史上最严 PIC／S GMP-2018 全文解读

史上最严PIC/SGMP-2018发布，全文解读2018年6月20日，PIC/S官网发布了新的GMP指南（PE009-14），新的指南修订了以下章节和附录：第三章：“厂房和设备”第五章：“生产”第八章：“投诉和召回”附录17：“实时放行检验和参数放行”修订后的GMP指南（PE009-14）将于2018年7月1日生效。新增及修订的条款翻译如下：PE009-14PIC/SGMPGUIDEPIC/SGMP指南CHAPTER3PREMISESANDEQUIPMENT第三章厂房设施和设备ProductionAreas生产区3.6Cross-contaminationshouldbepreventedforallproductsbyappropriatedesignandoperationofmanufacturingfacilities.Themeasurestopreventcross-contaminationshouldbecommensuratewiththerisks.QualityRiskManagementprinciplesshouldbeusedtoassessandcontroltherisks.应对生产设施采用适当的设计和操作以避免任何产品之间的交叉污染。防止交叉污染的措施应与风险相适应。应采用质量风险管理原则对这些风险进行评估和控制。1Dependingofthelevelofrisk,itmaybenecessarytodedicatepremisesandequipmentformanufacturingand/orpackagingoperationstocontroltheriskpresentedbysomemedicinalproducts.根据风险的水平，生产和/或包装操作应有专用的厂房设施及设备以控制来自其他产品的风险Dedicatedfacilitiesarerequiredformanufacturingwhenamedicinalproductpresentsariskbecause:当产品因下列原因存在风险时，应使用专用设施进行生产：i.theriskcannotbeadequatelycontrolledbyoperationaland/ortechnicalmeasures,风险无法通过操作和/或技术措施充分控制ii.scientificdatafromthetoxicologicalevaluationdoesnotsupportacontrollablerisk(e.g.allergenicpotentialfromhighlysensitisingmaterialssuchasbeta-lactams)or来自毒性评价的科学数据无法支持风险的可控性（例如，高致敏性物料，如β酰胺类）或iii.relevantresiduelimits,derivedfromthetoxicologicalevaluation,cannotbesatisfactorilydeterminedbyavalidatedanalyticalmethod.由毒性评价数据推倒出来的残留限度尚无有效的分析方法实现检测。2FurtherguidancecanbefoundinChapter5andinAnnexes2,3,4,5&6.更多指南详见章节5和附录2、3、4、5&6.CHAPTER5PRODUCTION第五章生产PREVENTIONOFCROSS-CONTAMINATIONINPRODUCTION防止生产过程交叉污染5.17.Normally,theproductionofnon-medicinalproductsshouldbeavoidedinareasandwithequipmentdestinedfortheproductionofmedicinalproductsbut,wherejustified,couldbeallowedwherethemeasurestopreventcross-contaminationwithmedicinalproductsdescribedbelowandinChapter3canbeapplied.Theproductionand/orstorageoftechnicalpoisons,suchaspesticides(exceptwheretheseareusedformanufactureofmedicinalproducts)andherbicides,shouldnotbeallowedinareasusedforthemanufactureand/orstorageofmedicinalproducts.通常，用于生产药品的设备和区域不得用于非药物产品生产，但是，如有充分理由，应用下列和第3章所述的防止药品交叉污染措施的情况下，允许生产非药物产品。技术性毒药生产和/或存储区域，如杀虫剂（除非用于制造医药产品的地方）和除草剂，不得用于药品生产和/或储存。35.18.Contaminationofastartingmaterialorofaproductbyanothermaterialorproductshouldbeprevented.Thisriskofaccidentalcross-contaminationresultingfromtheuncontrolledreleaseofdust,gases,vapours,aerosols,geneticmaterialororganismsfromactivesubstances,othermaterials(startingorin-process),andproductsinprocess,fromresiduesonequipment,andfromoperators’clothingshouldbeassessed.Thesignificanceofthisriskvarieswiththenatureofthecontaminantandthatoftheproductbeingcontaminated.Productsinwhichcross-contaminationislikelytobemostsignificantarethoseadministeredbyinjectionandthosegivenoveralongtime.However,contaminationofallproductsposesarisktopatientsafetydependentonthenatureandextentofcontamination.应防止起始物料或产品的被其他物料或产品污染。