上海EDMF编撰的培训资料

Technical Requirements for the Registration Dossier of EDMF/COS/CTD and Filing strategies in EU countries
EDMF/COS/CTD注册文件的技术要求及在欧盟国家的文件编撰策略Technical Requirements技术要求
•EDMF compilation in CTD format CTD格式的EDMF的编撰:
•a) Module 3.2. S. Drug Substance模块3.2. S. 药物物质
•b) Module 2.3 Quality Overall Summary模块2.3 质量概述
•CEP Procedure versus the DMF Procedure CEP程序对DMF程序
•Filing strategies in EU countries在欧盟国家的文件编撰策略
•Certification of suitability to the monographs of the European Pharmacopoeia针对欧洲药典专论的适应性证书
•Procedure ,Submission of the Dossier, Content of the Dossier/Expert Report, Assessment, Timetable, Follow-up程序，文件递交，文件内容/专家报告，评估，时间表，后续工作
How to get the guideline from the Internet ? 如何从互联网得到指南?
•www.emea.eu.int
•Human medicine or vet medicine人用药或兽药
•Guidance documents指南文件
•ICH
•QWP
•Approved guidelines批准的指南
•Guidelines under discussion讨论中的指南
Filing strategies文件编撰策略
•CEP
•ASMF/EDMF procedure ASMF/EDMF程序
•???
CEP Procedure versus the DMF Procedure CEP 程序对DMF 程序
•Guideline on Summary of requirements for active substances in the quality part of the dossier针对文件质量部分中活性物质要求的概述的指南
•Classification of active substances活性物质的分类:
1.New active substances used for the first time in a medicinal product在药品中第一次
使用的新的活性成分
2.Existing active substances not described in the European Pharmacopoeia在欧洲药
典中没有描述的现有的活性物质
3.Existing active substances described in the European Pharmacopoeia在欧洲药典中
有描述的现有的活性物质
Application for a marketing authorisation of a Medicinal Product药品市场许可申请requires information on the Active Substance (AS) 活性物质(AS)的要求信息:
1.Certificate of suitability to the Monograph of the European Monograph
针对欧洲药典专论的适应性证书
2.Active Substance Master File (ASMF ) procedure活性物质主文件(ASMF ) 程序
3.Full details of manufacture完整的制造细节
Feasible ways to submit可行的递交方式
Depending on the classification of the AS取决于活性物质的分类
1.For new active substances and substances not described in the Ph.Eur. :
ASMF/EDMF对于在欧洲药典中没有描述的物质和新的活性物质: ASMF/EDMF
2.For existing substances, descrribed in the Ph.Eur. : CEP or ASMF/EDMF对于在欧
洲药典中描述的现有的活性物质: CEP 或ASMF/EDMF
The AS manufacturer provides either AS 制造商提供下列两者中的一个:
•No 1) CEP or第1，CEP或
•No 2 the ASMF/EDMF (Applicants part be included in the MA) 第2，ASMF/EDMF (MA包括此申请部分)
Submission of the CEP/ CEP的递交
Generally avoiding any subsequent reassessment通常应避免下列任何的重新评估
AS manufacturer submits作为制造商递交:
•copy of the most curent CEP最新的CEP的复印件
•Written asurance that no significant changes in the manufacturing method have taken place书面保证：在采用的制造方法中没有发生重大变更
Applicant submits申请人递交:
•Results of batch analysis demonstrating compliance with the Ph.Eur. Monograph批分析结果要证明符合欧洲药典专论的要求
ASMF/EDMF procedure ASMF/EDMF程序
Guideline on Active Substance Master File procedure活性物质主文件程序的指南:
CPMP/QWP/227/02
Terms European Drug Master File (EDMF) and Active Substance Master File (ASMF) are interchangable欧洲药物主文件(EDMF)和活性物质主文件(ASMF)的条款可以通用
Overview EDMF content EDMF内容概览
Template letter of access and covering letter准阅信和封面信的模板
