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20140321 EMA/CHMP/CVMP/QWP/441071/2011- Rev.2 上市许可变更申请的稳定性试验指南
4 D4 s# {- N5 _5 w5 _/ \) |21 March 2014 EMA/CHMP/CVMP/QWP/441071/2011- Rev.2 Committee for Medicinal Products for Human Use (CHMP)/ Committee for Medicinal Products for Veterinary Use (CVMP) Guideline on stability testing for applications for variations to a marketing authorization 上市许可变更申请的稳定性试验指南 Draft Agreed by CHMP/CVMP Quality Working Party | June 2011 | 草案由CHMP/CVMP质量工作组通过 | 2011年6月 | Adoption by CHMP for release for consultation | June 2011 | CHMP通过并公布征求意见 | 2011年6月 | Adoption by CVMP for release for consultation | July 2011 | CVMP通过并公布告示意见 | 2011年7月 | End of consultation (deadline for comments) | 31 January 2012 | 公开征求意见结束 | 2012年1月31日 | Agreed by QWP | December 2013 | QWP通过 | 2013年12月 | Adoption by CHMP | February 2014 | CHMP采纳 | 2014年2月 | Adoption by CVMP | January 2014 | CVMP采纳 | 2014年1月 | Date for coming into effect | 6 months after publication | 生效日期 | 公布后6个月 |
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This guideline replaces Guideline on stability testing for applications for variations to a marketing authorisation previous version (CPMP/QWP/576/96 Rev 1, EMEA/CVMP/373/04). 本指南替代“上市批准后变更申请的稳定性试验指南”前版本(CPMP/QWP/576/96 Rev 1, EMEA/CVMP/373/04) Keywords | Stability, stability testing, stability data, chemical active substance, specification, variation | 关键词 | 稳定性，稳定性试验，稳定性数据，化学活性物质，质量标准，变更 |
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Table of contents | | | | Introduction (background) | | | | | | | | | | | | | | | | | | Change in the manufacturer of a starting material / reagent / intermediate used in the manufacturing process of the active substance or change in the manufacturer (including where relevant quality control testing sites) of the active substance, where no Ph. Eur. Certificate of Suitability is part of the approved dossier: Introduction of a manufacturer of active substance supported by an ASMF | 生产商变更：非CEP批准文件中活性物质生产工艺所用起始物料、试剂、中间体生产商变更，或活性物质生产商变更（包括相关质量控制检测场所）：引入一个由ASMF支持的活性物质生产商 | | Change in the manufacturer of a starting material / reagent / intermediate used in the manufacturing process of the active substance or change in the manufacturer (including where relevant quality control testing sites) of the active substance, where no Ph. Eur. Certificate of Suitability is part of the approved dossier: The proposed manufacturer uses a substantially different route of synthesis or manufacturing conditions, which may have a potential to change important quality characteristics of the active substance, such as qualitative and/or quantitative impurity profile requiring qualification, or physico-chemical properties impacting on bioavailability | 生产商变更：非CEP批准文件中活性物质生产工艺所用起始物料、试剂、中间体生产商变更，或活性物质生产商变更（包括相关质量控制检测场所）：拟报生产商使用显著不同的合成路线或生产条件，可能会对活性物质的质量特性有重大改变的情况，例如杂质谱数量和/或定性需要进行定性，或理化特性对生物利用度有影响 | | Change in the manufacturer of a starting material / reagent / intermediate used in the manufacturing process of the active substance or change in the manufacturer (including where relevant quality control testing sites) of the active substance, where no Ph. Eur. Certificate of Suitability is part of the approved dossier: Introduction of a new manufacturer of the active substance that is not supported by an ASMF and requires significant update to the relevant active substance section of the dossier | 生产商变更：非CEP批准文件中活性物质生产工艺所用起始物料、试剂、中间体生产商变更，或活性物质生产商变更（包括相关质量控制检测场所）：引入新的无ASMF支持的活性物质生产商，需要对申报文件有关活性物质部分进行重大更新时 | | Changes in the manufacturing process of the active substance: Substantial changes to the manufacturing process of the active substance which may have a significant impact on the quality, safety or efficacy of the medicinal product. | 活性物质生产工艺变更：对活性物质生产工艺有重大变更，可能会对药品质量、安全性或有效性有重大影响时 | | Changes in the manufacturing process of the active substance: The change relates to a herbal medicinal product and there is a change to any of the following: geographical source, manufacturing route or production | 活性物质生产工艺变更：变更是关于一种草药制品，对以下任何一项有变更时：来源地、生产路线或生产 | | Change in immediate packaging of the active substance: Qualitative and/or quantitative composition for sterile and non-frozen biological/immunological active substances | 活性物质内包装变更：无菌或非冷冻生物制品/免疫类活性物质组份和/或组成比例 | | Change in composition (excipients) of the finished product: Qualitative or quantitative changes in one or more excipients that may have a significant impact on the safety, quality or efficacy of the medicinal product. | 制剂组份（辅料）变更：一种或多种辅料性质或数量变更，可能会对药品安全、质量或有效性产生重大影响的 | | Change in coating weight of oral dosage forms or change in weight of capsule shells: Gastro-resistant, modified or prolonged release pharmaceutical forms where the coating is a critical factor for the release mechanism | 口服剂型包衣重量或胶囊壳重量变更：肠溶、改释或延释剂型中包衣在释放机理中作为关键因素时 | | Change in concentration of a single-dose, total use parenteral product, where the amount of the active substance per unit dose (i.e. the strength) remains the same | 单剂量剂型、全静脉药品的浓度变更，单剂药品中活性物质数量（即剂量）保持不变时 | | Replacement or addition of a manufacturing site for part or all of the manufacturing process of the finished product: Site where any manufacturing operation(s) take place, except batch release, batch control, and secondary packaging, for biological/immunological medicinal products, or for pharmaceutical forms manufactured by complex manufacturing processes | 使用另一生产场所替代部分或全部制剂生产，或增加一个生产场所：除以下操作外其它操作：批放行、批检验、外包装、生物制品/免疫制品，或由复杂生产工艺生产的药品 | | Change in the manufacturing process of the finished product, including an intermediate used in the manufacture of the finished product: Substantial changes to a manufacturing process that may have a significant impact on the quality, safety and efficacy of the medicinal product | 制剂生产工艺变更，包括用于制剂生产的中间体：生产工艺有重大变更，可能对制剂的质量、安全性和有效性有重大影响时 | | Change in the manufacturing process of the finished product, including an intermediate used in the manufacture of the finished product: Introduction of a non-standard terminal sterilisation method | 制剂生产工艺变更，包括用于制剂生产的中间体：引入一个非标终端灭菌方法 | | Change in the manufacturing