who验证指南2016年

1、1. INTRODUCTION简介1.1 Validation is an essential part of good practices including good manufacturing practices (GMP) (4) and good clinical practices (GCP).It is therefore an element of the pharmaceutical quality system. Validation, as a concept, incorporates qualification and should be applied over t

2、he life cycle of, e.g. the applicable product, process, system,equipment or utility.验证是包括 GMP 和 GCP在内的良好规范的必要部分。因此是制药质量体系的组成部分。验证这个概念包括确认并且应该在产品、工艺、系统、设备或设施的整个生命周期中被使用。1.2 These guidelines cover the general principles of validation and qualification. In additionto the main part, appendices on valida

3、tion and qualification (e.g. cleaning, computer and computerized systems, equipment, utilities and systems, and analytical methods) are included.这个指南包括验证和确认的一般原则。除了主体部分外，还包括确认和验证附件（如清洁、计算机和计算机化系统、设备、设施和系统以及分析方法）。1.3 The following principles apply:适用的原则如下 :the execution of validation should be in com

4、pliance with regulatory expectations; 验证的执行应该符合监管预期quality, safety and ef?cacy must be designed and built into the product; 质量、安全和效力应该被设计和构建到产品中quality cannot be inspected or tested into the product; 质量不能通过检查或测试赋予产品quality risk management principles should be applied in determining the need, scope a

5、nd extent of validation;应该应用质量风险管理规则来决定验证的需求、范围和程度ongoing review should take place to ensure that the validated state is maintained and opportunities for continuing improvement are identified.应该进行持续的回顾来确保维持验证状态并识别持续改进的机会1.4The implementation of validation work requires considerable resources such as

6、:验证工作的完成需要大量资源，例如time: generally validation work is subject to rigorous time schedules; 时间：一般验证工作需要有一个严密的时间表financial:validationoftenrequiresthetimeofspecialized personnel andexpensive technology.资金：验证经常需要专业人员和昂贵的技术human: disciplines engineering,validation requires the (e.g. a multidisciplinary info

7、rmation technology,collaboration of experts from various team, comprising quality assurance, manufacturing and other disciplines, asappropriate.).人员：验证需要不同学科专家的协作（例如一个多学科小组，视情况可能包括QA、工程、信息技术、生产以及其他学科人员）2. SCOPE范围2.1 These guidelines focus mainly on the overall concept of validation and are not inten

8、ded to be prescriptive in specific validation requirements. This document serves as general guidance only and the principles may be considered useful in its application in themanufacture and control of starting materials and finished pharmaceutical products (FPPs),as well as other areas. Validation

9、of specific processes and systems, for example, in sterile product manufacture, requires much more consideration and a detailed approach that isbeyond the scope of this document.这些指南主要关注验证的整体概念，无意规定具体的验证要求。用作GMP 检查官和生产商的基本指南 ， 本文件仅作为一个一般指南 ，其原则在其应用于起始物料及制剂的生产和控制时会比较有用 ，也应用于其他领域。特定工艺和产品的验证 ，例如无菌产品生产，

10、需要考虑更多内容 ，和更详细的方法 ，不在本文件范围之内。2.2 There are many factors affecting the different types of validation and it is, therefore, not intended to define and address all aspects related to one particular type of validation here.有很多因素会对不同类型的验证产生影响 ，因此，这里不会对某个特定类型的验证相关的所有方面进行定义和说明。2.3 The general text in the m

11、ain part of these guidelines may be applicable to validation and qualification of premises, equipment, utilities, systems,processesand procedures.这些指南的主体部分的一般内容可能适用于设施、设备、公用设施和系统、工艺和程序的验证和确认。3. GLOSSARY术语The definitions given below apply to the terms used in these guidelines. They may have different

12、 meanings in other contexts.本指南使用的术语定义如下。它们在其它环境中可能有不同的含义calibration . The set of operations that establish, under specified conditions, the relationship between values indicated by an instrument or system for measuring (for example, weight, temperature and pH), recording, and controlling, or the va

13、lues represented by a material measure, and the corresponding known values of a reference standard. Limits for acceptance of the results of measuring should be established.校准：change control (including change management) . A formal system by which qualified representatives of appropriate disciplines

