ICH\Q3C(R3)

INTERNATIONALCONFERENCEONHARMONISATIONOFTECHNICALREQUIREMENTSFORREGISTRATIONOFPHARMACEUTICALSFORHUMANUSEICHHARMONISEDTRIPARTITEGUIDELINEIMPURITIES:GUIDELINEFORRESIDUALSOLVENTSQ3C(R3)CurrentStep4versionParentGuidelinedated17July1997(RevisedPDEforTHFandNMPdated12September2002and28October2002incorporatedinNovember2005)ThisGuidelinehasbeendevelopedbytheappropriateICHExpertWorkingGroupandhasbeensubjecttoconsultationbytheregulatoryparties,inaccordancewiththeICHProcess.AtStep4oftheProcessthefinaldraftisrecommendedforadoptiontotheregulatorybodiesoftheEuropeanUnion,JapanandUSA.Q3C(R3)DocumentHistoryFirstHistoryDateNewCodificationCodificationNov.2005ParentGuideline:Impurities:GuidelineforResidualSolventsQ3CApprovalbytheSteeringCommitteeunderStep2andreleasefor6Q3Cpublicconsultation.November1996Q3CApprovalbytheSteeringCommitteeunderStep4and17Q3CrecommendationforadoptiontothethreeICHregulatorybodies.July1997RevisionofthePDEinformationforTHFcontainedintheParentGuidelineQ3C(M)PermissibleDailyExposure(PDE)forTetrahydrofuran(THF):20inQ3C(R1)forTHFrevisionofPDEbasedonnewtoxicologicaldata.JulyApprovalbytheSteeringCommitteeofthenewPDEforTHF2000underStep2andreleaseforpublicconsultation.Q3C(M)ApprovalbytheSteeringCommitteeunderStep4and12inQ3C(R1)forTHFrecommendationforadoptiontothethreeICHregulatorybodies.September2002RevisionofPDEinformationforNMPcontainedintheParentGuidelineQ3C(M)PermissibleDailyExposure(PDE)forN-Methylpyrrolidone20inQ3C(R2)forNMP(NMP):revisionofPDEbasedonnewtoxicologicaldata.JulyApprovalbytheSteeringCommitteeoftheRevisionunderStep22000andreleaseforpublicconsultation.Q3C(M)ApprovalbytheSteeringCommitteeunderStep4and12inQ3C(R2)forNMPrecommendationforadoptiontothethreeICHregulatorybodies.September2002Q3C(M)CorrigendumtocalculationformulaapprovedbytheSteering28inQ3C(R3)forNMPCommittee.October2002CurrentStep4versionQ3C,Q3C(M)TheparentguidelineisnowrenamedQ3C(R3)asthetwoupdatesNovemberQ3C(R3)forTHFand(PDEforN-MethylpyrrolidoneandPDEforTetrahydrofuran)and2005Q3C(M)forNMPthecorrigendumoftheupdateforNMPhavebeenaddedtotheparentguideline.iiIMPURITIES:GUIDELINEFORRESIDUALSOLVENTSICHHarmonisedTripartiteGuidelineTABLEOFCONTENTSPARTI:1.INTRODUCTION.....................................................................................................12.SCOPEOFTHEGUIDELINE...............................................................................13.GENERALPRINCIPLES.......................................................................................23.1ClassificationofResidualSolventsbyRiskAssessment..................................23.2MethodsforEstablishingExposureLimits.......................................................23.3OptionsforDescribingLimitsofClass2Solvents...........................................33.4AnalyticalProcedures........................................................................................43.5Reportinglevelsofresidualsolvents.................................................................44.LIMITSofRESIDUALSOLVENTS......................................................................54.1SolventstoBeAvoided.......................................................................................54.2SolventstoBeLimited.......................................................................................54.3SolventswithLowToxicPotential....................................................................74.4SolventsforwhichNoAdequateToxicologicalDatawasFound.....................7GLOSSARY.......................................................................................................................8APPENDIX1.LISTOFSOLVENTSINCLUDEDINTHEGUIDELINE..............9APPENDIX2.ADDITIONALBACKGROUND........................................................13A2.1EnvironmentalRegulationofOrganicVolatileSolvents..............................13A2.2ResidualSolventsinPharmaceuticals............................................................