process of the finished product, including an intermediate used in the manufacture of the finished product: Introduction or increase in the overage that is used for the active substance | 制剂生产工艺变更，包括用于制剂生产的中间体：引入或增加活性物质使用余量 | | Change in the batch size (including batch size ranges) of the finished product: The change relates to all other pharmaceutical forms manufactured by complex manufacturing processes | 制剂批量变更（包括批量范围）：变更是关于采用复杂生产工艺的所有其它药品剂型时 | | Change in immediate packaging of the finished product: Qualitative and quantitative composition: Sterile medicinal products and biological/immunological medicinal products | 制剂内包装变更：组成性质或数量：无菌制品和生物/免疫药品 | | Change in immediate packaging of the finished product: Qualitative and quantitative composition: The change relates to a less protective pack where there are associated changes in storage conditions and/or reduction in shelf life | 制剂内包装变更：组成性质或数量：变更是关于降低包装保护性时，且同时要求存贮条件变更和/或缩短货架期 | | Change in immediate packaging of the finished product: Change in type of container or addition of a new container: Sterile medicinal products and biological/immunological medicinal products | 制剂内包装变更：包装容器类型变更，或增加一种新的包装容器：无菌产品和生物制品/免疫产品 | | Change in shape or dimensions of the container or closure (immediate packaging): The change in shape or dimensions concerns a fundamental part of the packaging material, which may have a significant impact on the delivery, use, safety or stability of the finished product | 包装容器或密闭器（内包装）形状或尺寸变更：形状或尺寸变更涉及包装材料的基本部分，可能会对制剂的运输、使用、安全性或稳定性产生重大影响时 | | Change in pack size of the finished product: Change in fill weight/fill volume of sterile multidose (or single-dose) parenteral medicinal product, including biological/immunological medicinal products | 制剂包装规格变更：无菌（或单剂量）注射剂，包括生物制品/免疫制品的充填重量/充填体积变更 | | | | | | | | | | | | |
" r4 Q. A4 q, F: v @& e# ^Executive summary 实施摘要 This guideline provides guidance on the stability data which have to be generated in order to support a variation to a marketing authorisation. The guideline provides general guidance on stability testing for type IA and type IB variations and addresses the data requirements for common type II variations. 本指南提供为支持上市许可变更而需要产生的稳定性数据指南。本指南对IA和IB类变更的稳定性研究提供通用指南，也说明了常规2类变更的数据要求。 1. Introduction (background) 介绍（背景） This guideline describes the stability testing requirements for variations to a marketing authorisation after approval. This guideline is an extension of the CHMP and CVMP Guidelines on stability testing of existing active substances and related finished products and the respective ICH/VICH Guidelines for new active substances and drug products. It is intended to be applied in the European Union. 本指南描述了批准后的上市许可进行变更时所要求的稳定性研究。本指南是CHMP和CVMP“已有活性物质和有关制剂稳定性试验指南”和对应的ICH/VICH“新原料药和制剂指南”的延伸。它适用于欧盟以内。 The guideline seeks to illustrate the stability data required for variations to active substances and/or finished products. It is not always necessary to comply with this guideline when there are scientifically justifiable reasons for using alternative approaches (e.g., quality by design concept). However, the stability data outlined in this guideline reflects the usual expectation of the regulators. 本指南力图诠释活性物质和/或制剂变更时所需的稳定性数据。如果具有科学理由论证使用其它方法的合理性（例如，质量源于设计概念），也可以不符合本指南。但是，在本指南中所列出的稳定性数据要求反映了法规当局的一般期望。 While the guideline provides a general indication on the requirement for stability testing, it allows sufficient flexibility to encompass the variety of different practical situations required for specific scientific situations and characteristics of the material being evaluated. 由于本指南只是提供稳定性试验要求的通用指示，根据特定科学情形所要求的不同实践情况，以及所评估的物料的不同特性，可以进行变动。 2. Scope 范围 The purpose of this guideline is to outline the stability data which have to be generated in case of variations. It is applicable to chemical active substances and related finished products, herbal substances, herbal preparations and related herbal medicinal products. Radiopharmaceuticals, biologicals/immunologicals and products derived from biotechnology are not within the scope of this guideline. 本指南目的是列出变更所需产生的稳定性数据。指南适用于化学活性物质和有关的制 剂、草药物质、草药制品和相关草药制剂。辐射药品、生物制品/免疫制品和由生物技术衍生的药品不在本指南范围内。 Variations for active substances and finished products encompass a wide range of situations. The Guideline provides general guidance on stability testing in case of type I (A and B) variations. Furthermore, it addresses the information required for active substances and/or finished products in common type II variations as listed in section 6. 活性物质和制剂的变更包括很多种情形，本指南提供的是第1类（A和B）变更中稳定性试验的一般指南。另外，在第6部分列出的常规2类变更中活性物质和/或制剂所需的资料。 3. Legal basis 法规依据 This guideline should be utilised in conjunction with Commission Regulation (EC) No 1234/2008 as amended and the introduction and general principles section (4) of Annex I to Directives 2001/82 and 2001/83 as amended. 本指南就与(EC) No 1234/2008及其修订内容和指令2001/82和2001/83及其修订内容附录1第（4）部分一般原则一起使用。 4. General requirements 一般要求 In cases of variations which require generation of stability data on the finished product or the active substance, the stability studies required, including commitment batches, should always be continued up to the approved shelf-life / retest period and the authorities should be informed immediately if any problems with the stability appear during storage, e.g. if outside specification or potentially outside specification. 如果申请的变更需要产生制剂或活性物质的稳定性数据，稳定性研究，包括承诺批次，都应该持续至批准的货架期/复验期，如果在存贮期间稳定性出现任何问题，例如，超出质量标准或潜在超出质量标准，必须马上报告药监当局。 The scope and design of the stability studies for variations and changes are based on the knowledge and experience acquired of the active substances and finished products. The available information must be taken into account such as: 变更后稳定性研究的范围和设计应基于活性物质和制剂所需的知识和经验，必须考虑到诸如以下列出的可以获得的资料： a) For active substances: 活性物质 l the stability profile including the results of stress testing, if applicable (except herbals); l 稳定性概况，包括强降解试验结果，适用时（草药除外） l the supportive data; l 支持性数据 l the primary data of long term and accelerated* testing. l 长期和加速试验初期数据 b) For finished products: 制剂 l the supportive data; l 支持性数据 l the primary data of long term and accelerated* testing. l 长期和加速试验初期数据 In all variations, the applicant assesses whether the intended change has the potential to impact the quality characteristics and stability of the active substances and/or the finished products and consequently on their stability. 