EU GMP 附录15：确认与验证(中英对照)

EU GMP 附录15：确认与验证（中英对照）

EU Guidelines for

Good Manufacturing Practice for

Medicinal Products for Human and Veterinary Use

人用与兽用药品的生产质量管理规范的欧盟指南

Annex 15: Qualification and Validation

附录15：确认与验证

Legal basis for publishing the detailed guidelines: Article 47 of Directive 2001/83/EC on the Community code relating to medicinal products for human use and Article 51 of Directive 2001/82/EC on the Community code relating to veterinary medicinal products. This document provides guidance for the interpretation of the principles and guidelines of good manufacturing practice (GMP) for medicinal products as laid down in Directive 2003/94/EC for medicinal products for human use and Directive 91/412/EEC for veterinary use.

发布详细指南的法律依据：欧盟法规有关人用药品的第2001/83/EC法令的第47条和有关兽用药品的第2001/82/EC法令的第51条。本文件提供指南，用以解释在人用药品的第2003/94/EC法令和兽用药品的第91/412/EEC法令下的药品的生产质量管理规范的原则和指导。

Status of the document: Revision

文件状态：修订

Reasons for changes: Since Annex 15 was published in 2001 the manufacturing and regulatory environment has changed significantly and an update is required to this Annex to reflect this changed environment. This revision to Annex 15 takes into account changes to other sections of the EudraLex, Volume 4, Part I, relationship to Part II, Annex 11, ICH Q8, Q9, Q10 and Q11, QWP guidance on process validation, and changes in manufacturing technology.

变更原因：自从2001年附录15发布以后，生产和法规环境已经显著变化，本附录也需要进行更新，以反映变化的环境。本附录15的修订版考虑了欧盟药品法规第4卷，第I部分的其它章节的变化，第II部分的相应章节、附录11、ICH Q8、Q9、Q10和Q11，QWP有关工艺验证的指南，以及生产技术的变化。

Deadline for coming into operation: 1 October 2015

生效的最后期限：2015年10月1日

Principle

原则

This Annex describes the principles of qualification and validation which are applicable to the facilities, equipment, utilities and processes used for the manufacture of medicinal products and may also be used as supplementary optional guidance for active substances without introduction of additional requirements to EudraLex, Volume 4, Part II. It is a GMP requirement that manufacturers control the critical aspects of their particular operations through qualification and validation over the life cycle of the product and process. Any planned changes to the facilities, equipment, utilities and processes, which may affect the quality of the product, should be formally documented and the impact on the validated status or control strategy assessed. Computerised systems used for the manufacture of medicinal products should also be validated according to the requirements of Annex 11. The relevant concepts and guidance presented in ICH Q8, Q9, Q10 and Q11 should also be taken into account.

本附录描述了确认和验证的原则，适用于药品生产的设施、设备、公用系统和工艺；也可作为在欧盟药品法规第四卷第II部的未提到的有额外要求的原料药的可选性补充指南。它是GMP的要求，要求生产商通过贯穿于药品和工艺的产品生命周期的确认和验证，控制其生产操作的关键环节。需要正式记录任何可能影响药品质量的设施、设备、公用系统和工艺的计划性变更，需要评估对于验证状态或控制策略的影响。用于药品生产的计算机化系统应按照附录11的要求进行验证。相关概念和指南参见ICH Q8，同时参考Q10和Q11。

General

通则

A quality risk management approach should be applied throughout the lifecycle of a medicinal product. As part of a quality risk management system, decisions on the scope and extent of qualification and validation should be based on a justified and documented risk assessment of the facilities, equipment, utilities and processes. Retrospective validation is no longer considered an acceptable approach. Data supporting qualification and/or validation studies which were obtained from sources outside of the manufacturers own programmes may be used provided that this approach has been justified and that there is adequate assurance that controls were in place throughout the acquisition of such data.

