【最新动态】EMA工艺验证指南20100427

毒手药王邓智先

27 February 2014
EMA/CHMP/CVMP/QWP/BWP/70278/2012-Rev1
Committee for Medicinal Products for Human Use (CHMP)
Committee for Medicinal Products for Veterinary Use (CVMP)
Guideline on process validation for finished products - information and data to be provided in regulatory submissions
制剂工艺验证指南---在法规提交中要提供的资料和数据

Draft agreed by CHMP/CVMP Quality Working Party
2 February 2012
由CHMP/CVMP质量工作组通过草案
2012年2月2日
Adoption by CVMP for release for consultation
8 March 2012
CVMP同意公开征求意见
2012年3月8日
Adoption by CHMP for release for consultation
15 March 2012
CHMP同意公开征求意见
2012年3月15日
End of consultation (deadline for comments)
31 October 2012
征求意见结束（截止日期）
2012年10月31日
Agreed by QWP
8 November 2013
由QWP通过
2013年11月8日
Agreed by BWP
13 November 2013
由BWP通过
2013年11月13日
Adoption by CHMP
19 December 2013
由CHMP采用
2013年12月19日
Adoption by CVMP
15 January 2014
由CVMP采用
2014年1月15日
Date for coming into effect
6 months after publication
生效日期
公布后6个月
This guideline replaces the note for guidance on process validation (CPMP/QWP/848/96, EMEA/CVMP/598/99) including annex II – non-standard processes (CPMP/QWP/2054/03).
本指南替代工艺验证注释（CPMP/QWP/848/96, EMEA/CVMP/598/99），包括附录二----非标准工艺（CPMP/QWP/2054/03）。
Keywords

Process validation, continuous process verification, on-going process verification, critical process parameter, critical quality attribute, lifecycle, change control

关键词

工艺验证、持续工艺确认、关键工艺参数、关键质量属性、生命周期、变更控制






Table of contents

目录

Executive summary

实施摘要

1. Introduction (background)

介绍（背景）

2. Scope

范围

3. Legal basis

法规依据

4. General considerations

一般考虑

5. Process validation

工艺验证

5.1. Traditional process validation

传统工艺验证

5.2. Continuous process verification

持续工艺确认

5.3. Hybrid approach

混合方案

5.4. Design space verification

设计空间确认

6. Scale-up

放大生产

7. Post approval change control

批准后变更控制

8. Standard vs. non-standard methods of manufacture

标准VS非标准生产方法

Definitions

定义

References

参考文献

Annex I: Process validation scheme

附录I：工艺验证计划

Annex II: Standard/non-standard processes

附录II：标准/非标工艺




Executive summary 实施摘要

This guideline replaces the previous note for guidance on process validation (CPMP/QWP/848/96, EMEA/CVMP/598/99). The guideline is brought into line with ICH Q8, Q9 and Q10 documents and the possibility to use continuous process verification in addition to, or instead of, traditional process validation described in the previous guideline has been added and is encouraged. This guideline does not introduce new requirements on medicinal products already authorised and on the market, but clarifies how companies can take advantage of the new possibilities given when applying enhanced process understanding coupled with risk management tools under an efficient quality system as described by ICH Q8, Q9 and Q10.

本指南替代之前的工艺验证指南解释(CPMP/QWP/848/96, EMEA/CVMP/598/99)。本指南与ICH Q8，Q9和Q10文件相一致，提供在之前加入和鼓励采用的传统工艺验证这外，提供了使用持续工艺确认的可能性。本指南对已批准上市的药品未引入新要求，但阐述了公司在ICH Q8, Q9和Q10中描述的有效质量体系下，应用强化工艺理解与风险管理工具时，如何抓住所给的新的可能性。

1. Introduction (background) 介绍（背景）

Process validation can be defined as documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes (ICH Q7). Continuous process verification has been introduced to cover an alternative approach to process validation based on a continuous monitoring of manufacturing performance. This approach is based on the knowledge from product and process development studies and / or previous manufacturing experience.

工艺可定义为证明在建立的参数范围内操作的工艺可以重复有效地生产出符合其预定质量标准和质量属性的药品的书面证据(ICH Q7)。持续工艺验证被引入替代基于对工艺性能持续监测的工艺验证。这种方法是依据来自于产品和工艺研发和/或之前生产经验的知识。

Continuous process verification may be applicable to both a traditional and enhanced approach to pharmaceutical development. It may use extensive in-line, on-line or at-line monitoring and / or controls to evaluate process performance. It is intended that the combination of the advice provided in the Note for Guidance on Development Pharmaceutics (CPMP/QWP/155/96) and the Note for Guidance on Pharmaceutical Development (ICH Q8R2) together with this guideline should cover all of the critical elements in manufacturing process for inclusion in the dossier for regulatory submission for a pharmaceutical product for human use. For veterinary medicinal products, the applicable guidance is that provided in the Note for Guidance on Development Pharmaceutics for Veterinary Medicinal Products (EMEA/CVMP/315/98) together with this guideline. Although the ICH Q8 guideline is not applicable to veterinary medicinal products the principles detailed in this guideline may be applied to veterinary medicinal products should an applicant choose to apply an enhanced approach to pharmaceutical development and process validation. Process validation should not be viewed as a one-off event. Process validation incorporates a lifecycle approach linking product and process development, validation of the commercial manufacturing process and maintenance of the process in a state of control during routine commercial production.

