PICS验证指南(中英文)

2. INTRODUCTION

The basic principles and application of qualification and validation are described in Annex 15 to the PIC/S and EU Guide to GMP.

This document comprises individual Recommendations on four topics relating to Equipment Qualification and Process Validation in pharmaceutical manufacture, as follows: Ø Validation Master Plan

Ø Installation and Operational Qualification Ø Non-Sterile Process Validation Ø Cleaning Validation

The four Recommendations comprising this document define general principles pertaining to each of the topics. 2. 导言

PIC/S和EU GMP指导原则的附录15中对确认(Qualification)和验证(Validation)的基本原则及应用进行了阐述。

本文件包含了药物生产过中与设备确认和工艺验证相关的如下这四个方面的建议：

验证主计划 安装和运行确认 非无菌工艺验证 清洗验证

本文件中的建议确定了上述这四个方面的基本原则。

2.1 Purpose of the document

2.1.1 The topics of these Recommendation documents reflect some of the areas in pharmaceutical manufacture identified by both Inspectorates and the

Pharmaceutical Industry as requiring guidance additional to that given in the current PIC/S GMP Guide.

2.1.2 The purpose of this document is to provide guidance for GMP inspectors in reviewing the issues covered to use for training purposes and in preparation for inspections. 2.1 本文件的目的

2.1.1 这些建议性文件的主题涉及的是那些审计人员和制药企业都认为需要对现行PIC/S GMP指导原则进行补充的领域。

2.1.2 本文件的目的在于给GMP审计人员提供一个指导文件，可用于培训和检查的准备工作。

2.2 Scope of the document

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PIC/S 的验证指南

2.2.1 It is considered that the principles defined in the individual Recommendation documents can be applied equally in the manufacture of active pharmaceutical ingredients (APIs) and finished pharmaceuticals.

2.2.2 At the time of issue, this document reflected the current state of the art. It is not intended to be a barrier to technical innovation or the pursuit of excellence.

2.2.3 The advice in these Recommendations is not mandatory for industry. However, industry should consider these Recommendations as appropriate.

2.2.4 It should be noted that additional requirements not contained in these Recommendations pertain to computer systems impacting GMP. 2.2 范围

2.2.1 每个建议文件中所确定的原则既适用于原料药，也适用于制剂。

2.2.2 在公布时，本文件反映了当前的技术水平。但并不能因此而成为技术革新和追求卓越的一种障碍。

2.2.3 本文件中的建议并不强制制药企业执行。然而，制药企业应当要适当考虑这些建议。 2.2.4 需要注意的是本文件并未包括会影响GMP的计算机系统方面的附加要求。 2.3 Aims of Qualification and Validation

The qualification and validation process should establish and provide documentary evidence that:

2.3.1 The premises, the supporting utilities, the equipment and the processes have been designed in accordance with the requirements of GMP. This normally constitutes Design Qualification or DQ.

2.3.2 The premises, supporting utilities and the equipment have been built and installed in compliance with their design specifications. This constitutes Installation Qualification or IQ.

2.3.3 The premises, supporting utilities and the equipment operate in accordance with their design specifications. This constitutes Operational Qualification or OQ.

2.3.4 A specific process will consistently produce a product meeting its predetermined specifications and quality attributes. This constitutes Process Validation or PV. The term Performance Qualification or PQ may be used also.

2.3 确认和验证的目的

确认和验证的目的在于建立和提供如下这些方面的书面证据：

2.3.1 厂房，设施，设备和工艺是根据GMP要求进行设计的。这通常就是设计确认(DQ, Design Qualification).

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2.3.2 厂房，设施和设备是根据设计要求进行建造和安装的。这就是安装确认(IQ, Installation Qualification).

2.3.3 厂房，设施和设备的运行符合其设计要求。这就是运行确认(OQ, Operational Qualification).

2.3.4 一特定工艺能够持续地生产出符合预期质量标准和质量属性的产品。这就是工艺验证(PV, Process Validation)。也被称为性能确认(PQ, Performance Qualification) 2.4 Terminology

2.4.1 Terminology used in the four Recommendation documents which is not defined in the current glossary of the PIC/S Guide to GMP, is presented at the end of this document.

2.4.2 It is worth commenting on the interchangeability of terms typically accepted internationally. The term ‘validation’ is often assumed to encompass the elements of equipment qualification, both Installation Qualification and

Operational Qualification, in addition to validation of the process itself. However, for the purpose of these Recommendations, terms are not used interchangeably. 2.4 术语

2.4.1 本文件中所用到的术语，若现行PIC/S GMP 指导文件中没有对其进行解释，则在本文件的结尾处会有其解释。

2.4.2 有必要对术语的可替换性进行说明，特别是那些国际认可的术语。“验证(Validation)”通常被认为除了验证工艺本身外，也包括设备确认(equipment qualification)的安装确认和运行确证。然而，在本文件中，这些术语是不能互换的。

2.5 When to qualify and validate?

2.5.1 Any aspect of, including significant changes to, the premises, the facilities, the equipment or the processes, which may affect the quality of the product, directly or indirectly, should be qualified and validated.

2.5.2 The concept of equipment qualification is not a new one. Many suppliers have always performed equipment checks to confirm functionality of their equipment to defined specifications, both prior to and after installation.

2.5.3 Similarly, development, scale-up and transfer into production of products and processes is not a new concept. Terminology may change and even differ between users, but the basic concepts of validation are immutable.

2.5.4 However, documented records of qualification and validation work in general, have sometimes not been given sufficient consideration by either equipment suppliers or pharmaceutical companies in the past. As a consequence, companies have not always been able to provide documented evidence to

inspectors reflecting the time and effort spent in carrying out these activities.

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2.5 何时进行确认和验证

2.5.1 厂房，设施，设备或工艺的可能会直接或间接影响到产品质量的方方面面及其重大变更都应当要进行确认和验证。

2.5.2 设备确认(Equipment qualification)并不是一个新概念。很多供应商经常会在安装前或安装后进行设备核查(Equipment check)以确认其功能是否能符合已定标准。

2.5.3 类似的，产品和工艺的开发(Development), 放大(Scale-up)和投产(Transfer into production)也不是一个新概念。尽管术语会变化，甚至不同的用户有不同的术语，但验证的基本概念是不变的。

2.5.4 然而，在过去，一般来说，无论是设备供应商还是制药企业都没有对确认和验证工作的书面记录给予足够的重视。因此，公司经常不能向审计人员提供书面材料说明其何时和如何进行了这些确认和验证工作。

2.5.5 It is impossible to categorically define what and when qualification and validation are necessary, as manufacturing operations and facilities vary considerably in size and complexity.

2.5.6 It is a requirement of GMP that each pharmaceutical company identifies what qualification and validation work is required to prove control of the critical aspects of their particular operation. Common sense and an understanding of pharmaceutical processing go a long way towards determining what aspects of an operation are critical.

2.5.7 The key elements of a qualification and validation programme of a company should be clearly defined and documented in a Validation Master Plan.

2.5.8 High standards should be stringently applied to documenting the work programme.

2.5.5 不可能很明确地确定何时需对哪些具体的方面进行确认和验证，因为生产操作和设施在规模和复杂性上都有很大的不同。

2.5.6 GMP要求每个制药企业都要确定需要进行哪些确认和验证工作以证明特定操作的关键方面是受到控制的。人们对一个操作中哪些方面是关键的成为一个共识并充份理解还需要很长一段时间。

2.5.7 在验证方案中，公司应当要清楚地说明每个确认和验证项目的关键因素。 2.5.8 编定工作计划文件时，尽可能的考虑采用先进标准。

2.5.9 Considerable resources, in terms of time, money and personnel, are typically required by companies to implement a qualification and validation programme.

2.5.10 Qualification and validation may be addressed in a variety of acceptable ways. Each company will have a preferred methodology which will be considered on its own merits by the Inspector.

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2.5.11 The expertise of suppliers, contractors and consultants may be utilised for qualification and validation work. In such cases, the responsibility lies with the contract giver to ensure that the required standards for the quality of the work which is carried out, for programme control and for documentation are met. 2.5.12 Qualification and validation can not be considered once-off exercises, for example, the start-up of a new manufacturing operation. An ongoing programme should follow its first implementation.

2.5.9 公司在进行确认和验证项目时，是需要相当多的资源的，特别是时间，资金和人员方面的。

2.5.10 有很多种方式来进行确认和验证。每个公司会有其首选的一套方法，审计人员会根据其自身的特点来考虑。

2.5.11 确认和验证工作会需要供应商，合作者以及顾问的专业人员参加。在这种情况下，合同提供者有责任从项目控制和文件上确保验证工作质量。

2.5.12 确认和验证工作并不是一次性工作，比如说，新的生产操作的启动。在第一次执行之后，还应当要有后续工作。

2.6 Change Control

2.6.1 Commitment of the company to control change to premises, supporting utilities, materials, equipment and processes used in the manufacture of medicinal products is essential to ensure a continued validation status of the systems concerned.

2.6.2 This commitment should be stated in the relevant company documentation. For example, the Quality Manual, Quality Policy Documents or the Validation Master Plan. As part of its Quality Management System the company should have a defined and formalised Change Control Procedure. 2.6 变更控制

2.6.1 公司有义务对药品生产中所用到的厂房，设施，设备，物料和工艺的变更进行控制，并确保对所涉及系统处于持续的验证状态。

2.6.2 在相关公司文件中要对此义务进行说明。比如说，质量手册，质量方针文件、验证主计划。作为公司质量管理系统的一部分，公司应当要正式建立变更控制程序。 2.7 Responsibility for Qualification and Validation

2.7.1 The responsibility for qualification and validation in pharmaceutical manufacture is a multi-disciplinary one. The current PIC/S GMP Guide states that the heads of the Production and Quality Control departments generally have the responsibility:

\"To ensure that the appropriate validations are done.\"

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2.7 确认和验证的职责

2.7.1 制药企业中确认和验证的职责是方面的。现行PIC/S GMP 指导文件中说，通常来说生产部门和质量部门是有责任的。 “确保已做了适当的验证工作。”

2.7.2 While the GMP Guide specifically identifies the responsibility of the Production and Quality Control departments, in practice, other departments, like

Engineering and Research and Development as well as Contractors are usually involved in the programme.

