美国FDA关于制剂药厂cGMP的检查指南9310.docx

美国FDA关于制剂药厂cGMP的检查指南9310.docx

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美国FDA关于制剂药厂cGMP的检查指南9310

DosageFormDrugManufacturerscGMPs（10/93）

GUIDETOINSPECTIONSOFDOSAGEFORMDRUGMANUFACTURER'S-CGMPR'S

Note:

ThisdocumentisreferencematerialforinvestigatorsandotherFDApersonnel.ThedocumentdoesnotbindFDA,anddoesnoconferanyrights,privileges,benefits,orimmunitiesfororonanyperson（s）.

I.INTRODUCTION

ThisdocumentisintendedtobeageneralguidetoinspectionsofdrugmanufacturerstodeterminetheircompliancewiththedrugCGMPR's.ThisguideshouldbeusedwithinstructionsintheIOM,otherdruginspectionguides,andcomplianceprograms.AlistoftheinspectionguidesisreferencedinChapter10oftheIOM.Someoftheseguidesare:

oGuidetoInspectionsofBulkPharmaceuticalChemicals.

oGuidetoInspectionsofHighPurityWaterSystems.

oGuidetoInspectionsofPharmaceuticalQualityControlLaboratories.

oGuidetoInspectionsofMicrobiologicalPharmaceuticalQualityControlLaboratories.

oGuidetoInspectionsofLyophilizationofParenterals.

oGuidetoInspectionsofValidationofCleaningProcesses.

oGuidetoInspectionsofComputerizedSystemsinDrugProcessing.

oGuidelineonGeneralPrinciplesofProcessValidation.

II.CURRENTGOOD

MANUFACTURINGPRACTICE

REGULATIONS

Prescriptionvs.Non-prescription

AlldrugsmustbemanufacturedinaccordancewiththecurrentgoodmanufacturingpracticeregulationsotherwisetheyareconsideredtobeadulteratedwithinthemeaningoftheFD&CAct,Section501（a）

（2）（B）.RecordsrelatingtoprescriptiondrugsmustbereadilyavailableforreviewinaccordancewithSec.704（a）

（1）（B）oftheFD&CAct.IftheproductisanOTCdrugwhichiscoveredbyanNDAorANDA,FDAmayreview,copyandverifytherecordsunderSec.505（k）

（2）oftheFD&CAct.However,iftheproductisanOTCdrugforwhichthereisnoapplicationfiledwithFDA,thefirmisnotlegallyrequiredtoshowtheserecordstotheinvestigatorduringaninspectionbeingconductedunderSection704oftheFD&CAct.Nonetheless,allmanufacturersofprescriptionandOTCdrugsmustcomplywiththedrugCGMPRrequirements,includingthoseinvolvingrecords.Theinvestigatorshouldreviewtheserecordsaspartoftheinspectionindeterminingthefirm'scompliancewiththeCGMPregulations.Onrareoccasions,afirmmayrefusetoallowreviewofOTCrecordsstatingtheyarenotlegallyrequiredto.Whilethefirmmaybeundernolegalobligationtopermitreviewofsuchrecords,thisdoesnotrelievethefirmofitsstatutoryrequirementtocomplywiththegoodmanufacturingpracticesundersection501（a）

（2）（B）oftheFoodDrugandCosmeticAct,includingtherequirementsformaintainingrecords.

IfafirmrefusesreviewofOTCrecords,theinvestigatorshoulddeterminebyotherinspectionalmeanstheextentofthefirm'scompliancewithCGMPR's.InspectionalobservationsandfindingsthatCGMPR'sarenotbeingfollowedaretobecitedonaListofInspectionalObservations,FDA-483,forbothprescriptionandnon-prescriptiondrugs.

OrganizationandPersonnel[21CFR211SubpartB]

ThefirmmusthaveaqualitycontroldepartmentthathastheresponsibilityandauthorityasdescribedinthereferencedCFR.Thequalitycontroldepartmentmustmaintainitsindependencefromtheproductiondepartment,anditsresponsibilitiesmustbeinwriting.

Obtainthename,titleandindividualresponsibilitiesofcorporateofficersandotherkeyemployeesasindicatedintheIOM.

Inthedrugindustry,anemployee'seducationandtrainingfortheirpositionhasasignificantimpactontheproductionofaqualityproduct.Reportwhetherthefirmhasaformalizedtrainingprogram,anddescribethetypeoftrainingreceived.Thetrainingreceivedbyanemployeeshouldbedocumented.

Qualitycontrolmustdoproductannualreviewoneachdrugmanufactured,andhavewrittenannualreviewprocedures.Reviewthesereportsindetail.Thisreportwillquicklyletyouknowifthemanufacturingprocessisundercontrol.Thereportshouldprovideasummaryalllotsthatfailedin-processorfinishedproducttesting,andothercriticalfactors.Investigateanyfailures.

Qualitycontrolmustvalidatethemanufacturingprocessforeachdrugmanufactured.Reviewandevaluatethisdata.

BuildingsandFacilities[21CFR211SubpartC]

Reviewtheconstruction,size,andlocationofplantinrelationtosurroundings.Theremustbeadequatelighting,ventilation,screening,andproperphysicalbarriersforalloperationsincludingdust,temperature,humidity,andbacteriologicalcontrols.Theremustbeadequateblueprintswhichdescribethehighpuritywater,HEPA,andcompressedairsystems.Thesitemusthaveadequatelocker,toilet,andhandwashingfacilities.

