求EU-GMP附件15验证与确认草案中文翻译稿

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200107 EU GMP指南 附件15：确认和验证（中英文）

EUROPEAN COMMISSION

ENTERPRISE DIRECTORATE-GENERAL

Single market, regulatory environment, industries under vertical legislation

Pharmaceuticals and cosmetics

Brussels, July 2001

Working Party on Control of Medicines and Inspections

Final Version of Annex 15 to the EU Guide to

Good Manufacturing Practice

欧盟GMP附件15 终稿

Title: Qualification and validation

题目：确认和验证

First discussion in drafting group 起草组的初步讨论
Discussion at the working Party on Control of Medicines and Inspection for release for consultation 药物控制和检查工作组讨论	16 September 1999
Pharmaceutical Committee 药物委员会	28 September 1999
Released for consultation 讨论稿完成	30 October 1999
Deadline for comments 征求意见结束	28 February 2000
Final approval by Inspector’s working party 检查官工作组最终批准	December 2000
Pharmaceutical Committee (for information) 药物委员会（供参考）	April 2001
Date for coming into operation 实施日期	September 2001

Note that this document is based in the PICS/S recommendations

注意本文件基于PICS/S建议。

Table of Contents 目录

Page页

1. Qualification and Validation 确认和验证 3

2. Planning for Validation  验证计划 4

3. Documentation  文件 4

4. Qualification  确认 5

5. Processs Validation.  工艺验证 6

6. Cleaning Validation  清洁验证 7

7. Change Control  变更控制 8

8. Revalidation  再验证 9

9. Glossary  术语 10

QUALIFICATION AND VALIDATION 确认和验证

Principle 原则

1. This Annex describes the principles of qualification and validation which are applicable to the manufacture of medicinal products. It is a requirement of GMP that manufacturers identify what validation work is needed to prove control of the critical aspects of their particular operations. Significant changes to the facilities, the equipment and the processes, which may affect the quality of the product, should be validated. A risk assessment approach should be used to determine the scope and extent of validation. 本附件描述了确认和验证的原则，应用于药品生产。GMP要求生产者应识别需要进行哪些验证工作，以证明其特定操作中对关键方面的控制。对设施、设备和工艺的重大变更，如果对产品质量产生影响，应进行验证。可以采用评估的方法决定验证的范围和深度。

PLANNING FOR VALIDATION 验证计划

2. All validation activities should be planned. The key elements of a validation programme should be clearly defined and documented in a validation master plan (VMP) or equivalent documents.所有验证活动均应有计划。一个验证项目的关键要素应进行清楚界定，并在验证主计划（VMP）或相关文件中记录。

3. The VMP should be a summary document which is brief, concise and clear. 验证主计划是一个概述性文件，应简明扼要。

4. The VMP should contain data on at least the following: 验证主计划应最少包括以下内容

(a) validation policy; 验证方针

(b) organisational structure of validation activities; 验证活动的组织结构

(c) summary of facilities, systems, equipment and processes to be validated; 将验证的设施、系统、设备和工艺的概述

(d) documentation format: the format to be used for protocols and reports; 方案和报告的文件格式

(e) planning and scheduling; 计划和时间表

(f) change control; 变更控制

(g) reference to existing documents. 参考文献

5. In case of large projects, it may be necessary to create separate validation master plans. 如果是一个大项目，可能需要创建一个单独的验证主计划

DOCUMENTATION 文件

6. A written protocol should be established that specifies how qualification and validation will be conducted. The protocol should be reviewed and approved. The protocol should specify critical steps and acceptance criteria. 应有书面的验证方案说明如果实施确认和验证。方案应经过审核和批准，应说明关键步骤和可接受标准。

7. A report that cross-references the qualification and/or validation protocol should be prepared, summarising the results obtained, commenting on any deviations observed, and drawing the necessary conclusions, including recommending changes necessary to correct deficiencies. Any changes to the plan as defined in the protocol should be documented with appropriate justification. 应起草一份与确认和/或验证方案交叉索引的报告，总结所得到的结果，对所有偏差进行评价，作出结论，包括必要时建议的变更以纠正缺陷。对方案中计划的任何变更均应记录并作出适当的评价。

8. After completion of a satisfactory qualification, a formal release for the next step in qualification and validation should be made as a written authorisation. 在一个令人满意的确认完成后，应有一个正式的书面批准，确认和验证方可进行下一步骤。

