經(jīng)典word整理文檔，僅參考，雙擊此處可刪除頁眉頁腳。本資料屬于網(wǎng)絡(luò)整理，如有侵權(quán)，請聯(lián)系刪除，謝謝！《美國FDA認證與申辦指南》權(quán)威資訊系列美國洲際藥業(yè)有限公司電子郵件：TheAlliancePharm(US),Inc.美國洲際藥業(yè)有限公司GUIDETOINSPECTIONSVALIDATIONOFCLEANINGPROCESSES請注意：本指南是檢查官和其他FDA人員的參考材料。本指南不受FDA約束，并沒有賦予任何人任何權(quán)利、特權(quán)、收益或豁免權(quán)。Note:ThisdocumentisreferencematerialforinvestigatorsandotherFDApersonnel.ThedocumentdoesnotbindFDA,anddoesnoconferanyrights,privileges,benefits,orimmunitiesfororonanyperson(s).I．介紹I.INTRODUCTION建立了要驗證的清洗過程需要達到的要求。Validationofcleaningprocedureshasgeneratedconsiderablediscussionsinceagencydocuments,includingtheInspectionGuideforBulkPharmaceuticalChemicalsandtheBiotechnologyInspectionGuide,havebrieflyaddressedthisissue.TheseAgencydocumentsclearlyestablishtheexpectationthatcleaningprocedures(processes)bevalidated.一致性和統(tǒng)一性。同時，對清洗驗證需要了解的是，像其他過程驗證一樣，可能是否顯示出系統(tǒng)與要求相符和產(chǎn)生的結(jié)果是否符合預(yù)先定義的參數(shù)指標(biāo)。Thisguideisdesignedtoestablishinspectionconsistencyanduniformitybydiscussingpracticesthathavebeenfoundacceptable(orunacceptable).Simultaneously,onemustrecognizethatforcleaningvalidation,aswithvalidationofotherprocesses,theremaybemorethanonewaytovalidateaprocess.Intheend,thetestofanyvalidationprocessiswhetherscientificdatashowsthatthesystemconsistentlydoesasexpectedandproducesaresultthatconsistentlymeetspredeterminedspecifications.本指南只適用于化學(xué)殘留物的設(shè)備清洗。Thisguideisintendedtocoverequipmentcleaningforchemicalresiduesonly.II．背景Confidential&Proprietary美國FDA認證輔導(dǎo)權(quán)威資訊內(nèi)部資料1TheAlliancePharm(US),Inc.美國洲際藥業(yè)有限公司II.BACKGROUND對于FDA法規(guī)(部分133.4)中指出“設(shè)備***應(yīng)該按照清潔和有序的方式進行維護***?！痹?978CGMP法檢查官尋找由于對設(shè)備不當(dāng)?shù)那逑春途S護和/或不良的灰塵控制系統(tǒng)而帶來的總體不衛(wèi)生情況。而且，從歷史上對非青霉素藥品中的青霉素污染或藥品中的活性激素或荷爾蒙交叉污交叉污染。ForFDAtorequirethatequipmentbecleanpriortouseisnothingnew,the1963GMPRegulations(Part133.4)statedasfollows"Equipment***shallbemaintainedinacleanandorderlymanner***."Averysimilarsectiononequipmentcleaning(211.67)wasincludedinthe1978CGMPregulations.Ofcourse,themainrationaleforrequiringcleanequipmentistopreventcontaminationoradulterationofdrugproducts.Historically,FDAinvestigatorshavelookedforgrossinsanitationduetoinadequatecleaningandmaintenanceofequipmentand/orpoordustcontrolsystems.Also,historicallyspeaking,FDAwasmoreconcernedaboutthecontaminationofnonpenicillindrugproductswithpenicillinsorthecross-contaminationofdrugproductswithpotentsteroidsorhormones.Anumberofproductshavebeenrecalledoverthepastdecadeduetoactualorpotentialpenicillincross-contamination.導(dǎo)致FDA對由于不滿足要求的過程導(dǎo)致交叉污染的可能性的進一步關(guān)注的案例是，1988年對成品藥消膽胺樹脂USP的撤回。用于生產(chǎn)成品的原料藥被生產(chǎn)農(nóng)當(dāng)?shù)臏y試，也沒有對桶的清洗過程進行驗證。