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1、EMA 制剂成品生产指南 -2017 （中英文）GMP 办公室翻译组 翻译：王世华校对： Owen 欢迎加入 GMP 办公室翻译组 QQ 群： 307361958 此前 GMP 办公室发布了 EMA 制剂成品生产指南 -2017 版的新闻，现在该指南已由 GMP 办公室翻译组 - 旺仔翻译， 并校对完成。现将它发布出来分享给大家。 Executive summary 综述 略1. Introduction （background） 介绍（背景） 略 2. Scope 范围This guideline is applicable to the manufacture of the finishe
2、d dosage form of chemical and herbal medicinal products for human use intended for marketing authorisation. It also applies to variations for authorised products in cases where changes to the manufacturing process affecting the MA are proposed.这份指南适用于为取得上市许可证的人用化学药品和植物药品制剂成品生产。 同时，它也适用于已经批准的产品在计划实施变
3、更生产工艺 影响 MA 的变更情况。The principles described are in general also applicable to biological medicinal products. Where relevant, the principles of this guideline may also be applied to radiopharmaceuticals and to chemical investigational medicinal products. 陈述的原则基本上也适用于生物制品。 如有相关，这个指导原则也适用于放射性药品和化学试验药 品。
4、3. Legal basis 法定基础This guideline should be read in conjunction with Directive 2001/83/EC Article 8.3 (d), as amended where it is stated that the application for a marketing authorisation shall contain a description of the manufacturing method. 这个指 南应该与 2001/83/EC 指令 8.3 (d)章(d) Description of the m
5、anufacturing method.) 一起阅读 , 在上市许可申请中应该 包含一个生产方法的描述之处有所改进。The requirements on the description of the manufacturing method in the CTD Module 3 of marketing authorisation dossier are described in Annex 1, Part 1 (section 3.2.2.3) to this Directive. Further details on the information to be provided are
6、 outlined in this guideline. 在通用技术文件模 块3 上市许可申请文件关于生产方法的描述要求在这份指令 的附件 1 第 1 部分(3.2.2.3 节)有说明。 更多详细的信息在 这份指南中有提供。4. Manufacture 生产The headings of this guideline follow the structure of theCTD format Module 3, Section 3.2.P.3 Manufacture.这份指南的标题遵循 CTD 模块 3 下 3.2.P.3 节 生产 的结构。 Only product specific asp
7、ects of manufacture need to be described and included in the MA dossier; general elements of Good Manufacturing Practice (GMP), (ref. 3) should not be included. 只有生产的产品特性方面的描述需 要包括在 MA 的文档中，常规的 GMP 的要素不需要包括进 去。4.1. Manufacturer(s) 生产商For each stage of the manufacturing process, including packaging,
8、details should be given of all the individual sites involved (including those from the same company).生产工艺的每一步包括包装，所有的细节都需要考虑到每一个包 括在内的单独的产地(包括来自同一家公司那些产地) 。 The name, address and responsibility of each manufacturer, including contractors, should be provided. This applies also to all quality control
9、sites, including on-going stability testing if different from the manufacturing site(s). 每一家生产商包括合同商的名称、地址和职责都需 要提供。这个适用于所有质量控制场所，包括正在进行的稳 定性研究场所，如果与生产地址不同的话。The EU site responsible for batch release in the EU market should be specified. 要明确规定在欧盟市场上市产品由欧 盟的公司负责批放行。4.2. Batch Formula 批处方The batch for
10、mula for the intended batch size should be stated. In case a range of batch sizes is proposed, the range should be stated and the batch formula should be provided for at least the largest and smallest batch sizes. 根据拟定批量的批处方应该说明。如果拟定批量是一个范围， 则这个范围应该说明，应提供至少最大批量和最小批量的批 处方。An application for a range o
11、f batch sizes should be adequately justified as not adversely impacting the critical quality attributes (CQAs) of the finished product in accordance with the guideline on process validation (ref. 4). 对于批量为一个范围的申请应该根据工艺验证指南被充分 评估以防对成品的关键质量属性 ( CQAs )造成不利影响 (参 见 4 )。If the bulk product is assembled in
12、to different presentations or packs, the production batch size should be defined by the bulk before any division. When the length of thesubsequent processes and assembly is considered critical (e.g. filling time for aseptically manufactured products), the worst-case scenario of the division pattern
