FDA清洁验证审计指南Word文件下载.docx
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FDA清洁验证审计指南Word文件下载.docx
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TWEET
PINIT
MORESHARINGOPTIONS
GUIDETOINSPECTIONSVALIDATIONOFCLEANINGPROCESSES
Note:
ThisdocumentisreferencematerialforinvestigatorsandotherFDApersonnel.ThedocumentdoesnotbindFDA,anddoesnoconferanyrights,privileges,benefits,orimmunitiesfororonanyperson(s).
I.INTRODUCTION
Validationofcleaningprocedureshasgeneratedconsiderablediscussionsinceagencydocuments,includingtheInspectionGuideforBulkPharmaceuticalChemicalsandtheBiotechnologyInspectionGuide,havebrieflyaddressedthisissue.TheseAgencydocumentsclearlyestablishtheexpectationthatcleaningprocedures(processes)bevalidated.
Thisguideisdesignedtoestablishinspectionconsistencyanduniformitybydiscussingpracticesthathavebeenfoundacceptable(orunacceptable).Simultaneously,onemustrecognizethatforcleaningvalidation,aswithvalidationofotherprocesses,theremaybemorethanonewaytovalidateaprocess.Intheend,thetestofanyvalidationprocessiswhetherscientificdatashowsthatthesystemconsistentlydoesasexpectedandproducesaresultthatconsistentlymeetspredeterminedspecifications.
Thisguideisintendedtocoverequipmentcleaningforchemicalresiduesonly.
II.BACKGROUND
ForFDAtorequirethatequipmentbecleanpriortouseisnothingnew,the1963GMPRegulations(Part133.4)statedasfollows"
Equipment***shallbemaintainedinacleanandorderlymanner***."
Averysimilarsectiononequipmentcleaning(211.67)wasincludedinthe1978CGMPregulations.Ofcourse,themainrationaleforrequiringcleanequipmentistopreventcontaminationoradulterationofdrugproducts.Historically,FDAinvestigatorshavelookedforgrossinsanitationduetoinadequatecleaningandmaintenanceofequipmentand/orpoordustcontrolsystems.Also,historicallyspeaking,FDAwasmoreconcernedaboutthecontaminationofnonpenicillindrugproductswithpenicillinsorthecross-contaminationofdrugproductswithpotentsteroidsorhormones.Anumberofproductshavebeenrecalledoverthepastdecadeduetoactualorpotentialpenicillincross-contamination.
OneeventwhichincreasedFDAawarenessofthepotentialforcrosscontaminationduetoinadequateprocedureswasthe1988recallofafinisheddrugproduct,CholestyramineResinUSP.Thebulkpharmaceuticalchemicalusedtoproducetheproducthadbecomecontaminatedwithlowlevelsofintermediatesanddegradantsfromtheproductionofagriculturalpesticides.Thecross-contaminationinthatcaseisbelievedtohavebeenduetothereuseofrecoveredsolvents.Therecoveredsolventshadbeencontaminatedbecauseofalackofcontroloverthereuseofsolventdrums.Drumsthathadbeenusedtostorerecoveredsolventsfromapesticideproductionprocesswerelaterusedtostorerecoveredsolventsusedfortheresinmanufacturingprocess.Thefirmdidnothaveadequatecontrolsoverthesesolventdrums,didnotdoadequatetestingofdrummedsolvents,anddidnothavevalidatedcleaningproceduresforthedrums.
Someshipmentsofthispesticidecontaminatedbulkpharmaceuticalweresuppliedtoasecondfacilityatadifferentlocationforfinishing.Thisresultedinthecontaminationofthebagsusedinthatfacility'
sfluidbeddryerswithpesticidecontamination.Thisinturnledtocrosscontaminationoflotsproducedatthatsite,asitewherenopesticideswerenormallyproduced.FDAinstitutedanimportalertin1992onaforeignbulkpharmaceuticalmanufacturerwhichmanufacturedpotentsteroidproductsaswellasnon-steroidalproductsusingcommonequipment.Thisfirmwasamulti-usebulkpharmaceuticalfacility.FDAconsideredthepotentialforcross-contaminationtobesignificantandtoposeaserioushealthrisktothepublic.ThefirmhadonlyrecentlystartedacleaningvalidationprogramatthetimeoftheinspectionanditwasconsideredinadequatebyFDA.Oneofthereasonsitwasconsideredinadequatewasthatthefirmwasonlylookingforevideneeoftheabseneeofthepreviouscompound.Thefirmhadevidenee,fromTLCtestsontherinsewater,ofthepresenceofresiduesofreactionbyproductsanddegradantsfromthepreviousprocess.