OneeventwhichincreasedFDAawarenessofthepotentialforcrosscontaminationduetoinadequateprocedureswasthe1988recallofafinisheddrugproduct,CholestyramineResinUSP.Thebulkpharmaceuticalchemicalusedtoproducetheproducthadbecomecontaminatedwithlowlevelsofintermediatesanddegradantsfromtheproductionofagriculturalpesticides.Thecross-contaminationinthatcaseisbelievedtohavebeenduetothereuseofrecoveredsolvents.Therecoveredsolventshadbeencontaminatedbecauseofalackofcontroloverthereuseofsolventdrums.Drumsthathadbeenusedtostorerecoveredsolventsfromapesticideproductionprocesswerelaterusedtostorerecoveredsolventsusedfortheresinmanufacturingprocess.ThefirmdidnothaveadequateConfidential&Proprietary美國FDA認證輔導(dǎo)權(quán)威資訊內(nèi)部資料2TheAlliancePharm(US),Inc.美國洲際藥業(yè)有限公司controlsoverthesesolventdrums,didnotdoadequatetestingofdrummedsolvents,anddidnothavevalidatedcleaningproceduresforthedrums.一些被殺蟲劑污染的原料藥后來被運輸?shù)搅硗庖患以谄渌胤降墓S進行最后加工。這導(dǎo)致了由于工廠的流體床干燥器被殺蟲劑污染而把使用的包裝袋污染。生產(chǎn)殺蟲劑的。Someshipmentsofthispesticidecontaminatedbulkpharmaceuticalweresuppliedtoasecondfacilityatadifferentlocationforfinishing.Thisresultedinthecontaminationofthebagsusedinthatfacility'sfluidbeddryerswithpesticidecontamination.Thisinturnledtocrosscontaminationoflotsproducedatthatsite,asitewherenopesticideswerenormallyproduced.FDA在1992年對使用普通設(shè)備生產(chǎn)的活性激素產(chǎn)品和非激素產(chǎn)品的國外原料藥認為交叉污染的認為這是不夠的。其中的一個原因是，公司只尋找了TLC程中反應(yīng)副產(chǎn)品和降解物的殘留物的存在。FDAinstitutedanimportalertin1992onaforeignbulkpharmaceuticalmanufacturerwhichmanufacturedpotentsteroidproductsaswellasnon-steroidalproductsusingcommonequipment.Thisfirmwasamulti-usebulkpharmaceuticalfacility.FDAconsideredthepotentialforcross-contaminationtobesignificantandtoposeaserioushealthrisktothepublic.ThefirmhadonlyrecentlystartedacleaningvalidationprogramatthetimeoftheinspectionanditwasconsideredinadequatebyFDA.Oneofthereasonsitwasconsideredinadequatewasthatthefirmwasonlylookingforevidenceoftheabsenceofthepreviouscompound.Thefirmhadevidence,fromTLCtestsontherinsewater,ofthepresenceofresiduesofreactionbyproductsanddegradantsfromthepreviousprocess.III.常規(guī)要求III.GENERALREQUIREMENTSFDA要求公司具有詳細地記錄設(shè)備各種零件的清洗過程的書面程序（SOP's）。Confidential&Proprietary美國FDA認證輔導(dǎo)權(quán)威資訊內(nèi)部資料3TheAlliancePharm(US),Inc.美國洲際藥業(yè)有限公司何殘留物也必須清除掉（清潔劑、溶劑等）。FDAexpectsfirmstohavewrittenprocedures(SOP's)detailingthecleaningprocessesusedforvariouspiecesofequipment.Iffirmshaveonecleaningprocessforcleaningbetweendifferentbatchesofthesameproductanduseadifferentprocessforcleaningbetweenproductchanges,weexpectthewrittenprocedurestoaddressthesedifferentscenario.Similarly,iffirmshaveoneprocessforremovingwatersolubleresiduesandanotherprocessfornon-watersolubleresidues,thewrittenprocedureshouldaddressbothscenariosandmakeitclearwhenagivenprocedureistobefollowed.Bulkpharmaceuticalfirmsmaydecidetodedicatecertainequipmentforcertainchemicalmanufacturingprocessstepsthatproducetarryorgummyresiduesthataredifficulttoremovefromtheequipment.Fluidbeddryerbagsareanotherexampleofequipmentthatisdifficulttocleanandisoftendedicatedtoaspecificproduct.Anyresiduesfromthecleaningprocessitself(detergents,solvents,etc.)alsohavetoberemovedfromtheequipment.FDA要求公司具有驗證清洗過程的常規(guī)書面程序。