药用产品良好生产规范手册.docx

'PHARMACEUTICALINSPECTIONCONVENTIONPHARMACEUTICALINSPECTIONCO-OPERATIONSCHEME药品检验公约药品检验合作打算GUIDETOGOODMANUFACTURINGPRACTICEFORMEDICINALPRODUCTSPARTI药用产品良好生产规范指南第一部分目录第一章质量治理2第二章人员11第三章厂房设施17第四章文件25第五章生产41第六章质量操纵53第七章托付生产与托付检验62第八章产品投诉和召回66第九章自检69154/154 154/154 CHAPTER1第一章质量治理QUALITYMANAGEMENTPRINCIPLE原则Theholderofamanufacturingauthorisationmustmanufacturemedicinalproductssoastoensurethattheyarefitfortheirintendeduse,complywiththerequirementsoftheMarketingAuthorisationanddonotplacepatientsatriskduetoinadequatesafety,qualityorefficacy.Theattainmentofthisqualityobjectiveistheresponsibilityofseniormanagementandrequirestheparticipationandcommitmentbystaffinmanydifferentdepartmentsandatalllevelswithinthecompany,bythecompany’ssuppliersandbythedistributors.ToachievethequalityobjectivereliablytheremustbeacomprehensivelydesignedandcorrectlyimplementedsystemofQualityAssuranceIncorporatingGoodManufacturingPractice,andthusQualityControlandQualityRiskManagement.Itshouldbefully154/154 documentedanditseffectivenessmonitored.AllpartsoftheQualityAssurancesystemsshouldbeadequatelyresourcedwithcompetentpersonnel,andsuitableandsufficientpremises,equipmentandfacilities.Thereareadditionallegalresponsibilitiesfortheholderofthemanufacturingauthorisationandfortheauthorisedperson(s).生产许可证持有人必须生产药品，从而确保药品适合预期用途、符合相应的上市许可证或临床试验许可证要求，不因为安全性问题、质量问题或有效性问题而把患者置于风险之中。实现上述质量目标是公司高级治理人员的职责，并要求公司的供应商、销售商，公司内所有各级职员与许多不同部门的职员共同参与、一起努力。要可靠地实现这一质量目标，必须综合设计一个整合药品生产质量治理规范（GMP）和质量操纵、质量风险治理的制药质量保证体系并正确实施。质量体系应当全面文件化，并监察其有效性。整个制药质量体系应当配备充足的具有资质的人员，以及充分并适用的建筑物、设备和设施。生产许可证持有人以及质量受权人有额外的法律责任。ThebasicconceptsofQualityAssurance,Good154/154 ManufacturingPractice,QualityControlandQualityRiskManagementareinter-related.Theyaredescribedhereinordertoemphasisetheirrelationshipsandtheirfundamentalimportancetotheproductionandcontrolofmedicinalproducts.质量保证、药品生产质量治理规范、质量操纵以及质量风险治理的差不多概念是相互关联的。在那个地点对其进行描述是为了强调它们之间的联系以及其对药品生产和操纵的重要性。QUALITYASSURANCE质量保证1.1QualityAssuranceisawide-rangingconcept,whichcoversallmatters,whichindividuallyorcollectivelyinfluencethequalityofaproduct.Itisthesumtotaloftheorganisedarrangementsmadewiththeobjectiveofensuringthatmedicinalproductsareofthequalityrequiredfortheirintendeduse.QualityAssurancethereforeincorporatesGoodManufacturingPracticeplusotherfactorsoutsidethescopeofthisGuide.质量保证154/154 是一个宽泛的概念，涵盖所有因素，这些因素单独或共同阻碍产品质量。质量保证是为了保证药品质量符合预期用途，而进行的有组织的安排的总和。因此，质量保证中包含着药品生产质量治理规范以及本指南的范围内的其他因素。ThesystemofQualityAssuranceappropriateforthemanufactureofmedicinalproductsshouldensurethat:一个适当的质量保证体系应当确保：i.medicinalproductsaredesignedanddevelopedinawaythattakesaccountoftherequirementsofGoodManufacturingPractice;药品的设计和开发应考虑药品生产质量治理规范的要求；ii.productionandcontroloperationsareclearlyspecifiedandGoodManufacturingPracticeadopted;对生产和操纵操作进行明确规定，并符合药品生产质量治理规范的要求；iii.managerialresponsibilitiesareclearlyspecified;明确规定治理职责；iv.arrangementsaremadeforthemanufacture,supplyanduseofthecorrectstartingandpackagingmaterials;154/154 对下述活动均有协议约束：生产、供应、使用正确的起始物料与包装材料。v.allnecessarycontrolsonintermediateproducts,andanyotherinprocesscontrolsandvalidationsarecarriedout;对中间产品以及其他任何中间过程操纵与验证实施所有必要的操纵；vi.thefinishedproductiscorrectlyprocessedandchecked,accordingtothedefinedprocedures;成品依照确定的程序进行正确生产和检测；vii.medicinalproductsarenotsoldorsuppliedbeforeanauthorisedpersonhascertifiedthateachproductionbatchhasbeenproducedandcontrolledinaccordancewiththerequirementsofthemarketingauthorisationandanyotherregulationsrelevanttotheproduction,controlandreleaseofmedicinalproducts;质量受权人需签发证明以确认每一批次药品的生产和操纵均符合上市许可要求以及与药品生产、操纵和放行相关的任何其他法规要求，未经质量受权人签发证明的药品不得销售或供货；154/154 viii.satisfactoryarrangementsexisttoensure,asfaraspossible,thatthemedicinalproductsarestored,distributedandsubsequentlyhandledsothatqualityismaintainedthroughouttheirshelflife;药品贮存、发运和后续处理确保有中意的治理规程，从而尽量保证药品货架期内的质量ix.thereisaprocedureforself-inspectionand/orqualityaudit,whichregularlyappraisestheeffectivenessandapplicabilityofthequalityassurancesystem.有自检和/或质量审计规程，以定期评价质量保证体系的有效性与适用性。GOODMANUFACTURINGPRACTICEFORMEDICINALPRODUCTS(GMP)药品生产质量治理规范1.2GoodManufacturingPracticeisthatpartofQualityAssurancewhichensuresthatMedicinalproductsareconsistentlyproducedandcontrolledtothequalitystandardsappropriatetotheirintendeduseandas154/154 requiredbythemarketingauthorisationorproductspecification.GoodManufacturingPracticeisconcernedwithbothproductionandqualitycontrol.ThebasicrequirementsofGMParethat:药品生产质量治理规范是质量治理体系的一部分，保证按适合预期用途的质量标准及上市许可、临床试验许可或产品质量标准要求始终如一地生产及操纵产品。药品生产质量治理规范涉及生产和质量操纵。药品生产质量治理规范的差不多要求是：i.allmanufacturingprocessesareclearlydefined,systematicallyreviewedinthelightofexperienceandshowntobecapableofconsistentlymanufacturingmedicinalproductsoftherequiredqualityandcomplyingwiththeirspecifications;所有生产工艺得到明确规定、按照经验通过系统的审核，并通过证明表明有能力始终如一地生产具有所需质量且符合质量标准的药品ii.criticalstepsofmanufacturingprocessesandsignificantchangestotheprocessarevalidated;生产工艺的关键步骤以及重大的工艺变更差不多验证；154/154 iii.allnecessaryfacilitiesforGMPareprovidedincluding:提供了GMP需要的所有设施，包括：a.appropriatelyqualifiedandtrainedpersonnel;有适当资质并通过培训的职员；b.adequatepremisesandspace;充足的厂房与空间；c.suitableequipmentandservices;适当的设备及保养；d.correctmaterials,containersandlabels;恰当的材料、容器和标签；e.approvedproceduresandinstructions;经批准的规程与操作方法；f.suitablestorageandtransport;合适的贮存与运输；iv.instructionsandproceduresarewritteninaninstructionalforminclearandunambiguouslanguage,specificallyapplicabletothefacilitiesprovided;操作方法与规程应当使用有指导意义的方式来书写，同时条理清晰、用语明确，特不是要适用于相应的设施；154/154 v.operatorsaretrainedtocarryoutprocedurescorrectly;操作人员同意过正确执行规程的培训；vi.recordsaremade,manuallyand/orbyrecordinginstruments,duringmanufacturewhichdemonstratethatallthestepsrequiredbythedefinedproceduresandinstructionswereinfacttakenandthatthequantityandqualityoftheproductwasasexpected.Anysignificantdeviationsarefullyrecordedandinvestigated;在生产过程中进行了记录，可由手工和/或仪器记录，以证明规程和操作要求的所有步骤切实得到了执行，以及产品的质量和数量达到预期要求；所有重大偏差得到了完整记录、通过了调查vii.recordsofmanufactureincludingdistributionwhichenablethecompletehistoryofabatchtobetraced,areretainedinacomprehensibleandaccessibleform;生产记录包括销售记录以易明白且可获得的方式得到了保留，使整个批次的完整历史可追溯；154/154 viii.thedistribution(wholesaling)oftheproductsminimisesanyrisktotheirquality;降低产品销售过程中的质量风险；ix.asystemisavailabletorecallanybatchofproduct,fromsaleorsupply;有药品召回系统，确保任何一批产品都能从销售商或供应处收回；x.complaintsaboutmarketedproductsareexamined,thecausesofqualitydefectsinvestigatedandappropriatemeasurestakeninrespectofthedefectiveproductsandtopreventre-occurrence.对产品投诉进行检查，调查质量缺陷缘故，对缺陷产品采取适当措施并防止再次发生。QUALITYCONTROL质量操纵1.3QualityControlisthatpartofGoodManufacturingPracticewhichisconcernedwithsampling,specificationsandtesting,andwiththeorganisation,documentationandreleaseprocedureswhichensurethatthenecessaryandrelevanttestsareactuallycarriedoutandthatmaterialsarenotreleasedforuse,nor154/154 productsreleasedforsaleorsupply,untiltheirqualityhasbeenjudgedtobesatisfactory.ThebasicrequirementsofQualityControlarethat:质量控制是GMP的一部分，涉及取样、质量标准、检验，同样也涉及组织机构、文件和放行规程，以保证切实执行了必要的相关检验，同时确保物料或产品被判定符合要求之前不被放行使用或销售。质量操纵的差不多要求是：i.adequatefacilities,trainedpersonnelandapprovedproceduresareavailableforsampling,inspectingandtestingstartingmaterials,packagingmaterials,intermediate,bulk,andfinishedproducts,andwhereappropriateformonitoringenvironmentalconditionsforGMPpurposes;有充足的设施设备、通过培训的人员及通过批准的规程用于起始物料、包装材料、中间体、半成品与成品取样和检验，以及GMP要求的环境监测ii.samplesofstartingmaterials,packagingmaterials,intermediateproducts,bulkproductsandfinishedproductsaretakenbypersonnelandbymethodsapproved154/154 byQualityControl;由通过批准的人员按通过批准的方法对起始物料、包装材料、中间产品、半成品、成品取样；iii.testmethodsarevalidated;检验方法通过验证；iv.recordsaremade,manuallyand/orbyrecordinginstruments,whichdemonstratethatalltherequiredsampling,inspectingandtestingprocedureswereactuallycarriedout.Anydeviationsarefullyrecordedandinvestigated;由手工和/或仪器做了记录，以证明所有要求的取样、检查和检验规程切实得到了执行。任何偏差得到了完整记录和调查；v.thefinishedproductscontainactiveingredientscomplyingwiththequalitativeandquantitativecompositionofthemarketingauthorisation,areofthepurityrequired,andareenclosedwithintheirpropercontainersandcorrectlylabelled;成品中的活性成分符合上市许可或临床试验许可的定性和定量要求，及符合纯度要求，并贮存在适当的容器中、贴上正确的标签；154/154 vi.recordsaremadeoftheresultsofinspectionandthattestingofmaterials,intermediate,bulk,andfinishedproductsisformallyassessedagainstspecification.Productassessmentincludesareviewandevaluationofrelevantproductiondocumentationandanassessmentofdeviationsfromspecifiedprocedures;物料、中间体、半成品及成品的检查与检验结果有记录，成品按质量标准做了正式评估。产品评估包括回忆与评估相关生产文件，以及评估对特定规程的偏差；vii.nobatchofproductisreleasedforsaleorsupplypriortocertificationbyanauthorisedpersonthatitisinaccordancewiththerequirementsoftherelevantauthorisations;在质量受权人确认产品批次符合相应许可要求之前，任何批次不被放行销售或供货；viii.sufficientreferencesamplesofstartingmaterialsandproductsareretainedtopermitfutureexaminationoftheproductifnecessaryandthattheproductisretainedinitsfinalpackunless154/154 exceptionallylargepacksareproduced.留有足够的起始物料和成品对比样品，以备今后有需要的时候对产品进行检验，样品包装方式与对应的产品最终包装方式相同。PRODUCTQUALITYREVIEW产品质量回忆1.4Regularperiodicorrollingqualityreviewsofalllicensedmedicinalproducts,includingexportonlyproducts,shouldbeconductedwiththeobjectiveofverifyingtheconsistencyoftheexistingprocess,theappropriatenessofcurrentspecificationsforbothstartingmaterialsandfinishedproducttohighlightanytrendsandtoidentifyproductandprocessimprovements.Suchreviewsshouldnormallybeconductedanddocumentedannually,takingintoaccountpreviousreviews,andshouldincludeatleast:应当对所有获得批准的药品，包括仅供出口的药品，进行定期的或滚动式的质量回忆，质量回忆的目的是确认现有工艺的一致性、起始物料和成品现行质量标准的适宜性，强调任何趋势并识不产品和工艺改进点。通常应当每年回忆并文件化，回忆中还应当考虑往常的回忆情况，并至少应当包括：154/154 i.Areviewofstartingmaterialsincludingpackagingmaterialsusedintheproduct,especiallythosefromnewsources.回忆产品所用起始物料、包装材料，特不是来自新供应商的起始物料和包装材料，ii.Areviewofcriticalin-processcontrolsandfinishedproductresults.回忆关键中间过程操纵与成品结果。iii.Areviewofallbatchesthatfailedtomeetestablishedspecification(s)andtheirinvestigation.回忆未能符合既定质量标准的所有批次及其调查结果。iv.Areviewofallsignificantdeviationsornon-conformances,theirrelatedinvestigations,andtheeffectivenessofresultantcorrectiveandpreventativeactionstaken.回忆所有重大偏差或不符合事件与相关调查，以及后续纠正与预防措施的有效性。v.Areviewofallchangescarriedouttotheprocessesoranalyticalmethods.154/154 回忆工艺或分析方法的所有变更。vi.AreviewofMarketingAuthorisationvariationssubmitted/granted/refused,includingthoseforthirdcountry(exportonly)dossiers.回忆已递交的、已批准的或被拒绝的上市许可变更，包括已递交的、已批准的或被拒绝的第三国（仅供出口）上市许可变更资料。vii.Areviewoftheresultsofthestabilitymonitoringprogrammeandanyadversetrends.回忆稳定性监测程序的结果以及任何不良的趋势。viii.Areviewofallquality-relatedreturns,complaintsandrecallsandtheinvestigationsperformedatthetime.回忆与质量相关的所有退货、投诉与召回，以及当时实施的调查。ix.Areviewofadequacyofanyotherpreviousproductprocessorequipmentcorrectiveactions.回忆任何其他先前产品工艺或设备纠正措施的适宜性。x.Fornewmarketingauthorisationsandvariationstomarketingauthorisations,areviewofpost-marketing154/154 commitments.关于新的上市许可和上市许可变更，回忆上市后承诺。xi.Thequalificationstatusofrelevantequipmentandutilities,e.g.HVAC,water,compressedgases,etc.回忆相关设备与公用系统的确认状态，例如空气净化系统、制水系统、压缩空气系统等。xii.AreviewofanycontractualarrangementsasdefinedinChapter7toensurethattheyareuptodate.回忆第7章规定的所有合同、协议，以确保未过时。Themanufacturerandmarketingauthorisationholdershouldevaluatetheresultsofthisreviewandanassessmentmadeofwhethercorrectiveandpreventativeactionoranyrevalidationshouldbeundertaken.Reasonsforsuchcorrectiveactionsshouldbedocumented.Agreedcorrectiveandpreventativeactionsshouldbecompletedinatimelyandeffectivemanner.Thereshouldbemanagementproceduresfortheongoingmanagementandreviewoftheseactionsandthe154/154 effectivenessoftheseproceduresverifiedduringselfinspection.Qualityreviewsmaybegroupedbyproducttype,e.g.soliddosageforms,liquiddosageforms,sterileproducts,etc.wherescientificallyjustified.生产企业，或是上市许可证持有人，假如生产企业不是上市许可证持有人的话，应当在制药质量体系下评估产品质量回忆的结果，并评估是否应当釆取纠正与预防措施或是任何再验证。关于现有治理活动及这些治理活动的回忆，应当有治理规程，并通过自检确认这些规程的有效性。通过科学论证后，能够按产品类不进行质量回忆，例如固体剂型、液体剂型、无菌产品等。