ASMF/EDMF procedure ASMF/EDMF程序
Overall content of the ASMF/EDMF as indicated in NTA/CTD format Module 3按照NTA/CTD格式模块3的指示做ASMF/EDMF的全部内容
AP contains information non-condidental AP包含非保密的信息
RP contains remaining information such as RP包含剩余的如下信息:
•Detailed information on the manufacturing steps (reaction conditions, temperature etc.) 制造步骤的详细信息(反应条件，温度，等等)
•Evaluation of critical steps关键步骤的评估
•Quality control during manufacture制造中的质量控制
•Validation验证
ASMF/EDMF Submission ASMF/EDMF递交
EDMF can only be submitted in support of an MAA
EDMF只能在MAA的支持下递交
EDMF Holder should submit to the MA holder(EDMF的持有者递交到MA的持有者): ✓Copy of the latest version of the AP (AP的最近版本的复印件)
✓Copy of the QOS( QOS的复印件)
✓Letter of access AP contains information non-condidental EDMF Holder should submit to the authorities
EDMF持有者应当把AP包含的非保密内容的准阅信递交到官方部门
✓Complete EDMF with covering letter有封面信的完整EDMF
✓Letter of access准阅信
✓
Preparation and Filing of EDMF/ASMF for COS/CEP applicationies
申请COS/CEP的EDMF/ASMF文件制作
Technical Requirements技术要求
•EDMF compilation in CTD format CTD格式的EDMF的编写:
•a) Module 3.2. S. Drug Substance模块3.2. S. 药物物质
•b) Module 2.3 Quality Overall Summary模块2.3 质量综述
•CEP Procedure versus the DMF Procedure CEP程序对DMF程序
•Filing strategies in EU countries欧盟国家的文件编排策略
•Certification of suitability to the monographs of the European Pharmacopoeia欧洲药典专论的适应性证明
•Procedure ,Submission of the Dossier, Content of the Dossier/Expert Report,
Assessment, Timetable, Follow-up程序，文件的递交，文件目录/专家报告，评估，时间表，跟踪执行
Certification procedure COS证明程序
•Application at the EDQM (European Directorate for the Quality of Medicines) 在EDQM 申请（药品质量欧洲理事会）
•How to apply ? 怎样申请？
•Application form申请表
•Procedere程序
•Timetable时间表
CEP Certification of suitability to the monographs of the Ph. Eur. CEP欧洲药典专论的适应性证明
Scope范围:
•CEP is intended for substances for which a monograph ( general or specific) has been adopted CEP是针对那些已经被某个专论（大体的或详细的）所采用的物质•Organic or inorganic ( active or excipients) 有机的或无机的（活性成分或赋形剂）•Substances produced by fermentation发酵产生的物质
•Products with the risk of TSE有TSE风险的产品
The CEP certifies that by applying the relevant monograph (if necessary with annex ) it is possible to ensure that all possible impurities from this particular route of manufacture can be fully controlled. 通过应用相关的专论（附件，如果必要）CEP 证明，从特别的制造路线生产的所有可能的杂质都是能够被完全控制的。

How to Apply ?如何申请？
Submission递交
Submission of one SINGLE copy of the full dossier递交整个文件的一份拷贝
QOS in addition to paper copy , electronic submission preferably in WORD format or read-write pdf
QOS部分除了用文本文件，电子文本的递交最好用WORD文本或pdf
Samples of 1-2 representative commercial batches (about 10 g) 取1-2批有代表性的商业批次的样品(约10g)
Application format and Annex 1 – 5申请格式和附件1-5
Annexes
Annex 1 Letter of Authorisation ( if applicable) 附件一授权信(如果适用)
Annex 2 Letter of agreement ( if manufacturer not CEP holder) 附件二协议书(如果制造商不是CEP 的持有人)
Annex 3 Declaration that manufacture of the substance is according to the dossier and GMP rules附件三所提交文件中的药物是按照GMP规则制造的.