应评估来自生产过程中活性物质、其他物料（起始物料或生产过程物料）、产品的粉尘、气体、汽体、雾滴、基因物质或生物的非受控释放；设备残留；和操作人员衣服导致的潜在交叉污染风险。风险的严重性因污染物和受污染产品的性质而不同。那些通过注射给药和那些需要长期给药的产品的交叉污染则更为重要。但是，任何产品的污染都会导致病人用药安全的风险，取决于污染的性质和程度。45.19.Cross-contaminationshouldbepreventedbyattentiontodesignofthepremisesandequipmentasdescribedinChapter3.Thisshouldbesupportedbyattentiontoprocessdesignandimplementationofanyrelevanttechnicalororganizationalmeasures,includingeffectiveandreproduciblecleaningprocessestocontrolriskofcross-contamination.厂房设施和设备的设计应关注防止交叉污染，见章节3。这应依靠对工艺设计和实施任何相关技术和组织措施的关注，包括有效并可重现的清洁工艺以控制交叉污染的风险。5.20AQualityRiskManagementprocess,whichincludesapotencyandtoxicologicalevaluation,shouldbeusedtoassessandcontrolthecross-contaminationriskspresentedbytheproductsmanufactured.Factorsincluding;facility/equipmentdesignanduse,personnelandmaterialflow,microbiologicalcontrols,physico-chemicalcharacteristicsoftheactivesubstance,processcharacteristics,cleaningprocessesandanalyticalcapabilitiesrelativetotherelevantlimitsestablishedfromtheevaluationoftheproductsshouldalsobetakenintoaccount.TheoutcomeoftheQualityRiskManagementprocessshouldbethebasisfordeterminingthenecessityforandextenttowhichpremisesandequipmentshouldbededicatedtoaparticularproductorproductfamily.Thismayincludededicatingspecific5productcontactpartsordedicationoftheentiremanufacturingfacility.Itmaybeacceptabletoconfinemanufacturingactivitiestoasegregated,self-containedproductionareawithinamultiproductfacility,wherejustified.应使用质量风险管理，包括有效性和毒理学评价，来评估和控制所生产产品的交叉污染风险。设施/设备设计和使用，人流物流，微生物控制，活性物质的理化特性，工艺特性，清洁工艺和分析能力与通过产品评价建立的相关限度等因素也应被考虑。质量风险管理流程的结果应作为决定哪些厂房设施和设备应被专用于某一产品或某类产品的必要性和程度的基础。这可能包括专用特定产品接触部件或专用整个生产设施。在合理情况下，在多产品设施里面限制生产活动在一个隔离、独立的生产区域可能是可接受的。5.21TheoutcomeoftheQualityRiskManagementprocessshouldbethebasisfordeterminingtheextentoftechnicalandorganisationalmeasuresrequiredtocontrolrisksforcross-contamination.Thesecouldinclude,butarenotlimitedto,thefollowing:质量风险管理流程的结果应作为决定用以控制交叉污染风险的技术和组织措施的程度。这包括但不限于，如下：TechnicalMeasures技术措施6i.Dedicatedmanufacturingfacility(premisesandequipment);专用生产设施（厂房设施和设备）ii.Self-containedproductionareashavingseparateprocessingequipmentandseparateheating,ventilationandair-conditioning(HVAC)systems.Itmayalsobedesirabletoisolatecertainutilitiesfromthoseusedinotherareas;独立生产区域，配备单独的生产设备和单独的暖通空调系统（HVAC）。可以将特定公用系统独立于其他区域。iii.Designofmanufacturingprocess,premisesandequipmenttominimizeriskforcross-contaminationduringprocessing,maintenanceandcleaning;生产工艺，厂房设施和设备设计以减少生产、维护和清洁过程中的交叉污染风险。iv.Useof“closedsystems”forprocessingandmaterial/producttransferbetweenequipment;使用“封闭式系统”进行生产和设备间物料/产品转运v.Useofphysicalbarriersystems,includingisolators,ascontainmentmeasures;使用物理屏障系统作为限制措施，包括隔离器。vi.Controlledremovalofdustclosetosourceofthecontaminante.g.throughlocalisedextraction;污染源附近的粉尘应得到受控的清除，例如，通过除尘罩。