Wherethemarketingauthorisationholderisnotthemanufacturer,thereshouldbeatechnicalagreementinplacebetweenthevariouspartiesthatdefinestheirrespectiveresponsibilitiesinproducingthequalityreview.Theauthorizedpersonresponsibleforfinalbatchcertificationtogetherwiththemarketingauthorisationholdershouldensurethatthequalityreviewisperformedinatimelymannerandisaccurate.154/154 假如上市许可证持有人不是生产企业，各方之间应当签订技术协议，规定各自在产品貭量回忆中的责任。授权人和销售许可持有人负责最后一批认证，应确保及时准确的的进行质量回忆。QUALITYRISKMANAGEMENT质量风险治理1.5Qualityriskmanagementisasystematicprocessfortheassessment,control,communicationandreviewofriskstothequalityofthemedicinalproduct.Itcanbeappliedbothproactivelyandretrospectively.质量风险治理是一个用于药品质量风险评估、控制、交流与评审的系统过程。能够采纳前瞻性或回忆性形式。1.6Thequalityriskmanagementsystemshouldensurethat:质量风险治理的原则是：-theevaluationoftherisktoqualityisbasedonscientificknowledge,experiencewiththeprocessandultimatelylinkstotheprotectionofthepatient;质量风险评估是以科学知识和对工艺的经验为基础，并最终与爱护患者相关联。-thelevelofeffort,formalityanddocumentationofthequalityriskmanagementprocessiscommensurate154/154 withthelevelofrisk.质量风险治理过程的投入、正式程度与文件应当与风险水平相适应。ExamplesoftheprocessesandapplicationsofqualityriskmanagementcanbefoundinteraliainAnnex20.在附录20中所述的质量风险治理的过程与应用实例。154/154 CHAPTER2第二章人员PERSONNELPRINCIPLE原则Theestablishmentandmaintenanceofasatisfactorysystemofqualityassuranceandthecorrectmanufactureofmedicinalproductsreliesuponpeople.Forthisreasontheremustbesufficientqualifiedpersonneltocarryoutallthetaskswhicharetheresponsibilityofthemanufacturer.Individualresponsibilitiesshouldbeclearlyunderstoodbytheindividualsandrecorded.AllpersonnelshouldbeawareoftheprinciplesofGoodManufacturingPracticethataffectthemandreceiveinitialandcontinuingtraining,includinghygieneinstructions,relevanttotheirneeds.符合要求的质量保证体系的建立和维护以及154/154 药品的正确生产依靠于人。因此，必须有足够的有资质的人员来完成与生产企业职责相应的所有工作。每个人应当清晰地理解自己的职责并记录。所有人员都应当知晓与自己相关的药品生产质量治理规范差不多原则，同时同意培训与接着培训，这些培训包括与人员卫生相关的教育工作。GENERAL总则2.1.Themanufacturershouldhaveanadequatenumberofpersonnelwiththenecessaryqualificationsandpracticalexperience.Theresponsibilitiesplacedonanyoneindividualshouldnotbesoextensiveastopresentanyrisktoquality.生产企业应当配备足够数量并具有适当资质及实际经验的人员。为防止出现任何质量风险，每个人所承担的职责不应当过多。2.2.Themanufacturermusthaveanorganisationchart.Peopleinresponsiblepositionsshouldhavespecificdutiesrecordedinwrittenjobdescriptionsandadequateauthoritytocarryouttheirresponsibilities.Theirdutiesmaybedelegatedtodesignateddeputiesofasatisfactoryqualificationlevel.ThereshouldbenogapsorunexplainedoverlapsintheresponsibilitiesofthosepersonnelconcernedwiththeapplicationofGoodManufacturingPractice.154/154 生产企业必须具有组织机构图，针对各岗位职员应制定岗位职责讲明书，对岗位职责进行书面描述并给职员充分的授权来履行职责。这些职责能够委派给其他人，但受托人必须具有相应的资质。在药品生产质量治理规范实施过程中，职员职责之间应无缝衔接，同时没有无故的重叠。KEYPERSONNEL关键人员2.3.KeyPersonnelincludestheheadofProduction,theheadofQualityControl,andifatleastoneofthesepersonsisnotresponsibleforthereleaseofproductstheauthorisedperson(s)designatedforthepurpose.Normallykeypostsshouldbeoccupiedbyfull-timepersonnel.TheheadsofProductionandQualityControlmustbeindependentfromeachother.Inlargeorganisations,itmaybenecessarytodelegatesomeofthefunctionslistedin2.5.,2.6.and2.7.关键治理人员包括生产负责人和质量负责人，假如这些人中未有至少一人承担职责，则应当指定154/154 适当数量的质量受权人（至少一名）来履行该职责。通常，关键岗位人员应当为全职人员。生产负责人和质量负责人必须相互独立。构庞大的组织中，可能需要对第2.52.62.7条中所列的职责进行授权。2.4....2.5.TheheadoftheProductionDepartmentgenerallyhasthefollowingresponsibilities:生产负责人通常有以下职责：i.toensurethatproductsareproducedandstoredaccordingtotheappropriatedocumentationinordertoobtaintherequiredquality;确保产品按照造当的文件规定生产和贮存，从而达到质量要求；ii.toapprovetheinstructionsrelatingtoproductionoperationsandtoensuretheirstrictimplementation;批准与生产操作相关的规程，并确保规程得到严格执行；iii.toensurethattheproductionrecordsareevaluatedandsignedbyanauthorisedpersonbeforetheyaresenttotheQualityControlDepartment;在送到质量操纵部门前，确保生产记录通过授权人员评估和签字；iv.tocheckthemaintenanceofhisdepartment,premisesandequipment;检查本部门厂房、设施和设备进行了维护；154/154 v.toensurethattheappropriatevalidationsaredone;确保实施了适当的验证vi.toensurethattherequiredinitialandcontinuingtrainingofhisdepartmentpersonneliscarriedoutandadaptedaccordingtoneed.确保对本部门人员进行了必要的入职培训与持续培训，培训应符合实际需要。2.6.TheheadoftheQualityControlDepartmentgenerallyhasthefollowingresponsibilities:质量负责人通常有以下职责：i.toapproveorreject,asheseesfit,startingmaterials,packagingmaterials,andintermediate,bulkandfinishedproducts;决定批准或拒绝起始物料、包装材料、中间体、半成品与成品；ii.toevaluatebatchrecords;评估批记录iii.toensurethatallnecessarytestingiscarriedout;确保进行了所有必要的检验，154/154 iv.toapprovespecifications,samplinginstructions,testmethodsandotherQualityControlprocedures;批准质量标准、取样方法、检验方法以及其他质量操纵规程；v.toapproveandmonitoranycontractanalysts;批准和监督所有的受托检验方；vi.tocheckthemaintenanceofhisdepartment,premisesandequipment;检查本部门厂房、设施和设备进行维护；vii.toensurethattheappropriatevalidationsaredone;确保实施了适当的验证；viii.toensurethattherequiredinitialandcontinuingtrainingofhisdepartmentpersonneliscarriedoutandadaptedaccordingtoneed.确保对本部门人员进行了必要的入职培训与持续培训，培训应符合实际需要。OtherdutiesoftheQualityControlDepartmentaresummarisedinChapter6.质量操纵其他职责在第6章中汇总描述。154/154 2.7.TheheadsofProductionandQualityControlgenerallyhavesomeshared,orjointlyexercised,responsibilitiesrelatingtoquality.Thesemayinclude,subjecttoanynationalregulations:生产负责人和质量负责人通常共同承担或共同履行质量相关的职责，基于各国的规定不同，这些职责可能包括：Øtheauthorisationofwrittenproceduresandotherdocuments,includingamendments;批准书面程序和其他文件，其中包括修订文件；ØØthemonitoringandcontrolofthemanufacturingenvironment;生产环境监测与控制；ØØplanthygiene;车间卫生；ØØprocessvalidation;工艺验证ØØtraining;培训ØØtheapprovalandmonitoringofsuppliersofmaterials;批准和监管物料供应商；ØØtheapprovalandmonitoringofcontractmanufacturers;批准和监管受托生产企业ØØthedesignationandmonitoringofstorage154/154 conditionsformaterialsandproducts;对物料与产品的贮存条件进行确定和监管；Øtheretentionofrecords;保存记录ØthemonitoringofcompliancewiththerequirementsofGMP;监管药品生产质量治理规范要求的符合性；Øtheinspection,investigation,andtakingofsamples,inordertomonitorfactorswhichmayaffectproductquality.检查、调查和取样，从而对药品质量阻碍因素进行监控；TRAINING培训2.8.Themanufacturershouldprovidetrainingforallthepersonnelwhosedutiestakethemintoproductionareasorintocontrollaboratories(includingthetechnical,maintenanceandcleaningpersonnel),andforotherpersonnelwhoseactivitiescouldaffectthequalityoftheproduct.生产企业应对所有因工作需要进入生产区、贮存区或质量控制实验室的人员（包括技术、维护和清洁人员），以及其活动可能阻碍产品质量的其他人员进行培训。154/154 2.9.BesidethebasictrainingonthetheoryandpracticeofGoodManufacturingPractice,newlyrecruitedpersonnelshouldreceivetrainingappropriatetothedutiesassignedtothem.Continuingtrainingshouldalsobegiven,anditspracticaleffectivenessshouldbeperiodicallyassessed.Trainingprogrammesshouldbeavailable,approvedbyeithertheheadofProductionortheheadofQualityControl,asappropriate.Trainingrecordsshouldbekept.新职员除了同意药品生产质量治理规范的理论与实践基础培训，还应当同意与其工作相关的培训。也应当同意接着培训，同时应当定期评估培训的实际效果。应当有培训打算，培训打算应当通过生产负责人或质量负责人适当批准。应当保存培训记录。2.10.Personnelworkinginareaswherecontaminationisahazard,e.g.cleanareasorareaswherehighlyactive,toxic,infectiousorsensitisingmaterialsarehandled,shouldbegivenspecifictraining.154/154 某些区域的污染物假如是危害品，例如处理高活性、高毒性、高传染性或高致敏性物料的洁净区或处理区等，在该区域工作的人员应该通过专门的培训。2.11.Visitorsoruntrainedpersonnelshould,preferably,notbetakenintotheproductionandQualityControlareas.Ifthisisunavoidable,theyshouldbegiveninformationinadvance,particularlyaboutpersonalhygieneandtheprescribedprotectiveclothing.Theyshouldbecloselysupervised.应当最好不把参观者或未经培训的人员带到生产区或质量操纵区。假如一定要带入，应当事先告知他们相关信息，特不是注意个人卫生和穿戴工作服。应当对他们进行紧密监督。2.12.TheconceptofQualityAssuranceandallthemeasurescapableofimprovingitsunderstandingandimplementationshouldbefullydiscussedduringthetrainingsessions.在培训中，应对质量保证理念以及能够改善理解与实施的所有措施进行充分讨论。PERSONNELHYGIENE个人卫生2.13.Detailedhygieneprogrammesshouldbeestablishedandadaptedtothedifferentneedswithinthefactory.154/154 Theyshouldincludeproceduresrelatingtothehealth,hygienepracticesandclothingofpersonnel.Theseproceduresshouldbeunderstoodandfollowedinaverystrictwaybyeverypersonwhosedutiestakehimintotheproductionandcontrolareas.Hygieneprogrammesshouldbepromotedbymanagementandwidelydiscussedduringtrainingsessions.应制定详细的卫生规程并适应工厂内各种需要。应当包括与人员健康、卫生适应和着装相关的规程。在生产区和操纵区工作的所有职员应当理解并严格遵守这些规程。卫生规程应由治理人员进行改进，并在培训时进行充分讨论。2.14.Allpersonnelshouldreceivemedicalexaminationuponrecruitment.Itmustbethemanufacturer"sresponsibilitythatthereareinstructionsensuringthathealthconditionsthatcanbeofrelevancetothequalityofproductscometothemanufacturer"sknowledge.Afterthefirstmedicalexamination,examinationsshouldbecarriedoutwhennecessaryfortheworkandpersonalhealth.154/154 所有职员在入职前应当同意体检。生产企业有责任获悉相关指示，以确保卫生条件与产品质量相适应。初次体检后，在职员的工作或健康状况需要时，应重新进行体检。2.15.Stepsshouldbetakentoensureasfarasispracticablethatnopersonaffectedbyaninfectiousdiseaseorhavingopenlesionsontheexposedsurfaceofthebodyisengagedinthemanufactureofmedicinalproducts.应当采取措施尽最大可能地保证无传染病患者且无体表有伤口者从事药品生产。2.16.Everypersonenteringthemanufacturingareasshouldwearprotectivegarmentsappropriatetotheoperationstobecarriedout.进入生产区的所有人员应当穿着与其操作相适应的防护服。2.17.Eating,drinking,chewingorsmoking,orthestorageoffood,drink,smokingmaterialsorpersonalmedicationintheproductionandstorageareasshouldbeprohibited.Ingeneral,anyunhygienicpracticewithinthemanufacturingareasorinanyotherarea154/154 wheretheproductmightbeadverselyaffected,shouldbeforbidden.在生产区和贮存区，应当禁止饮食、饮水、咀嚼食物或吸烟，禁止存放食物、饮料、香烟或个人服用的药品。总之，杜绝在生产区内或其他可能对药品质量造成不良阻碍的区域内的任何不卫生行为。2.18.Directcontactshouldbeavoidedbetweentheoperator"shandsandtheexposedproductaswellaswithanypartoftheequipmentthatcomesintocontactwiththeproducts.操作人员应当幸免裸手直接接触药品以及与药品直接接触的设备表面。2.19.Personnelshouldbeinstructedtousethehand-washingfacilities.应指导职员使用洗手设施。2.20.Anyspecificrequirementsforthemanufactureofspecialgroupsofproducts,forexamplesterilepreparations,arecoveredintheSupplementaryGuidelines.154/154 不同类不产品的具体生产要求参见附录，如无菌制剂。154/154 CHAPTER3第三章厂房设施PREMISESANDEQUIPMENTPRINCIPLE原则Premisesandequipmentmustbelocated,designed,constructed,adaptedandmaintainedtosuittheoperationstobecarriedout.Theirlayoutanddesignmustaimtominimisetheriskoferrorsandpermiteffectivecleaningandmaintenanceinordertoavoidcross-contamination,buildupofdustordirtand,ingeneral,anyadverseeffectonthequalityofproducts.厂房与设备的选址、设计、建筑、改造及维护必须与所要实施的操作相适应。厂房和设备的设计和布局必须能最大限度降低发生差错的风险，能同意有效清洁和维护，从而幸免交叉污染、幸免积尘，总之，幸免对产品质量的任何不利阻碍PREMISES厂房General总则3.1.Premisesshouldbesituatedinanenvironmentwhich,whenconsideredtogetherwithmeasuresto154/154 protectthemanufacture,presentsminimalriskofcausingcontaminationofmaterialsorproducts.应依照厂房及生产爱护措施综合考虑选址问题，厂房所处的环境应能使物料或产品遭受污染的风险最小。3.2.Premisesshouldbecarefullymaintained,ensuringthatrepairandmaintenanceoperationsdonotpresentanyhazardtothequalityofproducts.Theyshouldbecleanedand,whereapplicable,disinfectedaccordingtodetailedwrittenprocedures.应当精心维护厂房，应当确保维修和维护活动不阻碍产品的质量。应当按照详细的书面规程清洁厂房，必要时消毒。3.3.Lighting,temperature,humidityandventilationshouldbeappropriateandsuchthattheydonotadverselyaffect,directlyorindirectly,eitherthemedicinalproductsduringtheirmanufactureandstorage,ortheaccuratefunctioningofequipment.厂房应有适当的照明、温湿度与通风，并确保在生产与贮存期间药品质量以及相关设备的性能不直接或间接地受其不良阻碍。3.4.Premisesshouldbedesignedandequippedsoasto154/154 affordmaximumprotectionagainsttheentryofinsectsorotheranimals.厂房的设计与装备应能最大程度防止昆虫或其他动物的进入。3.5.Stepsshouldbetakeninordertopreventtheentryofunauthorisedpeople.Production,storageandqualitycontrolareasshouldnotbeusedasarightofwaybypersonnelwhodonotworkinthem.应采取适当措施，防止未经批准的人员进入。生产、贮存和质量操纵区不应作为非本区工作人员的通道。ProductionArea生产区3.6.Inordertominimisetheriskofaseriousmedicalhazardduetocrosscontamination,dedicatedandself-containedfacilitiesmustbeavailablefortheproductionofparticularmedicinalproducts,suchashighlysensitisingmaterials(e.g.penicillins)orbiologicalpreparations(e.g.fromlivemicro-organisms).Theproductionofcertainadditionalproducts,suchascertainantibiotics,certainhormones,certaincytotoxics,certainhighlyactivedrugsand154/154 non-medicinalproductsshouldnotbeconductedinthesamefacilities.Forthoseproducts,inexceptionalcases,theprincipleofcampaignworkinginthesamefacilitiescanbeacceptedprovidedthatspecificprecautionsaretakenandthenecessaryvalidationsaremade.Themanufactureoftechnicalpoisons,suchaspesticidesandherbicides,shouldnotbeallowedinpremisesusedforthemanufactureofmedicinalproducts.为降低由交叉污染所致严峻医学危害风险，一些专门药品，如高致敏药品（如，青霉素类）或生物制剂（如，活性微生物类）必须采纳专用和独立的生产设施。某些抗生素、激素、细胞毒素、高活性药物和非药品，不应在同一生产设施内生产。