Annex 4 Letter of declaration of willingness to be inspected附件四愿意接受检查的声明信
Annex 5Letter of declaration regarding the use of material of human or animal origin附件五关于使用源于人或动物材料的声明信
Content of the Dossier文件目录
Revised Guideline implemented by 1 September 2005 PA/PH/CEP (04) 1 3 R January 2005 (2005年九月一日生效的修订版指南PA/PH/CEP (04) 1 3 R January 2005): •Quality Overall Summary QOS 2.3 according to the Notice to Applicants Volume 2 B质量综述QOS2.3根据<申请人通知>卷2B
•Summary of the content of the dossier文件内容的概述
•Discussion about the ability of the EP monograph to control the quality of the drug 讨论关于用欧洲药典专论的要求来控制药物质量的能力,
•in particular the declared potential impurities,or the necessity for alternative methods特别是药典公布的潜在杂质,或替代方法的必要性
•Justification where testing for possible impurities are omitted省略对可能杂质的检测的理由
•Imp. not detected in any batches or not present due to
a particular production在任何批次中不检测的或由于某种特别的产物而不存在的
杂质
General information 3.2.S 1一般信息3.2.S 1
•Commercialisation history of the substance : licensing history for medicinal products in Europe that contain the substance defined here物质的商业化历史:在欧洲药用产品的许可历史包括这里定义的物质
•Declarations : Annexes 1-5声明:附件1-5
•Annex 3, applied GMP should comply the ICH Q7A , if available a copy of the GMP certificate附件3,应用的GMP应符合ICH Q7A,如果有,GMP证书的复印件•If other parties are involved , details of their involvement , site addresses如果涉及第三方,详细的牵涉内容,地址
•Manufacturer of the final substance performs purification only, declarations on GMP and willigness to be inspected should be provided for the contract manufacturer如果制造商仅是由纯化得到最终物质的,那么GMP的声明和愿意接受检查的声明应由合同制造商提供
•Nomenclature化学名
•General properties 3.2.S 1.3常规属性3.2.S 1.3 :
•Physical characteristics , in case more than one grade .e.g. special particle size, compacted, particular polymorphic form one CEP only possible in case general specification is identical , otherwise different CEP with sub title物理属性,当不只一种级别时,如,特殊的颗粒度,压缩的,如果一般的规格是确定的,一个多态形式只能有一个CEP ,否则,有副标题的不同CEP
•Mixtures ( as explained in Substances for pharmaceutical ) API plus excipient only accapetable if this is defined in the monograph混合物( 见药物物质的解释)原料药加赋形剂只有在药典专论中有确认才是可接受的
•Claims regarding sterility etc. with reference to the monograph, freedom of pyrogens only if monograph foresees this关于无菌等的声明,参考专论,如果专论预见到焦精,而焦精的免用的声明
Manufacturer 3.2. S.2.1制造商3.2. S.2.1
•If different sites are involved for asingle defined process for manufacture or testing , this should be explained如果一个单独的已确定的制造工艺或检测涉及不同的现场,这需要解释.
•Make clear which production step is conducted at which sites明确哪个生产步骤是在哪个现场进行的.
•Names and addresses of each site should be given须给出每个现场的名称和地址
Content of the dossier for chemical purity and microbiological quality
文件内容：化学纯度和微生物质量
Description of the manufacturing process and Process controls 3.2.S 2.2制造工艺和工艺控制的描述3.2.S 2.2
•Flow Chart incl. Structural formula for starting material and all intermediates流程图包括起始物料和全部中间体结构式
•Include all steps of the process, from starting material to the isolated intermediates to the drug substance包括从起始物料到分离中间体再到得到药物物质的所有工艺步骤
•Detailed description: solvents , reagents ,catalysts , reaction conditions, inf. on intermediates, quantities of all materials for a batch of commercial batch size, yields for isolated intermediates详细描述：溶剂，试剂，催化剂，反应条件，中间体的信息，一个商业生产批次的所有材料的数量，分离出的中间体的产量•Specific emphasis on purification尤其强调纯度
