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4.II.2) Control of the final substance 原料药成品控制
4.II.2.1 Change in the specification parameters and/or limits of the final substance, starting material/intermediate/reagent used in the manufacturing process of the final substance 原料药成品、起始物料/中间体/用于成品生产工艺的试剂质量标准项目和/或限度变更 | | Specific documentation 要求的文件 | | a) Tightening of specification limits for the final substance 成品质量标准限度加严 | | | | b) Tightening of specification limits for a starting material/intermediate/reagent used in the manufacturing process of the final substance 起始物料/中间体/用于成品生产工艺的试剂质量标准加严 | | | | c) Addition of a specification parameter for a starting material/intermediate/reagent 起始物料/中间体/试剂质量标准项目增加 | | | | d) Addition of a specification parameter for the final substance 成品质量标准项目增加 | | | | e) Deletion of a non-significant specification parameter for the final substance/starting material/intermediate/reagent or deletion of a test procedure for a starting material/ intermediate/ reagent 删除成品/起始物料/中间体/试剂的不重要的质量标准项目，或删除起始物料/中间体/试剂检测方法 | | | | f) Deletion of a specification parameter which may have a significant effect on the overall quality of the final substance 删除成品质量标准中对成品质量不会形成重大影响的项目 | | | | g) Widening of the approved specification limits for the final substance to be in line with the limits of the Ph.Eur monograph/ICH/VICH guidelines 放宽已批准的成品质量标准限度，以与欧洲药典各论/ICH/VICH指南一致 | | | | h) Widening of the approved specification limits for the final substance 放宽已批准的成品质量标准限度 | | | | i) Widening of the approved specification limits for starting materials/intermediates, which may have a significant effect on the overall quality of the final substance 放宽已批准的起始物料/中间体质量标准限度，可能会对成品质量产生重大影响 | | | | | 1. The change does not result from unexpected events arising during manufacture e.g. new unqualified impurity; change in total impurity limits.
变更不是因为生产过程中的意外事件引起，例如，新的未知杂质、总杂质限度变化 | 2. Any change should be within the range of currently approved limits.
所有变更均应在已批准的限度范围内 | 3. The test procedure remains the same, or changes in the test procedure are minor.
检测方法保持相同，或对检测方法的变更轻微 | 4. Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way.
所有新的检测方法不涉及创新无标准术，或采用创新方式使用的标准技术 | 5. The test method is not a biological method or a method using a biological reagent for a biological substance (does not include standard pharmacopoeia microbiological methods).
检测方法不是生物方法，或采用生物试剂对生物物质进行检测的方法（不包括药典的标准微生物方法） | 6. For any material, the change does not concern a genotoxic impurity. If it involves the final substance, other than for residual solvents which must be in line with ICH/VICH limits, any new impurity control should be in line with the Ph.Eur.
所有物料的变更与基因杂质无关。如果相关，原料药成品，除残留溶剂外，应与ICH/VICH限度保持一致，所有新杂质的控制应与欧洲药典一致 | 7. The specification parameter does not concern a critical parameter for example any of the following: assay, impurities (unless a particular solvent is definitely not used in the manufacture of the active substance), any critical physical characteristics e.g. particle size, bulk or tapped density, identity test, water.
质量标准项目与关键参数无关，例如以下，含量、杂质（除绝对不会用于活性物质生产的特殊溶剂外），所有关键物理特性，例如，粒径、松密度或紧密度、鉴别测试、水分 | | 1. Comparative table of approved and proposed specifications.
已批准的和提议的质量标准对照表 | 2. Details of any new analytical method and validation data, where relevant.
所有新检测方法和验证数据的详细资料，如相关 | 3. Batch analysis data on two production batches of the final substance for all specification parameters.
两批成品的全检批分析数据 | 4. Justification/risk-assessment from the holder of the certificate of suitability as appropriate showing that the parameter is non-significant.
