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人用药品中使用的原料药流通质量管理规范基本原则指南(徐禾丰翻译)Ref.Ares2013148102-05/02/2013参考编号2013148102-2013年02月05日EUROPEANCOMMISSION欧盟委员会HEALTHANDCONSUMERSDIRECTORATE-GENERAL健康与消费者总司HealthSystemsandProducts健康体系与产品MedicinalProducts-Qualitysafetyandefficacy药品-质量、安全性与有效性Brussels布鲁塞尔,SANCO/D/6/SF/mg/ddg
1.d.62013179367GUIDELINESONTHEPRINCIPLESOFGOODDISTRIBUTIONPRACTICESFORACTIVESUBSTANCESFORMEDICINALPRODUCTSFORHUMANUSE人用药品中使用的原料药流通质量管理规范基本原则指南DRAFTSUBMITTEDFORPUBLICCONSULTATION 用于公共征求意见的草案Stakeholdersareinvitedtocommentonthisdraftby30April2013atthelatest.Responsesshouldbesentpreferablybye-mailto sanco-pharmaceuticalsd6@ec.europa.eumailto:sanco-pharmaceuticalsd6@ec.europa.eu\t_blankorbyposttoUnitSANCO/D/6DM2402/050BE-1049Brussels.诚邀各利益相关方于2013年4月30日前将对本草案的意见发送至邮箱sanco-pharmaceuticalsd6@ec.europa.eumailto:sanco-pharmaceuticalsd6@ec.europa.eu\t_blank,或用信函邮寄至UnitSANCO/D/6DM2402/050BE-1049BrusselsWhensendingyourcommentsandresponsesyoushouldstatewhetheryouareastakeholderassociationoraprivateindividual.Ifyourepresentanassociationpleaseindicateclearlywhattypeofassociationthisisactivesubstancemanufacturermedicinalproductsmanufacturerimporteretc..IfyourepresentacompanypleasestatewhetheritfallswithintheEUdefinitionofasmallandmedium-sizedenterprisei.e.lessthan€50millionannualturnoverandfewerthan250employees.当回复意见时,请注明您是利益相关的社会团体或是个人如果您代表社会团体,请明确注明类型原料药制造商、药品制造商、进口商等如果您代表公司,请注明其是否属于欧盟定义的中小企业即,年营业额小于5千万欧圆且雇员少于250人Allcommentsandresponseswillbemadepubliclyavailableonthe‘Europawebsite’onpharmaceuticalsoncetheconsultationperiodisover.Ifyoudonotwishyourcontributiontobemadepublicpleaseindicatethisclearlyandspecificallyinthedocumentationyousendusi.e.notjustinthecoveringletterore-mail.Inthiscaseonlyanindicationofthecontributorwillbedisclosed.征集期结束后,所有意见与回复将在“Europa网站”的制药部分公布如果您不希望将意见公开,请在您发送的文件上特别注明即,而不仅是在首页函或电子邮件中注明此种情况下,只公开投稿人ProfessionalorganisationsareinvitedtoregisterintheUnion’sRegisterforInterestRepresentativeshttp://europa.eu/transparency-register/http://europa.eu/transparency-register/\t_blanksetupaspartoftheEuropeanTransparencyInitiativetoprovidetheCommissionandthepublicatlargewithinformationabouttheobjectivesfundingandstructuresofinterestrepresentatives.我们邀请专业组织在欧盟注册页面进行登记http://europa.eu/transparency-register/http://europa.eu/transparency-register/\t_blank将其作为欧洲透明倡议的一部分,来向欧洲委员会以及公众提供其代表利益的目标、资金与结构的详细信息Scope范围
1.Forthepurposeoftheseguidelinesthedistributionofactivesubstancesformedicinalproductsforhumanusehereafter‘activesubstances’istheprocuringimportholdingsupplyingorexportingactivesubstances. 本指南中的人用药品使用的活性物质以下简称“原料药”流通包括原料药的采购、进口、持有、供应或出口
