欧盟GMP附录15：确认与验证(修订版英文+中文).docx

EUROPEAN COMMISSIONENTERPRISEDIRECTORATE-GENERALSingle market, regulatory environment, industries under vertical legislationPharmaceuticals and cosmeticsBrussels,30 March 2015EudraLex欧盟药品管理法Volume 4EU Guidelines forGood Manufacturing Practice forMedicinal Products for Human and Veterinary Use第四卷 欧盟人用和兽用药品GMP指南Annex 15: Qualification and Validation附录15:确认和验证Legal basis for publishing the detailed guidelines:Article 47 of Directive 2001/83/EC on the Community code relating to medicinal products for human use and Article 51 of Directive 2001/82/EC on the Community code relating to veterinary medicinal products. This document provides guidance for the interpretation of the principles and guidelines of good manufacturing practice (GMP) for medicinal products as laid down in Directive 2003/94/EC for medicinal products for human use and Directive 91/412/EEC for veterinary use.发布该细化指南的法律依据:人用药物欧共体法案指令2001/83/EC第47章和兽用药物欧共体法案指令2001/82/EC第51章。本文件为人药GMP指令2003/94/EC以及兽药GMP指令91/412/EEC的原则和指南提供诠释。Status of the document: Revision文件状态：修订版Reasons for changes:Since Annex 15 was published in 2001 the manufacturing and regulatory environment has changed significantly and an update is required to this Annex to reflect this changed environment. This revision to Annex 15 takes into account changes to other sections of the EudraLex, Volume 4, Part I, relationship to Part II, Annex 11, ICH Q8, Q9, Q10 and Q11, QWP guidance on process validation, and changes in manufacturing technology.变更原因：从2001年附录15发布以后，制药生产和法规环境都有了显著变化，需要相应的更新来反映变化的环境。本文对附录15所做的修订考虑了欧盟法规第四卷第一部分质量管理和第二部分活性物质作起始物料以及附录11计算机化系统的验证、ICH Q8药物研发、ICH Q9质量风向管理、ICH Q11药物研发和生产、质量工作组的工艺验证指南和生产技术的变化。Deadline for coming into operation:1 October 2015最终实施日期：2015年10月1日第 33 页 共33 页目 录原则2概述31.确认和验证的组织和计划32.文件，包括验证主计划53.设备、设施、公用工程和系统的确认阶段75.工艺验证106.运输确认197.包装验证208.公用工程的确认209.检验方法验证2110.清洁验证2111.变更控制2512.词汇表26PrincipleThis Annex describes the principles of qualification and validation which are applicable to the facilities, equipment, utilities and processes used for the manufacture of medicinal products and may also be used as supplementary optional guidance for active substances without introduction of additional requirements to EudraLex, Volume 4, Part II. It is a GMP requirement that manufacturers control the critical aspects of their particular operations through qualification and validation over the life cycle of the product and process. Any planned changes to the facilities, equipment, utilities and processes, which may affect the quality of the product, should be formally documented and the impact on the validated status or control strategy assessed. Computerised systems used for the manufacture of medicinal products should also be validated according to the requirements of Annex 11. The relevant concepts and guidance presented in ICH Q8, Q9, Q10 and Q11 should also be taken into account.原则本附录描述了确认与验证的基本原则，适用于药品生产中的设施、设备、公用系统及工艺,也可以用于第四卷第二部分活性物质作起始物料的附加要求中没有介绍部分的补充性、选择性指南。GMP要求生产商应通过确认和验证对整个生命周期内的产品和工艺涉及的关键操作中的关键因素来进行控制。所有影响产品质量的计划性变更（含设施、设备、工艺系统和工艺），都应当有正式文件或记录，并评估其对验证状态或是控制策略的影响。用于药品生产的计算机化系统也应根据附录11的要求进行验证。同时，应当考虑现行的ICH Q8、Q9、Q10、Q11中的相关理念和指南要求。General A quality risk management approach should be applied throughout the lifecycle of a medicinal product. As part of a quality risk management system, decisions on the scope and extent of qualification and validation should be based on a justified and documented risk assessment of the facilities, equipment, utilities and processes. Retrospective validation is no longer considered an acceptable approach. Data supporting qualification and/or validation studies which were obtained from sources outside of the manufacturers own programmes may be used provided that this approach has been justified and that there is adequate assurance that controls were in place throughout the acquisition of such data.