FDA清洁验证指南(中英文对照)

1of14ValidationofCleaningProcesses清洁工艺验证GUIDETOINSPECTIONSVALIDATIONOFCLEANINGPROCESSES清洁工艺验证检查指南MikeMaSortoutXiaoGangNote:ThisdocumentisreferencematerialforinvestigatorsandotherFDApersonnel.ThedocumentdoesnotbindFDA,anddoesnoconferanyrights,privileges,benefits,orimmunitiesfororonanyperson(s).注意：本指南是审计官和其他FDA人员的参考资料。FDA不受本指南的约束，也没有授予任何人任何权利、特权、收益或豁免权。2of14ContentI.INTRODUCTION简介...............................................................................................................................................3II.BACKGROUND背景................................................................................................................................................3III.GENERALREQUIREMENTS常规要求....................................................................................................................5IV.EVALUATIONOFCLEANINGVALIDATION清洁验证的评估..................................................................................6V.ESTABLISHMENTOFLIMITS确定限度.................................................................................................................11VI.OTHERISSUES其他问题.....................................................................................................................................12VII.REFERENCES参考资料.......................................................................................................................................133of14I.INTRODUCTION简介Validationofcleaningprocedureshasgeneratedconsiderablediscussionsinceagencydocuments,includingtheInspectionGuideforBulkPharmaceuticalChemicalsandtheBiotechnologyInspectionGuide,havebrieflyaddressedthisissue.TheseAgencydocumentsclearlyestablishtheexpectationthatcleaningprocedures(processes)bevalidated.自从机构文件，包括化学原料药制剂检查指南和生物技术制剂检查指南简明的提及清洁验证规程以来，就对清洁规程验证产生了大量的讨论。这些机构的文件明确建立了清洁规程验证的预期结果。Thisguideisdesignedtoestablishinspectionconsistencyanduniformitybydiscussingpracticesthathavebeenfoundacceptable(orunacceptable).Simultaneously,onemustrecognizethatforcleaningvalidation,aswithvalidationofotherprocesses,theremaybemorethanonewaytovalidateaprocess.Intheend,thetestofanyvalidationprocessiswhetherscientificdatashowsthatthesystemconsistentlydoesasexpectedandproducesaresultthatconsistentlymeetspredeterminedspecifications.设计本指南是为了通过讨论已发现的可接受（或不可接受）的实际操作来建立检查的一致性和统一性。同时必须认识到清洁验证和其他过程验证一样，某一过程的验证可能不止一种方式。最后，任何过程验证的检测是科学数据是否反映系统能始终如一按照既定标准运作并持续产生符合既定标准的结果。Thisguideisintendedtocoverequipmentcleaningforchemicalresiduesonly.本指南只适用于化学残留物的设备清洁。II.BACKGROUND背景ForFDAtorequirethatequipmentbecleanpriortouseisnothingnew,the1963GMPRegulations(Part133.4)statedasfollowsEquipment***shallbemaintainedinacleanandorderlymanner***.Averysimilarsectiononequipmentcleaning(211.67)wasincludedinthe1978CGMPregulations.Ofcourse,themainrationaleforrequiringcleanequipmentistopreventcontaminationoradulterationofdrugproducts.Historically,FDAinvestigatorshavelookedforgrossinsanitationduetoinadequatecleaningandmaintenanceofequipmentand/orpoordustcontrolsystems.Also,historicallyspeaking,FDAwasmoreconcernedaboutthecontaminationofnonpenicillindrugproductswithpenicillinsorthecross-contaminationofdrugproductswithpotentsteroidsorhormones.Anumberofproductshavebeenrecalledoverthepastdecadeduetoactualorpotentialpenicillincross-contamination.对于FDA来说，要求对设备在使用前进行清洁并不是稀奇的事情，1963年GMP法规（133.4部分）指出“设备***应该按照清洁和有序的方式来进行维护”。在1978CGMP法规中也包含了非常相似的有关设备清洗的章节(211.67)。当然，清洁设备的主要理由是防止药品被污染或掺假。在历史上，FDA检查官寻找由于对设备不当的清洗和维护和/或不良的灰尘控制系统而带来的总体不卫生情况。而且，从历史上来说，FDA更4of14加关注非青霉素药品被青霉素污染、或药品中的活性激素或荷尔蒙交叉污染。由于实际或潜在的青霉素的交叉污染所致，在过去的十年中有很多药品被召回。OneeventwhichincreasedFDAawarenessofthepotentialforcrosscontaminationduetoinadequateprocedureswasthe1988recallofafinisheddrugproduct,CholestyramineResinUSP.Thebulkpharmaceuticalchemicalusedtoproducetheproducthadbecomecontaminatedwithlowlevelsofintermediatesanddegradantsfromtheproductionofagriculturalpesticides.Thecross-contaminationinthatcaseisbelievedtohavebeenduetothereuseofrecoveredsolvents.Therecoveredsolventshadbeencontaminatedbecauseofalackofcontroloverthereuseofsolventdrums.Drumsthathadbeenusedtostorerecoveredsolventsfromapesticideproductionprocesswerelaterusedtostorerecoveredsolventsusedfortheresinmanufacturingprocess.Thefirmdidnothaveadequatecontrolsoverthesesolventdrums,didnotdoadequatetestingofdrummedsolvents,anddidnothavevalidatedcleaningproceduresforthedrums.1998年消美国专利药消胆胺树脂制剂的召回，使FDA进一步认识到因不当规程而导致交叉污染的可能性。用于生产药品的原料药被生产农用杀虫剂中产生的中间体和降解物污染。本案例中的交叉污染被认为是由于回收溶剂的重新使用。回收溶剂由于缺乏对溶剂桶的重新使用进行控制而被污染。用于储存杀虫剂生产过程中的回收溶剂的溶剂桶，后来又用于储存树脂生产过程的回收溶剂。公司未对这些溶剂桶进行适当的控制，也未对桶中的溶剂进行适当的测试，以及未对桶的清洗过程进行验证。Someshipmentsofthispesticidecontaminatedbulkpharmaceuticalweresuppliedtoasecondfacilityatadifferentlocationforfinishing.Thisresultedinthecontaminationofthebagsusedinthatfacility'sfluidbeddryerswithpesticidecontamination.Thisinturnledtocrosscontaminationoflotsproducedatthatsite,asitewherenopesticideswerenormallyproduced.部分被杀虫剂污染的原料药被运输到在其他地方的另外一家工厂进行最后加工。由于该工厂的流体床干燥器袋子被原料药中的杀虫剂污染，结果导致在该工厂地点生产的很多批次产品相应的被交叉污染，该地点在正常情况下是不生产杀虫剂的。FDAinstitutedanimportalertin1992onaforeignbulkpharmac