EMA制剂成品生产指南-2017(中英文)完整版

4 JJuly 2017

EMA/CHMP/QWP/245074/2015

Committee for Human Medicinal Products (CHMP)

Guideline on manufacture of the finished dosage form

制剂成品生产指南

This guideline replaces the “Note for Guidance on Manufacture of the Finishe

d Dosage Form”

(CPMP/QWP/486/95)

原创：2017-09-19 翻译组 GMP 办公室 翻译：王世华 校对：Owen

Executive summary 综述

This guideline replaces the note for guidance on the manufacture of the finish ed dosage form (CPMP/QWP/486/95). The note for guidance has been updat ed to reflect the requirements as laid down in the current legislation Directive 2001/83/EC, and to follow the format and content of the Common Technical D ocument (CTD) Module 3 dossier. It also addresses current manufacturing pra ctices in terms of complex supply chains and worldwide manufacture. In additi on, the content and principles of the ICH Q8 guideline (ref 1) are also taken int o account.

这份指南取代了制剂成品生产指南的条款（CPMP/QWP/486/95），指南条款的 更新反映了当前已提出的立法机构指令 2001/83/EC 的要求，并且遵循通用技术 文件模块 3 文件的格式和内容。从复杂的供应链和世界范围内生产的方面看，她 也代表了当前的生产活动。另外，也应考虑 ICH Q8 指南的内容和原则。

This guideline does not introduce new requirements on authorised medicinal p roducts for human use. However as stated in article 23 of Directive 2001/83/E C, after a marketing authorisation (MA 上市许可

证) has been approved, the authorisation holder should, in respect of the meth ods of manufacture and control take account of scientific and technical progre ss and introduce any changes that may be required to enable the medicinal pr oduct to be manufactured and controlled by means of generally accepted scie ntific methods.

这份指南没有对已授权的人用药品给出新的要求，然而在指令 2001/83/EC 23 章提到在一份上市许可批准之后，上市许可持有人应该在关于生产方法和控制方 面考虑科学和技术的改进，推行一些被要求的变更，通过一般可接受的科学方法 来进行药品的生产和控制。

1. Introduction (background) 介绍（背景）

The objective of the guideline on the manufacture of the finished dosage form is to provide clarification on the type and level of information that should be in cluded in the CTD Module 3 of the marketing authorisation application (MAA 上市许可申请) dossier with respect to the manufacturing process description 生产工艺描

述. This description should include information about critical steps and interme diates and provides a link between the pharmaceutical development, the prop osed control strategy and process validation. The guideline also addresses as pects related to outsourcing and new manufacturing practices such as comple x manufacturing chains or issues with prolonged holding times and transportat ion conditions. Detailed information about requirements of the sterilisation pro cess is provided in a separate guideline.

制剂成品生产指南的目的是为了在通用技术文件模块 3—上市许可申请文件中 关于生产工艺描述应该包含的信息的类型和详细程度提供说明。这个说明应该包 括关于关键步骤和中间体的信息，提供一个在药品研究、计划控制策略与工艺验

证之间的连接桥梁。这个指南同时也提到了关于外包和新的生产活动，比如复杂 生产链条或者延长存放时间和转移条件的观点。关于灭菌工艺详细信息的要求在 一份单独的指南中进行提供。 2. Scope 范围

This guideline is applicable to the manufacture of the finished 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 wh ere 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 t o 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。 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 auth orisation 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 manufacturing 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 provi ded are 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 the CTD 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 aspects of manufacture need to be described and includ ed 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, details sho uld 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 contrac tors, should be provided. This applies also to all quality control 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 specifie d.