CEP持有人对检测项目为非重大项目的论述/风险评估 |
4.II.2.2 Change in test procedure for the final substance or a starting material/reagent/ intermediate used in the manufacturing process of the final substance
原料药成品或用于成品生产工艺的起始物料/试剂/中间体检测方法变更 | | Specific documentation 要求的文件 | | a) Minor changes to a test procedure for the final substance. Editorial changes to a method description annexed to a certificate of suitability
对成品检验方法的微小变更。对CEP附录中检测方法的编辑性变更 | | | | b) Minor changes to a test procedure for a starting material/intermediate/reagent used in the manufacturing process of the final substance
对用于成品生产工艺的起始物料/中间体/试剂的检验方法微小变更 | | | | c) Changes to a test procedure (including replacement or addition for the biological substance/starting material/intermediate or changes to a biological method)
检测方法变更（包括替换或增加生物物质/起始物料/中间体或对生物方法的变更） | | | | | 1. Appropriate validation studies have been performed in accordance with the relevant guidelines and show that the updated test procedure is at least equivalent to the former test procedure.
根据相关指南进行了适当的验证研究，研究表明更新后的检测方法至少与之前的检测方法对等 | 2. There have been no changes of the total impurity limits; no new unqualified impurities are detected.
总杂质限度无变更，未检出新的未定性杂质 | 3. The method of analysis should remain the same (e.g. a change in column length or temperature, but not a different type of column or method).
分析方法保持相同（例如，对柱长度或温度变更，但没有改变柱子型号或方法） | 4. The test method is not a biological method, or a method using a biological reagent for a biological substance (does not include standard pharmacopoeial microbiological methods).
检测方法不是生物方法，也不是对生物物质采用生物试剂进行检测的方法（不包括标准的药典微生物方法） | | 1. Description of the analytical method, summary of validation data, revised specifications
分析方法描述，验证数据总结，修订后的质量标准 | 2. Comparative validation results, or if justified comparative analysis results showing that the approved test and the proposed one are equivalent.
验证结果的对比，对分析结果的对比表明所批准的方法与提议的方法是否对等 | 3. Updated description of the method in a format to be appended to the certificate of suitability.
按CEP附录的格式更新的方法描述 |
4.II.3 Container closure system 容器密闭系统 4.II.3.1 Change in immediate packaging of the final substance
成品的内包装变更 | | Specific documentation 要求的文件 | | a) Composition (when there is a re-test period mentioned on the certificate of suitability)
成份（如果CEP中涉及复验期时） | | | | b) Composition (when there is no re-test period mentioned on the certificate of suitability)
成份（如果CEP中未涉及复验期时） | | | | c) Composition for sterile substances
无菌原料药内包装的成份 | | | | | 1. The proposed packaging material must be at least equivalent to the approved material in respect of its relevant properties.
提议的包装材料在相关特性上必须至少与批准的包装材料对等 | 2. Relevant stability studies have been started under ICH conditions and relevant stability parameters have been assessed in at least two pilot scale or industrial scale batches and at least three months satisfactory stability data are at the disposal at time of implementation.
在根据ICH指南的条件进行相关的稳定性试验，对至少两个中试批次或工业批次进行了相关的稳定性试验项目评估，在实施时至少三个月满意的稳定性数据
NB: if the proposed packaging is more resistant than the existing packaging, the three months stability data do not yet have to be available.
注：如果提议的包装比已有包装阻隔能力更好，则不需要三个月稳定性数据
These studies must be finalized and the data will be provided immediately to EDQM if outside specifications or potentially outside specifications at the end of the re-test period (with proposed action).
如果复验期结束时，稳定性数据超出或可能超出质量标准，则这些研究必须完成，数据必须立即提供给EDQM。 | 3. The final substance is not a sterile, liquid or biological substance. | | 1. Comparison of the approved and proposed immediate packaging specifications, if applicable
已批准的和提议的内包装质量标准对照表，如适用 | 2. Appropriate data on the new packaging including a confirmation that the material complies with relevant pharmacopoeial requirements or EU legislation on plastic materials and objects in contact with foodstuffs.
新包装适当的数据，包括原料符合相关药典要求的确认，或欧盟对接触食品的塑料材料和物质的要求 | 3. A declaration from the holder of the certificate as appropriate that the required stability studies have been started under ICH conditions (with indication of the batch numbers concerned) and that, as relevant, the required minimum satisfactory stability data were at the disposal at time of implementation and that the available data did not indicate a problem. Assurance should also be given that the studies will be finalized and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved re-test period (with proposed action)
CEP持有人出具的根据ICH条件开始进行稳定性试验的申明（说明相关的批号），以及相关的在实施时对稳定性数据的最低要求，已有数据未能说明的问题。保证研究会完成，如果在批准的有效期结束时数据超出或可能超出质量标准，会将数据立即提交有关当局（以及提议的措施） | * If applicable supportive stability data as listed in current version of the “Guideline on stability testing for applications for variations to a marketing authorisation” (EMA/CHMP/CVMP/QWP/441071/2011).