关于这些产品，在专门情况下，能够采纳时期式生产，共用生产设施，但应采取特不防护措施并通过必要的验证。药品生产厂房不得用于生产杀虫剂和除草剂等工业毒性物品。3.7.Premisesshouldpreferablybelaidoutinsuchawayastoallowtheproductiontotakeplaceinareasconnectedinalogicalordercorrespondingtothe154/154 sequenceoftheoperationsandtotherequisitecleanlinesslevels.厂房应当按生产工艺流程及相应洁净级不要求适当布局。3.8.Theadequacyoftheworkingandin-processstoragespaceshouldpermittheorderlyandlogicalpositioningofequipmentandmaterialssoastominimisetheriskofconfusionbetweendifferentmedicinalproductsortheircomponents,toavoidcross-contaminationandtominimisetheriskofomissionorwrongapplicationofanyofthemanufacturingorcontrolsteps.工作区和中间物料贮存区应有足够的空间，使设备和物料能够有序存放，从而使不同药品或组分之间混淆的风险降至最低，幸免交叉污染，将任何生产或操纵步骤遗漏或出差错的风险降至最低。3.9.Wherestartingandprimarypackagingmaterials,intermediateorbulkproductsareexposedtotheenvironment,interiorsurfaces(walls,floorsandceilings)shouldbesmooth,freefromcracksandopenjoints,andshouldnotshedparticulatematterandshouldpermiteasyandeffectivecleaningand,if154/154 necessary,disinfection.起始物料、内包装材料、中间体或半成品暴露环境的内表面（墙壁、地面、天花板）应当平坦光滑、无裂缝、接口严密、无颗粒物脱落，便于有效清洁和必要时进行消毒。3.10.Pipework,lightfittings,ventilationpointsandotherservicesshouldbedesignedandsitedtoavoidthecreationofrecesseswhicharedifficulttoclean.Asfaraspossible,formaintenancepurposes,theyshouldbeaccessiblefromoutsidethemanufacturingareas.管道、照明设施、通风口和其他公用设施的设计和安装应幸免出现难以清洁的部位。应尽可能做到在生产区外部对它们进行维护。3.11.Drainsshouldbeofadequatesize,andhavetrappedgullies.Openchannelsshouldbeavoidedwherepossible,butifnecessary,theyshouldbeshallowtofacilitatecleaninganddisinfection.排水设施应大小适宜，安装防止倒灌的装置。应尽可能幸免明沟，不可幸免时，明沟宜浅，以方便清洁和消毒。3.12.Productionareasshouldbeeffectivelyventilated,154/154 withaircontrolfacilities(includingtemperatureand,wherenecessary,humidityandfiltration)appropriatebothtotheproductshandled,totheoperationsundertakenwithinthemandtotheexternalenvironment.应依照所处理的产品、生产操作要求及外部环境状况配置空调操纵设施（包括温度操纵、必要的湿度操纵和空气净化过滤)，使生产区具有有效的通风。3.13.Weighingofstartingmaterialsusuallyshouldbecarriedoutinaseparateweighingroomdesignedforthatuse.起始物料的称量通常应在专门设计的称量室内进行。3.14.Incaseswheredustisgenerated(e.g.duringsampling,weighing,mixingandprocessingoperations,packagingofdryproducts),specificprovisionsshouldbetakentoavoidcross-contaminationandfacilitatecleaning.在产尘区域（如，取样、称量、混合与加工、干燥产品包装)，应采取专门的措施幸免交叉污染并便于清洁。3.15.Premisesforthepackagingofmedicinalproducts154/154 shouldbespecificallydesignedandlaidoutsoastoavoidmix-upsorcross-contamination.应对药品包装厂房进行专门的设计和布局，以幸免混淆或交叉污染。3.16.Productionsareasshouldbewelllit,particularlywherevisualon-linecontrolsarecarriedout.生产区应有足够的照明，特不是产品在线目检区。3.17.In-processcontrolsmaybecarriedoutwithintheproductionareaprovidedtheydonotcarryanyriskfortheproduction.在生产区域内可进行中间过程操纵，但不得给生产带来风险。StorageAreas贮存区3.18.Storageareasshouldbeofsufficientcapacitytoalloworderlystorageofthevariouscategoriesofmaterialsandproducts:startingandpackagingmaterials,intermediate,bulkandfinishedproducts,productsinquarantine,released,rejected,returnedorrecalled.贮存区应有足够的空间，154/154 以便有序地存放各类物料和产品：起始物料、包装材料、中间体、半成品与成品，以及待验、合格、不合格、退回或召回的产品等。3.19.Storageareasshouldbedesignedoradaptedtoensuregoodstorageconditions.Inparticular,theyshouldbecleananddryandmaintainedwithinacceptabletemperaturelimits.Wherespecialstorageconditionsarerequired(e.g.temperature,humidity)theseshouldbeprovided,checkedandmonitored.贮存区的设计或建筑应确保良好的贮存条件。特不是，贮存区应当清洁并干燥，同时温度保持在可同意限度内。应提供药品所需的专门贮存条件（如，温度、湿度），并对其进行检查和监测。3.20.Receivinganddispatchbaysshouldprotectmaterialsandproductsfromtheweather.Receptionsareasshouldbedesignedandequippedtoallowcontainersofincomingmaterialstobecleanedwherenecessarybeforestorage.收货与发放区应当能爱护物料与产品免受天气阻碍。接收区的设计和装备配置应当确保进来的物料的外包装在贮存前可进行必要的清洁。154/154 3.21.Wherequarantinestatusisensuredbystorageinseparateareas,theseareasmustbeclearlymarkedandtheiraccessrestrictedtoauthorisedpersonnel.Anysystemreplacingthephysicalquarantineshouldgiveequivalentsecurity.通过存放在单独的区域来确保物料待验的状态，这些区域必须有醒目标识，只限经批准的人员进入。假如采纳其他方法替代物理隔离，则应当具有同等的安全性。3.22.Thereshouldnormallybeaseparatesamplingareaforstartingmaterials.Ifsamplingisperformedinthestoragearea,itshouldbeconductedinsuchawayastopreventcontaminationorcross-contamination.通常应当有起始物料单独的取样区。假如在贮存区取样，则应当以能防止污染或交叉污染的方式进行3.23.Segregatedareasshouldbeprovidedforthestorageofrejected,recalledorreturnedmaterialsorproducts.应当提供隔离的区域用于存放不合格、召回或退回的物料或产品。3.24.Highlyactivematerialsorproductsshouldbe154/154 storedinsafeandsecureareas.高活性物料或产品应存放在安全的区域内。3.25.Printedpackagingmaterialsareconsideredcriticaltotheconformityofthemedicinalproductsandspecialattentionshouldbepaidtothesafeandsecurestorageofthesematerials.印刷好的包装材料被认为是药品合格的关键材料，应当特不注意这些材料的安全贮存。QualityControlAreas质量操纵区3.26.Normally,QualityControllaboratoriesshouldbeseparatedfromproductionareas.Thisisparticularlyimportantforlaboratoriesforthecontrolofbiologicals,microbiologicalsandradioisotopes,whichshouldalsobeseparatedfromeachother.质量操纵实验室通常应与生产区隔离。这一点关于生物、微生物和放射性同位素操纵实验室特不重要，上述实验室还应彼此分开。3.27.Controllaboratoriesshouldbedesignedtosuittheoperationstobecarriedoutinthem.Sufficient154/154 spaceshouldbegiventoavoidmix-upsandcrosscontamination.Thereshouldbeadequatesuitablestoragespaceforsamplesandrecords.质量操纵实验室的设计应当适合预期的操作。应当给出足够空间以幸免混淆和交叉污染。应当有足够且适用的空间保存样品和记录。3.28.Separateroomsmaybenecessarytoprotectsensitiveinstrumentsfromvibration,electricalinterference,humidity,etc.必要时，应设置专门的仪器室，使高灵敏仪器免受震动、电磁、潮湿等因素的干扰。3.29.Specialrequirementsareneededinlaboratorieshandlingparticularsubstances,suchasbiologicalorradioactivesamples.在实验室中处理专门物质时应满足专门要求，如生物或放射性样品。AncillaryAreas辅助区3.30.Restandrefreshmentroomsshouldbeseparatefromotherareas.154/154 休息室和餐饮室应与其他区域分开。3.31.Facilitiesforchangingclothes,andforwashingandtoiletpurposesshouldbeeasilyaccessibleandappropriateforthenumberofusers.Toiletsshouldnotdirectlycommunicatewithproductionorstorageareas.更衣室、盥洗室与卫生间应当易于到达，并与使用人数相适应。卫生间不得与生产区或贮存区直接相连。3.32.Maintenanceworkshopsshouldasfaraspossiblebeseparatedfromproductionareas.Wheneverpartsandtoolsarestoredintheproductionarea,theyshouldbekeptinroomsorlockersreservedforthatuse.维修间应尽可能与生产区分开。存放在生产区内的维修用备件与工具，应放置在专门的房间或上锁的工具柜中。3.33.Animalhousesshouldbewellisolatedfromotherareas,withseparateentrance(animalaccess)andairhandlingfacilities.动物房应与其他区域严格分开，并设有专门的通道（动物通道）以及空气处理设施。EQUIPMENT设备154/154 3.34.Manufacturingequipmentshouldbedesigned,locatedandmaintainedtosuititsintendedpurpose.生产设备的设计、安放、维护应适用于预定用途。3.35.Repairandmaintenanceoperationsshouldnotpresentanyhazardtothequalityoftheproducts.设备的维修和维护不应危害产品质量。3.36.Manufacturingequipmentshouldbedesignedsothatitcanbeeasilyandthoroughlycleaned.Itshouldbecleanedaccordingtodetailedandwrittenproceduresandstoredonlyinacleananddrycondition.生产设备的设计应当便于完全清洁。应当按详细的书面规程清洁设备，并在清洁、干燥的条件下存放。3.37.Washingandcleaningequipmentshouldbechosenandusedinordernottobeasourceofcontamination.应选择并使用适当的方式对设备进行清洗和清洁，以幸免其成为污染源。3.38.Equipmentshouldbeinstalledinsuchawayastopreventanyriskoferrororofcontamination.154/154 设备的安装方式应有利于防止差错和污染。3.39.Productionequipmentshouldnotpresentanyhazardtotheproducts.Thepartsoftheproductionequipmentthatcomeintocontactwiththeproductmustnotbereactive,additiveorabsorptivetosuchanextentthatitwillaffectthequalityoftheproductandthuspresentanyhazard.生产设备不应当对产品有任何危害。与产品接触的部件不得与药品发生化学反应，或因添加或吸附物质而阻碍产品质量，从而造成任何危害。3.40.Balancesandmeasuringequipmentofanappropriaterangeandprecisionshouldbeavailableforproductionandcontroloperations.用于药品的生产和操纵的衡器和量具应具有适当量程和周密度。3.41.Measuring,weighing,recordingandcontrolequipmentshouldbecalibratedandcheckedatdefinedintervalsbyappropriatemethods.Adequaterecordsofsuchtestsshouldbemaintained.应当按照适当的方法定期对测量、称重154/154 、记录和操纵设备进行校准与核实。应当保留校准与核实的记录。3.42.Fixedpipeworkshouldbeclearlylabelledtoindicatethecontentsand,whereapplicable,thedirectionofflow.固定管路应当标明内容物，必要时还应当标明流向3.43.Distilled,deionizedand,whereappropriate,otherwaterpipesshouldbesanitisedaccordingtowrittenproceduresthatdetailtheactionlimitsformicrobiologicalcontaminationandthemeasurestobetaken.应按照书面规程消毒蒸馏水、去离子水管道，以及其他供水管路（必要时），书面规程中应详细规定微生物污染的纠偏限度及应采取的措施。3.44.Defectiveequipmentshould,ifpossible,beremovedfromproductionandqualitycontrolareas,oratleastbeclearlylabelledasdefective.尽量将有故障的设备搬出生产区和质量操纵区，或至少贴上醒目的标识。154/154 CHAPTER4第四章文件DOCUMENTATIONPRINCIPLE原则GooddocumentationconstitutesanessentialpartofthequalityassurancesystemandiskeytooperatingincompliancewithGMPrequirements.Thevarioustypesofdocumentsandmediausedshouldbefullydefinedinthemanufacturer"sQualityManagementSystem.Documentationmayexistinavarietyofforms,includingpaper-based,electronicorphotographicmedia.Themainobjectiveofthesystemofdocumentationutilisedmustbetoestablish,control,monitorandrecordallactivitieswhichdirectlyorindirectlyimpactonallaspectsofthequalityofmedicinalproducts.TheQualityManagementSystemshouldincludesufficientinstructionaldetailtofacilitateacommonunderstandingoftherequirements,inadditiontoprovidingforsufficientrecordingofthevarious154/154 processesandevaluationofanyobservations,sothatongoingapplicationoftherequirementsmaybedemonstrated.良好的文件治理是质量保证体系的重要组成部分，也是符合GMP运行要求的关键。应当在生产企业质量治理体系中全面规定文件的各种类型以及所使用的媒介。文件可能以多种形式存在，包括纸质、电子或图像形式。必须建立所用文件系统的要紧目的，是对其进行操纵和监督，以及记录针对直接或间接阻碍药品质量的所有活动。质量治理体系应当包括足够详细的释义，从而促进对各种要求的共识，另外应当充分记录各种过程与调查评估，从而使正在运用的各种要求能得到证明。TherearetwoprimarytypesofdocumentationusedtomanageandrecordGMPcompliance:instructions(directions,requirements)andrecords/reports.Appropriategooddocumentationpracticeshouldbeappliedwithrespecttothetypeofdocument.GMP符合性的治理与记录中有两个差不多类型的文件：规程（指示、要求）和记录/报告。应当依照不同类型的文件应用适当的文件治理规范。154/154 Suitablecontrolsshouldbeimplementedtoensuretheaccuracy,integrity,availabilityandlegibilityofdocuments.Instructiondocumentsshouldbefreefromerrorsandavailableinwriting.Theterm‘written’meansrecorded,ordocumentedonmediafromwhichdatamayberenderedinahumanreadableform.应当实施适当操纵，以确保文件的准确性、完整性、有效性和可读性。规程类文件应当正确无误并以书面形式提供。术语“书面”的意思是在介质上记录或文件化，相关数据可供人员阅读的形式。REQUIREDGMPDOCUMENTATION(BYTYPE)要求的GMP文件（按类不）SiteMasterFile:AdocumentdescribingtheGMPrelatedactivitiesofthemanufacturer.《场地主文件》：描述生产企业GMP相关活动的一个文件。Instructions(directions,orrequirements)type:规程（指示或要求）类型Specifications:Describeindetailtherequirementswithwhichtheproductsormaterialsusedorobtainedduringmanufacturehavetoconform.Theyserveas154/154 abasisforqualityevaluation.质量标准：详细描述了产品或生产中所用物料或生产所得物料必须符合的要求。质量标准是质量评价的基础。ManufacturingFormulae,Processing,PackagingandTestingInstructions:Providedetailallthestartingmaterials,equipmentandcomputerisedsystems(ifany)tobeusedandspecifyallprocessing,packaging,samplingandtestinginstructions.In-processcontrolsandprocessanalyticaltechnologiestobeemployedshouldbespecifiedwhererelevant,togetherwithacceptancecriteria.生产处方、工艺、包装与检验规程：提供所用全部起始物料、设备与计算机化系统（假如有），以及详细讲明所有加工、包装、取样与检验的操作。假如相关，应当详细讲明所用的中间过程操纵、过程分析技术及可同意标准。Procedures:(OtherwiseknownasStandardOperatingProcedures,orSOPs),givedirectionsforperformingcertainoperations.规程（或称为标准操作程序，SOP)154/154 ：对所实施的特定操作给予指示。Protocols:Giveinstructionsforperformingandrecordingcertaindiscreetoperations.方案：对某些审慎操作给出实施与记录指示。TechnicalAgreements:Areagreedbetweencontractgiversandacceptorsforoutsourcedactivities.技术协议：合同供方与受方之间就外包活动达成的协议。Record/Reporttype:记录/报告类型Records:Provideevidenceofvariousactionstakentodemonstratecompliancewithinstructions,e.g.activities,events,investigations,andinthecaseofmanufacturedbatchesahistoryofeachbatchofproduct,includingitsdistribution.Recordsincludetherawdatawhichisusedtogenerateotherrecords.Forelectronicrecordsregulatedusersshoulddefinewhichdataaretobeusedasrawdata.Atleast,alldataonwhichqualitydecisionsarebasedshouldbedefinedasrawdata.154/154 记录：提供各种活动的证据以证明符合指示的要求，例如，活动、事件、调查，以及每一批次产品的生产历史，包括其销售情况。记录中包括用来生成其他记录的原始数据。关于电子记录，固定的用户应当规定什么数据作为原始数据使用。至少，质量决策的所有基础数据应当规定为原始数据。CertificatesofAnalysis:Provideasummaryoftestingresultsonsamplesofproductsormaterials1togetherwiththeevaluationforcompliancetoastatedspecification.分析报告单：提供产品或物料样品G检验结果的汇总，并给出是否符合既定质量标准的评估。Reports:Documenttheconductofparticularexercises,projectsorinvestigations,togetherwithresults,conclusionsandrecommendations.报告：特定操作、项目或调查的实施情况的文件，其中包括结果、结论以及建议。