在所有变更中，申请人应评估所拟变更是否对质量特性和活性物质和/或制剂稳定性产生潜在影响，从而影响其稳定性 When stability data are required, the choice of test conditions, defined in this guideline refers to 如果要求提交稳定性数据，对测试条件的选择参见以下指南 l CHMP/ICH Guideline on Stability Testing of New Drug Substances and Products, l CHMP/ICH指南：新原料药和制剂稳定性试验指南 l CHMP/QWP Guideline on Stability Testing of Existing Active Substances and Related Finished Products, l CHMP/QWP指南：已有活性物质和有关制剂稳定性试验指南 l the CVMP/VICH Guideline on Stability Testing of New Veterinary Drug Substances and Medicinal Products l CVMP/VICH指南：新兽用原料药和制剂稳定性试验指南 l and the CVMP/QWP Note for Guidance on Stability Testing of Existing Active Substances and Related Finished Products, respectively. l CVMP/QWP指南解释：已有活性物质和有关制剂稳定性试验指南解释 Where appropriate, the concept of bracketing and matrixing as described in the CHMP/ICH and the CVMP/VICH Note for Guidance on Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Drug Products may be applied across related products. 适当时，在CHMP/ICH和CVMP/VICH指南“活性物质和制剂的稳定性试验所用括号法和矩阵法指南解释”中的括号和矩阵概念可以应用于覆盖相关产品。 The results of stability studies of the varied active substance/finished product, including the requested time period as defined below, using long term and accelerated* testing conditions, should be compared to studies performed on the unchanged active substance/finished product. This ensures that the change does not negatively impact the stability profile, i.e. that the specification limits of the active substance/finished product will still be met at the end of the proposed retest period/shelf-life. The comparison data of the unchanged product submitted with the variation may come from previous studies. 变更后活性物质/制剂的稳定性试验结果，包括以下定义要求的时间长度，长稳和加速条件，应与变更前活性物质/制剂所进行的研究相比较。这样才能保证变更不会对稳定性概况具有负面影响，即，在拟定的复验期/货架期结束时，仍能满足活性物质/制剂的质量标准限度。变更前后产品比较数据可以是来自之前的研究。 In relation to herbal substances, herbal preparations and related herbal medicinal products the guideline on quality of herbal medicinal products / traditional herbal medicinal products (EMA/CPMP/QWP/2819/00 Rev. 2), the guideline on specifications: test procedures and acceptance criteria for herbal substances, herbal preparations and herbal medicinal products / traditional herbal medicinal products (EMA/CPMP/QWP/2820/00 Rev. 2) should also apply. The testing of herbal substances and herbal preparations, testing at accelerated storage conditions or at the intermediate storage conditions may be omitted if justified by the applicant and if the storage conditions below 25° C are clearly labelled on the product. 关于草药物质、草药制品和相关草药制剂，适用“草药制剂/传统草药制剂质量指南” (EMA/CPMP/QWP/2819/00 Rev. 2)，“质量标准指南：草药物质、草药制品和草药药品/传统草药药品的检测程序和可接受标准”(EMA/CPMP/QWP/2820/00 Rev. 2)。如果申请人有论述，且产品明确标示存贮条件低于25° C，则草药物质和草药制品可不需要进行加速条件测试和中间存贮条件测试。 Where extrapolation of data is applicable, see Annex II for further information. 如果数据适用外推法，参见附件2获取更多信息。 5. Type I variations 第1类变更 If a variation to a marketing authorisation fulfils the conditions defined in the Commission Regulation (EC) No 1234/2008 for Type IA variations, and if stability data are required, the minimum set of data to be submitted with the variation is defined in the Guidelines on the details of the various categories of variations, on the operation of the procedures laid down in Chapters II, IIa, III and IV of Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products and on the documentation to be submitted pursuant to those procedures. 如果上市许可的变更满足“EC法规(EC) No 1234/2008”第IA类变更的条件，且要求提交稳定性数据，在“(EC) No 1234/2008中关于对人兽用药品上市后的变更检查，及根据这些程序进行变更所提交文件检查，第II，IIa，III和IV章中设定的操作程序、变更不同分类细节指南”中说明了需要提交的最低数据要求， A Type IB variation is the default category under the Commission Regulation (EC) No 1234/2008. The associated classification guideline provides examples of different types of Type IB changes that have been included in the guideline with recommended documentation. Where a change may impact stability, the required stability data at the time of submission are specified in the guideline. In other Type IB by default changes, which are not specifically described in the classification guideline, the required stability data has to be decided on a case by case basis. However, consideration should be given to specified requirements for any other similar changes which have actually been included as examples in the guideline. 根据(EC) No 1234/2008，第IB类变更是默认的变更类型。在指南相关的分类变更中提供了IB类变更不同类型的例子，以及推荐的文件。如果一个变更可能会影响到稳定性，其在提交时所要求的稳定性数据在指南中已有说明。在其它默认IB类变更中，如果在分类指南中并未特别描述，则是否需要提交稳定性数据应各案决定。但是，在决定时应考虑指南中作为例子的其它类似变更的指定要求。 6. Type II variations 第2类变更 The Commission Regulation (EC) No 1234/2008 defines Type II variations as major variations which may have a significant impact on the quality, safety or efficacy of medicinal products. Type II variations are defined in the Guidelines on the details of the various categories of variations, on the operation of the procedures laid down in Chapters II, IIa, III and IV of the Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products and on the documentation to be submitted pursuant to those procedures. However, data to be submitted with these variations are not defined in the majority of cases. 在(EC) No 1234/2008中定义了2类变更是重大变更，它们可能会药品质量、安全性或有效性产生重大影响。2类变更在指南“(EC) No 1234/2008中关于对人兽用药品上市后的变更检查，及根据这些程序进行变更所提交文件检查，第II，IIa，III和IV章中设定的操作程序、变更不同分类细节指南”中进行定义。但是，在大部分案例中，并未说明变更时需要提交哪些数据。 The following Type II variations refer to specific Type II variations as outlined in the Guidelines mentioned above. 以下2类变更参照了上述指南中列出的特定2类变更。 The stability data outlined below should to be part of the documentation at submission of the variation. 以下列出的稳定性数据应在变更时作为文件的一部分提交。 