持续工艺确认既适用于传统药品研发方法，也适用于加强药品研发方法。它采用广泛的在线监测和/或控制来评估工艺的性能。将研发药物指南解释(CPMP/QWP/155/96)、药物研发指南解释(ICH Q8R2)与本指南相结合，应可以覆盖人用药法规申报文件所需包括的生产工艺的关键因素。对于兽药产品，适用的指南为“兽药研发指南解释” (EMEA/CVMP/315/98)与本指南。尽管ICH Q8指南不适用兽药产品，本指南中的原则可以应用于兽药产品，申请人应选择性采用更好的方法来进行药品研发和工艺验证。工艺验证不应该作为是一次性的事情。工艺验证应将产品生命周期结合工艺研发、商业生产工艺验证、在常规商业化生产中控制状态的工艺维护相结合。

2. Scope 范围

This document is intended to provide guidance on the process validation information and data to be provided in regulatory submissions for the finished dosage forms of chemical medicinal products for human and veterinary use. The general principles also apply to active substances.

本文件意在提供关于人用和兽用化学药品制剂的申报时所需提交的工艺验证资料和数据的指南。一般原则也适用于活性物质。

However, information on validation of non-sterile active substances is not required in the dossier.

但是，在申报文件中并不要求提交非无菌原料药的验证信息。

In addition, expectations for active substances are contained in ICH Q11 and so the information is not repeated in this document.

另外，ICH Q11中包括了对原料药的建议，因此本文件中不再重复这些信息。

The principles described are also applicable to biological medicinal products. However, these should be considered on a case by case basis in view of the complex nature and inherent variability of the biological substance.

本文所述的原则也适用于生物制品。但是，生物制品的工艺验证应根据其复杂性和内在变因各案考查。

It is expected that the information / data requested in this guideline be present in the dossier at the time of regulatory submission.

在本指南中所要求的资料/数据应该包括在法规申报的文件中。

This document provides guidance on the validation of the manufacturing process, which can be considered as the second stage in the product lifecycle. The first stage (process design) is covered in the note for guidance on pharmaceutical development (ICH Q8R2/ EMEA/CVMP/315/98) and the third stage (on-going process verification) is covered under GMP (Annex 15).

本文件提供生产工艺验证指南，工艺验证可以当作产品生命周期的第二阶段。第一阶段（工艺设计）包括在药物研发指南解释（ICH Q8R2/ EMEA/CVMP/315/98）中，第三阶段（持续工艺确认）包括在GMP（附录15）中。

3. Legal basis 法律依据

This guideline has to be read in conjunction with the introduction and general principles section (4) of Annex I to Directive 2001/83/EC as amended and the introduction and general principles section (2) of Annex I to Directive 2001/82/EC as amended.

本指南应与指令2001/83/EC修订版本附录1第（4）部分中的介绍和一般原则，以及指令 2001/82/EC修订版附录1第（2）部分中的介绍和一般原则一起解读。

4. General considerations 一般考虑

Irrespective of whether a medicinal product is developed by a traditional approach or an enhanced approach, the manufacturing process should be validated before the product is placed on the market. In exceptional circumstances concurrent validation may be accepted. Please refer to GMP Annex 15 for further guidance. Process validation should confirm that the control strategy is adequate to the process design and the quality of the product. The validation should cover all manufactured strengths and all manufacturing sites used for production of the marketed product. A bracketing approach may be acceptable for different strengths, batch sizes and pack sizes. However, validation must cover all proposed sites. Process validation data should be generated for all products to demonstrate the adequacy of the manufacturing process at each site of manufacture. Validation should be carried out in accordance with GMP and data should be held at the manufacturing location and made available for inspection if not required in the dossier (see section .

工艺验证应确认控制策略对于工艺设计和产品质量来说已足够。验证应覆盖生产上市产品的所有生产场所和所有剂量产品。不同剂量、不同批量和包装规格可以括号法。但是，验证必须覆盖所有拟生产的场所。每个生产场所所有产品均应有工艺验证数据，以证明生产工艺的充分性。工艺验证应符合GMP，数据应保留在生产场所，如果申报文件中未要求（参见第8部分）则应该在检查过程中随时可提供。

Process validation can be performed in a traditional way, as described below, regardless of the approach to development taken. However, there is also the possibility to implement continuous process verification if an enhanced approach to development has been performed or where a substantial amount of product and process knowledge and understanding has been gained through historical data and manufacturing experience. A combination of traditional process validation and continuous process verification may be employed. The in-line, on-line or at-line monitoring that is often utilised for continuous process verification (discussed in section 5.2) provides substantially more information and knowledge about the process and might facilitate process improvements.

如下所述，不管采用了什么研发方法，工艺验证都可以采用传统方法。但是，如果已采用加强研发方法，或通过历史数据和生产经验已获得大量产品和工艺知识和理解，也存在实施持续工艺确认的可能性。可能要采用传统工艺验证和持续工艺确认相结合的方法。在线监控经常用于持续工艺确认（在第5.2部分中已讨论），提供大量的关于工艺的信息和知识，可能有利于工艺改进。

5. Process validation 工艺验证

5.1. Traditional process validation 传统工艺验证

Traditional process validation is normally performed when the pharmaceutical development and/or process development is concluded, after scale-up to production scale and prior to marketing of the finished product. As part of the process validation lifecycle, some process validation studies may be conducted on pilot scale batches if the process has not yet been scaled up to production scale.