质量风险管理的方法应该贯穿于药品生命周期的全过程。作为质量风险管理系统的一部分，确认和验证的范围和程度需要基于对设施、设备、公用系统和工艺的合理的文件化的风险评估来确定。回顾性验证不再被认为是一个可接受的方法。那些用来支持确认和/或验证研究的从生产商的外部资源获得的数据，都可以被使用，但需提供证明这个方法合理性的说明，并且保证在采集这些数据的过程中控制是恰当的。

1ORGANISING AND PLANNING FOR QUALIFICATION AND VALIDATION

确认与验证的组织和计划

1.1All qualification and validation activities should be planned and take the life cycle of

facilities, equipment, utilities, process and product into consideration.

应该计划所有的确认与验证活动，而且需要考虑设施、设备、公用系统、工艺和产品的生命周期。

1.2Qualification and validation activities should only be performed by suitably trained

personnel who follow approved procedures.

确认与验证活动应该只能由合适的经过培训的人员按照被批准的程序进行。

1.3Qualification/validation personnel should report as defined in the pharmaceutical quality

system although this may not necessarily be to a quality management or a quality assurance function. However, there should be appropriate quality oversight over the whole validation life cycle.

尽管对于质量管理或者质量保证功能来说没有必要性，但是确认/验证人员仍应该按照药品质量系统的要求的进行汇报。而且应该对整个验证的生命周期有恰当的质量监督。

1.4The key elements of the site qualification and validation programme should be clearly

defined and documented in a validation master plan (VMP) or equivalent document.

工厂确认与验证项目的关键要素，应该在验证主计划（VMP）或者等效文件中明确定义并记录。

1.5The VMP or equivalent document should define the qualification/validation system and

include or reference information on at least the following:

VMP或等效文件应该对确认/验证系统定义，同时至少包括或参考以下信息：

i.Qualification and Validation policy;

确认与验证方针;

ii.The organisational structure including roles and responsibilities for qualification and validation activities;

组织机构，包括确认与验证活动的角色和职责;

iii.Summary of the facilities, equipment, systems, processes on site and the qualification and validation status;

概述工厂的设施、设备、系统、现场工艺，以及确认与验证的状态;

iv.Change control and deviation management for qualification and validation;

确认与验证的变更控制和偏差管理;

v.Guidance on developing acceptance criteria;

制定可接受标准的指南;

vi.References to existing documents;

参考的现有文件；

vii.The qualification and validation strategy, including requalification, where applicable.

确认与验证策略，包括适当的再确认。

1.6For large and complex projects, planning takes on added importance and separate

validation plans may enhance clarity

对于大而复杂的项目来说，计划显得更加重要，独立的验证计划可能使项目更加清晰明了。

1.7A quality risk management approach should be used for qualification and validation

activities. In light of increased knowledge and understanding from any changes during the project phase or during commercial production, the risk assessments should be repeated, as required. The way in which risk assessments are used to support qualification and validation activities should be clearly documented.

应该将质量风险管理方法应用于确认与验证活动。随着从项目阶段或者商业生产中任何变更中获得的知识和增长的理解力，按需要应重复风险评估活动。应该详细记录用于支持确认与验证活动的风险评估方法。

1.8Appropriate checks should be incorporated into qualification and validation work to

ensure the integrity of all data obtained.

应该在确认与验证工作中加入恰当的核查活动，以确保所得到数据的完整性。

2DOCUMENTATION, INCLUDING VMP

文件管理，包括VMP

2.1Good documentation practices are important to support knowledge management

throughout the product lifecycle.

良好的文件管理规范对于支持产品生命周期的知识管理是十分重要的。

2.2All documents generated during qualification and validation should be approved and

authorised by appropriate personnel as defined in the pharmaceutical quality system.

确认与验证过程中产生的所有文件应该得到批准，并且由药品质量体系规定的恰当人员授权。

2.3The inter‐relationship between documents in complex validation projects should be

clearly defined.

在一个复杂的验证项目中，应该明确文件之间的相互关系。

2.4Validation protocols should be prepared which defines the critical systems, attributes

and parameters and the associated acceptance criteria.