GENERATIONANDCONTROLOFDOCUMENTATION文件的生成与操纵4.1Alltypesofdocumentshouldbedefinedandadhered154/154 to.Therequirementsapplyequallytoallformsofdocumentmediatypes.Complexsystemsneedtobeunderstood,welldocumented,validated,andadequatecontrolsshouldbeinplace.Manydocuments(instructionsand/orrecords)mayexistinhybridforms,i.e.someelementsaselectronicandothersaspaperbased.Relationshipsandcontrolmeasuresformasterdocuments,officialcopies,datahandlingandrecordsneedtobestatedforbothhybridandhomogenoussystems.Appropriatecontrolsforelectronicdocumentssuchastemplates,forms,andmasterdocumentsshouldbeimplemented.Appropriatecontrolsshouldbeinplacetoensuretheintegrityoftherecordthroughouttheretentionperiod.对所有类型的文件应进行规定并遵照实施。所有媒介形式的文件要求差不多上等同的。应对复杂的文件系统进行理解、规范文件化、验证并适当操纵。许多文件（规程和/或记录）可能以混合的格式存在，例如某部分文件154/154 是电子形式的而其他部分是纸质的。关于混合的和统一的文件系统，都需要明确阐述主文件、正式的复印件、数据处理与记录的关系和操纵措施。应当对如模板、表格之类的电子文件进行适当操纵，相应的主文件应当得到执行。采取适当的操纵措施确保记录在保存期内的文件的完整性。4.2Documentsshouldbedesigned,prepared,reviewed,anddistributedwithcare.TheyshouldcomplywiththerelevantpartsofProductSpecificationFiles,ManufacturingandMarketingAuthorisationdossiers,asappropriate.Thereproductionofworkingdocumentsfrommasterdocumentsshouldnotallowanyerrortobeintroducedthroughthereproductionprocess.应当对文件进行精心设计、起草、审核与发放。文件应当与相应的“产品规格标准文件”、“生产和上市许可注册资料”的相关内容一致。从主文件复制工作文件时，复制过程中不得引入任何差错。4.3Documentscontaininginstructionsshouldbeapproved,signedanddatedbyappropriateandauthorisedpersons.Documentsshouldhaveunambiguouscontentsandbeuniquelyidentifiable.Theeffectivedateshouldbedefined.154/154 含有操作讲明的文件应当由通过授权的适当人员批准、签字并签署日期。文件应当含有明确的内容并有唯一性标识。需要规定文件的生效日期。4.4Documentscontaininginstructionsshouldbelaidoutinanorderlyfashionandbeeasytocheck.Thestyleandlanguageofdocumentsshouldfitwiththeirintendeduse.StandardOperatingProcedures,WorkInstructionsandMethodsshouldbewritteninanimperativemandatorystyle.含有操作讲明的文件应当有序排版并易于检查。文件的样式与语言应当适应预期使用目的。标准操作程规、工作指令和操作方法应当用祈使句命令语气书写。4.5DocumentswithintheQualityManagementSystemshouldberegularlyreviewedandkeptup-to-date.Whenadocumenthasbeenrevised,systemsshouldbeoperatedtopreventinadvertentuseofsupersededdocuments.质量治理体系内的文件应当定期审核并保持只是时。当文档被修改后，系统应进行操作以防止废弃文档的无意使用。4.6Documentsshouldnotbehand-written;although,154/154 wheredocumentsrequiretheentryofdata,sufficientspaceshouldbeprovidedforsuchentries.文件不应采纳手写的形式；然而，当有些数据确实需要填写，必须为填写数据提供足够的空间。GOODDOCUMENTATIONPRACTICES文件质量治理规范4.7Handwrittenentriesshouldbemadeinclear,legible,indelibleway.手工填写的内容应清晰、可辨、不可消除。4.8Recordsshouldbemadeorcompletedatthetimeeachactionistakenandinsuchawaythatallsignificantactivitiesconcerningthemanufactureofmedicinalproductsaretraceable.应当在每项活动执行时做记录或是完成记录，记录的方式应当确保与药品生产有关的所有重大活动可追溯。4.9Anyalterationmadetotheentryonadocumentshouldbesignedanddated;thealterationshouldpermitthereadingoftheoriginalinformation.Whereappropriate,thereasonforthealterationshouldberecorded.154/154 文件中输入的任何更正必须签署姓名和日期；同时，更正应确保原始信息能够被读取。假如可能，应当记录更正的缘故。RETENTIONOFDOCUMENTS文件的保存4.10Itshouldbeclearlydefinedwhichrecordisrelatedtoeachmanufacturingactivityandwherethisrecordislocated.Securecontrolsmustbeinplacetoensuretheintegrityoftherecordthroughouttheretentionperiodandvalidatedwhereappropriate.应当清晰规定与每项生产活动有关的是哪个记录，并指明该记录的保存位置。必须有安全措施来确保记录在整个保存期的完整性，假如条件适合，应进行验证。4.11SpecificrequirementsapplytobatchdocumentationwhichmustbekeptforoneyearafterexpiryofthebatchtowhichitrelatesoratleastfiveyearsaftercertificationofthebatchbytheAuthorisedPerson,whicheveristhelonger.Forinvestigationalmedicinalproducts,thebatchdocumentationmustbekeptforatleastfiveyearsafterthecompletionorformaldiscontinuationofthelastclinicaltrialinwhichthe154/154 batchwasused.Otherrequirementsforretentionofdocumentationmaybedescribedinlegislationinrelationtospecifictypesofproduct(e.g.AdvancedTherapyMedicinalProducts)andspecifythatlongerretentionperiodsbeappliedtocertaindocuments.关于批文件有些专门要求，批文件必须保存到相应产品有效期后一年，或质量受权人放行产品后至少五年，执行这两者中期限较长的那一个。关于临床试验用药品，批文件必须保存到用该批产品所做的最后一次临床试验完成或正式停止后至少5年。关于文件保存的其他要求，在特定类型产品(例如，新型治疗药品）相关的法规中也有相应的描述，并规定某些文件要保存更长的时刻。4.12Forothertypesofdocumentation,theretentionperiodwilldependonthebusinessactivitywhichthedocumentationsupports.Criticaldocumentation,includingrawdata(forexamplerelatingtovalidationorstability),whichsupportsinformationintheMarketingAuthorisationshouldberetainedwhilsttheauthorisationremainsinforce.Itmaybeconsidered154/154 acceptabletoretirecertaindocumentation(e.g.rawdatasupportingvalidationreportsorstabilityreports)wherethedatahasbeensupersededbyafullsetofnewdata.Justificationforthisshouldbedocumentedandshouldtakeintoaccounttherequirementsforretentionofbatchdocumentation;forexample,inthecaseofprocessvalidationdata,theaccompanyingrawdatashouldberetainedforaperiodatleastaslongastherecordsforallbatcheswhosereleasehasbeensupportedonthebasisofthatvalidationexercise.关于其他类型的文件，保存期将取决于该文件所支持的商业活动。关键文件，包括原始数据（例如与验证和稳定性相关的数据），可能支持上市许可中的信息，应当在上市许可有效期内一直保存。关于某些数据（例如，支持验证报告或稳定性报告的原始数据），当这些数据被新数据代替时，能够淘汰旧数据。淘汰数据的理由应文件化，并考虑批文件的保存要求；例如，关于工艺验证数据，相应的原始数据的保存时限至少应与验证所支持的所有放行批批记录一样长。Thefollowingsectiongivessomeexamplesofrequired154/154 documents.Thequalitymanagementsystemshoulddescribealldocumentsrequiredtoensureproductqualityandpatientsafety.下列章节将举例讲明所需要的文件。质量治理体系应当描述保证产品质量与患者安全所需的所有文件。SPECIFICATIONS质量标准4.13Thereshouldbeappropriatelyauthorisedanddatedspecificationsforstartingandpackagingmaterials,andfinishedproducts.起始物料、包装材料及成品要有相应的质量标准，质量标准应通过适当批准并签署日期。Specificationsforstartingandpackagingmaterials起始物料与包装材料的质量标准4.14Specificationsforstartingandprimaryorprintedpackagingmaterialsshouldincludeorprovidereferenceto,ifapplicable:假如可能，起始物料、内包装材料或差不多印刷的包装材料质量标准应当包括或引用下列内容：a)Adescriptionofthematerials,including:154/154 物料描述，包括：-Thedesignatednameandtheinternalcodereference;指定的名称和内部参考代码；-Thereference,ifany,toapharmacopoeialmonograph;假如可能，参考药典各论；-Theapprovedsuppliersand,ifreasonable,theoriginalproducerofthematerial;所批准的供应商，假如合理的话，物料的原始生产厂家；-Aspecimenofprintedmaterials;已印刷好的样本；b)Directionsforsamplingandtesting;取样与检验指导；c)Qualitativeandquantitativerequirementswithacceptancelimits;带可同意限度的定量与定性的要求；d)Storageconditionsandprecautions;贮存条件及注意事项；e)Themaximumperiodofstoragebeforere-examination.复验之前的最长贮存期Specificationsforintermediateandbulkproducts中间体与半成品的质量标准154/154 4.15Specificationsforintermediateandbulkproductsshouldbeavailableforcriticalstepsorifthesearepurchasedordispatched.Thespecificationsshouldbesimilartospecificationsforstartingmaterialsorforfinishedproducts,asappropriate.不管是购入的依旧经处理所得的，用于关键工序的中间体或半成品都应当有质量标准。中间体或半成品的质量标准应当与起始物料或成品的质量标准有适当可比性。Specificationsforfinishedproducts成品质量标准4.16Specificationsforfinishedproductsshouldincludeorprovidereferenceto:成品的质量标准应当包括或引用：a)Thedesignatednameoftheproductandthecodereferencewhereapplicable;产品的指定名称和参考代码（假如有的话）；b)Theformula;处方c)Adescriptionofthepharmaceuticalformandpackagedetails;154/154 药品剂型描述与包装详细情况；d)Directionsforsamplingandtesting;取样与检验指导；e)Thequalitativeandquantitativerequirements,withtheacceptancelimits;带有可同意限度的定性与定量要求；f)Thestorageconditionsandanyspecialhandlingprecautions,whereapplicable;贮存条件与任何专门注意事项，假如有专门注意事项的话；g)Theshelf-life.货架期。MANUFACTURINGFORMULAANDPROCESSING生产处方与工艺操作法INSTRUCTIONS讲明Approved,writtenManufacturingFormulaandProcessingInstructionsshouldexistforeachproductandbatchsizetobemanufactured.待生产的每一个产品、每一种批量都应当有通过批准的书面生产处方与工艺操作法。154/154 4.17TheManufacturingFormulashouldinclude:生产处方应当包括：a)Thenameoftheproduct,withaproductreferencecoderelatingtoitsspecification;b)Adescriptionofthepharmaceuticalform,strengthoftheproductandbatchsize;产品名称，与质量标准相关的产品参考代码；c)Alistofallstartingmaterialstobeused,withtheamountofeach,described;mentionshouldbemadeofanysubstancethatmaydisappearinthecourseofprocessing;所用起始物料清单，并描述每种物料的使用量；应当注明在加工过程中可能消逝的任何物料；d)Astatementoftheexpectedfinalyieldwiththeacceptablelimits,andofrelevantintermediateyields,whereapplicable.写明带有可同意限度的预期终产量，假如可能，要描述相关中间体的产量。4.18TheProcessingInstructionsshouldinclude:154/154 工艺操作法应当包括：a)Astatementoftheprocessinglocationandtheprincipalequipmenttobeused;对加工场地和所用要紧设备的陈述；b)Themethods,orreferencetothemethods,tobeusedforpreparingthecriticalequipment(e.g.cleaning,assembling,calibrating,sterilising);预备关键设备（例如，清洁、组装、校准、灭菌）所用的方法或参照方法；c)Checksthattheequipmentandworkstationareclearofpreviousproducts,documentsormaterialsnotrequiredfortheplannedprocess,andthatequipmentiscleanandsuitableforuse;检查设备和工作站没有打算工艺以外的上批产品、文件或物料，同时设备是清洁、适用的；d)Detailedstepwiseprocessinginstructions[e.g.checksonmaterials,pretreatments,sequenceforaddingmaterials,criticalprocessparameters(time,tempetc)];154/154 详细的逐步工艺操作法[例如，物料检查、预处理、加料顺序、关键工艺参数（时刻、温度等)];e)Theinstructionsforanyin-processcontrolswiththeirlimits;带有限度的所有中间过程操纵操作法；f)Wherenecessary,therequirementsforbulkstorageoftheproducts;includingthecontainer,labelingandspecialstorageconditionswhereapplicable;必要时，产品的批量贮存要求；假如可能，包括容器、标签与专门存储条件；g)Anyspecialprecautionstobeobserved.需遵守的所有专门措施。PackagingInstructions|包装操作法4.19ApprovedPackagingInstructionsforeachproduct,packsizeandtypeshouldexist.Theseshouldinclude,orhaveareferenceto,thefollowing:每一种产品，每一包装量及包装类型均应有各自经批准的包装操作法。包装操作法通常应包括下述内容，或参照下述内容：a)Nameoftheproduct;includingthebatchnumberof154/154 bulkandfinishedproduct;产品名称；包括半成品与成品批号；b)Descriptionofitspharmaceuticalform,andstrengthwhereapplicable;假如可能，产品剂型与规格描述c)Thepacksizeexpressedintermsofthenumber,weightorvolumeoftheproductinthefinalcontainer;最终包装容器的包装量描述，可按照产品数量、质量或体积来描述；d)Acompletelistofallthepackagingmaterialsrequired,includingquantities,sizesandtypes,withthecodeorreferencenumberrelatingtothespecificationsofeachpackagingmaterial;列出全部包装材料的完整清单，包括数量、批量与类型，并写明每一种包装材料与质量标准相关的代码或参考码；e)Whereappropriate,anexampleorreproductionoftherelevantprintedpackagingmaterials,andspecimensindicatingwheretoapplybatchnumberreferences,andshelflifeoftheproduct;154/154 假如可能，印刷好的包装材料样张或复制品，以及标明产品批号和有效期打印位置的样张f)Checksthattheequipmentandworkstationareclearofpreviousproducts,documentsormaterialsnotrequiredfortheplannedpackagingoperations(lineclearance),andthatequipmentiscleanandsuitableforuse;检查设备和工作站没有打算包装操作以外的上批产品、文件或物料（生产线清场），同时设备是清洁、适用的；g)Specialprecautionstobeobserved,includingacarefulexaminationoftheareaandequipmentinordertoascertainthelineclearancebeforeoperationsbegin;需遵守的特不预防措施，包括对生产区和设备进行认真检查，确定在包装操作开始前包装生产线的清场差不多完成；h)Adescriptionofthepackagingoperation,includinganysignificantsubsidiaryoperations,andequipmenttobeused;154/154 包装操作描述，包括所有重要的辅助性操作及所用设备；i)Detailsofin-processcontrolswithinstructionsforsamplingandacceptancelimits.中间过程操纵的详细操作，包括取样指示和可同意限度。BatchProcessingRecord丨批工艺记录4.20ABatchProcessingRecordshouldbekeptforeachbatchprocessed.ItshouldbebasedontherelevantpartsofthecurrentlyapprovedManufacturingFormulaandProcessingInstructions,andshouldcontainthefollowinginformation:所加工的每一批产品均应当保存一份批工艺记录。批工艺记录应当以现行批准的生产处方和工艺操作法的相关内容为依据，应当包含下列信息：a)Thenameandbatchnumberoftheproduct;产品名称与批号；b)Datesandtimesofcommencement,ofsignificantintermediatestagesandofcompletionofproduction;生产开始、完成日期和时刻，重要中间工序开始、完成日期和时刻；154/154 c)Identification(initials)oftheoperator(s)whoperformedeachsignificantstepoftheprocessand,whereappropriate,thenameofanypersonwhocheckedtheseoperations;每个重要工序操作者的姓名（首字母缩写），适用的话，还应当包括检查这些操作的所有人员的姓名；d)Thebatchnumberand/oranalyticalcontrolnumberaswellasthequantitiesofeachstartingmaterialactuallyweighed(includingthebatchnumberandamountofanyrecoveredorreprocessedmaterialadded);每一起始物料的批号和/或分析操纵号，以及实际称量的数量（包括投入的经回收或返工所得物料的批号及数量）；e)Anyrelevantprocessingoperationoreventandmajorequipmentused;所有相关生产的操作或活动，以及所用要紧设备；f)Arecordofthein-processcontrolsandtheinitialsoftheperson(s)carryingthemout,andtheresultsobtained;中间过程操纵记录和操作人员的姓名（154/154 首字母缩写），以及所得结果；g)Theproductyieldobtainedatdifferentandpertinentstagesofmanufacture;不同工序和特定时期所得产品的产量；h)Notesonspecialproblemsincludingdetails,withsignedauthorisationforanydeviationfromtheManufacturingFormulaandProcessingInstructions;对专门问题的注释，包括与生产处方和工艺操作法有任何偏差的详细讲明，这种偏差应经签字批准；i)Approvalbythepersonresponsiblefortheprocessingoperations.由工艺操作负责人批准。Note:Whereavalidatedprocessiscontinuouslymonitoredandcontrolled,thenautomaticallygeneratedreportsmaybelimitedtocompliancesummariesandexception/out-of-specification(OOS)datareports.