20090113 PI 030-1 PICS 原料药检查备忘(中英文)

20090113PI030-1PIC/S原料药检查备忘PHARMACEUTICALINSPECTIONCONVENTIONPHARMACEUTICALINSPECTIONCO-OPERATIONSCHEMEPI030-113January2009AIDE-MEMOIRE备忘INSPECTIONOFACTIVEPHARMACEUTICALINGREDIENTS原料药检查?PIC/SJanuary2009Reproductionprohibitedforcommercialpurposes.Reproductionforinternaluseisauthorised,providedthatthesourceisacknowledged.TABLEOFCONTENTS目录DocumentHistory文件历史Introduction介绍Purpose目的Scope范围Aide-Memoire备忘RevisionHistory巾修订历史1.DOCUMENTHISTORY文件历史AdoptionbyCommittee被委员会采用12.11.2009EntryintoforceofPI030-1实施01.03.2009INTRODUCTION介绍TheadoptionofICHQ7asthefirsttrulyharmonisedGMPguidelineforactivepharmaceuticalingredients(APIs)andtheassociateddevelopmentofregulatoryframeworkstoimplementtheguidelineasaregulatorystandardmarkthebeginningofaneweraofregulationformedicines.采用ICHQ7作为真正意义上的原料药统一GMP指南，并伴随着法规框架的发展以实施指南作为法规的标准，标志着药品法规的一个新纪元。TheadoptionofICHQ7byPIC/SoccurredinMay2001withthecurrentversionoftheguidelinehavingbeenavailablesince1September2007asGMPPE009(PartII).2001年5月PIC/S采用了ICHQ7,现行版本指南GMPPE009（第二部分）在2007年9月1日公布.TheprimaryobjectiveforimplementingICHQ7isthereductionoftherisksassociatedwiththemanufacturingqualityofAPIsandthiscannotbeachievedwithoutaneffectiveinspectionsystemwhichaddressesthespecificaspectsoftheglobalAPIindustry.实施ICHQ7的基本目标是减少原料药生产质量所伴随的风险，要达到这个目标，必须制订有效的检查体系，以说明全球原料药行业的各个独特方面。PURPOSE目的ItisrecognisedthatduetotheirbackgroundandexperiencethemajorityofGMPinspectorsaremorefamiliarwiththeinspectionoffinishedproducts.大家已认识到鉴于GMP检查人员的背景和经验，大部分检查人员对制剂检查更为熟悉。Therefore,toassistinspectorsnotspecialisedintheinspectionofAPImanufacturersthisdocumenthasbeendevelopedtoprovidetrainingandguidanceforthepreparationandperformanceofsuchinspections.因此，为帮助非原料药生产商专门检查人员，制订本文，以给这样的检查准备和实施过程提供培训和指南。ThisAide-MemoireshouldalsocontributetoaharmonisedapproachforinspectionsofAPImanufacturersbetweenthedifferentPIC/SMembers.本备忘同时也对PIC/S不同成员之间对原料药生产商检查方法进行协调统一。SCOPE范围4.1Atthetimeofissue,thisdocumentreflectedthecurrentstateoftheart.Itisnotintendedtobeabarriertotechnicalinnovationorthepursuitofexcellence.本文件代表签发时所能达到的最高水平，并无意成为技术革新或追求卓越的障碍。ThisAide-Memoirefocusesonthepreparationforinspectionsandchaptersand/orsectionsofGMPPE009(PartII)whicharespecifictotheinspectionofAPImanufacturersorcriticalforthequalityofAPIs.ForsectionswhichincluderequirementssimilartothoseinGMPGuidePartIdevotedtoFinishedProductssuchaspersonnel,documentation,etc.,pleasereferdirectlytoGMPPE009(PartII).本备忘主要内容是关于检查的准备，和GMPPE009(第二部分)的各章节和/或部分的准备，针对的是原料药生产商的检查或原料药质量的关键点。对于与GMP指南第一部分制剂相似的要求，例如人员、文件等，请直接参考GMPPE009(第二部分)。AIDEMEMOIRE备忘1.PreparationofAPIinspection原料药检查准备InspectionElement检查要素Workflow工作流程Supportingdocuments支持性文件Inspectionhistory检查历史Reviewthereportsofanyrecentinspectionscarriedoutandtheoutcome审核所有最近的检查报告及检查结果Inspectionreports检查报告Ifappropriate,contacttheinspectoratethatconductedthelastinspectiontoverifytheinformation适当时，联系前次检查人员确认相关信息BasicinformationrelatedtotheAPIs与原料药有关的基本信息DeterminethenumberofdifferentAPIsproducedatthesite检查在该场所生产的原料药品种ProductsQualityReview(s)(PQR)产品质量回顾PQRDeterminetheclassificationoftheAPIs(antibiotics,hormones,

cytostaticsetc.）检查原料药的类别（抗生素、激素、细胞抑制剂等）DeterminetheintendeduseoftheAPIs(topic,oral,injectable,inhalation,etc.)检查原料药的用途(局部、口服、注射、吸入等)ForeachAPI,establish;-grade(freezedried,micronised,sterile,etc.);-batchsize;and—numberofbatchesproducedperyear对每种原料药，—级别(冻干、微粉、无菌等)—批量，及—每年生产的批次数量Basicinformationrelatedtothesite与工厂相关的基本信息Determineifthefacilitiesaremultipurposeordedicated检查设施是多产品共用还是专用SiteMasterFile工厂主文件IfAPIsarepotentorhighlytoxicdeterminethecontainmentmeasuresReviewalistofmanufacturingequipment检查生产设备清单