13、(e.g. in respect of total filling time) should be indicated.如果散装品被收集或包装成不同的形式，则生产批量应该根据分装之前的散装 品来定义。当随后的工艺和装配的时间长度被认为是关键参 数(比如无菌产品的灌装时间) ，最坏情况的分配模式(比 如关于总的灌装时间)应该要说明。The batch size for a product to be marketed should normally be compatible with production scale equipment. It should be sufficiently l
14、arge to be representative of commercial manufacturing to enable demonstration of a state of control. For example, a commercial batch size for solid oral dosage forms should be at least 100,000 units unless justification is provided (e.g. orphan medicinal products) (ref. 4). 上市产品的批量通常应该与设备的生产 能力相匹配。它
15、应该充分地最大限度地代表商业化生产，并 经能够证明处于受控状态。比如，一个口服固体制剂的商业 生产批量至少在 100,000 个单位以上， 除非提供正当理由 (比 如孤儿药品) (参见 4)If sub-batches are prepared and combined for subsequent processing, this should be justified as the final batch isrequired to be homogeneous, their formulae and the number of sub-batches per intended batch
16、 size should be stated. In addition, if a batch is sub-divided towards the end of the process to reflect equipment processing capability, this should be clearly indicated (e.g. solid dosage form manufacture where sub lots are required due to equipment capacity). The number of sub-batches per intende
17、d batch size should be stated.如果亚批制备后会在随后的工序中合并，这种情况应该以最终批来定批量，而且 要求是均质的，他们的处方和亚批的数量在每一批预定的批 量中要说明。此外，如果一批在最后的工序分成亚批以适应 设备的工艺能力，这种情况应明确(比如固体制剂生产中当 亚批批量要适合于设备工艺能力) 。每批预定批量中亚批的 数量应明确。In case of continuous manufacture, the information about batch size in traditional terms might not be relevant; however
18、, information as to how a batch is defined should be provided (e.g. expressed in terms of a period of time or a quantity of product, and may be expressed as ranges). 当连续生产，这个传统意义上的批量信息似乎意义不大。然 而，如何定义一批的概念信息需要提供(比如批可以表达为 一个时间段或者一定数量的产品，也可以定义为某个范围内的产品)The names, quantities and reference to the quality
19、 standards of all ingredients used in the course of the manufacture should be stated. Ingredients which are removed from the product during the production process, such as granulation liquids, solvents and gases should be included but their quantities may be expressed as ranges. 在生产过程中用到的所有的成分的名称、数量
20、和参考的质量 标准需要说明。在生产过程中从产品中挥发的成分，比如制 粒溶液、溶剂和气体应该包括进来，但是他们的数量可以表 示为一个范围。Ingredients that are optionally used, such as acids and alkalis for pH adjustment, should also be mentioned. Formula overages must be clearly indicated in quantitative terms and justified in the pharmaceutical development section of
21、 the dossier. Upper and lower acceptance limits for the actual quantity of each ingredient may be stated in the batch formula; however, the proposed acceptance limits should be justified. When the quantity of an active ingredient to be used is calculated from the actual assay value of the batch of t
22、hat active ingredient (factorisation), this should be stated and justified. If another ingredient is used to keep the total mass per batch equal to the quantity provided for in the batch manufacturing formula, this should also be indicated. 选择性使用的成分，比如调节 PH 值的酸和碱，也应该要说明，处方的过量投料也应该在数量 的条款中说明，并且在药品研发阶
23、段文件中对此要进行评诂。 每一种成分的实际数量的最高和最低接收限度应在批处方 中应明确。而且，这个拟定可接受限度应该被评估。当使用 原料的数量是根据原料的实际含量计算出来的（因式分解） ， 这种情况应明确说明和评估。如何让其他的成分来保持与所 提供批生产处方的每批总重量相平衡，这种情况也应明确。4.3. Description of Manufacturing Process and Process Controls 生产工艺和过程控制General aspects 一般考虑A narrative description of the full manufacturing process sh
24、ould be provided, accompanied by a flow chart describing each step of the process including in-process controls and showing at each stage where materials enter the process. In case a design space is proposed, this should be clearly identified and described.应提供所有的生产工艺过程描述，同时有一个流程图描述每一步工艺过程， 包括过程控制和在每
25、一个工序显示物料从哪里进入该流程。 为了设计一个预计的结构流程，这个需要被清楚地确认和描The manufacturing process description should be adequately justified in 3.2.P.2 by development data, in particular as regards any process operating conditions or ranges. The description of a manufacturing process with wide ranges (wider than would normally