6.1. (B.I.a.1.b) Change in the manufacturer of a starting material / reagent / intermediate used in the manufacturing process of the active substance or change in the manufacturer (including where relevant quality control testing sites) of the active substance, where no Ph. Eur. certificate of suitability is part of the approved dossier: Introduction of a manufacturer of active substance supported by an ASMF 生产商变更：非CEP批准文件中活性物质生产工艺所用起始物料、试剂、中间体生产商变更，或活性物质生产商变更（包括相关质量控制检测场所）：引入一个由ASMF支持的活性物质生产商 In case of an introduction of a manufacturer of the active substance that is supported by an ASMF stability data should be included in the applicants part of the ASMF. 如果引入一个由ASMF支持的活性物质生产商，则稳定性数据应包括在ASMF的公开部分。 In relation to stability data, of the active substance, the recommendations given in the guideline on stability testing of existing active substances and finished products should be utilised. 活性物质的稳定性数据应依据“已有活性物质和制剂的稳定性试验指南”。 If the quality characteristics/impurity profile of the active substance are changed in a way that may impact the stability of the finished product, additional stability data on the finished product, in long term and accelerated* conditions, six months data on at least two batches of at least pilot scale batch size are recommended. 如果活性物质的质量特性/杂质谱变化可能会影响制剂的稳定性，则建议提交制剂至少中试批量的至少2批6个月的长稳和加速条件稳定性数据。 6.2. (B.I.a.1.c) Change in the manufacturer of a starting material / reagent / intermediate used in the manufacturing process of the active substance or change in the manufacturer (including where relevant quality control testing sites) of the active substance, where no Ph. Eur. certificate of suitability is part of the approved dossier: The proposed manufacturer uses a substantially different route of synthesis or manufacturing conditions, which may have a potential to change important quality characteristics of the active substance, such as qualitative and/or quantitative impurity profile requiring qualification, or physico-chemical properties impacting on bioavailability 生产商变更：非CEP批准文件中活性物质生产工艺所用起始物料、试剂、中间体生产商变更，或活性物质生产商变更（包括相关质量控制检测场所）：拟报生产商使用显著不同的合成路线或生产条件，可能会对活性物质的质量特性有重大改变的情况，例如杂质谱数量和/或定性需要进行定性，或理化特性对生物利用度有影响 In relation to stability data of the active substance, the recommendations given in the guideline on stability testing of existing active substances and finished products should be utilised. 活性物质稳定性数据，应依据“已有活性物质和制剂的稳定性试验指南”。 If the quality characteristics of the active substance are changed in a way that may impact the stability of the finished product, additional stability data on the finished product, in long term and accelerated* testing conditions, six months data on at least two batches of at least pilot scale batch size are recommended. 如果活性物质的质量特性变化可能会对制剂的稳定性产生影响，则建议提交至少中试批量至少2批6个月长稳和加速条件下稳定性数据。 6.3. (B.I.a.1.g) Change in the manufacturer of a starting material / reagent / intermediate used in the manufacturing process of the active substance or change in the manufacturer (including where relevant quality control testing sites) of the active substance, where no Ph. Eur. certificate of suitability is part of the approved dossier: Introduction of a new manufacturer of the active substance that is not supported by an ASMF and requires significant update to the relevant active substance section of the dossier 生产商变更：非CEP批准文件中活性物质生产工艺所用起始物料、试剂、中间体生产商变更，或活性物质生产商变更（包括相关质量控制检测场所）：引入新的无ASMF支持的活性物质生产商，需要对申报文件有关活性物质部分进行重大更新时 In relation to stability data of the active substance, the recommendations given in the guideline on stability testing of existing active substances and finished products should be utilised. 活性物质稳定性数据，应依据“已有活性物质和制剂的稳定性试验指南”。 If the quality characteristics of the active substance are changed in a way that may impact the stability of the finished product, additional stability data on the finished product, in long term and accelerated* testing conditions, six months data on at least two batches of at least pilot scale batch size are recommended. 如果活性物质的质量特性变化可能会对制剂的稳定性产生影响，则建议提交至少中试批量至少2批6个月长稳和加速条件下稳定性数据。 6.4. (B.I.a.2.b) Changes in the manufacturing process of the active substance: Substantial changes to the manufacturing process of the active substance which may have a significant impact on the quality, safety or efficacy of the medicinal product 活性物质生产工艺变更：对活性物质生产工艺有重大变更，可能会对药品质量、安全性或有效性有重大影响时 In variations to the manufacturing process of the active substance, the following approaches may be considered as acceptable: 对于活性物质生产工艺变更，以下方法都认为是可以接受的： If the quality characteristics (e.g. physical characteristics, impurity profile) of the active substance are changed in a way that stability may be compromised, comparative stability data are recommended in long term and accelerated* testing conditions, on the active substance before and after the change: 如果活性物质的质量特性（例如，物理特性、杂质谱）变化可能会使稳定性变差，则建议提交活性物质在变更前后长稳和加速条件稳定性对比数据。 l for active substances known to be stable: three months data on at least one batch of at least pilot scale batch size (see Annex I for the definition of stable active substance). l 对于已知稳定的活性物质：至少在中试批量至少1批3个月数据（参见附录1稳定活性物质的定义） l for active substances known to be unstable: six months data on at least three batches of at least pilot scale batch size. l 对于已知不稳定的活性物质：至少在中试批量至少3批6个月数据 If the quality characteristics of the active substance are changed in a way that may impact the stability of the finished product, additional stability data on the finished product, in long term and accelerated* testing conditions, six months data on at least two batches of at least pilot scale batch size are recommended. 如果活性物质的质量特性变化可能会对制剂的稳定性产生影响，则建议提交至少中试批量至少2批6个月长稳和加速条件下稳定性数据。 6.5. (B.I.a.2.d) Changes in the manufacturing process of the active substance: The change relates to a herbal medicinal product and there is a change to any of the following: geographical source, manufacturing route or production活性物质生产工艺变更：变更是关于一种草药制品，对以下任何一项有变更时：来源地、生产路线或生产 In variations to the manufacturing process of the active substance, the following approaches may be considered as acceptable: 对于活性物质生产工艺变更，以下方法都认为是可以接受的： If the quality characteristics (e.g. physical characteristics, impurity profile) of the active substance are changed in a way that stability may be compromised, comparative stability data are recommended in long term and accelerated* term testing conditions, on the active substance before and after the change: 如果活性物质的质量特性（例如，物理特性、杂质谱）变化可能会使稳定性变差，则建议提交活性物质在变更前后长稳和加速条件稳定性对比数据。 