPDEbasedonnewtoxicologicaldata.ApprovalbytheSteeringCommitteeunderStep2andreleaseforpublicconsultation.26March2010Q3C(R5)ApprovalofthePDEforCumenebytheSteeringCommitteeunderStep4andrecommendationforadoptiontothethreeICHregulatorybodies.ThePDEforCumenedocumenthasbeenintegratedaspartIVinthecoreQ3C(R4)GuidelinewhichwasthenrenamedQ3C(R5).TheTable2,Table3andAppendix1havebeenupdatedtoreflecttherevisionofthePDEforCumene.4February2011RevisionofPDEinformationforMethylisobutylketonecontainedintheParentGuidelineandtoincludeaPDEforTriethylamineQ3C(R6)PermissibleDailyExposure(PDE)forTriethylamineandMethylisobutylketone:revisionofPDEbasedonnewtoxicologicaldata.ApprovalbytheAssemblyunderStep2andreleaseforpublicconsultation.9November2016Q3C(R6)ApprovalofthePDEforTriethylamineandMethylisobutylketonebytheAssemblyunderStep4andrecommendationforadoptiontothethreeICHregulatorybodies.ThePDEforTriethylamineandMethylisobutylketonedocumenthasbeenintegratedaspartVinthecoreQ3C(R5)GuidelinewhichwasthenrenamedQ3C(R6).TheTable2,Table3andAppendix1havebeenupdatedtoreflecttherevisionofthePDEforTriethylamineandMethylisobutylketone.9November2016CorrectionofthePDEforEthyleneglycolQ3C(R7)CorrectionforthePDEandconcentrationlimitforEthyleneglycolonTable2page6,asperthecorrectvaluecalculatedinPharmeuropa,Vol.9,No.1,Supplement,April1997S36.15October2018IMPURITIES:GUIDELINEFORRESIDUALSOLVENTSICHHarmonisedGuidelineTABLEOFCONTENTSPARTI:1.INTRODUCTION(1)2.SCOPEOFTHEGUIDELINE(1)3.GENERALPRINCIPLES(2)3.1ClassificationofResidualSolventsbyRiskAssessment(2)3.2MethodsforEstablishingExposureLimits(2)3.3OptionsforDescribingLimitsofClass2Solvents(3)3.4AnalyticalProcedures(4)3.5Reportinglevelsofresidualsolvents(4)4.LIMITSofRESIDUALSOLVENTS(5)4.1SolventstoBeAvoided(5)4.2SolventstoBeLimited(6)4.3SolventswithLowToxicPotential(7)4.4SolventsforwhichNoAdequateToxicologicalDatawasFound(8)GLOSSARY(9)APPENDIX1.LISTOFSOLVENTSINCLUDEDINTHEGUIDELINE(10)APPENDIX2.ADDITIONALBACKGROUND(14)A2.1EnvironmentalRegulationofOrganicVolatileSolvents(14)A2.2ResidualSolventsinPharmaceuticals(14)APPENDIX3.METHODSFORESTABLISHINGEXPOSURELIMITS(15)PARTII:PDEforTetrahydrofuran(18)PARTIII:PDEforN-Methylpyrrolidone(NMP)(20)PARTIV:PDEforCumene(22)PARTV:PDEforTriethylamineandPDEofMethylisobutylketone(26)1PARTI:IMPURITIES:GUIDELINEFORRESIDUALSOLVENTSHavingreachedStep4oftheICHProcessattheICHSteeringCommitteemeetingon17July1997,thisGuidelineisrecommendedforadoptiontothethreeregulatorypartiestoICH1.INTRODUCTIONTheobjectiveofthisguidelineistorecommendacceptableamountsforresidualsolventsinpharmaceuticalsforthesafetyofthepatient.Theguidelinerecommendsuseoflesstoxicsolventsanddescribeslevelsconsideredtobetoxicologicallyacceptableforsomeresidualsolvents.Residualsolventsinpharmaceuticalsaredefinedhereasorganicvolatilechemicalsthatareusedorproducedinthemanufactureofdrugsubstancesorexcipients,orinthepreparationofdrugproducts.Thesolventsarenotcompletelyremovedbypracticalmanufacturingtechniques.Appropriateselectionofthesolventforthesynthesisofdrugsubstancemayenhancetheyield,ordeterminecharacteristicssuchascrystalform,purity,andsolubility.Therefore,thesolventmaysometimesbeacriticalparameterinthesyntheticprocess.Thisguidelinedoesnotaddresssolventsdeliberatelyusedasexcipientsnordoesitaddresssolvates.However,thecontentofsolventsinsuchproductsshouldbeevaluatedandjustified