FDAexpectsfirmstohavewrittengeneralproceduresonhowcleaningprocesseswillbevalidated.FDA求的再驗證時間。FDAexpectsthegeneralvalidationprocedurestoaddresswhoisresponsibleforperformingandapprovingthevalidationstudy,theacceptancecriteria,andwhenrevalidationwillberequired.FDA要求公司在對每個生產(chǎn)系統(tǒng)或設(shè)備進行研究之前準(zhǔn)備特定的書面驗證協(xié)議。這些協(xié)議應(yīng)當(dāng)涉及樣本程序，采用的分析方法以及這些方法的靈敏性等問題。FDAexpectsfirmstopreparespecificwrittenvalidationprotocolsinadvanceforthestudiestobeperformedoneachmanufacturingsystemorpieceofequipmentwhichshouldaddresssuchissuesassamplingprocedures,andanalyticalmethodstobeusedincludingthesensitivityofthosemethods.FDA要求公司按照協(xié)議來進行驗證研究，并將這些研究結(jié)果記錄備案。FDAexpectsfirmstoconductthevalidationstudiesinaccordancewiththeprotocolsandtodocumenttheresultsofstudies.Confidential&Proprietary美國FDA認證輔導(dǎo)權(quán)威資訊內(nèi)部資料4TheAlliancePharm(US),Inc.美國洲際藥業(yè)有限公司FDA否有效。數(shù)據(jù)應(yīng)當(dāng)證明，殘留物級別已經(jīng)達到“可接受的程度”。FDAexpectsafinalvalidationreportwhichisapprovedbymanagementandwhichstateswhetherornotthecleaningprocessisvalid.Thedatashouldsupportaconclusionthatresidueshavebeenreducedtoan"acceptablelevel."IV.清洗驗證的評估IV.EVALUATIONOFCLEANINGVALIDATION的清洗步驟進行有效性評估，這樣的做法不足為奇。當(dāng)對清洗設(shè)備進行評估時，洗嗎？手擦清洗跟洗滌劑清洗相比應(yīng)該伴隨什么過程？從批次到批次的手工清洗過程與從產(chǎn)品到產(chǎn)品有什么樣的變化？由于我們必須確定整個過程的有效性，源。Thefirststepistofocusontheobjectiveofthevalidationprocess,andwehaveseenthatsomecompanieshavefailedtodevelopsuchobjectives.Itisnotunusualtoseemanufacturersuseextensivesamplingandtestingprogramsfollowingthecleaningprocesswithouteverreallyevaluatingtheeffectivenessofthestepsusedtocleantheequipment.Severalquestionsneedtobeaddressedwhenevaluatingthecleaningprocess.Forexample,atwhatpointdoesapieceofequipmentorsystembecomeclean?Doesithavetobescrubbedbyhand?Whatisaccomplishedbyhandscrubbingratherthanjustasolventwash?Howvariablearemanualcleaningprocessesfrombatchtobatchandproducttoproduct?Theanswerstothesequestionsareobviouslyimportanttotheinspectionandevaluationofthecleaningprocesssinceonemustdeterminetheoveralleffectivenessoftheprocess.Answerstothesequestionsmayalsoidentifystepsthatcanbeeliminatedformoreeffectivemeasuresandresultinresourcesavingsforthecompany.間體的不同批次之間），公司只需要達到“設(shè)備看起來是清潔”的標(biāo)準(zhǔn)就行了。批次之間的清洗過程并不需要驗證。Confidential&Proprietary美國FDA認證輔導(dǎo)權(quán)威資訊內(nèi)部資料5TheAlliancePharm(US),Inc.美國洲際藥業(yè)有限公司Determinethenumberofcleaningprocessesforeachpieceofequipment.Ideally,apieceofequipmentorsystemwillhaveoneprocessforcleaning,howeverthiswilldependontheproductsbeingproducedandwhetherthecleanupoccursbetweenbatchesofthesameproduct(asinalargecampaign)orbetweenbatchesofdifferentproducts.Whenthecleaningprocessisusedonlybetweenbatchesofthesameproduct(ordifferentlotsofthesameintermediateinabulkprocess)thefirmneedonlymeetacriteriaof,"visiblyclean"fortheequipment.Suchbetweenbatchcleaningprocessesdonotrequirevalidation.1.設(shè)備設(shè)計1.EquipmentDesign清洗系統(tǒng)，這是非常令人擔(dān)心的。例如，應(yīng)當(dāng)使用沒有球閥的清潔管道。當(dāng)使用不清潔球閥時（在原料藥企業(yè)中很常見），清洗過程會更困難些。