FDA官员原料药检查指南手册7356.002F

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FoodandDrugAdministration

ComplianceProgramGuidanceManual PROGRAM 7356.002F

CHAPTER56-DRUGQUALITYASSURANCE

SUBJECT:

*ACTIVEPHARMACEUTICALINGREDIENTS(APIs)*

IMPLEMENTATIONDATE

UponReceipt

COMPLETIONDATE

Continuing

DATAREPORTING

PRODUCTCODES

PRODUCT/ASSIGNMENTCODES

IndustryCodes:54and56

SeeBelow

56002F-ActivePharmaceuticalIngredientProcessInspections(DrugQualityAssurance)

56008A-DrugProductSurveillance,CDERInitiated

56008H-DrugProductSurveillance,ImportedDrugs,CDERandDistrictInitiatedSurveys

56R806-ForeignRoutineDrugSurveillanceInspections*

FIELDREPORTINGREQUIREMENTS

OAIALERTS

Whenthedistrictbecomesawareofanysignificantadverseinspectional,analytical,orotherinformationthatcouldorshouldaffecttheagency'snewproductapprovaldecisionswithrespecttoan*activepharmaceuticalingredientmanufacturerreferencedinanapplication,*thedistrictshouldimmediatelynotifyHFC-240,MedicalProductsQualityAssuranceStaff,viaEMSorFAX.HFC-240willthenconveytheinformationbyFAXorequivalentexpeditiousmeanstothe*DivisionofManufacturingandProductQuality(HFD-320)inCDER'sOfficeofCompliance.*

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PROGRAM

7356.002F

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PROCESSPROFILEREPORTING

*InDecember1995,attherequestofCDER,theMedicalProductsQualityAssuranceStaff(HFC-240)addedprofileclassesCSN(NonSterileAPIbyChemicalSynthesis)andCSS(SterileAPIbyChemicalSynthesis)tothedrugprofileclassificationsystem.Thischangewasrequestedbecauseseparateprofileclassesexistedfornonsterileandsterileactivepharmaceuticalingredientsproducedbyfermentationprocesses,butthesamedidnotholdtrueforactivepharmaceuticalingredientsproducedbychemicalsynthesisprocesses.Inimplementingthechange,however,MPQASdidnoteliminatetheprofileclass"CCS"becausedeletingthelatterwouldhavecausedalossofhistoryintheGWQAPprofilingsystem.Therefore,effectivewiththisprogramcircular,discontinueusingProfileclassCCS(ChemicalSynthesisCrudeDrug)anduseonlythefollowingsevenbulkprofileclassestoreporttheprocessescoveredduringAPIinspections:*

FULLDESCRIPTION PROFILECLASS

NonSterileAPIbyChemicalSynthesis CSN

SterileAPIbyChemicalSynthesis CSS

NonSterileAPIbyFermentation CFN

SterileAPIbyFermentation CFS

Plant/AnimalExtractionAPI CEX

BiotechnologyAPI CBI

CrudeBulkNotElsewhereClassified(i.e.,producers CRU*ofbulkintermediates,andcontractmicronizersofAPIs)

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.

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.Theseconceptsinclude,amongothers,buildingqualityintotheproduct,employingappropriatelyqualifiedandtrainedpersonnel,establishingadequatewrittenproceduresandcontrols,establishingasystemofin-processandendproducttests,processvalidation,andensuringstabilityofAPIsfortheintendedperiodofuse.*

The*September1991FDAGuidetoInspectionsofBulkPharmaceuticalChemicals,reformattedinMay1994withminoreditorialchanges,containsgeneralguidanceastotheextentandapplicationofGMP/validationconceptstoAPIproductionandagencyexpectationsregardingtestsforimpuritiesandimpurityprofiles.Thisguidemustbeusedforinspectionofbothforeignanddomesticfacilitiestopromoteinspectionalconsistencyanduniformity.*

*Atpresent,FDAexpectsAPImanufacturerstoapplyCGMPstoallstepsofanAPIprocess,beginningwiththeuseofstartingmaterials,andtovalidatecriticalprocessstepsthatimpactthequalityandpurityofthefinalAPI.Thisapproachrecognizesthatthecontrolneededishighlydependentonthemanufacturingprocessandthatthelevelofcontrolincreasesthroughoutthesynthesisastheprocessproceedsfromearlyintermediatestepstofinalisolationandpurificationsteps.Thisapproachalsoallows

<appropriate<levelsofcontrol,dependingontheprocessitself(i.e.,fermentationprocessvs.chemical

synthesis)andtheriskorcriticalnessassociatedwiththespecificprocessstepbeingperformed.