III.GENERALREQUIREMENTS
FDAexpectsfirmstohavewrittenprocedures(SOP'
s)detailingthecleaningprocessesusedforvariouspiecesofequipment.Iffirmshaveonecleaningprocessforcleaningbetweendifferentbatchesofthesameproductanduseadifferentprocessforcleaningbetweenproductchanges,weexpectthewrittenprocedurestoaddressthesedifferentscenario.Similarly,iffirmshaveoneprocessforremovingwatersolubleresiduesandanotherprocessfornon-watersolubleresidues,thewrittenprocedureshouldaddressbothscenariosandmakeitclearwhenagivenprocedureistobefollowed.Bulk
pharmaceuticalfirmsmaydecidetodedicatecertainequipmentforcertainchemicalmanufacturingprocessstepsthatproducetarryorgummyresiduesthataredifficulttoremovefromtheequipment.Fluidbeddryerbagsareanotherexampleofequipmentthatisdifficulttocleanandisoftendedicatedtoaspecificproduct.Anyresiduesfromthecleaningprocessitself(detergents,solvents,etc.)alsohavetoberemovedfromtheequipment.
FDAexpectsfirmstohavewrittengeneralproceduresonhowcleaningprocesseswillbevalidated.
FDAexpectsthegeneralvalidationprocedurestoaddresswhoisresponsibleforperformingandapprovingthevalidationstudy,theacceptancecriteria,andwhenrevalidationwillberequired.
FDAexpectsfirmstopreparespecificwrittenvalidationprotocolsinadvanceforthestudiestobeperformedoneachmanufacturingsystemorpieceofequipmentwhichshouldaddresssuchissuesassamplingprocedures,andanalyticalmethodstobeusedincludingthesensitivityofthosemethods.FDAexpectsfirmstoconductthevalidationstudiesinaccordancewiththeprotocolsandtodocumenttheresultsofstudies.
IV.
FDAexpectsafinalvalidationreportwhichisapprovedbymanagementandwhichstateswhetherornotthecleaningprocessisvalid.Thedatashouldsupportaconclusionthatresidueshavebeenreducedtoan"
acceptablelevel."
EVALUATIONOFCLEANINGVALIDATION
Thefirststepistofocusontheobjectiveofthevalidationprocess,andwehaveseenthatsomecompanieshavefailedtodevelopsuchobjectives.Itisnotunusualtoseemanufacturersuseextensivesamplingandtestingprogramsfollowingthecleaningprocesswithouteverreallyevaluatingtheeffectivenessofthestepsusedtocleantheequipment.Severalquestionsneedtobeaddressedwhenevaluatingthecleaningprocess.Forexample,atwhatpointdoesapieceofequipmentorsystembecomeclean?
Doesithavetobescrubbedbyhand?
Whatisaccomplishedbyhandscrubbingratherthanjustasolventwash?
Howvariablearemanualcleaningprocessesfrombatchtobatchandproducttoproduct?
Theanswerstothesequestionsareobviouslyimportanttotheinspectionandevaluationofthecleaningprocesssinceonemustdeterminetheoveralleffectivenessoftheprocess.Answerstothesequestionsmayalsoidentifystepsthatcanbeeliminatedformoreeffectivemeasuresandresultinresourcesavingsforthecompany.
Determinethenumberofcleaningprocessesforeachpieceofequipment.Ideally,apieceofequipmentorsystemwillhaveoneprocessforcleaning,howeverthiswilldependontheproductsbeingproducedandwhetherthecleanupoccursbetweenbatchesofthesameproduct(asinalargecampaign)orbetweenbatchesofdifferentproducts.Whenthecleaningprocessisusedonlybetweenbatchesofthesameproduct(ordifferentlotsofthesameintermediateinabulkprocess)thefirmneedonlymeetacriteriaof,"
visiblyclean"
fortheequipment.Suchbetweenbatchcleaningprocessesdonotrequirevalidation.
1.EquipmentDesign
Examinethedesignofequipment,particularlyinthoselargesystemsthatmayemploysemi-automaticorfullyautomaticclean-in-place(CIP)systemssincetheyrepresentsignificantconcern.Forexample,sanitarytypepipingwithoutballvalvesshouldbeused.Whensuchnonsanitaryballvalvesareused,asiscommoninthebulkdrugindustry,thecleaningprocessismoredifficult.
Whensuchsystemsareidentified,itisimportantthatoperatorsperformingcleaningoperationsbeawareofproblemsandhavespecialtrainingincleaningthesesystemsandvalves.Determinewhetherthecleaningoperatorshaveknowledgeofthesesystemsandtheleveloftrainingandexperieneeincleaningthesesystems.Alsocheckthewrittenandvalidatedcleaningprocesstodetermineifthesesystemshavebeenproperlyidentifiedandvalidated.
Inlargersystems,suchasthoseemployinglongtransferlinesorpiping,checktheflowchartsandpipingdiagramsfortheidentificationofvalvesandwrittencleaningprocedures.Pipingandvalvesshouldbetaggedandeasilyidentifiablebytheoperatorperformingthecleaningfunction.Sometimes,inadequatelyidentifiedvalves,bothonprintsandphysically,haveledtoincorrectcleaningpractices.
Alwayscheckforthepreseneeofanoftencriticalelementinthedocumentationofthecleaningprocesses;
identifyingandcontrollingthelengthoftimebetweentheendofprocessingandeachcleaningstep.Thisisespeciallyimportantfortopicals,suspensions,andbulkdrugoperations.Insuchoperations,thedryingofresidueswilldirectlyaffecttheefficiencyofacleaningprocess.
Whetheror
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