ReviewalistofSOPs检查SOP清单Reviewtheflowofpersonnelandmaterialsthroughfinishingareas检查成品区域人流图和物流图SMF工厂主文件Ifmanufacturingoperations,productsorservices,areoutsourcedestablishthenameandaddressofthesubcontractorsSMF工厂主文件外包服务机构的名称和地址Basicinformationrelatedtoprocesses与工艺有关的基本信息Review:-APIspecificationsandtestmethods;-Processflowcharts;Basicinformationrelatedtoprocesses与工艺有关的基本信息Review:-APIspecificationsandtestmethods;-Processflowcharts;-Detaileddescriptionoftheprocess;—Stabilitystudiesresults;Pharmacopoeia;CEP;ASMF(previouslyDMF),CTDpart3.2;BatchManufacturingRecordifappropriate药典、EP、ASMF（之前的的DMF）、CTD第3.2部分、批生产记录（适用时）生产记录（适用时）-Impurityprofile;—APIstartingmaterialsdefinitionetc.检查--原料药质量标准和检验方法—工艺流程—详细工艺描述--稳定性试验结果—杂质谱

—原料药起始物料定义等Ifappropriate,contactassessorsofthedossiers适用时，联系文档的评估人员Reviewvalidationstatus检查验证状态ValidationMasterPlan;listofactivitiesscheduled验证主计划，计划活动的清单Changes变更Reviewrecentmajorchanges(newproduct,equipment,buildingrenovationorextensionetc.)检查最近的主要变更(新产品、设备、建筑、改造或扩建等)Reviewscheduledmajorchanges检查计划的主要变更2.QualityManagementSystem质量管理体系Areaofoperations/items操作区域/项目Notes注意点Crucialquestions/Showme关键问题/给我看Supportingdocuments支持性文件InternalApprovedanddocumentedAreinternalauditsbeingaudits(Selfschedule,whichcoversperformedasscheduled?Can2.40inspections)allGMPactivitiestheybesubstitutedbythird

2.QualityManagementSystem质量管理体系Areaofoperations/items操作区域/项目Notes注意点Crucialquestions/Showme关键问题/给我看Supportingdocuments支持性文件内审available批准并记录的内审计划，应包括所有GMP活动partyaudits?Howisthefrequencyofinternalauditsdetermined?内审是否按计划进行？是否由第二方审计？内审的频次如何决定？Compositionoftheteamappropriate内审小组人员适当IsthecompositionoftheauditteamdeterminedaccordingtoanSOP?Hasconsiderationbeengivento:-Conflictofinterest-Codeofconduct-Qualifications-Independencefromtheareabeingaudited(e.g.WhoinspectstheQAfunction)审计小组是否根据SOP组成？是否考虑以下—利益冲突—实施要求―资质

2.QualityManagementSystem质量管理体系Areaofoperations/items操作区域/项目Notes注意点Crucialquestions/Showme关键问题/给我看Supportingdocuments支持性文件--独立于被审计区域（例如谁审计QA功能）QualificationofanyHowisthesuitabilityof2.40,3.30externalauditorsexternalauditorsassessed?外部审计员资质外审员的适用性如何评估？EffectivenessoftheHowdoesthecompanyensure2.41systemtoplanthethatcorrectiveactionsarecorrectiveandeffectiveandarecompletedpreventiveactionsinatimelymanner?HowdoVerificationofthetheychecktheeffectivenesscompletionofanactionofpreventiveactions?系统制订纠正和预防措施公司如何保证纠正措施有效，并的有效性及进完成？如何检查预防措施的有效性？计划完成后的确认TheflowofinformationHowistheresponsible2.41,2.18iseffectivemanagementinformedaboutthe信息流有效resultsoftheaudits?如何将审计结果通知有关管理层？ProductRegularPQRsperformedIsthedataevaluatedforthe2.50,2.51Qualityinatimelymanner(e.g.presenceoftrends,andareReview(PQR)withinthreemonthsfromtheseactedupon?Are

2.QualityManagementSystem质量管理体系Areaofoperations/items操作区域/项目Notes注意点Crucialquestions/Showme关键问题/给我看Supportingdocuments支持性文件年度产品回顾theendoftheperiodcomplaint.beingevaluated).Dataout-of-specification(OOS)fromin-processanddeviationcontrols,batchreleaseinvestigations,reported.analysisandotherkeyconsideredandevaluatedinqualityindicatorsethePQRs?ArethePQRresultsincludedusedtore-evaluatethe适当的方式定期进行年度expectedmonitoringrangesin产品回顾（例如，时间周期BatchManufacturingRecords?数据是否评估趋势，是否对趋势结束刖3个月进行评估）。应包括中控数据、产品放行采取行动？客诉、OOS和偏差调分析和其它关键质量指标。查在PQR中是否报告、考虑和评估？PQR结果是否用于对批生产记录中的监控范围进行再评估？AreviewofOOS,criticalArerequiredchanges2.5,6.61,IPCandAPItestresults,highlightedinthePQRs6.72,8.36,deviations,complaints.implementedthroughthe11.15returnsandrecalls,nonchangecontrolsystem?conformancesandrelatedPQR中强调的所要求的变更是否investigations.通过变更控制系统实施？includingtheeffectivenessofthecorrectiveandpreventiveactions