传统工艺验证一般在药物研发和/或工艺研发结束后，在放大至生产规模后，成品上市前进行。作为工艺验证生命周期的一部分，如果有些工艺还没有放大到生产规模，部分工艺验证研究可能会在中试批次进行。

It should be noted that pilot batch size should correspond to at least 10% of the production scale batch (i.e. such that the multiplication factor for the scale-up does not exceed 10). For solid oral dosage forms this size should generally be 10% of the maximum production scale or 100,000 units whichever is the greater[1]. Where the intended batch size is less than 100,000 units, the predictive value of the pilot batches may be limited and a justified approach should be followed. For other dosage forms the pilot batch size should be justified taking into account risk to the patient of failure of the dosage form. Since it is not generally considered useful to conduct full validation studies on pilot scale batches, the process validation scheme outlined in Annex I of this guideline should be completed for each product for subsequent execution at production scale; bracketing may be acceptable. The process validation scheme to be followed should be included in the dossier. The scheme should include a description of the manufacturing process, the tests to be performed and acceptance criteria, a description of the additional controls in place and the data to be collected. A justification for the chosen process validation scheme should be presented in Module 3 and the Quality Overall Summary for human medicines and in Part 2.B and the Pharmaceutical Detailed and Critical Summary for veterinary medicines.

要注意的是中试生产批应至少对应商业生产批量的10%（即，放大生产倍数不应超过10）。该规模的固体口服剂型一般应为最大生产批量的10%或10万个单位剂量，取其中大者。如果要生产的批量小于10万剂型单位，中试批次预期值可能受限，则需要采用经过评估的方法。对于其它剂型，中试批量的论述要考虑剂型失败给患者带来的风险。由于一般认为在中试规模批次进行全验证研究是没有用的，因此在本指南附录1中列出的工艺验证计划应在之后的各产品生产规模时进行完善，可以接受括号法。申报文件中应包括要执行的工艺验证计划。计划中应包括工艺描述、要实施的测试和可接受标准、附加控制的描述和要收集的数据。要在人药申报文件模块3和质量综述、兽药申报文件第2.B部分和药品详情和关键摘要中放入为什么选择该工艺验证计划的论述。

In certain cases however, it is considered necessary to provide production scale validation data in the marketing authorisation dossier at the time of regulatory submission, for example when the product is a biological / biotech product or where the applicant is proposing a non-standard method of manufacture (see section 8 and Annex II). In these cases, data should be provided in the dossier on a number of consecutive batches at production scale prior to approval. The number of batches should be based on the variability of the process, the complexity of the process /product, process knowledge gained during development, supportive data at commercial scale during technology transfer and the overall experience of the manufacturer. Data on a minimum of 3 production scale batches should be submitted unless otherwise justified. Data on 1 or 2 production scale batches may suffice where these are supported by pilot scale batches and a justification as highlighted above.

在某些情况下，可能认为有必要在上市许可申报资料中提交生产批量的验证数据，例如，如果产品是生物/生物技术制品，或者申请人所拟的工艺为非标生产方法（参见第8部分和附录二）。这种情况下，要在批准前在申报资料中包括采用生产批量所获得的连续批次数据。批次数应基于工艺变动情况、工艺/产品复杂程度、在研发阶段所获得的工艺知识、在技术转移中所获得的商业批量中的支持数据，以及生产商的总体经验。除非另有论述，否则至少需要提交3批生产批量的数据。如果另有中试批量数据支持，以及上述高亮显示的论述提供，则仅提供1或2批生产批量数据也是可以的。

译者：未见哪里有高亮显示的内容。

The studies should address critical steps of manufacture, by conducting additional testing as necessary.

研究应说明关键生产工艺步骤，必要时增加检测。

5.2. Continuous process verification 持续工艺确认

Continuous process verification is an alternative approach to traditional process validation in which manufacturing process performance is continuously monitored and evaluated (ICH Q8).

持续工艺确认是传统工艺验证的一种替代方式，是指生产工艺的性能被持续地监控和评估（ICH Q8）。

Continuous process verification can be used in addition to, or instead of, traditional process validation.

持续工艺确认可以用于补充，或替代传统工艺验证。

It is a science and risk-based real-time approach to verify and demonstrate that a process that operates within the predefined specified parameters consistently produces material which meets all its critical quality attributes (CQAs) and control strategy requirements. In order to enable continuous process verification, companies should perform, as relevant, extensive in-line, on-line or at-line controls and monitor process performance and product quality on each batch. Relevant data on quality attributes of incoming materials or components, in-process material and finished products should be collected. This should include the verification of attributes, parameters and end points, and assessment of CQA and critical process parameter (CPP) trends. Process analytical technology (PAT) applications such as NIR spectroscopy with or without feedback loop (e.g. end point determination of blend homogeneity, determination of granules surface area, determination of content uniformity with large sample size) and Multivariate Statistical Process Control (MSPC) can be viewed as enablers for continuous process verification.

确认和证明一个工艺如果在预定的特定参数范围内操作，即可以稳定生产出符合所有CQA和控制策略要求的物料是一个科学并基于风险的实时方法。为了进行持续工艺确认，公司应相应地实施众多的在线控制和工艺性能监控，以及各批产品质量监控。应收集进厂物料或组件、制程中物料和成品的质量属性相关数据，还应该包括对属性、参数和终点，和CQA和CPP趋势的评估。工艺分析技术PAT工具，如具有或不具有反馈回路的NIR光谱（例如，混合均一性终点测试，颗粒表面积测试，样品量较大时含量均一性测试），和多变量统计学工艺控制MSPC可以当作持续工艺确认的工具。

Sufficient knowledge and understanding of the process is required in order to support continuous process verification. However, the scope and extent of continuous process verification will be influenced by a number of factors including:

为了支持持续工艺确认，需要对工艺有足够的知识和理解。但是，持续工艺确认的程度会受到一些因素的影响，包括

— prior development and manufacturing knowledge from similar products and/or processes;

— 从同类产品和/或工艺中获得的研发生产前的知识

— the extent of process understanding gained from development studies and commercial manufacturing experience;

— 在研发获得的对工艺理解的程度，以及商业生产经验

— the complexity of the product and/or manufacturing process;

— 产品和/或生产工艺的复杂性

— the level of process automation and analytical technologies used;

— 工艺自动化水平和使用的分析技术水平

— for legacy products, with reference to the product lifecycle, process robustness and manufacturing history since point of commercialization as appropriate.

