FDA清洁验证审计指南Word文件下载.docx

FDA清洁验证审计指南Word文件下载.docx

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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