2.QualityManagementSystem质量管理体系Areaofoperations/items操作区域/项目Notes注意点Crucialquestions/Showme关键问题/给我看Supportingdocuments支持性文件conductedAreviewofchangesconductedStabilityprogramdataverified对00S、关键中控和原料药检查结果、偏差、客诉、退货和召回、不符合及相关的调查，包括纠正与预防措施的有效性评估的回顾。对已实施的变更的回顾稳定性数据的确认Baseduponthereview,thevalidationstatusofamanufacturingprocessisevaluatedandrecorded基于审核，生产工艺的验证状态应进行评估和记录2.5,12.60Complaints客诉AllqualityrelatedcomplaintsrecordedandinvestigatedaccordingHowarecomplaintsreported,includingorally,recordedandinvestigated?15.10

2.QualityManagementSystem质量管理体系Areaofoperations/items操作区域/项目Notes注意点Crucialquestions/Showme关键问题/给我看Supportingdocuments支持性文件toawrittenprocedure客诉如何记录，包括口头、书面所有质量相关客诉应根据记录和调查？书面程序进行记录和调查ComplaintrecordsIsthenatureofthecomplaint15.11includeallrelevantcorrectlyreported-i.e.isdetails(dateandsourceitpossibletoestablishifofthecomplaint,naturethereisarecurringproblem?ofthecomplaint.客诉的特性是否正确报告---即referencestobatch如果是一个反复发生的问题，是numberandproduction否可能识别date)客诉记录包括所有相关细节（客诉日期和来源、客诉属性、相关的批号和生产日期）ThecomplaintHastheimpactofthis15.11investigationreportcomplaintonotherbatchesidentifiescorrectivebeenconsidered?actionsandfollow是否考虑到该客诉对其它批次up/preventiveactions的影响？客诉调查报告制订纠正措施、跟踪/预防措施ThefinalreportDoesthecorrectiveaction15.11

2.QualityManagementSystem质量管理体系Areaofoperations/items操作区域/项目Notes注意点Crucialquestions/Showme关键问题/给我看Supportingdocuments支持性文件specifiesthekindofcorrectlyaddresstheresponseprovidedtotheproblem,oritisfocusedonoriginatorofthe"customersatisfaction”？complaintandthe(i.e.thecompanylookedfordecisiononthestatusoftherootcauseoftheproblem,theproductorsimply"reimbursed”the最终报告批出需要向投诉者给出的回复类型，产品状态的决定originatorofthecomplaint?）Wassourceofthecomplaintremovedinaneffectivemannerthroughpreventiveactions?纠正措施是否正确改正了问题，或者其是否关注“客户满意”？（即公司找到问题的根本原因，还是简单敷衍投诉人？）通过预防措施是否有效消除客诉原因？ComplaintrecordsandArecomplaintscorrectly13.12-13,reportsareevaluatedinevaluatedinPQRs?(i.e.is15.12thePQRsinordertothereanyevaluationofidentifytrends,productreoccurrenceandtrends?)Arerelatedfrequencies,andcorrective/preventiveseverity客诉记录和报告在年报中actionsmanagedthroughthechangecontrolsystem?

2.QualityManagementSystem质量管理体系Areaofoperations/items操作区域/项目Notes注意点Crucialquestions/Showme关键问题/给我看Supportingdocuments支持性文件进行评估，以便分析其趋势、产品相关频次和严重性客诉在年报中是否正确评估？（即是否对再次发生和趋势进行分析）纠正预防措施是否通过变更控制系统进行管理？Recalls召回The“recallsSOP”specifiesthethreshold(bywayofexamplecases,orothermeans)forwhicharecallshallbeconsideredThe"recallsSOP”specifieswhocaninitiatearecall,andhowtherecallprocessshallbemanaged.(i.e.whoistobeinformed,andhowrecalledgoodsaretobetreatedandstored)召回SOP应说明在什么情况下考虑召回(列举样例，或其它方式)。召回SOP应说明谁启动召回，如何管理召回流程(即要通知谁，如Istherecallprocessclearlydocumentedandeasytofollow?是否清楚写明召回过程，易于执行？15.13,15.14

2.QualityManagementSystem质量管理体系Areaofoperations/items操作区域/项目Notes注意点Crucialquestions/Showme关键问题/给我看Supportingdocuments支持性文件何召回产品，如何处理和存贮）TherecallprocedureIstherearequirementto15.15clearlydefineshowtoinformtheauthorities,andinformtheregulatoryrequestcooperation(intermsauthoritiesinthecaseofadvicesand/oractions),ofrecallrelatedtoaincaseswheretherecallisseriousproblemrelatedtoapotentially召回程序应清楚定义当召life-threateningsituation?回与一个严重问题相关时，如果召回与潜在生命威胁情况如何通知药监当局相关，是否要求通知药监当局，要求合作（例如建议和/或措施）3.Personnel人员Areaofoperations/items操作区域/项目Notes注意点Crucialquestions/Showme关键问题/给我看Supportingdocuments支持性文件Cf.Scope4.2参考范围4.24.Buildingandfacilities厂房和设施