— 对于已有产品，参考产品生命周期、工艺耐用性和自从商业化以来的生产历史（适用时）

A discussion on the appropriateness and feasibility of the continuous process verification strategy should be included in the development section of the dossier and should be supported with data from at least laboratory or pilot scale batches. A description of the continuous process verification strategy including the process parameters and material attributes that will be monitored, as well as the analytical methods that will be employed, should be included as described in Annex 1, with cross-reference to the validation section of the dossier. Actual data generated during continuous process verification at production scale should be available at the site for inspection. The applicant should define the stage at which the process is considered to be under control and the validation exercise completed prior to release of the product to the market, and the basis on which that decision will be made. The discussion should include a justification for the number of batches to be used based on the complexity and expected variability of the process and existing manufacturing experience of the manufacturing site. Continuous process verification would be considered the most appropriate method for validating continuous processes.

在申报资料的研发部分，应包括持续工艺确认策略的适当性和可行性讨论，并使用至少是实验室规模或中试规模批次的数据加以支持。持续工艺确认策略的内容应包括：要监控的工艺参数和物料属性、要采用的分析方法，应该如附录1中所述，交叉引用至申报文件的验证部分。在生产规模持续工艺确认中所产生的实际数据应受检查现场可以获得。申请人应定义工艺步骤受控起始点，和将产品放行上市销售前所完成的验证工作，以及做出该决定的根据。讨论应包括根据工艺复杂性和预期变化，以及在生产场所内已有生产经验来决定批次数的论述。在验证连续生产的工艺时，持续工艺确认被认为是最适当的方式。

Continuous process verification can be introduced at any time in the lifecycle of the product. It can be used for the initial commercial production, to re-validate commercialised products as part of process changes or to support continual improvement.

持续工艺确认可以在产品生命周期的任何时间引入。它可以用于初始的商业化生产，作为工艺变更的一部分对商业产品进行再验证，或用于支持持续改进。

Continuous process verification is dependent on compliance with GMP principles and requirements.

持续工艺确认是独立于GMP原则和要求符合性的。

Pharmaceutical quality systems (PQS) as described in ICH Q10 can complement GMP requirements. However, GMP matters and PQS should not be included in the submission as they are assessed and handled by GMP inspectors as appropriate.

在ICH Q10里所述药品质量体系PQS可以补充GMP要求，但是，GMP事宜和PQS不应该包括在申报资料中，因为它们是由GMP审计官在适当时进行评估的。

5.3. Hybrid approach 混合方案

It may be necessary to use either the traditional process validation or the continuous process verification approach for different steps within the manufacturing process. It should be clear in the dossier which approach to validation has been taken for which steps in the manufacturing process.

在生产工艺的不同步骤可能需要采用传统工艺验证或持续工艺确认方法。在文件中应清楚说明生产工艺哪个步骤采用了哪种验证方法。

The validation requirements in terms of batch size and number of batches would depend on the extent to which continuous process verification has been used. For non-standard processes (as defined in section  if continuous process verification does not address the critical unit operation(s) the process validation requirements highlighted in section 5.1 should be applied unless otherwise justified.

验证中关于批量和批次数的要求取决于所使用的持续工艺确认的深度。对于非标工艺（如第8部分所定义），如果持续工艺确认未包括对关键单元操作的确认，如无其它论述，则适用第5.1部分中高亮显示的工艺验证要求。

5.4. Design space verification 设计空间确认

A design space will normally be developed at laboratory or pilot scale. During scale-up the commercial process is generally conducted and validated in a specific area of the design space, defined as the target interval or Normal Operating Range (NOR). During the product lifecycle, moving from one area to another within the design space (i.e. change in the NOR) may represent higher or unknown risks not previously identified during initial establishment of the design space.

设计空间一般是在实验室或中试规模时建立的。在放大过程中，一般会实施商业化工艺，在设计空间的内一个特定区域进行验证，把它定义为目标区间，或常规操作范围NOR。在整个产品生命周期中，在设计空间内从一个区间移动至另一个区间（即NOR的变更）可能代表更高或未知风险，这些风险可能在初期设计空间建立期间并未能预先识别。

For this reason and depending on how the design space was originally established and how the process was validated, there will be situations where it will be necessary to confirm the suitability of the design space and verify that all product quality attributes are still being met in the new area of operation within the design space. This is termed ‘design space verification’.

因为上述原因，根据设计空间初始建立情况，和工艺验证情况，会需要对设计空间的适当性进行确认，对于在设计空间内一个新的操作空间生产出的产品是否满足所有质量属性应进行确认。这称为“设计空间确认”。

If the parameters investigated during development of the design space have not been shown to be scale independent and the process has been validated using traditional process validation, design space verification would be required and a verification protocol should be provided in the dossier.