•Max. batch size with experience acquired , reference to batches in the dossier经验中所获得的最大批量，参考文件中的批次
•In case of pilot scale batches yet, CEP can be granted providing scale up is immediately reported to the EDQM. 仍处在中试批次中，如果批放大后立即报告EDQM，也可以获得CEP
•For sterile products , variable or alternative batch sizes to be justified对于无菌产品，可变的或交替的批量要被评估
•Isemi-synthetically manufactured API , fermented starting material well characterised, possible carrying impurities半合成制造的原料药，已经完全定性的发酵起始物料，可能的运载杂质。

•Declaration of use/non use of material of animal origin使用或未使用源于动物的材料声明
•Different manufacturing sites and methods or alternatives could be described in one dossier , in case proof is given for each case sepcification and imp. Profile is exactly the same不同的或替代的制造地点和方法，如果对每种情况的规格和杂质都有证据，可以在一个文件中进行描述。

概况是完全相同的。

•Responsibilities of different sites不同现场的责任
•In case of alternative processes, batch analysis results to be presented to demonstrate no significant diff. in impurity profiles如果有替代工艺，提出的批分析结果要证明在杂质概况中没有重大的差别。

•Re-processing , if re-application of a step already used再加工，再申请，如果一个工
艺步骤已经使用
• Re-working –application of steps different from the described process not acceptable
与所描述的工艺不同的步骤的返工申请不可接受
• Recovery ( mother liquors or filtrates ) of reactants, intermediates or final
substance , acceptable in case of approved procedures 如果规程经过批准，回收的（母液或滤液）反应物，中间体或最终物质可接受，
• Recovery of the substance without further purification is re-working, not
acceptable 没有进一步纯化的回收物质进行返工，不可接受
• Blending of production batches to obtain larger size is acceptable, providing each
incorporated batch is individually tested and meets specification, prior to blending 如果每个混合前的小批都是被独立检测过的，并且符合标准，混合小批以获得大批是可接受的，
Schematic description （图解）
3.2.S.2.3 Control of materials 物料控制
• Specification of raw materials and solvents , appropriate 原料和溶剂的规格，适当的 • In case a class I solvent could be present in a solvent , specification and test method;
e.g Benzene in Toluol 如果在溶剂中可能有一类溶剂应注明其规格和检测方法；如：甲苯中的苯
• Starting material : justification, characterisation, specification , including potential
impurities 起始物料: 评定，性状，规格，包括潜在杂质
• Discussion of possible carrying through of impurities 讨论运行中可能的杂质 • Analytical test methods description 分析检测方法的描述
• In case the synthesis of API consits of only one or a few steps , manufacture of the
staring material should be given 如果原料药的合成仅有一步或几步构成，起始物料的制造应详细描述
• If more than one supplier of the starting material is used, batch analysis results from
the API manufactured from the different suppliers to be given 如果所使用的起始物料的供应商不只一个，从不同的供应商生产而来的原料药的批分析结果应被提供。

3.2.S 2.4 Control of Critical steps and intermediates 关键步骤和中间体的控制： :
•Critical steps definition: where process conditions , test requirements or other relevant parameters must be controlled within the predetermined limits to ensure that AS meets specification关键步骤的定义：工艺条件，检测要求或其他相关参数必须控制在预先确定的限度内的以确保AS符合标准
•Description of In Process controls过程控制的定义
•Intermediates中间体:
•Information on the quality and control of intermediates质量信息和中间体的控制3.2.S.2.5 Process validation and/or evaluation工艺验证和/或评估
•Process Validation should be provided as appropriate应提供适当的工艺验证:
•Sterilisation process, including filtration and aseptic processing消毒工艺，包括过滤和无菌工艺