应该制定验证方案，该方案定义了关键系统、属性和参数，以及相关的可接受标准。

2.5Qualification documents may be combined together, where appropriate, e.g. installation

qualification (IQ) and operational qualification (OQ).

如果合适，可以将确认文件合并到一起。如，安装确认和运行确认。

2.6Where validation protocols and other documentation are supplied by a third party

providing validation services, appropriate personnel at the manufacturing site should confirm suitability and compliance with internal procedures before approval. Vendor protocols may be supplemented by additional documentation/test protocols before use.

当验证方案和其它文件由提供验证服务的第三方提供时，药厂合适的人员应当在批准前确认与公司相关程序的适用性及符合性。供应商方案可以在使用前通过附加的文件/测试方案进行补充。

2.7Any significant changes to the approved protocol during execution, e.g. acceptance

criteria, operating parameters etc., should be documented as a deviation and be scientifically justified.

对于批准方案在执行中发生的任何显著变更（如，可接受标准、运行参数等）都应当作为偏差被记录并作合理的解释。

2.8Results which fail to meet the pre‐defined acceptance criteria should be recorded as a

deviation and be fully investigated according to local procedures. Any implications for the validation should be discussed in the report

不符合先前所定义的可接受标准的结果应该作为偏差被记录，并依据原有规程进行充分调查。应该在报告中对验证造成的任何影响进行讨论。

2.9The review and conclusions of the validation should be reported and the results obtained

summarised against the acceptance criteria. Any subsequent changes to acceptance criteria should be scientifically justified and a final recommendation made as to the outcome of the validation.

应该记录验证的审查结果和结论，即使该结论不符合可接受标准的。任何对于可接受标准的相应变更都应该得到合理的解释，最终的建议作为本次验证的结论。

2.10A formal release for the next stage in the qualification and validation process should be

authorised by the relevant responsible personnel either as part of the validation report approval or as a separate summary document. Conditional approval to proceed to the next qualification stage can be given where certain acceptance criteria or deviations have

not been fully addressed and there is a documented assessment that there is no significant impact on the next activity.

在确认与验证活动中下一阶段的正式发布，需要由相关负责人员进行授权，可以作为验证报告批准的一部分或者一份独立的概要文件。在某一可接受标准或者偏差还没有完全解释时，若有一份评估文件以证明这对下一阶段的活动没有显著影响的，那么可以有条件的批准通过进入下一阶段。

3QUALIFICATION STAGES FOR EQUIPMENT, FACILITIES, UTILITIES AND SYSTEMS.

设备、设施、公用系统和系统的确认阶段

3.1Qualification activities should consider all stages from initial development of the user

requirements specification through to the end of use of the equipment, facility, utility or system. The main stages and some suggested criteria (although this depends on individual project circumstances and may be different) which could be included in each stage are indicated below:

确认活动应该考虑从最初的用户需求说明编写到最后的设备、设施、公用系统或系统使用的所有阶段。主要阶段和各阶段可能的一些建议的标准如下（尽管不同项目环境条件下可能有所不同）：

User requirements specification (URS)

用户需求说明

3.2The specification for equipment, facilities, utilities or systems should be defined in a URS

and/or a functional specification. The essential elements of quality need to be built in at this stage and any GMP risks mitigated to an acceptable level. The URS should be a point of reference throughout the validation life cycle.

对于设备、设施、公用系统或系统的规格应该在URS和/或功能说明中定义。必要的质量要素应该在这一阶段明确并将GMP风险降至可接受的水平。URS应该是贯穿验证生命周期中的一个参考点。

Design qualification (DQ)

设计确认

3.3The next element in the qualification of equipment, facilities, utilities, or systems is DQ

where the compliance of the design with GMP should be demonstrated and documented.

The requirements of the user requirements specification should be verified during the design qualification.