2.7.2 GMP指导文件中明确指明了生产部门和质量部门的责任，实际上，通常验证项目也会涉及到其它部门，比如说，工程部，研发部以及合作者。

2.7.3 It is the responsibility of the pharmaceutical company to define the respective responsibilities of its personnel and of external contractors in the qualification and validation programme. This should form part of the Validation Master Plan. However, the Quality Assurance function of a company should normally have a critical role in overseeing the whole qualification and validation process.

2.7.4 It is recommended that the validation programme be actively co-ordinated and managed by the company. To this end, validation teams are often formed with specific roles identified and assigned to individual team members. It is imperative that the most senior level of management within the company understands the personnel, time and financial resources required to execute a qualification and validation programme and commits the necessary resources to the work.

2.7.3 制药企业有责任确定其内部人员和外部合作者在确认或验证项目中各自的责任。这应当是验证主文件的一部分。然而，公司的QA(Quality Assurance function) 通常要起到对整个确认和验证的整个过程进行监控的关键作用。

2.7.4 建议公司对验证工作进行积极地协调和管理。为达到这个目的，通常建立验证小组并明确各个验证小组成员的责任。公司的最高管理层应当要理解，一个验证项目所需要的人力，时间和资金，并要为工作的开展提供必要的资源。 3. Interrelationship between qualification and validation

Design specification/Qualificatin - Installation Qualification - Operational Qualification - Process Validation or Performance Qualification - Change Control - Design specification/Qualification

3. 确认和验证之间的关系

设计确认 - 安装确认 - 运行确认 - 工艺验证(性能确认) - 变更控制-设计确认

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4. VALIDATION MASTER PLAN 4.1. Principle

4.1.1 Validation in general requires a meticulous preparation and careful planning of the various steps in the process. In addition, all work involved should be carried out in a structured way according to formally authorised standardised working and administrative procedures. In addition validation is characterised by: Ø Multidisciplinary approach: A specific characteristic of validation work is that it requires the collaboration of experts of various disciplines such as pharmacists, technologists, metrologists, chemical analysts, microbiologists, engineers, experts on Q.A. validation etc..

4. 验证主计划 4.1. 基本原则

4.1.1 通常验证需要对工艺中的各个工序进行细致的准备的和安排。此外，应当要根据正式批准的标准工作和管理程序来有计划地开展所有相关工作。此外，验证还有如下特征： 多学科方法：验证具有一个独特的特征那就是验证工作需要各方面专家的合作，比如药剂人员，工艺人员，计量人员，分析人员，生物技术人员，工程人员及QA验证专家等。 Ø Time constraints: Generally validation work is submitted to rigorous time schedules. These studies are always the last stage prior to taking new processes, facilities into routine operation.

Ø Costs: Validation studies are costly as they require time of highly specialised personnel and expensive technology.

4.1.2 The above factors require a well organised and structured approach that should be adequately described in a Validation Master Plan (VMP).

严格的时间期限：一般来说，验证工作需要有严格的时间安排。通常验证是采用新工艺、新设备进行带进常规操作之前的最后一个研究阶段。

成本：验证研究是成本很高的，因为它们需要专业人员的时间和昂贵的技术。

4.1.2 验证的上述这些因素验证的实现需要有一个很好的组织机构。验证主计划(Validation Master Plan, VMP)中应当要对此进行足够详细地描述。

4.2 Purpose

4.2.1 The VMP should present an overview of the entire validation operation, its organisational structure, its content and planning. The core of the VMP being the list / inventory of the items to be validated and the planning schedule. 4.2.2 A VMP helps management:

- to know what the validation programme involves with respect to time,

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people and money, and to

- understand the necessity for the programme; 4.2 目的

4.2.1 验证主计划(VMP)应当要对整个验证操作，组织机构，内容和计划进行全面安排。验证方案(VMP)的核心是列出所有需要验证项目及其时间安排。 4.2.2 验证主计划(VMP)有助于管理层： - 知道验证项目所涉及到的时间，人员和资金； - 理解验证的必要性。

A VMP helps all members of the validation team: - to know their tasks and responsibilities. A VMP helps GMP inspectors:

- to understand the firm's approach to validation and the set up an organisation of all validation activities. 验证方案(VMP)也有助于验证小组的所有成员： - 知道他们各自的任务和职责。

验证方案(VMP)也有助于GMP检查人员：

- 理解公司进行验证的方法和进行所有验证活动所建立的组织。

4.3 Definition

4.3.1 A Validation Master Plan is a document that summarises the firm's overall philosophy, intentions and approach to be used for establishing performance adequacy. 4.3 定义

4.3.1 验证计划(VMP)是对公司的整个体系，及用于建立性能充分性的方法进行综述的文件。

4.4 Scope

4.4.1 All validation activities relating to critical technical operations, relevant to product and process controls within a firm should be included in a VMP. This includes qualification of critical manufacturing and control equipment.

§4.4.2 It should comprise all Prospective, Concurrent, Retrospective Validations as well as Re-validations.

4.4.3 In case of large projects like the construction of a new facility, often the best

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approach is to create a separate VMP. (In such situations the VMP should be part of the total project management.) 4.4 范围

4.4.1 验证主计划(VMP)应当要包括所有和关键技术操作相关的验证活动，所有和公司内产品和工艺控制相关的验证活动。它还包括关键生产设备的控制设备的确认。 4.4.2 它包括：前瞻性验证同步验证，回顾性验证以及再验证。

4.4.3 如果是一些大型项目，比如说建造新的厂房等，最好的办法往往是单独编写一份验证主计划(VMP)。(在这种情况下，验证主计划(VMP)应当是整个项目管理的一部分。) 4.5 Format and Content

4.5.1 The VMP should be a summary document and should therefore be brief, concise and clear. It should not repeat information documented elsewhere but refer to existing documents such as Policy Documents, SOP's and Validation Protocols/Reports.

The VMP should be agreed by management. 4.5 格式和内容

4.5.1 验证主计划(VMP)是个概述性文件，因此它应当要简洁明了。验证主计划(VMP)不需要重复在其它地方已有的文件，只需参考这些文件即可，比如方针文件，标准操作规程(SOP) 和验证方案/报告等。

验证主计划(VMP)应当要经过管理部门批准。

4.5.2 A VMP should contain data on the following subjects / proposed chapters. Introduction

4.5.2.1 Firm's validation policy, general description of the scope of those operations covered by the VMP, location and schedule (including priorities). Organisational Structure of All Validation Activities

4.5.2 一个验证主计划(VMP)应当要包括如下这几方面的资料。 导言

4.5.2.1 公司的验证方针，验证主计划(VMP)所包含的所有操作的概述，地点和时间安排(包括先后顺序)。

所有验证活动的组织结构

4.5.2.2 Personnel responsibility for - the VMP,

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- protocols of individual validation projects, - validation work,

- report and document preparation and control,

- approval / authorisation of validation protocols and reports in all stages of validation processes,

- tracking system for reference and review, - training needs in support of validation. 4.5.2.1 如下工作的人员职责 - 验证主计划(VMP) - 每个验证项目的具体方案 - 验证工作

- 报告和文件的准备和控制

- 验证过程中每个阶段的具体验证方案和报告的批准 - 引用和评审的跟踪系统 - 验证所需的培训。

Plant / Process / Product Description

4.5.2.3 Provides a cross reference to other documents. A rationale for the inclusion or exclusion of validations, for the validation approach and the extent of validation should be included. 工厂/工艺/产品描述

4.5.2.3 提供其它文件的引用号。应当要包括是否要进行验证的理由说明，验证方法和验证程度的理由说明。

Note: A common principle in validation studies is to challenge processes, systems etc. The rationale behind any challenge and or “worst case” situation should be explained. Consideration can be given to the

grouping of products / processes for the purpose of validating \"worst case\" situations. Where \"worst case\" situations cannot be simulated, the rationale for the groupings made should be defined. Specific Process Considerations

4.5.2.4 Under this heading specific characteristics / requirements of the plant / process etc. that are critical for yielding a quality product and need extra attention may be briefly outlined here.

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注：验证的基本原则是对工艺，系统等进行挑战。对于所有还未到达“最坏情况”的情形都要进行理由说明。为了对“最坏情况”进行验证，可以考虑对产品/工艺进行分组。当“最坏情况”不能被模拟时，则应当要确定所做分组的理由。

特殊工艺考虑

4.5.2.4 在该标题下，要简要说明那些工厂和工艺等的特殊性质和要求，它们对生产出符合质量的产品是至关重要的，或者是需要额外注意的。

List of Products / Processes / Systems to be Validated

4.5.2.5 All validation activities comprised in the VMP should be summarised and compiled in a matrix format. Such matrix should provide an overview and contain:

Ø all items covered by the VMP that are subject to validation describing the extent of validation required [i.e. IQ, OQ and/or PQ]. It should include validation of analytical techniques which are to be used in determining the validation status of other processes or systems,

Ø the validation approach, i.e. Prospective, Retrospective or Concurrent, Ø the Re-validation activities,

Ø actual status and future planning. 需验证产品/工艺/系统的列表

4.5.2.5 验证主计划(VMP)中所包含的所有验证活动都应当要以矩阵的形式进行概述和编排。这样的矩阵应当要提供一个概述，并包括如下内容：

验证主计划(VMP)中所包含的所有项目，这些项目对验证所需的程序进行了描述“也就是IQ，OQ，和/或PQ”。它也应当要包括那些用于确定工艺和系统的验证状态所用的分析技术的验证。

验证方法，也就是前瞻性验证，回顾性验证和同步验证。 再验证活动

实际状态和将来的安排。

Key Acceptance Criteria

4.5.2.6 General statement on key acceptance criteria for the items listed under (4.5.2.5) above.

Documentation Format

4.5.2.7 The format to be used for protocols and reports should be described or referred to. Required SOP's

4.5.2.8 List of relevant SOP’s should be presented.

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关键合格标准

4.5.2.6 上述项目的关键合格标准的综述。 文件格式

4.5.2.7 应当要对方案和报告所用的格式进行描述或参引。 所需的标准操作规程(SOP) 4.5.2.8 列出所有相关的SOP

Planning & Scheduling

4.5.2.9 An estimate of staffing (including training needs), equipment and other specific requirements to complete the validation effort should be described in the VMP. A time plan of the project with detailed planning of subprojects. This time plan could be included in the above mentioned matrix (4.5.2.5). A VMP requires regular updating. 规划和时间安排

4.5.2.9 验证主计划(VMP)中应当要对完成整个验证所需的人员(包括所需的培训)，设备和其它特殊要求进行估计。整个项目的时间安排，及子项目的详细规划。这个时间安排可以包括在上述的矩阵中(4.5.2.5)。验证安排需要进行定期更新。

Change Control

4.5.2.10 A statement of the company's commitment to controlling critical changes to materials, facilities, equipment or processes (including analytical techniques), should be included. 变更控制

4.5.2.10 公司应当承诺要对物料，设备，设备或工艺(包括分析技术)的重大变更进行控制。 5. INSTALLATION AND OPERATIONAL QUALIFICATION

Recommendations for the Installation Qualification and Operational

Qualification of equipment involved in the manufacture of pharmaceutical products. 5.1 Principle

5.1.1 Installation and Operational Qualification exercises assure through appropriate performance tests and related documentation and records that equipment and ancillary systems or sub-systems have been commissioned correctly and that

all future operations will be reliable and within prescribed or specified operating limits.