QUALIFICATION 确认

Design qualification 设计确认

9. The first element of the validation of new facilities, systems or equipment could be design qualification (DQ). 新的设施、系统或设备验证的首个要素是设计确认（DQ）。

10. The compliance of the design with GMP should be demonstrated and documented. 应论证设计符合GMP要求并记录。

Installation qualification 安装确认

11. Installation qualification (IQ) should be performed on new or modified facilities, systems and equipment. 新的或经过改造的设施、系统和设备应进行安装确认（IQ）。

12. IQ should include, but not be limited to the following: 安装确认应包括，但不仅限于以下内容

(a) installation of equipment, piping, services and instrumentation checked to current engineering drawings and specifications; 应将设备、管道、支持系统和建设的安装情况按照现行的工程图纸和要求进行检查；

(b) collection and collation of supplier operating and working instructions and maintenance requirements; 收集和核对供应商的操作和工作指令和维护要求

(c) calibration requirements; 校正要求

(d) verification of materials of construction. 建筑材料的确认

Operational qualification 运行确认

13. Operational qualification (OQ) should follow Installation qualification. 运行确认（OQ）应在安装确认完成后进行

14. OQ should include, but not be limited to the following: 运行确认应包括但不仅限于以下内容

(a) tests that have been developed from knowledge of processes, systems and equipment; 根据工艺、系统和设备已有知识设计的测试

(b) tests to include a condition or a set of conditions encompassing upper and lower operating limits, sometimes referred to as “worst case” conditions. 包括了覆盖高低操作限度的一个条件或一系列条件的测试，有时也称为“最差情况”条件

15. The completion of a successful Operational qualification should allow the finalisation of calibration, operating and cleaning procedures, operator training and preventative maintenance requirements. It should permit a formal "release" of the facilities, systems and equipment. 一个完整的运行确认应包括已最终确定的校正、操作和清洁程序、操作人员培训和预防性维护要求。对设施、系统和设备应有一个正式的“放行”。

Performance qualification 性验确认

16. Performance qualification (PQ) should follow successful completion of Installation qualification and Operational qualification. 性验确认（PQ）应在安装确认和运行确认成功完成之后进行。

17. PQ should include, but not be limited to the following: 性能确认应包括但不限于下列内容

(a) tests, using production materials, qualified substitutes or simulated product, that have been developed from knowledge of the process and the facilities, systems or equipment; 根据已知的设施、系统和设备知识设计的测试、所用的生产物料、确认过的替代物或模拟产品。

(b) tests to include a condition or set of conditions encompassing upper and lower operating limits. 包括了覆盖高低操作限度的一个条件或一系列条件的测试。

18. Although PQ is described as a separate activity, it may in some cases be appropriate to perform it in conjunction with OQ. 尽管性能确认是设计作为一个独立的活动，在有些情况下也可以将其与运行确认一起实施。

Qualification of established (in-use) facilities, systems and equipment （在用）设施、系统或设备的确认

19. Evidence should be available to support and verify the operating parameters and limits for the critical variables of the operating equipment. Additionally, the calibration, cleaning, preventative maintenance, operating procedures and operator training procedures and records should be documented. 应有证据支持或确认对设备进行操作的关键变量操作参数和限度。另外，校正、清洁、预防性维护、操作程序和操作培训程序和记录应被记录。

PROCESS VALIDATION 工艺验证

General 概述

20. The requirements and principles outlined in this chapter are applicable to the manufacture of pharmaceutical dosage forms. They cover the initial validation of new processes, subsequent validation of modified processes and re-validation. 在本章中列出的要求和原则应用于药物制剂生产的验证，包括新工艺首次验证、工艺改进后的后续验证和再验证。

21. Process validation should normally be completed prior to the distribution and sale of the medicinal product (prospective validation). In exceptional circumstances, where this is not possible, it may be necessary to validate processes during routine production (concurrent validation). Processes in use for some time should also be validated (retrospective validation). 工艺验证一般应在药品销售前完成（前验证）。在一些例外情况下，不可能进行前验证，则可能在常规生产时进行验证（同步验证）。在用工艺有时也需要进行验证（回顾性验证）。

22. Facilities, systems and equipment to be used should have been qualified and analytical testing methods should be validated. Staff taking part in the validation work should have been appropriately trained. 生产中使用的设施、系统和设备应已确认，分析方法应已验证。参与验证工艺的员工应已被适当培训。