概述质量风险管理的方法应作为质量风险管理系统的一部分贯穿于药品的整个生命周期，应基于对设施、设备、公用系统和工艺的论证和书面风险评估决定确认和验证的范围和程度。回顾性验证不再被认为是可接受的方式。如果方法经过论证，并且获取数据的整个过程中有足够的保证性控制措施，也可以使用从生产商自身程序以外获得的用于支持确认和/或验证研究的数据。1. ORGANISING AND PLANNING FOR QUALIFICATION AND VALIDATION1. 确认和验证的组织和计划1.1.All qualification and validation activities should be planned and take the life cycle of facilities, equipment, utilities, process and product into consideration.1.1. 所有的确认和验证都应当被计划，并考虑到设施、设备、公用系统、工艺和产品的生命周期。1.2.Qualification and validation activities should only be performed by suitably trained personnel who follow approved procedures.1.2. 确认和验证活动应只能由经过培训合格的人员严格按照批准的程序实施。1.3.Qualification/validation personnel should report as defined in the pharmaceutical quality system although this may not necessarily be to a quality management or a quality assurance function. However, there should be appropriate quality oversight over the whole validation life cycle.1.3. 确认或验证人员应按照药品质量体系中指定要求进行报告，尽管并不一定是报告给质量管理或质量保证部门。然而，对于整个验证生命周期来说，应当有合适的质量监督。1.4.The key elements of the site qualification and validation programme should be clearly defined and documented in a validation master plan (VMP) or equivalent document.1.4. 应当在验证主计划（VMP）或其等同文件中，清晰地界定和记录现场确认与验证程序的关键性要素。1.5. The VMP or equivalent document should define the qualification/validation system and include or reference information on at least the following:1.5. 验证主计划或其等同文件中应定义确认/验证体系，至少包括如下信息：i. Qualification and Validation policy;i. 确认与验证的方针政策。ii. The organisational structure including roles and responsibilities for qualification and validation activities;ii. 在确认和验证活动中的组织结构，包括分工和职责。iii.Summary of the facilities, equipment, systems, processes on site and the qualification and validation status;iii. 现场设施、设备、系统、工艺汇总表及其确认和验证状态。iv.Change control and deviation management for qualification and validation;iv. 确认与验证活动的变更控制和偏差管理。v. Guidance on developing acceptance criteria;v. 开发可接受标准的指南。vi.References to existing documents;vi. 现有文件的参考资料。vii.The qualification and validation strategy, including requalification, where applicable.vii. 确认与验证的策略，适当时应包括再确认。1.6.For large and complex projects, planning takes on added importance and separate validation plans may enhance clarity1.6. 对于大型和复杂的项目，增加计划重点和独立的验证计划将有助于明晰要做的工作。1.7.A quality risk management approach should be used for qualification and validation activities. In light of increased knowledge and understanding from any changes during the project phase or during commercial production, the risk assessments should be repeated, as required. The way in which risk assessments are used to support qualification and validation activities should be clearly documented.1.7. 在确认与验证活动中应使用质量风险管理的方法，随着在项目开展或者商业化生产的过程中的知识积累及理解加深，应当根据需要对风险进行不断地重复评估，并清楚地记录确认与验证的风险评估所采用的方法。1.8. Appropriate checks should be incorporated into qualification and validation work to ensure the integrity of all data obtained.1.8. 应将适当的检查加入到确认和验证工作中，以保证所获得的数据的完整性。2. DOCUMENTATION, INCLUDING VMP2. 文件，包括验证主计划2.1. Good documentation practices are important to support knowledge management throughout the product lifecycle.2.1. 在产品的生命周期中，良好的文件管理对于知识管理而言是非常重要的。2.2. All documents generated during qualification and validation should be approved and authorised by appropriate personnel as defined in the pharmaceutical quality system.2.2. 