7vii.Dedicationofequipment,dedicationofproductcontactpartsordedicationofselectedpartswhicharehardertoclean(e.g.filters),dedicationofmaintenancetools;专用设备、专用产品接触部件或者专用难以清洁的部件，专用维修工具。viii.Useofsingleusedisposabletechnologies;应用一次性使用技术ix.Useofequipmentdesignedforeaseofcleaning;使用设计以易于清洁的设备x.Appropriateuseofair-locksandpressurecascadetoconfinepotentialairbornecontaminantwithinaspecifiedarea;使用合适的气闸和压差梯度将潜在的污染物尘埃限制在某一特定区域xi.Minimisingtheriskofcontaminationcausedbyrecirculationorre-entryofuntreatedorinsufficientlytreatedair;将未经处理或未充分处理的空气再循环或再次进入空调系统导致的污染风险降至最低。xii.Useofautomaticcleaninplacesystemsofvalidatedeffectiveness;使用经验证的自动在线清洗系统xiii.Forcommongeneralwashareas,separationofequipmentwashing,dryingandstorageareas.对于公用一般清洗区域，专用设备清洗、干燥和存放区域。OrganisationalMeasures8组织措施i.Dedicatingthewholemanufacturingfacilityoraself-containedproductionareaonacampaignbasis(dedicatedbyseparationintime)followedbyacleaningprocessofvalidatedeffectiveness;在某一生产阶段专用整个生产设施或一个独立的生产区域（错开时间实现专用），然后进行清洁，清洁工艺需经验证有效。ii.Keepingspecificprotectiveclothinginsideareaswhereproductswithhighriskofcross-contaminationareprocessed;在具有高度交叉污染风险的产品处理区域内保持特定的防护服iii.CleaningverificationaftereachproductcampaignshouldbeconsideredasadetectabilitytooltosupporteffectivenessoftheQualityRiskManagementapproachforproductsdeemedtopresenthigherrisk;应在每次生产活动后进行清洁确认，应考虑可检测的方法，以支持被认为存在较高风险的产品的质量风险管理方法的有效性iv.Dependingonthecontaminationrisk,verificationofcleaningofnonproductcontactsurfacesandmonitoringofairwithinthemanufacturingareaand/oradjoiningareasinordertodemonstrateeffectivenessofcontrolmeasuresagainstairbornecontaminationorcontaminationbymechanicaltransfer;9根据污染的风险，确认非产品接触表面的清洁并监测生产区域内和/或相邻区域的空气以证实空气污染或设备转运污染的控制措施的有效性。v.Specificmeasuresforwastehandling,contaminatedrinsingwaterandsoiledgowning;废弃物处理、污染冲洗水和脏手套的特殊措施vi.Recordingofspills,accidentaleventsordeviationsfromprocedures;记录泄漏、意外事故或偏离规程的偏差vii.Designofcleaningprocessesforpremisesandequipmentsuchthatthecleaningprocessesinthemselvesdonotpresentacross-contaminationrisk;设计厂房设施和设备的清洁工艺以使清洁工艺本身存在交叉污染风险。viii.Designofdetailedrecordsforcleaningprocessestoassurecompletionofcleaninginaccordancewithapprovedproceduresanduseofcleaningstatuslabelsonequipmentandmanufacturingareas;设计清洁工艺的详细记录以确保清洁完整符合批准的规程并在设备和生产区域使用清洁状态标识。ix.Useofcommongeneralwashareasonacampaignbasis;在某一生产阶段使用共用一般清洗区域10x.Supervisionofworkingbehaviourtoensuretrainingeffectivenessandcompliancewiththerelevantproceduralcontrols.监督工作行为以确保效果并符合相关程序控制。STARTINGMATERIALS起始物料5.27Theselection,qualification,approvalandmaintenanceofsuppliersofstartingmaterials,togetherwiththeirpurchaseandacceptance,shouldbedocumentedaspartofthepharmaceuticalqualitysystem.Thelevelofsupervisionshouldbeproportionatetotherisksposedbytheindividualmaterials,takingaccountoftheirsource,manufacturingprocess,supplychaincomplexityandthefinalusetowhichthematerialisputinthemedicinalproduct.Thesupportingevidenceforeachsupplier/materialapprovalshouldbemaintained.Staffinvolvedintheseactivitiesshouldhaveacurrentknowledgeofthesuppliers,thesupplychainandtheassociatedrisksinvolved.Wherepossible,startingmaterialsshouldbepurchaseddirectlyfromthemanufacturerofthestartingmaterial.