如果在设计空间发展阶段所调查的参数并未显出与放大不相关，且工艺采用了传统工艺验证方法进行验证，则需要对设计空间进行确认，并在文件中提供确认方案。

If continuous process verification has been utilised, this may contribute towards ensuring the validity of the design space throughout the product lifecycle. In this case, a design space verification strategy should be included as part of the continuous process verification strategy.

如果采用了持续工艺确认，则有助于保证在产品生命周期内设计空间的有效性。这种情况下，设计空间确认策略应作为持续工艺确认策略的一部分。

Depending on the change and the extent of movement within the design space (i.e. distance from validated target/NOR or new area of design space with higher or unknown risk) protocols for verification may include controls of quality attributes (QA’s) and process parameters (PP’s) not included in the routine control system (e.g. monitoring or testing of QA’s and PP’s that are expected to be scale dependant and when applicable, equipment dependant). It is not necessary to verify entire areas of the Design Space or the edge of failure. In principle more than one area of the design space should be verified but a stepwise approach taking into consideration the need to adjust the NOR within the approved design space during product lifecycle is acceptable.

根据变更情况，以及在设计空间内移动程度（），确认方案可能包括质量属性控制（QA）和工艺参数控制（PP），这两项并不包括在常规控制系统中（例如对不受放大和设施影响的QA和PP监控和测试）。不需对设计空间的整个区间，或失效边缘进行确认。原则上，应该对设计空间内不止一个区间进行确认，但在整个产品生命周期内，由于会在批准的设计空间对NOR进行调整的需要，因而进行分步确认方式也是可以接受的。

6. Scale-up 放大生产

In order to avoid the repetition of lengthy and costly tests, it is necessary to gather information during properly designed development and process optimisation studies, when scaling up from laboratory through pilot to production scale. Such information provides the basis for justification that scale-up can be achieved without a consequent loss in quality. Those parts of the process likely to be critical in scale-up should be identified in section 3.2.P.2 (Veterinary Part 2.A.4) and defined in section 3.2.P.3 (Veterinary Part 2. of the dossier.

在从化验室规模经过试生产规模再放大至生产规模时，为了避免长时间及昂贵的检测，需要在适当的设计研发和工艺优化研究过程中收集相关信息。这些信息是论述放大生产不会对质量产生负面影响的基础。在放大过程中可能比较关键的工艺部分应在3.2.P.2（兽药第2.A.4部分）和3.2.P.3（兽药第2B部分）文件中识别。

Where ranges of batch sizes are proposed, it should be justified that variations in batch size would not adversely alter the CQAs of the finished product. It is envisaged that those parameters listed in the process validation scheme (Annex I of this guideline) will need to be re-validated once further scale-up is proposed post-authorisation unless the process has been proven to be scale independent or continuous process verification is employed.

如果申请了批量范围，应论述批量变动对制剂的CQA不会产生负面影响。除非已经证明放大是独立的，或者采用了持续工艺确认方法，否则认为这些列在工艺验证计划中的参数（本指南附录I）在获得上市批准后如果申请批量放大后即需要进行再验证。

7. Post approval change control 批准后变更控制

Clearly defined procedures are needed to control changes proposed in production processes. These procedures are part of GMP and would not normally be specified in the dossier. Such procedures should control planned changes, ensure that sufficient supporting data are generated to demonstrate that the revised process will result in a product of the desired quality, consistent with the approved control strategy and ensure that all aspects are thoroughly documented and approved including whether regulatory approval is needed by way of variation.

需要清楚界定对生产工艺进行变更控制要遵守的程序。这些程序是GMP的一部分，一般在文件里说明。这些程序应对计划变更进行控制，保证会产生充分的支持性数据来证明修订后的工艺会使用得产品具备所需的品质，与所批准的控制策略保持一致，保证所有事项均被完整记录和批准，包括是否需要提交变更申请获得法规批准。

Refer to the European Commission guidance on Type I and Type II variations (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 authorizations for medicinal products for human use and veterinary medicinal products and on the documentation to be submitted pursuant to those procedures ) and Regulation 712/2012/EC for details on the changes which would require a variation.

参见欧洲委员会关于第I类和第II类变更指南（关于人用兽用药品上市后变更检查，及需要提交的文件规定，欧洲委员会法令EC1234/2008，2008年11月24日，第II章IIa节，第III章和第IV章中变更详细分类），及712/2012/EC法令关于申请变更的详细要求。

8. Standard vs. non-standard methods of manufacture 标准VS非标准生产方法

This section is only relevant for processes which have been validated using traditional process validation. It is not relevant for those processes where continuous process verification is employed (see sections 5.1 and 5.2). According to section 5.1, full production-scale data should be provided in the dossier for non-standard products or processes which were validated using traditional process validation. It is possible for the applicant to justify that the product process can be considered standard for a particular manufacturer / site taking into account the risk to the patient of failure of the product or process. Such justifications are assessed on a case by case basis, but the information provided by the applicant (for each manufacturing site) should include:

本部分仅与采用传统工艺验证方法进行验证的工艺相关，与采用持续工艺确认的工艺不相关（参见第5.1和5.2部分）。根据第5.1部分，非标工艺或采用传统工艺验证方法进行验证的工艺的申报资料需要提供生产规模的数据。申请人也可以对产品工艺进行论述，证明考虑到产品或工艺失败对患者的风险，该工艺对于一个特定的生产商/生产场所来说，可以作为标准工艺。这类论述应是各案进行评估，但由申请人（对每个生产场所）提供的资料应包括：

— experience with the same or essentially similar product or process (number of products authorised / marketed in the EU/EEA and number of batches (including information on scale) manufactured);

— 同样或基本类似产品或工艺（在EU/EEA地区获批准/上市的产品数，及生产批数（包括规模信息））的经验

— ? the names/ marketing authorisation numbers in the relevant EU/EEA member state should be provided.