设备、设施、公用系统或系统的确认的下一阶段的工作是DQ，这一阶段中证明设计符合GMP，并进行记录。在设计确认过程中，应当核实用户需求说明的要求。

Factory acceptance testing (FAT) /Site acceptance testing (SAT)

工厂验收测试/现场验收测试

3.4Equipment, especially if incorporating novel or complex technology, may be evaluated, if

applicable, at the vendor prior to delivery.

设备，尤其是具备新的或者复杂技术时，如果可行，可在供应商交货前进行评估。

3.5Prior to installation, equipment should be confirmed to comply with the URS/functional

specification at the vendor site, if applicable.

如果可行，设备在安装前应在供应商处确认与URS或者功能说明的符合性。

3.6Where appropriate and justified, documentation review and some tests could be

performed at the FAT or other stages without the need to repeat on site at IQ/OQ if it can be shown that the functionality is not affected by the transport and installation.

如果能证明运输和安装不会影响设备的功能，文件审核和一些测试只要在FAT阶段进行即可，而不需要在现场IQ/OQ期间再次重复，这样是合适的也是合理的。

3.7FAT may be supplemented by the execution of a SAT following the receipt of equipment

at the manufacturing site.

可以在生产现场收到设备后进行SAT，以对作为FAT的补充。

Installation qualification (IQ)

安装确认

3.8IQ should be performed on equipment, facilities, utilities, or systems.

设备、设施、公用系统或系统都需要IQ确认。

3.9IQ should include, but is not limited to the following:

IQ包括但不仅限于以下内容：

i.Verification of the correct installation of components, instrumentation, equipment,

pipe work and services against the engineering drawings and specifications;

确认组件、仪器仪表、设备、管道工程和服务设施按照设计图纸和规格说明正确

安装。

ii.Verification of the correct installation against pre‐defined criteria;

确认按照预定标准正确安装。

iii.Collection and collation of supplier operating and working instructions and maintenance requirements;

收集并核对供应商的操作手册和维修要求。

iv.Calibration of instrumentation;

仪表校准

v.Verification of the materials of construction.

材质的确认

Operational qualification (OQ)

运行确认

3.10OQ normally follows IQ but depending on the complexity of the equipment, it may be

performed as a combined Installation/Operation Qualification (IOQ).

通常IQ结束后开始OQ执行，但根据设备的复杂程度，也可以将二者合并为IOQ执行。

3.11OQ should include but is not limited to the following:

OQ包括并不仅限于以下内容：

i.Tests that have been developed from the knowledge of processes, systems and

equipment to ensure the system is operating as designed;

依据工艺、系统和设备相关知识制定测试内容，以证明系统是按照设计进行运行。

ii.Tests to confirm upper and lower operating limits, and /or “worst case” conditions.

测试需要确认设备运行的上下限，和/或最差条件。

3.12The completion of a successful OQ should allow the finalisation of standard operating

and cleaning procedures, operator training and preventative maintenance requirements.

OQ完成后，应当建立标准操作和清洁程序、操作人员培训以及预防维护保养要求。

Performance qualification (PQ)

性能确认

3.13PQ should normally follow the successful completion of IQ and OQ. However, it may in

some cases be appropriate to perform it in conjunction with OQ or Process Validation.

PQ通常应该在IQ和OQ圆满完成后执行。但是在某些情况下也可以被融合在OQ或者工艺验证中实现。

3.14PQ should include, but is not limited to the following:

PQ包括但不仅限于以下内容：

i.Tests, using production materials, qualified substitutes or simulated product proven

to have equivalent behaviour under normal operating conditions with worst case

batch sizes. The frequency of sampling used to confirm process control should be

justified;

测试所用生产物料、合格的替代物或者模拟产品应被证明在正常操作条件和最差

批量下具有等效特性。应该确认工艺控制的取样频率是合理的。

ii.Tests should cover the operating range of the intended process, unless documented evidence from the development phases confirming the operational ranges is available.

测试应该涵盖预期工艺操作范围，除非有来自研发阶段的书面证据证明有现成的

操作范围。

4RE‐QUALIFICATION

再确认

4.1Equipment, facilities, utilities and systems should be evaluated at an appropriate

frequency to confirm that they remain in a state of control.

