清洁验证英文版.docx
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清洁验证英文版.docx
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清洁验证英文版
ValidationofCleaningProcesses(7/93)
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.Oneofthereasonsitwasconsideredinadequatewasthatthefirmwasonlylookingforevidenceoftheabsenceofthepreviouscompound.Thefirmhadevidence,fromTLCtestsontherinsewater,ofthepresenceofresiduesofreactionbyproductsanddegradantsfromthepreviousprocess.
III.GENERALREQUIREMENTS
FDAexpectsfirmstohavewrittenprocedures(SOP's)detailingthecleaningprocessesusedforvariouspiecesofequipment.Iffirmshaveonecleaningprocessforcleaningbetweendifferentbatchesofthesameproductanduseadifferentprocessforcleaningbetweenproductchanges,weexpectthewrittenprocedurestoaddressthesedifferentscenario.Similarly,iffirmshaveoneprocessforremovingwatersolubleresiduesandanotherprocessfornon-watersolubleresidues,thewrittenprocedureshouldaddressbothscenariosandmakeitclearwhenagivenprocedureistobefollowed.Bulkpharmaceuticalfirmsmaydecidetodedicatecertainequipmentfor
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