确认与验证产生的所有文件都应当由药品质量管理体系规定的人批准和授权。2.3. The inter-relationship between documents in complex validation projects should be clearly defined.2.3. 在复杂的验证项目中，应清楚地说明文件之间的内在关系。2.4. Validation protocols should be prepared which defines the critical systems, attributes and parameters and the associated acceptance criteria.2.4. 制定验证方案的时候，应当定义关键系统、属性、参数及相关的可接受标准。2.5. Qualification documents may be combined together, where appropriate, e.g. installation qualification (IQ) and operational qualification (OQ).2.5. 确认文件适当的时候可以合并，例如IQ和OQ的文件可以合并在一起。2.6. Where validation protocols and other documentation are supplied by a third party providing validation services, appropriate personnel at the manufacturing site should confirm suitability and compliance with internal procedures before approval. Vendor protocols may be supplemented by additional documentation/test protocols before use.2.6. 如果验证方案和其它文件记录由验证服务第三方提供，应当由企业内部的合适人员确认其适用性，满足内部规定后方可批准。在使用之前，可由附加的文件或测试对供应商提供的方案进行补充。2.7. Any significant changes to the approved protocol during execution, e.g. acceptance criteria, operating parameters etc., should be documented as a deviation and be scientifically justified.2.7. 在执行期间，对已批准方案的任何重大变更，如可接受标准、操作参数等，均需按照偏差记录在册，并进行科学合理的评判。2.8. Results which fail to meet the pre-defined acceptance criteria should be recorded as a deviation and be fully investigated according to local procedures. Any implications for the validation should be discussed in the report。2.8. 若验证结果不符合预定的可接受标准需作为偏差处理，并按照内部规程进行全面调查。任何与偏差关联的东西都应当在验证报告中进行讨论。2.9. The review and conclusions of the validation should be reported and the results obtained summarised against the acceptance criteria. Any subsequent changes to acceptance criteria should be scientifically justified and a final recommendation made as to the outcome of the validation.2.9. 验证的评价和结论都应当被报告，且结果应与可接受标准比对，对可接受标准的任何后期变更都应当进行科学的评判，并在验证结果中做出最终建议。2.10. A formal release for the next stage in the qualification and validation process should be authorised by the relevant responsible personnel either as part of the validation report approval or as a separate summary document. Conditional approval to proceed to the next qualification stage can be given where certain acceptance criteria or deviations have not been fully addressed and there is a documented assessment that there is no significant impact on the next activity.2.10. 由相关的负责人对确认与验证过程中的阶段性放行，既可以作为验证报告批准的一部分，也可以是单独的总结文件。因某个可接受标准未达到或偏差未关闭，并通过评估确定对下一阶段活动无显著影响，可以有条件的放行进入下一阶段。3. QUALIFICATION STAGES FOR EQUIPMENT, FACILITIES, UTILITIES AND SYSTEMS.3. 设备、设施、公用工程和系统的确认阶段3.1. Qualification activities should consider all stages from initial development of the user requirements specification through to the end of use of the equipment, facility, utility or system. The main stages and some suggested criteria (although this depends on individual project circumstances and may be different) which could be included in each stage are indicated below:3.1. 设备、设施、公用工程或系统的确认活动应当贯穿其用户需求说明书的制定到使用的各个阶段，主要阶段及其要求如下：User requirements specification (URS)用户需求说明（URS）3.2. The specification for equipment, facilities, utilities or systems should be defined in a URS and/or a functional specification. The essential elements of quality need to be built in at this stage and any GMP risks mitigated to an acceptable level. The URS should be a point of reference throughout the validation life cycle.3.2. 设备、设施、公用工程或系统的说明应当在URS文件和/或功能说明中定义，应考虑质量的关键性因素，并把GMP风险降低到可接受水平。URS应该是整个验证生命周期中的参照。