This"controlallmanufacturingsteps,validatecriticalprocesssteps"approachisembodiedinthedraftFDAGuidanceforIndustryontheManufacture,ProcessingorHoldingofActivePharmaceuticalIngredients,whichwasreleasedforpublicdiscussiononSeptember20,1996.ThelattercanbeobtainedfromCDER<sDrugInformationBranch,HFD-210,orcanbedownloadedfromCDER<sHomePageat

<

/cder/api.htm.

<*

PARTII-IMPLEMENTATION

OBJECTIVE

TheprimaryobjectiveofthiscomplianceprogramistoprovidecomprehensiveCGMPinspectionalcoverageofthedomesticandforeignactivepharmaceuticalingredient(API)industryinallprofileclasses(processes).

PROGRAMMANAGEMENTINSTRUCTIONS

*Thisprogramcircularappliesonlytoactivepharmaceuticalingredientsintendedforuseindrugproducts.Anactivepharmaceuticalingredientisdefinedasanysubstancethatisrepresentedforuseinadrugandthat,whenusedinthemanufacturing,processing,orpackagingofadrug,becomesanactiveingredientorafinisheddosageformofthedrug.Althoughtheagencyhasusedtheterms<bulkpharmaceuticalchemicals<and<bulkdrugsubstances<todescribethesematerials,FDAisawarethattheterm<activepharmaceuticalingredient<hasinternationalrecognition.Inlightofthisandforaddedclarity,theagencyisadoptingthetermactivepharmaceuticalingredientforuseinthiscomplianceprogram.*

*Ownersoroperatorsofalldomesticdrugestablishments,toincludeAPIs,notexemptundersection510(g)oftheFederalFood,Drug,andCosmeticAct,asamended,or21CFR207.10arerequiredtoregisterandtosubmitalistofeverydrugincommercialdistribution.Foreigndrugmanufacturersarenotrequiredtoregister,althoughtheyarerequiredtolistalldrugsimportedorofferedforimportintotheUnitedStates.Referto21CFR207.40foradditionalinformationondruglistingrequirementsforforeigndrugestablishments.*

Althoughthecurrentgoodmanufacturingpractice(CGMP)regulations,21CFR210and211,donotapplytoAPIs,activepharmaceuticalingredientsaresubjecttothebroadrequirementofSection501(a)(2)(B)oftheActinthattheymustbepreparedinconformancewithcurrentgoodmanufacturingpractice.*NodistinctionismadebetweenAPIsandfinishedpharmaceuticalsintheAct,andfailureofeithertocomplywithCGMPconstitutesaviolationoftheAct.*Therefore,inthisdocument,thetermCGMPreferstothelatter,ratherthan21CFR210and211provisions.

EXCLUSION

*Thisprogramcirculardoesnotapplytothesterilizationandasepticprocessingstepsofsterileactivepharmaceuticalingredients,whicharecoveredbyComplianceProgram7356.002A,SterileDrugProcessInspections.TheFDAhaslongmaintainedthatsterileAPIsarefinisheddrugproductssubjecttotheCGMPregulationforfinishedpharmaceuticals(21CFR210and211)becausethesearerepackedasfinisheddosageformsunderasepticconditionswithoutfurtherpurificationorprocessing.*

PARTIII-INSPECTIONAL

*Inspectionsofactivepharmaceuticalingredientmanufacturers,whetherforeignordomestic,shouldbeconductedbyexperiencedinvestigatorswitheducationand/ortraininginfermentation,chemicalsynthesis,recombinantDNA,andotherbiotechnologymanufacturingmethods.Useofchemistsand/ormicrobiologistsduringAPIinspectionsisrecommended,particularlyforevaluatinglaboratoryoperations(e.g.,analyticalmethodsevaluation,analyticaldata,labproceduresandinstrumentation),analyticalreviewofmethodsusedtoestablishimpurityprofiles,fermentationmanufacturingprocesses,andcomplexmulti-stepchemicalsynthesisprocesses.*

*InvestigatorsconductingAPIinspectionsmustunderstandthebasicdifferencesbetweentheprocessesusedfortheproductionofAPIsandthoseusedforfinisheddosageforms.APIsareusuallyproducedbychemicalsynthesis,recombinantDNAtechnology,fermentation,enzymaticreactions,recoveryfromnaturalmaterials,orcombinationsoftheseprocesses.TheproductionofAPIstypicallyinvolvessignificantchangesofstartingmaterialsorintermediatesbyvariouschemical,physical,andbiologicalprocessingsteps.Purificationistheultimateobjective.