26、 be accepted as normal operating ranges) or described only by an upper or lower limit, generally requires a more thorough discussion and/or scientific rationale in the manufacturing process development section. 生产工艺描述在 3.2.P.2 研发数据中 应该被充分的评估，特别是关于任何工艺操作条件和范围。 生产工艺中带有较大范围(比正常可接受操作范围更大)或 者只有最高或最低的限度的描
27、述，一般要求在生产工艺研究 阶段做一个更加深入的讨论或者提供细致严谨的科学原理。 Full scale manufacturing process validation is not requested at the time of application for certain types of products (ref. 4). If the result of such full scale study is not available at the time of submission, it is expected that process parameters settings
28、identified during manufacturing process development are laid down in the process description. In the event that any changes are required to the registered process parameters as a resultof full scale process validation studies, these changes should be applied for via post approval variation, in accor
29、dance with the variation Regulation （ref. 5, ref. 6）.大生产批量的生产工艺验证在产品申报阶段是不要求的（参考 4）。如果这种大批量生产研究的结果不能在提交申请时获得， 那么可以预计这个工艺参数设置确认是在生产工艺研究期 间在工艺流程描述中设定的。如果要变更注册工艺参数作为 大生产工艺验证研究的结果，这些变更申请需要走批准后产 品变更流程，按照变更管理要求执行（参考 5 、参考 6） . Where specifically relevant for the product, any required environmental conditi
30、ons during manufacture should be stated e.g. low humidity for an effervescent tablet.当对产品有特定价值，在生产过程中任何环境条件的要求都要说明， 比如易吸潮的片子需要低湿环境。Depending on the nature of the process and the product （e.g. sterile products）, manufacturing durations of critical steps and hold times should be stated and justified.根
31、据工艺和产品的自然属性（比如无菌制剂） ，生产期间的关键 步骤和存放时间需要明确和评估。The steps at which process controls, intermediate tests or final product controls are conducted should be identified. 在过程控制的步骤如中间产品检测或者最后的产品控制需要指明并且要确认。Consideration should be given in 3.2.P.2 to what extent the assurance of quality of the finished product
32、 is founded on the manufacturing process itself. The significance of the process description and process controls as part of the overall control strategy should be outlined based on development studies and evaluated. Indeed, every finished product manufacturing process should have an associated cont
33、rol strategy suitable for its intended purpose. It is expected that different control strategies may be utilised in case real time release testing (RTRT) (ref. 7) is proposed, a design space is claimed (ref. 1), a continuous manufacture or a standard manufacture is performed. 3.2.P.2 中提到关于要保证成品的质量到什
34、么程度被发现在 于生产工艺本身。工艺流程的描述和过程控制作为整个控制 策略的一部分应该基于研究开发和评估得出的，每一个成品 的生产工艺都应该有一个相关的控制阶段以适应它预期目 标。料想不同的控制策略可能用于实时放行检测是可以推荐 的(参考 7)，一个设计流程要求一个连续的生产或者一个标 准的生产流程能执行。Expected level of detail in the manufacturing process description 在生产工艺描述中预期的详细水平Although it is expected that the process description is considere
35、d in relation to the control strategy (ref. 1), there is a need to describe the manufacturing process in relevant detail since consistent quality of a product cannot be safeguarded by end product testing alone.虽然希望大家在工艺流程中考虑控制策略 (参考 1 )，但还是有必要对生产 工艺进行详细描述，因为始终如一的产品质量不能只靠最后 的检测来保证。It is important tha
36、t the process description is comprehensive, including process steps in a sequential manner with batch size(s), operating principle and equipment type(s) for each unit operation (mere reference to “ suitable equipment” is not sufficient; conversely, detailssuch as the serial number and model are not
37、required). Equipment working capacity should be stated where appropriate. To make the process fully understandable and to allow assessment of the validity of the process, steps in the process should have the necessary detail in terms of appropriate process parameters along with their target values o