注：若对通过验证的工艺进行连续监测与操纵，自动生成的报告可能只限于符合性综述和例外/超标结果（OOS）报告。BatchPackagingRecord批包装记录154/154 4.21ABatchPackagingRecordshouldbekeptforeachbatchorpartbatchprocessed.ItshouldbebasedontherelevantpartsofthePackagingInstructions.每批产品或非全批量产品都应当保存批包装记录。包装记录应当以包装操作法的相关部分为依据。Thebatchpackagingrecordshouldcontainthefollowinginformation:批包装记录应当包含下列信息：a)Thenameandbatchnumberoftheproduct;产品名称以及批号；b)Thedate(s)andtimesofthepackagingoperations;包装操作日期和时刻；c)Identification(initials)oftheoperator(s)whoperformedeachsignificantstepoftheprocessand,whereappropriate,thenameofanypersonwhocheckedtheseoperations;每个重要工序操作者的姓名（首字母缩写），适用的话，还应包括检查这些操作的所有人员的姓名；d)Recordsofchecksforidentityandconformitywith154/154 thepackaginginstructions,includingtheresultsofin-processcontrols;与包装操作法一致性和符合性的检查记录，包括中间操纵结果；e)Detailsofthepackagingoperationscarriedout,includingreferencestoequipmentandthepackaginglinesused;包装操作的详细情况，包括所用设备及包装生产线的编号；f)Wheneverpossible,samplesofprintedpackagingmaterialsused,includingspecimensofthebatchcoding,expirydatingandanyadditionaloverprinting;假如可能，所用印刷包装材料的样张，包括印有批号、有效期及任何其他套印的印刷包装材料的样张；g)Notesonanyspecialproblemsorunusualeventsincludingdetails,withsignedauthorisationforanydeviationfromthePackagingInstructions;对专门问题及异常事件的详细注释，包括对偏离包装操作法的所有偏差，偏差应当通过签字批准；h)Thequantitiesandreferencenumberor154/154 identificationofallprintedpackagingmaterialsandbulkproductissued,used,destroyedorreturnedtostockandthequantitiesofobtainedproduct,inordertoprovideforanadequatereconciliation.Wheretherearetherearerobustelectroniccontrolsinplaceduringpackagingtheremaybejustificationfornotincludingthisinformation;记录所有放行、使用、销毁或退库的印刷包装材料和待包装产品的数量以及参考编码或识不号，同时记录所得产品的数量，便子进行物料平衡检査。若在包装过程中有良好的电子操纵，则批包装记录中能够不包括上述信息；i)Approvalbythepersonresponsibleforthepackagingoperations.由包装操作负责人批准。PROCEDURESANDRECORDS规程与记录Receipt接收4.22Thereshouldbewrittenproceduresandrecordsforthereceiptofeachdeliveryofeachstartingmaterial,(includingbulk,intermediateorfinishedgoods),154/154 primary,secondaryandprintedpackagingmaterials.应当有每一种起始物料（包括半成品、中间体或成品）、内包装材料、外包装材料和印刷包装材料每次交货接收的书面规程与记录。4.23Therecordsofthereceiptsshouldinclude:接收记录应当包括；a)Thenameofthematerialonthedeliverynoteandthecontainers;交货单上和包装容器上所注物料的名称；b)The"in-house"nameand/orcodeofmaterial(ifdifferentfroma);所用物料的内部名称和/或代码[如与a)不同];c)Dateofreceipt;接收日期；d)Supplier’snameandmanufacturer’sname;供应商以及生产企业的名称；e)Manufacturer’sbatchorreferencenumber;生产企业的批号或参考码；f)Totalquantityandnumberofcontainersreceived;154/154 收到总量和包装容器数量；g)Thebatchnumberassignedafterreceipt;接收后分配的批号；h)Anyrelevantcomment.其他有关讲明。4.24Thereshouldbewrittenproceduresfortheinternallabeling,quarantineandstorageofstartingmaterials,packagingmaterialsandothermaterials,asappropriate.应当有起始物料、包装材料或其他物料的适当的内部标识、待检和贮存的书面规程。Sampling取样4.25Thereshouldbewrittenproceduresforsampling,whichincludethemethodsandequipmenttobeused,theamountstobetakenandanyprecautionstobeobservedtoavoidcontaminationofthematerialoranydeteriorationinitsquality.应当有取样的书面规程，包括取样方法和取样用设备、取样量以及为幸免物料污染或阻碍质量采取的任何措施。154/154 Testing检验4.26Thereshouldbewrittenproceduresfortestingmaterialsandproductsatdifferentstagesofmanufacture,describingthemethodsandequipmenttobeused.Thetestsperformedshouldberecorded.应当有物料和不同生产时期产品的书面检验规程，描述所用方法和使用设备。应当记录所实施的检验。Other其他4.27Writtenreleaseandrejectionproceduresshouldbeavailableformaterialsandproducts,andinparticularforthecertificationforsaleofthefinishedproductbytheAuthorisedPerson(s).AllrecordsshouldbeavailabletotheAuthorisedPerson.Asystemshouldbeinplacetoindicatespecialobservationsandanychangestocriticaldata.应当有物料和产品放行与拒绝的书面规程，特不是由质量受权人放行上市销售的成品。质量受权人应当有权获得所有的记录。应当有一个系统来指示专门的问题以及对关键数据的任何变更。4.28Recordsshouldbemaintainedforthedistribution154/154 ofeachbatchofaproductinordertofacilitaterecallofanybatch,ifnecessary.应当保存每一批产品的销售记录，以便必要时关心召回相关批次产品。4.29Thereshouldbewrittenpolicies,procedures,protocols,reportsandtheassociatedrecordsofactionstakenorconclusionsreached,whereappropriate,forthefollowingexamples:假如有下述活动，应当有相应的书面方针、规程、方案与报告以及所采取措施或所得结论的相关记录：-Validationandqualificationofprocesses,equipmentandsystems;工艺、设备与系统的验证与确认；-Equipmentassemblyandcalibration;设备的装配和校准；-Technologytransfer;技术转移；-Maintenance,cleaningandsanitation;维护、清洁和消毒；154/154 -Personnelmattersincludingsignaturelists,traininginGMPandtechnicalmatters,clothingandhygieneandverificationoftheeffectivenessoftraining;人员相关事宜，包括签名表、GMP与技术事务培训、着装及卫生培训，并证实培训的有效性；-Environmentalmonitoring;环境监测；-Pestcontrol;虫害操纵；-Complaints;投诉；-Recalls;召回；-Returns;退货；-Changecontrol;变更操纵；-Investigationsintodeviationsandnon-conformances;偏差与不符合事件调查；-Internalquality/GMPcomplianceaudits;内部质量/GMP符合性审计;-Summariesofrecordswhereappropriate(e.g.productqualityreview);假如可能，记录汇总（例如，产品质量回忆）；-Supplieraudits.154/154 供应商审计。4.30Clearoperatingproceduresshouldbeavailableformajoritemsofmanufacturingandtestequipment.应当有要紧生产和检验设备的明确的操作规程。4.31Logbooksshouldbekeptformajororcriticalanalyticaltesting,productionequipment,andareaswhereproducthasbeenprocessed.Theyshouldbeusedtorecordinchronologicalorder,asappropriate,anyuseofthearea,equipment/method,calibrations,maintenance,cleaningorrepairoperations,includingthedatesandidentityofpeoplewhocarriedtheseoperationsout.应当有产品加工所用要紧或关键分析测试、生产设备以及分析与生产所在区域的日志。假如可能，应当按时刻顺序进行记录，其中包括操作所用区域、设备/方法、校准、维护、清洁或修理操作，以及实施日期和操作人员身份。4.32AninventoryofdocumentswithintheQualityManagementSystemshouldbemaintained.应当保存质量治理体系内的文件清单。154/154 154/154 CHAPTER5第五章生产PRODUCTIONPRINCIPLEProductionoperationsmustfollowclearlydefinedprocedures;theymustcomplywiththeprinciplesofGoodManufacturingPracticeinordertoobtainproductsoftherequisitequalityandbeinaccordancewiththerelevantmanufacturingandmarketingauthorisations.生产操作必须遵守明确的规程；必须符合药品生产质量治理规范差不多原则，以确保所得到的产品达到必需的质量标准，并符合药品生产许可和药品上市许可的要求。GENERAL5.1.Productionshouldbeperformedandsupervisedbycompetentpeople.应当由具有资质的人员从事生产和监督生产。5.2.Allhandlingofmaterialsandproducts,suchasreceiptandquarantine,sampling,storage,labelling,dispensing,processing,packaginganddistribution154/154 shouldbedoneinaccordancewithwrittenproceduresorinstructionsand,wherenecessary,recorded.所有物料与产品的处理，如收料与待验、取样、贮存、贴签、配料、加工、包装及销售均应当依照书面规程或操作法进行，必要时进行记录。5.3.Allincomingmaterialsshouldbecheckedtoensurethattheconsignmentcorrespondstotheorder.Containersshouldbecleanedwherenecessaryandlabelledwiththeprescribeddata.所有到物资料均应当通过核实，以确保按照订单交付。必要时应清洁物料外包装，并贴签标注规定的信息。5.4.Damagetocontainersandanyotherproblemwhichmightadverselyaffectthequalityofamaterialshouldbeinvestigated,recordedandreportedtotheQualityControlDepartment.外包装损坏或其他可能对物料质量有不良阻碍的问题，应予调查、记录，并向质量操纵部门报告。5.5.Incomingmaterialsandfinishedproductsshouldbephysicallyoradministrativelyquarantinedimmediately154/154 afterreceiptorprocessing,untiltheyhavebeenreleasedforuseordistribution.所有到物资料和成品在接收或加工后应立即采纳物理手段或治理手段按待验要求存放，直至放行使用或放行销售。5.6.Intermediateandbulkproductspurchasedassuchshouldbehandledonreceiptasthoughtheywerestartingmaterials.外购的中间体与半成品应按照接收起始物料来治理。5.7.Allmaterialsandproductsshouldbestoredundertheappropriateconditionsestablishedbythemanufacturerandinanorderlyfashiontopermitbatchsegregationandstockrotation.生产企业应为所有物料与产品建立适当的贮存条件，并分批有序贮存和周转。5.8.Checksonyields,andreconciliationofquantities,shouldbecarriedoutasnecessarytoensurethattherearenodiscrepanciesoutsideacceptablelimits.应当对产量和物料平衡进行核实，确保其在可同意范围内。5.9.Operationsondifferentproductsshouldnotbe154/154 carriedoutsimultaneouslyorconsecutivelyinthesameroomunlessthereisnoriskofmix-uporcrosscontamination.同一房间内不应同时或连续进行不同产品的生产操作，除非无混淆或交叉污染的风险。5.10.Ateverystageofprocessing,productsandmaterialsshouldbeprotectedfrommicrobialandothercontamination.在生产的每一时期，应爱护产品和物料免受微生物和其他污染。5.11.Whenworkingwithdrymaterialsandproducts,specialprecautionsshouldbetakentopreventthegenerationanddisseminationofdust.Thisappliesparticularlytothehandlingofhighlyactiveorsensitisingmaterials.在处理干燥物料或产品时，应釆取专门措施，防止粉尘的产生和扩散。在处理高活性或敏感物料时尤其需要注意这一点。5.12.Atalltimesduringprocessing,allmaterials,bulkcontainers,majoritemsofequipmentandwhereappropriateroomsusedshouldbelabelledorotherwise154/154 identifiedwithanindicationoftheproductormaterialbeingprocessed,itsstrength(whereapplicable)andbatchnumber.Whereapplicable,thisindicationshouldalsomentionthestageofproduction.加工期间，所有物料、半成品容器、要紧设备以及必要的操作室均应贴签标识或以其他方式标明所加工的产品或物料、规格（如适用）和批号。如有必要，还应标明生产时期。5.13.Labelsappliedtocontainers,equipmentorpremisesshouldbeclear,unambiguousandinthecompany"sagreedformat.Itisoftenhelpfulinadditiontothewordingonthelabelstousecolourstoindicatestatus(forexample,quarantined,accepted,rejected,clean,...).容器、设备或设施所用标识应清晰明了，其格式应通过企业批准。除了标签上的措词外，使用不同颜色的标签通常有助于区分被标识物的状态（如，待验、合格、不合格或清洁……）。5.14.Checksshouldbecarriedouttoensurethatpipelinesandotherpiecesofequipmentusedforthetransportationofproductsfromoneareatoanotherare154/154 connectedinacorrectmanner.应当核实从一个区域输送产品至另一个区域的管道和其他设备差不多正确连接。5.15.Anydeviationfrominstructionsorproceduresshouldbeavoidedasfaraspossible.Ifadeviationoccur,itshouldbeapprovedinwritingbyacompetentperson,withtheinvolvementoftheQualityControlDepartmentwhenappropriate.应当尽可能幸免出现任何操作法或规程偏差。一旦出现偏差，应由主管人员签字批准，必要时，质量操纵部门参与处理。5.16.Accesstoproductionpremisesshouldberestrictedtoauthorisedpersonnel.生产厂房应仅限于经批准的人员出入。5.17.Normally,theproductionofnon-medicinalproductsshouldbeavoidedinareasandwiththeequipmentdestinedfortheproductionofmedicinalproducts.一般情况下，用于药品生产的设备或生产区应幸免生产非医药类产品。154/154 PREVENTIONOFCROSS-CONTAMINATIONINPRODUCTION生产过程中交叉污染的预防5.18.Contaminationofastartingmaterialorofaproductbyanothermaterialorproductmustbeavoided.Thisriskofaccidentalcross-contaminationarisesfromtheuncontrolledreleaseofdust,gases,vapours,spraysororganismsfrommaterialsandproductsinprocess,fromresiduesonequipment,andfromoperators"clothing.Thesignificanceofthisriskvarieswiththetypeofcontaminantandofproductbeingcontaminated.Amongstthemosthazardouscontaminantsarehighlysensitisingmaterials,biologicalpreparationscontaininglivingorganisms,certainhormones,cytotoxics,andotherhighlyactivematerials.Productsinwhichcontaminationislikelytobemostsignificantarethoseadministeredbyinjection,thosegiveninlargedosesand/oroveralongtime.154/154 必须防止起始物料或产品被其他物料或产品污染。生产过程中的物料、产品、设备表面残留物以及操作人职员作服有可能不受操纵地释放尘埃、气体、蒸汽、喷溅物或生物体，从而导致偶发性的交叉污染风险。风险大小因污染物和被污染产品的种类而异。最具危害性的污染物则是高敏感物料、含有活性微生物的生物制品、某些激素、细胞毒性物质以及其他高活性物料。对注射剂、大剂量给药和/或长期使用的药品而言，产品污染的危害性最为严峻。5.19.Cross-contaminationshouldbeavoidedbyappropriatetechnicalororganisationalmeasures,forexample:应当采取适当的技术手段或治理措施防止交叉污染，如：a)productioninsegregatedareas(requiredforproductssuchaspenicillins,livevaccines,livebacterialpreparationsandsomeotherbiologicals),orbycampaign(separationintime)followedbyappropriatecleaning;在隔离区内生产（产品要求，如青霉素类、活疫苗、活菌制剂以及一些其他生物制品）；或适当清洁后进行时期式（按时刻间隔）生产；b)providingappropriateair-locksandairextraction;154/154 设置适当的气锁和排风；c)minimisingtheriskofcontaminationcausedbyrecirculationorre-entryofuntreatedorinsufficientlytreatedair;尽可能降低因空气循环使用、未经处理或未充分处理的空气再次进入生产区所致污染的风险；d)keepingprotectiveclothinginsideareaswhereproductswithspecialriskofcross-contaminationareprocessed;在容易发生交叉污染的产品加工区内，操作人员应穿防护服；e)usingcleaninganddecontaminationproceduresofknowneffectiveness,asineffectivecleaningofequipmentisacommonsourceofcrosscontamination;由于设备清洁不充分是常见的交叉污染源，应采纳已知效果的清洁和去除污染规程；f)using"closedsystems"ofproduction;使用“密闭系统”生产；g)testingforresiduesanduseofcleaningstatuslabelsonequipment.154/154 对残留物进行检测，并使用设备清洁状态标识。5.20.Measurestopreventcross-contaminationandtheireffectivenessshouldbecheckedperiodicallyaccordingtosetprocedures.应按设定的规程，定期核实防止交叉污染的措施及其有效性。VALIDATION验证5.21.ValidationstudiesshouldreinforceGoodManufacturingPracticeandbeconductedinaccordancewithdefinedprocedures.Resultsandconclusionsshouldberecorded.验证研究应强化药品生产质量治理规范，并按照预定的规程进行。应记录验证结果和结论。5.22.Whenanynewmanufacturingformulaormethodofpreparationisadopted,stepsshouldbetakentodemonstrateitssuitabilityforroutineprocessing.Thedefinedprocess,usingthematerialsandequipmentspecified,shouldbeshowntoyieldaproductconsistentlyoftherequiredquality.154/154 釆用新生产处方或方法前，应证实其适用于常规工艺。使用指定物料和设备时，预定的生产工艺应当能持续稳定地生产出符合质量要求的产品。