2.Activitiesconsistingofre-packagingre-labellingordividingupofactivesubstancesaremanufacturingactivitiesandassucharesubjecttotheguidelinesonGoodManufacturingPracticeofactivesubstances.对原料药进行重新包装、重新贴标签或分装属制造范畴,受原料药生产质量管理规范指南的约束QualitySystem 质量体系
3.Distributorsofactivesubstancesshoulddevelopandmaintainaqualitysystemsettingoutresponsibilitiesprocessesandriskmanagementprinciples.原料药流通企业应当制定并保持一个质量体系,建立职责、流程及风险管理的基本原则
4.Thequalitysystemshouldbeadequatelyresourcedwithcompetentpersonnelandsuitableandsufficientpremisesequipmentandfacilities.该质量体系应当有充足的胜任人员、适当且足够的房屋、设备与设施等资源
5.Thesizestructureandcomplexityofdistributor’sactivitiesshouldbetakenintoconsiderationwhendevelopingormodifyingthequalitysystem.在制定或修订质量体系时,应当考虑流通企业活动的规模、结构与复杂性Personnel人员
6.Amanagementrepresentativeshouldbeappointedineachdistributionpointwhoshouldhavedefinedauthorityandresponsibilityforensuringthataqualitysystemisimplementedandmaintained.Heshouldfulfilhisresponsibilitiespersonally. 各流通现场应当指定一名管理者代表,应当规定其职权与职责,确保质量体系的实施与保持管理者代表应当亲自履行其职责
7.Keypersonnelinvolvedinthewarehousingofactivesubstancesshouldhavetheappropriateabilityandexperiencetoguaranteethatactivesubstancesareproperlystoredandhandled. 原料药仓储中所涉及到的关键人员应当具备恰当的能力与经验,以保证原料药正确存储与处理
8.Personnelshouldbetrainedinrelationtothedutiesassignedtothemandthetrainingsessionsrecorded. 应当针对人员职责进实施培训,且应当有培训记录Documentation 文件
9.Alldocumentationshouldbemadeavailableonrequestofcompetentauthorities.ElectronicdocumentationshouldcomplywithChapter
5.4ofPartIIofEudralextheRulesGoverningMedicinalProductsintheEuropeanUnionVolume4EUGuidelinestoGoodManufacturingPracticeforMedicinalProductsforHumanandVeterinaryUse-hereafter‘EU-GMP’oritsAnnex11GuidelinesonComputerisedSystems.应当按主管官方要求提供所有文件电子文件应当符合欧盟药品法规第四卷第二部分的第
5.4章欧盟人用与兽用药品生产质量管理规范指南-以下简称“欧盟药品生产质量管理规范”或其第11附录计算机化系统指南要求Orders订货
10.WhereactivesubstancesareprocuredfromadistributorofactivesubstancesthatdistributorshouldberegisteredaccordingtoArticle52aofDirective2001/83/EU.若从流通企业采购原料药,此流通企业应当已经按第2001/83/EU法令第52a条进行注册Procedures规程
11.Writtenproceduresshoulddescribethedifferentoperationswhichmayaffectthequalityoftheactivesubstancesorofthedistributionactivity:receiptandcheckingofdeliveriesstoragecleaningandmaintenanceofthepremisesincludingpestcontrolrecordingofthestorageconditionssecurityofstocksonsiteandofconsignmentsintransitwithdrawalfromsaleablestockrecordsincludingrecordsofclientsordersreturnedproductsrecallplansetc.Theseproceduresshouldbeapprovedsignedanddatedbythepersonresponsibleforthequalitysystem.应当有书面规程来描述可能会影响原料药质量或流通活动的不同操作交付物品的接收与检查、储存,厂房清洁与维护包括虫害控制、存储条件记录、现场库存与委托运输安全性、从可供出货库存收回、记录,包括记录客户订单、退回产品、召回计划等这些规程应当由质量体系负责人来批准、签署并注明日期Records记录