l for active substances known to be stable: three months data on at least one batch of at least pilot scale batch size (see Annex I for the definition of stable active substance). l 对于已知稳定的活性物质：至少在中试批量至少1批3个月数据（参见附录1稳定活性物质的定义） l for active substances known to be unstable: six months data on at least three batches of at least pilot scale batch size. l 对于已知不稳定的活性物质：至少在中试批量至少3批6个月数据 If the quality characteristics of the active substance are changed in a way that may impact the stability of the finished product, additional stability data on the finished product, in long term and accelerated* testing conditions, six months data on at least two batches of at least pilot scale batch size are recommended. 如果活性物质的质量特性变化可能会对制剂的稳定性产生影响，则建议提交至少中试批量至少2批6个月长稳和加速条件下稳定性数据。 6.6. (B.I.c.1.b) - Change in immediate packaging of the active substance: Qualitative and/or quantitative composition for sterile and non-frozen biological/immunological active substances活性物质生产工艺变更：变更是关于一种草药制品，对以下任何一项有变更时：来源地、生产路线或生产 (Note: According to the scope this guideline is not applicable to biological/immunological active substances). （注：根据范围，本指南不适用于生物制品/免疫类活性物质） In case of a change to the immediate packaging of a sterile active substance the following approach may be considered as acceptable: 如果变更的是无菌活性物质内包装，则以下方法被认为是可以接受的： Comparative stability data are required using long term and accelerated* testing conditions of six months in duration on at least 2 batches of at least pilot scale of the active substance. 活性物质至少在中试批量至少2批6个月长稳和加速条件下稳定性对比数据。 6.7. (B.II.a.3.b.2) Change in composition (excipients) of the finished product: Qualitative or quantitative changes in one or more excipients that may have a significant impact on the safety, quality or efficacy of the medicinal product. 制剂组份（辅料）变更：一种或多种辅料性质或数量变更，可能会对药品安全、质量或有效性产生重大影响的 In case of a change in the composition of the finished product, the following approaches may be considered as acceptable: 如果是制剂组分变更，以下方法被认为是可以接受的 For conventional dosage forms (e.g. conventional release solid dosage form, solutions) and when the active substance is known to be stable, comparative stability data, 6 months in duration, long term and accelerated* testing conditions on at least two batches of at least pilot scale are recommended. 对于传统剂型（例如，传统释放固体剂型、溶液），如果活性物质已知是稳定性，则建议提交至少中试批量至少2批6个月长稳和加速条件下稳定性对比数据。 For critical dosage forms (e.g. modified release form) or when the active substance is known to be unstable, comparative stability data 6 months in duration, long term and accelerated* stability testing conditions on at least three primary batches are recommended. Two of three batches should be at least pilot scale; the third batch may be smaller. 对于临界剂型（例如，改释剂型），或如果活性物质已知是不稳定的，则建立至少3批6个月长稳和加速稳定条件下对比数据。3批中至少有2批必须至少是中试批量，第3批批量可以小一些。 6.8. (B.II.a.4.b) Change in coating weight of oral dosage forms or change in weight of capsule shells: Gastro-resistant, modified or prolonged release pharmaceutical forms where the coating is a critical factor for the release mechanism口服剂型包衣重量或胶囊壳重量变更：肠溶、改释或延释剂型中包衣在释放机理中作为关键因素时 In variations to the coating weight of oral dosage forms, the following approach may be considered as acceptable: 口服剂型包衣重量变更时，以下方法被认为是可以接受的： Comparative stability data, 6 months in duration, long term and accelerated* stability testing conditions on at least three primary batches are recommended. Two of three batches should be at least pilot scale; the third batch may be smaller. 建议提交至少3批6个月长稳和加速条件下稳定性对比数据。3批中至少2批应至少为中试批量，第3批批量可以较小。 6.9. (B.II.a.5.) Change in concentration of a single-dose, total use parenteral product, where the amount of the active substance per unit dose (i.e. the strength) remains the same单剂量剂型、全静脉药品的浓度变更，单剂药品中活性物质数量（即剂量）保持不变时 In variations in concentration of single-dose, total use parenteral product, the following approaches may be considered as acceptable: 单剂量、全静脉药品浓度变更时，以下方法被认为是可以接受的： Comparative stability data, 6 months in duration, long term and accelerated* stability testing conditions on at least three primary batches are recommended. Two of three batches should be at least pilot scale; the third batch may be smaller. 建议提交至少3批6个月长稳和加速条件下稳定性对比数据。3批中2批至少应为中试批量，第3批可以小一些。 6.10. (B.II.b.1.c) Replacement or addition of a manufacturing site for part or all of the manufacturing process of the finished product: Site where any manufacturing operation(s) take place, except batch release, batch control, and secondary packaging, for biological/immunological medicinal products, or for pharmaceutical forms manufactured by complex manufacturing processes使用另一生产场所替代部分或全部制剂生产，或增加一个生产场所：除以下操作外其它操作：批放行、批检验、外包装、生物制品/免疫制品，或由复杂生产工艺生产的药品 (Note: According to the scope this guideline is not applicable to biological/immunological active substances and related finished products). （注：根据范围，本指南不适用于生物制品/免疫类活性物质和有关制剂） In variations (replacement or addition) to a manufacturing site for part or all of the manufacturing process of the finished product, the following approaches may be considered as acceptable: 对制剂全部或部分生产工艺的生产场所提出变更（替代或增加）时，以下方法被认为是可以接受的： If the quality characteristics (e.g. physical characteristics, impurity profile) of the finished product are changed in a way that stability may be compromised, comparative stability data are recommended in long term and accelerated* testing conditions, on the finished product before and after the change: 如果制剂的质量特性（例如，物理特性、杂质谱）的变化会使稳定性变差，则建议提交变更前后制剂长期和加速条件下稳定性试验对比数据。 For conventional dosage forms (e.g. conventional release solid dosage form, solutions) and when the active substance is known to be stable, comparative stability data, 6 months in duration, long term and accelerated* testing conditions on at least two batches of at least pilot scale are recommended. 对于传统剂型（例如，传统释放固体剂型、溶液），如果活性物质已知是稳定性，则建议提交至少中试批量至少2批6个月长稳和加速条件下稳定性对比数据。 For critical dosage forms (e.g. modified release form) or when the active substance is known to be unstable, comparative stability data, 6 months in duration, long term and accelerated* stability testing conditions on at least three primary batches are recommended. Two of three batches should be at least pilot scale; the third batch may be smaller. 