3.Personnel人员Areaofoperations/items操作区域/项目Notes注意点Crucialquestions/Showme关键问题/给我看Supportingdocuments支持性文件Cf.Scope4.2参考范围4.2Areaofoperations/items操作区域/项目Notes注意点Crucialquestions/Showme关键问题/给我看Supportingdocuments支持性文件General一般Productprotectionincreasesfromearlythroughtofinalmanufacturingsteps对产品的保护应随着生产步骤的推后而增加HaveproceduresbeenimplementedtoprotecttheAPIfromcontaminationduringthefinalstagesofmanufacture?(e.g.sieving,millingandpackaging)是否实施程序以保证原料药在生产的最终阶段不受污染？(例如过筛、磨粉和包装)4.10Thelevelofproductprotectionisdependentupontheproducttypeandtheexpectedtimeofexposuretotheenvironment对产品保护的要求依据于产品类型，和暴露于环境的HaveproceduresbeenimplementedtoprotecttheAPIwhenexposedtoeachstageofthemanufacturingenvironment(sampling,loading,unloading,etc.)?是否实施程序以在各生产阶段暴露于环境中时对原料药4.103.Personnel人员3.Personnel人员3.Personnel人员3.Personnel人员Areaofoperations/items操作区域/项目Crucialquestions/ShowAreaofoperations/items操作区域/项目Crucialquestions/ShowSupportingNotes注意点medocuments关键问题/给我看支持性文件Cf.Scope4.2参考范围4.2时间APIswithmicrobiologicalspecificationsrequireadditionalcontrols有微生物质量标准的原料药需要额外控制进行？（取样、装卸料等）Whataretheadditionalcontrols?额外控制有哪些？4.10是否有进行控制以保证在周边区域/邻近区域的活动不是实际的污染源？SMF4.43Havecontrolsbeenimplementedtoensurethathighlytoxicnonpharmaceuticalmaterials(herbicides,pesticides,etc.)arenotmanufacturedinthesamebuilding/equipmentasSMF4.433.Personnel人员Areaofoperations/items操作区域/项目Notes注意点Crucialquestions/Showme关键问题/给我看Supportingdocuments支持性文件Cf.Scope4.2参考范围4.2APIsspecificareas/activities原料药指定区域/活动Tankfarms贮罐区Solventrecoveryplant溶剂回收车间WashingroomsusedforAPIs.是否有进行控制以保证高毒性非药用物质（除草剂、杀虫剂等）不与原料药使用相同的建筑/设备？Arethegeneralconditionoftanksandancillaryequipment（pumps,pipes,vents,etc.）appropriatefortheirintendeduse?Arealltanksandassociatedpipesappropriatelylabelledandsecure?贮罐和辅助设备（泵、管道、通风设施等）是否有一个通用条件要求，适用于其用途？是否所有贮罐和相连接的管道适当标签和保护？Seerecoverychapter参见回收章节Arewashingareas7.21,7.224.10,4.113.Personnel人员3.Personnel人员3.Personnel人员3.Personnel人员Areaofoperations/items操作区域/项目Notes注意点Crucialquestions/Showme关键问题/给我看Supportingdocuments支持性文件Cf.Scope4.2参考范围4.2清洁间appropriatelymanagedandControlrooms控制间controlled?(equipmentflow,storageofdirtyandcleanequipment,labelling)清洁区域是否适当管理和控制？（设备流程、脏的和清洁设备的存贮、标识）Havecomputerisedsystemsbeenvalidated?Havethebackupsystemsbeenverified?Areproceduresinplacefortheanalysisofdata?所用的计算机系统是否验证？备用系统是否确认？是有否数据分析程序?5.4Compressedair/nitrogen/otherutilities压缩空气/氮气/其它公用系PIC/SAide-MemoireonUtilities(PI009)PIC/S对公用系统的备忘Areaofoperations/items操作区域/项目Notes注意点Crucialquestions/Showme关键问题/给我看Supportingdocuments支持性文件Cf.Scope4.2参考范围4.2(PI009)Sewageandrefuse三废Iswasteeffectivelyremovedfromproductionareas(e.g.usingclosedsystemslikecontainersorplasticbagstopreventcontaminationofotherareas)?废话是否从生产区域有效移除（例如采用封闭系统如容器或塑料袋，以防止其对其它区域造成污染）？4.60Areallwastedisposalsystemscorrectlyidentified?是否对所有废物处理系统进行正确识别?4.60HVAC空调净化系统DoestheHVACsystemprovideanappropriateenvironmentforfinishingareaswhereAPIsareexposed?空调净化系统是否为原料药4.21,4.223.Personnel人员Areaofoperations/items操作区域/项目Notes注意点Crucialquestions/Showme关键问题/给我看Supportingdocuments支持性文件Cf.Scope4.2参考范围4.2暴露区域提供适当的环境？Water水Drinking(potable)wateracceptableifsuitableforintendeduse饮用水可用于适当的用途ArerecordsofCoAavailable?Hastestingatanappropriatefrequencybeenconducted?DoespotablewatermeetattheminimumWHOguidelines(e.g.freefromchemicalssuchascarcinogens,toxicsubstances,metals,organochlorinepesticides,lindane,DDT,organiccompounds,etc;radiologicalsandmicro-organisms)检验报告记录是否可提供？