38、r ranges (mere reference to“ typical ” set points isnot acceptable). Where criticality is assigned to process parameters, the description of the process parametersshould not only be restricted to CPPs, but also to those parameters important for manufacturing process consistency. Non-critical process
39、 parameters and also parameters for which the impact on quality attribute cannot be ruled out and which are considered to be important for the execution and/or the consistent performance of any particular process step, and consequently its output, should be described at an appropriate level of detai
40、l. A well described manufacturing process is essential to understand what is critical and what is supportive. Any information which is considered to be purely supportive should be justified and clearly identified.全面而详细的工艺描述是很重要的，包括以一定批量的先后次序的工艺步骤 和每一个单元操作的操作原理和设备型号 （仅仅参考“合适的 设备”是不够的，相反地， 一些细节比如编号和模型
41、是没有要 求的）。设备工作能力必要时应该说明。为了使工艺充分被 理解，允许做工艺合理性评估，关于合适的工艺参数在工艺 步骤中应该有必要的细节描述以为达到他们的目标值或范 围（仅仅参考“典型”设置控制点是不被接受的） 。当把关键性 用于工艺参数时，工艺参数的描述应该不仅仅局限于关键工 艺参数而且要把那些对于维持生产工艺一致的重要参数也 纳入进来。对于影响质量属性的非关键工艺参数和类似的参 数不能排除在外，哪些被认为对于某特定的步骤的执行或维 持始终如一的表现很重要参数也不能排除在外。因此应以合 适水平详细描述来体现他们。一个良好的生产工艺描述对于 理解什么是关键参数、什么是支持性参数是很有必要的
42、，任 何被认为是纯粹的支持性的信息要经过评估和明确说明。 The same requirements apply to the level of detail in the manufacturing process description irrespective of the development approach, i.e. if the product has been developed by the minimal (traditional) or enhanced approach. 同样的要求也适用于生产工艺描述细节程度而 不管它的研发方式，比如，不管这个产品是以小试验(传统
43、 的)还是放大试验的方式。In case of continuous manufacturing, the description of manufacturing process is expected to be provided in the same way. 如果是持续生产，生产工艺描述希望以同样的 方式提供。An example of what type of details should be included in the manufacturing description is presented in the Annex. 附件中提供了一个在生产工艺描述中应该包括什么类型的
44、 细节的示例。Technical adaptations in the manufacturing process生产工艺的技术调整It would generally be expected that, regardless of the number of finished product manufacturing sites proposed, essentially the same manufacturing process should be applied for a specific medicinal product. However, some technical ada
45、ptations might be necessary if more than one manufacturer or manufacturing site for the finished product is foreseen. Technical adaptations are equally acceptable within a manufacturer/ manufacturing site given appropriate justification. Depending upon equipment availability, different types of equi
46、pment could be used for the same manufacturing processing step.通常情况下， 不管生产厂家计划生产的成品数量是多少，对于某一具体药品， 本质上其生产工艺是相同。然而，如果将有超过一家生产商 或者一个生产场地，则必不可少的会有一些技术调整。在一 个公司或者一个生产地址内做技术调整并进行适当评估是 可以接受的，跟据设备性能，不同类型的设备可能用于同一 个生产工艺步骤。Where technical adaptations are proposed in the manufacturing process, these adaptatio
47、ns should be fully justified and supported by evidence, showing that all steps proposed will consistently produce any intermediate and finished product that comply with the in-process controls and the product specifications. Irrespective of any differences in the manufacturing process, the finished
48、product should comply with the same release and shelf-life specifications. 当建议在生产工艺上做技术调整，这些调整 应该被充分评估和有证据支持，显示所有的推荐步骤能持续 生产任何中间产品和成品，并且符合过程控制要求和产品质 量标准。不管生产工艺有何不同，成品应该符合同样的放行 标准和有效期内标准。Where relevant, the justified technical adaptations in various steps of the manufacturing process of one or more m
49、anufacturers and corresponding in-process controls should also be transparently shown in separate flow-charts. On presentation of separate flow-charts in a dossier the different manufacturing steps should be listed and the adaptations should be compared to each other by the applicant. The applicant should justify that the adaptation, on the basis of using different types of equipment, does not have any significant influence on the finished product quality a