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Dateofimplementation:1March2010Introduction:TheholderofaCertificateofsuitabilityshallinformtheEDQMofanychangetotheinformationinthecertificationdossierbysendinganapplicationformandallnecessarydocumentsdemonstratingthattheconditionslaiddowninthepresentguidelinearemet.ClassificationofchangesThechangeshavebeenclassifiedinthreecategories(notification/minor/major)dependingonthepotentialimpactofthechangeonthequalityofthefinalsubstance.Thesethreecategoriesarebasedonthose(IA-IAIN/IB/II)oftheCommissionRegulation(EC)No1234/2008concerningtheexaminationofvariationstothetermsofmarketingauthorisationformedicinalproductsforhumanuseandveterinarymedicinalproducts.Anychangenotclassifiedasanotificationoramajorchangeshouldbeclassifiedasaminorchangeexceptinthefollowingcaseswhereanewapplicationshouldbesubmitted:-additionofanewrouteofsynthesisand/oranewmanufacturingsitewherethespecificationsofthefinalsubstancearedifferentfromtheonealreadyapproved-transfertoanewholderthatisnotthesamelegalentityastheapprovedone,wherethetransferdoesnotoccurbecauseofamergerorbecausethecompanyissold,andwherethemanufacturerdoesnottakeouttheCertificateofsuitabilityintheirownname.ThechangesrelatedtoPh.Eur.monographrevisionsoranyotherregulatoryrequirementsaretreatedseparatelyandgenerallyinitiatedbytheEDQM.执行日期：2010年3月1日介绍：欧洲药典适用性证书持有人必须向EDQM报告所有与申报文件有关的变更，申报时应填写申请表格和所有必要的资料，证明变更符合现行指南的规定。变更分类根据变更对最终产品可能产生的影响程度，变更分为三类（通知/微小/重大）。分类原则是根据EC法规1234/2008(IA-IAIN/IB/II)：EC成员国审核人用和兽用制剂销售许可证变更规定所有未划为通知或者重大变更的变更都是微小变更，但以下情形必须按新证书申请办理：-增加新合成途径或新生产场地，而且成品质量标准发生变化。-持有人转让，新持有人与现行法人不同，这种转让不是公司合并、出售的结果，生产厂也没有以自己名义获取原有证书。欧洲药典修订或其它法规要求而产生的变更另论，通常由EDQM发起。DocumentationtobeprovidedForanyrevisionthedocumentationshouldconsistof:-acoverletter-theapplicationform,dulyfilledandlistingallthechangesappliedfor-adescriptionofeachchangetogetherwithajustification-datashowing,whenapplicable,thattheconditionshavebeenmet-updateoftherelevantsection(s)ofthedossier(presentedinEU-CTDformat).-thespecificdocumentsdescribedbelowforeachchangeandsupportingthechange-supportiveinformation,includingcomparativedatawiththepreviousversionofthedossier(intabularformat),showingtheapprovedandtheproposedsectionandhighlightingthechangesConsequentialchangesshouldbeidentifiedandtherelationbetweenthechangesshouldbedescribed.Eachtimebatchdataareneeded:-theyshouldbeinaccordancewiththespecificationsofthecurrentPh.Eur.monographandwhenrelevantwiththeadditionalrequirementsincludedintheCertificateofsuitability-themanufacturingsite,themanufacturingdateandthesizeofthebatchesshouldbespecified.-quantitativeresultsshouldbepresentednumerically(i.e.notingeneraltermssuchas“complies”)andwiththeappropriatenumberofdecimalplaces.需要申报的文件所有变更的申报文件必须包括以下内容：-附函-申请表，列出申请的变更-变更内容并说明变更的合理性-若适用的的话，表明符合条件的数据-更新申报文件相关的章节（按EU-CTD格式）-下述各种变动所要求的具体文件-支持性信息，包括与原版本的对比数据（以表格格式），表明原内容及现内容，强调变更应该识别间接的变更，并描述变更之间的关系。所有变更都需要申报批分析数据：-而且必须现行欧洲药典标准、以及CEP证书附加的有关要求。-必须说明生产场地、生产日期和生产批量。-应以数字形式表示定量结果（即：不得笼统表达为“合格”等），数位应合理。Thechangesarepresentedinfivesections:-Notifications(NandT)-TypicalminorrevisionsforCertificatesofsuitabilityforchemicalpurityandmicrobiologicalqualityorforTSECertificatesofsuitability-Majorrevisions(MAJ)-Renewal-TransferofholdershipEditorialchangesshouldnotbesubmittedasseparatevariationsbutshouldbereportedatthesametimeaschangesconcerningtherespectivepartofthedossier.Inanycase,adeclarationshouldbeprovidedthatthecontentoftheconcernedpartofthedossierhasnotbeenchangedbytheeditorialchanges(exceptforthechangeitself).以下分五节讨论各种变更情况：通知（N和T）化学纯度和微生物质量的CEP证书或TSE证书的典型微小变更重大变更（MAJ）更新证书持有人转让文字性变更不应作为单独的变更提交，但当文件相关部分变更时应当同时报告。不管怎么样，应该申明：除了变更本身之外，文件相关部分的内容没有因文字性的变更而发生变更。NOTIFICATIONS(IN/AN)Notificationsaresplitintoimmediatenotificationsandnotificationswithannualreporting.1.Immediatenotifications(IN):IN1)Changeinthenameand/oraddressofthecertificateholderofthefinalsubstance(formerN1)Conditions:-thecertificateholdershallremainthesamelegalentity(exceptwherethecompanyissoldorincaseofamerger).SpecificDocumentation:-aformaldocumentfromarelevantofficialbody(e.g.ChamberofCommerce)inwhichthenewnameorthenewaddressismentioned-allupdateddeclarations(annexestotheapplicationform).通知（（IN/AN）通知分为立即通知和年度报告的通知1.立即通知ININ1原料药证书持有人名称或地址变更（以前的N1）条件：-证书持有人法人地位不变（公司出让或被兼并除外）。文件要求：-官方出具（如：商会）的有关新名称和新地址的正式文件-所有更新的声明（见申请表附录）IN2)Changeinthenameand/oraddressofthemanufacturingsiteforthefinalsubstance(formerN2)Conditions:-thelocationofthemanufacturingsiteshallremainthesame.SpecificDocumentation:-aformaldocumentfromarelevantofficialbody(e.g.ChamberofCommerce)inwhichthenewnameorthenewaddressismentioned-updateddeclarationsofmanufactureinaccordancewiththedossierandaccordingtoGMPrulesandofwillingnesstobeinspected.IN2原料药生产场所名称或地址变更（以前的N2）条件：生产场所具体位置应保持不变。文件要求：-官方出具（如：商会）的有关新名称和新地址的正式文件-更新的声明：按申报文件和GMP法规组织生产及愿意接受检查的声明IN3)Deletionofanymanufacturingsiteforthefinalsubstance(formerN3)Conditions:-thedeletionshouldnotbeduetocriticaldeficienciesconcerningmanufacturing.SpecificDocumentation:-thejustificationofthedeletion.IN3原料药生产场地的取消（以前的N3）条件：取消不应该是由于与生产有关的严重缺陷文件要求：证明取消的合理性。IN4)Changeoradditionofamanufactu