5.23.Significantamendmentstothemanufacturingprocess,includinganychangeinequipmentormaterials,whichmayaffectproductqualityand/orthereproducibilityoftheprocessshouldbevalidated.应对阻碍产品质量和/或工艺重现性的重大工艺变更进行验证，其中包括设备或物料的任何变更。5.24.Processesandproceduresshouldundergoperiodiccriticalrevalidationtoensurethattheyremaincapableofachievingtheintendedresults.关键的工艺和规程应定期进行再验证，确保其仍可达到预定结果。STARTINGMATERIALS起始物料5.25.Thepurchaseofstartingmaterialsisanimportantoperationwhichshouldinvolvestaffwhohaveaparticularandthoroughknowledgeofthesuppliers.起始物料采购是至关重要的操作，对供应商有详细、全面了解的人员应当参与采购。5.26.Startingmaterialsshouldonlybepurchasedfrom154/154 approvedsuppliersnamedintherelevantspecificationand,wherepossible,directlyfromtheproducer.Itisrecommendedthatthespecificationsestablishedbythemanufacturerforthestartingmaterialsbediscussedwiththesuppliers.Itisofbenefitthatallaspectsoftheproductionandcontrolofthestartingmaterialinquestion,includinghandling,labellingandpackagingrequirements,aswellascomplaintsandrejectionproceduresarediscussedwiththemanufacturerandthesupplier.起始物料只能从相关规范中列入的、经批准的供应商处采购，应尽可能直接向生产企业购买。起始物料的质量标准，建议由药品生产企业与供应商共同商定。所购起始物料生产和操纵的各个方面，包括装卸、贴签、包装要求、投诉以及拒收程序，最好也由药品生产企业与供应商共同商定。5.27.Foreachdelivery,thecontainersshouldbecheckedforintegrityofpackageandsealandforcorrespondencebetweenthedeliverynoteandthesupplier"slabels.154/154 每次交付时，应当检查容器外包装完整性、铅封，以及交货单与供应商标签内容是否一致。5.28.Ifonematerialdeliveryismadeupofdifferentbatches,eachbatchmustbeconsideredasseparateforsampling,testingandrelease.如一次交付是不同批次的物料，必须考虑按批分不取样、检验及放行。5.29.Startingmaterialsinthestorageareashouldbeappropriatelylabelled(seeChapter5,Item13).Labelsshouldbearatleastthefollowinginformation:仓储区内的起始物料应有适当的标识（见本章5.13)。标识应当至少标明下述内容：lØthedesignatednameoftheproductandtheinternalcodereferencewhereapplicable;指定的产品名称和企业内部的物料代码（假如可能）；lØabatchnumbergivenatreceipt;接收时给定的批号；lØwhereappropriate,thestatusofthecontents(e.g.inquarantine,ontest,released,rejected);154/154 假如可能，物料状态（如，待验、检验中、放行、拒绝）：lØwhereappropriate,anexpirydateoradatebeyondwhichretestingisnecessary.假如可能，有效期或复验日期。Whenfullycomputerisedstoragesystemsareused,alltheaboveinformationshouldnotnecessarilybeinalegibleformonthelabel.关于完全计算机化的仓储治理系统，则不必以可读的方式在标签上标出上述信息。5.30.Thereshouldbeappropriateproceduresormeasurestoassuretheidentityofthecontentsofeachcontainerofstartingmaterial.Bulkcontainersfromwhichsampleshavebeendrawnshouldbeidentified(seeChapter6,Item13).应有适当的规程或措施，确保辨识每一容器中的起始物料。已取样的半成品容器也需要进行辨识(见第6章6.13)。5.31.OnlystartingmaterialswhichhavebeenreleasedbytheQualityControlDepartmentandwhicharewithintheirshelf-lifeshouldbeused.154/154 只能使用经质量操纵部门放行并在货架期内的起始物料。5.32.Startingmaterialsshouldonlybedispensedbydesignatedpersons,followingawrittenprocedure,toensurethatthecorrectmaterialsareaccuratelyweighedormeasuredintocleanandproperlylabelledcontainers.应当由指定的人员按照书面规程配制起始物料，以确保物料正确并经准确称量或计量，然后装入洁净并进行适当标记的容器中。5.33.Eachdispensedmaterialanditsweightorvolumeshouldbeindependentlycheckedandthecheckrecorded.配制的每一物料及其质量或体积应由他人独立复核，并有复核记录。5.34.Materialsdispensedforeachbatchshouldbekepttogetherandconspicuouslylabelledassuch.每一批配好的物料应集中存放，并标上相应的明显标识。PROCESSINGOPERATIONS-INTERMEDIATEANDBULKPRODUCTS生产操作：中间体及半成品5.35.Beforeanyprocessingoperationisstarted,stepsshouldbetakentoensurethattheworkareaand154/154 equipmentarecleanandfreefromanystartingmaterials,products,productresiduesordocumentsnotrequiredforthecurrentoperation.在任何加工开始前，应当采取措施来保证工作区与设备是清洁的，无任何与本批操作无关的起始物料、产品、产品残留或文件5.36.Intermediateandbulkproductsshouldbekeptunderappropriateconditions.中间体与半成品应当在适当的条件下贮存。5.37.Criticalprocessesshouldbevalidated(see"VALIDATION"inthisChapter).关键工艺应当通过验证（见本章的“验证”)。5.38.Anynecessaryin-processcontrolsandenvironmentalcontrolsshouldbecarriedoutandrecorded.应当实施任为必要的中间过程操纵与环境监测，并予以记录。5.39.Anysignificantdeviationfromtheexpectedyieldshouldberecordedandinvestigated.对显著偏离预期产量的情况，应当有记录并进行调査。PACKAGINGMATERIALS包装材料154/154 5.40.Thepurchase,handlingandcontrolofprimaryandprintedpackagingmaterialsshouldbeaccordedattentionsimilartothatgiventostartingmaterials.内包装材料与印刷好的包装材料的采购、处理与操纵要求与起始物料相似。5.41.Particularattentionshouldbepaidtoprintedmaterials.Theyshouldbestoredinadequatelysecureconditionssuchastoexcludeunauthorisedaccess.Cutlabelsandotherlooseprintedmaterialsshouldbestoredandtransportedinseparateclosedcontainerssoastoavoidmix-ups.Packagingmaterialsshouldbeissuedforuseonlybyauthorisedpersonnelfollowinganapprovedanddocumentedprocedure.应特不注意印刷好的包装材料。应当存放在足够安全的条件下，以免未经批准的人员猎取。切割式标签或其他散装印刷材料应当分不置于封闭容器内贮存与运输，以防混淆。只能由专人按照经批准的书面规程发放包装材料。5.42.Eachdeliveryorbatchofprintedorprimarypackagingmaterialshouldbegivenaspecificreference154/154 numberoridentificationmark.每批或每次发放的己印刷包装材料或内包装材料，均应设置特定的批号/编号或识不标志。5.43.Outdatedorobsoleteprimarypackagingmaterialorprintedpackagingmaterialshouldbedestroyedandthisdisposalrecorded.过期的或废弃的印刷包装材料或内包装材料，应予销毁并有相应记录。PACKAGINGOPERATIONS包装操作5.44.Whensettingupaprogrammeforthepackagingoperations,particularattentionshouldbegiventominimisingtheriskofcross-contamination,mix-upsorsubstitutions.Differentproductsshouldnotbepackagedincloseproximityunlessthereisphysicalsegregation.当制定包装操作规程时，应当特不注意釆取措施最大程度降低交叉污染、混淆或差错的风险。除非有物理隔离，不应当在相邻区域内包装不同产品。5.45.Beforepackagingoperationsarebegun,steps154/154 shouldbetakentoensurethattheworkarea,packaginglines,printingmachinesandotherequipmentarecleanandfreefromanyproducts,materialsordocumentspreviouslyused,ifthesearenotrequiredforthecurrentoperation.Theline-clearanceshouldbeperformedaccordingtoanappropriatecheck-list.在包装操作开始前，应采取适当措施，确保工作区、包装线、印刷机及其他设备已处于清洁状态，没有任何之前批次使用但与本批包装无关的产品、物料或文件。应按照清场核对单的要求进行清场。5.46.Thenameandbatchnumberoftheproductbeinghandledshouldbedisplayedateachpackagingstationorline.每一包装操作场所或包装线，应标明包装中的产品名称和批号。5.47.Allproductsandpackagingmaterialstobeusedshouldbecheckedondeliverytothepackagingdepartmentforquantity,identityandconformitywiththePackagingInstructions.154/154 向包装部门发放所有产品和所需包装材料时，应当核对数量、标识，且与包装指令相符。5.48.Containersforfillingshouldbecleanbeforefilling.Attentionshouldbegiventoavoidingandremovinganycontaminantssuchasglassfragmentsandmetalparticles.待灌装容器在灌装前应当清洁。应当注意幸免并清除容器中所有玻璃碎片、金属颗粒类污染物。5.49.Normally,fillingandsealingshouldbefollowedasquicklyaspossiblebylabelling.Ifitisnotthecase,appropriateproceduresshouldbeappliedtoensurethatnomix-upsormislabellingcanoccur.通常，产品灌装、封口后应当尽快贴签。否则，应当使用适当的规程，以确保可不能混淆或贴错标签。5.50.Thecorrectperformanceofanyprintingoperation(forexamplecodenumbers,expirydates)tobedoneseparatelyorinthecourseofthepackagingshouldbecheckedandrecorded.Attentionshouldbepaidtoprintingbyhandwhichshouldbere-checkedatregularintervals.154/154 应当检查任何单独印刷或包装过程中的印刷操作（如，代码、有效期）是否正确，并予以记录。应当注意手工印刷情况并定期进行重复检查。5.51.Specialcareshouldbetakenwhenusingcut-labelsandwhenover-printingiscarriedoutoff-line.Roll-feedlabelsarenormallypreferabletocut-labels,inhelpingtoavoidmix-ups.使用切割式标签以及离线套印标签时，应当特不小心。与切割式标签相比，卷筒式标签通常比切割式标签更便于防止混淆。5.52.Checksshouldbemadetoensurethatanyelectroniccodereaders,labelcountersorsimilardevicesareoperatingcorrectly.应当捡查电子读码机、标签计数器或其他类似装置，确保准确运行。5.53.Printedandembossedinformationonpackagingmaterialsshouldbedistinctandresistanttofadingorerasing.包装材料上印刷或模压的内容应清晰、不褪色、不易檫去。5.54.On-linecontroloftheproductduringpackaging154/154 shouldincludeatleastcheckingthefollowing:包装期间，产品的在线操纵至少应当检查下述内容：a)generalappearanceofthepackages;包装的总体外观；b)whetherthepackagesarecomplete;包装是否完整c)whetherthecorrectproductsandpackagingmaterialsareused;使用的产品和包装材料是否正确；d)whetheranyover-printingiscorrect;所有的套印内容是否正确；e)correctfunctioningoflinemonitors.在线监控装置的功能是否正常。Samplestakenawayfromthepackaginglineshouldnotbereturned.样品从包装线取走后不应当再返还5.55.Productswhichhavebeeninvolvedinanunusualeventshouldonlybereintroducedintotheprocessafterspecialinspection,investigationandapprovalbyauthorisedpersonnel.Detailedrecordshouldbekeptofthisoperation.154/154 只有通过专门检查、调查，并由授权人员批准后，出现异常情况时的产品方可返回包装操作。此过程应当有详细记录。5.56.Anysignificantorunusualdiscrepancyobservedduringreconciliationoftheamountofbulkproductandprintedpackagingmaterialsandthenumberofunitsproducedshouldbeinvestigatedandsatisfactorilyaccountedforbeforerelease.在物料平衡检查中，发觉半成品、已印刷的包装材料以及数量有显著或异常差异时，应当进行调查，未得到合理解释前，不得放行。5.57.Uponcompletionofapackagingoperation,anyunusedbatch-codedpackagingmaterialsshouldbedestroyedandthedestructionrecorded.Adocumentedprocedureshouldbefollowedifuncodedprintedmaterialsarereturnedtostock.包装结束时，应当全部销毁已打印批号的剩余包装材料，并有记录。如将未打印批号的印刷包装材料退库，应当遵守书面规程。FINISHEDPRODUCTS成品5.58.Finishedproductsshouldbeheldinquarantine154/154 untiltheirfinalreleaseunderconditionsestablishedbythemanufacturer.在按企业所制定的标准最终放行前，产品应当待验贮存。5.59.TheevaluationoffinishedproductsanddocumentationwhichisnecessarybeforereleaseofproductforsalearedescribedinChapter6(QualityControl).产品放行销售前，评价成品及其必需的文件见第6章（质量操纵）。5.60.Afterrelease,finishedproductsshouldbestoredasusablestockunderconditionsestablishedbythemanufacturer.成品放行后，应当按药品生产企业规定的条件存放成品。REJECTED,RECOVEREDANDRETURNEDMATERIALS拒收的、回收的以及退回的物料5.61.Rejectedmaterialsandproductsshouldbeclearlymarkedassuchandstoredseparatelyinrestrictedareas.Theyshouldeitherbereturnedtothesuppliersor,whereappropriate,reprocessedordestroyed.154/154 Whateveractionistakenshouldbeapprovedandrecordedbyauthorisedpersonnel.拒收的物料和不合格的产品均应有清晰醒目的标志，并各自存放在单独的操纵区内。能够退给供应商，假如可能的话，也能够返工或销毁。不管采纳哪种方式处理，均应经授权人员批准并进行记录。5.62.Thereprocessingofrejectedproductsshouldbeexceptional.Itisonlypermittedifthequalityofthefinalproductisnotaffected,ifthespecificationsaremetandifitisdoneinaccordancewithadefinedandauthorisedprocedureafterevaluationoftherisksinvolved.Recordshouldbekeptofthereprocessing.不合格产品返工应属例外。只有不阻碍最终产品质量、符合质量标准，且依照详细的经批准的规程对相关风险评估后，才同意返工处理。返工应当有相应记录。5.63.Therecoveryofallorpartofearlierbatches,whichconformtotherequiredqualitybyincorporationintoabatchofthesameproductatadefinedstageofmanufactureshouldbeauthorisedbeforehand.This154/154 recoveryshouldbecarriedoutinaccordancewithadefinedprocedureafterevaluationoftherisksinvolved,includinganypossibleeffectonshelflife.Therecoveryshouldberecorded.只有经预先批准，方可将往常生产的所有或部分批次的合格产品，在某一确定的生产工序合并到同一产品的一个批次中予以回收。应对相关的质量风险（包括可能对产品货架期的阻碍）进行评估后，方可按预定的规程进行回收处理。回收应有相应记录。5.64.Theneedforadditionaltestingofanyfinishedproductwhichhasbeenreprocessed,orintowhicharecoveredproducthasbeenincorporated,shouldbeconsideredbytheQualityControlDepartment.对返工处理后或回收合并的成品，质量操纵部门应当考虑进行额外的检验。5.65.Productsreturnedfromthemarketandwhichhaveleftthecontrolofthemanufacturershouldbedestroyedunlesswithoutdoubttheirqualityissatisfactory;theymaybeconsideredforre-sale,re-labellingorrecoverywithasubsequentbatchonly154/154 aftertheyhavebeencriticallyassessedbytheQualityControlDepartmentinaccordancewithawrittenprocedure.Thenatureoftheproduct,anyspecialstorageconditionsitrequires,itsconditionandhistory,andthetimeelapsedsinceitwasissuedshouldallbetakenintoaccountinthisassessment.Whereanydoubtarisesoverthequalityoftheproduct,itshouldnotbeconsideredsuitableforre-issueorre-use,althoughbasicchemicalre-processingtorecoveractiveingredientsmaybepossible.Anyactiontakenshouldbeappropriatelyrecorded.从市场上退回并已脱离药品生产企业操纵的产品应当予以销毁，除非对其质量无可置疑；只有经质量操纵部门依照书面规程严格评价后，方可考虑将退回的产品重新销售、重新贴签，或在后续的批次中回收。评价时，应当考虑产品的性质、所需的专门贮存条件、产品的现状和历史，以及发放与退回之间的间隔时刻等因素。即使有可能利用基础化学方法从退货中回收活性成分，但假如对产品质量存有任何怀疑时，就不应再考虑产品的重新发放或重新使用。所有的活动均应有相应记录。154/154 154/154 CHAPTER6第六章质量操纵QUALITYCONTROLPRINCIPLE原则QualityControlisconcernedwithsampling,specificationsandtestingaswellastheorganisation,documentationandreleaseprocedureswhichensurethatthenecessaryandrelevanttestsarecarriedout,andthatmaterialsarenotreleasedforuse,norproductsreleasedforsaleorsupply,untiltheirqualityhasbeenjudgedsatisfactory.QualityControlisnotconfinedtolaboratoryoperations,butmustbeinvolvedinalldecisionswhichmayconcernthequalityoftheproduct.TheindependenceofQualityControlfromProductionisconsideredfundamentaltothesatisfactoryoperationofQualityControl(seealsoChapter1).154/154 质量操纵涉及取样、质量标准与检验，以及组织、文件与放行规程，这些差不多上为了确保开展了相关必要的检验，同时在按要求判定之前，物料不被放行使用、产品不被放行销售。质量操纵不局限于实验室操作，还必须包括所有与产品质量有关的决定。质量操纵独立于生产是有效进行质量操纵的基础。