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 formula for the intended batch size should be stated. In case a rang e of batch sizes is proposed, the range should be stated and the batch formul a 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 of batch sizes should be adequately justified as not adversely impacting the critical quality attributes (CQAs) of the finished produ ct 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 into different presentations or packs, the prod uction batch size should be defined by the bulk before any division. When the length of the subsequent processes and assembly is considered critical (e.g. fi lling time for aseptically manufactured products), the worst-case scenario of th e division pattern (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 wi th production scale equipment. It should be sufficiently large to be representati ve of commercial manufacturing to enable demonstration of a state of control. For example, a commercial batch size for solid oral dosage forms should be a t least 100,000 units unless justification is provided (e.g. orphan medicinal pro ducts) (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 sh ould be justified as the final batch is required to be homogeneous, their formul ae and the number of sub-batches per intended batch size should be stated. I n addition, if a batch is sub-divided towards the end of the process to reflect e quipment processing capability, this should be clearly indicated (e.g. solid dos age form manufacture where sub lots are required due to equipment capacity) . The number of sub-batches per intended 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 traditio nal terms might not be relevant; however, information as to how a batch is defi ned should be provided (e.g. expressed in terms of a period of time or a quant ity 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 standards of all ingredients used in the course of the manufacture should be stated. Ingredients which ar e removed from the product during the production process, such as granulatio n liquids, solvents and gases should be included but their quantities may be e xpressed as ranges.

在生产过程中用到的所有的成分的名称、数量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 adjustme nt, should also be mentioned. Formula overages must be clearly indicated in q uantitative terms and justified in the pharmaceutical development section of th e dossier. Upper and lower acceptance limits for the actual quantity of each in gredient may be stated in the batch formula; however, the proposed acceptan ce limits should be justified. When the quantity of an active ingredient to be us ed is calculated from the actual assay value of the batch of that active ingredi ent (\"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 should be provided, a ccompanied by a flow chart describing each step of the process including in-p rocess controls and showing at each stage where materials enter the process. In case a design space is proposed, this should be clearly identified and desc ribed.

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述。

The manufacturing process description should be adequately justified in 3.2.P .2 by development data, in particular as regards any process operating conditi ons or ranges. The description of a manufacturing process with wide ranges ( wider than would normally be accepted as normal operating ranges) or descri bed only by an upper or lower limit, generally requires a more thorough discus sion and/or scientific rationale in the manufacturing process development sect ion.

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 app lication for certain types of products (ref. 4). If the result of such full scale stud y is not available at the time of submission, it is expected that process parame ters' settings identified during manufacturing process development are laid do wn in the process description. In the event that any changes are required to th e registered process parameters as a result of full scale process validation stu dies, these changes should be applied for via post approval variation, in accor 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 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 control s 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 quali ty of the finished product is founded on the manufacturing process itself. The significance of the process description and process controls as part of the ove rall control strategy should be outlined based on development studies and eva luated. Indeed, every finished product manufacturing process should have an associated control strategy suitable for its intended purpose. It is expected tha t 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 m anufacture or a standard manufacture is performed.

在 3.2.P.2 中提到关于要保证成品的质量到什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 considered in relation to the control strategy (ref. 1), there is a need to describe the manufacturing pro cess in relevant detail since consistent quality of a product cannot be safeguar ded 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 that the process description is comprehensive, including proces s steps in a sequential manner with batch size(s), operating principle and equi pment type(s) for each unit operation (mere reference to “suitable equipment” is not sufficient; conversely, details such as the serial number and model are not required). Equipment working capacity should be stated where appropriat e. To make the process fully understandable and to allow assessment of the v alidity of the process, steps in the process should have the necessary detail in terms of appropriate process parameters along with their target values or ran ges (mere reference to “typical” set points is not acceptable). Where criticality is assigned to process parameters, the description of the process parameters should not only be restricted to CPPs, but also to those parameters important for manufacturing process consistency. Non-critical process parameters and a lso parameters for which the impact on quality attribute cannot be ruled out an d which are considered to be important for the execution and/or the consistent performance of any particular process step, and consequently its output, sho uld be described at an appropriate level of detail. A well described manufactur ing process is essential to understand what is critical and what is supportive. Any information which is considered to be purely supportive should be justifie d 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，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 proce ss 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（传统的）还是放大试验的方式。

