欧盟GMP附录15确认和验证中英文新版
欧盟GMP附录15确认和验证
欧盟GMP附录15确认和验证
ANNEX 15 附件15
Qualification and Validation
确认和验证
Table of Contents 目录
1. Qualification and Validation 确认和验证
2. Planning for Validation 验证计划
3. Documentation 文件
4. Qualification 确认
5. Process Validation 工艺验证
6. Cleaning Validation 清洁验证
7. Change Control 变更控制
8. Revalidation 再验证
9. Glossary 术语表
Qualification and Validation 确认和验证
Principle 原理
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.
1.本附件描述了确认和验证的原理，适用于医药产品的生产者。这是GMP指导生产者明确他们整个操作中哪些是需要对其进行控制的关键方面。在设施、设备和工艺等，对
产品质量会产生重大影响的改变需要进行验证。风险评估用来进行验证的未来预测。
PLANNING FOR VALIDATION 验证计划
2. All validation activities should be planned. The key elements of a validation program should be clearly defined and documented in a validation master plan (VMP) or equivalent documents.
所有验证活动都要进行规划。验证计划的关键组成部分应该明确定义并在验证主计划
（VMP）或类似文件中写明。
3. The VMP should be a summary document which is brief, concise and clear. VMP是一个简短、简明而清晰的综述性文件。
4. The VMP should contain data on at least the following:
VMP应该至少包括以下资料：
(a) Validation policy;
验证方针
(b) Organizational structure of validation activities;
验证组织机构
(c) Summary of facilities, systems, equipment and processes to be validated; 需要验证的设备、系统、仪器、工艺的汇总
(d) Documentation format: the format to be used for protocols and reports; 文件模版：制定草案和报告的模版
(e) Planning and scheduling;
计划和时间表
(f) Change control;
变更控制
(g) Reference to existing documents.
引用已有文件
5. In case of large projects, it may be necessary to create separate validation master plans.
如果项目庞大，则需要制定分开的验证主计划。
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.
应该制定一份书面草案来指导确认和验证工作的实施。该方案要进行审核和批准。该
方案要写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, summarizing 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. 制定确认和/或验证方案的交叉引用对照报告，来对所得结果进行总结、对任何观察到
的偏差进行评论、以便得出必要的结论，包括推荐进行必要变更以改正缺陷。在该计
划中定义的任何变更都应该有书面记录，并应有合理的解释。
8. After completion of a satisfactory qualification, a formal release for the next step in qualification and validation should be made as a written authorization.
当确认完成后，要对其验证和确认的书面版本进行正式的发放。
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).
一台新仪器、新系统或者新设备的第一个验证步骤应该是设计确认（DQ）。
10.The compliance of the design with GMP should be demonstrated and documented. 设计与GMP要求是否符合要进行实例证明并编写成文件形式。
Installation qualification 安装确认
11.Installation qualification (IQ) should be performed on new or modified facilities, systems and equipment.
安装确认（IQ）用于新的或者改造后的设施、系统和设备。
12.IQ should include, but not be limited to the following:
IQ应该包括以下内容，但不局限于此。
(a) Installation of equipment, piping, services and instrumentation checked to current engineering drawings and specifications;
设备、管道、设施和仪器的安装要符合其图纸和标准要求。
(b) Collection and collation of supplier operating and working instructions and maintenance requirements;
收集和整理供应商的操作说明书以及维护资料。
(c) calibration requirements; 校验要求
(d) Verification of materials of construction. 材质确认
Operational qualification 运行确认
13.Operational qualification (OQ) should follow Installation qualification. 运行确认（OQ）在安装确认之后进行。
14.OQ should include, but not be limited to the following:
OQ应该包括以下内容，但不局限于此：
(a) tests that have been developed from knowledge of processes, systems and equipment;
从工艺、系统和设备常识中发展而来的检查
(b) tests to include a condition or a set of conditions encompassing upper and lower operating limits, sometimes referred to as “worst case” conditions. 检查应包括条件要求或者一组围绕操作限度上下限的条件，有时要包括“最差情况”
的条件。
15.The completion of a successful Operational qualification should allow the finalization of calibration, operating and cleaning procedures, operator training and preventative maintenance requirements. It should permit a formal "release" of the facilities, systems and equipment.
一份完整的成功的运行确认应该包括结论性的校正、操作和清洁程序，操作者培训和
预防性维护要求。此步骤的完成相当于允许设施、系统和设备正式“发放”。
Performance qualification 性能确认
16. Performance qualification (PQ) should follow successful completion of Installation qualification and Operational qualification.
性能确认（PQ）应该在安装确认和运行确认成功完成的基础上进行。
17. PQ should include, but not be limited to the following:
PQ应该包括以下内容，但不仅限于此：
(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;
使用生产材料，经确认的代替品或者模拟产品的、从工艺、系统和设备常识中发展而
来的检查。
(b) Tests to include a condition or set of conditions encompassing upper and lower operating limits.