如果在“上市许可变更申报中稳定性试验指南”(EMA/CHMP/CVMP/QWP/441071/2011)现行版本中已列出了适用的支持性稳定性数据。 |
4.II.3.2 Change in the specification parameters and/or limits of the immediate packaging of the final substance
对成品内包装的质量标准项目和/或限度的变更 | | Specific documentation 要求的文件 | | Any change in the specification parameters and/or limits
所有对质量标准和/或限度的变更 | | | | | 1. The change does not result from unexpected events arising during manufacture of the packaging material or during storage of the final substance.
变更不是因为包装材料的生产过程中的意外事件导致，也不是国为原料药成品存贮期间的意外导致 | 2. The test procedure remains the same, or changes in the test procedure are minor.
检测方法保持相同，或对检测方法有轻微变更 | 3. Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way.
所有新检测方法均与创新非标准技术无关，与创新标准技术无关 | | 1. Comparative table of current and proposed specifications.
当前的与提议的质量标准的对照表格 |
4.II.3.3 Change in the composition/specification of the secondary packaging of the final substance
原料药成品外包装的成份/质量标准的变更 | | Specific documentation 要求的文件 | | | | | | | | | | | 1. The composition of the secondary packaging of the final substance remains the same.
原料药成品的外包装成份保持不变 | | 1. Comparison of the approved and proposed secondary packaging specification.
已批准的和提议的外包装的对照表格 |
4.II.4 Stability 稳定性 4.II.4.1 Change in the re-test period or storage conditions of the final substance
成品复验期或存贮条件变更 | | Specific documentation 要求的文件 | | a) Removal or reduction of an approved re-test period
删除或缩短已批准的复验期 | | | | b) Addition of a re-test period for the final substance and/or change in the storage conditions for the final substance
增加成品的复验期和/或对成品存贮条件进行变更 | | | | c) Extension of the re-test period of the final substance and/or change in the storage conditions for the final substance
延长成品复验期和/或放宽成品存贮条件 | | | | d) Change to more restrictive storage conditions
加严存贮条件 | | | | e) Change to an approved stability protocol
变更已批准的稳定性试验方案 | | | | | 1. The change should not be the result of unexpected events arising during manufacture or because of stability concerns.
变更原因不是生产过程的意外事件，或稳定性原因 | 2. The changes do not concern a widening of the acceptance criteria in the parameters tested, a removal of stability indicating parameters or a reduction in the frequency of testing.
变更不会放宽测试项目的可接受标准、不会删除稳定性指示项目、不会导致减少检测频次 | | 1. Justification of the removal/reduction of the re-test period or to more restrictive storage conditions.
删除/缩短复验期或加严存贮条件的理由陈述 | 2. Results of long-term and accelerated stability studies for at least two pilot or production scale batches.
至少两个中试批准或生产批量下长期和加速稳定性试验结果 | 3. Appropriate data on the packaging material including a confirmation that the material complies with relevant pharmacopoeial requirements or EU legislation on plastic materials and objects in contact with foodstuffs.
包装材料的适当数据，包括确认包材符合相应的药典要求或欧盟关于与食品接触的塑料材料和物品的法规要求 | 4. Updated results of stability studies for at least two pilot or production scale batches.
至少两个中试批准或生产批次稳定性试验数据更新 | 5. Justification for the proposed changes.