In case of continuous manufacturing, the description of manufacturing proces

s 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 de

scription 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 prod uct manufacturing sites proposed, essentially the same manufacturing proces s should be applied for a specific medicinal product. However, some technical adaptations might be necessary if more than one manufacturer or manufactur ing site for the finished product is foreseen. Technical adaptations are equally acceptable within a manufacturer/ manufacturing site given appropriate justific

ation. Depending upon equipment availability, different types of equipment co uld 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, thes e adaptations should be fully justified and supported by evidence, showing tha t all steps proposed will consistently produce any intermediate and finished pr oduct that comply with the in-process controls and the product specifications. I rrespective of any differences in the manufacturing process, the finished prod uct 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 man ufacturing process of one or more manufacturers and corresponding in-proces s controls should also be transparently shown in separate flow-charts. On pre sentation of separate flow-charts in a dossier the different manufacturing step s should be listed and the adaptations should be compared to each other by t he applicant. The applicant should justify that the adaptation, on the basis of u sing different types of equipment, does not have any significant influence on t he finished product quality and this should be supported by data. The in-proce ss controls and corresponding acceptance limits should also be described. W here any technical adaptations are proposed at different manufacturing sites, t he information should always be presented in the same Module 3 section, but if required differentiated for each manufacturing site.

如有必要，在一个或多个生产商的各个的生产工艺步骤进行合理的技术调整和相 应的过程控制也应该在单独的流程图中清楚地显示出来。在一个文档中提交的单 独的流程图，申请人应将不同的生产步骤列清楚，分清楚各自调整的内容。申请 人应该能解释这些调整，基于使用不同型号的设备，对成品的质量不能有任何显 著的影响，并且这个应该有数据支持。过程控制和相应的接受限度也应该说明。 当在不同的生产地址推荐任何的技术调整时，这些信息总是要在模块 3 节中呈现 一致，但是如果要求的话，应该将每个生产地址的都区分开。

The following examples illustrate the possible use of technical adaptations for different manufacturing processing steps.

下面的例子说明技术调整可能在不同生产工艺步骤中应用

Liquid dosage forms 液体制剂

Preparation of solutions can be performed e.g. in simple stainless steel tanks equipped with a stirrer and/or homogeniser or in advanced mixing/homogenisi

ng equipment which can be run under vacuum. 溶液的配制可以这样做，比如

在一个简易的装配有搅拌器或者均质机的不锈钢罐，或者在一个高级的在真空下 能运转混合或均质的设备。

Solid oral dosage forms 口服固体制剂

Different equipment can be used for: 以下工序可以使用不同的设备

• Wet granulation (wet granulation by high shear, low shear or fluid bed granul ation);

湿法制粒（高速剪切湿法制粒机、低速剪切湿法制粒机或者流化床喷雾制粒） • Granule drying (e.g. fluid bed, tray drying, one pot (high shear granulation/dr

ying) systems);

颗粒烘干（比如流化床干燥、托盘干燥、一个容器（高速剪切制粒/干燥）系统） • Dry granulation (roller compaction or slugging); 干法制粒（滚压法或直压法） • Sizing/delumping (e.g. oscillating, rotating or hammer mill);筛分/过筛（比如摇 摆、旋转或挤压）

• Coating (e.g. pan, fluidized bed coating); 包衣（比如平底锅、流化床包衣） • Dry blending (e.g. high shear blender, IBC blender, conical screw blender, V blender);

干混（比如高速剪切混合机、IBC 混合机（自动提升旋转混合机），锥形混合机， V 型混合机）

• Tablet compression on a fully automatic or manually controlled tablet press. 在一个全自动或手动控制的压片机上压片

In contrast to technical adaptations as described above, alternative manufactu ring processes, which use different principles and may or may not lead to diffe rences in the in-process control and/or finished product quality are not accept able (e.g. using different sterilisation procedures – terminal sterilisation of end product vs. aseptic manufacture using sterile filtration – possibly to reflect the use of different containers with different heat resistance properties; or wet gra nulation vs. dry granulation).

相比于前面提到的技术调整，使用不同原理的可供替代的生产工艺可能会也可能 不会导致过程控制不同和成品质量不能被接受（比如使用不同的灭菌程序-最终 产品的终端灭菌相对于无菌生产用的无菌过滤器-可能反映在使用不同的带有不 同加热电阻特性的容器，或者湿法制粒相对于干法制粒）。

4.4. Controls of Critical Steps and Intermediates 关键步骤和中间产品的控制

All critical steps and intermediates identified during the manufacture of the fini shed product should be listed in this section including any in-process controls, applied test methods and acceptance criteria.