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5. 安装和运行确认

药品生产过程中所用到设备的安装确认和运行确认的建议 5.1 原则 运行确认

5.1.1 安装确认和运行确认通过适当的性能测试和相关的文件与记录确保设备和辅助系统或子系统都是正确的，将来的所有操作都是可靠的，都会在规定或指定的操作范围内。 5.1.2 These Recommendations outline the principles and basic requirements for the Installation and Operational Qualification of systems or subsystems (equipment) including support systems used in the manufacture of all pharmaceutical products, (including active pharmaceutical ingredients) (APIs). The

Recommendations are intended to cover installation and operation of new or modified systems or sub-systems.

5.1.3 The detail and scope of a qualification exercise is in many respects related to the complexity of the equipment involved and the critical nature of that

equipment with respect to the quality of the final product. Nevertheless, the basic principles should be adhered to whether it is the installation and operation of a simple piece of equipment or an autoclave.

5.1.2 这些建议概述了所有药品生产(包括原料药API)过程中所用到的系统，或子系统(设备)包括支持系统的安装确认和运行确认的基本原则和基本要求。这些建议涵盖了新建或改造系统或子系统的安装和运行。

5.1.3 确认的详细程度和范围在很多方面是和所涉及设备的复杂性及设备能影响药品质量的关键属性息息相关的。然而，无论是设备的简单零件或是一个高压锅的安装和操作都应当要遵从这些基本原则。

5.1.4 The basic principles are as follows:

(a) The equipment should be correctly installed in accordance with an installation plan, as per supplier and any special (purchaser) requirements,

(b) The requirements for calibration, maintenance and cleaning developed as draft procedures should be reviewed and finally issued as authorised standard operating procedures (SOPs) as part of the SOP programme of the company,

(c) Operating requirements should be established and tests conducted to assure equipment is operating correctly, under normal and “worst case” conditions,

(d) Operator training requirements pertaining to the new equipment should be finalised and documented.

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5.1.4 基本原则如下：

(a) 设备的安装应当要符合安装设计(Installation Plan),需根据供应商的要求或其它特定要求进行正确地安装。

(b) 草拟校验，维护和清洗要求的程序，并对其进行审阅，最终批准作为正式的标准操作规程(SOP)，成为公司SOP系统的一部分。

(c) 确立正确的操作要求，并要进行检测确保设备在正常情况下和“最坏情况”下都能得到正确地运行。

(d) 对于新的设备，应当要确立操作者培训要求，并形成文件。

5.1.5 At various stages in a validation exercise there is need for protocols, documentation, procedures, equipment, specifications, acceptance criteria for test results to be reviewed, checked and authorised. It would be expected that representatives of the main professional disciplines, e.g. Engineering, Research & Development, Manufacturing, Quality Control and Quality Assurance, involved in manufacture are actively involved in these undertakings with the final authorisation given by a validation committee or the Quality Assurance representative.

5.1.5 在实施验证的每个阶段，都需要对具体方案，文件，程序，设备，质量标准，检测结果的合格标准进行审阅，复核和批准。希望在生产过程中所涉及到的主要部门比如工程部，研发部，生产部，QC和QA的人员，经过验证委员会或QA的批准后，能积极地参与到验证中来。

5.2 Installation Qualification (l.Q.) - Overview Statement

5.2.1 Installation Qualification is an essential step preceding the Process Validation exercise. It is normally executed by the Engineering group. The installation of equipment, piping, services and instrumentation is undertaken and checked to engineering drawings Piping & Instrument Diagrams, (P&IDs) and Plant functional Specifications developed during the project planning stage. During the project planning stage, Installation Qualification should involve the identification of all system elements, service conduits and gauges and the preparation of a documented record that all installed equipment satisfies the planned requirements.

5.2.2 Identification and documenting of maintenance requirements for each installed item and the collection and collation of supplier operating and working

instructions, maintenance and cleaning requirements, should form the minimum documentation for a satisfactory Installation Qualification. 5.2 安装确认 (IQ) - 概述

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5.2.1 安装确认是在工艺验证前所必需要完成的工作。它通常是由工程部门来实施完成的。需根据工程管路图和在项目规划阶段开发的工厂功能标准来进行设备，管路，维护和仪器的安装与核查。安装确认(IQ)应当要包括系统各个部分，管路和仪表的标识及所有安装好的设备符合既定要求的书面记录。

5.2.2 确定每个已安装设备的维护要求，并形成文件。收集和比较供应商的操作的工作手册，维护和清洗要求。这些都是一个合格的安装确认所必要的文件。

5.3 Installation Qualification - Essential Elements Installation of Equipment

5.3.1. The installation of equipment singularly or as a group (plant) should follow well defined plans. The plans will have been developed and finalised following progression through a number of design stages. The plans will normally be available and documented as Equipment Specifications, Plant functional

Specifications and Piping & Instrument Diagrams (P&IDs). During the design stage, an effective Change Management procedure should be in place. All changes to the original design criteria should be documented and after that, appropriate modifications made to Equipment Specifications, Plant functional Specifications and Piping & Instrument Diagrams (P&IDs).

5.3.2 During the final phases of the design stage the facilities and equipment necessary for calibration requirements will need to be identified. 5.3 安装确认 - 必备项 设备的安装

5.3.1 无论是单个设备的安装，还是一组设备的安装，都应当要符合确定的规划。这个规划是根据一系列的设计阶段的进展而发展起来，并最终确定的。这个规划通常会被写成设备标准，工厂功能标准和管路和设备图。在设计阶段，应当要有有效的变更管理程序。对原有的设计标准进行了任一更改，都应进行记录，并要对设备标准，工厂功能标准及管路和设备图做相应的更新。

5.3.2 在设计阶段的后期，应当要标明需要进行校验的设施和设备。

Calibration Requirements

5.3.3 (a) confirmation of calibration of calibrating equipment with reference to the appropriate national standard,

(b) calibration of measuring devices utilised in the Operational Qualification stage, where confirmation of calibration is unavailable,

(c) calibration of measuring devices related to installed equipment,

(d) identification of calibration requirements for measuring devices for the future use of the equipment. 校准要求

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5.3.3 (a) 确认已根据合适的国家标准对校准设备进行了校准。 (b) 对运行确认(OQ)阶段所用到的计量装置进行校准。 (c) 对和已安装的设备有关的计量装置进行校准。

(d)设备在以后使用过程中所用到的计量装置的校准要求需要确定。

Checking of Suppliers

5.3.4 For complicated or large pieces of equipment, a pharmaceutical manufacturer may elect to undertake a pre-delivery check of the equipment at the supplier's assembly facility, this pre-delivery check cannot substitute for the Installation Qualification. However, it is acknowledged that the checks conducted and documented at this stage may duplicate a number of the checks conducted at the Installation Qualification stage, hence, there could be a reduction in the scope of the Installation Qualification checks. 供应商的核查

5.3.4 对于复杂的或是大件的设备，制药企业可能会选择去供应商的组装车间对设备进行发货前的核查，但发货前的核查并不能代替安装确认。然而，这个阶段所用的核查和整理的文件可能会和在安装确认(IQ)阶段所做的一些核查是一样，因此，在可能适当减少一些安装确认的核查工作。

Checking at Users

5.3.5 Installation Qualification requires a formal and systematic check of all installed equipment against the equipment supplier's specifications and additional criteria identified by the user as part of the purchase specifications. At the Installation Qualification, all equipment, gauges and services should be given a serial (or other reference) number and a check conducted that the installed equipment (or plant) has been installed in accord with the current (approved) version of the Piping & Instrument Diagram (P&ID).

5.3.6 Confirmation of compliance of the operating criteria for the equipment, as installed, with the Plant functional Specifications and Process Flow Diagrams should be documented. 用户的核查

5.3.5 安装确认(IQ)需要根据设备供应商的质量标准和用户采购标准对所有的已安装设备进行正式系统的核查。在安装确认时，所有的设备，仪表和维修设备都应当要有标识号，并核查已安装的设备(或工厂)是安照现行已批准的设备图进行安装的。

5.3.6 要有文件说明确认了已安装设备与工厂功能标准和工艺流程图之间的一致性。 Installation Qualification

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5.3.7 At the Installation Qualification stage the company should document preventative maintenance requirements for installed equipment. At this stage new equipment and the preventative maintenance requirements should be added to the preventative maintenance schedule of the pharmaceutical manufacturer. Cleaning, including sanitisation and/or sterilisation requirements for the

equipment, should be developed in draft documentation form from equipment supplier specifications and operating procedures. The draft cleaning

documentation should be finalised following experience and observation at the Operational Qualification stage and then verified at the Performance Qualification stage. 安装确认 (IQ)

5.3.7 在安装确认阶段，公司应当要将安装设备的预防性维护要求整理成文件。在这个阶段，应当要将新设备和预防性维护要求添加到制药企业的预防性维护计划中去。应当要根据设备供应商规格和操作规程草拟设备的清洗要求，包括消毒和/或无菌要求。经过运行确认(OQ)的观察和性能确认(PQ)阶段的的确认之后，应将草拟的设备清洗要求正式确定。 5.4 Operational Qualification (O.Q) - Overview Statement

5.4.1 Operational Qualification is an exercise oriented to the engineering function, generally referred to as commissioning. Studies on the critical variables

(parameters) of the operation of the equipment or systems will define the critical characteristics for operation of the system or sub-system. All testing equipment should be identified and calibrated before use. Test methods should be authorised, implemented and resulting data collected and evaluated.