检查应包括一个条件或者一组围绕操作限度上下波动的条件。
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PQ被描述为一个独立的活动，但是在某些情况下它会与OQ结合起来。 Qualification of established (in-use) facilities, systems and equipment.
已建立（使用中）设施、系统和设备的确认。
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.
必须有证据支持和证明操作设备关键变量的操作参数和限度。另外，校准、清洁、预
防性维护、操作程序和操作者培训程序和记录也要以文件形式记录。
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.
本章所列要求和原理适用于药品剂型生产者。本章涵盖了新工艺的最初验证，改良工
艺的后续验证和重新验证。
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).
工艺验证通常应该在医药产品分发销售（预验证）前完成。如有例外情况使工艺验证不能如期进行，则必须在日常生产过程中进行验证（同步验证）。使用中工艺有时也应该进行验证（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.
所使用的设施、系统和设备应事先经过确认，而且使用的分析测定方法也要经过验
证。验证工作中的相关人员都要进行过良好的培训。
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，设备和工艺应该定期进行评估检测以确保其运行仍然在正常允许的状态下。
Prospective validation 预验证
24.Prospective validation should include, but not be limited to the following: 预验证包括以下内容，但不仅限于此：
(a) short description of the process; 工艺简短描述
(b) Summary of the critical processing steps to be investigated;
所考察的关键工艺步骤的总结
(c) List of the equipment/facilities to be used (including
measuring/monitoring/recording equipment) together with its calibration status. 所使用的设备/设施（包括测量、监视、记录仪器），以及各自的校正情况的列表
(d) finished product specifications for release; 发放成品标准
(e) list of analytical methods, as appropriate; 适宜分析方法列表
(f) Proposed in-process controls with acceptance criteria;
被提倡的过程中控制以及其可接受标准
(g) Additional testing to be carried out, with acceptance criteria and analytical validation, as appropriate;
适宜的必要的附加测试，包括可接受标准，分析验证。
(h) sampling plan; 取样计划
(i) methods for recording and evaluating results 记录和评估结果的方法
(j) functions and responsibilities; 功效和责任
(k) Proposed timetable. 提议的时间表
https://www.sodocs.net/doc/2910675333.html,ing 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.
在常规条件下，使用该已确定的工艺（包括指定的成分）可能生产出一系列批次的最终
产品。理论上讲，工艺运行执行的次数和观察到的结果，应该足以建立变化和趋势的
普通范围，并足以提供较为充足的评估数据。所以通常意义上接受三个连续的、最终
参数均合格的批次/运行，可以作为对于工艺的验证。
26.Batches made for process validation should be the same size as the intended industrial scale batches.
工艺验证批次的生产规模应该与已定的工业生产批次相同。
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 authorization.
如果该验证批次要进行销售或者供应，则其生产的条件要完全符合GMP要求，并要包括令人满意的验证结果和销售批准。
Concurrent validation 同步验证
28.In exceptional circumstances it may be acceptable not to complete a validation program before routine production starts.
在特殊情况下可以接受在常规生产开始之前没有完成验证的情况。
29.The decision to carry out concurrent validation must be justified, documented and approved by authorized personnel.
关于进行同步验证的决定，必须要有权威人士进行决策、文件性证明以及批准。
30.Documentation requirements for concurrent validation are the same as specified for prospective validation.
对于同步验证的文件要求与预验证相同。
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已经完善的工艺，对于近期在产品组成、操作程序或者设备方面
有过变更的情况是不适用的。
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. 该工艺验证应该以历史数据为基础。有关步骤要求制定详细方案和数据回顾结果的报告，以便得出结论和建议。
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该包括——但是不局限于：批处理和包装记录，工艺工职流程
图，维护保养记录表，人员变更记录，加工能力研究，成品数据，包括趋势卡片和耐
储存性结果。
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. 用于回顾性验证的批次，必须在所有回顾期间生产的批次中选择具有代表性的批次，
包括任何没有达到标准的批次，并且在数量上应该足以示范工艺过程的一致性。也许
需要进行保留样品的额外测试，以得到必要数量或种类的数据来回对工艺进行回顾性
的验证。
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，通常要对10到30个连续批次的数据进行检查来评估工艺的一致性，如果可以证明正确性，那么也可以使用稍少的批次进行。
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.
清洁验证是为了确保清洁程序的有效性而进行的。对于产品残留物清除、清洁剂和微
生物污染的限度选择，理论上应该以相关原料为基础。这些限度应该是可以达到的并
且是可以被证实的。
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.