13APPENDIX3.METHODSFORESTABLISHINGEXPOSURELIMITS...........14PARTII:PDEFORTETRAHYDROFURAN......................................................................................17PARTIII:PDEFORN-METHYLPYRROLIDONE(NMP).................................................................19iPARTI: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.Ifthecalculationresultsinalevel1ResidualSolventImpuritiesequaltoorbelowthatrecommendedinthisguideline,notestingofthedrugproductforresidualsolventsneedbeconsidered.If,however,thecalculatedlevelisabovetherecommendedlevel,thedrugproductshouldbetestedtoascertainwhethertheformulationprocesshasreducedtherelevantsolventleveltowithintheacceptableamount.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,April1997.2ResidualSolventImpurities3.3OptionsforDescribingLimitsofClass2SolventsTwooptionsareavailablewhensettinglimitsforClass2solvents.Option1:TheconcentrationlimitsinppmstatedinTable2canbeused.Theywerecalculatedusingequation(1)belowbyassumingaproductmassof10gadministereddaily.1000xPDEConcentration(ppm)=(1)doseHere,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.ComponentAmountinAcetonitrilecontentDailyexposureformulationDrugsubstance0.3g800ppm0.24mgExcipient10.9g400ppm0.36mgExcipient23.8g800ppm3.04mgDrugProduct5.0g728ppm3.64mgExcipient1meetstheOption1limit,butthedrugsubstance,excipient2,anddrugproductdonotmeettheOption1limit.Nevertheless,theproductmeetstheOption2limitof4.1mgperdayandthusconformstotherecommendationsinthisguideline.3ResidualSolventImpuritiesConsideranotherexampleusingacetonitrileasresidualsolvent.Themaximumadministereddailymassofadrugproductis5.0g,andthedrugproductcontainstwoexcipients.Thecompositionofthedrugproductandthecalculatedmaximumcontentofresidualacetonitrileisgiveninthefollowingtable.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%.4ResidualSolventImpuritiesIfClass1solventsarelikelytobepresent,theyshouldbeidentifiedandquantified."Likelytobepresent"referstothesolventusedinthefinalmanufacturingstepandtosolventsthatareusedinearliermanufacturingstepsandnotremovedconsistentlybyavalidatedprocess.IfsolventsofClass2orClass3arepresentatgreaterthantheirOption1limitsor0.5%,respectively,theyshouldbeidentifiedandquantified.4.LIMITSOFRESIDUALSOLVENTS4.1SolventstoBeAvoidedSolventsinClass1shouldnotbeemployedinthemanufactureofdrugsubstances,excipients,anddrugproductsbecauseoftheirunacceptabletoxicityortheirdeleteriousenvironmentaleffect.However,iftheiruseisunavoidableinordertoproduceadrugproductwithasignificanttherapeuticadvance,thentheirlevelsshouldberestrictedasshowninTable1,unlessotherwisejustified.1,1,1-TrichloroethaneisincludedinTable1becauseitisanenvironmentalhazard.Thestatedlimitof1500ppmisbasedonareviewofthesafetydata.TABLE1.Class1solventsinpharmaceuticalproducts(solventsthatshouldbeavoided).SolventConcentrationlimitConcern(ppm)Benzene2CarcinogenCarbontetrachloride4Toxicandenvironmentalhazard1,2-Dichloroethane5Toxic1,1-Dichloroethene8Toxic1,1,1-Trichloroethane1500Environmentalhazard4.2SolventstoBeLimitedSolventsinTable2shouldbelimitedinpharmaceuticalproductsbecauseoftheirinherenttoxicity.PDEsaregiventothenearest0.1mg/day,andconcentrationsaregiventothenearest10ppm.Thestatedvaluesdonotreflectthenecessaryanalyticalprecisionofdetermination.Precisionshouldbedeterminedaspartofthevalidationofthemethod.5ResidualSolventImpuritiesTABLE2.Class2solventsinpharmaceuticalproducts.SolventPDE(mg/day)Concentrationlimit(ppm)Acetonitrile4.1410Chlorobenzene3.6360Chloroform0.660Cyclohexane38.838801,2-Dichloroethene18.71870Dichloromethane6.06001,2-Dimethoxyethane1.0100N,N-Dimethylacetamide10.91090N,N-Dimethylformamide8.88801,4-Dioxane3.83802-Ethoxyethanol1.6160Ethyleneglycol6.2620Formamide2.2220Hexane2.9290Methanol30.030002-Methoxyethanol0.550Methylbutylketone0.550Methylcyclohexane11.81180N-Methylpyrrolidone48.44840Nitromethane0.550Pyridine2.0200Sulfolane1.6160Tetralin1.0100Toluene8.98901,1