5.4.2 It is important at this stage to assure all operational test data conform with pre-determined acceptance criteria for the studies undertaken.

5.4 运行确认 (OQ) - 概述

5.4.1 运行运行确认是项调整技术功能的工作，通常被称之为试运行(commissioning)。 进行设备或系统操作的关键变量的研究，确定系统或子系统操作的关键性质。所用的检测设备在使用前都应进行标识和校验。批准和执行检测方法，并对检测结果进收集和评估。 5.4.2 在这个阶段，确保所有操作的检测结果符合预定的合格标准是很重要的。

5.4.3 It is expected that during the Operational Qualification stage the manufacturer

should develop draft standard operating procedures (SOPs) for the equipmentand services operation, cleaning activities, maintenance requirements and calibration schedules.

5.4.4 An effective change control procedure should be operational and encompass the whole project from the pre-planning stage through to the final acceptance of the Process Validation exercise.

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5.4.3 在运行运行确认阶段，期望生产厂家能草拟出设备和维护计划，清洗活动，维护要求和校验计划的标准操作规程。

5.4.4 应当要有切实可行的变更控制程序在运行，涵盖整个项目的所有过过程，从预规划阶段到最终的工艺验证合格。

5.5 Operational Qualification - Essential Elements

5.5.1 The conduct of an Operational Qualification should follow an authorised protocol. The critical operating parameters for the equipment or the plant should be identified at the Operational Qualification stage. The plans for the Operational Qualification should identify the studies to be undertaken on the critical variables, the sequence of those studies and the measuring equipment to be used and the acceptance criteria to be met. Studies on the critical variables should

incorporate specific details and tests that have been developed from specialist knowledge of the process and how the equipment will work (defined in design criteria and specifications).

5.5 运行运行确认(OQ) - 必备项

5.5.1 应当按照已批准的方案进行运行运行确认。在运行确认阶段应当要确认设备或工厂的关键参数。运行运行确认计划应当要确定这些内容：需对关键变量进行哪些研究，这些研究的先后顺序，要用到的测量设备，所要符合的合格标准。关键变量的研究应当要包括细节和检测及设备是如何工作的（这在设计标准中应有定义）。

5.5.2 Where applicable, simulated product may be used to conduct the Operational Qualification. Studies on the critical variables should include a condition or a set of conditions encompassing upper and lower processing or operating limits and circumstances; commonly referred to as \"worst case\" conditions. Such conditions should not necessarily induce product or process failure.

5.5.2 如果可行的话，在进行运行运行确认时应当要采用模拟产品。关键变量的研究应当要包括一系列条件，包括操作的上下限和环境，通常被称之为“最坏情况”条件。这些条件不表示是导致产品不合格或工艺失败的条件。

5.5.3 The completion of a successful Operational Qualification should allow the finalisation of operating procedures and operator instructions documentation for the equipment. This information should be used as the basis for training of operators in the requirements for satisfactory operation of the equipment.

5.5.4 Draft cleaning procedures developed at the lnstallation Qualification stage should be finalised after a satisfactory Operational Qualification exercise and issued as standard operating procedures (SOPs). Where applicable, these

procedures should be validated as part of the Performance Qualification phase.

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5.5.3 成功完成运行确认之后应当可以确定设备的操作规程和操作者指南。这些资料是对操作者进行培训的基础，使操作者能成功的操作设备。

5.5.4 安装确认阶段所起草的清洗程序，在成功完成运行确认之后，也定当得以确定，成为正式的SOP。如果可行的话，这些SOP应当在性能确认(PQ)阶段进行验证。 5.5.5 The completion of satisfactory lnstallation Qualification and Operational Qualification exercises should permit a formal \"release\" of the equipment/plant for the next stage in the validation exercise (Process Validation). The release should not proceed unless calibration, cleaning, preventative maintenance and operator training requirements have been finalised and documented. The release should take the form of written authorisations for both Installation Qualification and Operational Qualification.

5.5.5 在成功完成安装确认和运行运行确认工作之后，设备就可以准许正式进入下一个阶段的验证工作中去了(工艺验证)。在准许之前，应当要完成校准，清洗，预防性维护和操作者培训及其相应文件。准许时应当要有安装确认和运行确认的书面批准件。 5.6 Re-Qualification

5.6.1 Modifications to, or relocation of, equipment should only follow satisfactory review and authorisation of the documented change proposal through the change control procedure. Part of the review procedure should include

consideration of re-qualification of the equipment. Minor changes or changes having no direct impact on final or in-process product quality should be handled through the documentation system of the preventative maintenance programme. 5.6 再确认

5.6.1 只有根据变更控制程序对将要进行的变更进行了充份的评审和批准之后，才能进行设备的更改和移位。评审程序应当要考虑设备的再确认。对于细小变更或对最终产品或中间产品质量没有直接影响的变更，应当通过预防性维护程序的文件体系进行处理。 5.7 Qualification of Established (in-use) Equipment

5.7.1 While it is not possible to undertake the details of an Installation Qualification for established equipment nor the detailed approach for an Operational

Qualification, nevertheless there should be data available that 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 for the use of the

equipment should be documented and in use as standard operating procedures (SOPs).

5.7 已有(使用中)设备的确认

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5.7.1 当不可能对已有设备进行具体的安装或运行确认的话，也应当要有资料支持和确证设备关键变量的操作参数和限度范围。此外，应当要书面的设备校准，清洗，预防性维护，操作规程和操作者培训程序，作为有相应的操作SOP。

6. NON-STERILE PROCESS VALIDATION 6.1 Principle

Process Validation is the means of ensuring, and providing documentary evidence that processes(within their specified design parameters) are capable of repeatedly and reliably producing a finished product of the required quality. The requirements and principles outlined in these recommendations are applicable to the manufacture and packaging of non-sterile pharmaceutical dosage forms. They cover the initial validation of new processes, subsequent validation of modified processes and Re-validation. 6. 非无菌工艺验证 6.1 基本原则

工艺验证是确保工艺(在指定的设计参数范围内)有能力持续地，可靠地生产出符合所需质量的产品的一种方法，并提供书面证明性资料。这些建议中所概述的的要求和基本原则适用于非无菌剂型的生产和包装。包括新工艺的初验证，更新工艺的后续验证和再验证。 6.2 General

6.2.1 Any manufacturing or packaging process will involve a number of factors that may affect product quality. These factors will be identified during the

development of a product and will facilitate process optimisation studies. On completion of development and optimisation, Process Validation provides a structured way of assessing methodically the factors that impact on the final product.

6.2.2 It would normally be expected that Process Validation be completed prior to the manufacture of finished product that is intended for sale (Prospective Validation). Where this is not possible, it may be necessary to validate

processes during routine production (Concurrent Validation). Processes which have been in use for some time should also be validated (Retrospective Validation). 6.2 基本要求

6.2.1 任一生产工艺或包装工艺都会涉及一系列可能会影响产品质量的因素。在产品的开发和工艺优化研究阶段应确定这些因素。在完成了开发和优化之后，工艺验证提供了结构化的方式对那些会影响最终产品质量的因素进行了系统评估。

6.2.2 通常希望在商业批生产之前就完成工艺验证(前瞻性验证)。如果不能实现的话，则需要对在日常生产中对工艺进行验证(同步验证)。已经生产了一定时间的工艺也是需要验证的。(回顾性验证)

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6.2.3 In theory a validation exercise should only need to be carried out once for any given process. In practice however the process rarely remains static. Changes occur in components (raw materials and packaging materials), equipment is modified and the process environment cannot be assumed to remain as during the initial validation. A regular programme of Re-validation is essential.

6.2.4 The company's policy and approach to Process Validation should be clearly defined.

6.2.3 从理论上说，任一工艺只需进行一次验证。但实际上工艺很难保持不变。比如说，组分发生了变化(原辅料和包装材料)，设备发生了更改，工艺环境不能保持和初验证时的一样。所以定期进行再验证是必要的。 6.2.4 需明确确定公司的工艺验证方针和方法。

6.3 Prospective Validation

6.3.1 During product development the production process should be broken down into individual steps. Each step should be evaluated on the basis of experience or theoretical considerations to determine the critical factors/parameters that may affect the quality of the finished product.

6.3.2 A series of experiments should be devised to determine the criticality of these factors. Representatives from Production, QC/QA, Engineering, and in some cases Research and Development will normally be involved in this process. These experiments may incorporate a challenge element to determine the

robustness of the process. Such a challenge is generally referred to as a \"worst case\" exercise. The use of starting materials on the extremes of the

specification may indicate the ability of the process to continue producing finished product to the required specification. 6.3 回顾性验证

6.3.1 在产品开发阶段需将生产工艺各个步骤分开。对于每个步骤，都应当要更据实际经验和理论来确定可能会影响最终产品质量的关键因素和参数。

6.3.2 需设计一系列的实验来确定这些因素的的关键性。在这个过程中，需要生产人员，QC/QA，工程人员参与进来，有时候还需要开发部门人员的参与。这些实验可能需要对某个因素进行挑战，以确定工艺的耐用性。这种挑战通常被称之为“最坏情况”运行。使用处于质量标准合格边缘的起始物质会指示出工艺持续生产出合格产品的能力。 6.3.3 Each experiment should be planned and documented fully in an authorised protocol. This document will have the following elements: (a) A description of the process, (b) A description of the experiment,

(c) Details of the equipment/facilities to be used (including

measuring / recording equipment) together with its calibration status, (d) The variables to be monitored,

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(e) The samples to be taken - where, when, how and how many,

(f) The product performance characteristics/attributes to be monitored,together with the test methods,

(g) The acceptable limits, (h) Time schedules,

(i) Personnel responsibilities,

(j) Details of methods for recording and evaluating results, including statistical analysis.