检验频次是否恰当？自来水是否符合WHO最低要求指南(例如无致癌、有毒化学物质，金属、有机氯杀虫剂、林丹、DDT、有机化合物等；辐射物和微生物)4.30,4.31,PIC/SAide-MemoireonUtilities(PI009)WHOGuidelinesfordrinking-waterquality参见PIC/S关于公用系统的备忘(PI009)WHO饮用水质量指南3.Personnel人员3.Personnel人员3.Personnel人员Areaofoperations/items3.Personnel人员Areaofoperations/items操作区域/项目Notes注意点Crucialquestions/Showme关键问题/给我看Supportingdocuments支持性文件Cf.Scope4.2参考范围4.24.33Non-sterileAPIintendedtobeusedinasteriledrug用于无菌产品的非无菌原料药Isthewaterusedinthefinalisolationandpurificationstepsmonitoredandcontrolledformicrobialcounts,objectionableorganismsandendotoxins?4.34Ifwatersourcedfromriver,wells,etc.andtreatedbythemanufacturer,hasthetreatmentprocessbeenvalidated?Havetheaffectsofseasonalvariationandhumanactivityonthewaterqualitybeenaddressed?Istheprocessmonitored?如果水源为河、井等，由生产商处理，处理流程是否经过验证？季节性变化和人类活动对水质量产生的影响是否有说明？对工艺是否进行监控？用于最后分离和精制步骤的水是否进行微生物限度和阳Areaofoperations/items操作区域/项目Crucialquestions/ShowSupportingNotes注意点medocuments关键问题/给我看支持性文件Cf.Scope4.2参考范围4.2性菌、细菌内毒素监控Design设计Definedareasorothercontrolsystemfordifferentactivities(storage,sampling,quarantine,production,etc.)对不同活动定义区域或其它控制系统(存贮、取样、待检、生产等)4.14,SMFFlowofmaterialsandpersonnel物流和人流Potentialcontaminationandcross-contaminationhasbeenpreventedbythelocationandplacementofequipment在布局和设备定位理防止潜在污染和交叉污染4.11Aretheflowofmaterialsandpersonnelappropriatefortheprocesses?Areappropriateindicationsdisplayedincriticalareas(gowning4.133.Personnel人员Areaofoperations/items操作区域/项目Notes注意点Crucialquestions/Showme关键问题/给我看Supportingdocuments支持性文件Cf.Scope4.2参考范围4.2Containment限制Designofthemultipurposeusecontainmentarea多功能使用的限制区域设计instructions,labellingforclean/uncleanareas,incoming/outcomingmaterials,etc.）物流和人流是否与工艺适合？关键区域是否恰当标示（更衣指令、洁净区/非洁净区标识、进入/出去物料等）Hasthecontainmentareabeenqualifiedformultipurposeuse?限制区域作为多功能区域是否经过确认？IfHVACisnotdedicated,whatcontrolsareinplacetopreventcross-contamination?如果空调净化系统不是专用,采用什么方式预防交叉污染？4.223.Personnel人员3.Personnel人员3.Personnel人员Areaofoperations/items操作区域/项目Notes注意点Crucialquestions/Showme关键问题/给我看Supportingdocuments支持性文件Cf.Scope4.2参考范围4.2PenicillinsandcephalosporinsOtherhighlysensitizing,toxic,potentmaterials青霉素和头抱类产品、其它高致敏性、毒性、高效价物料Aretheyproducedindedicatedareas?Aresensitizing,toxicandpotentmaterialseitherproducedindedicatedareasorarevalidatedinactivationand/orcleaningproceduresestablishedandmaintained.是否在专用区域内生产？致敏性、毒性、高效价物料在专用区域内生产，或灭活和/或清洁程序已建立并经过验证，并进行维护4.404.41Controlstopreventcross-contamination防止交叉污染控制Haveprocedurestopreventcross-contaminationbeenestablished?Istheperformaneeoftheseproceduresbeingmonitored?Arestaffsexhibitingappropriatebehaviourandpersonalgowningtechniquestopreventcross4.42Areaofoperations/Areaofoperations/items操作区域/项目Crucialquestions/ShowSupportingNotes注意点medocuments关键问题/给我看支持性文件Cf.Scope4.2参考范围4.2contamination?4.42是否建立防止交叉污染的程序？这些程序的效果是否有监控？员工行为和更衣要求是否能防止交叉污染？4.42Aremeasuresinplacetoensurethatcross-contaminationfromequipment,materialsandpersonnelmovingfromonededicatedareatoanotherareaisavoided?是否有措施来保证避免设备、物料和人员从一个专用区域到另一个专用区域移动时所带来的交叉污染？5.Processequipment工艺设备Areaofoperations/itemsNotes注意点Crucialquestions/Showme关键问题/给我看Supportingdocuments支持性文件