— 提供在相关EU/EEA成员国上市许可的名称和数量

— amount of knowledge gained during the development of the product (number and scale of batches manufactured at each manufacturing site involved);

— 在产品研发过程中获得的知识量（各涉及的生产场所所生产的批数和规模）

— history of GMP compliance of manufacturing sites for that type of process The applicant should clearly state (in section 3.2.P.3.5 of the dossier for human medicines, in section 2.B of the dossier for veterinary medicines) whether they consider the manufacturing process to be standard or non-standard and the justification for their decision for new marketing authorisation applications.

— 该类工艺生产场所GMP符合性历史。申请人应清楚说明（在人用药文件3.2.P.3.5部分，在兽药文件2.B部分）其将生产工艺作为标准还是非标准工艺，其新上市许可申报决定的论述

Please see Annex II for further information on products / processes considered to be nonstandard.

关于作为非标准工艺/产品的详细信息，参见附录II。


Definitions 定义 （翻译略）

At-line: 在线

Measurement where the sample is removed, isolated from, and analysed in close proximity to the process stream.

将样品取出，具有独立形态，在接近工艺流程场所对其进行测试

Bracketing approach: 括号法

A validation scheme / protocol designed such that only batches on the extremes of certain predetermined and justified design factors, e.g., strength, batch size, pack size are tested during process validation. The design assumes that validation of any intermediate levels is represented by the validation of the extremes. Where a range of strengths is to be validated, bracketing could be applicable if the strengths are identical or very closely related in composition (e.g., for a tablet range made with different compression weights of a similar basic granulation, or a capsule range made by filling different plug fill weights of the same basic composition into different size capsule shells). Bracketing can be applied to different container sizes or different fills in the same container closure system.

一份设计的验证计划/方案，在工艺验证中仅实施特定预定的和论述过的设计因素的极限值的批次，例如，剂量、批量、包装量。设计假定任何中间水平的验证均能由极端值的验证所代表。如果要验证一个剂量范围，括号法可以应用于剂量相当或配方相近（例如，具有不同压片重量范围，而制粒相似的片剂，或者胶囊尺寸不同因此装量不同，而配方相同的胶囊剂）。括号法可以应用于不同容器尺寸或在相同容器密闭系统中不同充填量的情况。

Control strategy: 控制策略

A planned set of controls, derived from current product and process understanding that ensures process performance and product quality. The controls can include parameters and attributes related to active substance and finished product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. (ICH Q10)

来自于对目前产品和工艺的理解，用于保证工艺性能和产品质量的一系列计划好的控制。控制可以包括与活性物质和制剂物料和组件相关的参数和属性、设施和设备操作条件、中控IPC、制剂质量标准和相关方法及监控频次。(ICH Q10)

Continuous process verification: 持续工艺确认

An alternative approach to process validation in which manufacturing process performance is continuously monitored and evaluated. (ICH Q8)

工艺验证的可替代方法，在该确认中对生产工艺性能进行持续监控和评估（ICH Q8）

Critical process parameter (CPP): 关键工艺参数

A process parameter whose variability has an impact on a critical quality attribute and therefore should be monitored or controlled to ensure the process produces the desired quality. (ICH Q8)

变动会对关键质量属性产生影响的工艺参数，因而需要进行监控或控制以保证工艺能生产出所需的质量（ICH Q8）

Critical quality attribute (CQA): 关键质量属性

A physical, chemical, biological or microbiological property or characteristic that should be within an appropriate limit, range, or distribution to ensure the desired product quality. (ICH Q8)

必须保持在一个适当的限度、范围或分布的一个物理、化学、生物或微生物属性或特性，以保证产品具有所需质量

Design space: 设计空间

The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide 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 and would normally initiate a regulatory post approval change process. Design space is proposed by the applicant and is subject to regulatory assessment and approval. (ICH Q8)

被证明会给产品质量提供保证的输入变量（例如，物料属性）的多维组合或相互作用和工艺参数。在设计空间内工作不会被认为是一个变更。超出设计空间则被认为是一个变更，一般会引发一个批准后法规变更过程。设计空间应由申请人拟定，经过法规评审和批准（ICH Q8）。

Enhanced approach: 强化方法

A development approach where risk management and scientific knowledge is used to identify and understand the material attributes and process parameters which influence the critical quality attributes of a product.

采用风险管理和科学知识来识别和理解会对产品的关键质量属性产生影响的物料属性和工艺参数所使用的研发方法。

In-line: 在线测试

Measurement where the sample is analysed within the process stream and not removed from it.

样品仍在工艺流程中，并不取出而进行的测试。

Lifecycle: 生命周期

All phases in the life of a product from the initial development through marketing until the product’s discontinuation. (ICH Q8)

产品从研发开始经过上市直到退市的所有生命阶段（ICH Q8）。

Ongoing process verification: 进行中的工艺确认

Documented evidence that the process remains in a state of control during commercial manufacture.

证明商业化生产的工艺仍保持在其受控状态的文件证据。

On-line: 在线

Measurement where the sample is diverted from the manufacturing process and not returned to the process stream.

将样品从生产工艺分离且不返回生产流程所进行的测试。

Pharmaceutical quality system (PQS): 药品质量体系

Management system to direct and control a pharmaceutical company with regard to quality. (ICH Q10)

对制药公司质量进行指导和控制的管理体系（ICH Q10）。

Process validation: 工艺验证

The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes.