6.3.3 每个实验都应当完全按照已批准的具体方案进行安排，并整理成文件。这个文件应当包括如下元素： (a) 工艺描述， (b) 实验描述，

(c) 所用设备/设施(包括测量/记录设备)的详细描述，及其校验状态。 (d) 要监控的变量，

(e) 取样 - 何处，何时，如何和样品数量， (f) 需监控的产品性能/属性指标，及其检测方法， (g) 接收标准， (h) 时间安排， (i) 人员职责，

(j) 记录方法和评估结果的详述，包括统计分析。

6.3.4 All equipment, the production environment and analytical testing methods to be used should have been fully validated, (Installation/ Operational Qualification). Staff taking part in the validation work should have been appropriately trained. In practice, Operational Qualification may be carried out using batches of actual product. This work may also fulfil the requirements of Prospective Validation. This approach to validation should not be adopted as a standard practice however.

6.3.5 Master Batch Documentation can be prepared only after the critical parameters of the process have been identified and machine settings, component specifications and environmental conditions have been determined.

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6.3.4 所有的设备，生产环境和分析方法都应当要经过充分的验证,（安装确认/运行确认）。所有参与验证工作的人员都要得到适当的培训。实际上，运行确认是可以采用实际产品批次的。这项工作也符合前瞻性验证的要求。但是这种验证方法并不是标准规范。 6.3.5 只有在确定了关键工艺参数，设备到位，原料质量标准和环境参数确立之后，才可以准备主批记录(Master Batch Documentation)。

6.3.6 Using this defined process (including specified components) a series of batches of the final product should be produced. 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, giving product of the desired

quality would constitute a proper validation of the process. In practice, it may take some considerable time to accumulate this data.

6.3.6 应当要用这个指定的生产工艺连续生产几批最终产品。理论上，工艺运行的次数和观察应当要足以建立变量的正常范围和趋势，并提供足够的数据用于评估。一般认为根据最终批准的参数进行生产的三个连续批号，能有合格的质量的话，就可以形成一个适当的工艺验证。实际上，这可能会需要相当的时间来积累这些数据。

6.3.7 It is preferred that the batches made should be the same size as the intended batch size for full scale production. This may not always be practical due to a shortage of available starting materials and in such cases the effect of the reduced batch size should be considered in the design of the protocol. When full scale production starts, the validity of any assumptions made should be demonstrated.

6.3.8 During the processing of the batch/run, extensive testing should be performed on the product at various stages. Detailed testing should also be done on the final product and its package.

6.3.7 最好是批量要和计划中的大生产的批量大小要一致。有时候会遇到起始物质短缺的情况，这种情况下，在方案设计中应当要考虑批量减少的影响。一旦开始了大生产，所有假设的正确性都应当要得到阐述。

6.3.8 在批生产过程中，每个阶段都应当要进行足够的检测。对最终产品和包装也要进行全面的检测。

6.3.9 The batches/runs under validation should be documented comprehensively. The following items should be included in the validation report:

(a) A description of the process - Batch/Packaging Document, including details of critical steps,

(b) A detailed summary of the results obtained from in-process and final testing, including data from failed tests. When raw data are not included reference should be made to the sources used and where it can be

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found,

(c) Any work done in addition to that specified in the protocol or any deviations from the protocol should be formally noted along with an explanation,

(d) A review and comparison of the results with those expected, (e) Formal acceptance/rejection of the work by the team/persons

designated as being responsible for the validation, after completion of any corrective action or repeated work.

6.3.9 被验证的批次，其相关的文件应当要很充分。在验证报告中应当要包括如下内容： (a) 工艺描述 - 批文件/包装文件，包括关键步骤的详细描述，

(b) 概述从过程控制和最终检测中所获得的检测结果，需包括不合格的。当原始数据没有包括在其中时，应该要有其参引号，并标明其保管在何处。

(c) 对于所有方案之外所做的工作和偏差都应当记录在案，并对其进行解释。 (d) 对结果进行审核，并和期望值进行比较。

(e) 在完成了整改工作或重做工作之后，验证负责委员会/人应当要对验证工作给出一个合格/不合格的正式结论。

6.3.10 Upon completion of the review, recommendations should be made on the extent of monitoring and the in-process controls necessary for routine production. These should be incorporated into the Batch Manufacturing or Packaging Record or into appropriate standard operating procedures (SOPs). Limits,

frequencies and actions to be taken in the event of the limits being exceeded should be specified.

6.3.10 在完成了评审的基础上，需对日常生产中所需的过程控制和监控程序给出建议。这些会作为批生产或包装记录的一部分，或者写成标准操作规程(SOP)。还要说明限度，频次，及一旦出现了超出限度，所要采取的措施。

6.3.11 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 and the Marketing Authorisation (if applicable). The premises used should be named on a Manufacturing Authorisation and this Authorisation should allow the manufacture/assembly of the particular type of product. Where appropriate, the batch must be formally certified by a Qualified Person before release.

6.3.11 如果验证批是要销售的话，则其生产的条件要完全符合GMP和制剂上市许可(如果可行的话)要求。在制剂上市许可中会标明所用的车间，该制剂上市许可将允许某一特定剂型的生产。如果合适的话，这些批次在放行之前需经过有资格人员的正式确认。 6.4 Concurrent Validation

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6.4.1 In certain circumstances it may not be possible to complete a validation

programme before routine production starts. In these cases it will be known in advance that the finished product will be for sale or supply. Circumstances

where this is likely are, for example, when a process is being transferred to a third party contract manufacturer/assembler. 6.4 同步验证

6.4.1 在有些情况下，在开始日常生产之前，不能完成验证项目。在这些情况下，是会事先知道这些制剂是要销售的。这些情况往往是工艺边转让给第三方合同生产者/装配者。 6.4.2 In addition there are many instances when it is appropriate to validate a process during routine production. Such instances are, for example, where the product

is a different strength of a previously validated product, a different tablet shape or where the process is well understood.

6.4.2 此外，有很多情况下，在正常生产中对工艺进行验证也是合适的。这些情况有，比如说，先前已验证制剂的剂量发生了改变，片剂形状发生了改变。

6.4.3 It is important in these cases however, that the premises and equipment to be used have been validated previously and that the decision to carry out Concurrent Validation is made by appropriately authorised people.

6.4.4 Documentation requirements are the same as specified for Prospective Validation and the testing to be carried out in-process and on the finished

product will be as specified in approved protocols. The completed protocols and reports should be reviewed and approved before product is released for sale or supply.

6.4.3 在这些情况下，重要的是所用的车间和设备在这之前要已经验证过，且要由有足够权威的人员给出进行同步验证的决定。

6.4.4 在文件方面的要求是和前瞻性验证的要求是一样的，在方案中需指明过程控制检测项目和最终产品的检测项目。在产品销售之前，完整的方案和报告需审阅并批准。 6.5 Retrospective Validation

6.5.1 There are many processes in routine use in many companies that have not undergone a formally documented validation process.

6.5.2 Validation of these processes is possible, using historical data to provide the necessary documentary evidence that the process is doing what it is believed to do. The steps involved in this type of validation still require the preparation of a protocol, the reporting of the results of the data review, leading to a conclusion and recommendation. 6.5 回顾性验证

6.5.1 在许多公司，日常生产的很多工艺都没有进行过正式的备有证明文件的工艺验证。 6.5.2 对这些工艺进行验证是可能的，通过历史资料提供必要的书面证据说明所用的工艺是可靠的。该类验证所涉及的步骤包括制订方案，实验结果审评报告，给出结论和建议。 6.5.3 This type of validation exercise is only acceptable for well established processes and will be inappropriate where there have been recent changes in the

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composition of the product, operating procedures or equipment.

6.5.4 The source of data for this validation may include batch documents, process control charts, maintenance log books, records of personnel changes, process capability studies (reflected in a CpK),finished product data, including trend cards, and storage stability results.

6.5.3 这类验证只适用于完善的工艺，若最近对产品的组成，操作程序或设备进行了更改，则该类验证就不适用了。

6.5.4 这类验证所需的资料来源包括，批文件，工艺控制流程，维护日志，人员变更记录，工艺能力研究，最终产品的资料，还包括趋势卡和稳定性研究结果。

6.6 Re-validation

6.6.1 Re-validation provides the evidence that changes in a process and/or the process environment, introduced either intentionally or unintentionally, do not adversely affect process characteristics and product quality. 6.6 再验证

6.6.1 再验证提供了证据说明工艺和/或工艺环境的变化，无论是有意的或是无意的，都不会对工艺特点和产品质量产生负面影响。

6.6.2 There are two basic categories of Re-validation:

(a) Re-validation in cases of known change (including transfer of processes from one company to another or from one site to another), (b) Periodic Re-validation carried out at scheduled intervals. 6.6.2 再验证的的两大类型：

(a) 当发生了已知变更时进行再验证(包括将工艺转让给另一个公司，或从一个生产地点移到另一个生产地点)，

(b) 在一定的时间间隔进行阶段性再验证。

6.6.3 A system should be in place (refer to Validation Master Plan requirements) to ensure both situations are addressed. Documentation requirements will be the same as for the initial validation of the process, and in many cases similar protocols can be employed.

6.6.4 The definition of what constitutes a change to a process or process environment needs to be agreed. Guidance on this is given below.

6.6.3 要有适当的系统来保证这两种情况下再验证的进行。文件要求和工艺最初的验证相同，在很多情况下所用的方案也是类似的。

6.6.4 需对工艺和工艺环境的变更进行定义，详述如下。

6.6.5 The need for periodic Re-validation of non-sterile processes is considered to be a lower priority than for sterile processes. In the case of standard processes on conventional equipment a data review similar to what would be required for Retrospective Validation may provide an adequate assurance that the process continues under control. In addition the following points should also be considered:

(a) The occurrence of any changes in the master formula, methods or

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starting material manufacturer,

(b) Equipment calibrations carried out according to the established programme,

(c) Preventative maintenance carried out according to the programme, (d) Standard operating procedures (SOPs) up to date and being followed, (e) Cleaning and hygiene programme still appropriate,

(f) Unplanned changes or maintenance to equipment or instruments.