12.Recordsshouldbemadeatthetimeeachoperationistakenandinsuchawaythatallsignificantactivitiesoreventsaretraceable.Recordsshouldbeclearandreadilyavailable.Theyshouldberetainedforaperiodoffiveyearsatleast.应当在每次操作时进行记录,并且以能对所有重要活动或事件可追溯的方式进行记录记录应当清晰易得,并且至少保留五年
13.Recordsshouldbekeptofeachpurchaseandsaleshowingthedateofpurchaseorsupplynameoftheactivesubstancebatchnumberandquantityreceivedorsuppliedandnameandaddressoftheoriginalmanufacturer.Recordsshouldensurethetraceabilityoftheoriginanddestinationofproductssothatallthesuppliersoforthosesuppliedwithanactivesubstancecanbeidentified.Documentsthatshouldberetainedandavailableinclude: 应当保存好历次采购与销售记录,标明采购或供应的日期、原料药的名称、接收或供应的批号与数量、原始制造企业的名称与地址记录应当确保产品原产地与目的地可追溯性,以便能对所有的原料药供应商或其供应产品进行识别应当获取并保留的文件包括·Identityoforiginalmanufacturer原始制造企业的身份·Addressoforiginalmanufacturer原始制造企业地址·Purchaseorders采购订单·Billsofladingtransportationanddistributionrecords 提单、运输与流通记录·Receiptdocuments 接收文件·Nameordesignationofactivesubstance原料药名称或命名·Manufacturer’sbatchnumber制造企业批号·AllauthenticCertificatesofAnalysisincludingthoseoftheoriginalmanufacturer所有可信的分析证明,包括原制造企业的分析证明·Retestorexpirydate复验期或有效期Premisesandequipment 厂房与设备
14.Premisesandequipmentshouldbesuitableandadequatetoensureproperconservationprotectione.g.narcoticsanddistributionofactivesubstances.Monitoringdeviceswhereusedshouldbecalibrated.应当有适当并且充足的厂房与设备,确保原料药的保存、防护如,*********品与流通如使用监控设备,应当对其进行校准Receipt 接收
15.Areasforreceivingactivesubstancesshouldprotectdeliveriesfrombadweatherduringunloading.Thereceptionareashouldbeseparatefromthestoragearea.Deliveriesshouldbeexaminedatreceiptinordertocheckthatcontainersarenotdamagedallsecuritysealsarepresentandthattheactivesubstanceandtheconsignmentcorrespondtotheorder.原料药接收区域应当能够在恶劣天气下对交付物卸载提供防护接收区域应当与存储区域相分离应当在接收时对交付物进行检查,确定容器没有损坏、具有所有安全性铅封,并且原料药与发运物与订单相符
16.Activesubstancessubjecttospecificstoragemeasurese.g.narcoticsproductsrequiringaspecificstoragetemperatureorhumidityshouldbeimmediatelyidentifiedandstoredinaccordancewithwritteninstructionsandwithrelevantlegislativeprovisions.需要特殊存储措施的原料药如,麻醉品、需要特定存储温度或湿度的产品等,应当立即进行标识并按照书面指示和相关法规条款进行存储
17.Wherethedistributorsuspectsthatanactivesubstanceprocuredorimportedbyhimisfalsifiedheshouldinformthenationalcompetentauthorityinwhichheisregistered.流通企业如怀疑其采购或进口的原料药是伪造的,其应当通知流通企业注册国主管官方Storage 存储
18.Activesubstancesshouldnormallybestoredapartfromothergoodsandundertheconditionsspecifiedbythemanufacturere.g.controlledtemperatureandhumiditywhennecessary.Theseconditionsshouldbemonitoredperiodicallyandrecordsmaintained.Therecordsshouldbereviewedregularlybythepersonresponsibleforthequalitysystem.原料药通常应当在制造企业所指定的条件如,必要的受控温度和湿度下与其它货物分开储存应当对这些条件进行定期监测,并保存记录应当由质量体系负责人对记录进行定期审核