证明在建立的参数范围内操作的工艺可以重复有效地生产出符合其预定质量标准和质量属性的药品的书面证据。

Traditional approach: 传统方法

A product development approach where set points and operating ranges for process parameters are defined to ensure reproducibility.

一种产品研发方法，该方法对工艺参数设定控制点或操作范围以保证其再现性。


References 参考文献

Commission Regulation (EC) No 712/2012 of 3 August 2012 amending Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products.

人药和兽药上市后变更检查

Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use.

共同体人药代码

Directive 2001/82/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to veterinary medicinal products.

共同体兽药代码

Eudralex volume 4 (GMP guidelines), Annex 15 (Qualification and validation).

EU GMP指南附录15（确认和验证）

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 authorizations for medicinal products for human use and veterinary medicinal products and on the documentation to be submitted pursuant to those procedures.

变更分类指南

ICH Q8 (R2) (Pharmaceutical development).

药品研发

ICH Q9 (Quality risk management).

质量风险管理

ICH Q10 (Pharmaceutical quality system).

药品质量体系

ICH Q11 (Development and manufacture of drug substances (chemical entities and biotechnological / biological entities).

原料药研发和生产（化学实体和生物技术/生物实体）

Note for guidance on development pharmaceutics (CPMP/QWP/155/96).

研发药品指南注释

Note for guidance on development pharmaceutics for veterinary medicinal products (EMEA/CVMP/315/98).

兽药制剂药物研发指南注释

Note for guidance on quality of modified release products (CPMP/QWP/604/96).

改性释放药品质量指南注释

Note for guidance on the quality of modified release dosage forms for veterinary use (EMEA/CVMP/680/02).

兽用改性释放剂型质量指南注释


Annex I: Process validation scheme

附录1：工艺验证流程

Traditional process validation 传统工艺验证

Where validation data on production scale batches are not provided with the application and traditional process validation as described in section 5.1 is proposed, the process validation scheme described below should be submitted by the applicant. This should outline the formal process validation studies to be conducted on production scale batches (the number of batches used would depend on the variability of the process, the complexity of the process / product and the experience of the manufacturer, but would usually be a minimum of 3 consecutive batches).

如果生产批量的工艺验证数据未提交在申报资料中，且采用了5.1部分所描述的传统工艺验证，则以下工艺验证流程应由申请人提交。提交的资料中应列出将要对生产批量（批次取决于工艺变动程度、工艺/产品复杂性，生产者的经验，但一般最少需要3批连续批次）进行的正式工艺验证研究。

The information from these studies will be available for verification post authorisation by the supervisory authority. The process validation scheme should be submitted in the marketing authorisation dossier and should include the following information as a minimum:

这些研究所产生的数据应可以用于确认已批准的上市许可。工艺验证流程应在上市许可申报中提交，最少应包括以下资料：

— short description of the process with a summary of the critical processing steps or critical process parameters to be monitored during validation;

— 工艺简短描述，验证中需要监控的关键工艺和关键工艺参数的汇总

— finished product release specification (references to the dossier);

— 成品放行质量标准（参考申报文件）

— details of analytical methods (references to the dossier);

— 分析方法详细信息（参考申报文件）

— in-process controls proposed with acceptance criteria;

— 中控及可接受标准

— additional testing intended to be carried out (e.g. with proposed acceptance criteria and analytical validation as appropriate);

— 需要实施的附加测试（例如，适当的已拟定的可接受标准和分析方法验证）

— sampling plan - where, when and how the samples are taken;

— 取样计划，取样的时间、地点、方式

— details of methods for recording and evaluation of results;

— 方法详细记录，对结果评估

— proposed timeframe.

— 预定的时间

Following completion of the scheme, a report containing the following information and signed by the appropriate authorised person should be generated and made available for inspection:

在经过一个完整的过程后，应形成一份报告，由相应有授权的人员签字，并提供检查用。报告应包括以下内容：

— batch analytical data;

— 批检测数据

— certificates of analysis;

— 分析报告

— batch production records;

— 批生产记录

— report on unusual findings, modifications or changes found necessary with appropriate rationale;

— 异常发现报告，适当理由所导致的修订或变更

— conclusions.

— 结论

Where the results obtained show significant deviations from those expected, the regulatory authorities need to be informed immediately. In such cases, corrective actions should be proposed and any proposed changes to the manufacturing process should receive appropriate regulatory approval by way of variation.

如果所得结果显示已显著偏离预期，则需要立即通知药监当局。这种情况下，要拟定纠正措施，所有拟定的生产工艺变更均应通过变更算途径经过适当的法规批准。

Continuous process verification 持续工艺确认

In cases where continuous process verification is proposed (as described in section 5.2) a continuous process validation scheme should be submitted by the applicant. This should outline the monitoring to be performed on production scale batches. The information obtained will be available for verification post authorisation by the supervisory authority. The continuous process verification scheme should be submitted in the marketing authorisation dossier and should include, as appropriate, the following information on the monitoring proposed:

如何拟采用持续工艺确认（如5.2部分所述），则申请人应提交一份持续工艺验证计划。计划中要列出在生产规模批次中所需实施的监控。所获得的资料在上市后要能让药监监管机构获得。持续工艺确认计划应在上市许可申报文件中提交，其中应包括（适当时）以下关于拟定监控资料

— details of on-line / in-line / at-line monitoring including parameters tested, number of samples, size of samples and frequency of monitoring

— 在线监控细节，包括所测试的参数、样品数量、样品规模和监控频次

— details of Analytical Methods (References to the dossier);

— 分析方法详细信息（参照文件）

— acceptance criteria;

— 可接受标准

— information/ data including, as appropriate, information on statistical models or tools used to determine whether the continuous verification data supports the ability of the process and controls to produce reproducible product at a commercial scale;

— 信息/数据，包括所用的统计模型或工具，这些工具用来决定持续确认数据是否支持工艺能力，是否能控制在商业批量下可以重复生产出产品

— if a design space has been developed, how the proposed monitoring will contribute to design space verification.