GENERAL总则6.1.EachholderofamanufacturingauthorisationshouldhaveaQualityControlDepartment.Thisdepartmentshouldbeindependentfromotherdepartments,andundertheauthorityofapersonwithappropriatequalificationsandexperience,whohasoneorseveralcontrollaboratoriesathisdisposal.AdequateresourcesmustbeavailabletoensurethatalltheQualityControlarrangementsareeffectivelyandreliablycarriedout.每个生产许可证持有人都应当有一个质量操纵部门。质量操纵部门应当独立于其他部门，该部门负责人应当具有适当的资质和经验，该负责人能够同时治理一个或几个实验室。必须有足够的资源来保证有效且可靠地实施质量操纵措施。6.2.TheprincipaldutiesoftheheadofQualityControlaresummarisedinChapter2.TheQuality154/154 ControlDepartmentasawholewillalsohaveotherduties,suchastoestablish,validateandimplementallqualitycontrolprocedures,keepthereferencesamplesofmaterialsandproducts,ensurethecorrectlabellingofcontainersofmaterialsandproducts,ensurethemonitoringofthestabilityoftheproducts,participateintheinvestigationofcomplaintsrelatedtothequalityoftheproduct,etc.Alltheseoperationsshouldbecarriedoutinaccordancewithwrittenproceduresand,wherenecessary,recorded.质量操纵负责人要紧职责在第2章已有概述。总体而言，质量操纵部门还有其他职责，如建立、验证和实施所有质量操纵规程，保存物料和产品的对比样品，保证物料和产品包装容器的正确标识，保证开展产品稳定性考察，参与产品质量相关的投诉调查等。所有这些操作都应当按照书面的规程来执行，必要时进行记录。6.3.Finishedproductassessmentshouldembraceallrelevantfactors,includingproductionconditions,resultsofin-processtesting,areviewofmanufacturing(includingpackaging)documentation,154/154 compliancewithFinishedProductSpecificationandexaminationofthefinalfinishedpack.成品的评估应当涵盖所有相关因素，包括生产条件、中间过程操纵检验结果、生产文件（包括包装)的回忆、成品是否符合质量标准要求以及对最终包装的检查。6.4.QualityControlpersonnelshouldhaveaccesstoproductionareasforsamplingandinvestigationasappropriate.质量操纵人员应当有权进入生产区域进行取样和调查。GOODQUALITYCONTROLLABORATORYPRACTICE质量操纵实验室治理规范6.5.ControlLaboratorypremisesandequipmentshouldmeetthegeneralandspecificrequirementsforQualityControlareasgiveninChapter3.质量操纵实验室设施与设各应当符合第3章描述的质量操纵区域总体要求与特定要求。6.6.Thepersonnel,premises,andequipmentinthelaboratoriesshouldbeappropriatetothetasksimposedbythenatureandthescaleofthemanufacturing154/154 operations.Theuseofoutsidelaboratories,inconformitywiththeprinciplesdetailedinChapter7,ContractAnalysis,canbeacceptedforparticularreasons,butthisshouldbestatedintheQualityControlrecords.实验室的人员、设施与设备应与生产操作性质与规模所要求开展的检验任务相适应。因为专门缘故，在遵守第7章合同分析中给出的详细原则的条件下，使用外部实验室是可同意的，但应当在质量操纵记录上体现出来。DOCUMENTATION文件治理6.7.LaboratorydocumentationshouldfollowtheprinciplesgiveninChapter4.AnimportantpartofthisdocumentationdealswithQualityControlandthefollowingdetailsshouldbereadilyavailabletotheQualityControlDepartment:实验室文件治理应当符合第4章给出的原则。实验室文件治理专门重要的一部分是关于质量操纵的内容，质量操纵部门应当有下列文件：lØspecifications;质量标准；154/154 lØsamplingprocedures;取样规程；lØtestingproceduresandrecords(includinganalyticalworksheetsand/orlaboratorynotebooks);检验规程与记录（包括分析用的工作簿和/或实验室笔记本）；lØanalyticalreportsand/orcertificates;分析报告和/或证明；lØdatafromenvironmentalmonitoring,whererequired;必要时的环境监测数据；lØvalidationrecordsoftestmethods,whereapplicable;适当的分析方法验证记录；lØproceduresforandrecordsofthecalibrationofinstrumentsandmaintenanceofequipment.仪器和设备的校准、保养规程与记录。6.8.AnyQualityControldocumentationrelatingtoabatchrecordshouldberetainedforoneyearaftertheexpirydateofthebatch.任何与批记录有关的质量操纵文件应当保留至该批有效期后一年，及基于第2001/83EC号法令第51(3)条，质量受权人签发放行证明后至少5年。154/154 6.9.Forsomekindsofdata(e.g.analyticaltestsresults,yields,environmentalcontrols,...)itisrecommendedthatrecordsinamannerpermittingtrendevaluationbekept.关于某些类型的数据（如分析检验结果、产量、环境操纵)，建议这类数据的保存方式应当便于进行趋势评价。6.10.Inadditiontotheinformationwhichispartofthebatchrecord,otheroriginaldatasuchaslaboratorynotebooksand/orrecordsshouldberetainedandreadilyavailable.其他原始资料，如实验室笔记本和/或记录，作为批记录的一部分，应当保存并容易读取。SAMPLING取样6.11.Thesampletakingshouldbedoneinaccordancewithapprovedwrittenproceduresthatdescribe:应当按经批准的书面规程取样，规程内容包括：lØthemethodofsampling;取样方法；lØtheequipmenttobeused;使用的设备；lØtheamountofthesampletobetaken;取样量；154/154 lØinstructionsforanyrequiredsub-divisionofthesample;分配样品所需要的任何讲明；lØthetypeandconditionofthesamplecontainertobeused;所用样品容器的类型和条件；lØtheidentificationofcontainerssampled;样品容器的标识；lØanyspecialprecautionstobeobserved,especiallywithregardtothesamplingofsterileornoxiousmaterials;需要注意的专门事项，特不是无菌和有害物料的取样；lØthestorageconditions;贮存条件；lØinstructionsforthecleaningandstorageofsamplingequipment.取样设备的清洁和贮存讲明。6.12.Referencesamplesshouldberepresentativeofthebatchofmaterialsorproductsfromwhichtheyaretaken.Othersamplesmayalsobetakentomonitorthemoststressedpartofaprocess(e.g.beginningorendofaprocess).154/154 批物料或批产品的对比样品应当有代表性。其他样品能够用来监测最重要的生产过程（如工艺的开始或结束)。6.13.Samplecontainersshouldbearalabelindicatingthecontents,withthebatchnumber,thedateofsamplingandthecontainersfromwhichsampleshavebeendrawn.盛放样品的容器应当贴标签标明内容物、批号、取样日期以及从何种容器中取样。6.14.Referencesamplesfromeachbatchoffinishedproductsshouldberetainedtilloneyearaftertheexpirydate.Finishedproductsshouldusuallybekeptintheirfinalpackagingandstoredundertherecommendedconditions.Samplesofstartingmaterials(otherthansolvents,gasesandwater)shouldberetainedforatleasttwoyearsafterthereleaseoftheproductiftheirstabilityallows.Thisperiodmaybeshortenediftheirstability,asmentionedintherelevantspecification,isshorter.Referencesamplesofmaterialsandproductsshouldbeofasizesufficienttopermitatleastafullre-examination.154/154 每一批成品的对比样品应该保留到有效期后一年。成品通常应该按最后的包装形式储存在推举的条件下。起始物料的样品(除了溶剂、气体和水)若稳定性同意应该保留产品公布后至少两年。若其在相关规范中提到的稳定性差，这段时刻可能会缩短。物料和产品的对比样本的大小应满足至少一个完整的复查。TESTING检验6.15.Analyticalmethodsshouldbevalidated.Alltestingoperationsdescribedinthemarketingauthorisationshouldbecarriedoutaccordingtotheapprovedmethods.分析方法应当通过验证。上市许可中描述的检验操作应当按照批准的方法来实施。6.16.Theresultsobtainedshouldberecordedandcheckedtomakesurethattheyareconsistentwitheachother.Anycalculationsshouldbecriticallyexamined.应当记录并检查得到的结果，确保相互一致。任何计算都应当通过严格的检查。6.17.Thetestsperformedshouldberecordedandtherecordsshouldincludeatleastthefollowingdata:154/154 记录所做的测试，至少记录以下数据：a)nameofthematerialorproductand,whereapplicable,dosageform;物料或产品的名称，必要时标明剂型；b)batchnumberand,whereappropriate,themanufacturerand/orsupplier;批号，如可能应标明生产企业和/或供应商；c)referencestotherelevantspecificationsandtestingprocedures;参考的相关质量标准与检验规程；d)testresults,includingobservationsandcalculations,andreferencetoanycertificatesofanalysis;检验结果，包括观看值与计算值，以及引用任何检验报告单；e)datesoftesting;检验日期；f)initialsofthepersonswhoperformedthetesting;实施检验的人员的签字；g)initialsofthepersonswhoverifiedthetestingandthecalculations,whereappropriate;154/154 对检验与计算进行复核的人员的签字（签姓名首字母/缩写），在适当的情况下；h)aclearstatementofreleaseorrejection(orotherstatusdecision)andthedatedsignatureofthedesignatedresponsibleperson.放行或拒绝（或其他决定状况）的清晰描述，指定责任人员签名和签署曰期。6.18.Allthein-processcontrols,includingthosemadeintheproductionareabyproductionpersonnel,shouldbeperformedaccordingtomethodsapprovedbyQualityControlandtheresultsrecorded.所有中间过程操纵，包括生产人员在生产区域进行的操纵，都应当按照质量操纵部门批准的方法进行，并记录结果。6.19.Specialattentionshouldbegiventothequalityoflaboratoryreagents,volumetricglasswareandsolutions,referencestandardsandculturemedia.Theyshouldbepreparedinaccordancewithwrittenprocedures.154/154 应当特不注意实验室试剂、玻璃量具和溶液、对比品和培养基的质量。应当依照书面规程来预备6.20.Laboratoryreagentsintendedforprolongeduseshouldbemarkedwiththepreparationdateandthesignatureofthepersonwhopreparedthem.Theexpirydateofunstablereagentsandculturemediashouldbeindicatedonthelabel,togetherwithspecificstorageconditions.Inaddition,forvolumetricsolutions,thelastdateofstandardisationandthelastcurrentfactorshouldbeindicated.若要延长实验室试剂的使用期，应当标明配制日期并有配制者签名。不稳定试剂和培养基的标签上应当标明有效期以及专门贮存条件。另外，应当标明滴定液最近一次标化日期和最近一次校正因子。6.21.Wherenecessary,thedateofreceiptofanysubstanceusedfortestingoperations(e.g.reagentsandreferencestandards)shouldbeindicatedonthecontainer.Instructionsforuseandstorageshouldbefollowed.Incertaincasesitmaybenecessarytocarry154/154 outanidentificationtestand/orothertestingofreagentmaterialsuponreceiptorbeforeuse.必要时，检验所用物质（如，试剂和对比品）的容器上应当标明接收日期、使用和贮存讲明。某些情况下，在试剂接收后或使用前，可能需要进行鉴不试验和/或其他试验。6.22.Animalsusedfortestingcomponents,materialsorproducts,should,whereappropriate,bequarantinedbeforeuse.Theyshouldbemaintainedandcontrolledinamannerthatassurestheirsuitabilityfortheintendeduse.Theyshouldbeidentified,andadequaterecordsshouldbemaintained,showingthehistoryoftheiruse.组分、物料或产品检验用动物在使用前应当适当隔离治理。应当用适当的方法饲养和治理动物，确保适用于预期用途。应当对动物进行鉴定，并留存适当的记录，以便追溯动物的使用历史。ON-GOINGSTABILITYPROGRAMME持续稳定性考察6.23.Aftermarketing,thestabilityofthemedicinalproductshouldbemonitoredaccordingtoacontinuousappropriateprogrammethatwillpermitthedetectionof154/154 anystabilityissue(e.g.changesinlevelsofimpurities,ordissolutionprofile)associatedwiththeformulationinthemarketedpackage.药品上市后，应当按照适当的连续程序监测稳定性，如此能够检测到市售包装中的药物任何稳定性问题（例如，杂质水平或溶出情况的变化)。6.24.Thepurposeoftheon-goingstabilityprogrammeistomonitortheproductoveritsshelflifeandtodeterminethattheproductremains,andcanbeexpectedtoremain,withinspecificationsunderthelabelledstorageconditions.持续稳定性考察的目的是在产品有效期内监测产品，并确定在标识的贮存条件下贮存时，产品质量符合，同时期望能符合质量标准。6.25.Thismainlyappliestothemedicinalproductinthepackageinwhichitissold,butconsiderationshouldalsobegiventotheinclusionintheprogrammeofbulkproduct.Forexample,whenthebulkproductisstoredforalongperiodbeforebeingpackagedand/or154/154 shippedfromamanufacturingsitetoapackagingsite,theimpactonthestabilityofthepackagedproductshouldbeevaluatedandstudiedunderambientconditions.Inaddition,considerationshouldbegiventointermediatesthatarestoredandusedoverprolongedperiods.Stabilitystudiesonreconstitutedproductareperformedduringproductdevelopmentandneednotbemonitoredonanon-goingbasis.However,whenrelevant,thestabilityofreconstitutedproductcanalsobemonitored.持续稳定性考察要紧适用于已销售的带包装的药品，但也应当考虑对半成品进行持续稳定性考察。例如，在包装前，半成品贮存了专门长一段时刻，和/或从生产场地运送到包装场地，这时就要评估并研究周围环境对已包装的半成品的稳定性的阻碍。另外，还要考虑超期贮存和使用的中间体。重组产品的稳定性研究在产品开发时期进行，不需要进行持续稳定性监测。尽管如此，必要时也应当对重组产品的稳定性进行监测。6.26.Theon-goingstabilityprogrammeshouldbedescribedinawrittenprotocolfollowingthegeneral154/154 rulesofChapter4andresultsformalisedasareport.Theequipmentusedfortheon-goingstabilityprogramme(stabilitychambersamongothers)shouldbequalifiedandmaintainedfollowingthegeneralrulesofChapter3andannex15.依照第4章总则的要求，应当有持续稳定性考察书面方案，并将结果形成报告。依照第3章总则和附录15的要求，持续稳定性考察所用设备（其中包括稳定性试验箱）应当通过确认并得到维护。6.27.Theprotocolforanon-goingstabilityprogrammeshouldextendtotheendoftheshelflifeperiodandshouldinclude,butnotbelimitedto,thefollowingparameters:持续稳定性考察方案应当延长到货架期结束，应当包括但不限于以下内容：•numberofbatch(es)perstrengthanddifferentbatchsizes,ifapplicable每个规格的批号、不同的批量大小，假如有的话•relevantphysical,chemical,microbiologicaland154/154 biologicaltestmethods相关物理、化学、微生物学和生物学检验方法；•acceptancecriteria可同意标准；•referencetotestmethods参考的检验方法；•descriptionofthecontainerclosuresystem(s)包装方式描述；•testingintervals(timepoints)检验间隔（时刻点）；•descriptionoftheconditionsofstorage(standardisedICHconditionsforlongtermtesting,consistentwiththeproductlabelling,shouldbeused)贮存条件描述（长期试验应当执行ICH规定的条件，同时应当与产品标签所示条件一致）;•otherapplicableparametersspecifictothemedicinalproduct.其他与药品相关的专门参数。6.28.Theprotocolfortheon-goingstabilityprogrammecanbedifferentfromthatoftheinitiallong-termstabilitystudyassubmittedinthemarketingauthorizationdossierprovidedthatthisisjustified154/154 anddocumentedintheprotocol(forexamplethefrequencyoftesting,orwhenupdatingtoICHrecommendations).持续稳定性考察方案能够不同于在上市许可注册资料中提交的最初长期稳定性研究，但应当有合理性评估并在考察方案中描述（例如，检测频率能够不同，或依照ICH指南推举的做法有更新）。6.29.Thenumberofbatchesandfrequencyoftestingshouldprovideasufficientamountofdatatoallowfortrendanalysis.Unlessotherwisejustified,atleastonebatchperyearofproductmanufacturedineverystrengthandeveryprimarypackagingtype,ifrelevant,shouldbeincludedinthestabilityprogramme(unlessnoneareproducedduringthatyear).Forproductswhereon-goingstabilitymonitoringwouldnormallyrequiretestingusinganimalsandnoappropriatealternative,validatedtechniquesareavailable,thefrequencyoftestingmaytakeaccountofarisk-benefitapproach.Theprincipleofbracketingandmatrixingdesignsmay154/154 beappliedifscientificallyjustifiedintheprotocol.考察批次和检验频率应当提供出充分的数据，以便进行趋势分析。除非另有合理性评估，每种规格、每种内包装类型的产品每年至少有一批纳入持续稳定性考察打算（除非当年没有生产）。关于持续稳定性考察中通常需要使用动物进行检测的产品，假如没有适当的可替代且通过验证的做法，可考虑风险-收益方法来确定检测频率。假如在考察方案时有科学论证，可运用正交矩阵设计的原则。6.30.Incertainsituations,additionalbatchesshouldbeincludedintheon-goingstabilityprogramme.Forexample,anon-goingstabilitystudyshouldbeconductedafteranysignificantchangeorsignificantdeviationtotheprocessorpackage.Anyreworking,reprocessingorrecoveryoperationshouldalsobeconsideredforinclusion.