19.Whenspecifictemperatureorhumiditystorageconditionsarerequiredstorageareasshouldbeequippedwithrecordersorotherdevicesthatwillindicatewhenthespecifictemperatureorhumidityrangehasnotbeenmaintained.Controlshouldbeadequatetomaintainallpartsoftherelevantstorageareawithinthespecifiedtemperatureorhumidityranges.若储存条件对温度或湿度有特殊要求,存储区应当配备记录仪器或其它设备,对未能满足特定温度或湿度范围的情况予以显示应当将储存区域的所有相关部分充分控制在特定温度或湿度的范围内
20.Thestoragefacilitiesshouldbecleanandfreefromlitterdustandpests.Adequateprecautionsshouldbetakenagainstspillageorbreakageattackbymicro-organismsandcrosscontamination.存储设施应当保持清洁,无垃圾、灰尘与虫害应当采取充分的预防措施,防止泄漏或破损、微生物侵害与交叉污染等
21.Thereshouldbeasystemtoensurestockrotation‘firstexpiryretestdatefirstout’withregularandfrequentchecksthatthesystemisoperatingcorrectly.Productsbeyondtheirexpirydateorshelf-lifeshouldbeseparatedfromusablestockandnotbesupplied.应当该有一个系统,确保存货周转“先到有效期先出先到复验期先出”,并且定期而经常性检查系统是否正常运行超出有效期或保质期的产品应当与可使用库存相隔离,而且不能供应
22.Activesubstanceswithbrokensealsdamagedpackagingorsuspectedofpossiblecontaminationshouldbewithdrawnfromsaleablestockandifnotimmediatelydestroyedtheyshouldbekeptinaclearlyseparatedareasothattheycannotbesoldinerrororcontaminateothergoods. 应当将铅封损坏、包装破损,或怀疑可能受到污染的原料药从可销售库存中收回,并且如果不能立即销毁,应当将其保存在清晰的隔离区域,使其能不能错误销售或污染其它货物
23.Shortagesthatrequiresregisteredimporterstonotifyrelevantcustomersofanyinterruptiontosupplythattheimporterordistributorbecomesawareof.注册的进口企业需要通知相关客户有关进口企业或流通企业已经觉察到的任何因中断供应所导致的短缺Deliveriestocustomers 客户交付
24.SupplieswithintheEUshouldbemadeonlytoregistereddistributorsofactivesubstancesaccordingtoArticle52aofDirective2001/83/EUortoauthorisedmanufacturersaccordingtoArticle40ofDirective2001/83/EU. 欧盟范围内,仅可供应给已经按照第2001/83/EU号法令的第52a条注册的原料药流通企业,或根据第2001/83/EU号法令的第40条获得授权的制造企业
25.Activesubstancesshouldbetransportedinsuchawaythat:原料药应当以如下方式运输atheiridentificationisnotlost;不丢失其标识;btheydonotcontaminateandarenotcontaminatedbyotherproductsormaterials;不污染其它产品或物料,也不被其它产品或物料污染;cadequateprecautionsaretakenagainstspillagebreakageortheft;采取适当预防措施,防止泄漏、破损或被盗窃;dtheyaresecureandnotsubjectedtounacceptabledegreesofheatcoldlightmoistureorotheradverseinfluencenortoattackbymicro-organismsorpests.确保运输安全并切不会遭受不可接受程度的热、冷、光、水分或其它不良影响,也不会遭受微生物或害虫侵害
26.Wheretransportationoftheactivesubstanceiscontractedoutthedistributorshouldensurethatthecontractacceptorknowsandfollowstheappropriatetransportandstorageconditions.在原料药委托运输时,应当确保合同受方了解并遵循适当的运输与贮存条件
27.Activesubstancesrequiringcontrolledtemperaturestorageshouldalsobetransportedbyappropriatelyspecializedmeans. 需要控制存储温度的原料药应当用特定的方式进行运输
28.Asystemshouldbeinplacebywhichthedistributionofeachbatchofactivesubstancecanbereadilydeterminedtopermititsrecall. 应当有适当的系统,确保所流通的每个批次原料药能容易判断其是否需要召回TransferofInformation 信息传递