申请的变更的理由陈述 |
4.II.5) Design Space and Post-Approval Change Management Protocols 设计空间和已批准的变更管理方案 4.II.5.1 Introduction of a new design space or extension of an approved design space for the final substance, concerning: 针对成品以下内容引入新的设计空间，或扩展已批准的设计空间 | | Specific documentation 要求的文件 | | a) One unit operation in the manufacturing process of the final substance including the resulting in-process controls and/or test procedures
成品生产工艺的一个单元操作，包括对应的中控检测和/或检验方法 | | | | b) Test procedures for starting materials/reagents/intermediates and/or the final substance
起始物料/试剂/中间体和/或成品的检验方法 | | | | | 1. The design space has been developed in accordance with relevant European and international scientific guidelines. Results from product, process and analytical development studies (e.g. interaction of the different parameters forming the design space have to be studied, including risk assessment and multivariate studies, as appropriate) demonstrating where relevant that a systematic mechanistic understanding of material attributes and process parameters to the critical quality attributes of the final substance has been achieved.
根据相关欧洲和国际科学指南进行研发的设计空间。产品、工艺和分析研发结果（例如组成设计空间的不同参数的相互影响研究、包括必要时的风险评估和多变量研究）表明获得原料药成品的关键质量属性的工艺参数和原料属性已有系统性的理解。 | 2. Description of the design space in tabular format, including the variables (material attributes and process parameters, as appropriate) and their proposed ranges.
以表格方式展现的设计空间描述，包括变量（物料属性和工艺参数，适当时）及其申请的范围 | 3. Amendment of the relevant section(s) of the dossier in CTD format.
CTD格式申报文件的相关部分的增补 |
4.II.5.2 Introduction of a post approval change management protocol related to the final substance
引入一个与成品有关的已批准的变更管理方案 | | Specific documentation 要求的文件 | | | | | | | 1. Detailed description for the proposed change.
对申请变更的详细描述 | 2. Change management protocol related to the final substance.
与成品相关的变更管理方案 | 3. Amendment of the relevant section(s) of the dossier in CTD format.
CTD格式的申报文件的相关部分的增补 |
4.II.5.3 Deletion of an approved change management protocol related to the final substance
删除与成品有关的已批准的变更管理方案 | | Specific documentation 要求的文件 | | | | | | | 1. The deletion of the approved change management protocol related to the final substance is not a result of unexpected events or out of specification results during the implementation of the change(s) described in the protocol and does not have any effect on the already approved information in the dossier.
删除与原料药成品有关的已批准的变更管理方案，删除原因不是由于意外事件，或在实施方案中描述的变更时的超标结果，对申报文件中已批准的信息无任何影响 | | 1. Justification for the proposed deletion.
删除的理由陈述 | 2. Amendment of the relevant section(s) of the dossier.
对申报文件相关部分的增补 |
4.II.5.4 Changes to an approved change management protocol
对已批准的变更管理方案的变更 | | Specific documentation 要求的文件 | | a) Major changes to an approved change management protocol
对已批准的变更管理方案的重大变更 | | | | b) Minor changes to an approved change management protocol that do not change the strategy defined in the protocol
对已批准的变更管理方案的轻微变更，不影响方案中定义的策略 | | | | | 1. Declaration that any change should be within the range of currently approved limits.
申明所有变更均在目前批准的限度范围内 |
4.II.5.5 Implementation of change foreseen in an approved change management protocol
对已批准的变更管理方案中已预见的变更的实施 | | Specific documentation 要求的文件 | | a) The implementation of the change requires no further supportive data
对变更的实施不需要更多的支持性数据 | | | | b) The implementation of changes requires further supportive data
变更的实施需要更的支持性数据 | | | | | 1. The proposed change has been performed fully in line with the approved change management protocol.
申请的变更完全按照已批准的变更管理方案进行实施 | | 1. Reference to the approved change management protocol.
对已批准的变更管理方案的索引 | 2. Declaration that the change is in accordance with the approved change management and that the study results meet the acceptance criteria specified in the protocol.
申明变更与已批准的变更管理一致，且研究结果符合方案中给出的可接受标准 | 3. Amendment of the relevant section(s) of the dossier in CTD format.
CTD格式的申报文件中相关部分的增补 | 4. Results of the studies performed in accordance with the approved change management protocol.
根据已批准的变更管理方案所进行的研究的结果 |
This type of changes applies to TSE and double certificates of suitability except when specified in the conditions. 本类变更适用于TSE和双证，以下情形除外 4.III.1 Change in source country/ in source of material
原料来源或来源国家变更 | | Specific documentation 要求的文件 | | a) Deletion of a source country or deletion of a tissue used in the preparation of the final product
删除国家来源或删除原料药成品制备过程中使用的某种组织 | | | | b) Change/addition of a source country of tissues for TSE risk material
变更/删除TSE风险原料来源国 | | | | | 1. There is no change to the manufacturing process and there should be at least one remaining tissue and one remaining source country.
