EU GMP Annex 15 Qualification and Validation.docx

EU GMP annex 15 Qualification and Validation (draft)Brussels, 6 February 2014 SANCO/TSE/ The received contributions together with the identity of contributors will be made publicly available, unless the contributor objects to publication of his or her personal data on the grounds that such publication would harm his or her legitimate interests. In this case the contribution may be published in anonymous form. Otherwise the contribution will not be published nor will, in principle, its content be taken into account. For more information on the processing of your personal data in the context of this consultation, read the specific Privacy Statement available at: link to Privacy Statement EudraLexThe Rules Governing Medicinal Products in the European UnionVolume 4EU Guidelines for Good Manufacturing Practicefor Medicinal Products for Human and Veterinary UseAnnex 15: Qualification and Validation 欧盟人用及兽用药品GMP指导原则 附件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. Status of the document: Revision 1 文件状态：修订Proposed document time table: Deadline for comments on the draft concept paperFebruary 2013Draft guideline discussion in the GMDP IWGJune 2013Draft guideline discussion with other groupsJune - September 2013Comments by GMDP IWG and PIC/SOctober 2013Adoption of Final Draft for public consultation - Delayed due to additional GMDP IWG comments 2014(November 2013) - JanuaryStart of public consultation - delayed(December 2013) -February 2014End of public consultation (deadline for comments)(March 2014) - May 2014Re-discussion in GMDP IWGSeptember 2014Expected adoption by ECOctober 2014Reasons for changes: Update as per concept paper on revision of Annex 15. Summary of changes: This change to annex 15 takes into account changes to other sections of the EU-GMP Guide Part I, Annex 11, ICH Q8, Q9, Q10 and Q11, QWP guidance on process validation and changes in manufacturing technology. 变更概述：附件15的变更综合考虑了EU GMP 第一部分 附件11，ICH Q8, Q9, Q10 and Q11, QWP指南中关于工艺验证的变更内容以及生产技术的变化。Deadline for coming into operation: to be determined. 生效时间：待定重要的修订内容：l 本附件综合了ICH Q8制药研发， Q9质量风险管理， Q10制药质量体系，Q11原料药研发制造的内容。l 引入新的术语，例如进行中验证策略（ongoing validation strategy）；l 回顾性验证和再验证的概念已经删除；l 在设备使用中，关于设备确认的信息几乎被忽略；l 增加运输确认的命名，包装验证；l 设施验证和分析方法验证有新的要求；l 工艺验证有2种不同的方法，一种是现代的“持续验证”方法，另一种是传统方法。但在任何情况下，应当证明工艺的耐用性；l 工艺验证的分组方法（Bracketing approaches）；l 在工艺持续确认与传统工艺验证之间的混合方法仍然有些模糊（fuzzy）；l 关于清洁验证的“清洁”标准不再是唯一的标准；l 设备清洁验证的分组具有了明确的可能性，但需要创建；l 清洁验证的接受标准取绝于毒理数据PDE(permitted daily exposure 每天允许暴露量)；l 清洗验证的批次根据风险评估来决定，不在强求进行3个批次；l 生产批次很少的产品，对于清洁验证的理念也有了新的要求；l 要求研究和制定的清洁后的有效期；Table of content 目录Principle 原则5General 通则51ORGANISING AND PLANNING FOR QUALIFICATION AND VALIDATION6确认、验证的组织和计划62DOCUMENTATION INCLUDING VMP 文件，包括VMP73QUALIFICATION STAGES FOR EQUIPMENT, FACILITIES AND UTILITIES9设备、设施和公用系统确认阶段94PROCESS VALIDATION 工艺验证125VERIFICATION OF TRANSPORTATION 运输确认196VALIDATION OF PACKAGING 包装验证207VALIDATION OF UTILITIES 公用系统验证208VALIDATION OF TEST METHODS 检验方法验证219CLEANING VALIDATION 清洁验证2110RE-QUALIFICATION 再确认2411CHANGE CONTROL 变更控制24GLOSSARY 术语25QUALIFICATION AND VALIDATION 确认和变更Principle 原则This 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. 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 be validated according to the requirements of Annex 11. The relevant concepts and guidance presented in ICH Q8, Q10 and Q11 should also be taken into account. .本附件描述了确认和验证的原则，本原则适用于药品生产的施舍、设备、公用系统和工艺。是生产商通过产品和工艺整个生命周期进行确认和验证对生产操作关键方面进行控制的GMP 要求。在设施、设备和工艺等，对产品质量会产生重大影响计划变更需要进行记录，对验证状态或者控制策略进行评估。药品生产中使用的计算机化系统需要根据附件11的要求进行验证。相关概念在ICH Q8有呈现, 并综合考虑了Q10 以及Q11指南中的相关概念。General 通则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 validation and qualification should be based on a justified and documented risk assessment of the facilities, equipment, utilities and processes. The principles in ICH Q8, Q9, Q10 and Q11 or other systems guaranteeing at least the same level of product quality and security should be used to support validation and qualification activities. 质量风险管理方法应该应用与整个药品的生命周期中。作为质量风险管理体系的一部分，确认和验证范围及程度的决定应该基于对设施、设备、公用系统和工艺的评估，评估应合理并有文件记录。应当使用ICH Q8, Q9, Q10 ，Q11以及其他能保证至少相同质量水平和安全的文件以支持确认和验证活动。Data supporting qualification and/or validation studies which were obtained from sources outside of the manufacturers own validation programme 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. 来自公司自己验证项目以外的数据可以用于支持确认/验证研究，只要此数据的验证方法合理并对数据的获得过程中有足够的保证。1 ORGANISING AND PLANNING FOR QUALIFICATION AND VALIDATION 确认、验证的组织和计划1.1 All qualification and validation activities should be planned and take the life cycle of equipment, process and product into consideration. 所有的确认和验证活动都要进行计划，考虑设备、工艺和产品的证明周期。