起始物料供应商的选择、确认、批准和维护，以及购买和验收，应有文件规定，作为制药质量体系的一部分。监督的水平应与物料的风险相适应，考虑其来源、生产工艺、供应链完整性及其在药品中的最终用途。11应保存每一供应商/物料批准的支持性证据。从事这些活动的人员应拥有对供应商、供应链和相关风险的最新知识。如可能，其实物料应直接从起始物料供应商处购买。5.28Thequalityrequirementsestablishedbythemanufacturerforthestartingmaterialsshouldbediscussedandagreedwiththesuppliers.Appropriateaspectsoftheproduction,testingandcontrol,includinghandling,labelling,packaginganddistributionrequirements,complaints,recallsandrejectionproceduresshouldbedocumentedinaformalqualityagreementorspecification.生产商建立的对起始物料的质量要求应与供应商讨论并达成一致。应在正式的质量协议或规范中规定生产、检验和控制的有关方面，包括处理、贴标、包装和运输要求、投诉、召回和拒签程序。5.29Fortheapprovalandmaintenanceofsuppliersofactivesubstancesandexcipients,thefollowingisrequired:对于活性成分和辅料供应商的批准和维护，应符合如下要求：Activesubstances活性成分Supplychaintraceabilityshouldbeestablishedandtheassociatedrisks,fromactivesubstancestartingmaterialstothefinishedmedicinalproduct,shouldbeformallyassessedandperiodicallyverified.Appropriatemeasuresshouldbeputinplacetoreduceriskstothequalityoftheactivesubstance.12应建立供应链的可追溯性并且相关风险，从活性成分起始物料到成品，应被正式评估并定期确认。应有适当措施降低活性成分的质量风险。Thesupplychainandtraceabilityrecordsforeachactivesubstance(includingactivesubstancestartingmaterials)shouldbeavailableandberetainedbythemanufacturerofthemedicinalproduct.应有每一活性成分（包括活性成分起始物料）的供应链和可追溯记录，并由药品生产商保存。Auditsshouldbecarriedoutatthemanufacturersanddistributorsofactivesubstancestoconfirmthattheycomplywiththerelevantgoodmanufacturingpracticeandgooddistributionpracticerequirements.Theholderofthemanufacturingauthorisationshallverifysuchcomplianceeitherbyhimself/herselforthroughanentityactingonhis/herbehalfunderacontract.Forveterinarymedicinalproducts,auditsshouldbeconductedbasedonrisk.应对活性成分生产商和分销商进行审计以确认其符合相关GMP/GDP要求。生产许可持有人应自行或通过合同第三方对此进行确认。对于兽用药物产品，应基于风险进行审计。AuditsshouldbeofanappropriatedurationandscopetoensurethatafullandclearassessmentofGMPismade;consideration13shouldbegiventopotentialcross-contaminationfromothermaterialsonsite.Thereportshouldfullyreflectwhatwasdoneandseenontheauditwithanydeficienciesclearlyidentified.Anyrequiredcorrectiveandpreventiveactionsshouldbeimplemented.审计应有适当的持续时间和范围以确保进行完整清晰的GMP评估。应考虑与工厂其他物料之间的潜在交叉污染。报告应充分反应审计时做了什么、看到了什么以及发现了哪些缺陷。任何要求的纠正和预防措施应得到实施。Furtherauditsshouldbeundertakenatintervalsdefinedbythequalityriskmanagementprocesstoensurethemaintenanceofstandardsandcontinueduseoftheapprovedsupplychain.后续审计应通过质量风险管理流程定期开展以确保的维护和经批准供应链的持续使用。Excipients辅料ExcipientsandexcipientsuppliersshouldbecontrolledappropriatelybasedontheresultsofaformalisedqualityriskassessmentinaccordancewiththePIC/SGuidelinePI045-1‘GuidelinesontheformalisedriskassessmentforascertainingtheappropriateGoodManufacturingPracticeforexcipientsofmedicinalproductsforhumanuse’.14应基于一份正式的质量风险评估的结果对辅料和辅料供应商进行适当控制，根据PIC/S指南PI045-1“确定人用药用辅料适用GMP的正式风险评估指南”进行。