对生产工艺无变更，至少保留一个组织和一个来源国 | | 1. Direct comparison of the approved/proposed source of material.
已批准的和提议的原料来源的直接比较 |
4.III.2 Change or addition of a manufacturing site/manufacturer for a starting material/an intermediate or the final product
变更或增加原料药成品或起始物料/中间体的生产场所/生产商 | | Specific documentation 要求的文件 | | a) The proposed manufacturer for the final product is part of the same group as the approved manufacturer
所提议的原料药成品的生产商与已批准的生产商属同一集团 | | | | b) Change/addition of a manufacturing site for a starting material/an intermediate or where other TSE materials are processed
变更/增加起始物料/中间体，或有其它TSE物料生产的场所 | | | | | 1. No change in the manufacturing process, in the materials or in the origin of the materials used in the process.
生产工艺无变更，用于生产的原料种类和原料来源无变更 | | 1. A declaration from the holder of the certificate of suitability that the manufacturing process Is identical to that already approved.
CEP持有人的申明：生产工艺与已批准的相同 | 2. A declaration from the holder of the certificate of suitability that no other TSE risk material is processed in the new manufacturing site.
CEP持有人的申明：在新的生产场所未生产其它TSE风险物料 | 3. Updated declarations of manufacture in accordance with the dossier and according to GMP rules/quality system and of willingness to be inspected.
生产商更新申明：根据CEP文件和根据GMP/质量体系要求进行生产，愿意接受检查 | 4. Information on the quality assurance system (including traceability) applied in the new manufacturing site.
新生产场所实施质量保证体系信息（包括可追溯性） |
4.III.3 Change in the quality assurance system applied in the manufacturing site
生产场所质量保证体系变更 | | Specific documentation 要求的文件 | | | | | | | 1. The new quality assurance system is at least equivalent to the approved one.
新的质量保证体系至少与已批准的那个对等 | 2. No change in the manufacturing process (including process parameters) or in the specifications of the final substance.
生产工艺无变更（包括工艺参数），成品质量标准无变更 | | 1. Updated information on the quality assurance system (including traceability).
质量保证体系（包括可追溯性）更新信息 | 2. Updated declarations of manufacture in accordance with the dossier and according to GMP rules/quality system and of willingness to be inspected.
生产商更新申明：根据CEP文件和GMP要求/质量体系要求进行生产、愿意接受检查 |
4.III.4 Chang in the manufacturing process of the final substance
原料药成品生产工艺变更 | | Specific documentation 要求的文件 | | a) Minor change in the manufacturing process (including process parameters)
生产工艺轻微变更（包括工艺参数） | | | | b) Substantial changes in the manufacturing process that are likely to affect the TSE risk
可能会对TSE风险产生影响的生产工艺显著变更 | | | | | 1. The change has no impact on the TSE risk.
对TSE风险无影响的变更 | 2. The certificate of suitability covers only the TSE risk and does not cover the chemical purity and microbiological quality.
CEP仅覆盖TSE风险，未覆盖化学纯度和微生物质量 | | 1. Comparison of the approved and proposed process.
已批准的和提议的工艺对比 | 2. A declaration from the holder of the certificate of suitability that the change has no impact on the TSE risk.
CEP持有人申明：变更对TSE风险无影响 |
4.III.5 Minor change in the specification of the final substance
原料药成品质量标准微小变更 | | Specific documentation 要求的文件 | | | | | | | 1. The change has no impact on the TSE risk.
变更对TSE风险无影响 | 2. The certificate of suitability covers only the TSE risk and does not cover the chemical purity and microbiological quality.
CEP仅覆盖TSE风险，不覆盖化学纯度和微生物质量 | | 1. Comparison of the approved and proposed process.
已批准的和提议的工艺对照 | 2. A declaration from the holder of the certificate of suitability that the change has no impact on the TSE risk.
CEP持有人申明：变更对TSE风险无影响 |
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发表于 2014-8-9 18:28:44
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