Design qualification (DQ)设计确认3.3. The next element in the qualification of equipment, facilities, utilities, or systems is DQ where the compliance of the design with GMP should be demonstrated and documented. The requirements of the user requirements specification should be verified during the design qualification.3.3. 确认活动的第二阶段就是设计确认，这里应当用文件证明其符合GMP要求，还应当对用户需求说明中的要求进行确认。Factory acceptance testing (FAT) /Site acceptance testing (SAT)工厂验收测试（FAT）/现场验收测试（SAT）3.4. Equipment, especially if incorporating novel or complex technology, may be evaluated, if applicable, at the vendor prior to delivery.3.4. 如果需要的话，设备（尤其是新型或复杂的设备）在供应商发货前应在其产地被充分的评估。3.5. Prior to installation, equipment should be confirmed to comply with the URS/functional specification at the vendor site, if applicable.3.5. 如果需要的话，在供应商的现场，设备应在安装之前被确认是否符合URS或功能说明的要求。3.6. Where appropriate and justified, documentation review and some tests could be performed at the FAT or other stages without the need to repeat on site at IQ/OQ if it can be shown that the functionality is not affected by the transport and installation.3.6. 合适的话，经过评估，文件审核和部分测试可以在FAT时或其他阶段进行，如果能够证明其功能在运输和安装中未受影响，就不需要在IQ/OQ时重复进行已经做过的审核和测试了。3.7. FAT may be supplemented by the execution of a SAT following the receipt of equipment at the manufacturing site.3.7. 在药品生产场地收到设备后，可以紧接着做SAT作为FAT的补充。Installation qualification (IQ)安装确认（IQ）3.8. IQ should be performed on equipment, facilities, utilities, or systems.3.8. 设备、设施、公用工程或系统应进行安装确认。3.9. IQ should include, but is not limited to the following:3.9. 安装确认包括但不限于以下内容：i. Verification of the correct installation of components, instrumentation, equipment, pipe work and services against the engineering drawings and specifications;i. 对照设计图纸和说明书，对组件、仪表、设备、管道和服务的安装正确性进行确认。ii. Verification of the correct installation against pre-defined criteria;ii. 按照预先设定的标准对安装正确性进行确认。iii. Collection and collation of supplier operating and working instructions and maintenance requirements;iii. 收集并核对供应商操作、工作指令和维护要求。iv. Calibration of instrumentation;iv. 仪表校准。v. Verification of the materials of construction.v. 核对部件的材质。Operational qualification (OQ)运行确认（OQ）3.10. OQ normally follows IQ but depending on the complexity of the equipment, it may be performed as a combined Installation/Operation Qualification (IOQ).3.10. OQ一般紧跟着IQ，但是根据设备的复杂情况，OQ也可以合并在安装/运行方案中执行(IOQ)。3.11. OQ should include but is not limited to the following:3.11. 运行确认包括但不限于以下内容：i. Tests that have been developed from the knowledge of processes, systems and equipment to ensure the system is operating as designed;i. 根据工艺、系统和设备的相关知识开展测试，以确保其可以像设计的那样运行。ii. Tests to confirm upper and lower operating limits, and /or “worst case” conditions.ii. 对其上下操作线或最差工况进行测试。3.12. The completion of a successful OQ should allow the finalisation of standard operating and cleaning procedures, operator training and preventative maintenance requirements.3.12. 成功的完成OQ后，就可以进行标准操作规程、清洁规程、员工培训、预防性维护的最终定稿。Performance qualification (PQ)性能确认（PQ）3.13. PQ should normally follow the successful completion of IQ and OQ. However, it may in some cases be appropriate to perform it in conjunction with OQ or Process Validation.3.13. 性能确认一般是在安装确认和运行确认成功完成之后。但是，在有些情况下，也可以将其与运行确认或工艺验证合并进行。3.14. PQ should include, but is not limited to the following:3.14. 性能确认包括但不限于以下内容：i. Tests, using production materials, qualified substitutes or simulated product proven to have equivalent behaviour under normal operating conditions with worst case batch sizes. The frequency of sampling used to confirm process control should be justified;i. 