操作区域/项目操作区域/项目Thissectionistobedevelopedatthenextrevisionofthe5.Aide-Memoire5.本部分将在下一版本备忘中加入6.Documentationandrecords文件和记录Areaofoperations/items操作区域/项目Notes注意点Crucialquestions/Showme关键问题/给我看Supportingdocuments支持性文件Cf.Scope4.2参见范围4.27.Materialsmanagement物料管理Areaofoperations/items操作区域/项目Notes注意点Crucialquestions/Showme关键问题/给我看Supportingdocuments支持性文件Suppliers供应商Criticalmaterialsandtheirsuppliers关键物料及其供应商Havesuppliercontrolproceduresbeendefinedandimplemented?是否制订关实施供应商控制程序？7.11SupplierevaluationHavethefollowingbeenconsideredinsupplier7.31供应商评估供应商评估controlprocedures?供应商评估供应商评估controlprocedures?ApprovedsupplierslistApprovedsupplierslistDoesthelistincludethe7.12,7.137.20ApprovedsupplierslistApprovedsupplierslistDoesthelistincludethe7.12,7.137.20-areviewofthehistoryofsupplier-completionofaquestionnairebythesupplierincludinginformationaboutqualitysystem,qualitycertifications,thirdpartyaudits,sitemasterfileetc…-asupplierauditincludingQClabs(consideredforcriticalmaterials)-evaluationofsamples(fornewsuppliers)以下内容在制订供应商管理程序时是否考虑？—检查供应商历史—由供应商填写包括质量体系、质量证书、第三方审计、工厂主文件等信息的问卷—对供应商进行审计，包括对QC化验室(对关键物料应考虑)—对样品进行评估(新供应商)批准的供应商名单StartingAdditionalrecordsmaterialfromanimaloriginwithTSErisk具有TSE风险的动物来源起始物料附加记录nameandaddressofthemanufacturer(notonlytrader)?Isitanupdatedandcontrolleddocument?Isitavailableforpeopleinchargeofreceivinggoods?清单是否包括生产商(不仅仅是贸易商)的名称和地址？文件是否更新和受控？接收物料的人员是否可以获得？-Originofrawmaterials:country,supplychain,veterinaryinspection/certificates,ageofanimals-Typeoftissueused,collectionmethod,riskofcrosscontaminationduringthecollection-Manufacturingprocess:overviewoftheprocess,reductionoftheTSErisk(validation),riskofcrosscontamination,cleaningvalidation-Traceability:supplychain,availabilityoftheinformationbacktotheslaughterhouses/Nationalorinternationalguidancedocuments(e.g.EPgeneralmonograph5.2.8)animals—原料来源：国家、供应链、兽药检查/证书、动物年龄—所用组织类型，采集方法,采集过程中交叉污染的风险—生产工艺：工艺概览、降低TSE风险（验证）、交叉污染风险、清洁验证—可追踪性：供应链、可追踪至屠宰场所/动物Changecontrol变更控制Storage存贮Changecontrol变更控制Storage存贮7.14,13.7.20Changesareeffectivelymanagedthroughthechangecontrolsystem通过变更控制系统对变更进行有效控制Transportationandstorageforrawmaterials,andintermediatesrequiringspecialhandling有特殊要求的原料和中间体的运输和存贮IstheChangeControlsystemusedtomanagechangestomaterialsandsuppliers?变更控制系统是否也用于管理物料和供应商的变更？Whatsystemsareinplacetoensureappropriatetransportandstorageconditionshavebeenmaintained?采用什么体系保证对运输和存贮条件的适当维护？Validatedelectronicsystemsformaterialstatuscontrolareacceptable.Insuchcases,physicalsegregationmaynotbe5.40,Validatedelectronicsystemsformaterialstatuscontrolareacceptable.Insuchcases,physicalsegregationmaynotbe5.40,Wherestatuscontrolof10.11,materialisbyphysical7.20locationarethelocationswellmarked?Isaccesstotheselocationsrestrietedtodesignatedpersonnel?required经过验证的物料状态控制电子系统是可以接受的。在这种情况下，物理隔离可能不需要。Wherestatuscontrolofmaterialisbyelectronicmeans,isaccesstotheelectronicsystemrestrietedtodesignatedpersonnel?如果物料状态控制采用物理方式，是否所有区域均进行了标识？进入这些区域是否仅限于受权的人员？如果物料状态由电子方式进行控制，进入电子系统的许可是否仅限于受权的人员？BulkmaterialsNondedicatedtankers散装物料非专用槽车Doesthecleaningprocedure,andcertificateofcleaning,fornon-dedicatedtankerscoveraccessoryparts,includingtransferhoses?非专用槽车的清洁程序和清洁证书是否包括了所有必要的部件，包括输送用软管？7.227.22,8.517.22,8.51Note:Section7.22isapplicabletoreusablecontainers注：7.22适用于重复使用的容器Ifnondedicatedreusablecontainersareused,isthereevidencethattheyareproperlycleaned?如果容器重复使用，是否有证据证明进行了适当的清洁？Sampling取样Sampling取样Samplingplan取样计划Aresamplingplans7.33appropriateforeachtypeExtentandfrequencyof7.31Extentandfrequencyof7.31IfreducedtestingExtentandfrequencyof7.31Extentandfrequencyof7.31Ifreducedtestingofrawmaterialbeingselectedfortesting?Doeseachsamplingplanincludearationalefortheselectedmethod?取样计划是否适用于每种原料类型？每个取样计划是否包括了选择方法的合理性论述？Samplingenvironmentsappropriateforthematerialsbeingsampled取样环境是否与需要取的样品相适应？7.34Samplingenvironmentsappropriateforthematerialsbeingsampled取样环境是否与需要取的样品相适应？7.34取样环境是否考虑所取样品的特性？取样计划是否考虑物料类型、受微生物污染的可能性、所用生产步骤的特殊性、原料药所用于制剂剂型？Analysis分析Identitytesting鉴别测试Iseachbatchidentitytested?每个批次是否进行鉴别测试？7.30testing检测的项目和频次performed,howwasthesupplierapproved?Atwhatesting检测的项目和频次是否实施部分检测，供应商如何批准？多少频次进行全检？8.Productionandinprocesscontrols生产和中控Areaofoperations/items操作区域/项目Notes注意点Crucialquestions/Showme关键问题/给我看Supportingdocuments支持性文件Generalconsiderationsontheproductionoperationsandonfacilities生产操作和公用设施的一般考虑Alltheproductionoperationsverifiedforcompliancewiththeproductiondocumentsspecifiedin6.2,6.3,6.4,6.5oftheGMPGuide,andtheprocessdescribedintheASMFormodule3,part3.2.1ofCTDorasdescribedbyICHM4Q所有生产操作应与GMP指南中6.2,6.3，6.4，6.5要求的生产文件一致，与ASMF中描述的生产工艺一Areproductionoperationsactuallyperformedindedicatedormultipurposefacilities?生产实际操作是在专用还是共用厂房中进行？Arethecriticalparametersrecordedandcontrolled?关键参考是否记录和控制？Doformalproceduresdescribingtheproductionprocessexist?8.PIC/SAide-MemoireontheInspectionofBiotechnologymanufactures(1.4)PIC/S关于生物技术生产检查备忘(1.4)