•In case the monograph indicates specific additional requirements compliance should be demonstraeted如果药典专论中指出专门附加的要求，准则应该被证明•For biological substances , specific microbial grade, suitable inactivation should be demonstrated对于生物物质，专门的微生物指标，适当的失活应当被证明
3.2.S 2.6 Manufacturing process development制造工艺开发
•Description and discussion描述和讨论
3.2.S.3 Characterisation性状
3.2.S 3.1 Elucidication of Structure and other Characteristics结构分析和其他性状:
•Evidence of chemical structure化学结构的证据:
•Elemental analysis, IR spectra, NMR, MS, UV spectra元素分析，红外光谱，核磁共振，质谱，紫外光谱
•Evidence of structure of key intermediates, X-Ray christallography, optical rotation 关键中间体的结构证据，X-射线晶型图，旋光度
•Physico-chemical Characteristics物理化学特性:
•Polymorphism, Melting point, DSC多态性，熔点，DSC
•Solubility溶解度
•pKa and pH values pKa 和pH 值
3.2.S 3.2 Impurities杂质:
•Requirements concerning related substances according to the general monograph Substances for Pharmaceutical Use (2034) and关于相关物质的要求，根据总的专论《药品使用的物质（2034）》
•the Guideline Control of impurities of pharmacopoeial substances ( QWP 1529/04) should be met应符合《药品物质的杂质控制指南》( QWP 1529/04)•Possible impurities considered as potential impurities arising from the synthesis should be discussed , indicating origin ( staring material, reagent, solvent,catalyst, intermediate or degradation product应该对可能的杂质进行讨论，对认为是在合成中出现的潜在杂质，指出杂质起源（起始物料，试剂，溶剂，催化剂，中间体或降解产物
•Discussion of possible routes of degradation讨论降解可能的路线
•Analytical methods ( LOD and LOQ) 分析方法( LOD 和LOQ)
•Suitability of the methods of the monograph to control the quality of the substance must be discussed and demonstrated必须讨论和证明药典规定的原料药质量控制方法的适应性
•Additional impurities above the reporting threshold demonstrating that Ph. Eur Method is suitable添加的杂质在报告的阈值之上，以此证明欧洲药典的方法是合适的
•If Ph. Eur, method not suitable alternative test method including validation is required如果欧洲药典的方法不适应，则需要替代的检测方法，并包括其相关的验证。

•Chromatograms for production batches, with peak area results生产批次有峰面积结果的图谱
•Additional related substances , identification and qualification accord. to the Guidance Imp. In new Drug Substances ( ICH/2737/99) 附加的相关物质，鉴别和验证符合《在新原料药中的杂质的指南》( ICH/2737/99)
•Other impurities : residuals of toxic reagents, residues of acids or bases should be discussed其它杂质：有毒试剂的残留，酸或碱的残留应被讨论
•Consider relevant guidelines考虑相关的指南
•Residual catalysts , possible carryover, justified control limits required催化剂残留，可能的运行产物，所要求的合理的控制限度
3.2.S.4 Control of the Active substance活性物质的控制
• 3.2.S 4.1 Specification规格:
•Description描述
•Identification鉴别
•Impurities杂质
•Assay含量
•Additional tests附加的检测
•Reference to : Impurities testing guideline ( ICH/2737/99) Note for Guidance on Specifications ( ICH /367/96) 参考：杂质检测指南( ICH/2737/99) 关于规格的指南的注解( ICH /367/96)
•In case monograph under revision , new draft will be taken into consideration如果专论在审核中，可以考虑新的草案
Specification of the Active Substance活性物质的规格
•ICH/367/96 Note for Guidance on Specifications ICH/367/96规格指南的注释:
•Guidance for setting acceptance criteria建立可接受的标准的指南
•Justification of specifications规格的说明
•Selection of test procedures , pharmacopoeial tests检测规程，药典检测方法的选择•ICH/2737/99 Impurities testing guideline（ICH/2737/99 杂质检测指南）
•Classification of impurities; residual solvents, starting material, intermediates, by-products, degradation products杂质的分类；残留溶剂，起始物料，中间体，副产物，降解产物
•Reporting impurities, quantitative results numerical terms ! 报告杂质，以数据定量的结果！
•Reporting threshold, identification threshold, qualification threshold报告阈值，鉴别阈值，验证阈值