所有的关键步骤和中间产品检验在本节中成品生产过程要确认，包括任何的过程 控制、应用的检验方法和可接受标准。

For complex control strategies (e.g. use of models for process control, continu ous manufacturing), emphasis should be given on the frequency of in-process controls and it should be clearly stated how release testing and product relea se decisions are made. Information of how unexpected deviations from the ap proved manufacturing process would be detected and managed should be pro vided to assure that the intended quality of the product is retained.

对于复杂的控制环节（比如应用模型来过程控制、连续生产），需要强调的是在 过程控制频率上应该明确,应明确说明如何做放行检测和产品放行决定。如何发 现和处理从批准的生产工艺中意外发生的偏差的信息应提供，以保证能达到预期 的产品质量。

The fact that a process parameter in a manufacturing step is controlled and ve rified to be within a range that does not affect a critical quality attribute (CQA) does not make it non-critical by default. While the risk is reduced, monitoring with established acceptance criteria should be included in the description to a ssure a sufficient regulatory oversight. The justification for the identification of steps as critical or non-critical should be provided, including a link to experime ntal data in the pharmaceutical development section (e.g. risk assessment tab le), if applicable.

一个被控制和确认在一定范围内的且不会影响关键质量属性的生产步骤中的工 艺参数不能被错误地认为是一个非关键参数。当风险降低了，用已建立起来的可 接受标准来监控方法应该包括在描述中，以保证一个充分的正规的监管。作为区 分关键或非关键步骤的判断依据也要提供，包括在药品研发阶段的试验数据的一 个连接（比如风险评估表），如适用。

Storage of intermediate and bulk products 中间产品和散装品的储存

An intermediate product is defined as partly processed material that must und ergo further processing steps before it becomes bulk product e.g. solution prio r to filling, granulates, uncoated tablets etc.

中间产品定义为部分过程物料，在它成为散装品之前仍需要做进一步加工工序， 比如灌装前的溶液，未包衣的素片等。

A bulk product is defined as any product which has completed all processing s teps, up to but not including, final packaging.

散装品是指任何完成全部的加工工序将要但是还没有进行最后包装的产品。

A manufacturing process generally involves a series of unit operations, where intermediate product is processed to become bulk product.

一个生产工艺通常包括一系列的单元操作，就是将中间产品加工成散装品的过程。

In some cases, the intermediate may be stored, and if necessary, transported in a suitable container before further processing. It may also be subject to con firmatory testing prior to further processing to confirm that quality attributes ha ve not changed and therefore any additional testing details should be provide d. Hold time validation for the storage of intermediate product is a GMP matter and normally need not be presented routinely in the application for a marketin g authorisation. However, some specific types of products (e.g. sterile product s, biological products) may require presentation of data relevant to the type of product and this should be taken into consideration depending on the charact eristics of that particular product.

在某种情况下，中间产品可以储存，如果有必要的话，在进行下一步工序之前放 到一个适合的容器进行转移。在进行下一工序之前，中间产品也需要经过确定的 检测以保证他的质量属性没有改变，因此任何增加的检测项目都需要提供。中间 产品的存放时间验证是一项 GMP 问题，通常不需要体现在 MA 申请资料中。然 而，某些特殊类型的产品（比如无菌制剂、生物制剂）可能要求提交关于这类产 品的数据，这个应该根据特殊的产品特性来考虑。

It should be stated whether storage is required before final packaging and if s o, under what temperature, humidity or other environmental conditions. The le vel of information to be provided in the documentation is dependent on the nat ure of the bulk product.

应该说明散装品在最终包装之前是否需要储存，如果需要，在什么样的温度、湿 度和其他环境条件下。这些基于散装品的属性存放条件的信息需要在文件中提供。

Where relevant, the maximum holding times of the bulk product or, alternativel y, the maximum batch manufacturing time from start of product manufacture t o completion of packaging into the final primary container for marketing shoul d be stated, appropriately justified and supported by data in relevant parts of t he dossier (e.g. challenging the maximum hold time in process validation studi es or providing dedicated stability studies for the bulk storage).