Examinethedesignofequipment,particularlyinthoselargesystemsthatmayemploysemi-automaticorfullyautomaticclean-in-place(CIP)systemssincetheyrepresentsignificantconcern.Forexample,sanitarytypepipingwithoutballvalvesshouldbeused.Whensuchnonsanitaryballvalvesareused,asiscommoninthebulkdrugindustry,thecleaningprocessismoredifficult.這些系統(tǒng)是否被正確的鑒定和驗證。Whensuchsystemsareidentified,itisimportantthatoperatorsperformingcleaningoperationsbeawareofproblemsandhavespecialtrainingincleaningthesesystemsandvalves.Determinewhetherthecleaningoperatorshaveknowledgeofthesesystemsandtheleveloftrainingandexperienceincleaningthesesystems.Alsocheckthewrittenandvalidatedcleaningprocesstodetermineifthesesystemshavebeenproperlyidentifiedandvalidated.圖和標(biāo)簽鑒定不當(dāng)，會導(dǎo)致不正確的清洗操作。Inlargersystems,suchasthoseemployinglongtransferlinesorpiping,checktheflowchartsandpipingdiagramsfortheidentificationofvalvesConfidential&Proprietary美國FDA認證輔導(dǎo)權(quán)威資訊內(nèi)部資料6TheAlliancePharm(US),Inc.美國洲際藥業(yè)有限公司andwrittencleaningprocedures.Pipingandvalvesshouldbetaggedandeasilyidentifiablebytheoperatorperformingthecleaningfunction.Sometimes,inadequatelyidentifiedvalves,bothonprintsandphysically,haveledtoincorrectcleaningpractices.其重要。在這些操作中，殘留物的烘干將直接影響到清洗過程的效率。Alwayscheckforthepresenceofanoftencriticalelementinthedocumentationofthecleaningprocesses;identifyingandcontrollingthelengthoftimebetweentheendofprocessingandeachcleaningstep.Thisisespeciallyimportantfortopicals,suspensions,andbulkdrugoperations.Insuchoperations,thedryingofresidueswilldirectlyaffecttheefficiencyofacleaningprocess.是否使用CIP有污水留在清洗后的設(shè)備中。WhetherornotCIPsystemsareusedforcleaningofprocessingequipment,microbiologicalaspectsofequipmentcleaningshouldbeconsidered.Thisconsistslargelyofpreventivemeasuresratherthanremovalofcontaminationonceithasoccurred.Thereshouldbesomeevidencethatroutinecleaningandstorageofequipmentdoesnotallowmicrobialproliferation.Forexample,equipmentshouldbedriedbeforestorage,andundernocircumstancesshouldstagnantwaterbeallowedtoremaininequipmentsubsequenttocleaningoperations.原質(zhì)，所以這對無菌處理熱原質(zhì)控制的立場來看也特別重要。Subsequenttothecleaningprocess,equipmentmaybesubjectedtosterilizationorsanitizationprocedureswheresuchequipmentisusedforsterileprocessing,orfornonsterileprocessingwheretheproductsmaysupportmicrobialgrowth.Whilesuchsterilizationorsanitizationproceduresarebeyondthescopeofthisguide,itisimportanttonotethatcontrolofthebioburdenthroughadequatecleaningandstorageofequipmentisimportanttoensurethatsubsequentsterilizationorsanitizationproceduresachievethenecessaryassuranceofsterility.ThisisalsoparticularlyimportantfromthestandpointofthecontrolConfidential&Proprietary美國FDA認證輔導(dǎo)權(quán)威資訊內(nèi)部資料7TheAlliancePharm(US),Inc.美國洲際藥業(yè)有限公司ofpyrogensinsterileprocessingsinceequipmentsterilizationprocessesmaynotbeadequatetoachievesignificantinactivationorremovalofpyrogens.2.