14、review proposed or actual changes that might affect a validated status. The intent is to determine the need for action that would ensure that the system is maintained in a validated state (reference working document QAS/15.639/Rev.1 - unpublished).变更控制 （包括变更管理 ）cleaning validation. Documented eviden

15、ce to establish that cleaning procedures are removing residues to predetermined levels of acceptability, taking into consideration factors such as batch size, dosing, toxicology and equipment size.清洁验证commissioning. The setting up, adjustment and testing of equipment or a system to ensure that it me

16、ets all the requirements, as specified in the user requirement specification, and capacities as specified by the designer or developer. Commissioning is carried out before qualification and validation.试车computer validation (including computerized system validation). Confirmation by examination and p

17、rovision of objective documented evidence that computerized system specifications conform to user needs and intended uses, and that all requirements can be consistently fulfilled.计算机验证 （包括计算机化系统验证）concurrent validation. Validation carried out during routine production of products intended for sale.同

18、步验证design qualification. Documented verification that the proposed design of facilities, systems and equipment is suitable for the intended purpose.设计确认good engineering practices. Established engineering methods and standardsthat are applied throughout the project life -cycle to deliver appropriate,

19、 cost-effective solutions.良好工程规范installationqualification.Documented verification that the installations (such as machines,computer system components, measuring devices, utilities and manufacturing areas)used in aprocessor system areappropriatelyselectedandcorrectlyinstalled in accordance withestabl

20、ished specifications.安装确认operationalqualification.Documented verificationthat the system or subsystemoperates asintended over all anticipated operating ranges.运行确认performancequalification.Documented verification that the equipment or system performsconsistentlyand reproduciblywithindefinedspecificat

21、ionsand parameters in its normaloperating environment(i.e. inthe production environment). (In the context of systems, theterm “ processvalidationmay” also be used.)性能确认process validation. The collection and evaluation of data, throughout the product life cycle, which provides documented scientific e

22、vidence that a process is capable of consistently delivering quality products.工艺验证prospective validation. Validation carried out during the development stage on the basis of a risk analysis of the production process, which is broken down into individual steps; these are then evaluated on the basis o

23、f past experience to determine whether they may lead to critical situations.前验证qualification. Documented evidence that premises, systems or equipment are able to achieve the predetermined specifications properly installed, and/or work correctly and lead to theexpected results. Qualification is often

24、 a part (the initial stage) of validation, but the individual qualification stepsalone do not constitute processvalidation.确认revalidation. Repeated validation of a previously validated system (or a part thereof) to ensure continued compliance with established requirements.再验证 ：对先前已验证的系统（或它的一部分 ）的重复验

25、证来确保持续符合既定标准。standard operating procedure. An authorized written procedure giving instructions for performing operations not necessarily specific to a given product or material but of a more general nature (e.g. equipment operation, maintenance and cleaning; validation; cleaning of premises and envi

26、ronmental control; sampling and inspection). Certain standard operating procedures may be used to supplement product-specific master batch production documentation.标准操作规程validation. Action of proving and documenting that any process, procedure or method actually and consistently leads to the expecte

27、d results.验证validationmaster plan. The validation master plan is a high- level document that establishesan umbrella validation plan forthe entire project and summarizes the manufacturersoverallphilosophyand approach, tobe used for establishing performanceadequacy. It providesinformationon the manufa

28、cturer s validationwork programme and defines details ofandtimescalesfor the validation work to beperformed, includinga statement oftheresponsibilities of thoseimplementing the plan.验证主计划validationprotocol. A document describing the activities to be performed during a validation,includingthe accepta

29、ncecriteria for the approval of a processor system or a part thereof for intended use.验证方案validationreport. A document in which the records, results and evaluation of validation areassembled and summarized. It may also contain proposals for the improvement of processes and/or systemsand/or equipment

30、.验证报告verification. The application of methods, procedures, tests and other evaluations, in addition to monitoring, to determine compliance with established requirements and specifications.核实worst case. A condition or set of conditions encompassing the upper and lower processing limits for operating