如有必要，散装品的最大存放时间或者从起始物料开始生产到完成包装进入最终 的市售包装容器的最长批生产时间应该要说明，在文件的相关部分提供适当的评 估和数据支持（比如在工艺验证研究时做最长存放时间挑战试验或者提供散装品 专属的稳定性研究资料）

The reasons for any prolonged storage/processing times should be stated and be consistent with GMP. Time limits for processing should be minimised and l imits should be justified and appropriate to ensure product quality. As a gener al rule, prolonged storage means more than 30 days for solid oral dosage for ms and more than 24 hours for sterile products. Where relevant, stability data to support the holding time should be provided on at least two pilot scale batc hes. The stability studies should be performed at relevant temperature and hu midity with regards to the expected bulk storage conditions (if relevant temper ature and humidity during storage does not correspond with ICH condition, oth er conditions should be used).

任何延长储存或生产时间的情况都要说明理由，并且要符合 GMP 的要求。过程 时间限度应该尽量短，这个限度应该被评估并且适合于保证产品质量。通常来说， 延期储存意味着口服固体制剂超过 30 天、无菌产品超过 24 小时。如有必要，

应提供至少两批试验批的存放时间稳定性研究数据。做稳定性研究的相关温度和 湿度条件应考虑预期的散装品存放条件（如果储存过程的相关的温度和湿度与 ICH 规定的条件不一致，其他的条件也可以使用的。）

The product shelf-life should be calculated according to the Note for Guidance on the start of shelf-life of the finished dosage form (ref. 9). If other approach es to calculate the start of shelf life are proposed, these should be described a nd justified by the inclusion of supporting data from batches that represent the full proposed holding time of the bulk product (intermediate) in the finished pr oduct stability program.

产品有效期（货架期）应根据成品制剂起始有效期的指南的条款计算出来（参考 9）。如果应用其他的方法计算起始有效期，通过在成品稳定性项目中代表散装 品的整个计划存放时间的批次的支持性数据来说明和评估。

For transportation of bulk product (intermediate) between manufacturing sites guidance is given in GMP Annex 15 on how transport should be taken into co nsideration. The impact of short or longer excursions outside of the original st orage conditions should be discussed, where necessary, supported by accele rated or real time stability data.

关于散装品（中间产品）在生产地址间转移的指南见 GMP 附录 15 关于如何转 移应该纳入考虑范围。短期或者较长时间暴露在原始储存条件下的影响需要经过 讨论，如有必要，通过加速或长期稳定性研究来支持。

The suitability of the proposed bulk product (intermediate) container closure s ystem for bulk storage (and transport if relevant) should be justified in relevant parts of the dossier. The materials used for the bulk container closure system should be described along with the control specification for primary bulk pack aging.

在文件的相关部分，预期的散装品（中间产品）的容器密闭系统对于散装品的储 存（和运输如适用）的适应性需要被评估。用于散装品容器密闭系统的物料应该 与散装品内包材的控制标准要一道说明。

4.5. Process Validation and/or Evaluation 工艺验证和评价

Description, documentation, and results of the validation and/or evaluation stu dies should be provided in this section. For more details see Process Validatio n guideline (ref. 4).

工艺验证和评价研究的描述、文件和结果应该在这节提供。更多详细内容参见工 艺验证指南（参考 4）。

Definitions 定义

Control Strategy: 控制策略

A planned set of controls, derived from current product and process understan ding that ensures process performance and product quality. The controls can i nclude parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-pro cess controls, finished product specifications, and the associated methods an d frequency of monitoring and control (ref. 8).

一套计划控制设置，是从当前产品和工艺理解得出的，以保证过程表现和产品质 量。控制项目包括原料和制剂产品物料和组份的参数和属性、设施和设备操作条 件、过程控制、成品质量标准和相关的方法和监测和控制的频率（参考 8）。

Critical Process Parameter (CPP): 关键工艺参数

A process parameter whose variability has an impact on a critical quality attrib ute and therefore should be monitored or controlled to ensure the process pro

duces the desired quality (ref. 1).