6.6.5 非无菌工艺的阶段性再验证的必要性要低于无菌工艺。如果是在传统设备上所行的标准工艺，类似于回顾性验证所需要的资料评审就可以足以确保工艺仍然是能得到控制的。此外，还需考虑如下这些：

(a) 配方，起始物质生产商所用的方法所发生的变更。 (b) 根据已建立的程序进行的设备校准。 (c) 根据程序进行的预防性维护。 (d) 最新的和所遵循的SOP。 (e) 仍然适用的清洗和卫生程序。 (f) 设备和仪器的计划外变更或维护。

6.7 Change Control

6.7.1 Change control is an important element in any Quality Assurance system. Written procedures should be in place to describe the actions to be taken if a change is proposed to a product component, process equipment, process

environment (or site), method of production or testing or any other change that may affect product quality or support system operation. 6.7 变更控制

6.7.1 变更控制在任一质量保证体系中都是一个重要的因素。对于任何要对产品组分，工艺设备，工艺环境（地点），制备方法，检测方法进行的更改或其它任何可能会对产品质量或支持系统操作产生负面影响的变更，都应当要有书面的程序规定所要采取的措施。 6.7.2 All changes should be formally requested, documented and accepted by representatives of Production, QC/QA, R&D, Engineering and Regulatory Affairs as appropriate. The likely impact (risk assessment) of the change on the

product should be evaluated and the need for, and the extent of Re-validation discussed. The change control system should ensure that all notified or requested changes are satisfactorily investigated, documented and authorised.

6.7.3 Products made by processes subjected to changes should not be released for sale without full awareness and consideration of the change by responsible staff, including (where appropriate) the Qualified Person.

6.7.2 所有的变更都应当要由生产部，QC/QA，R&D, 工程部和法规事务部的代表正式提出，整理成文件并认可。应对很有可能产生的影响（风险评估）进行评估，并讨论再验证的必要性和所需进行的程度。变更控制系统应确保所有变更都得到了很好的研究，文件化和批准。

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6.7.3 根据变更了的工艺生产出来的产品，若负责人员对变更并不完全知情或没有进行充分考虑，是不能批准销售的。

6.7.4 Changes that are likely to require Re-validation are as follows: (a) Changes of raw materials (physical properties such as density, viscosity, particle size distribution may affect the process or product), (b) Change of starting material manufacturer,

(c) Changes of packaging material (e.g. substituting plastic for glass), (d) Changes in the process (e.g. mixing times, drying temperatures),

(e) Changes in the equipment (e.g. addition of automatic detection systems). Changes of equipment which involve the replacement of

equipment on a 'like for like' basis would not normally require a Revalidation, (f) Production area and support system changes (e.g. rearrangement of areas, new water treatment method),

(g) Transfer of processes to another site,

(h) Unexpected changes (e.g. those observed during self-inspection or during routine analysis of process trend data). 6.7.4 需要再验证的变更如下：

(a) 原料的变更（物理性质，比如密度，粘性，粒径分布等，是会影响到工艺或产品的）， (b) 起始原料生产者的变更，

(c) 包装材料的变更（比如用塑料的换玻璃的）， (d) 工艺的变更（比如，搅拌次数，干燥温度），

(e) 设备的变更（如增加了自动检测系统）。类似设备的变更一般不需要进行再验证。 (f) 生产区域和支持系统发生的变更（如区域的重新安排，新的水处理方法）。 (g) 工艺转移到另一个地点

(h) 不期望的变更（如在自检或工艺趋势资料日常分析中所发现的）。

7. CLEANING VALIDATION 7.1 Principle

7.1.1 Pharmaceutical products and active pharmaceutical ingredients (APIs) can be contaminated by other pharmaceutical products or APIs, by cleaning agents, by micro-organisms or by other material (e.g. air-borne particles, dust, lubricants, raw materials, intermediates, auxiliaries). In many cases, the same equipment may be used for processing different products. To avoid contamination of the following pharmaceutical product, adequate cleaning procedures are essential. 7. 清洗验证 7.1 原则

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7.1.1 其它的制剂或原料药，清洗剂，微生物或其它物料(如空气浮尘，灰尘，润滑剂，原料，中间体，辅剂等)都可能会污染制剂或原料药。在很多情况下，同一设备用于多个产品的生产。为了避免对后续产品产生污染，充分的清洗程序是必要的。

7.1.2 Cleaning procedures must strictly follow carefully established and validated methods of execution. This applies equally to the manufacture of

pharmaceutical products and active pharmaceutical ingredients (APIs). In any case, manufacturing processes have to be designed and carried out in a way that contamination is reduced to an acceptable level.

7.1.3 Cleaning Validation is documented evidence that an approved cleaning procedure will provide equipment which is suitable for processing of pharmaceutical products or active pharmaceutical ingredients (APIs).

7.1.2 清洗程序应该要严格遵守慎重建立并验证过的实施方法。制剂生产和原料药生产在这方面的要求是一样的。无论如何，在生产工艺的设计和实施过程中，应当要尽量减少污染，使其降到合格水平。

7.1.3 清洗验证是一书面证据，说明已批准的清洗程序能使设备适用于制剂或原料药的生产。

7.1.4 Objective of the Cleaning Validation is the confirmation of a reliable cleaning procedure so that the analytical monitoring may be omitted or reduced to a minimum in the routine phase.

7.1.4 清洗验证的目的在于确认清洗程序是可靠的，这样可以将日常分析监测工作省略或减少到最少。

7.2 Purpose and Scope

7.2.1 These Recommendations describe the validation of cleaning procedures for the removal of contaminants associated with the previous products, residues of cleaning agents as well as the control of potential microbial contaminants.

7.2.2 These Recommendations apply to the manufacture of pharmaceutical products (final dosage forms) and of active pharmaceutical ingredients (APIs). 7.2 目的和范围

7.2.1 这些建议对清洗程序验证进行了叙述，清洗程序的目的在于去除前一产品、清洗剂的残留及控制潜在的微生物污染。

7.2.2 这些建议适用于制剂和原料药的生产。

7.3 General

7.3.1 Normally only cleaning procedures for product contact surfaces of the equipment need to be validated. Consideration should be given to non-contact parts into which product may migrate. For example, seals, flanges, mixing shaft,

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fans of ovens, heating elements etc. 7.3 总则

7.3.1 通常，只需对于接触产品的设备表面的清洗程序进行验证的。对于非直接接触，但产品有可能会移动进去的部位，也要进行考虑。比如说，封口，法兰，搅拌轴，烘箱风扇，加热元件等)。

7.3.2 Cleaning procedures for product changeover in the case of marketed products should be fully validated.

7.3.3 Generally in case of batch-to-batch production it is not necessary to clean after each batch. However, cleaning intervals and methods should be determined. 7.3.2 对于销售产品的交替生产，其清洗程序要得到充分的验证。

7.3.3 通常来说，如果是同一产品的连续生产，则不需要每批生产之后都要进行一次清洗，则可确定一定的时间间隔和清洗方法。

7.3.4 Several questions should be addressed when evaluating the cleaning process. For example:

Ø At what point does a piece of equipment or system become clean? Ø What does visually clean mean?

Ø Does the equipment need to be scrubbed by hand?

Ø What is accomplished by hand scrubbing rather than just a solvent wash? Ø How variable are manual cleaning processes from batch to batch and product to product?

Ø What is the most appropriate solvent or detergent?

Ø Are different cleaning processes required for different products in contact with a piece of equipment?

Ø How many times need a cleaning process be applied to ensure adequate cleaning of each piece of equipment?

7.3.4 在对一清洗程序进行评估时，有几个问题是需说明的，比如： - 在何点开始对设备或系统进行清洗？ - 表面清洗(Visually Clean)指的是什么？ - 是否需要对设备进行手工擦洗？

- 用溶剂洗了之后，还要进行手工擦洗，其目的在于什么？ - 人工清洗程序在批与批之间和产品与产品之间是如何变化的？ - 最适合的溶剂或清洁剂是什么？

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- 对于同一设备，生产了不同的产品是否需要不同的清洗程序？ - 清洗过程需进行几次才可以确保设备的每个零件都得到了充分的清洗？

7.3.5 Cleaning procedures for products and processes which are very similar, do not need to be individually validated. It is considered acceptable to select a

representative range of similar products and processes concerned and to justify a validation programme which addresses the critical issues relating to the selected products and processes. A single validation study under consideration of the “worst case” can then be carried out which takes account of the relevant criteria. This practice is termed \"Bracketing\".

7.3.6 At least three consecutive applications of the cleaning procedure should be performed and shown to be successful in order to prove that the method is validated.

7.3.5 类似产品和类似工艺的清洗程序是不需要逐个进行验证的。可行的方法是为这些类似产品和类似工艺选择一个有代表性的范围，然后根据所选产品和工艺的相关关键问题确定一合理的验证方案。再考虑相关合格标准的基础上，则单独开展“最坏情况”的验证研究。这类验证工作也被称之为“括号法”。

7.3.6 一清洗程序至少要成功应用于三个连续批号，才能说其是已经验证的。 7.3.7 Raw materials sourced from different suppliers may have different physical properties and impurity profiles. Such differences should be considered when designing cleaning procedures, as the materials may behave differently.

7.3.8 Control of change to validated cleaning procedures is required. Re-validation should be considered under the following circumstances:

(a) Re-validation in cases of changes to equipment, products or processes, (b) Periodic Re-validation at defined intervals.

7.3.7 来自于不同供应商的原料可能会有不同的物理性质和杂质情况。因此在设计清洗程序时，要考虑到这些差异。

7.3.8 已验证清洗程序的变更控制是必要的。在下面这些情况下应当要考虑再验证： (a) 设备，产品或工艺发生了更改

(b) 在一定时间间隔进行的阶段性再验证。

7.3.9 Manual methods should be reassessed at more frequent intervals than clean-inplace (CIP) systems.

7.3.10 It is usually not considered acceptable to \"test until clean\". This concept involves cleaning, sampling and testing, with repetition of this sequence until an acceptable residue limit is attained. For the system or equipment with a validated cleaning process, this practice of \"test until clean\" should not be

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required. The practice of \"test until clean\" is not considered to replace the need to validate cleaning procedures.

7.3.9 人工清洗应当要比在线清洗系统（CIP system））））））））更多的进行重评估。 7.3.10 一般认为“测试到通过清洗”“Test until clean\"是不可行的。这个概念涉及到清洗，取样和检测，并一直重复到残留量达到了合格限度。对于已有验证过清洗程序的系统或设备，则不需要“测试到通过清洗”“Test until clean\".。“测试到通过清洗”“Test until clean\"不能用来代替清洗程序验证。

7.3.11 Products which simulate the physicochemical properties of the substance to be removed may be used instead of the substances themselves, where such substances are either toxic or hazardous.

