FDA官员原料药检查指南手册7356.002F(1)

EDIT:MadeavailablebyORA/OE/DCIQA01/29/03-undatedMSWordfilereceivedfromCDER&tableformatrevisedFoodandDrugAdministrationComplianceProgramGuidanceManualPROGRAM7356.002F*CurrentChanges*FORMFDA2438g(ComputerGenerated,05/98)PAGE1of30TRANSMITTALNO.98-17(05/20/98)CHAPTER56-DRUGQUALITYASSURANCESUBJECT:*ACTIVEPHARMACEUTICALINGREDIENTS(APIs)*IMPLEMENTATIONDATEUponReceiptCOMPLETIONDATEContinuingDATAREPORTINGPRODUCTCODESPRODUCT/ASSIGNMENTCODESIndustryCodes:54and56SeeBelow56002F-ActivePharmaceuticalIngredientProcessInspections(DrugQualityAssurance)56008A-DrugProductSurveillance,CDERInitiated56008H-DrugProductSurveillance,ImportedDrugs,CDERandDistrictInitiatedSurveys56R806-ForeignRoutineDrugSurveillanceInspections*FIELDREPORTINGREQUIREMENTSOAIALERTSWhenthedistrictbecomesawareofanysignificantadverseinspectional,analytical,orotherinformationthatcouldorshouldaffecttheagency'snewproductapprovaldecisionswithrespecttoan*activepharmaceuticalingredientmanufacturerreferencedinanapplication,*thedistrictshouldimmediatelynotifyHFC-240,MedicalProductsQualityAssuranceStaff,viaEMSorFAX.HFC-240willthenconveytheinformationbyFAXorequivalentexpeditiousmeanstothe*DivisionofManufacturingandProductQuality(HFD-320)inCDER'sOfficeofCompliance.*EDIT:MadeavailablebyORA/OE/DCIQA01/29/03-undatedMSWordfilereceivedfromCDER&tableformatrevisedPROGRAM7356.002F*CurrentChanges*FORMFDA2438g(ComputerGenerated,05/98)PAGE2of30TRANSMITTALNO.98-17(05/20/98)PROCESSPROFILEREPORTING*InDecember1995,attherequestofCDER,theMedicalProductsQualityAssuranceStaff(HFC-240)addedprofileclassesCSN(NonSterileAPIbyChemicalSynthesis)andCSS(SterileAPIbyChemicalSynthesis)tothedrugprofileclassificationsystem.Thischangewasrequestedbecauseseparateprofileclassesexistedfornonsterileandsterileactivepharmaceuticalingredientsproducedbyfermentationprocesses,butthesamedidnotholdtrueforactivepharmaceuticalingredientsproducedbychemicalsynthesisprocesses.Inimplementingthechange,however,MPQASdidnoteliminatetheprofileclassCCSbecausedeletingthelatterwouldhavecausedalossofhistoryintheGWQAPprofilingsystem.Therefore,effectivewiththisprogramcircular,discontinueusingProfileclassCCS(ChemicalSynthesisCrudeDrug)anduseonlythefollowingsevenbulkprofileclassestoreporttheprocessescoveredduringAPIinspections:*FULLDESCRIPTIONPROFILECLASSNonSterileAPIbyChemicalSynthesisCSNSterileAPIbyChemicalSynthesisCSSNonSterileAPIbyFermentationCFNSterileAPIbyFermentationCFSPlant/AnimalExtractionAPICEXBiotechnologyAPICBICrudeBulkNotElsewhereClassified(i.e.,producersCRU*ofbulkintermediates,andcontractmicronizersofAPIs)EDIT:MadeavailablebyORA/OE/DCIQA01/29/03-undatedMSWordfilereceivedfromCDER&tableformatrevisedPROGRAM7356.002F*CurrentChanges*FORMFDA2438g(ComputerGenerated,05/98)PAGE3of30TRANSMITTALNO.98-17(05/20/98)REPORTINGTOFORENSICCHEMISTRYCENTER(FCC):*Inordertoassurethatforeignfirmssupplytherequestedprofilesamplesanddocumentation(SeePage12,Items1&2),theForensicChemistryCenter(FCC)shouldreceiveacopyofthecoversheetforallinspectionsofforeignactivepharmaceuticalingredientmanufacturers.Thecoversheetendorsementshouldincludeaphoneandfaxnumberofthecontactpersonatthefirm.Ifasampleisnotcollectedbytheinvestigatorduringtheinspection,thecoversheetshouldalsostatethatthemanufacturerwasinstructedtocollectandshipasampleandapplicablerecordsdirectlytoFCCasperAppendixB.Thiswillpermitproperfollow-upbyFCCandalsoservetoidentifytheinvestigatorwhowillreceiveacopyoftheannotatedcollectionreportpreparedbyFCC.Onaquarterlybasis,FCCwillsendasummaryofsampletestingresultstotheForeignInspectionTeam(FIT),HFD-322.Thecontainer/closureandproductinformationobtainedfromAppendixBwillbeincludedintheActivePharmaceuticalIngredientDatabasesandmadeavailabletoDistrictImportOfficestohelppreventcounterfeitAPIsfromenteringtheUnitedStatesmarket.*REPORTINGTOCDERSDIVISIONOFMANUFACTURINGANDPRODUCTQUALITY:Fordomesticinspectionsofactivepharmaceuticalingredientmanufacturers,submitacopyoftheEIRcoversheet,FD-483,andDistrictissuedcopyofWarningLetters(afterCDERreviewandconcurrence)toCDER'sDivisionofManufacturingandProductQuality,HFD-320,forreviewandtrendanalysis.EDIT:MadeavailablebyORA/OE/DCIQA01/29/03-undatedMSWordfilereceivedfromCDER&tableformatrevisedPROGRAM7356.002F*CurrentChanges*FORMFDA2438g(ComputerGenerated,05/98)PAGE4of30TRANSMITTALNO.98-17(05/20/98)PARTI-BACKGROUND*Sincethelate1980's,theU.S.FoodandDrugAdministrationhasintensifieditsinspectionalcoverageofactivepharmaceuticalingredient(API)manufacturers.Thisisdue,inpart,toanincreasedawarenessthatAPIqualityplaysapotentiallysignificantroleinthequality,efficacy,andsafetyoffinisheddosageformpharmaceuticals.Forexample,physicalpropertiesofAPIsformulatedintosolidoraldosageforms,suspensions,andtopicalsmayadverselyaffectdrugproductdissolution/bioavailability.Inaddition,extremelysmallquantitiesofunidentifiedoruncharacterizedimpuritiesindrugsmaycauseseriouspatientsideeffects.FDAhaslongrecognizedthatCGMPconcepts,embodiedinthegoodmanufacturingpracticeregulationsforfinishedpharmaceuticals(21CFR210and211),arevalidandcanbeappliedtoAPIprocesses