一个工艺参数的可变性对一个关键质量属性有影响，因此它应该被监测和控制以 保证过程产品符合预期的质量（参考 1）。

Critical Quality Attribute (CQA): 关键质量属性

A physical, chemical, biological or microbiological property or characteristic th at should be within an appropriate limit, range, or distribution to ensure the de sired product quality (ref. 1).

一个物理的、化学的、生物的或者微生物的性质或特征应该在一个合适的限度、 范围或者分布，以保证符合预期的产品质量（参考 1）。

Design Space: 设计范围

The multidimensional combination and interaction of input variables (e.g., mat erial attributes) and process parameters that have been demonstrated to provi de assurance of quality. Working within the design space is not considered as a change. Movement out of the design space is considered to be a change a nd would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment a nd approval (ref. 1).

多重的结合体和输入变量的相互作用（比如物料属性）和工艺参数要被提供证明 能保证质量。在设计范围内操作不能被认为是一种变更。如果超出了设计范围可 以认为是一个变更，通常要执行一个批准产品变更管理程序。设计范围是申请人 推荐的而且它是经过正规的评估和批准（参加 1）。

Hold Time: 存放时间

Hold time can be considered as the established time period for which material

s (dispensed raw materials, intermediates and bulk dosage form awaiting final packaging) may be held under specified conditions and will remain within the defined specifications (ref. 11).

存放时间可以被认为是为物料（称量后原辅料、中间产品和待最后包装的散装品） 确认的时间周期，它可以在规定的条件下存放并且维持既定的标准。

Real Time Release Testing: 实时放行测试

The ability to evaluate and ensure the quality of in-process and/or final produc t based on process data, which typically include a valid combination of measu red material attributes and process controls (ref. 1). 评估和保证过程中或者最

终产品质量的能力基于过程数据，通常包括一个合理的检测物料属性和过程控制 的结合体（参考 1）。

References 参考文献

1. ICH Q8 (R2) (Pharmaceutical development), EMA/CHMP/ICH/167068/2004 ;

2. Directive 2001/83/EC of the European Parliament and of the Council of 6 N ovember 2001 on the Community code relating to medicinal products for hum an use;

3. Eudralex volume 4 (GMP guidelines);

4. Guideline on process validation for finished products - information and data to be provided in regulatory submissions EMA/CHMP/CVMP/QWP/BWP/7027 8/2012 Rev. 1;

5. Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for h uman use and veterinary medicinal products;

6. Guidelines on the details of the various categories of variations, on the oper

ation 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 examina tion of variations to the terms of marketing authorisations for medicinal produc ts for human use and veterinary medicinal products and on the documentation to be submitted pursuant to those procedures;

7. Guideline on Real time release testing EMA/CHMP/QWP/811210/2009-Rev 1;

8. ICH Q10 (Pharmaceutical quality system). EMA/CHMP/ICH/214732/2007; 9. Note for guidance on the start of shelf-life of the finished dosage form CPM P/QWP/072/96/ EMEA/CVMP/453/01;

10. Guideline on Good Distribution Practice of medicinal products for human u se 2013/C 343/01;

11. Supplementary guidelines on GMP: General guidance on hold-time studie s. In: WHO Expert, Committee on Specifications for Pharmaceutical Preparati ons: forty-ninth report. Geneva: World Health Organization; 2015: Annex 4 (W HO Technical Report Series, No. 992)

Annex 附件

The following example of manufacturing process description aims at clarifying the regulatory expectations in terms of level of detail. It is proposed as an illus tration of what could be provided in a dossier, depending on the development approach followed. The process parameters listed are for guidance purposes and not mandated. Process description should always be considered case by case, and should be filed according to the individual manufacturing process a s developed and validated.