23. Facilities, systems, equipment and processes should be periodically evaluated to verify that they are still operating in a valid manner. 设施、系统、设备和工艺应进行周期性评价，以确认其仍处于验证过的操作要求。

Prospective validation 前验证

24. Prospective validation should include, but not be limited to the following: 前验证应包括但不限于以下内容

(a) short description of the process; 对工艺的简单描述

(b) summary of the critical processing steps to be investigated; 关键工艺步骤概述

(c) list of the equipment/facilities to be used (including measuring/ monitoring/recording equipment) together with its calibration status 生产用设备/设备的清单（包括测量、监控、记录设备）及其校正状态

(d) finished product specifications for release; 成品放行标准

(e) list of analytical methods, as appropriate; 分析方法清单，适当时

(f) proposed in-process controls with acceptance criteria; 建议的中控及可接受标准

(g) additional testing to be carried out, with acceptance criteria and analytical validation, as appropriate; 需要的额外测试，及可接受标准，分析方法验证，适当时

(h) sampling plan; 取样计划

(i) methods for recording and evaluating results 结果的记录和评估方法

(j) functions and responsibilities; 功能和职责

(k) proposed timetable. 建议的时间表

25. Using this defined process (including specified components) a series of batches of the final product may be produced under routine conditions. In theory the number of process runs carried out and observations made should be sufficient to allow the normal extent of variation and trends to be established and to provide sufficient data for evaluation. It is generally considered acceptable that three consecutive batches/runs within the finally agreed parameters, would constitute a validation of the process. 采用给定的工艺（包括指定的组件），在常规条件下生产一系列的批次成品。理论上来说，验证批准的数目和所观察的现象应足以证明变更的常规控制情况，足以建立趋势，提供充分数据进行评价。一般来说，在最终批准的参数范围内生产三个连续批次/三轮生产被认为是可以接受的。

26. Batches made for process validation should be the same size as the intended industrial scale batches. 进行工艺验证的批量应与计划的商业生产的批量相同。

27. If it is intended that validation batches be sold or supplied, the conditions under which they are produced should comply fully with the requirements of Good Manufacturing Practice, including the satisfactory outcome of the validation exercise, and with the marketing authorisation.如果计划将验证批准进行销售或用于下一步生产，生产条件应完全符合GMP要求，包括验证实施结果应符合既定要求，并具有上市批准。

Concurrent validation 同步验证

28. In exceptional circumstances it may be acceptable not to complete a validation programme before routine production starts. 在例外情况下，在未完成验证前进行常规生产开始也是可以接受的。

29. The decision to carry out concurrent validation must be justified, documented and approved by authorised personnel. 实施同步验证的决定需要进行论证、记录，并由授权人批准。

30. Documentation requirements for concurrent validation are the same as specified for prospective validation. 同步验证的文件要求与前验证相同。

Retrospective validation 回顾性验证

31. Retrospective validation is only acceptable for well-established processes and will be inappropriate where there have been recent changes in the composition of the product, operating procedures or equipment. 回顾性验证仅适用于生产情况良好的工艺，不适用于最近对产品组成、操作程序或设备进行变更的情况。

32. Validation of such processes should be based on historical data. The steps involved require the preparation of a specific protocol and the reporting of the results of the data review, leading to a conclusion and a recommendation. 对上述类别工艺的验证应基于历史数据。验证包括准备方案、报告对数据的回顾、得出的结论和建议。

33. The source of data for this validation should include, but not be limited to batch processing and packaging records, process control charts, maintenance log books, records of personnel changes, process capability studies, finished product data, including trend cards and storage stability results. 该验证的数据来源应包括，但不仅限于批生产和包装记录、工艺控制图表、维护日志、人员变更记录、工艺能力研究、成品数据，包括趋势图和存贮稳定性结果。

34. Batches selected for retrospective validation should be representative of all batches made during the review period, including any batches that failed to meet specifications, and should be sufficient in number to demonstrate process consistency. Additional testing of retained samples may be needed to obtain the necessary amount or type of data to retrospectively validate the process. 回顾性验证的批次应具有代表性，能代表在回顾周期中所有生产批次的情况，包括不符合质量标准的所有批次，应包括有足够的批次来证明工艺的一致性。可能需要对留样进行额外测试，以获得必要的数据类型和数目，来支持工艺的回顾性验证。