5.30Foreachdeliveryofstartingmaterialthecontainersshouldbecheckedforintegrityofpackage,includingtamperevidentsealwhererelevant,andforcorrespondencebetweenthedeliverynote,thepurchaseorder,thesupplier’slabelsandapprovedmanufacturerandsupplierinformationmaintainedbythemedicinalproductmanufacturer.Thereceivingchecksoneachdeliveryshouldbedocumented.对于起始物料的每一次交付，应检查容器包装完整性，包括开启留痕签（如有），以及提货单、购买订单、供应商标签和药品生产商维护的已批准生产商和供应商信息之间的一致性。每一次交付均应记录接收检查。5.34OnlystartingmaterialswhichhavebeenreleasedbytheQualityControlDepartmentandwhicharewithintheirretestdateshouldbeused.只有当起始物料得到QC部门放行并在其复验期内，才可以被使用。5.35Manufacturersoffinishedproductsareresponsibleforanytestingofstartingmaterials3asdescribedinthemarketingauthorisationdossier.Theycanutilisepartialorfulltestresultsfromtheapprovedstartingmaterialmanufacturerbutmust,asa15minimum,performidentificationtesting4ofeachbatchaccordingtoAnnex8.制剂成品生产商负责起始物料的所有检验。他们可以使用起始物料供应商的部分或全部检验结果，但前提是，至少，根据附录8对每一批次进行鉴别检验。注：3Asimilarapproachshouldapplytopackagingmaterialsasstatedinsection5.45.类似方法适用于包装材料，见5.45.4Identitytestingofstartingmaterialsshouldbeperformedaccordingtothemethodsandthespecificationsoftherelevantmarketingauthorisationdossier.起始物料的鉴别检验应按照相关上市许可档案中描述的方法和标准进行。5.36Therationalefortheoutsourcingofthistestingshouldbejustifiedanddocumentedandthefollowingrequirementsshouldbefulfilled:应论证使用外包机构来执行这些检验的合理性并进行记录，应满足如下要求：i.Specialattentionshouldbepaidtothedistributioncontrols(transport,wholesaling,storageanddelivery)inordertomaintain16thequalitycharacteristicsofthestartingmaterialsandtoensurethattestresultsremainapplicabletothedeliveredmaterial;应特别关注运输控制（运输、分发、储存和交付）以保持起始物料的质量特性并确保检验结果仍然能够代表说交付的物料。ii.Themedicinalproductmanufacturershouldperformaudits,eitheritselforviathirdparties,atappropriateintervalsbasedonriskatthesite(s)carryingoutthetesting(includingsampling)ofthestartingmaterialsinordertoassurecompliancewithGoodManufacturingPracticeandwiththespecificationsandtestingmethodsdescribedinthemarketingauthorisationdossier;药品生产商应基于风险在适当间隔对执行检验（包括取样）的场地进行审计，亲自或通过第三方机构，以确保符合GMP和上市许可档案中描述的标准和检验方法。iii.Thecertificateofanalysisprovidedbythestartingmaterialmanufacturer/suppliershouldbesignedbyadesignatedpersonwithappropriatequalificationsandexperience.Thesignatureassuresthateachbatchhasbeencheckedforcompliancewiththeagreedproductspecificationunlessthisassuranceisprovidedseparately;起始物料生产商/供应商提供的检验报告书（COA）应由经过适当确认和经验的指定人员签名。签名应确保每个批次都经过检查符合商定的产品标准，除非另有规定。17iv.Themedicinalproductmanufacturershouldhaveappropriateexperienceindealingwiththestartingmaterialmanufacturer(includingexperienceviaasupplier)includingassessmentofbatchespreviouslyreceivedandthehistoryofcompliancebeforereducingin-housetesting.Anysignificantchangeinthemanufacturingortestingprocessesshouldbeconsidered;药品生产商应具有处理起始物料生产商的适当经验（包括通过供应商的经验），包括评估先前收到的批次以及在减少内部检验之前的合规历史。