— 如果研发了一个设计空间，拟定的监控将如何证明对设计空间的确认


Annex II: Standard/non-standard processes

附录2：标准/非标工艺

For the purposes of this guideline the designation of a process as non-standard is determined by a combination of the nature of the active substance, the nature of the finished product, the actual process itself and the production experience of the manufacturer. All biological products are considered to be non-standard.

本指南中说明了一个工艺是否作为非标工艺取决于活性物质的特性、制剂的特性、实际工艺本身、生产商的生产经验综合因素。所有生物制品均应作为非标工艺。

The following categories are examples of products or processes which could be considered as nonstandard, and for which production scale validation data should be provided in the marketing authorisation application dossier unless otherwise justified:

以下是一些可能会被认为是非标工艺的类型例子，这些情形下，除非另有论述，否则在上市申报资料中，需要提供生产规模的验证数据：

1. the manufacture of specialised pharmaceutical dose forms;

特殊药品剂型的生产

2. the incorporation of some new technology into a conventional process;

一些新技术与传统工艺的结合

3. (highly) specialised processes involving new technologies or an established process known, or likely, to be complex and therefore to require particular care;

涉及新技术的特殊工艺，或已知工艺，或很可能比较复杂因而需要特别注意的工艺

4. non-standard methods of sterilisation.

非标灭菌方法

In addition a manufacturing process type not previously approved for pharmaceutical products within the EU is usually considered a non-standard process.

如果一种药品的生产工艺类型之前在欧盟没有被批准过，一般会被认为是一个非标工艺。

1. Specialised pharmaceutical dose forms 特殊的药品剂型

A non exhaustive list of types of products which might be considered as “specialised” is provided below for illustrative purposes:

以下是可能被作为“特殊”工艺对待的产品类型的不完全清洁，仅供帮助理解

— preparations for metered dose inhalation in the lungs e.g., pressurised metered dose inhaler (MDI’s) and dry powder inhalers (DPI’s);

— 定量吸入喷雾剂，例如，压力喷雾剂MDI和干粉喷雾剂DPI

— suspensions, emulsions or other liquid dispersed sterile products;

— 混悬剂、乳膏剂或其它液体分散无菌产品

— modified release preparations;

— 改释制剂

— unit dose products containing drugs in low content (≤2% of composition);

— 低含量单元剂量药物（≤组分的2%）

— other specialised dose forms e.g., parenteral depot preparations based on biodegradable polymers, liposomal preparations, micellar preparations, nanoparticulate preparations.

— 其它特殊剂型，例如，采用可生物降解的聚合物制剂的非肠道给药、脂质体凝胶剂、胶束制剂、纳米制剂

2. Conventional pharmaceutical processes incorporating new technologies 传统药品工艺与新技术相结合

A conventional process is well established and approved, and could, for example, include such activities as tabletting using wet granulation. However, the introduction of a new technology into such a conventional process e.g., a new drying technology not commonly used by the pharmaceutical industry, might result in the need for full-scale validation data based on a case-by-case consideration of the product and process development studies.

建立的很好并经过批准的传统工艺包括，例如，湿粒压片。但是，引入新技术到传统工艺中，例如，不常用于制药行业的新的干燥技术，可能会需要根据各案实际产品和工艺研发情况进行全批量验证。

3. Specialised processes or established processes known to be complex 特殊工艺或已知复杂的工艺

— processes with critical steps such as lyophilisation, microencapsulation;

— 具有例如冻干、微囊等的关键步骤的工艺

— processes where the physicochemical properties of the active substance or a key excipient (e.g., lubricant, coating agent) may give rise to processing or scale-up difficulties, or stability problems during manufacture at larger scale;

— 活性物质或关键辅料（例如，润滑剂、包衣剂）理化特性可能会增加工艺难度，或使批量放大产生困难，或在更大批量生产时有稳定性问题

— aseptic processing.

— 无菌工艺

4. Non-standard methods of sterilization 非标灭菌方法

— terminal sterilisation by moist heat using conditions other than pharmacopoeial reference conditions;

— 采用非药典对照条件下湿热终端灭菌

— terminal sterilisation by irradiation using less than 25 KGy.

— 采用不超过25千戈瑞终端辐射灭菌


[1] In the case of veterinary medicinal products, the minimum pilot batch size may be smaller than 100,000 units where justified.
对于兽药，如果经过论述，最小中试批量可以小于100,000个包装单元。

怀谷

学习了，谢谢！

一沙一叶

这么好的资料为啥就一个人回复啊

江寒315

一沙一叶 发表于 2014-9-22 22:12
这么好的资料为啥就一个人回复啊

因为大家不懂，也不用，
哎，整天喊GMP，整天玩生产，玩工艺，这么好的文件在这里慢慢长草。
新版的欧盟ANNEX15 ，同样提到要按照这个文件办事。

禁色殇城贳爱

这个资料就这样埋没了

zjl1810

新人来学习，文件考古，顶帖报道。