Incontrast,finisheddrugproductsareformulatedfrombulkrawmaterialsthatareusuallysubjectedtosomedegreeofqualitycontrolbytheusers(dosageformmanufacturers).Mostimportant,themanufacturingprocessesforfinishedpharmaceuticalstypicallydonotinvolvepurificationsteps.

Forthesereasons,themanufacturingandqualitycontrolsemployedinAPIproductionandtheirapplicationthroughouttheprocess(i.e.,stringencyofcontrols,writteninstructions,in-processcontrols,sampling,testing,monitoring,anddocumentationemployedinearlyprocessingstepsvs.laterisolationandpurificationsteps)differsomewhatfromthosefoundinfinisheddosageformplants.Thesedifferences,however,aresimplyreflectionsofdifferentmanufacturingprocesses,notinherentdifferencesintheimportanceofGMPsforthetwotypesofproduction.*

*Sincemanufacturersofactivepharmaceuticalingredientsareoftenreferencedinmanydrugapplications,eachinspectionshouldcoverasmanyAPIprocessesasisfeasible.ThisstrategywillmaximizetheuseofagencyresourcesandavoidrepeatedvisitstothesamemanufacturingsitetocoverdifferentAPIprofileclassesreferencedinsubsequentapplications.Thus,effectivewiththisCPrevision,allinspectionsofAPImanufacturers,regardlessofhowtheseareinitiated,willbe"GMPqualifyinginspections."InspectionsshouldcoverthespecificAPIprofileclassesreferencedintheassignmentandallotherAPIprofileclassesnotinspectedinthelasttwoyears.

ForforeignAPIfirms,investigatorsshouldonlycoverprofileclassesforAPIsintendedtobemarketedoralreadymarketedintheUnitedStates.

APIsselectedforcoverageshouldincludethosereferencedindrugapplications,aretherapeuticallysignificant,areintendedforuseinparenteraldrugproducts,aredifficulttomanufacture,orthoseonrecordashavingpastcomplianceproblems.However,thisdoesnotprecludetheselectionoflesstherapeuticallysignificantactivepharmaceuticalingredientstoevaluatespecificAPIprocesses(profileclasses)notpreviouslygivenin-depthcoverageatthefacility.

InvestigatorsconductingAPIinspectionsshouldunderstandthegeneralinspectionstrategysetforthinPartIIofthisprogram.RecognizingthatAPIfirmsvarygreatlyinsize,diversityofoperations,andqualityassurancesystems,investigatorsshouldcarefullyplantheirinspectionalstrategyateachfirm.OfparticularconcernareAPImanufacturingoperationslocatedindevelopingcountries.*Impuritiesandcontaminantspresentincomponents,processwater,andsolventsusedintheproductionofAPIsmaycarryoverintotheactivepharmaceuticalingredientandmaynotbedetectedbyanalyticaltestsconductedbyeithertheAPImanufacturerorthedosageformmanufacturer.Duringinspections,investigatorsshouldreviewthequalityofprocesswaterandsolventsusedinisolationandpurificationsteps,thefirm'sproceduresforpreventingAPIcontamination/cross-contamination,proceduresforcontrollingimpurities,andtheproceduresandtestmethodsforestablishingacompleteimpurityprofileforeachAPIprocess.*ThesearecoveredindetailintheSeptember1991FDAGuidetoInspectionofBulkPharmaceuticalChemicalsandits"AppendixA."