致，或与ICHM4Q致，或与ICHM4Q或CTD模块3第3.2.1部分描述的工艺一致Doproductionoperationscorrespondwiththedefinedprocess?生产操作是否与定义的工艺一致？Isthefacilitymonitoredtoensureappropriateconditionsaremaintained?是否对设施进行监控以保证维护适当的条件？Hasthemethodofmonitoringbeenverified?监控方法是否经过确认？Isanappropriatelevelofprotectiongiventocentrifuges,filters,ovens,etc?对离心机、过滤器、烘箱等是否有给予适当的保护？Doesthemonitoringofthequalityofwaterdemonstratethatthespecificationhasbeenmet对水质量的监控是否能保证其符合质量标准Arethecriticalparameterstrended?关键参数是否有趋势?DotheparametersstatedintheregisteredfilerelatetotheoperationsdocumentedintheBatchRecord?Compliancetoregisteredfileandgeneralconsistency与注册文件一致及一般性符Compliancetoregisteredfileandgeneralconsistency与注册文件一致及一般性符1.1§1.1§Registeredfile注册文件-Specificationsforintermediatesandfinishedproduct以下参数是否在注册文件中说明--工艺参数--中控—中间体和成品质量标准DoesthefacilityDoesthefacility18.11havethecapabilitytomanufacturethebatchsizeoftheAPIsproduced?设施是否有能力生产出原料药的批量？Istheinspectedsite'saddressconsistentwiththeregisteredfile?被检查的场所地址是否与注册场所一致？Areallproductionareasdeclaredintheregisteredfile?注册文件中是否指明所有生产区域？ProductionOperations生产操作Rawmaterials:Dispensingareasurfaces,equipmentandenvironment原料：配料区表面、设备和环境8.10,AredispensingareasProductionOperations生产操作Rawmaterials:Dispensingareasurfaces,equipmentandenvironment原料：配料区表面、设备和环境8.10,Aredispensingareasandequipmentfitforpurpose?配料区和设备是否符合其用途？.52Arecontainerssuitableandappropriatelylabelled?Ismaterialstatuscontrolled?是否所有容器均适用并Arecontainerssuitableandappropriatelylabelled?Ismaterialstatuscontrolled?是否所有容器均适用并58.15适当标签？物料状态是否受控？AreallcriticalactivitieswitnessedCriticalweighingactivitiesindependentlyconfirmedandverified关键称重活动进行单独确认or适当标签？物料状态是否受控？AreallcriticalactivitieswitnessedCriticalweighingactivitiesindependentlyconfirmedandverified关键称重活动进行单独确认orsubjecttoequivalentcontrols?Doproductionpersonnelverifythatmaterialsarecorrectpriortouse?是否所有关键活动均有第二人复核或有等同的控制？生产人员是否在使用前复核物料正确？8.12,8.13YieldwithinexpectedrangeYieldwithinexpectedrange收率在期望的范围内8.14yieldrangesbeenset?Isthebatchyieldwithinrange?Forcriticalprocesssteps,aredeviationsinyieldinvestigated?是否设定了适当的收率范围？批收率是否在范围内？关键工艺步骤收率偏差是否进行了调查？DeviationsdocumentedandinvestigatedAredeviationsdocumentedandexplained?Hasan8.20,8.218.20,8.218.20,8.218.20,8.21偏差记录和调查Processstatusindicated工艺状态指示ReprocessingandReworkingappropriatelycontrolled返工和再加工应适当控制investigationbeenperformedforcriticaldeviationsand,ifnecessary,correctiveactionsimplemented?偏差是否记录和解释？关键偏差是否进行调查，必要时实施纠正措施？Foreachmajorunitofequipmentistheprocessingstatusidentified?对每个主要设备单元，工艺状态是否进行标识？Whatsystemsareinplacetotrackmaterialsforrework,orreprocessing,andtopreventunauthoriseduse?跟踪再加工、返工物料,防止未授权使用的系统是怎样的？