设备使用生产物料、合格替代物或模拟产品在最差批量工况的正常操作条件下进行测试，被证明具有等同表现。工艺控制的取样频次应当经过充分证明。ii. Tests should cover the operating range of the intended process, unless documented evidence from the development phases confirming the operational ranges is available.ii. 测试应覆盖预期工艺的操作范围，除非有文件证明在研发阶段确认过操作范围。4. RE-QUALIFICATION4. 再确认4.1. Equipment, facilities, utilities and systems should be evaluated at an appropriate frequency to confirm that they remain in a state of control.4.1. 应当对设备、设施、公用工程和系统保持合适的评估频率，以确保其依然在受控状态。4.2. Where re-qualification is necessary and performed at a specific time period, the period should be justified and the criteria for evaluation defined. Furthermore, the possibility of small changes over time should be assessed.4.2. 如果需要在一个特定时间周期内进行再验证，则应对该时间周期进行论证，并确定评估的标准。此外，应评估随着时间推移产生小变更的可能性。5. PROCESS VALIDATION5. 工艺验证General通则5.1. The requirements and principles outlined in this section are applicable to the manufacture of all pharmaceutical dosage forms. They cover the initial validation of new processes, subsequent validation of modified processes, site transfers and ongoing process verification. It is implicit in this annex that a robust product development process is in place to enable successful process validation.5.1. 本节提出的要求和原则适用于所有药品剂型，包括新工艺的初次验证、工艺变更后的验证、现场转移及持续的工艺验证。本附录认为一个成熟稳定的研发工艺有助于确保工艺验证的成功。5.2. Section 5 should be used in conjunction with the current EMA guideline on Process Validation.5.2. 第五节应该和现行的欧洲药品局关于工艺验证的指南联合使用。5.2.1. The guideline on Process Validation is intended to provide guidance on the information and data to be provided in the regulatory submission only. However GMP requirements for process validation continue throughout the lifecycle of the process5.2.1. 本工艺验证指南仅仅为提交给药政当局的相关信息和数据提供指导。然而，GMP对工艺验证的要求依然是贯穿于工艺的整个生命周期。5.2.2. This approach should be applied to link product and process development. It will ensure validation of the commercial manufacturing process and maintenance of the process in a state of control during routine commercial production.5.2.2. 本方法适用于关联产品和工艺开发，它可以确保商业化的生产工艺和工艺维护在商业化生产期间处于受控状态。5.3. Manufacturing processes may be developed using a traditional approach or a continuous verification approach. However, irrespective of the approach used, processes must be shown to be robust and ensure consistent product quality before any product is released to the market. Manufacturing processes using the traditional approach should undergo a prospective validation programme, wherever possible, prior to certification of the product. Retrospective validation is no longer an acceptable approach.5.3. 可以使用传统方法或持续改进的方法对生产工艺进行开发。但是，不管使用何种方法，工艺都必须是成熟稳定的，并确保在产品上市之前其质量的一致性。使用传统方法开发的生产工艺在产品放行前都应当经过前验证。回顾性验证不再是可接受的方式。5.4. Process validation of new products should cover all intended marketed strengths and sites of manufacture. Bracketing could be justified for new products based on extensive process knowledge from the development stage in conjunction with an appropriate ongoing verification programme.5.4. 新产品的工艺验证应当包括所有计划上市的规格和生产场所。基于开发阶段大量的工艺知识，结合适当的正在进行中的验证程序，新产品可以经过论证采用界定法。5.5. For process validation of products which are transferred from one site to another or within the same site, the number of validation batches could be reduced by the use of a bracketing approach. However, existing product knowledge, including the content of the previous validation, should be available. Different strengths, batch sizes and pack sizes/container types may also use a bracketing approach, if justified.5.5. 对于同一地点内或者两个不同地点之间的场地转移的工艺验证，可以使用界定法减少验证批次。但是，必须保证现有的产品知识（