Duringinspections,investigatorsshouldreviewthebatchesmanufacturedduringthelastyeartodeterminenotonlythosereleased,butanyrejections.Thefirm<spolicyonreprocessingandreworkingofAPIsshouldalsobeexamined.Somebatchesstartoffasapharmaceuticalgradeandthenbecometechnicalgrade.Thiscouldindicateaproblemwiththevalidatedprocess.Inaddition,equipmentcleaningvalidationshouldbereviewedtoassurethatthefirmcanremoveresidues,microbialcontamination,andendotoxinstoacceptablelevelswhentheendproductisintendedforparenteralorliquiddosageforms.

*ForAPIinspectionsinitiatedbyapreapprovalassignment,reviewguidanceprovidedinCP7346.832,Pre-ApprovalInspections/Investigations,andassesstheauthenticityandaccuracyofdatacontainedindrugapplicationsanddrugmasterfiles.Reportinspectionaltimeundertheappropriateprogramassignmentcodes(PACs)referencedinbothcomplianceprograms,basedoncoverageaffordedtoeachprogram.*

*CHANGESINTHEFOREIGNDRUGINSPECTIONPROGRAM

BeginninginFY97,ORAandCDERagreedtoimplementseveralchangestotheforeigndruginspectionprogramtostreamlinethecompliancereviewprocess.TheDivisionofEmergencyandInvestigationalOperations(ORO/DEIO),willcontinuetoworkwithforeigngovernmentsinschedulingforeigninspections,makingtravelarrangementsforinspectionteams,andresolvinglogisticalproblems.

However,newproceduresareineffectforhandlingaforeignfirm'sresponsetoanFD-483,submittingestablishmentinspectionreports,andcommentingonaforeignfirm'sresponsetoanFD-483.

InvestigatorsshouldinstructmanagementatforeignfirmstosubmittheoriginalwrittenresponsetoanFD-483directlytoCDER'sOfficeofCompliancewithacopytotheleadinvestigator.Theoriginalresponsewithappropriatedocumentationshouldbesubmittedtothefollowingaddress:

FoodandDrugAdministrationForeignInspectionTeam,HFD-322

DivisionofManufacturingandProductQualityCenterforDrugEvaluationandResearch

7520StandishPlace

Rockville,Maryland20855-2737

Investigatorsandanalystswillsubmitwrittencommentsregardingaforeignfirm'sresponsetoanFD-483directlytoCDER'sForeignInspectionTeam(FIT).Afterappropriatedistrictofficereviewandendorsement,allforeignestablishmentinspectionreports(EIRs)willbepromptlyforwardedtoFITforreviewandfinalclassification.FITwillcontinuetoissueWarningLetters,UntitledLettersandothercorrespondencetoforeignfirms.FITwillalsorecommendautomaticdetentionofforeignfirms/products,makerecommendationstoreviewunits,andrequestfollow-upinspections,asappropriate.*

INSPECTION

ReviewtheSeptember1991FDAGuidetoInspectionsofBulkPharmaceuticalChemicals,(ReformattedMay1994)tobecomefamiliarwiththevariousareasandtopicsthatmustbeconsideredwhenconductingAPIinspections.Appendix<A<ofthisCPprogramisasummaryofareastobecoveredduringAPIinspections.Photocopythisappendixandtakewithyou

duringinspections.Alsoobtainacopyofthedrugapplicationand/orDrugMasterFile(DMF),asapplicable,andreviewthesebeforeinitiatingtheinspection.

Third(field)copiesofapplications,*supplementsandannualreports*arenowrequired(Referto21CFR314.440)andsuchcopiesaresubmittedbydomesticfirmsdirectlytotheapplicant'shomeFDAdistrictoffice.Foreign*applicants*arerequiredtosubmitthirdcopiesofapplicationstothesameheadquartersunitsreceivingthefirstandsecondcopies.ThesearemadeavailablebyDEIOtoinvestigatorsbeforeinitiationofforeigninspections.