对于临界剂型（例如，改释剂型），或如果活性物质已知是不稳定的，则建立至少3批6个月长稳和加速稳定条件下对比数据。3批中至少有2批必须至少是中试批量，第3批批量可以小一些。 6.11. (B.II.b.3.b) Change in the manufacturing process of the finished product, including an intermediate used in the manufacture of the finished product: Substantial changes to a manufacturing process that may have a significant impact on the quality, safety and efficacy of the medicinal product制剂生产工艺变更，包括用于制剂生产的中间体：生产工艺有重大变更，可能对制剂的质量、安全性和有效性有重大影响时 In variations to the manufacturing process of the finished product, the following approaches may be considered as acceptable: 制剂生产工艺变更时，以下方法被认为是可以接受的： If the quality characteristics (e.g. physical characteristics, impurity profile) of the finished product are changed in a way that stability may be compromised, comparative stability data are recommended in long term and accelerated* testing conditions, on the finished product before and after the change: 如果制剂的质量特性（例如，物理性质、杂质概况）发生变更，可能使稳定性变差，则建议提交制剂变更前后长期和加速条件下稳定性试验对比数据。 For conventional dosage forms (e.g. conventional release solid dosage form, solutions) and when the active substance is known to be stable, comparative stability data, 6 months in duration, long term and accelerated* testing conditions on at least two batches of at least pilot scale are recommended. 对于传统剂型（例如，传统释放固体剂型、溶液），如果活性物质已知是稳定性，则建议提交至少中试批量至少2批6个月长稳和加速条件下稳定性对比数据。 For critical dosage forms (e.g. modified release form) or when the active substance is known to be unstable, comparative stability data, 6 months in duration, long term and accelerated* stability testing conditions on at least three primary batches are recommended. Two of three batches should be at least pilot scale; the third batch may be smaller. 对于临界剂型（例如，改释剂型），或如果活性物质已知是不稳定的，则建立至少3批6个月长稳和加速条件下稳定性对比数据。3批中至少有2批必须至少是中试批量，第3批批量可以小一些。 6.12. (B.II.b.3.d) - Change in the manufacturing process of the finished product, including an intermediate used in the manufacture of the finished product: Introduction of a non-standard terminal sterilisation method制剂生产工艺变更，包括用于制剂生产的中间体：引入一个非标终端灭菌方法 In variations to the manufacturing process of the finished product, the following approaches may be considered as acceptable: 制剂生产工艺变更时，以下方法被认为是可以接受的： If the quality characteristics (e.g., impurity profile) of the finished product are changed in a way that stability may be compromised, comparative stability data are recommended in long term and accelerated* testing conditions, on the finished product before and after the change: 如果制剂的质量特性（例如，物理性质、杂质概况）发生变更，可能使稳定性变差，则建议提交制剂变更前后长期和加速条件下稳定性试验对比数据。 For conventional dosage forms (e.g. solutions) and when the active substance is known to be stable, comparative stability data, 6 months in duration, long term and accelerated* testing conditions on at least two batches of at least pilot scale are recommended. 对于传统剂型（例如，传统释放固体剂型、溶液），如果活性物质已知是稳定性，则建议提交至少中试批量至少2批6个月长稳和加速条件下稳定性对比数据。 For critical dosage forms (e.g. suspensions or emulsions for injection) or when the active substance is known to be unstable, comparative stability data, 6 months in duration, long term and accelerated* stability testing conditions on at least three primary batches are recommended. Two of three batches should be at least pilot scale; the third batch may be smaller. 对于临界剂型（例如，改释剂型），或如果活性物质已知是不稳定的，则建立至少3批6个月长稳和加速条件下稳定性对比数据。3批中至少有2批必须至少是中试批量，第3批批量可以小一些。 6.13. (B.II.b.3.e) Change in the manufacturing process of the finished product, including an intermediate used in the manufacture of the finished product: introduction or increase in the overage that is used for the active substance制剂生产工艺变更，包括用于制剂生产的中间体：引入或增加活性物质使用余量 In variations to the manufacturing process of the finished product, the following approaches may be considered as acceptable: 制剂生产工艺变更时，以下方法被认为是可以接受的： If the quality characteristics (e.g. content of active substance) of the finished product are changed in a way that stability may be compromised, comparative stability data are recommended in long term and accelerated* testing conditions, on the finished product before and after the change: 如果制剂的质量特性（例如，物理性质、杂质概况）发生变更，可能使稳定性变差，则建议提交制剂变更前后长期和加速条件下稳定性试验对比数据。 For conventional dosage forms (e.g. conventional release solid dosage form, solutions) and when the active substance is known to be stable, comparative stability data, 6 months in duration, long term and accelerated* testing conditions on at least two batches of at least pilot scale are recommended. 对于传统剂型（例如，传统释放固体剂型、溶液），如果活性物质已知是稳定性，则建议提交至少中试批量至少2批6个月长稳和加速条件下稳定性对比数据。 For critical dosage forms (e.g. modified release form) or when the active substance is known to be unstable, comparative stability data, 6 months in duration, long term and accelerated* stability testing conditions on at least three primary batches are recommended. Two of three batches should be at least pilot scale; the third batch may be smaller. 对于临界剂型（例如，改释剂型），或如果活性物质已知是不稳定的，则建立至少3批6个月长稳和加速条件下稳定性对比数据。3批中至少有2批必须至少是中试批量，第3批批量可以小一些。 6.14. (B.II.b.4.d) Change in the batch size (including batch size ranges) of the finished product: The change relates to all other pharmaceutical forms manufactured by complex manufacturing processes制剂批量变更（包括批量范围）：变更是关于采用复杂生产工艺的所有其它药品剂型时 In variations to the batch size of the finished product, the following approaches may be considered as acceptable: 制剂批量变更时，以下方法被认为是可以接受的： If the quality characteristics (e.g. impurity profile) of the finished product are changed in a way that stability may be compromised, comparative stability data are recommended in long term and accelerated* testing conditions, on the finished product before and after the change: 如果制剂的质量特性（例如，物理性质、杂质概况）发生变更，可能使稳定性变差，则建议提交制剂变更前后长期和加速条件下稳定性试验对比数据。 For conventional dosage forms manufactured by a complex manufacturing process and when the active substance is known to be stable, comparative stability data, 6 months in duration, long term and accelerated* testing conditions on at least two batches of at least pilot scale are recommended. 对于传统剂型（例如，传统释放固体剂型、溶液），如果活性物质已知是稳定性，则建议提交至少中试批量至少2批6个月长稳和加速条件下稳定性对比数据。 