在某种情况下，持续稳定性考察中应当增加额外批次。例如，工艺或包装过程中发生了任何显著变更或显著偏差批次。任何重新加工、返工或回收操作的批次也应当考虑做持续稳定性考察。6.31.Resultsofon-goingstabilitystudiesshouldbe154/154 madeavailabletokeypersonneland,inparticular,totheAuthorisedPerson(s).Whereon-goingstabilitystudiesarecarriedoutatasiteotherthanthesiteofmanufactureofthebulkorfinishedproduct,thereshouldbeawrittenagreementbetweenthepartiesconcerned.Resultsofon-goingstabilitystudiesshouldbeavailableatthesiteofmanufactureforreviewbythecompetentauthority.关键人员，特不是质量受权人，应当有权获得持续稳定性考察的结果。假如持续稳定性考察所在场地与半成品和成品的生产场地不同，则各方需要有书面协议。生产场地在同意官方检查时，在生产场地应当有持续稳定性考察结果。6.32.Outofspecificationorsignificantatypicaltrendsshouldbeinvestigated.Anyconfirmedoutofspecificationresult,orsignificantnegativetrend,shouldbereportedtotherelevantcompetentauthorities.Thepossibleimpactonbatchesonthemarketshouldbeconsideredinaccordancewithchapter8oftheGMPGuideandinconsultationwiththe154/154 relevantcompetentauthorities.应当调查超标数据或显著的非典型趋势。应当向官方机构报告任何经确认的超标数据或显著的负面趋势。依照本GMP指南第8章的要求，应当考虑超标数据或显著的负面趋势对已销售批次可能造成的阻碍，并征求相关官方机构的意见。6.33.Asummaryofallthedatagenerated,includinganyinterimconclusionsontheprogramme,shouldbewrittenandmaintained.Thissummaryshouldbesubjectedtoperiodicreview.应当书面汇总生成的所有数据并保存，包括对稳定性考察的任何临时结论。应当定期回忆稳定性数据汇总。154/154 CHAPTER7第七章托付生产与托付检验CONTRACTMANUFACTUREANDANALYSISPRINCIPLE原则Contractmanufactureandanalysismustbecorrectlydefined,agreedandcontrolledinordertoavoidmisunderstandingswhichcouldresultinaproductorworkofunsatisfactoryquality.TheremustbeawrittencontractbetweentheContractGiverandtheContractAcceptorwhichclearlyestablishesthedutiesofeachparty.Thecontractmustclearlystatethewayinwhichtheauthorizedpersonreleasingeachbatchofproductforsaleexerciseshisfullresponsibility.托付生产和托付检验应当得到适当的界定、协调及操纵，以幸免误解，这些误解可能会对产品或工作的质量产生不利阻碍。托付方和受托方必须签订书面合同，明确各方的职责。合同中必须清晰地描述获授权人对每批出售产品进行确认放行的方式，使获授权人的全部职责得到履行。Note:ThisChapterdealswiththeresponsibilitiesof154/154 manufacturerstowardstheComponentAuthoritiesoftheParticipatingAuthoritieswithrespecttothegrantingofmarketingandmanufacturingauthorisations.Itisnotintendedinanywaytoaffecttherespectiveliabilityofcontractacceptorsandcontractgiverstoconsumers.注：本章涉及的职责是指就成员国官方机构批准上市许可和生产许可而言生产企业的职责。本章无意以任何方式阻碍托付方和受托方各自对消费者的责任。GENERAL总则7.1.Thereshouldbeawrittencontractcoveringthemanufactureand/oranalysisarrangedundercontractandanytechnicalarrangementsmadeinconnectionwithit.应当有书面合同规定相关产品或操作的外包活动，并规定相关的任何技术约定。7.2.Allarrangementsforcontractmanufactureandanalysisincludinganyproposedchangesintechnicalorotherarrangementsshouldbeinaccordancewiththemarketingauthorisationfortheproductconcerned.154/154 外包活动所有事项包括任何提议的技术变更或其他事项的变更应当符合相关产品上市许可的要求。THECONTRACTGIVER托付方7.3.TheContractGiverisresponsibleforassessingthecompetenceoftheContractAcceptortocarryoutsuccessfullytheworkrequiredandforensuringbymeansofthecontractthattheprinciplesandGuidelinesofGMPasinterpretedinthisGuidearefollowed.托付方有责任评估受托方成功实施所需工作的能力，并确保通过合同约束使本章所述GMP原则及指南得到遵守。7.4.TheContractGivershouldprovidetheContractAcceptorwithalltheinformationnecessarytocarryoutthecontractedoperationscorrectlyinaccordancewiththemarketingauthorisationandanyotherlegalrequirements.TheContractGivershouldensurethattheContractAcceptorisfullyawareofanyproblemsassociatedwiththeproductortheworkwhichmightposeahazardtohispremises,equipment,personnel,154/154 othermaterialsorotherproducts.托付方应当向受托方提供正确开展托付活动所需的所有信息和知识，确保托付活动符合上市许可要求及其他法规要求。托付方应当确保受托方充分知晓产品或与工作有关的任何问题，这些问题可能会给受托方的设施、设备、人员、其他物料或其他产品造成不利阻碍。7.5.TheContractGivershouldensurethatallprocessedproductsandmaterialsdeliveredtohimbytheContractAcceptorcomplywiththeirspecificationsorthattheproductshavebeenreleasedbyanauthorisedperson.托付方应确保受托方交付给他的全过程产品和物料符合规格要求，或者产品通过授权人放行。THECONTRACTACCEPTOR受托方7.6.TheContractAcceptormusthaveadequatepremisesandequipment,knowledgeandexperience,andcompetentpersonneltocarryoutsatisfactorilytheworkorderedbytheContractGiver.Contractmanufacturemaybeundertakenonlybyamanufacturerwhoistheholderof154/154 amanufacturingauthorisation.受托方必须有使托付方中意的工作能力，例如有适当的设施、设备、知识、经验，以及有资质的人员。合同生产只能由持有生产许可的制造商进行生产。7.7.TheContractAcceptorshouldensurethatallproductsormaterialsdeliveredtohimaresuitablefortheirintendedpurpose.受托方应当确保收到的所有产品或物料都适用于预期目的。7.8.TheContractAcceptorshouldnotpasstoathirdpartyanyoftheworkentrustedtohimunderthecontractwithouttheContractGiver"spriorevaluationandapprovalofthearrangements.ArrangementsmadebetweentheContractAcceptorandanythirdpartyshouldensurethatthemanufacturingandanalyticalinformationismadeavailableinthesamewayasbetweentheoriginalContractGiverandContractAcceptor.在托付方没有事先评估和批准的条件下，受托方不得将任何受托的任务转给第三方。受托方与第三方的协议应当确保154/154 生产和分析的信息与原始托付方和受托方一致。7.9.TheContractAcceptorshouldrefrainfromanyactivitywhichmayadverselyaffectthequalityoftheproductmanufacturedand/oranalysedfortheContractGiver.受托方应幸免任何可能会对托付方产品生产和/或分析质量产生不良阻碍的活动。THECONTRACT合同7.10.AcontractshouldbedrawnupbetweentheContractGiverandtheContractAcceptorwhichspecifiestheirrespectiveresponsibilitiesrelatingtothemanufactureandcontroloftheproduct.Technicalaspectsofthecontractshouldbedrawnupbycompetentpersonssuitablyknowledgeableinpharmaceuticaltechnology,analysisandGoodManufacturingPractice.Allarrangementsformanufactureandanalysismustbeinaccordancewiththemarketingauthorisationandagreedbybothparties.托付方与受托方应当签订合同，合同应当规定各自154/154 关于产品生产和操纵分析的责任。合同技术方面的内容应当由具有相应资质、对制药技术、分析和药品生产质量治理规范有适当知识的人员拟定。生产和分析的所有的约定都必须符合上市许可的要求，并经各方同意。7.11.ThecontractshouldspecifythewayinwhichtheauthorisedpersonreleasingthebatchforsaleensuresthateachbatchhasbeenmanufacturedandcheckedforcompliancewiththerequirementsofMarketingAuthorisation.7.12.Thecontractshoulddescribeclearlywhoisresponsibleforpurchasingmaterials,testingandreleasingmaterials,undertakingproductionandqualitycontrols,includingin-processcontrols,andwhohasresponsibilityforsamplingandanalysis.Inthecaseofcontractanalysis,thecontractshouldstatewhetherornottheContractAcceptorshouldtakesamplesatthepremisesofthemanufacturer.合同应当清晰描述由谁负责采购、物料的检验及放行、实施生产与质量操纵，包括中间过程操纵、负责取样和分析154/154 的人员。至于合同分析，合同应规定是否由受托方在生产的前提下进行取样。7.13.Manufacturing,analyticalanddistributionrecords,andreferencesamplesshouldbekeptby,orbeavailableto,theContractGiver.Anyrecordsrelevanttoassessingthequalityofaproductintheeventofcomplaintsorasuspecteddefectmustbeaccessibleandspecifiedinthedefect/recallproceduresoftheContractGiver.托付方应保存或能获得生产、分析与销售记录以及对比样品的所有记录。托付方必须能够获得投诉产品或疑似缺陷产品的质量评价记录，并在相应缺陷/召回的规程中予以规定。7.14.ThecontractshouldpermittheContractGivertovisitthefacilitiesoftheContractAcceptor.合同应当同意托付方参观受托方的设施7.15.Incaseofcontractanalysis,theContractAcceptorshouldunderstandthatheissubjecttoinspectionbythecompetentAuthorities.若合同分析有问题，受托方应该由主管机关对其进行检查。154/154 CHAPTER8第八章产品投诉和召回COMPLAINTSANDPRODUCTRECALLPRINCIPLE原则Allcomplaintsandotherinformationconcerningpotentiallydefectiveproductsmustbecarefullyreviewedaccordingtowrittenprocedures.Inordertoprovideforallcontingencies,asystemshouldbedesignedtorecall,ifnecessary,promptlyandeffectivelyproductsknownorsuspectedtobedefectivefromthemarket.必须按照书面规程认真审核潜在缺陷产品所有投诉与其他信息。为了使所有意外事件都能得到适当的处理，应当设计一个召回系统，以便在必要时能迅速、有效地从市场召回已知有缺陷或疑似有缺陷的产品。COMPLAINTS投诉8.1.Apersonshouldbedesignatedresponsibleforhandlingthecomplaintsanddecidingthemeasurestobetakentogetherwithsufficientsupportingstaffto154/154 assisthim.Ifthispersonisnottheauthorisedperson,thelattershouldbemadeawareofanycomplaint,investigationorrecall.应当指定人员负责处理投诉和决定所采取的措施，同时应当有足够的支持团队来协助他。假如不由质量受权人负责，则质量受权人应当知晓任何投诉、调查或召回。8.2.Thereshouldbewrittenproceduresdescribingtheactiontobetaken,includingtheneedtoconsiderarecall,inthecaseofacomplaintconcerningapossibleproductdefect.应当有书面规程描述要采取的行动，包括涉及潜在产品缺陷的投诉时，要考虑召回。8.3.Anycomplaintconcerningaproductdefectshouldberecordedwithalltheoriginaldetailsandthoroughlyinvestigated.ThepersonresponsibleforQualityControlshouldnormallybeinvolvedinthestudyofsuchproblems.应当记录任何涉及产品缺陷的投诉的原始细节并进行完全调查。质量操纵部门负责人通常应当参与此类问题调查。154/154 8.4.Ifaproductdefectisdiscoveredorsuspectedinabatch,considerationshouldbegiventocheckingotherbatchesinordertodeterminewhethertheyarealsoaffected.Inparticular,otherbatcheswhichmaycontainreworksofthedefectivebatchshouldbeinvestigated.假如在一批产品中发觉或怀疑有缺陷，应当考虑对其他批次进行检査，以确定其他批次是否也受到阻碍。特不是，假如其他批产品含有缺陷批的重新加工部分，则应当调查其他批次。8.5.Allthedecisionsandmeasurestakenasaresultofacomplaintshouldberecordedandreferencedtothecorrespondingbatchrecords.应当记录针对投诉作出的决定和采取的所有措施，并引用相关批记录。8.6.Complaintsrecordsshouldbereviewedregularlyforanyindicationofspecificorrecurringproblemsrequiringattentionandpossiblytherecallofmarketedproducts.154/154 应当定期对投诉记录进行回忆，找出特征问题或重复出现的问题，从而加强关注或可能召回上市产品。8.7.Specialattentionshouldbegiventoestablishingwhetheracomplaintwascausedbecauseofcounterfeiting.特不需要注意的是，应当确定是否是由假药引起的投诉。8.8.TheCompetentAuthoritiesshouldbeinformedifamanufacturerisconsideringactionfollowingpossiblyfaultymanufacture,productdeterioration,detectionofcounterfeitingoranyotherseriousqualityproblemswithaproduct.假如生产企业正在考虑对可能的生产错误、产品变质、发觉伪造或任何其他严峻产品质量问题釆取措施，生产企业应当通知官方机构。RECALLS召回8.9.Apersonshouldbedesignatedasresponsibleforexecutionandco-ordinationofrecallsandshouldbesupportedbysufficientstafftohandlealltheaspectsoftherecallswiththeappropriatedegreeofurgency.Thisresponsiblepersonshouldnormallybeindependent154/154 ofthesalesandmarketingorganisation.Ifthispersonisnottheauthorisedperson,thelattershouldbemadeawareofanyrecalloperation.应当指定人员负责召回工作的开展和协调，同时依照问题的紧急程度，有足够的支持团队来协助他处理召回的各方面工作。通常，召回负责人应当独立于销售和市场部门。假如不是质量受权人负责，则质量受权人应当知晓所有的召回情况。8.10.Thereshouldbeestablishedwrittenprocedures,regularlycheckedandupdatedwhennecessary,inordertoorganiseanyrecallactivity.应当制定书面的召回规程，并定期检查，必要时进行修订，以便依照该规程能组织任何召回活动。8.11.Recalloperationsshouldbecapableofbeinginitiatedpromptlyandatanytime.应当在任何时候都能够立即启动召回。8.12.AllCompetentAuthoritiesofallcountriestowhichproductsmayhavebeendistributedshouldbeinformedpromptlyifproductsareintendedtoberecalledbecausetheyare,oraresuspectedof,being154/154 defective.假如产品因已知缺陷或疑似缺陷需要召回，应当立即通知该产品可能销售到的所有国家的主管机构。8.13.Thedistributionrecordsshouldbereadilyavailabletotheperson(s)responsibleforrecalls,andshouldcontainsufficientinformationonwholesalersanddirectlysuppliedcustomers(withaddresses,phoneand/orfaxnumbersinsideandoutsideworkinghours,batchesandamountsdelivered),includingthoseforexportedproductsandmedicalsamples.产品召回负责人应当容易获得产品销售记录，销售记录应当包括所有批发商和直销客户的充分资料(地址、工作时刻和非工作时刻联系电话和/或传真号码、销售的批号和数量)，包括出口产品和药品样品的上述信息。8.14.Recalledproductsshouldbeidentifiedandstoredseparatelyinasecureareawhileawaitingadecisionontheirfate.召回的产品应当有明显标识并隔离存放在安全场所，以待作出处理决定。154/154 8.15.Theprogressoftherecallprocessshouldberecordedandafinalreportissued,includingareconciliationbetweenthedeliveredandrecoveredquantitiesoftheproducts.应当记录召回进程，并签发最后的召回报告，包括交付产品和收回产品的数量平衡情况。8.16.Theeffectivenessofthearrangementsforrecallsshouldbeevaluatedregularly.应当定期评估召回程序的有效性。154/154 CHAPTER9第九章自检SELFINSPECTIONPRINCIPLESelfinspectionsshouldbeconductedinordertomonitortheimplementationandcompliancewitGoodManufacturingPracticeprinciplesandtoproposenecessarycorrectivemeasures.为了监督药品生产质量治理规范差不多原则的执行及符合性，并提出必要的纠正措施，应当进行自检。9.1.Personnelmatters,premises,equipment,documentation,production,qualitycontrol,distributionofthemedicinalproducts,arrangementsfordealingwithcomplaintsandrecalls,andselfinspection,shouldbeexaminedatintervalsfollowingapre-arrangedprogrammeinordertoverifytheirconformitywiththeprinciplesofQualityAssurance.应当按预定的程序，对人员情况、设施、设备、文件治理、生产治理、质量操纵、药品销售、投诉和召回的处理以及自检进行154/154 定期检查，以证实与质量保证原则的符合性。9.2.Selfinspectionsshouldbeconductedinanindependentanddetailedwaybydesignatedcompetentperson(s)fromthecompany.Independentauditsbyexternalexpertsmayalsobeuseful.应当由公司指定的具有资质的人员以独立、详细的方式执行自检。外部专家进行的独立审计也有所关心。9.3.Allselfinspectionsshouldberecorded.Reportsshouldcontainalltheobservationsmadeduringtheinspectionsand,whereapplicable,proposalsforcorrectivemeasures.Statementsontheactionssubsequentlytakenshouldalsoberecorded.所有自检应当有记录。自检报告中应当包括自检过程中的所有观看结果，以及建议的纠正措施，假如有的话。也应当记录随后釆取的措施。154/154'