29.Distributorsshouldtransferallqualityorregulatoryinformationreceivedfromanactivesubstancemanufacturertothecustomerandfromthecustomertotheactivesubstancemanufacturer.流通企业应当将所有从原料药制造企业收到的质量或药政信息传递给客户,并将客户的质量或药政信息传递给原料药制造企业
30.Thedistributorwhosuppliestheactivesubstancetothecustomershouldprovidethenameandaddressoftheoriginalactivesubstancemanufacturerandthebatchnumberssupplied.AcopyoftheoriginalCertificateofAnalysisfromthemanufacturershouldbeprovidedtothecustomer.为客户供应原料药的流通企业应当提供原始原料药制造企业的名称与地址以及批号应当将来自制造企业的原始分析证明一份副本提供给客户
31.Thedistributorshouldalsoprovidetheidentityoftheoriginalactivesubstancemanufacturertoregulatoryauthoritiesuponrequest.Theoriginalmanufacturercanrespondtotheregulatoryauthoritydirectlyorthroughitsauthorisedagentsdependingonthelegalrelationshipbetweentheauthorisedagentsandtheoriginalactivesubstancemanufacturer.Inthiscontext‘authorised’referstoauthorisedbythemanufacturer.如药政主管官方需要,流通企业还应当提供原始原料药制造企业身份根据授权代理以及原始制造企业的法律关系,原始制造企业可以直接或通过其授权的代理人向药政主管官方进行回复此处的“授权”是指制造企业进行的授权
32.ThespecificguidanceforCertificatesofAnalysisisincludedinSection
11.4ofPartIIoftheEU-GMP. 分析证明的具体指南见欧盟药品生产质量管理规范第二部分的第
11.4节Returns 退货
33.Returnedactivesubstancesshouldbeidentifiedassuchandquarantined. 应当对已经退回的原料药进行标识并且进行并待检隔离
34.Iftheconditionsunderwhichreturnedactivesubstanceshavebeenstoredorshippedbeforeorduringtheirreturnortheconditionoftheircontainerscastsdoubtontheirqualitytheyshouldbedestroyedbyappropriatemeans. 如果怀疑退回的原料药在退回前或退回过程中的储存或运输条件或其容器条件对原料药质量产生不利影响,应当用恰当方式对其进行销毁
35.Activesubstanceswhichhaveleftthecareofthedistributorshouldonlybereturnedtosaleablestockif: 如果原料药已经脱离流通企业控制,仅仅在下列情况下才可将其退回到可供销售库atheactivesubstanceisintheoriginalunopenedcontainersandingoodcondition; 原料药处于原始未开封容器中并且处于良好的条件下;bitisdemonstratedthattheactivesubstancehavebeenstoredandhandledunderproperconditions;可证明原料药在适当条件下存储与处理;ctheremainingshelflifeperiodisacceptable;余下的保质期是可以接受的;dtheyhavebeenexaminedandassessedbyapersonauthorisedtodoso.经授权人员检验并评估合格
36.Thisassessmentshouldtakeintoaccountthenatureoftheactivesubstanceanyspecialstorageconditionsitrequiresandthetimeelapsedsinceitwassupplied.Specialattentionshouldbegiventoproductsrequiringspecialstorageconditions.Ifnecessaryadviceshouldbesoughtfromthemanufactureroftheactivesubstance. 评估应当考虑原料药的性质、其要求的特定储存条件,以及其从供应开始经过的时间应当特别注意产品需要的特殊贮存条件如必要,应当征询原料药制造企业的建议
37.Recordsofreturnedactivesubstancesshouldbemaintained.Foreachreturndocumentationshouldinclude: 应当保留原料药的退回记录每次的退货记录应当包括Nameandaddressoftheconsignee收货人名称与地址Activesubstancebatchnumberandquantityreturned退回的原料药批号与数量Reasonforreturn退货理由Useordisposalofthereturnedactivesubstance退回原料药的使用或处理