7.3.11 当所涉及的产品是有毒的或高危的，则可用具有类似物理性质的产品来代替这些产品本身。

7.4 Documentation

7.4.1 A Cleaning Validation Protocol is required laying down the procedure on how the cleaning process will be validated. It should include the following: Ø The objective of the validation process,

Ø Responsibilities for performing and approving the validation study, Ø Description of the equipment to be used,

Ø The interval between the end of production and the beginning of the cleaning procedures, 7.4 文件

7.4.1 需要有清洗验证方案，在其中会制订程序来说明如何进行清洗过程验证。它应当包括如下内容： － 验证的目的，

－ 进行和批准验证研究的责任， － 所用设备的描述，

－ 生产结束和清洗程序开始之间的间隔，

Ø Cleaning procedures to be used for each product, each manufacturing system or each piece of equipment,

Ø The number of cleaning cycles to be performed consecutively, Ø Any routine monitoring requirement,

Ø Sampling procedures, including the rationale for why a certain sampling method is used,

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Ø Clearly defined sampling locations,

Ø Data on recovery studies where appropriate,

Ø Analytical methods including the limit of detection and the limit of quantitation of those methods,

Ø The acceptance criteria, including the rationale for setting the specific limits,

Ø Other products, processes, and equipment for which the planned validation is valid according to a “bracketing” concept, Ø When Re-validation will be required. － 每个产品、生产线、设备的清洗程序 －连续进行的清洗循环的次数， －常规监测内容

－ 取样程序，包括采用该取样程序的理由， － 明确确定取样点，

－ 回收率研究的研究资料，如果可行， － 分析方法及方法的检测限和定量限， － 合格标准，包括设定限度的理由，

－ 根据“包括法Bracketing”概念，该验证所适用的其它产品，工艺和设备， － 何时需要进行再验证。

7.4.2 The Cleaning Validation Protocol should be formally approved by the Plant Management, to ensure that aspects relating to the work defined in the protocol, for example personnel resources, are known and accepted by the management. Quality Assurance should be involved in the approval of protocols and reports. 7.4.3 A Final Validation Report should be prepared. The conclusions of this report should state if the cleaning process has been validated successfully.

Limitations that apply to the use of the validated method should be defined (for example, the analytical limit at which cleanliness can be determined). The report should be approved by the Plant Management.

7.4.2 清洗验证方案应当要由工厂管理层正式批准，这样才能确保管理层对方案中所确定工作所涉及的各方面是知情并接受的，如比说，人力资源。QA应当要参与方案和报告的批准。

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7.4.3 要有最终的验证报告。验证报告要给清洗过程是否已得到成功验证的结论。要规定所用分析方法的（比如，在什么分析限度，清洁度是可测的。）该报告要经工厂管理层批准

7.4.4 The cleaning process should be documented in an SOP.

7.4.5 Records should be kept of cleaning performed in such a way that the following information is readily available:

Ø the area or piece of equipment cleaned, Ø the person who carried out the cleaning, Ø when the cleaning was carried out, Ø the SOP defining the cleaning process,

Ø the product which was previously processed on the equipment being cleaned.

7.4.4 清洗过程要写成相应的SOP。

7.4.5 对所做的清洗，要保留其记录，记录应当要包括如下内容： － 所清洗的设备和区域， － 进行清洗的人员， － 进行清洗的时间， － 清洗的SOP，

－ 先前在该设备上生产的产品。

7.4.6 The cleaning record should be signed by the operator who performed the cleaning and by the person responsible for Production and should be reviewed by Quality Assurance.

7.4.6 清洗记录应当要由清洗操作者和负责生产的人签名，并由QA审核。

7.5 Personnel

7.5.1 Operators who perform cleaning routinely should be trained in the application of validated cleaning procedures. Training records should be available for all training carried out.

7.5.2 It is difficult to validate a manual, i.e. an inherently variable/cleaning procedure. Therefore, operators carrying out manual cleaning procedures should be supervised at regular intervals. 7.5 人员

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7.5.1 应当要对负责日常清洗的操作工进行培训，使其懂得已验证清洗程序的应用。对于所开展过的培训都要有培训记录。

7.5.2 由于其固有的不确定性，对人工清洗程序进行验证是很困难的。因此，应定期检查参与人工清洗程序的员工。

7.6 Equipment

7.6.1 The design of the equipment should be carefully examined. Critical areas (those hardest to clean) should be identified, particularly in large systems that employ semi-automatic or fully automatic clean-in-place (CIP) systems.

7.6.2 Dedicated equipment should be used for products which are difficult to remove (e.g. tarry or gummy residues in the bulk manufacturing), for equipment which is difficult to clean (e.g. bags for fluid bed dryers), or for products with a high safety risk (e.g. biologicals or products of high potency which may be difficult to detect below an acceptable limit). 7.6 设备

7.6.1 需仔细研究设备的配置，确定关键区域（这些最难清洗的地方），特别是应用了半自动或全自动在线清洗系统的大型系统。

7.6.2 对于难去除的产品（如，大型生产中的柏油状或粘性残留物），难清洗的设备（如，流化床干燥器用的袋子），或有高度安全风险的产品（如，有着高效生物制品达到可接收标准很难进行检测），应当要使用专用设备。

7.7 Microbiological Aspects

7.7.1 The existence of conditions favourable to reproduction of micro organisms (e.g. moisture, temperature, crevices and rough surfaces) and the time of storage should be considered. The aim should be to prevent excessive microbial contamination. 7.7 微生物方面

7.7.1 对于适宜于微生物繁殖的环境(如：湿度，温度，缝隙和粗燥的表面)及储存时间都要进行考虑。目的在于防止过多的微生物污染。

7.7.2 The period and when appropriate, conditions of storage of equipment before cleaning and the time between cleaning and equipment reuse, should form part of the validation of cleaning procedures. This is to provide confidence that

routine cleaning and storage of equipment does not allow microbial proliferation. 7.7.2 清洁程序的验证还应该包括设备使用后到清洗之间的以及清洗后到下一次使用之间的时间和保存要求。此举的目的在于确认日常清洗及设备的储存不会引起微生物的繁殖。

7.7.3 In general, equipment should be stored dry, and under no circumstances should

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stagnant water be allowed to remain in equipment subsequent to cleaning operations.

7.7.3 设备通常需要保存在干燥的环境中，且不允许在清洗之后有水份的残留。 7.8 Sampling

7.8.1 Samples should be drawn according to the Cleaning Validation Protocol. 7.8 取样

7.8.1 应当要根据清洗验证方案进行取样。

7.8.2 There are two methods of sampling that are considered to be acceptable, direct surface sampling (swab method) and indirect sampling (use of rinse solutions). A combination of the two methods is generally the most desirable, particularly in circumstances where accessibility of equipment parts can mitigate against direct surface sampling.

7.8.2 有两种可行的取样方法，表面直接取样法(擦拭法)和间接取样法(使用淋洗溶液)。两种方法结合使用通常被认为是最理想的。特别是当表面直接取样难以实现时。 A. Direct Surface Sampling

(i) The suitability of the material to be used for sampling and of the sampling medium should be determined. The ability to recover samples

accurately may be affected by the choice of sampling material. It is important to ensure that the sampling medium and solvent are satisfactory and can be readily used. A. 表面直接取样法

(i) 应当要确定取样工具和取样介质的适用性。取样工具的选择会影响到取样的准确性。确保取样媒介和溶剂是适用的这一点是很重要的。

B. Rinse Samples

(i) Rinse samples allow sampling of a large surface area. In addition, inaccessible areas of equipment that cannot be routinely disassembled can be evaluated. However, consideration should be given to the solubility of the contaminant.

B. 淋洗液取样

(i) 淋洗液取样可以对较大的表面进行取样。此外，也可以对不易到达的区域和设备中平时不拆卸下来的部分进行评估。不过，需考虑污染物的溶解性。

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(ii) A direct measurement of the product residue or contaminant in the relevant solvent should be made when rinse samples are used to validate the cleaning process.

(ii) 当淋洗液取样用于清洗程序的验证时，需使用直接测量法来测量溶剂中的产品和污染物残留。

7.9 Detergents

7.9.1 The efficiency of cleaning procedures for the removal of detergent residues should be evaluated. Acceptable limits should be defined for levels of detergent after cleaning. Ideally, there should be no residues detected. The possibility of detergent breakdown should be considered when validating cleaning procedures. 7.9 清洗剂

7.9.1 应当要对清洗程序去除清洗剂的能力进行评估。需规定清洗后清洗剂含量的合格限度。理想的是没有残留检出。在进行清洗程序验证时，还要考虑清洗剂分解的可能性。 7.9.2 The composition of detergents should be known to the manufacturer. If such information is not available, alternative detergents should be selected whose composition can be defined. As a guide, food regulations may be consulted. The manufacturer should ensure that he is notified by the detergent supplier of any critical changes in the formulation of the detergent.

7.9.2 生产商应当要知晓清洗剂的成分。如果不知道它的成分的话，则应当要选择其它成分已知的清洗剂。也可以参考食品法规。生产商要确保清洗剂供应商能将清洗剂配方的关键变更的信息通知他。

7.10 Analytical Methods

7.10.1 The analytical methods should be validated before the Cleaning Validation Study is carried out. 7.10 分析方法

7.10.1 在进行清洗验证之前，应当要验证所用的分析方法。

7.10.2 The analytical methods used to detect residuals or contaminants should be specific for the substance to be assayed and provide a sensitivity that reflects the level of cleanliness determined to be acceptable by the company.

7.10.2 用于检测残留和污染物的分析方法应当要对待测物质有选择性，并要有良好的灵敏度，能检测清洗的清洁程度。

7.10.3 The analytical methods should be challenged in combination with the sampling

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methods used, to show that the contaminants can be recovered from the

equipment surface and to show the level of recovery as well as the consistency of recovery. This is necessary before any conclusions can be made based on the sample results. A negative result may also be the result of poor sampling techniques.