35. For retrospective validation, generally data from ten to thirty consecutive batches should be examined to assess process consistency, but fewer batches may be examined if justified. 对于回顾性验证，一般来说应检查十至三十个连续批次，以对工艺一致性进行评价，但如果经过论证，也可以采用更少的指认进行检查。

CLEANING VALIDATION 清洁验证

36. Cleaning validation should be performed in order to confirm the effectiveness of a cleaning procedure. The rationale for selecting limits of carry over of product residues, cleaning agents and microbial contamination should be logically based on the materials involved. The limits should be achievable and verifiable. 当需要确认清洁程序的有效性时，应进行清洁验证。产品残留、清洁剂和微生物污染的限度选择的合理性应与所涉及的物料有逻辑联系。设定的限度应可以达到，应可以确认。

37. Validated analytical methods having sensitivity to detect residues or contaminants should be used. The detection limit for each analytical method should be sufficiently sensitive to detect the established acceptable level of the residue or contaminant. 用于残留或污染检测的方法应经过验证，具有足够的灵敏度。每个分析方法的检测限的灵敏度应可以检测出所设定的残留或污染物的可接受限度。

38. Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to noncontact parts. The intervals between use and cleaning as well as cleaning and reuse should be validated. Cleaning intervals and methods should be determined. 一般来说，仅需要验证与产品接触的设备表面的清洁程序，但仍需要考虑到非接触部分。使用后到清洁操作的时间间隔、清洁完成后到再使用时间的间隔应进行验证。需要确定清洁间隔和清洁方法。

39. For cleaning procedures for products and processes which are similar, it is considered acceptable to select a representative range of similar products and processes. A single validation study utilising a “worst case” approach can be carried out which takes account of the critical issues. 对于产品和工艺类似时的清洁程序，可以选择这些类似的产品和工艺中一个具有代表性的范围，可以采用“最坏情况”方法，考虑最关键的因素进行一个验证。

40. Typically three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated. 在验证清洁程序时，可以进行具有代表性的三个连续的清洁程序。

41. "Test until clean". is not considered an appropriate alternative to cleaning validation. “测试直至清洁”不可以作为清洁验证的代替方法。

42. Products which simulate the physicochemical properties of the substances to be removed may exceptionally be used instead of the substances themselves, where such substances are either toxic or hazardous. 在例外情况下，如果需要被清除的药品成份有毒性或危险性，可以采用具有相同的物理化学性质的替代物质来进行验证。

CHANGE CONTROL 变更控制

43. Written procedures should be in place to describe the actions to be taken if a change is proposed to a starting material, product component, process equipment, process environment (or site), method of production or testing or any other change that may affect product quality or reproducibility of the process. Change control procedures should 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 specifications. 应有书面程序说明在起始物料、产品组件、工艺设备、工艺环境（或场所）、生产方法或检测方法或其它任何影响产品质量或工艺重现性的变更发生时，需要采用的措施。变更控制程序应保证有充分的的支持性数据，证明修改后的工艺将使用产品具有理想的质量，与批准的质量标准一致。

44. All changes that may affect product quality or reproducibility of the process should be formally requested, documented and accepted. The likely impact of the change of facilities, systems and equipment on the product should be evaluated, including risk analysis. The need for, and the extent of, requalification and re-validation should be determined. 所有可能影响产品质量或工艺重现性的变更均应有书面申请、记录和接受。可能对产品产生影响的设施、系统和设备的变更应进行评价，包括风险分析。应决定再确认和再验证的需求、深度。

REVALIDATION 再验证

45. Facilities, systems, equipment and processes, including cleaning, should be periodically evaluated to confirm that they remain valid. Where no significant changes have been made to the validated status, a review with evidence that facilities, systems, equipment and processes meet the prescribed requirements fulfils the need for revalidation. 设施、系统、设备和工艺，清洁，均应进行周期性评价，以确认其仍处于有效状态。如果没有对重大变更影响验证状态，可以对设施、系统、设备和工艺符合所描述的要求证据进行回顾，以满足再验证的要求。

GLOSSARY 术语

Definitions of terms relating to qualification and validation which are not given in the glossary of the current EC Guide to GMP, but which are used in this Annex, are given below.

在本附件中用到，但在EC GMP指南中未收载的与确认和验证相关的术语定义如下

Change Control

A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect the validated status of facilities, systems, equipment or processes. The intent is to determine the need for action that would ensure and document that the system is maintained in a validated state.