应该使用经确认的、对于检测残留物或污染物具有灵敏度的分析方法。每一种分析方
法的检测限度应该足够灵敏来检测出符合可接受标准要求的残留物或污染物。
38.Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to non-contact parts. The intervals between use and cleaning as well as cleaning and reuse should be validated. Cleaning intervals and methods should be determined.
一般情况下，仅仅对于和产品接触的设备表面需要进行清洁验证。也要考虑到非接触
部分。要对使用清洁间隔以及清洁再使用间隔进行验证。清洁间隔和方法应该是确定的。
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 utilizing a “worst case” approach can be carried out which takes account of the critical issues.
对于相似产品和工艺的清洁程序，选择相似产品和工艺具有代表性的范围是可以接受的。当考虑到关键结果时，可以利用“最坏情况”来进行单独的验证研究。
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.
应该使用典型的连续三次清洁程序并保证结果成功，以证明该方法是经过验证的。
41."Test until clean" is not considered an appropriate alternative to cleaning validation.
一直测试直到干净为止这种作法在清洁验证中是错误的。
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.
当要被清除的物质有毒或者存在危险性时，要使用产品而非该物质本身，产品同该物
质具有相似的物理化学特性。
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.
如果有原料、产品组成、工艺设备、加工环境（或场地）、生产方法或检测或任何其他可能对产品质量或者工艺重现性产生影响的变更时，已定要有相应的书面指导处理程序。变更控制程序应该确保足够的支持数据的一致性以显示经过修订的工艺可以保证
生产出符合要求质量的产品和规定标准的组成。
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,
re-qualification and re-validation should be determined.
所有可能对产品质量或工艺重现性产生影响的变更应该正式进行提出、写成文件并被
接受。应该对生产设施、系统和设备的变更中可能存在的冲突进行评估，包括风险分析。对于重新确认和重新验证范围的要求应该事先确定。
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，包括清洁，应该定期进行评估已确保其各自情况是符合标
准要求的。如果验证方面没有明显的变更，设施、系统、设备和工艺达到了要求，则
对其进行审核后重新验证就算完成了。
GLOSSARY术语表
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.
与确认和验证有关的、在欧共体指导GMP术语表中没有列出，但是在附件中使用到的词如下所示：
Change Control 变更控制
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.
一个正式系统
Cleaning Validation 清洁验证
Cleaning validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing medicinal products. 清洁验证是用一套文件来证明用于药品生产的设备已经通过了清洁程序。
Concurrent Validation 同步验证
Validation carried out during routine production of products intended for sale. 用于销售的产品生产过程中进行的验证。
Design qualification (DQ) 设计确认(DQ）
The documented verification that the proposed design of the facilities, systems and equipment is suitable for the intended purpose.
本文件确认所提供的设施、系统和设备的设计是与预期要求一致的。
Installation Qualification (IQ) 安装确认(IQ）
The documented verification that the facilities, systems and equipment, as installed or modified, comply with the approved design and the manufacturer’s recommendations.
本文件确认设施、系统和设备的安装或改进是完全根据批准的设计和生产者的推荐所
进行的。
Operational Qualification (OQ) 操作确认(OQ）
The documented verification that the facilities, systems and equipment, as installed or modified, perform as intended throughout the anticipated operating ranges.
用文件确认安装或改进的设施、系统和设备，表现失重按照预先规定的操作范围进
行。
Performance Qualification (PQ) 运行确认(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.
用文件确认安装连接好的设施、系统和设备，在经过批准的工艺方法和产品标准基础上，可以有效并可重复性的运行。
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.
用文件证明该工艺，在规定参数下操作，可以有效并重复性良好的运行，并可以生产
出符合预期标准和质量要求的产品。
Prospective Validation 预验证
Validation carried out before routine production of products intended for sale. 销售用产品生产之前进行的验证。
Retrospective Validation 回顾性验证
Validation of a process for a product which has been marketed based upon accumulated manufacturing, testing and control batch data.
以积累的生产、检验和控制批次数据为基础的、已经上市产品的工艺验证。
Re-Validation 再验证
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.
一个重复性的工艺验证，用来保证符合变更控制程序的工艺/设备方面的变更不会对工
艺性质和产品质量产生负面影响。
Risk analysis 风险分析
Method to assess and characterize the critical parameters in the functionality of an equipment or process.
评估和确定设备或工艺的功能性临界参数的方法。
Simulated Product 模拟产品
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.
在验证中，同产品的物理或化学性质（例如粘度、粒径、pH等）相似的材料。许多情况下可以用安慰剂产品批来代替。
System系统
A group of equipment with a common purpose.
一组具有相同目的的设备。
Worst Case 最坏情况
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.
指的是一个或一组围绕工艺限度和环境标准上下限波动的范围，包括标准操作程序，
并包括相对理想条件下的产品或工艺失败的最大机会。这样的条件不一定会引起产品
或工艺的失败。