Thefirmmustprovideadequatespacefortheplacementofequipmentandmaterialstopreventmix-upsinthefollowingoperations:

oreceiving,sampling,andstorageofrawmaterials;

omanufacturingorprocessing;

opackagingandlabeling;

ostorageforcontainers,packagingmaterials,labeling,andfinishedproducts;

oproductionandcontrollaboratories.

Equipment[21CFR211SubpartD]

Reviewthedesign,capacity,construction,andlocationofequipmentusedinthemanufacturing,processing,packaging,labeling,andlaboratories.Describethemanufacturingequipmentincludingbriefdescriptionsofoperatingprinciples.Considertheuseofphotographs,flowcharts,anddiagramstosupplementwrittendescriptions.

Newequipmentmustbeproperlyinstalled,andoperateasdesigned.DetermineiftheequipmentchangewouldrequireFDApre-approvaland/orrevalidationofthemanufacturingprocess.Theequipmentmustbecleanedbeforeuseaccordingtowrittenprocedures.Thecleaningmustbedocumentedandvalidated.

Theequipmentshouldnotadverselyeffecttheidentity,strength,quality,orpurityofthedrug.Thematerialusedtomanufacturetheequipmentmustnotreactwiththedrug.Also,lubricantsorcoolantsmustnotcontaminatethedrug.

Theequipmentshouldbeconstructedandlocatedtoeasecleaning,adjustments,andmaintenance.Also,itshouldpreventcontaminationfromotherorpreviousmanufacturingoperations.Equipmentmustbeidentifiedastoitscleaningstatusandcontent.Thecleaningandmaintenanceoftheequipmentareusuallydocumentedinalogbookmaintainedintheimmediatearea.Determineiftheequipmentisofsuitablecapacityandaccuracyforuseinmeasuring,weighing,ormixingoperations.Iftheequipmentrequirescalibration,theymusthaveawrittenprocedureforcalibratingtheequipmentanddocumentthecalibration.

ComponentsandProductContainers[21CFR211SubpartE]

Inspectthewarehouseanddeterminehowcomponents,drugproductcontainers,andclosuresarereceived,identified,stored,handled,sampled,tested,andapprovedorrejected.Theymusthavewrittenprocedureswhichdescribehowtheseoperationsaredone.Challengethesystemtodecideifitisfunctioningcorrectly.Ifthehandlingandstorageofcomponentsarecomputercontrolled,theprogrammustbevalidated.

Thereceivingrecordsmustprovidetraceabilitytothecomponentmanufacturerandsupplier.Thereceivingrecordsforcomponentsshouldcontainthenameofthecomponent,manufacturer,supplierifdifferentfromthemanufacturer,andcarrier.Inaddition,itshouldincludethereceivingdate,manufacturer'slotnumber,quantityreceived,andcontrolnumberassignedbythefirm.

Checksanitaryconditionsinthestoragearea,stockrotationpractices,retestdates,andspecialstorageconditions（protectionfromlight,moisture,temperature,air,etc.）.Inspectglandularandbotanicalcomponentsforinsectinfestation.

Componentsorfinishedproductadulteratedbyrodents,insects,orchemicalsmustbedocumentedandsubmittedforseizure.

Collecttheevidenceevenifthefirmplanstovoluntarilydestroytheproduct.Bealertforcomponents,colors,andfoodadditivesthatmaybenewdrugsubstances,appeartohavenouseintheplantorappeartobefromanunknownsupplier.CheckthecolorsagainsttheColorAdditivesStatusListintheIOMDetermineifthecolorisapprovedforitsintendeduse,andrequiredstatementsaredeclaredonthedruglabel.

Componentsmightbereceivedatmorethanonelocation.ComponentsmustbehandledinaccordancewiththedrugCGMP'sincludingcomponentsusedintheresearchanddevelopmentlab.Determinehowcomponentsareidentifiedafterreceiptandquarantineduntilreleased.Componentsmustbeidentifiedsothestatus（quarantine,approved,orrejected）isknown.Reviewthecriteriaforremovingcomponentsfromquarantineandchallengethesystem.Determinewhatrecordsaremaintainedinthestorageareatodocumentthemovementofcomponentstootherareas,andhowrejectedcomponentshandled.Thecomponentcontainerhasanidentificationcodeaffixedtoit.Thisuniquecodeprovidestraceabilityfromthecomponentmanufacturertoitsuseinthefinishedproduct.

Reviewthesamplingandtestingproceduresforcomponents,andtheprocessbywhichapprovedmaterialsarereleasedforuse.Decideifthesepracticesareadequateandfollowed.

Determinethevalidity,andaccuracyofthefirm'sinventorysystemfordrugcomponents,containers,closuresandlabeling.Challengethecomponentinventoryrecordsbyweighingalotandcomparingtheresultsagainstthequantityremainingontheinventoryrecord.Significantdiscrepanciesintheserecordsshouldbeinvestigated.

Evaluatethefollowingtodeterminewhetherthefirmhasshownthatthecontainersandclosuresarecompatiblewiththeproduct,willprovideadequateprotectionforthedrugagainstdeteriorationorcontamination,arenota