清洗過程記錄程序和記錄2.CleaningProcessWrittenProcedureandDocumentation明白常規(guī)的標(biāo)準(zhǔn)操作規(guī)范（SOP），而其他人使用批記錄或要求明確記錄每個執(zhí)過程的復(fù)雜性、操作員的能力及對操作員的培訓(xùn)培訓(xùn)情況而變化。Examinethedetailandspecificityoftheprocedureforthe(cleaning)processbeingvalidated,andtheamountofdocumentationrequired.WehaveseengeneralSOPs,whileothersuseabatchrecordorlogsheetsystemthatrequiressometypeofspecificdocumentationforperformingeachstep.Dependinguponthecomplexityofthesystemandcleaningprocessandtheabilityandtrainingofoperators,theamountofdocumentationnecessaryforexecutingvariouscleaningstepsorprocedureswillvary.過程就足夠了。Whenmorecomplexcleaningproceduresarerequired,itisimportanttodocumentthecriticalcleaningsteps(forexamplecertainbulkdrugsynthesisprocesses).Inthisregard,specificdocumentationontheequipmentitselfwhichincludesinformationaboutwhocleaneditandwhenisvaluable.However,forrelativelysimplecleaningoperations,themeredocumentationthattheoverallcleaningprocesswasperformedmightbesufficient.其它因素，如清洗歷史、清洗后發(fā)現(xiàn)的殘留物級別、和測試結(jié)果的可變性，也可當(dāng)?shù)脑u估，如果認為操作員的執(zhí)行有問題，就需要更多的文件（指南）和培訓(xùn)。Otherfactorssuchashistoryofcleaning,residuelevelsfoundaftercleaning,andvariabilityoftestresultsmayalsodictatetheamountofConfidential&Proprietary美國FDA認證輔導(dǎo)權(quán)威資訊內(nèi)部資料8TheAlliancePharm(US),Inc.美國洲際藥業(yè)有限公司documentationrequired.Forexample,whenvariableresiduelevelsaredetectedfollowingcleaning,particularlyforaprocessthatisbelievedtobeacceptable,onemustestablishtheeffectivenessoftheprocessandoperatorperformance.Appropriateevaluationsmustbemadeandwhenoperatorperformanceisdeemedaproblem,moreextensivedocumentation(guidance)andtrainingmayberequired.3.分析方法3.AnalyticalMethods留物回收率（如50％或者90％）的分析方法，對使用的分析方法進行挑戰(zhàn)。這下）。Determinethespecificityandsensitivityoftheanalyticalmethodusedtodetectresidualsorcontaminants.Withadvancesinanalyticaltechnology,residuesfromthemanufacturingandcleaningprocessescanbedetectedatverylowlevels.Iflevelsofcontaminationorresidualarenotdetected,itmeanthatthereisnoresidualcontaminantpresentaftercleaning.Itonlymeansthatlevelsofcontaminantgreaterthanthesensitivityordetectionlimitoftheanalyticalmethodarenotpresentinthesample.Thefirmshouldchallengetheanalyticalmethodincombinationwiththesamplingmethod(s)usedtoshowthatcontaminantscanberecoveredfromtheequipmentsurfaceandatwhatlevel,i.e.50%recovery,90%,etc.Thisisnecessarybeforeanyconclusionscanbemadebasedonthesampleresults.Anegativetestmayalsobetheresultofpoorsamplingtechnique(seebelow).4.取樣4.Sampling法是使用沖洗溶液。Therearetwogeneraltypesofsamplingthathavebeenfoundacceptable.Themostdesirableisthedirectmethodofsamplingthesurfaceoftheequipment.Anothermethodistheuseofrinsesolutions.Confidential&Proprietary美國FDA認證輔導(dǎo)權(quán)威資訊內(nèi)部資料9TheAlliancePharm(US),Inc.美國洲際藥業(yè)有限公司a.材料可以妨礙測試。例如，發(fā)現(xiàn)藥簽上粘合劑的干擾樣品的分析。因此，在早期被使用是很重要的。a.DirectSurfaceSampling-Determinethetypeofsamplingmaterialusedanditsimpactonthetestdatasincethesamplingmaterialmayinterferewiththetest.Forexample,theadhesi