设备、设施、公用系统和系统应有一个合适的周期进行评估，以确认仍维持在受控状态。

4.2Where re‐qualification is necessary and performed at a specific time period, the period

should be justified and the criteria for evaluation defined. Furthermore, the possibility of small changes over time should be assessed.

如果再确认是必要的，并且在一个特定的时间周期进行时，这个时间周期应是合理的，评估的标准需要进行定义。此外，应该评估随时间推移出现的小变更的可能性。

5PROCESS VALIDATION

工艺验证

General

通则

5.1The requirements and principles outlined in this section are applicable to the

manufacture of all pharmaceutical dosage forms. They cover the initial validation of new processes, subsequent validation of modified processes, site transfers and ongoing process verification. It is implicit in this annex that a robust product development process is in place to enable successful process validation.

本章节所提的要求和原则适用于所有剂型的生产。包括了新工艺的初次验证，以及改良工艺后续验证、现场转移和持续工艺确认。本附录说明了一个充分的产品研发过程可以保证成功的工艺验证。

5.2Section 5 should be used in conjunction with the current EMA guideline on Process

Validation.

章节5可以结合现行的EMA工艺验证指南一同使用。

5.2.1The guideline on Process Validation is intended to provide guidance on the

information and data to be provided in the regulatory submission only. However

GMP requirements for process validation continue throughout the lifecycle of

the process

工艺验证指南的目的仅仅是对提交的注册申报信息和数据提供指导。而GMP

对工艺验证的要求涵盖工艺的整个生命周期。

5.2.2This approach should be applied to link product and process development. It will

ensure validation of the commercial manufacturing process and maintenance of

the process in a state of control during routine commercial production.

该方法应链接产品和工艺研发。用以确保商业化生产工艺的验证和日常商业

生产中受控工艺的维护。

5.3Manufacturing processes may be developed using a traditional approach or a continuous

verification approach. However, irrespective of the approach used, processes must be shown to be robust and ensure consistent product quality before any product is released to the market. Manufacturing processes using the traditional approach should undergo a prospective validation programme, wherever possible, prior to certification of the product. Retrospective validation is no longer an acceptable approach.

生产工艺的研发可能采用的是一个传统的方法或者一个连续的确认方法。然而不论采用任何方法，必须在产品投放至市场前证明工艺是可靠的，产品质量是一致的。

如果可能，应该在产品认证之前，对来自传统方法的生产工艺进行前瞻性验证。回顾性验证不再是可接受的方法。

5.4Process validation of new products should cover all intended marketed strengths and

sites of manufacture. Bracketing could be justified for new products based on extensive process knowledge from the development stage in conjunction with an appropriate ongoing verification programme.

新产品的工艺验证应当包括所有预期的产品规格和生产场地。基于来自研发阶段的广泛的工艺知识，并结合合适的持续确认程序，括号法经过论证可以用于新产品的工艺验证。

5.5For process validation of products which are transferred from one site to another or

within the same site, the number of validation batches could be reduced by the use of a bracketing approach. However, existing product knowledge, including the content of the previous validation, should be available. Different strengths, batch sizes and pack sizes/container types may also use a bracketing approach, if justified.

对于工艺验证中产品由一个生产场所转移至另外的生产场所或者产品在同一个生产场所中转移，可以通过括号法减少验证的批次。但是要确保现有的产品知识，包括以往验证内容，应该是可用的。如果经过论证，括号法也可用于不同规格、不同批量、包装大小和容器类型。

5.6For the site transfer of legacy products, the manufacturing process and controls must

comply with the marketing authorisation and meet current standards for marketing authorisation for that product type. If necessary, variations to the marketing authorisation should be submitted.

对于遗留产品的生产场所转移，生产工艺和控制方法都要符合销售许可和产品的当前注册标准。必要时，需要提交销售许可的变更。

5.7Process validation should establish whether all quality attributes and process parameters,