For critical dosage forms (e.g. modified release form) or when the active substance is known to be unstable, comparative stability data, 6 months in duration, long term and accelerated* stability testing conditions on at least three primary batches are recommended. Two of three batches should be at least pilot scale; the third batch may be smaller. 对于临界剂型（例如，改释剂型），或如果活性物质已知是不稳定的，则建立至少3批6个月长稳和加速条件下稳定性对比数据。3批中至少有2批必须至少是中试批量，第3批批量可以小一些。 6.15. (B.II.e.1.a.3) Change in immediate packaging of the finished product: Qualitative and quantitative composition: Sterile medicinal products and biological/immunological medicinal products制剂内包装变更：组成性质或数量：无菌制品和生物/免疫药品 (Note: According to the scope this guideline is not applicable to biological/immunological active substances and related finished products). （注：根据范围，本指南不适用于生物制品/免疫类活性物质和有关制剂） In case of a change to the immediate packaging of the finished product the following approach may be considered as acceptable: 在对制剂内包装进行变更时，以下方法被认为是可以接受的： In the case of less protective packaging or when a risk of interaction occurs for a sterile medicinal product, comparative stability data are recommended using long term and accelerated* testing conditions of six months in duration on at least three primary batches of the finished product. Two of three batches should be at least pilot scale; the third batch may be smaller. 如果变更后的包装保护性降低，或无菌药品有与内包装发生相互反应的风险，则建议提交制剂至少3批6个月长稳和加速条件下稳定性对比数据。3批中至少2批应至少为中试批量，第3批批量可以较小。 6.16. (B.II.e.1a.4) Change in immediate packaging of the finished product: Qualitative and quantitative composition: The change relates to a less protective pack where there are associated changes in storage conditions and/or reduction in shelf life. 制剂内包装变更：组成性质或数量：变更是关于降低包装保护性时，且同时要求存贮条件变更和/或缩短货架期 In case of a change to the immediate packaging of the finished product the following approach may be considered as acceptable: 制剂内包装申请变更时，以下方法被认为是可以接受的： In the case of less protective packaging or when a risk of interaction occurs, mainly for semi-solid or liquid dosage forms, comparative stability data are recommended using long term and accelerated* testing conditions of six months in duration on at least three primary batches of the finished product. Two of three batches should be at least pilot scale; the third batch may be smaller. 如果变更后的包装保护性降低，或药品，主要是半固体或液体剂型，有与内包装发生相互反应的风险，则建议提交制剂至少3批6个月长稳和加速条件下稳定性对比数据。3批中至少2批应至少为中试批量，第3批批量可以较小。 6.17. (B.II.e.1.b.2) Change in immediate packaging of the finished product: Change in type of container or addition of a new container: Sterile medicinal products and biological/immunological medicinal products制剂内包装变更：包装容器类型变更，或增加一种新的包装容器：无菌产品和生物制品/免疫产品 (Note: According to the scope this guideline is not applicable to biological/immunological active substances and related finished products). （注：根据范围，本指南不适用于生物制品/免疫类活性物质和有关制剂） In case of a change to the immediate packaging of the finished product the following approach may be considered as acceptable: 制剂内包装申请变更时，以下方法被认为是可以接受的： In the case of less protective packaging or when a risk of interaction occurs, mainly for semi-solid or liquid dosage forms, comparative stability data are recommended using long term and accelerated* testing conditions of six months in duration on at least three primary batches of the finished product. Two of three batches should be at least pilot scale; the third batch may be smaller. 如果变更后的包装保护性降低，或药品，主要是半固体或液体剂型，有与内包装发生相互反应的风险，则建议提交制剂至少3批6个月长稳和加速条件下稳定性对比数据。3批中至少2批应至少为中试批量，第3批批量可以较小。 6.18. (B.II.e.4.b) Change in shape or dimensions of the container or closure (immediate packaging): The change in shape or dimensions concerns a fundamental part of the packaging material, which may have a significant impact on the delivery, use, safety or stability of the finished product包装容器或密闭器（内包装）形状或尺寸变更：形状或尺寸变更涉及包装材料的基本部分，可能会对制剂的运输、使用、安全性或稳定性产生重大影响时 In variations to the immediate packaging of the finished product, which may have a significant impact of the stability of the finished product, the following approach may be considered as acceptable: 制剂内包装申请变更，且对制剂稳定性可能有重大影响时，以下方法被认为是可以接受的： If the quality characteristics (e.g. impurity profile) of the finished product are changed in a way that stability may be compromised, comparative stability data are recommended in long term and accelerated* testing conditions, on the finished product before and after the change: 如果制剂的质量特性（例如杂质概况）发生变化，可能使稳定性变差，则建议至少提交制剂变更前后的长期和加速条件下稳定性对比数据。 For conventional dosage forms manufactured by a complex manufacturing process and when the active substance is known to be stable, comparative stability data, 6 months in duration, long term and accelerated* testing conditions on at least two batches of at least pilot scale are recommended. 对于传统剂型（例如，传统释放固体剂型、溶液），如果活性物质已知是稳定性，则建议提交至少中试批量至少2批6个月长稳和加速条件下稳定性对比数据。 For critical dosage forms (e.g. modified release form) or when the active substance is known to be unstable, comparative stability data, 6 months in duration, long term and accelerated* stability testing conditions on at least three primary batches are recommended. Two of three batches should be at least pilot scale; the third batch may be smaller. 对于临界剂型（例如，改释剂型），或如果活性物质已知是不稳定的，则建立至少3批6个月长稳和加速条件下稳定性对比数据。3批中至少有2批必须至少是中试批量，第3批批量可以小一些。 6.19. (B.II.e.5.c) Change in pack size of the finished product: Change in fill weight/fill volume of sterile multidose (or single-dose) parenteral medicinal product, including biological/immunological medicinal products制剂包装规格变更：无菌（或单剂量）注射剂，包括生物制品/免疫制品的充填重量/充填体积变更 (Note: According to the scope this guideline is not applicable to biological/immunological active substances and related finished products). （注：根据范围，本指南不适用于生物制品/免疫类活性物质和有关制剂） In case of such a change to the pack size of the finished product the following approach may be considered as acceptable: 制剂包装规模申请变更时，以下方法被认为是可以接受的： If the quality characteristics (e.g. impurity profile) of the finished product are changed in a way that stability may be compromised, comparative stability data are recommended in long term and accelerated* testing conditions, on the finished product before and after the change: 如果制剂的质量特性（例如杂质概况）发生变化，可能使稳定性变差，则建议至少提交制剂变更前后的长期和加速条件下稳定性对比数据。 