下面是生产过程描述的示例，旨在于说明法规期望的细节程度。作为示例推荐 说明在文件中要提供些什么，根据随后的研发流程。所列举的工艺参数的目的只 是为了提供指导的而不是要强制实施的。工艺描述应该被认为具体问题具体分析， 所以应该根据研发和验证各自的生产工艺分别提出。

To explain the description presented in Section 3.P.3.3 (starts with Narrative d escription), some elements from manufacturing process development are repr oduced below:

解释一下在 3.P.3.3 节中提到的描述（叙述性描述开始），从研发生产工艺转载 过来的要素如下：

Finished product: 200 mg tablet 成品：200mg/片 Process step: granulation 工艺步骤：制粒

Operating principle: wet high shear granulation 湿法高速剪切制粒 Equipment type: vertical high shear granulator 立式高速剪切制粒机

Non exhaustive list of process parameters possibly considered during develop

ment (“early development list”): 可能在研发过程中考虑得不全面的工艺参数清 单（早期的研发清单） • Delumping sieve size. 过筛筛网尺寸

• Mixing time for granulation solution preparation. 制粒溶液制备的混合时间 • Mixing speed for granulation solution preparation. 制粒溶液制备的混合速度 • Fill volume. 灌装体积 • Premix time. 预混时间

• Premix impeller speed. 预混叶轮转速 • Premix chopper speed. 预混剪切速度 • Granulation solution pressure. 制粒溶液压力

• Granulation solution feed pump speed. 制粒溶液输液泵速度 • Granulation solution flow rate. 制粒溶液流速 • Granulation solution amount. 制粒溶液数量

• Impeller rotation speed for the different granulation phases. 在不同制粒阶段 叶轮的转动速度

• Chopper rotation speed for the different granulation phases. 在不同制粒阶段 切刀的转动速度

• Wet massing time. 湿法制粒时间 • Product temperature. 产品温度

• Wet mass screen size. 湿法整粒筛网尺寸

This early development list is not expected to be provided in the dossier, unle ss a formal risk assessment of the process is claimed, but is meant to emphas ize that many more parameters are considered during development than thos e presented in the following reduced list, which is retained in the process desc ription.

早期的研发清单不需要在申请资料中提供，除非声明有一个正式的工艺风险评估， 但是这就强调意味着在研发过程需要考虑比那些罗列在下面的简化清单中更多 的参数。

List of parameters that have been demonstrated during development as needi ng to be controlled or monitored during the unit operation (“final development l ist”):

示范了一个在研发过程中单元操作时需要控制和监控的参数清单（最终的研发清 单）

• Fill volume. 灌装体积 • Premix time. 预混时间

• Granulation solution flow rate. 制粒溶液流速 • Granulation solution amount. 制粒溶液数量

• Impeller rotation speed for the different phases. 不同制粒阶段叶轮转速 • Chopper rotation speed for the different phases. 不同制粒阶段切刀转速 • Wet massing time. 湿法制粒时间 • Wet mass screen size. 湿法制粒筛网尺寸

Section 3.2.P.3.3

Narrative description (common to minimal (traditional) and to enhanced devel

opment approaches): 叙述性描述（对小试研究（传统的）和放大研究方式是一

样的）

1. Weigh and delump the required amount of active substance and intra-granu lar excipients. 称量和过筛需求数量的原料和待制粒的辅料。 2. Weigh the required amount of binder excipient and purified water; charge th e purified water in a mixing vessel and dissolve the binder excipient; mix until

a clear solution is obtained. 称量需求数量的粘合剂和纯化水，在混合容器中倒 入纯化水，溶解粘合剂，混合直到得到清澈的溶液。 3. Load active substance, intra-granular excipient 1, intra-granular excipient 2 and intra-granular excipient 3 in the bowl of the high shear mixer granulator.

将原料和待制粒的辅料 1、待制粒辅料 2 和待制粒辅料 3 投入高速剪切制粒机锅 中。

4. Mix the dry material. 混合干粉

5. Wet the dry mix (from step 4) with the granulation solution (from step 2) add ed by fine atomization through a binary nozzle. 通过一个双层喷嘴将制粒溶液 （从第 2 步）喷雾加入，润湿混合后的干粉（从第 4 步）。 6. Wet mass the blend with impeller. 湿法混合制粒

7. Screen the wet mass through in-line sizing mill unit and transfer to fluid bed

dryer. 湿颗粒通过在线的上料过筛单元进行湿法整粒，然后转移到流化床干燥。

Process parameters settings (minimal development approach): 工艺参数设置 （小试研究方式）

#The quantity of water to be used is calculated as a percentage of the total we ight of the dry components of the inner phase (intra-granular components). W ater is removed during processing.