*Investigatorsshouldreviewallavailableinformationincludingpriorinspectionalinformation,FD-483sandresponses,anyWarningLetters,thefirm'scompliancehistory,sampleanalysisresults,complaints,recalls,etc.,topreparefortheinspection.Fordomesticinspections,theinformationisavailablefromthePre-ApprovalMonitors(PAMs)ateachDistrictOffice.Forforeigninspections,theinformationisavailablefromDEIOorFIT.*

*AdditionalsuggestedreferencesthatInvestigatorsandChemistsshouldbefamiliarwithinclude:thedraftGuidanceforIndustry-Manufacture,ProcessingorHoldingofActivePharmaceuticalIngredients;USP<1086>ImpuritiesinOfficialArticles;andtherecentchangesintestsforthepresenceofforeignsubstancesandimpurities,containedinPage3636ofUSP-NFSupplement6,effectiveMay15,1997.Inaddition,theInvestigatorshouldcontacttheForensicChemistryCenter(FCC)todeterminewhichAPIsshouldbesampled,sothatduplicatesarenotcollectedduringdifferentinspections.*

*TheInvestigatorshouldconsulttheCDERCaseOfficerforclarificationoftheassignmenttoassurethattheyareawareofthepreviousdeficienciesatthefirm.Duringtheinspection,assurethatallthefirm<spromisedactionsareeffectiveatcorrectingtheproblems.Iftheinspectiondeterminesthatthefirmhasresolvedallthedeficiencies,submittheinformationforinputintotheCARScomputersystem.*

*Conducta"GMPqualifyinginspection"ateachAPImanufacturercoveringtheproductsandprocessesspecifiedintheassignment.Inaddition,coverinasfaraspossible,APIprocessesthathavenotbeeninspectedinthelasttwoyears.Also,conductanin-depthinspection,toincludeexaminingpertinentsystemsandprocesses,whenevertheDistrictreceivesadverseinformationregardingafirm'sabilitytoproduceAPIsofacceptablequality.*

DuringinspectionsofAPImanufacturers:

*DetermineifthefirmhasmadeprocesschangesbycomparingcurrentoperationsagainsttheEstablishmentInspectionReport(EIR)forthepreviousinspection.AlsocomparethecurrentoperationswiththosefiledintheDrugMasterFileorthedrugapplicationtodeterminewhetherthefirmiscomplyingwithcommitmentsmadetotheagency.Thefollowingchangesaretypicalofthosethatwouldwarrant*extensivecoverage*duringtheinspection:

Newpotentialforcross-contaminationarisingthroughchangesinAPIprocessesorproductlines,toincludeprocessingnumerousAPIsofvaryingtherapeuticsignificanceincommonequipmentand/orfacilities.

Useofnewtechnologyrequiringnewexpertise,significantlynewequipmentornewfacilities.

*Recentchangesinstartingmaterials,intermediates,equipment,facilities,supportsystems,processingsteps,packagingmaterials,andcomputersoftwarethatarenotreferencedintheDMForapplication.*

Verifythatthesizeofthelargestbatchdoesnotexceedthemaximumworkingcapacityofthefirm'slargestblenderthatisusedforblendingofAPIbatches.

Reviewthefirm'scomplaintfile.Determinewhetherthepatternofcomplaints(orotherinformationavailabletotheDistrict)andthefirm'srecordsofinternalrejectionor

*reprocessing/reworking*ofAPIbatcheswarrantexpandingtheinspection.Lookforweaknessesinthefirm'sprocesses,systemsorcontrols.

InvestigatethereturnofAPIsforanyreason.DeterminewhetherthefirmconductsinvestigationsonreturnedproductstofindoutiftheseAPIsfailedtomeetspecificationsorwerecontaminated.AlsodeterminethefinaldispositionofreturnedAPIs,i.e.,whetherreprocessedordestroyed.

Iftheinspectionisinitiatedbecausethefirm*isreferencedasanAPIsupplierinadrugapplication(NDA,ANDA,AADA),evaluateoperationsagainstcommitmentsintheapplicationand/ordrugmasterfile.Also,verifytheauthenticityandaccuracyofdatasubmittedintheapplicationand/orDMF.*

*ObtainacopyoftheimpurityprofileforeachactivepharmaceuticalingredientprocesscoveredduringtheinspectionandcomparethesetotheimpurityprofilessubmittedintheDrugMasterFile.*

AllEstablishmentInspectionReportsforAPImanufacturersmustinclude:

Historyofbusiness,andanycorporateaffiliations.

Names,titles,*andcompletemailingaddressofmostresponsibleofficialswhoshouldreceivecorrespondencefromFDA.*

AlistofAPIsmanufactured(orcategoriesofproductsifmany)alongwiththegeneralmanufacturingprocessforeach(forexample,chemicalsynthesisnon-sterile,fermentation,extractionofnaturalproducts,etc.).