8.168.17,14.2;14.3TimeLimits时间限制Timelimitsforprocessoperations,andforthestorageofintermediatesWheretimelimitshavebeenset,arethesebeingmet?Aredeviations工艺操作、中间体存documentedand贮的时间限制evaluated?如果有设定时间限制,是否符合该时间限度?偏差是否记录和评估?In-processSamplingandWrittenProceduresDowrittenprocedures8.30Controlsavailablefortheexisttomonitorand中控取样和控制monitoringandcontrolthecontrolofproductionprocess?productionprocessAretheprocedures生产工艺监控应有书basedupon面程序development/historicalinformation?面程序是否有生产工艺监控的书面程序？程序是否基于研发/历史信息?AcceptanceCriteriaDothein-process8.31appropriatetocontrolsandprocessstep/stageacceptancecriteria工艺步骤相适应的可becomemorestringent接受标准forthelaterprocessingsteps?中控和可接受标准在接近成品的工艺步骤是否更严格?Criticalin-processcontrolsaredocumentedandapprovedbytheHastheQualityUnitgivenapprovalforin-processcontrols?质量部门对中控进行批8.32QualityUnit准吗？关键中控是否记录并由质量部门批准8.338.33In-processcontrolsperformedanddocumentedbyqualifiedstaff中控是否由有资质的员工实施并记录Arequalifiedstaffsperformingin-processcontrols?Areadjustmentsmadetoprocessesinaccordancewithpre-establishedandvalidatedlimits?AreIPCresultsdocumentedinthebatchrecord?中控是否由有资质的员工实施？对工艺的调整是否与预设定的和验证过的限度一致？中控结果是否在批记录中记录？8.348.34SamplingProceduresdocumentedandscientificallysound取样程序应记录并科学合理Aretherewrittensamplingprocedureswhicharescientificallysound?书面的取样程序是否科学合理？AresamplingproceduresdesignedAresamplingproceduresdesignedtoprevent8.35Inprocesssampling:Preventionof8.408.40BlendingBatchesofIntermediatesorAPIs中间体或原料药混批contaminationandassuranceoftheintegrityofthesample中控取样：防止污染、保证样品完整性Blendingofbatchesdefinedandcontrolled对混批进行定义并使受控contaminationandensuretheintegrityofthesample?取样程序的设备是否可以防止污染并保证样品完整性？Doesthecompanyblendbatchesandisthisprocessdefinedandcontrolled?公司是否有混批行为？混合工艺是否定义并受控？8.408.40Onlybatchesmeetingapprovedspecificationsmaybeblended只有符合批准的质量标准的批次可以被混Haveallinputbatchesbeenmanufacturedbythesameprocess,beenindividuallytestedandmeetspecification?所有用于混合的批准是否由相同的工艺生产、经过独立检测并符合质量标准？8.43Istheblendedbatchtestedforconformancewithspecification?8.43混合批次是否经检测符合质量标准?Traceabilityofmaterialusedinablendedbatch用于混合批次的物料的追踪性Validationofthehomogeneityoftheblendedbatch混合批次的均一性验证Isitpossibletoidentifyalltheinputbatchesthatmakeuptheblendedbatch?是否可能识别出所有用于混合的投料批次？IstheblendingoperationvalidatedtoshowhomogeneityofthecombinedbatchwherephysicalattributesofAPI'sarecriticalinthedosageform?如果原料药的物理属性在制剂生产中很关键，混合操作均一性是否经过验证？8.448.458.468.46Impactofblendingprocessonproductstability混合工艺对产品稳定性的影响Doestheblendingoperationadverselyaffectproductstability?Ifsohavefurtherstabilitytestsbeenperformed.混合操作对产品稳定性是否有不良影响？如果有，则需要进行稳定性试验。Expiry/RetestdateExpiry/Retestdatedetermination有效期/复验期决定8.47混合批次的有效期/复验期是否根据用于混合投料批次的最早的批次的有效期/复验期制订？Contamination污染控制ControlPreventionofcontaminationofbatchesbycarryoverfromapreviousbatch防止前