应用的水的重量是根据待制粒的干粉总重的百分比计算出来的（待制粒的组份）， 水在生产过程中蒸发了。

Process parameters settings (enhanced development approach): 工艺参数设 置（放大研究方式）

*Ranges established on the basis of multivariate evaluation. 经过多方评价设 置的范围

#The quantity of water to be used is calculated as a percentage of the total we ight of the dry components of the inner phase (intra-granular components). Th

e absolute volume of water used may vary between 12 and 18% w/w, implyin g a variable binder concentration in the granulation solution over this range. W

ater is removed during processing.水的重量根据干粉（待制粒组份）总重的一 定百分比计算出来的，水的总体积可能在 12-18%w/w 之间变化，含有加入到颗 粒中的粘合剂浓度变化也在这个范围。水在生产过程中蒸发了。

Notes for the above examples: 上述示例注释

• The same basic requirements apply to the level of detail provided in terms of the manufacturing processing steps and parameters listed in section 3.2.P.3. 3 whatever the approach to pharmaceutical development (minimal or enhance d). However, depending upon the level of process understanding that has bee n gained during development and also the control strategy, the way the inform ation is presented may be slightly different and the manufacturing process will reflect any justified and supported flexibilities when an enhanced developmen t approach has been followed (e.g. wide ranges established on a multivariate basis).

同样基本的要求适用于在生产工艺步骤和 3.2.P.3.3 节中所列参数的详细描述程 度，不管药品研发以什么方式（小试还是放大）。然而，取决于在研发阶段和控 制阶段获得的工艺理解水平，这种信息表达方式略微不同，当一个放大研究方式 进行的时候，生产工艺会反射出任何正当合理的、可支持的弹性变化（比如大的 范围建立在一个多元的基础之上）

• The manufacturing process principle is described. 生产工艺的原理要说明 • The equipment type is described. 设备型号要说明

• Process parameters are described (with target values or ranges) leading to a comprehensive description of the unit operation; for applications able to assig n criticality to process parameters, both critical and non-critical parameters ar

e described. 工艺参数要说明（带目标值和范围）导出一个单元操作的详尽描述， 申请中要指明工艺参数的关键性，关键和非关键参数都要描述。 • There is a reduced list of process parameters remaining in the description co mpared to the ”early development list” as the following has been taken into ac count: − Nature of the active substance (e.g. the active substance is chemicall y stable and thus there is no need to describe the environmental and product t

emperatures); 有一个简化的工艺参数清单保留在叙述中，对比“早期的研发清单” 作为后续的考虑：-原料属性（比如原料是化学稳定的，因此不需要描述环境和 产品的温度）

− Degree of complexity of the dosage form (e.g. the proportion of active subst ance in the tablet formulation is high and thus there is no need to describe the

pre mixing step in detail); 制剂的复杂程度（比如原料在片剂处方的比例很高， 因此就不需要在预混步骤详细描述）

− Degree of complexity of the process (e.g. the delumping of raw materials be fore processing is an optional step and thus there is no need to describe the d elumping sieve size; the preparation of the binder solution is a straight forward operation which is merely monitored by the visual control of the final solution t hus there is no need to describe the mixing parameters; the granulation soluti on addition is adequately summarized by the output “flow rate” thus there is n o need to describe the liquid pressure and the pump speed). 工艺的复杂程度

（比如原料的过筛在加工之前是一个可选的操作步骤，因此不需要描述过筛的尺 寸；粘合剂的配置是一个很简单的操作，只需要目视监控一下最终溶液，因此不 需要描述混合参数；制粒溶液的添加参数通过“流速”就足以归纳，因此也不需要 描述液体压力和泵的速度。）