任何生产或检验过程的重大变更均应被考虑。v.Themedicinalproductmanufacturershouldalsoperform(orviaaseparatelyapprovedcontractlaboratory)afullanalysisatappropriateintervalsbasedonriskandcomparetheresultswiththematerialmanufacturer’sorsupplier’scertificateofanalysisinordertocheckthereliabilityofthelatter.Shouldthistestingidentifyanydiscrepancythenaninvestigationshouldbeperformedandappropriatemeasurestaken.Theacceptanceofcertificatesofanalysisfromthematerialmanufacturerorsuppliershouldbediscontinueduntilthesemeasuresarecompleted.药品生产商还应根据风险在适当的时间间隔内（或通过单独批准的合同实验室）进行全面检验，并将结果与物料生产商或供应商的检验证书（COA）进行比较，以检查后者的可靠性。如果此测试发现任何差异，18则应执行调查并采取适当措施。在这些措施完成之前，来自物料生产商或供应商的检验报告书应不得再接受。PACKAGINGMATERIALS包装材料5.45Theselection,qualification,approvalandmaintenanceofsuppliersofprimaryandprintedpackagingmaterialsshallbeaccordedattentionsimilartothatgiventostartingmaterials.内包材和印字包材供应商的选择、确认、批准和维持应给予与起始物料类似的关注。PRODUCTSHORTAGEDUETOMANUFACTURINGCONSTRAINTS由于制造约束导致产品短缺5.71Themanufacturershouldreporttothemarketingauthorisationholder(MAH)anyconstraintsinmanufacturingoperationswhichmayresultinabnormalrestrictioninthesupply.ThisshouldbedoneinatimelymannertofacilitatereportingoftherestrictioninsupplybytheMAH,totherelevantcompetentauthorities,inaccordancewithitslegalobligations.生产商应向上市许可持有人（MAH）报告任何可能导致供应异常限制的制约因素。这应及时进行，以便于MAH根据其法律义务向有关主管部门报告供应限制。CHAPTER8COMPLAINTSANDPRODUCTRECALL19第八章投诉和产品召回PRINCIPLE原则Inordertoprotectpublicandanimalhealth,asystemandappropriateproceduresshouldbeinplacetorecord,assess,investigateandreviewcomplaintsincludingpotentialqualitydefects,andifnecessary,toeffectivelyandpromptlyrecallmedicinalproductsforhumanorveterinaryuseandinvestigationalmedicinalproductsfromthedistributionnetwork.QualityRiskManagementprinciplesshouldbeappliedtotheinvestigationandassessmentofqualitydefectsandtothedecision-makingprocessinrelationtoproductrecallscorrectiveandpreventativeactionsandotherrisk-reducingactions.GuidanceinrelationtotheseprinciplesisprovidedinChapter1.为确保公众和动物安全，应有一个系统和适当的规程来记录、评估、调查和回顾投诉，包括潜在的质量影响，和必要时，迅速有效地从分销网络上召回人用/兽用/临床试验用药品。应使用质量风险管理原则来调查和评估质量影响，并运用于产品召回纠正和预防措施以及其他风险降低行动的决策流程。有关这些原则的指南见章节1.AllconcernedCompetentAuthoritiesshouldbeinformedinatimelymannerincaseofaconfirmedqualitydefect(faultymanufacture,productdeterioration,detectionoffalsification,20non-compliancewiththemarketingauthorisationorproductspecificationfile,oranyotherseriousqualityproblems)withamedicinalorinvestigationalmedicinalproductwhichmayresultintherecalloftheproductoranabnormalrestrictioninthesupply.Insituationswhereproductonthemarketisfoundtobenon-compliantwiththemarketingauthorisation,theremaybearequirementtonotifyconcernedCompetentAuthorities.Referenceshouldbemadetorelevantlegislativerequirements.一旦确定药品或临床试验用药品存在可能导致产品召回或供应异常的质量缺陷（生产缺陷、产品变质、发现造假、不符合上市许可或产品标准文件、或任何其他严重质量问题），应及时通知所有有关监管机构。在市售产品中发现不符合上市许可的情况下，应通知有关监管当局。