31、parameters and circumstances, within SOPs,which pose the greatest chance of product or process failure when compared to ideal conditions. Such conditions do not necessarily include product or process failure.最差条件4. RELATIONSHIPBETWEENVALIDATIONAND QUALIFICATION验证与确认的关系4.1 Qualification and validatio

32、n are essentially the same. The term quali?cation is normally used for equipment and utilities, and validation for systems and processes. Inthis sense, quali?cation can be seen as part of validation.确认和验证本质上是一样的。确认通常用于设备和设施，而验证则用于系统和工艺。在这层意义上 ，确认可以被看做是验证的一部分。4.2Where the term “ validation is used” i

33、n the document, the same principles may beapplicable for “ qualification在文件中使用术语“验证 ” 的规则同样适用于“ 确认 ”5. VALIDATION验证Approaches to validation验证的方法5.1 Manufacturers should organize and plan validation in a manner that will ensure product quality, safety and efficacy throughout its life cycle.生产商应该组织和计划

34、验证以保证产品在其生命周期内的质量、安全和有效。5.2 The scope and extentofqualificationandvalidationshouldbebased onriskmanagement principles.确认和验证的范围和程度应该基于风险管理规则。5.3 Statistical calculations should be applied, where appropriate, and provide scientific evidence that the process, system or other related aspect is appropria

35、tely validated.适当时 ，应该使用统计学计算并提供工艺、系统或其它相关方面有效的科学证据5.4 Qualification and validation should be done in accordance with predetermined protocols,and the results appropriately documented, e.g. in reports.确认和验证应该按照预定的方案执行并且结果应被适当的记录，如在报告中。5.5 There should be an appropriate and effective quality system en

36、suring the organization and management of validation.应有适当的和有效的质量体系来保证验证的组织和管理。5.6 Senior management should ensure that there are sufficient resources to perform validation in a timely manner. Management and persons responsible for quality assurance should be actively involved in the process and auth

37、orization of protocols and reports.高级管理层应该确保充分的资源来及时地执行验证。 管理层和质量保证负责人应该积极参与方案和报告的批准活动中。5.7 Personnel with appropriate qualification and experience should be responsible for performing validation.有适当资质和经验的人员应该对验证的执行负责。5.8 There should be a specific programme or schedule to support planning and execu

38、tion of validation activities.应有专门的计划或时间表来支持计划和执行验证活动。5.9 Validation should be performed in a structured way according to the documented protocols and procedures.验证应该按照文件化的方案和规程以一种有组织的方式执行。5.10 Qualification and validation should be performed:确认和验证应该被执行：? for new premises, equipment, utilities and s

39、ystems,and processesand procedures;新设施、设备、公用设施和系统 ，以及新的工艺和程序；? when changesare made, depending on the outcome of risk assessment;当发生变更时 ，根据风险评估的结果；? where necessary or indicated based on the outcome of periodic review.基于定期回顾的结果表明需要的5.11 A written report on the outcome of the validation should be pre

40、pared.应该对验证的结果准备一份书面报告。5.12 The scope and extent of validation should be based on knowledge and experience, and the outcome of quality risk management principles as described in the World Health Organization (WHO) guidelines on quality risk management . Where necessary worst -case situations or spec

41、ific challenge tests should be considered for inclusion in the validation, for example, stress load and volume verification in computer system validation.验证的范围和程度应该基于知识和经验，以及描述于WHO 质量风险管理指南 中的质量风险管理管理规则的结果来决定。6. DOCUMENTATION文件6.1 -Qualification and validation should be done according to written pro

42、cedures.确认和验证应该按照书面程序执行6.2 Documents associated with qualification and validation include:与确认和验证相关的文件包括：? validation master plan (VMP);验证主计划 （ VMP）? standard operating procedures (SOPs);标准操作规程 （SOP）? specifications;规范? protocols and reports;方案和报告? risk assessmentoutcomes;风险管理结果? processflow charts;工

43、艺流程图? operator manuals;操作手册? training records;培训记录? calibration proceduresand records;校准规程和记录? sampling plans;取样计划? testing plans and methods;测试计划和方法? statistical methodsand results;统计学方法和结果? history of qualification or validation;确认或验证历史? plan for ensuring review of validation status;确保回顾验证状态的计划? p