•NMT 2g/day Ident. 0.1 %, Qualif. 0.15 %(NMT 2g/天，鉴别的0.1%, 数量0.15%) •MT 2g/day Ident. 0.05 %, Qualif. 0.05 % (MT 2g/天，鉴别的0.05 %,数量0.05 %)
3.2.S
4.2 Analytical Proecedures分析规程
•Details of the analytical procedures分析规程的详细内容
•In case of TLC methods in the monograph, suitability to detect imp. at relevant threshold( 0.05% or 0.03 % acc. Max. daily dose) 如果是在专论中的TLC方法，在相关阈值内杂质检测的适应性( 0.05% 或0.03 % 根据日常最大计量) •TLC method only accepted in rare cases , 仅在很少的情况下，可接受TLC方法•Requirements of suitability , detection and quantification limit have to be considered 应考虑适应性，检测限和定量限的要求
3.2.S
4.3 Validation of Analytical Procedures分析规程的验证
•Reference to validation of analytical methods (ICH 381/95 and ICH 281/95); 分析方法验证的参考(ICH 381/95 和ICH 281/95)
•Typical chromatograms典型的图谱
•For additional methods acc. To the general methods of the Ph. Eur, like for residual solvents applicability is sufficient对于附加的方法，根据欧洲药典的一般方法，象残留溶剂，适应性就足够了
3.2.S
4.4 Batch Analysis批分析
•Description of batches and results of batches批次描述和批次结果
•Results below 1 % for related substances should be reported with 2 digits结果小于1％的相关物质应用2位数报告
•Present actual figures whenever possible instead of only‚complies…现在的实际数据，每当可能时只是代替“遵守”
•Analytical results from min. 2 batches, maximum batch size分析结果从最少2批到最大批数量
•Results should include : Date of manufacture, batch size and batch number, place of manufacture, results of analytical test, use of batches结果应当包括: 制造日期, 批大小和批号, 制造地点, 分析检测结果, 批的使用
3.2.S
4.5 Justification of Specification规格的解释
•See Note for Guidance on Specification, impurity testing guideline, residual solvents 查看指南中有关规格，杂质检测指南，残留溶剂的注解
3.2.S 5 Reference Standards or Materials对照品或对照物
•Specifications, full analytical and physico-chemical charcterisation, impurities etc.
规格，完整的分析和物理化学特性，杂质等
•Reference substances ( primary and secondary) incl. full analytical results or Ph.
Eur. CRS对照品（基准和二级）包括完整的分析结果或EP标准品
3.2.S 6 Container Closure System容器密闭系统
•Description of bulk storage container closure存放物料的密闭容器的说明
•Specification of primary packaging material ( e.g. Poleythylene bags) ad secondary packaging ( e.g. fibre drums, metal drums) 第一层包装材料（例如聚乙烯袋）和第二层包装（例如纤维桶，金属桶）的规格
3.2.S 7 Stability稳定性
3.2.S 7.2 Post approval stability Protocol and commitment公布批准的稳定性方案和执行
•Retest period may be attributed based on extrapolation , see NfG on stability testing 复测周期可以基于外推法来定性，参见NfG 稳定性试验
3.2.S 7.3 Stability Data稳定性数据
•Detailed results in tabular format,以表格形式的详细结果
•Stability testing according to ICH guideline根据ICH指南进行稳定性试验
•information on the analytical procedures ( validation if necessary ) 基于分析规程（如果必要须验证）的信息
References参考文献
•Notice to applicants (NTA) Volume 2 B CTD Module 3 S通知申请者(NTA) 第2册
B CTD 模块3 S
•Guideline on the chemistry of new active substances新活性物质化学部分指南
•Validation of analytical methods , Analytical procedures methodology ICH ICH 分析方法验证, 分析规程方法学
•Stability testing, photostability testing ICH ICH 稳定性试验, 光稳定性试验
•Impurities testing guideline , residual solvents ICH. ICH 杂质试验指南，残留溶剂•Note for Guidance on Specifications指南中关于规格的注意
Application form – Request for New Certificate of Suitability
申请表－－新适应性证书的要求
Certification procedure证明程序
•Application at the EDQM (European Directorate for the Quality of Medicines) 申请EDQM (European Directorate for the Quality of Medicines)
•How to apply如何申请?
•Application form申请表
•Procedere程序
•Timetable时间表
How to Apply ?
如何申请?