应参考有关的立法规定。Incaseofoutsourcedactivities,acontractshoulddescribetheroleandresponsibilitiesofthemanufacturer,themarketingauthorisationholderand/orsponsorandanyotherrelevantthirdpartiesinrelationtoassessment,decision-making,anddisseminationofinformationandimplementationofrisk-reducingactionsrelatingtoadefectiveproduct.GuidanceinrelationtocontractsisprovidedinChapter7.Suchcontractsshouldalsoaddresshowtocontactthoseresponsibleateachpartyforthemanagementofqualitydefectandrecallissues.21如是外包活动，合同中应描述生产商、上市许可持有人和/或赞助商和其他相关第三方机构在有关缺陷产品的评估、决策、以及信息传递和实施风险降低措施方面的角色和责任。有关合同的指南见章节7。该合同还应包括如何联系各方负责的质量缺陷管理和召回问题。PERSONNELANDORGANISATION人员和组织8.1Appropriatelytrainedandexperiencedpersonnelshouldberesponsibleformanagingcomplaintandqualitydefectinvestigationsandfordecidingthemeasurestobetakentomanageanypotentialrisk(s)presentedbythoseissues,includingrecalls.Thesepersonsshouldbeindependentofthesalesandmarketingorganisation,unlessotherwisejustified.IfthesepersonsdonotincludetheAuthorisedPersoninvolvedinthecertificationforreleaseoftheconcernedbatchorbatches,thelattershouldbemadeformallyawareofanyinvestigations,anyrisk-reducingactionsandanyrecalloperations,inatimelymanner.应由经适当培训和经验的人员负责投诉管理和质量缺陷调查，负责决定需要采取的措施管理这些问题所带来的任何潜在风险，包括召回。这些人员应独立于销售和市场部门，除非有其他合理理由。如果这些人员未包括从事有关批次放行的许可人，则后者应及时正式地了解任何调查，风险降低措施和召回行动。228.2Sufficienttrainedpersonnelandresourcesshouldbemadeavailableforthehandling,assessment,investigationandreviewofcomplaintsandqualitydefectsandforimplementinganyrisk-reducingactions.SufficienttrainedpersonnelandresourcesshouldalsobeavailableforthemanagementofinteractionswithCompetentAuthorities.应有经过充分培训的人员和资源来处理、评估、调查和回顾投诉和质量缺陷，并实施任何风险降低措施。与监管当局接触也同样需要经过充分培训的人员和资源。8.3Theuseofinter-disciplinaryteamsshouldbeconsidered,includingappropriatelytrainedQualityManagementpersonnel.应考虑使用跨学科团队，包括经适当培训的质量管理人员。8.4Insituationsinwhichcomplaintandqualitydefecthandlingismanagedcentrallywithinanorganisation,therelativerolesandresponsibilitiesoftheconcernedpartiesshouldbedocumented.Centralmanagementshouldnot,however,resultindelaysintheinvestigationandmanagementoftheissue.在投诉和质量缺陷处理由一个组织集中管理的情况下，应规定各相关方的角色和。集中管理不应导致调查和问题管理的延误。PROCEDURESFORHANDLINGANDINVESTIGATINGCOMPLAINTSINCLUDINGPOSSIBLEQUALITYDEFECTS23投诉处理和调查程序，包括可能的质量缺陷8.5Thereshouldbewrittenproceduresdescribingtheactionstobetakenuponreceiptofacomplaint.Allcomplaintsshouldbedocumentedandassessedtoestablishiftheyrepresentapotentialqualitydefectorotherissue.应有书面规程描述收到投诉后需要采取的行动。所有投诉应被记录并评估以确定是否有潜在的质量缺陷或其他问题。8.6Specialattentionshouldbegiventoestablishingwhetheracomplaintorsuspectedqualitydefectrelatestofalsification.应特别关注投诉或可疑质量缺陷是否与造假有关。8.7Asnotallcomplaintsreceivedbyacompanymayrepresentactualqualitydefects,complaintswhichdonotindicateapotentialqualitydefectshouldbedocumentedappropriatelyandcommunicatedtotherelevantgrouporpersonresponsiblefortheinvestigationandmanagementofcomplain