*ForforeignAPImanufacturers,thenames,titles,completemailingaddress,telephoneandFaxnumberofthefirm'sU.S.Agent,RegulatoryAgent,and/orImporter/Broker.*

*ForforeignAPImanufacturers,areportofallactivepharmaceuticalingredientsimportedintotheUnitedStatesinthelastthreeyears,theirconsignees,andanestimateofthefrequencyandquantityofshipmentstotheseconsignees.*

Adescriptionofareas/processesinspected(i.e.,whatareas,systemsandprocesseswereinspected,whowasinterviewed,whatmanufacturingactivitieswereongoingduringtheinspection).

Adescriptionofanynon-drugmanufacturingactivitiesconductedbythefirm,suchasprocessingpesticidesorothertoxicchemicals.Ifnonpharmaceuticalsareprocessedinthesamefacilityand/orequipmentwithAPIs,reportprecautionstakenbythefirmtopreventorminimizethepotentialforcross-contamination.

AdescriptionofallAPImicronizingormillingoperations,whetherconductedin-houseorbyacontractmicronizer.Fullydescribetheprecautionstakenbythefirmtopreventorminimizethepotentialforcross-contamination.Duringinspectionsofcontractmicronizers,

obtainacompletelistofallactivepharmaceuticalingredientsmicronizedandreportthesource(owners)ofthesematerials.

*Acopyofthefirm'sprocessvalidationprotocol.Reportthestatusofallvalidationefforts.Ifnotcompleted,obtainandsubmitthefirm'swrittentimetableshowingwhenprocessvalidationwillbecompleted.*

AreportofanyadversefindingsasrequiredbytheInvestigationsOperationsManual(IOM).

SAMPLING

*AprofilesampleoftheactivepharmaceuticalingredientshouldbecollectedforanalysisbytheForensicChemistryCenter,FCC(HFR-MA500)andNortheastRegionalLab(NRL).ThesesamplesoftheAPIshouldnotbeconfusedwithprofilesamplesofactivescollectedtogetherwithfinishedproductsamplesunderthePre-ApprovalInspections/InvestigationsComplianceProgram,CP7346.832.

Dependinguponthecost,thesampleshouldconsistof25-50gramsofactivedrugsubstancefromthreedifferentlots,collectedinduplicate.Documentationthatshouldaccompanythesamplemustinclude:

AflowchartandbriefnarrativedescriptionoftheAPImanufacturingprocess;

Amaterialsafetydatasheetfortheactivepharmaceuticalingredient;

ACertificateofAnalysis*(COA)*foreachlot;*inaddition,adescriptionofthecomputersystemthatwasutilizedtogeneratetheCOAandtheprecautionstakenbythefirmtosafeguardtheintegrityofthecomputerdataagainstemployeemanipulation.*

Acopyofanypotential/establishedimpurityprofilesandapplicablemethodologies;

Theanalyticalmethodology(iftheinspectioninvolvesanewchemicalentity).*

*Duringforeigninspections,itisoftendifficultfortheinvestigatortocollectprofilesamplesofAPIs.Ifasampleisnotcollected,theinvestigatorshouldidentifythelot(s)tobesampledandinstructthemanufacturertocollectandshipthesampleandapplicablerecordsdirectlytotheFCC.TheFCCwillprepareanannotatedcollectionreportandforwardtheduplicateportionandcopyofrecordstotheNRL.Aninformationcopywillalsobesenttotheleadinvestigator.*

*Whencollectingsamplesforprofileanalysis,protectthesefromtracecontamination.Inallinstances,avoidusingmetalspatulas.Useaplasticcontainerandclosureforsamplingandsubmitanemptycontainerasacontrolsub.Ifaplasticspatulaisused,alsosubmitanunusedspatulaasa

sub-sample.Identifyeachcontainerwiththesamplenumber,theproductnameandlotnumber,manufacturer,dateandinitialsofthesampler.Weardisposable,talc-free,polyethyleneglovesduringthesamplingactivity.Thepreferredsamplingmethodisbydirecttransferandreplacingtheglovesbetweeneachsubsample. Multipleproductlotsmaybesubmittedunderonecollectionreport.*

Toestablishalabeling/containerforensicdatabase,obtainthefollowinginformationduringinspectionsofforeignAPIfirms.Identifythisinformationwith