Technical Advice to Applicants and Holders of Certificates of Suitability (CEP)
对适应性证书(CEP)的申请者和持有者的技术建议
Technical Advice技术建议
Request for Technical advice for CEP /CEP技术建议的要求:
Write a letter to EDQM写信给EDQM
Mention the name and address of the applicant陈述申请者的名字和地址
Make reference to the relevant Ph.Eur. Monograph制作与欧洲药典专论相关的参考 Name of the substance /material物质/物料的名字
If applicable number of the corr. CEP是否是正确的CEP的适用号码
Charge of 1000 €1000 €（欧元）费用
•Payment should include ref. To …Technical Advice‟付款方式应当包括参考‘技术建议’
•Follow instructions at EDQM website EDQM网站上的遵循指令
•Submission either by email to certification@可以选择用电子邮件递交到certification@
•or EDQM certification Unit或EDQM认证部门
•226 Avenue de Colmar ( entrance rue Schertz)
•F-67029 Strasbourg France
•Technical questions or questions about the planning of the procedure技术询问或关于程序计划的询问
•Phrase Questions clearly add necessary supplementary information询问语句清晰，加上必要的补充信息
•EDQM will organize provision of the advice in a hearing EDQM将在一场听证中组织建议的条款
•Hearings must be booked in advance听证必须预先登记
•Takes place at EDQM在EDQM发生
•Once a month, next meetings October 6, November 3 and December 1st每月一次, 下次会议十月六日, 十一月三日和十二月1日
•Note : Procedure does not replace the submission or assessment of the CEP application注意: 程序并不代替CEP申请的递交或评定
Hearing at EDQM在EDQM 听证
Procedure for Revision / Renewals of Certificates of Suitability (CEP)
适应性证书(CEP)的修订/更新程序
Revision / Renewal修订/更新
Guideline on Requirements for Revision/Renewal of certificates证书的修订/更新要求的指南:
Holder of a CEP shall inform the EDQM of any change in the information CEP的持有者应当把任何变更信息告知EDQM
Classification of changes : three categories变更的分类: 三类
Notification (N)/minor (R or T)/major通知(N)/次要的(R or T)/主要的
Note : any change not classified as notification or minor change should be classified as a Major Change注意: 任何没有被《通知》或次要变更归类的变更应当被归类为
主要变更
Documentation to be provided须提供的文件:
Justification of the change变更的说明
Application form, enclosing a comparative list of updated sections申请表，包括一个更新章节的对照表
Specific documents as described in the Guideline on Requirements for Revision/ renewal of certificates在证书的修订/更新要求的指南中有对具体文件的描述
Notifications (N) 通知(N) :
Change in name or address of CEP holder or the name of the manufacturerCEP持有者的名字或地址，或者制造商名字的变更
Change in name or address of the manufacturing site制造场所的地址或名字变更
Deletion of any manufacturing site任何制造场所的删除
Deletion of a manufacturer of any intermediate/staring material任何中间体/起始原料的制造商的删除
Change in batch size of final substance, intermediate up to 10 fold to original batch 最终物质，中间体比原始批次扩大10倍的，批量的变更
Change in batch size downscaling批量缩减的变更
Minor Change to a test procedure检测程序的次要变更
Tightening of the specification limits规格限度的严格化
Change in the code product/reference number or in the brand of the final substance 产品代码/参考号或最终产品商标的变更
Amendment to stability data further to a commitment修订稳定性数据进一步到稳定性声明
Removal of the re-test period from the CEP从CEP上去除复检期
TSE certificate , deletion of source country etc. TSE证书，删除原料国家等内容
Minor Changes/Revisions (R) 次要变更/修订(R) :
Minor Change in manufacturing process, conditions制造工艺的次要变更，条件：: no change in imp. Profile, not sterilisation step, synthetic route remains the same杂质概况，非消毒步骤没有变更，合成路线保持相同
Change in batch size of substance or intermediate more than 10 fold , conditions :changes in manufacturing process only necessitated by scale up, no biological or sterile product, change does not affect reproducibility a test procedure 原料药或中间体的批量变更超过10倍，条件：工艺的变更只有在扩大规模，非生物的或非无菌产品时是可行的，变化不影响到检测程序的再现性
Specification of the final substance /intermediate /reagent , addition of a new test parameter change or replacement of a test procedure最终物质/中间体/反应物的规格，增加的新的检测参数的变更或检测程序的替换，