,2-Trichloroethene0.880Xylene*21.72170*usually60%m-xylene,14%p-xylene,9%o-xylenewith17%ethylbenzene6ResidualSolventImpurities4.3SolventswithLowToxicPotentialSolventsinClass3(showninTable3)mayberegardedaslesstoxicandoflowerrisktohumanhealth.Class3includesnosolventknownasahumanhealthhazardatlevelsnormallyacceptedinpharmaceuticals.However,therearenolong-termtoxicityorcarcinogenicitystudiesformanyofthesolventsinClass3.Availabledataindicatethattheyarelesstoxicinacuteorshort-termstudiesandnegativeingenotoxicitystudies.Itisconsideredthatamountsoftheseresidualsolventsof50mgperdayorless(correspondingto5000ppmor0.5%underOption1)wouldbeacceptablewithoutjustification.Higheramountsmayalsobeacceptableprovidedtheyarerealisticinrelationtomanufacturingcapabilityandgoodmanufacturingpractice.Table3.Class3solventswhichshouldbelimitedbyGMPorotherquality-basedrequirements.AceticacidHeptaneAcetoneIsobutylacetateAnisoleIsopropylacetate1-ButanolMethylacetate2-Butanol3-Methyl-1-butanolButylacetateMethylethylketonetert-ButylmethyletherMethylisobutylketoneCumene2-Methyl-1-propanolDimethylsulfoxidePentaneEthanol1-PentanolEthylacetate1-PropanolEthylether2-PropanolEthylformatePropylacetateFormicacidTetrahydrofuran4.4SolventsforwhichNoAdequateToxicologicalDatawasFoundThefollowingsolvents(Table4)mayalsobeofinteresttomanufacturersofexcipients,drugsubstances,ordrugproducts.However,noadequatetoxicologicaldataonwhichtobaseaPDEwasfound.Manufacturersshouldsupplyjustificationforresiduallevelsofthesesolventsinpharmaceuticalproducts.Table4.Solventsforwhichnoadequatetoxicologicaldatawasfound.1,1-DiethoxypropaneMethylisopropylketone1,1-DimethoxymethaneMethyltetrahydrofuran2,2-DimethoxypropanePetroleumetherIsooctaneTrichloroaceticacidIsopropyletherTrifluoroaceticacid7ResidualSolventImpuritiesGLOSSARYGenotoxicCarcinogens:Carcinogenswhichproducecancerbyaffectinggenesorchromosomes.LOEL:Abbreviationforlowest-observedeffectlevel.Lowest-ObservedEffectLevel:Thelowestdoseofsubstanceinastudyorgroupofstudiesthatproducesbiologicallysignificantincreasesinfrequencyorseverityofanyeffectsintheexposedhumansoranimals.ModifyingFactor:Afactordeterminedbyprofessionaljudgmentofatoxicologistandappliedtobioassaydatatorelatethatdatasafelytohumans.Neurotoxicity:Theabilityofasubstancetocauseadverseeffectsonthenervoussystem.NOEL:Abbreviationforno-observed-effectlevel.No-Observed-EffectLevel:Thehighestdoseofsubstanceatwhichtherearenobiologicallysignificantincreasesinfrequencyorseverityofanyeffectsintheexposedhumansoranimals.PDE:Abbreviationforpermitteddailyexposure.PermittedDailyExposure:Themaximumacceptableintakeperdayofresidualsolventinpharmaceuticalproducts.ReversibleToxicity:Theoccurrenceofharmfuleffectsthatarecausedbyasubstanceandwhichdisappearafterexposuretothesubstanceends.StronglySuspectedHumanCarcinogen:Asubstanceforwhichthereisnoepidemiologicalevidenceofcarcinogenesisbuttherearepositivegenotoxicitydataandclearevidenceofcarcinogenesisinrodents.Teratogenicity:Theoccurrenceofstructuralmalformationsinadevelopingfetuswhenasubstanceisadministeredduringpregnancy.8ResidualSolventImpuritiesAPPENDIX1.LISTOFSOLVENTSINCLUDEDINTHEGUIDELINESolventOtherNamesStructureClassAceticacidEthanoicacidCH3COOHClass3Acetone2-PropanoneCH3COCH3Class3Propan-2-oneAcetonitrileCH3CNClass2AnisoleMethoxybenzeneOCHClass33BenzeneBenzolClass11-Butanoln-ButylalcoholCH3(CH2)3OHClass3Butan-1-ol2-Butanolsec-ButylalcoholCH3CH2CH(OH)CH3Class3Butan-2-olButylacetateAceticacidbutylesterCH3COO(CH2)3CH3Class3tert-Butylmethyl2-Methoxy-2-methyl-propane(CH3)3COCH3Class3etherCarbontetrachlorideTetrachloromethaneCCl4Class1ChlorobenzeneClClass2ChloroformTrichloromethaneCHCl3Class2CumeneIsopropylbenzeneCH(CH)Class332(1-Methyl)ethylbenzeneCyclohexaneHexamethyleneClass21,2-Dichloroethanesym-DichloroethaneCH2ClCH2ClClass1EthylenedichlorideEthylenechloride1,1-Dichloroethene1,1-DichloroethyleneH2C=CCl2Class1Vinylidenechloride1,2-Dichloroethene1,2-Dichloroethylene