FDA制剂厂检查指南.docx

FDA制剂厂检查指南.docx

《FDA制剂厂检查指南.docx》由会员分享，可在线阅读，更多相关《FDA制剂厂检查指南.docx（45页珍藏版）》请在冰豆网上搜索。

FDA制剂厂检查指南

GUIDETOINSPECTIONSOF

DOSAGEFORMDRUGMANUFACTURER'S-CGMPR'S

Note:

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

I.INTRODUCTION

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

◆GuidetoInspectionsofBulkPharmaceuticalChemicals.

◆GuidetoInspectionsofHighPurityWaterSystems.

◆GuidetoInspectionsofPharmaceuticalQualityControlLaboratories.

◆GuidetoInspectionsofMicrobiologicalPharmaceuticalQualityControlLaboratories.

◆GuidetoInspectionsofLyophilizationofParenterals.

◆GuidetoInspectionsofValidationofCleaningProcesses.

◆GuidetoInspectionsofComputerizedSystemsinDrugProcessing.

◆GuidelineonGeneralPrinciplesofProcessValidation.

II.CURRENTGOODMANUFACTURINGPRACTICEREGULATIONS

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,allmanufacturersofprescriptionandOTCdrugsmustcomplywiththedrug

CGMPRrequirements,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:

◆receiving,sampling,andstorageofrawmaterials;

◆manufacturingorprocessing;

◆packagingandlabeling;

◆storageforcontainers,packagingmaterials,labeling,andfinishedproducts;

◆productionandcontrollaboratories.

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,and

approvedorrejected.Theymusthavewrittenprocedureswhichdescribehow

theseoperationsaredone.Challengethesystemtodecideifitis

functioningcorrectly.Ifthehandlingandstorageofcomponentsare

computercontrolled,theprogrammustbevalidated.

Thereceivingrecordsmustprovidetraceabilitytothecomponent

manufacturerandsupplier.Thereceivingrecordsforcomponentsshould

containthenameofthecomponent,manufacturer,supplierifdifferentfrom

themanufacturer,andcarrier.Inaddition,itshouldincludethereceiving

date,manufacturer'slotnumber,quantityreceived,andcontrolnumber

assignedbythefirm.

Checksanitaryconditionsinthestoragearea,stockrotationpractices,

retestdates,andspecialstorageconditions（protectionfromlight,

moisture,temperature,air,etc.）.Inspectglandularandbotanical

componentsforinsectinfestation.

Componentsorfinishedproductadulteratedbyrodents,insects,orchemicals

mustbedocumentedandsubmittedforseizure.

Collecttheevidenceevenifthefirmplanstovoluntarilydestroythe

product.Bealertforcomponents,colors,andfoodadditivesthatmaybenew

drugsubstances,appeartohavenouseintheplantorappeartobefroman

unknownsupplier.CheckthecolorsagainsttheColorAdditivesStatusList

intheIOMDetermineifthecolorisapprovedforitsintendeduse,and

requiredstatementsaredeclaredonthedruglabel.

Componentsmightbereceivedatmorethanonelocation.Componentsmustbe

handledinaccordancewiththedrugCGMP'sincludingcomponentsusedinthe

researchanddevelopmentlab.Determinehowcomponentsareidentifiedafter

receiptandquarantineduntilreleased.Componentsmustbeidentifiedsothe

status（quarantine,approved,orrejected）isknown.Reviewthecriteriafor

removingcomponentsfromquarantineandchallengethesystem.Determinewhat

recordsaremaintainedinthestorageareatodocumentthemovementof

componentstootherareas,andhowrejectedcomponentshandled.The

componentcontainerhasanidentificationcodeaffixedtoit.Thisunique

codeprovidestraceabilityfromthecomponentmanufacturertoitsuseinthe

finishedproduct.

Reviewthesamplingandtestingproceduresforcomponents,andtheprocess

bywhichapprovedmaterialsarereleasedforuse.Decideifthesepractices

areadequateandfollowed.

Determinethevalidity,andaccuracyofthefirm'sinventorysystemfordrug

components,containers,closuresandlabeling.Challengethecomponent

inventoryrecordsbyweighingalotandcomparingtheresultsagainstthe

quantityremainingontheinventoryrecord.Significantdiscrepanciesin

theserecordsshouldbeinvestigated.

Evaluatethefollowingtodeterminewhetherthefirmhasshownthatthe

containersandclosuresarecompatiblewiththeproduct,willprovide

adequateprotectionforthedrugagainstdeteriorationorcontamination,are

notadditiveorabsorptive,andaresu