Conditions: change is not a result of unexpected events, new test procedure not a novel non-standard technique, new test procedure validated ,test results of at least two batches条件: 变更不是意外事件的结果，新检测程序不是异常的非标准技术,新检测程序被验证，至少两批的检测结果
Change in the manufacturer or addition of a new manufacturer of starting material or intermediate , conditions: specifications and route of synthesis identical,not a
biological substance,test results of 2 batches 在制造商内或新起始原料或中间体制造商的增加的变更, 条件：规格和合成路线确认，非生物物质，两批检测结果
For “double” CEP chemical purity and TSE risk , change in source of material 由于“双”CEP化学纯和TSE风险，对原料的变更
Conditions: no change in manufacturing process, specification remains the same, substance not biological条件：制造工艺没有变更，规格保持相同，非生物物质
Change in the manufacturing site or addition of a new site for the finished substance 变更制造现场或附加一个新的生产成品的场所
conditions: quality control specifications, method of preparation, detailed route of synthesis are identical, not a biological substance条件：质量控制规格，准备方法，详细的合成路线确定，非生物制品
Change in the Re-test period of the final substance and /or storage conditions最终物质复检期的变更和/或储藏条件的变更
Conditions: stability studies accord. to the relevant guidelines, change not result of unexpected events , substance not biological条件：根据相关的指南进行稳定性研究，变更不是源于不可预料事件的发生，非生物制品
Additional Minor Changes for TSE certificates因为TSE证书附加的次要变更
Procedure程序:
Notifications: Determination of validity of a notification within 2 weeks,通知：在两周内确定一个通知的生效
If notification incomplete , request rejected, no asking for additional questions , applicant has to resubmit如果通知未完成，要求被拒绝，不可有其它的问题，申请人不得不重新递交
Multiple simultaneous notifications possible: max 3 changes, fees and deadlines are increased多个内容同时通知的可能：最多3个变更，费用和截止日期增加
Minor Changes次要变更:
T 0 , within 5 days after receipt, letter of acknowledgement of receipt T 0 ，在接收后5天内，确认接受信
T 30 days either approval and revised certificate or request for additional information T 30 ，批准并修改证书的日期或要求附加信息的日期
New T 0 at receipt of additional information, new T 30 and approval or rejection新T 0 在附加信息接受时，新T 30和批准或退回
Multiple changes: max 3 changes, fees and deadlines are extended increased多项变更：最多3个变更，费用和截止日期相应的增加
Major Changes主要变更:
T 0 , within 5 days after receipt, letter of acknowledgement of receipt T 0 ，在接收后5天内，确认接受信
T 90 days either approval and revised certificate or request for additional information ( clock stop) T 90，批准并修改证书的日期或要求附加信息的日期（计时停止）
New T 0 when response received at EDQM , new T 30 and approval or rejection新T0当收到EDQM的回复，新T 30和批准或退回
Multiple changes: only one major together with minor/or notification is possible多
种变更：只有一个主要变更和次要变更/或通知是可行的
Quinquennial renewal五年一次的更新:
Application 6 months prior to expiry date有效期前6个月的申请
T 0 , within 5 days after receipt, letter of acknowledgement of receipt /T 0 ，在接收后5天内，确认接受信
T 120 days either approval and renewed certificate or request for additional information ( clock stop)/ T 120批准并修改证书的日期或要求附加信息的日期（计时停止）
If clock stop applicant to submit within 30 days如果计时停止，申请人要在30日内递交
New T 0 when response received at EDQM , new T 30 and approval or new request for information新T0当收到EDQM的回复，新T 30和批准或退回
Monograph revisions专论修订:
Letter by EDQM to applicant /EDQM给申请者的信:
Holder is requested to submit an update to the dossier within 30 days要求持有者在30天内递交一个更新的文件
T 0, receipt and start of evaluation no letter from EDQM（T 0，接受和评估开始，没有EDQM的来信）
T 120 days acknowledgement of valid data or request for additional information ( clock stop)/T 120批准并修改证书的日期或要求附加信息的日期（计时停止）
If clock stop applicant to submit within 30 days如果计时停止，申请人要在30日内递交
New T 0 when response received at EDQM , new T 30 and approval or new request for information新T0当收到EDQM的回复，新T 30和批准或对内容的新要求。