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1、GUIDETOINSPECTIONSOFSTERILEDRUGSUBSTANCEMANUFACTURERSNote:ThisdocumentisreferencematerialforinvestigatorsandotherFDApersonnel.ThedocumentdoesnotbindFDA,anddoesnoconferanyrights,privileges,benefits,orimmunitiesfororonanyperson(s).Oneofthemoredifficultprocessesto
2、inspectandonewhichhaspresentedconsiderableproblemsovertheyearsisthatofthemanufactureofsterilebulkdrugsubstances.Withinthepastseveralyears,therehavebeenanumberofbatchesofsterilebulkdrugsubstancesfromdifferentmanufacturerswhichexhibitedmicrobiologicalcontaminatio
3、n.Onemanufacturerhadapproximately100batchescontaminatedina6monthtimeperiod.Anotherhadapproximately25batchescontaminatedinasimilarperiod.Othermanufacturershavehadrecallsduetothelackofassuranceofsterility.AlthoughtheInspectionGuideforBulkDrugSubstancesprovidessom
4、edirectionfortheinspectionofthesterilebulkdrugsubstance,itdoesnotprovidethedetaileddirectionneeded.I.INTRODUCTIONInthemanufactureofthesterilebulkpowders,itisimportanttorecognizethatthereisnofurtherprocessingofthefinishedsterilebulkpowdertoremovecontaminantsorim
5、puritiessuchasparticulates,endotoxinsanddegradants.Aswithotherinspections,anyrejectedbatches,alongwiththevariousreasonsforrejection,shouldbeidentifiedearlyintheinspectiontoprovidedirectionfortheinvestigator.Forexample,listsofbatchesrejectedand/orretestedoverape
6、riodoftimeshouldbeobtainedfromthemanufacturertoprovidedirectionforcoveragetobegiventospecificprocessesorsystems.Becausesomeoftheactualsterilebulkoperationsmaynotbeseen,andbecauseofthecomplexityoftheprocess,itisparticularlyimportanttoreviewreportsandsummaries,su
7、chasvalidationstudies,rejectlists,EnvironmentalMonitoringSummaryReports,QAInvestigationLogs,etc.ThesesystemsandothersarediscussedintheBasicInspectionGuide.Thisisparticularlyimportantfortheforeignsterilebulkdrugsubstancemanufacturerwheretimeislimited.Intheprepar
8、ationforasterilebulkdrugsubstanceinspection,aflowchartwiththemajorprocessingstepsshouldbeobtained.Generally,themanufactureofasterilebulksubstanceusuallyincludesthefollowings