38.Onlyappropriatelytrainedandauthorisedpersonnelshouldreleaseactivesubstancestobereturnedtostock.Activesubstancesreturnedtosaleablestockshouldbeplacedsuchthatthe‘firstexpiryre-testdatefirstout’systemoperateseffectively.只有经过适当培训并授权的人员才能将退回的原料药放行入库退回到可销售库存的原料药,应当按照“先到期先出先到复验期先出”系统有效运作ComplaintsandRecalls 投诉与召回
39.Allqualityrelatedcomplaintswhetherreceivedorallyorinwritingshouldberecordedandinvestigatedaccordingtoawrittenprocedure. 所有与质量有关的投诉,无论口头的还是书面投诉,都应当按书面规程进行记录与调查
40.Complaintrecordsshouldinclude: 投诉记录应当包括Nameandaddressofcomplainant投诉人的名称与地址Nameandwhereappropriatetitleandphonenumberofpersonsubmittingthecomplaint 提交投诉人员的姓名如果适当,头衔与电话号码Complaintnatureincludingnameandbatchnumberoftheactivesubstance投诉性质包括原料药的名称与批号Datethecomplaintisreceived收到投诉的日期Actioninitiallytakenincludingdatesandidentityofpersontakingtheaction 最初采取的措施包括采取行动的日期和行动人员身份Anyfollow-upactiontaken采取的任何后续措施Responseprovidedtotheoriginatorofcomplaintincludingdateresponsesent提供给原始投诉企业的回复包括发送回复日期Finaldecisiononactivesubstancebatchorlot对原料药批次的最终决定
41.Recordsofcomplaintsshouldberetainedinordertoevaluatetrendsproductrelatedfrequenciesandseveritywithaviewtotakingadditionalandifappropriateimmediatecorrectiveaction.TheseshouldbemadeavailabletocompetentauthoritiesoftheMemberStatesonwhoseterritorytheproductsweredistributed. 应当保存投诉记录,以评价趋势、与产品相关的频率、严重性及采取而外的措施,如果适当,立即所采取的纠正措施产品所流通的成员国主管官方应当可获取上述资料
42.Ifthesituationwarrantsthedistributorshouldreviewthecomplaintwiththeoriginalactivesubstancemanufacturerinordertodeterminewhetheranyfurtheractioneitherwithothercustomerswhomayhavereceivedthisactivesubstanceorwiththeregulatoryauthorityorbothshouldbeinitiated.Theinvestigationintothecauseforthecomplaintorrecallshouldbeconductedanddocumentedbytheappropriateparty. 如情况准许,流通企业应当与原始原料药制造企业一道审核投诉,以确定是否与已经收到该原料药的客户或药政主管官方,或两者一起,采取进一步措施应当由适当方对投诉与召回的原因进行调查并记录
43.Whereacomplaintisreferredtotheoriginalactivesubstancemanufacturertherecordmaintainedbythedistributorshouldincludeanyresponsereceivedfromtheoriginalactivesubstancemanufacturerincludingdateandinformationprovided. 若投诉涉及到原始原料药制造企业,流通企业所保存的纪录应当涵盖来自于原始原料药制造企业的所有回复包括日期与所提供的信息
44.Intheeventofaseriousorpotentiallylife-threateningsituationlocalnationaland/orinternationalauthoritiesshouldbeinformedandtheiradvicesought. 应当将严重事件或潜在危及生命的情况、告知地方、国家,和/或,国际机构应当并征求其意见
45.Thereshouldbeawrittenprocedurethatdefinesthecircumstancesunderwhicharecallofanactivesubstanceshouldbeconsidered. 应当该有书面规程来确定原料药召回的条件
46.Therecallprocedureshoulddesignatewhoshouldbeinvolvedinevaluatingtheinformationhowarecallshouldbeinitiatedwhoshouldbeinformedabouttherecallandhowtherecalledmaterialshouldbetreated. 该召回规程应当指定,谁参与信息评价、如何启动召回、应当将召回通知谁,以及如何处理召回物料Self-inspections 自检
45.Thedistributorshouldconductandrecordself-inspectionsinordertomonitortheimplementationofandcompliancewiththisguideline.流通企业应当实施自检并进行记录,以对本指南的实施与符合性进行监控。