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GuidanceforIndustryGenotoxicandCarcinogenicImpuritiesinDrugSubstancesandProducts:RecommendedApproachesDRAFTGUIDANCEThisguidancedocumentisbeingdistributedforcommentpurposesonly.Commentsandsuggestionsregardingthisdraftdocumentshouldbesubmittedwithin60daysofpublicationintheFederalRegisterofthenoticeannouncingtheavailabilityofthedraftguidance.SubmitcommentstotheDivisionofDocketsManagement(HFA-305),FoodandDrugAdministration,5630FishersLane,rm.1061,Rockville,MD20852.AllcommentsshouldbeidentifiedwiththedocketnumberlistedinthenoticeofavailabilitythatpublishesintheFederalRegister.ForquestionsregardingthisdraftdocumentcontactDavidJacobson-Kramat301-796-0175.U.S.DepartmentofHealthandHumanServicesFoodandDrugAdministrationCenterforDrugEvaluationandResearch(CDER)December2008PharmacologyandToxicologyI:\7834dft.doc12/03/08GuidanceforIndustryGenotoxicandCarcinogenicImpuritiesinDrugSubstancesandProducts:RecommendedApproachesAdditionalcopiesareavailablefrom:OfficeofCommunicationsDivisionofDrugInformationCenterforDrugEvaluationandResearchFoodandDrugAdministration10903NewHampshireAve.,Bldg.51,rm.2201SilverSpring,MD20993-0002E-mail:druginfo@fda.hhs.govFax:301-847-8714(Tel)301-796-3400(CDER)December2008PharmacologyandToxicologyTABLEOFCONTENTSI.INTRODUCTION.............................................................................................................1II.BACKGROUND...............................................................................................................2A.ICHGuidancesforIndustryRelatingtoDrugImpuritiesandResidualSolvents..................3B.EMEAProposedGuidelineonLimitsofGenotoxicImpurities................................................4III.RECOMMENDEDAPPROACHESFORINITIALASSESSMENTOFGENOTOXICPOTENTIALOFIMPURITIES...........................................................6IV.RECOMMENDEDAPPROACHESFORHANDLINGGENOTOXICANDCARCINOGENICIMPURITIES...................................................................................7A.PreventionofGenotoxicandCarcinogenicImpurityFormation..............................................7B.ReductionofGenotoxicandCarcinogenicImpurityLevels......................................................71.AcceptableLevelstoSupportMarketingApplications....................................................................72.AcceptableLevelsduringClinicalDevelopment...........................................................................10C.AdditionalCharacterizationofGenotoxicandCarcinogenicRisk.........................................11D.ConsiderationsforFlexibilityinApproach...............................................................................12APPENDIXA:DECISIONTREEFLOWDIAGRAM.........................................................13ContainsNonbindingRecommendationsDraft—NotforImplementationGuidanceforIndustry1123456GenotoxicandCarcinogenicImpuritiesinDrugSubstancesandProducts:RecommendedApproaches78Thisdraftguidance,whenfinalized,willrepresenttheFoodandDrugAdministration’s(FDA’s)current9thinkingonthistopic.Itdoesnotcreateorconferanyrightsfororonanypersonanddoesnotoperateto10bindFDAorthepublic.Youcanuseanalternativeapproachiftheapproachsatisfiestherequirementsof11theapplicablestatutesandregulations.Ifyouwanttodiscussanalternativeapproach,contacttheFDA12staffresponsibleforimplementingthisguidance.IfyoucannotidentifytheappropriateFDAstaff,call13theappropriatenumberlistedonthetitlepageofthisguidance.141516171819202122232425262728293031323334353637383940I.INTRODUCTIONThisguidanceisintendedtoinformpharmaceuticalmanufacturersoftheFoodandDrugAdministration’s(FDA’s)currentthinkingregardinggenotoxicandcarcinogenicimpuritiesindrugsubstancesanddrugproducts,includingbiologicproductsthatareregulatedbytheCenterforDrugEvaluationandResearch(CDER).Thisguidanceprovidesrecommendationsonhowtoevaluatethesafetyoftheseimpuritiesduringclinicaldevelopment(investigationalnewdrugapplications(INDs))andformarketingapplications(newdrugapplications(NDAs),biologicslicenseapplications(BLAs),andabbreviatednewdrugapplications(ANDAs)).Thisguidanceprovidesrecommendedexposurethresholdsontheclinicalexposuretogenotoxicorcarcinogenicimpurities.Alsoprovidedareadditionaltestingandexposurethresholdrecommendationsforsituationswherethereareknownortheoreticalsafetyconcernsbasedonavailabledata,structuralalerts,and/orassessmentofthesyntheticpathway.ThisguidanceisintendedasanadjuncttotheICHguidancesforindustryQ3A(R2)ImpuritiesinNewDrugSubstances,Q3B(R2)ImpuritiesinNewDrugProducts,andQ3C(R3)Impurities:ResidualSolventsthatdealwiththetopicofimpuritiesinamoregeneralfashion.2ThisguidanceprovidesspecificrecommendationsregardingthesafetyqualificationofimpuritieswithknownorsuspectedgenotoxicorcarcinogenicpotentialwhiletheICHguidancesprovideonlygeneraldirection.Thisguidanceaddressessyntheticimpuritiesanddegradantsindrugsubstances,butdoesnototherwiseaddressthegenotoxicityorcarcinogenici