变更控制：一个正式的体系，在该体系中，具有资质的代表根据适当的原则对提议或实际已发生的、可能影响设施、系统、设备或工艺的验证状态的变更进行评价，以决定是否需要采取行动来保证和记载系统维持在经过验证过的状态。

Cleaning Validation

Cleaning validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing medicinal products.

清洁验证：指记录的证据，说明一个经过批准的清洁程序能保证某设备适用于药品的处理。

Concurrent Validation

Validation carried out during routine production of products intended for sale.

同步验证：在常规的生产期间，对用于销售的产品进行的验证。

Design qualification (DQ)

The documented verification that the proposed design of the facilities, systems and equipment is suitable for the intended purpose.

设计确认（DQ）：书面确认一个提议的设施、系统和设备设计适用于既定的目的。

Installation Qualification (IQ)

The documented verification that the facilities, systems and equipment, as installed or modified, comply with the approved design and the manufacturer’s recommendations.

安装确认（IQ）：书面确认设施、系统和设备的安装或改造符合批准的设计和生产商的建议。

Operational Qualification (OQ)

The documented verification that the facilities, systems and equipment, as installed or modified, perform as intended throughout the anticipated operating ranges.

运行确认（OQ）：书面确认设备、系统和设备在经过安装或改造后，满足期望的操作范围。

Performance Qualification (PQ)

The documented verification that the facilities, systems and equipment, as connected together, can perform effectively and reproducibly, based on the approved process method and product specification.

性能分析（PQ）：书面确认设施、系统和设备在连接完成后，根据批准的工艺方法和产品质量标准，可以有效重复其性能指标。

Process Validation

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.

工艺验证：书面确认根据已建立的参数，某工艺可以有效地重复生产一种药品，并符合预定的质量标准和质量属性。

Prospective Validation

Validation carried out before routine production of products intended for sale.

前验证：在用于销售产品的常规生产前进行的验证。

Retrospective Validation

Validation of a process for a product which has been marketed based upon accumulated manufacturing, testing and control batch data.

回顾性验证：对已上市的产品，基于累积的各批生产、检测和控制数据进行的工艺验证。

Re-Validation

A repeat of the process validation to provide an assurance that changes in the process/ equipment introduced in accordance with change control procedures do not adversely affect process characteristics and product quality.

再验证：重复进行的工艺验证，保证根据变更控制程序引入的工艺/设备的变更对工艺特性和产品质量不会产生负面影响。

Risk analysis

Method to assess and characterise the critical parameters in the functionality of an equipment or process.

风险分析：一种评价和界定设备或工艺的功能性关键参数的方法。

Simulated Product

A material that closely approximates the physical and, where practical, the chemical characteristics (e.g. viscosity, particle size, pH etc.) of the product under validation. In many cases, these characteristics may be satisfied by a placebo product batch.

模拟产品：与需验证产品的物理、化学特性（例如粘度、粒度、pH值等）非常相近的物料。在很多情况下，空白产品（安慰剂）批次即可满足上述要求。（注：空白产品即只有辅料，不添加活性成份）

System

A group of equipment with a common purpose.

系统：为同一目的服务的一组设备

Worst Case

A condition or set of conditions encompassing upper and lower processing limits and circumstances, within standard operating procedures, which pose the greatest chance of product or process failure when compared to ideal conditions. Such conditions do not necessarily induce product or process failure.

最坏情况：一个或一系列条件，包括了在标准操作程序中较高和较低工艺限度和环境，与理想条件相比最可能导致产品或工艺失败的条件。这些条件并不一定会导致产品或工艺失败。

幻影

ryujiang 发表于 2014-10-13 16:31
人家要的是2014年的新草案~~不是2001年的版本

哦，那就靠你了。

幻影

ryujiang 发表于 2014-10-13 16:34
https://www.ouryao.com/forum.php?mod=viewthread&tid=236666&highlight=%C8%B7%C8%CF%D3%EB%D1%E9%D6%A4
...

我回贴了，竟然资源没有收藏？

幻影

ryujiang 发表于 2014-10-13 16:42
你不回帖的帖子~~应该是少数~~

多数。毕竟今年刚来。

毛毛球

这个是个好资料

4__ur__love

{:soso_e113:}谢谢

201300

00107 EU GMP指南 附件15：确认和验证（中英文）