.Sincethereisnotherapeuticbenefitfromresidualsolvents,allresidualsolventsshouldberemovedtotheextentpossibletomeetproductspecifications,goodmanufacturingpractices,orotherquality-basedrequirements.Drugproductsshouldcontainnohigherlevelsofresidualsolventsthancanbesupportedbysafetydata.Somesolventsthatareknowntocauseunacceptabletoxicities(Class1,Table1)shouldbeavoidedintheproductionofdrugsubstances,excipients,ordrugproductsunlesstheirusecanbestronglyjustifiedinarisk-benefitassessment.Somesolventsassociatedwithlessseveretoxicity(Class2,Table2)shouldbelimitedinordertoprotectpatientsfrompotentialadverseeffects.Ideally,lesstoxicsolvents(Class3,Table3)shouldbeusedwherepractical.ThecompletelistofsolventsincludedinthisguidelineisgiveninAppendix1.Thelistsarenotexhaustiveandothersolventscanbeusedandlateraddedtothelists.RecommendedlimitsofClass1and2solventsorclassificationofsolventsmaychangeasnewsafetydatabecomesavailable.Supportingsafetydatainamarketingapplicationforanewdrugproductcontaininganewsolventmaybebasedonconceptsinthisguidelineortheconceptofqualificationofimpuritiesasexpressedintheguidelinefordrugsubstance(Q3A,ImpuritiesinNewDrugSubstances)ordrugproduct(Q3B,ImpuritiesinNewDrugProducts),orallthreeguidelines.2.SCOPEOFTHEGUIDELINEResidualsolventsindrugsubstances,excipients,andindrugproductsarewithinthescopeofthisguideline.Therefore,testingshouldbeperformedforresidualsolventswhenproductionorpurificationprocessesareknowntoresultinthepresenceofsuchsolvents.Itisonlynecessarytotestforsolventsthatareusedorproducedinthemanufactureorpurificationofdrugsubstances,excipients,ordrugproduct.Althoughmanufacturersmaychoosetotestthedrugproduct,acumulativemethodmaybeusedtocalculatetheresidualsolventlevelsinthedrugproductfromthelevelsintheingredientsusedtoproducethedrugproduct.Ifthecalculationresultsinalevelequaltoorbelowthatrecommendedinthisguideline,notestingofthedrugproductforresidualsolventsneedbeconsidered.If,however,thecalculatedlevelisabovetherecommendedlevel,thedrugproductshouldbetestedtoascertainwhethertheImpurities:GuidelineforResidualSolventsformulationprocesshasreducedtherelevantsolventleveltowithintheacceptableamount.Drugproductshouldalsobetestedifasolventisusedduringitsmanufacture.Thisguidelinedoesnotapplytopotentialnewdrugsubstances,excipients,ordrugproductsusedduringtheclinicalresearchstagesofdevelopment,nordoesitapplytoexistingmarketeddrugproducts.Theguidelineappliestoalldosageformsandroutesofadministration.Higherlevelsofresidualsolventsmaybeacceptableincertaincasessuchasshortterm(30daysorless)ortopicalapplication.Justificationfortheselevelsshouldbemadeonacasebycasebasis.SeeAppendix2foradditionalbackgroundinformationrelatedtoresidualsolvents.3.GENERALPRINCIPLES3.1ClassificationofResidualSolventsbyRiskAssessmentTheterm"tolerabledailyintake"(TDI)isusedbytheInternationalProgramonChemicalSafety(IPCS)todescribeexposurelimitsoftoxicchemicalsand"acceptabledailyintake"(ADI)isusedbytheWorldHealthOrganization(WHO)andothernationalandinternationalhealthauthoritiesandinstitutes.Thenewterm"permitteddailyexposure"(PDE)isdefinedinthepresentguidelineasapharmaceuticallyacceptableintakeofresidualsolventstoavoidconfusionofdifferingvaluesforADI'softhesamesubstance.ResidualsolventsassessedinthisguidelinearelistedinAppendix1bycommonnamesandstructures.Theywereevaluatedfortheirpossiblerisktohumanhealthandplacedintooneofthreeclassesasfollows:Class1solvents:SolventstobeavoidedKnownhumancarcinogens,stronglysuspectedhumancarcinogens,andenvironmentalhazards.Class2solvents:SolventstobelimitedNon-genotoxicanimalcarcinogensorpossiblecausativeagentsofotherirreversibletoxicitysuchasneurotoxicityorteratogenicity.Solventssuspectedofothersignificantbutreversibletoxicities.Class3solvents:SolventswithlowtoxicpotentialSolventswithlowtoxicpotentialtoman;nohealth-basedexposurelimitisneeded.Class3solventshavePDEsof50mgormoreperday.3.2MethodsforEstablishingExposureLimitsThemethodusedtoestablishpermitteddailyexposuresforresidualsolventsispresentedinAppendix3.SummariesofthetoxicitydatathatwereusedtoestablishlimitsarepublishedinPharmeuropa,Vol.9,No.1,Supplement,April1997.Impurities:GuidelineforResidualSolvents3.3OptionsforDescribingLimitsofClass2SolventsTwooptionsareavailablewhensettinglimitsforClass2solvents.Option1:TheconcentrationlimitsinppmstatedinTable2canbeused.Theywerecalculatedusingequation(1)belowbyassumingaproductmassof10gadministereddaily.Concentration(ppm)1000xPDEdose=(1)Here,PDEisgivenintermsofmg/dayanddoseisgivening/day.Theselimitsareconsideredacceptableforallsubstances,excipients,orproducts.Thereforethisoptionmaybeappliedifthedailydoseisnotknownorfixed.IfallexcipientsanddrugsubstancesinaformulationmeetthelimitsgiveninOption1,thenthesecomponentsmaybeusedinanyproportion.Nofurthercalculationisnecessaryprovidedthedailydosedoesnotexceed10g.Productsthatareadministeredindosesgreaterthan10gperdayshouldbeconsideredunderOption2.Option2:ItisnotconsiderednecessaryforeachcomponentofthedrugproducttocomplywiththelimitsgiveninOption1.ThePDEintermsofmg/dayasstatedinTable2canbeusedwiththeknownmaximumdailydoseandequation(1)abovetodeterminetheconcentrationofresidualsolventallowedindrugproduct.Suchlimitsareconsideredacceptableprovidedthatithasbeendemonstratedthattheresidualsolventhasbeenreducedtothepracticalminimum.Thelimitsshouldberealisticinrelationtoanalyticalprecision,manufacturingcapability,reasonablevariationinthemanufacturingprocess,andthelimitsshouldreflectcontemporarymanufacturingstandards.Option2maybeappliedbyaddingtheamountsofaresidualsolventpresentineachofthecomponentsofthedrugproduct.ThesumoftheamountsofsolventperdayshouldbelessthanthatgivenbythePDE.ConsideranexampleoftheuseofOption1andOption2appliedtoacetonitrileinadrugproduct.Thepermitteddailyexposuretoacetonitrileis4.1mgperday;thus,theOption1limitis410ppm.Themaximumadministereddailymassofadrugproductis5.0g,andthedrugproductcontainstwoexcipients.Thecompositionofthedrugproductandthecalculatedmaximumcontentofresidualacetonitrilearegiveninthefollowingtable.ComponentAmountinformulationAcetonitrilecontentDailyexposureDrugsubstance0.3g800ppm0.24mgExcipient10.9g400ppm0.36mgExcipient23.8g800ppm3.04mgDrugProduct5.0g728ppm3.64mgExcipient1meetstheOption1limit,butthedrugsubstance,excipient2,anddrugproductdonotmeettheOption1limit.Nevertheless,theproductmeetstheOption2limitof4.1mgperdayandthusconformstotherecommendationsinthisguideline.Impurities:GuidelineforResidualSolventsConsideranotherexampleusingacetonitrileasresidualsolvent.Themaximumadministereddailymassofadrugproductis5.0g,andthedrugproductcontainstwoexcipients.Thecompositionofthedrugproductandthecalculatedmaximumcontentofresidualacetonitrilearegiveninthefollowingtable.ComponentAmountinAcetonitrilecontentDailyexposureformulationDrugsubstance0.3g800ppm0.24mgExcipient10.9g2000ppm1.80mgExcipient23.8g800ppm3.04mgDrugProduct5.0g1016ppm5.08mgInthisexample,theproductmeetsneithertheOption1northeOption2limitaccordingtothissummation.Themanufacturercouldtestthedrugproducttodetermineiftheformulationprocessreducedthelevelofacetonitrile.Ifthelevelofacetonitrilewasnotreducedduringformulationtotheallowedlimit,thenthemanufacturerofthedrugproductshouldtakeotherstepstoreducetheamountofacetonitrileinthedrugproduct.Ifallofthesestepsfailtoreducethelevelofresidualsolvent,inexceptionalcasesthemanufacturercouldprovideasummaryofeffortsmadetoreducethesolventleveltomeettheguidelinevalue,andprovidearisk-benefitanalysistosupportallowingtheproducttobeutilisedwithresidualsolventatahigherlevel.3.4AnalyticalProceduresResidualsolventsaretypicallydeterminedusingchromatographictechniquessuchasgaschromatography.Anyharmonisedproceduresfordetermininglevelsofresidualsolventsasdescribedinthepharmacopoeiasshouldbeused,iffeasible.Otherwise,manufacturerswouldbefreetoselectthemostappropriatevalidatedanalyticalprocedureforaparticularapplication.IfonlyClass3solventsarepresent,anon-specificmethodsuchaslossondryingmaybeused.ValidationofmethodsforresidualsolventsshouldconformtoICHguidelinesTextonValidationofAnalyticalProceduresandExtensionoftheICHTextonValidationofAnalyticalProcedures.3.5ReportinglevelsofresidualsolventsManufacturersofpharmaceuticalproductsneedcertaininformationaboutthecontentofresidualsolventsinexcipientsordrugsubstancesinordertomeetthecriteriaofthisguideline.Thefollowingstatementsaregivenasacceptableexamplesoftheinformationthatcouldbeprovidedfromasupplierofexcipientsordrugsubstancestoapharmaceuticalmanufacturer.Thesuppliermightchooseoneofthefollowingasappropriate:•OnlyClass3solventsarelikelytobepresent.Lossondryingislessthan0.5%.•OnlyClass2solventsX,Y,...arelikelytobepresent.AllarebelowtheOption1limit.(HerethesupplierwouldnametheClass2solventsrepresentedbyX,Y,...)•OnlyClass2solventsX,Y,...andClass3solventsarelikelytobepresent.ResidualClass2solventsarebelowtheOption1limitandresidualClass3solventsarebelow0.5%.Impurities:GuidelineforResidualSolventsIfClass1solventsarelikelytobepresent,theyshouldbeidentifiedandquantified."Likelytobepresent"referstothesolventusedinthefinalmanufacturingstepandtosolventsthatareusedinearliermanufacturingstepsandnotremovedconsistentlybyavalidatedprocess.IfsolventsofClass2orClass3arepresentatgreaterthantheirOption1limitsor0.5%,respectively,theyshouldbeidentifiedandquantified.4.LIMITSOFRESIDUALSOLVENTS4.1SolventstoBeAvoidedSolventsinClass1shouldnotbeemployedinthemanufactureofdrugsubstances,excipients,anddrugproductsbecauseoftheirunacceptabletoxicityortheirdeleteriousenvironmentaleffect.However,iftheiruseisunavoidableinordertoproduceadrugproductwithasignificanttherapeuticadvance,thentheirlevelsshouldberestrictedasshowninTable1,unlessotherwisejustified.1,1,1-TrichloroethaneisincludedinTable1becauseitisanenvironmentalhazard.Thestatedlimitof1500ppmisbasedonareviewofthesafetydata.TABLE1.Class1solventsinpharmaceuticalproducts(solventsthatshouldbeavoided).ConcernSolventConcentrationlimit(ppm)Benzene2CarcinogenCarbontetrachloride4Toxicandenvironmentalhazard1,2-Dichloroethane5Toxic1,1-Dichloroethene8Toxic1,1,1-Trichloroethane1500Environmentalhazard