44、lan for ensuring maintaining a validated state.确保维持验证状态的计划7. VALIDATIONMASTERPLAN验证主计划7.1 A manufacturershould have a VMP which reflects the key elements of validation. Itshould be concise and clear and contain at least the following:生产商应有一份VMP 反映验证的关键要素。它应该简洁清晰并至少包括? title page and authorization (a

45、pproval signatures and dates);：书名页和批准 （批准签名和日期 ）? table of contents;目录? abbreviations and glossary;缩写和术语? validation policy;验证方针? philosophy, intention and approach to validation;验证的原理、目的和方法? roles and responsibilities of relevant personnel;相关人员的角色和责任? resources to ensure validation is done;确保验证执行的资

46、源? outsourced services (selection, qualification, management through life cycle);外包服务 （选择、确认和生命周期管理 ）? deviation management in validation;验证偏差管理? change control in validation;验证变更控制? risk management principles in validation;验证风险管理规则? training;培训? scope of validation;验证的范围? documentation required in

47、qualification and validation such as procedures, certificates,protocols and reports;确认和验证所需的文件，如规程、证书、方案和报告? premises qualification;设施确认? utilities qualification;公用设施确认? equipment qualification;设备确认? processvalidation;工艺验证? cleaning validation;清洁验证? personnel qualification such as analyst qualificat

48、ion;人员确认例如分析人员确认? analytical method validation;分析方法验证? computerized system validation;计算机化系统验证? establishing acceptancecriteria;建立接受标准? life -cycle managementincluding retirement policy;生命周期管理包括退役的方针? requalification and revalidation;再确认和再验证? relationship with other quality managementelements;与其他质量管

49、理要素的关系? validation matrix;验证矩阵? references.参考文献7.2 The VMP should be reviewed at regular intervals and kept up to date according to current GMP.VMP 应该每隔一段时间回顾并保持持续符合现行GMP8. QUALIFICATIONAND VALIDATIONPROTOCOLS确认和验证方案8.1 There should be qualification and validation protocols describing the qualificat

50、ion and validation to be performed.应有确认和验证方案描述所要执行的确认和验证。8.2 As a minimum the protocols should include the following significant background information:方案应该至少包括下列重要的背景信息：? the objectives;目的? the site;场所? the responsible personnel负责的人员? description of the standard operating procedures (SOPs)to be fol

51、lowed;所遵循的标准操作规程描述? equipment or instruments to be used;所使用的设备或仪器? standards and criteria as appropriate;适当的标准? the stage of validation or qualification;验证或确认的阶段? the processesand/or parameters;工艺和 / 或参数? sampling, testing and monitoring requirements;取样，测试和监测需求? stress testing where appropriate;压力测试

52、 （如适用 ）? calibration requirements;校准需求? predetermined acceptance criteria for drawing conclusions;预定的用于下定结论的接受标准? review and interpretation of results;结果的审核和分析? change control, deviations;变更控制、偏差? archiving and retention.归档和保留8.3 There should be a description of the way in which the results will be

53、analysed, including statistical analysis where appropriate.应有一个结果分析方法，包括统计学分析 （如使用 ）的描述8.4 The protocol should be approved prior to use. Any changes to a protocol should be approved prior to implementation of the change.方案应该在使用前被批准。方案的任何变更应在实施前被批准。9. QUALIFICATIONAND VALIDATIONREPORTS确认和验证报告9.1 Ther

54、e should be written reports on the qualification and validation performed.应有所执行的确认和验证的书面报告9.2 Reports should reflect the protocols and procedures followed and include at least the title and objective of the study; make reference to the protocol; reference to the appropriate risk assessment; details of materials, equipment, programmes and cycles used; procedures and test methods with appropriate traceability.报告应该反映所遵循的方案和规程并至少包括题目和目的；方案的参考；适当的风险评估的参考；所使用的材料、设备、计划和周期的描述；适当的规程和测试方法追溯9.3 Results should berecordedandbein complian