7.10.3 分析方法需和所用的取样方法结合起来进行考察，确定污染物是否能从设备表面回收，回收率和回收效果是否始终如一。在根据样品结果做出任何结论之前必须做好这项工作。取样方法的不合理，也可能会导致结果不合理。

7.11 Establishment of Limits

7.11.1 The pharmaceutical company's rationale for selecting limits for product residues should be logically based on a consideration of the materials involved and their therapeutic dose. The limits should be practical, achievable and verifiable. 7.11 建立限度

7.11.1 制药企业应当要根据所使用的物料及它们的治疗剂量来选择产品的残留限度。这个限度应当是切合实际的，可达到的且可确证的。

7.11.2 The approach for setting limits can be:

Ø product specific Cleaning Validation for all products,

Ø grouping into product families and choosing a \"worst case\" product,

Ø grouping into groups of risk (e.g. very soluble products, similar potency,highly toxic products, difficult to detect).

7.11.2限度的设定可从以下几个途径入手： 对所有产品进行清洁验证；

将产品分类，然后找出具有“最差条件”的产品，；

对可能存在风险进行分类（比如，按照易溶的产品，（含量）规格相近的产品，毒性产品，难检测的产品进行分类），（来制定限度）。

7.11.3 Carry-over of product residues should meet defined criteria, for example the most stringent of the following three criteria:

(a) No more than 0.1% of the normal therapeutic dose of any product will appear in the maximum daily dose of the following product,

(b) No more than 10 ppm of any product will appear in another product,

7.11.3 产品残留的累积量应当要符合指定的合格标准，比如说，如下这三个合格标准中最严格的一个：

(a) 不超过正常治疗量的0.1%。

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(b) 在其它产品中的残留量，不超过10ppm。

(c) No quantity of residue should be visible on the equipment after cleaning procedures are performed. Spiking studies should determine the concentration at which most active ingredients are visible,

(c) 在用清洗程序清洗之后的设备上不应有可见的残留。加样研究确定在何浓度下活性成分是可见的。

(d) For certain allergenic ingredients, penicillins, cephalosporins or potent steroids and cytotoxics, the limit should be below the limit of detection by best available analytical methods. In practice this may mean that dedicated plants are used for these products.

(d) 对于某些过敏性物质，青霉素，头孢菌素或类固醇和细胞毒素等，其限度应当要低于目前最好的分析方法的检测限。实际上，这意味着需要用专用车间来生产这些产品。 7.11.4 One cannot ensure that the contaminate will be uniformly distributed throughout the system. It is also an invalid conclusion to make the assumption that a

residual contaminant would be worn off the equipment surface uniformly or that the contamination might only occur at the beginning of the batch.

7.11.4 如果不能确保污染物在整个系统中是均匀分布的。则假设污染物残留能从设备表面均匀的去除是不对的，也不能假设污染物仅存在于第一批中。

7.11.5 In establishing residual limits, it may not be adequate to focus only on the principal reactant since chemical variations (active decomposition materials) may be more difficult to remove.

7.11.5 在确立残留限度时，仅仅考虑主要的反应物是不够的，因为化学变异产物（降解物质）可能更难去除。

8. GLOSSARY

Definitions of terms relating to qualification and validation which are not given in the glossary of the current PIC/S and EU Guide to GMP, but which are used in the four Recommendations which comprise this document, are given below. 8. 术语表

本文件中所用到的确认和验证相关术语，若在现行PIC/S GMP 指导文件中没有对其进行解释，则在本文件的结尾处会有其解释，如下：

Change Control

A formal system by which qualified representatives of appropriate disciplines review proposed or actual changes that might affect a validated status. The

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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

变更控制为一正式系统，各相关部门的指定人员根据该系统对拟进行的和已进行的可能会影响到验证状态的变更进行评估。其目的在于确定是否需要采取措施确保系统处在一验证过的状态。

Change Management

A less formal approach to change control that is generally utilised during the preliminary planning and design stage of a project. (Many companies will elect to move straight to a change control system in a design stage of a complex project. This has the advantage of formality, more accurate records and documentation as well as a strong traceability and accountability feature). 变更管理

变更管理为一正式性略低于变更控制的方法，一般被用于项目的最初规划和设计阶段。（在复杂项目的设计阶段，很多公司选择直接采用变更控制系统。其优点在于有正式性，更准确的记录和文件及强的可追溯性和可靠性。

Commissioning

An engineering term that covers all aspects of bringing a system or sub-system to a position where it is regarded as being ready for use in pharmaceutical manufacture. Commissioning involves all the basis requirements of Installation Qualification (IQ) and Operational Qualification (OQ). 试运行

试运行是个工程术语，它包括将一系统或子系统移至一将应用于药品生产的地点所涉及的方方面面。试运行涉及安装确认（IQ）和运行确认（OQ）的所有基本要求。 Concurrent Validation

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

对销售批次的正常生产进行的验证。

Critical variable Study

A study that serves to measure variables (parameters) critical to the satisfactory operation of a piece of equipment or plant and to assure their operation within monitored and controlled limits. Examples of variables would be pressure, temperature, flow rates, time etc.

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关键变量研究

关键变量研究旨在测量合格操作设备或车间的关键变量（参数），并确保它们的运行都在控制的限度内。这些变量有，压力，温度，流速，时间等。

Installation Qualification (IQ)

The performance and documentation of tests to ensure that equipment (such as machines, measuring equipment) used in a manufacturing process, are appropriately selected, correctly installed and work in accordance with established specifications. 安装确认（IQ）

安装确认是进行一系列测试，并将这些测试记录在案，以确保生产中所用的设备（比如，机器，测量设备等）是适用的，安装正确的，且能根据所确立的标准运行。 Limit of Detection

The lowest amount of analyte in a sample which can be detected but not

quantitated as an exact value. The Limit of Detection is mostly a parameter of limit tests. 检测限

被分析物在样品中能被检出但不需要对其进行准确定量的最低量。通常，检测限是限度实验的一个参数。

Limit of Quantitation

The lowest amount of analyte in a sample which can be quantitatively

determined with defined precision and accuracy under the stated experimental conditions. 定量限

在所述实验条件下，在指定的精密度和准确度下，被分析物在样品中能被定量分析的最低量。

Operational Qualification (OQ)

Documented verification that the system or sub-system performs as intended throughout all anticipated operating ranges. 运行确认（OQ）

运行确认为一书面确认，它确认了该系统或子系统在整个所预期的操作范围内能很好地运行。

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Process Validation

Documented verification that the integrated system functions as intended, in its normal operating environment. (The term Performance Qualification may be used also). 工艺验证

工艺验证为一书面确认,它确认了整个系统在其正常的操作环境下能正常地运行。（有时也用性能确认（PQ）这个术语）。

Note: Processes may be proven also by documented verification through appropriate testing that the finished product produced by a specified process meets all release requirements. This may be called Product Qualification.

注：也可通过一系列的测试对工艺进行验证，形成文件已确保通过指定的工艺生产的制剂符合所有的要求。这也可被称之为产品确认。

Piping & Instrument Diagrams (P&IDs)

Engineering schematic drawings that provide details of the interrelationship of equipment, services, material flows, plant controls and alarms. The P&ID also provide the reference for each tag or label used for identification. 管路＆仪器图（ P＆IDs)

工程示意图，说明了设备，维修，物流，车间控制和预警系统之间的相互关系。管路＆设施图也为每个标识性记号和标签提供了参考。

Pre-Determined Acceptance Criteria

The criteria assigned, before undertaking testing, to allow evaluation of test results to demonstrate compliance with a test phase of delivery requirement. 事先确立的合格标准

在进行检测前所指定的合格标准，用于检测结果的评估以论证移交要求测试阶段的符合性。

Plant functional Specifications

Specifications that document functions, standards and permitted tolerances of systems (plant) or system components (equipment) and which define the operating capabilities of the equipment. 车间功能规格

Prepared by HU Kai / December 29, 2004

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PIC/S 的验证指南

对系统（车间）或系统组件（设备）的功能，标准和允许的偏差进行文件说明的规格，并定义了设备的运行能力。

Process Capability Study

A process capability study is a statistical method that compares process information (e.g. X and s) to the upper and lower specification limits. 工艺能力研究

工艺能力研究是一统计方法，它对工艺数据和规格限度的上下限进行了比较。 Prospective Validation

Establishing documented evidence that a process, procedure, system,

equipment or mechanism used in manufacture does what it purports to do based on a pre-planned validation protocol. 前验证

建立书面文件，证明生产中所用工艺，程序，系统，设备或机器是能符合其预先规划好的验证方案中声称所能实现的程度的。

Qualification

Identification of equipment attributes related to the performance of a particular function or functions and allocation of certain limits or restrictions to those attributes. 确认

确定和设备功能相关的属性，并为这些属性设定一定的限度和。 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

根据已有的生产，检测和控制批数据对一已进行销售的产品的工艺进行验证。 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

Prepared by HU Kai / December 29, 2004

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PIC/S 的验证指南

重复进行的验证，确保根据变更控制程序进行的工艺/设备上的变更不会对工艺特点和产品质量产生负面影响。

Sensitivity

Capacity of the test procedure to record small variations in concentration of a component, with a defined degree of precision.

在一定的精密度下，分析方法反应组分浓度细微变化的能力。

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

和验证产品物理性质非常接近的产品，有时候根据实际情况，要求化学性质也要接近（如，粘性，粒径，pH等）。在很多情况下，空白产品批就能符合这些要求。

Validation Master Plan

A document providing information on the company’s validation work programme. It should define details of and timescales for the validation work to be performed. Responsibilities relating to the plan should be stated. 验证主计划

公司验证工作项目的相关信息文件。它要详述所用进行验证工作的细节和时间安排。还需说明相关的职责。

Validation Protocol

A written plan stating how validation will be conducted, including test

parameters, product characteristics, production equipment and decision points on what constitutes acceptable test results. 验证方案

书面计划，说明应如何开展验证工作，包括参数，产品特点，生产设备和判断点。 Validation Report

Document reporting the validation activities, the validation data and the conclusions drawn. 验证报告

Prepared by HU Kai / December 29, 2004

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PIC/S 的验证指南

验证报告是报告验证文件，验证资料和所得结论的文件。

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SOP中运行限度的上限和下限，最坏情况和理想情况相比，会最大程度地引起产品或工艺的失败。但是这样的条件不应该总是导致产品或工艺的失败。

Prepared by HU Kai / December 29, 2004

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