Comparative stability data are recommended using long term and accelerated* testing conditions of six months in duration on at least three primary batches of the finished product. Two of three batches should be at least pilot scale; the third batch may be smaller. 稳定性对比数据建议采用至少3批制剂6个月长期和加速条件下的。3批中的2批应至少为中试批量，第3批可以小一些。 7. Commitment batches 承诺批次 For Type IA and IB variations that require the generation of stability data on the finished product, adequate follow up studies on commitment batches are necessary. 对于要求提交制剂稳定性数据的IA和IB类变更，还需要对承诺批次进行充分的跟踪研究。 For Type II variations that require the generation of stability data on the finished product, at least the first production scale batch manufactured according to the approved variation should be placed on long term stability testing protocol. The stability testing protocol is as described in the original application unless it has previously been varied. Stability studies need to be continued to cover the entire shelf-life. The results of these stability studies should be made available on request and the authorities should be informed if any problems appear with the stability studies. 对于需要提交制剂稳定性数据的II类变更，根据批准的变更，至少应有1批生产批量的产品被放入长期稳定性试验方案中。除非之前已有变更，否则应遵守与初始申报中所述一致的稳定性试验方案。稳定性研究需要持续并覆盖整个生命周期。这些稳定性研究的结果应在药监当局要求时提供，如果稳定性研究出现任何问题，则应立即通知药监当局。 References 参考文献 Guidelines on the details of the various categories of variations, on the operation of the procedures laid down in Chapters II, IIa, III and IV of the Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products and on the documentation to be submitted pursuant to those procedures (OJ, 2013/C 223/01, Volume 56, 2 August 2013, p. 1) (EC) No 1234/2008中关于对人兽用药品上市后的变更检查，及根据这些程序进行变更所提交文件检查，第II，IIa，III和IV章中设定的操作程序、变更不同分类细节指南 Guideline on Stability Testing of New Drug Substances and Products (CPMP/ICH/2736/99-ICH Q1A) 新原料药和制剂稳定性试验指南 Guideline on Stability Testing of New Veterinary Drug Substances and Medicinal Products (CVMP/VICH/899/99 Rev.1-VICH GL3) 新兽用原料药和制剂稳定性试验指南 Guideline on Stability Testing of Existing Active Substances and Related Finished Products (CPMP/QWP/122/02 Rev. 1 corr) 已有活性物质和相关制剂稳定性试验指南 Note for Guidance on Stability Testing of Existing Active Substances and Related Finished Products (EMEA/CVMP/QWP/846/99-Rev.1) 已有活性物质和相关制剂稳定性试验指南解释 Note for Guidance on Bracketing and Matrixing Designs for Stability Testing of Drug Substances and Drug Products (CPMP/ICH/4104/00-ICH Q1D) 原料药和制剂稳定性试验括号法和矩阵法设计指南解释 Bracketing and matrixing designs for stability testing of new veterinary drug substances and medicinal products (EMEA/CVMP/VICH/581467/2007-VICH GL45) 新兽用原料药和制剂稳定性试验括号法和矩阵法设计 Note for Guidance on Evaluation of Stability Data (CPMP/ICH/420/02) 稳定性数据评估指南解释 Guideline on Statistical Evaluation of Stability Data (EMA/CVMP/VICH/858875/2011 稳定性数据统计学评估指南 Note for guidance on quality of herbal medicinal products / traditional herbal medicinal products (EMA/CPMP/QWP/2819/00 Rev. 2 草药制剂/传统草药制剂质量指南解释 Note for guidance on specifications: test procedures and acceptance criteria for herbal substances, herbal preparations and herbal medicinal products / traditional herbal medicinal products (EMA/CPMP/QWP/2820/00 Rev. 2) 质量标准指南解释：草药物质、草药制品和草药制剂/传统草药制剂检测方法和可接受标准 *according to ICH/VICH conditions; where appropriate; intermediate storage conditions, if applicable * 根据ICH/VICH条件，适当时，中间存贮条件，适用时 Annex I 附录1 An active substance is considered as stable if it is within the initial specifications when stored at 25°C/ 60 % RH or 30°C/65% RH, respectively, (2 years) and 40°C/75 %RH (6 months). 如果原料药在25°C/ 60 % RH 或 30°C/65% RH存贮2年，40°C/75 %RH存贮6个月后其质量仍符合初始质量标准，则认为原料药是稳定的。 Annex II 附录2 Where the data submitted, long term 25?C/60% RH or 30°C/65% RH, respectively, and accelerated 40?C/75% RH or, in case of aqueous products in semi-permeable containers, the respective storage conditions defined in the CHMP and CVMP Guidelines on Stability Testing of Active Substances and Related Finished Products, show that there is no adverse effect on the stability of the active substance/finished product, the retest period/shelf life originally granted can normally be retained, based on comparison with the original data submitted. However, where the data demonstrate an adverse change in product stability, a new shelf life must be assigned. Based on a case-by-case decision, extrapolation of data may be applied. 如果是提交长期 25?C/60% RH 或 30°C/65% RH，以及加速40?C/75% RH稳定性数据，或水性产品包装于半透容器中，根据CHMP和CVMP“原料药和有关制剂稳定性指南”中定义的存贮条件下所得的稳定性数据，数据显示活性物质/制剂稳定性并未受到负面影响，则基于与原始提交数据的对比，一般可以保留原始批准的复验期/货架期。但是，如果数据证明对产品稳定性有负面影响，则必须给定新的货架期。这种情况应基于各案做决定，也可以采用数据外推法。 If real time data are supported by results from studies conducted under accelerated or intermediate storage conditions, the retest period/shelf-life may be extended beyond the end of real time studies. Normally, in those cases in which long-term and accelerated data show little or no change over time and little or no variability the proposed retest period can be extrapolated up to twice but should not be more than 12 months beyond the period covered by long–term data. The degree up to which extrapolation will be acceptable following to a change to the active substance or finished product that shows an adverse effect to the stability will largely depend on the change over time, variability of data observed, proposed storage conditions and extent of statistical analyses performed. It will always have to be a case-by-case decision. For more detailed information on statistical evaluation of stability data please refer to the CHMP/ICH Note for Guidance on Evaluation of Stability Data or the CVMP/VICH Guideline on Statistical Evaluation of Stability Data in case of veterinary medicinal products. 如果有加速或中间存贮条件下研究结果支持实时数据，则复验期/货架期可以延长超过实时研究的时长。一般，如果长期和加速数据显示出整个试验时间内没有或仅有很小的变化，可以外推至2倍时长，但不应超过长稳数据时长加12个月。显示出对稳定性有不良影响的活性物质或制剂产品的变更，其数据外推至何程度是可以接受的，在很大程度上依赖于在一定时间内的变化、观察到数据的变化程度、拟定的存贮条件以及所进行的统计学分析的程度。这种情况必须各案做出决定。更多稳定性数据的统计学评估信息，参见“稳定性数据评估指南CHMP/ICH解释”或“兽用制剂稳定性数据统计学评估CVMP/VICH指南”。 | 
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