1.2 Validation activities should only be performed by suitably trained personnel who follow approved validation procedures. 验证活动只能是接受过适当培训的人员按照批准的规程进行。1.3 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 oversight over the whole validation life cycle. 验证人员应该按照药品质量体系中的规定进行报告，但这不一定是作为质量管理或者质量保证的职能；但是整个验证周期应有适当的监控。1.4 The key elements of the site validation programme should be clearly defined and documented in a validation master plan (VMP) or equivalent document. 现场验证的关键项目应在验证主计划或者相关文件中清晰列出和记录。1.5 The VMP should be a summary document which is brief, concise, clear and contain data on at least the following: 验证主计划应该是个概述性文件，简短、简明、清晰并至少包含以下资料：a) Validation policy. 验证方针b) The organisational structure for validation activities. 验证组织机构c) Summary of the facilities, systems, equipment, processes on site and the current validation status. 要验证的设施、系统、设备、工艺的汇总以及当前的验证状态。d) Template formats to be used for protocols and reports. 方案和报告模板e) Planning and scheduling. 计划和时间表f) Change control and deviation management for validation. 验证的变更控制和偏差管理g) Handling of acceptance criteria 可接受标准的处理h) References to existing documents. 对已有文件的引用i) An assessment of the resources required. 所要求的资源的评估j) The ongoing validation strategy, including revalidation and/ re-qualification, where applicable.进行中的验证策略，包括再验证和再确认，如有必要k) Confirmation that the materials used for validation are of the required quality and suppliers are qualified to the appropriate level. . 确认验证适用的资料符合质量要求，供应商为批准的供应商。1.6 For large and complex projects, planning takes on added importance and it may be necessary to create a separate VMP. 对于较大和复杂的项目，计划就尤为重要，必要时可分开制定验证主计划。1.7 A quality risk management approach should be used for validation activities with risk assessments repeated, as required, in light of increased knowledge and understanding from any changes during the project phase or during commercial production. The way in which risk assessments are used to support validation activity should be clearly documented. 鉴于在项目过程中或商业化生产中随着知识积累和认识的增加，质量风险管理的方法在验证活动中反复使用。用于支持验证的风险评估应当有清晰的记录。2 DOCUMENTATION INCLUDING VMP 文件包括验证主计划2.1 Good documentation practices are important to support knowledge management throughout the validation lifecycle. GMP 在整个验证过程中对于提供知识管理尤为重要。2.2 All documents generated during validation should be approved and authorised by appropriate personnel as defined in the pharmaceutical quality system. 验证过程中产生的所有文件应该由适当的人员按照药品质量体系进行审核批准。2.3 The relationship between documents in complex validation projects should be clearly defined and any inter-relationships documented. 对于较复杂的验证项目中文件之间的关系以及记录的文件之间的关系应当有清晰的说明。2.4 A written validation protocol should be prepared which defines the critical systems, attributes and parameters which are important and the acceptance criteria for each. 准备书面验证方案，规定关键系统，属性重要参数以及各项的接受标准。2.5 Where validation protocols are supplied by a third party, the manufacturer should confirm suitability and compliance with company procedures before approval. 当验证方案由第三方提供时，生产商在批准之前要确定其适用性并符合公司规程。2.6 Any changes to the approved protocol during execution should be documented as a deviation and be scientifically justified. 执行期间批准的方案的任何变更都要作为偏差进行记录并科学处理。2.7 Results which fail to meet the pre-defined acceptance criteria should be recorded as a deviation, be fully investigated and any implications for the validation discussed in the report. 不符合既定接受标准的结果要按照偏差进行记录，进行全面调查并在报告中评估对验证的影响。2.8 The 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. 将偏差结论进行报告，将总结获得的结果与接收标准对比。任何可接收标准的变更都要经过科学的证明并验证结果给出最终结论。2.9 A formal release for the next step in the 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 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. 验证过程中，上一阶段的验证或确认活动符合标准并经过相关人员批准后方可进行一下阶段活动，作为验证批准报告的一部分或者作为单独的总结文件。当上一阶段的某些活动不能满足标准或者偏差未进行完全处理时，经评估对下一阶段的活动没有重大影响时，对上一阶段的活动可进行有条件批准。3 QUALIFICATION STAGES FOR EQUIPMENT, FACILITIES AND UTILITIES 设备、设施和公用系统确认阶段3.1 Validation and qualification activities should consider all stages from initial development of the user requirements specification or initial process development through to the end of use of the equipment, facility or process. 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: 验证和确认应该考虑从URS设计或者初始工艺开发到设备设施或工艺使用结束的所有阶段。主要阶段和每个阶段的一些建议性的标准（尽管标准会因项目和环境的不同而不同）如下：User requirements specification (URS) 用户需求3.2 The specification for new facilities, systems or equipment 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 minimised. The URS should be a point of reference throughout the validation life cycle. URS或者功能性说明里应该规定新设施、系统或设备的规格。本阶段需要构建质量基本要素并将GMP风险最小化。用户需求应为贯穿验证生命周期的参考点。Design qualification (DQ) 设计确认3.3 The next element in the validation of new facilities, systems or equipment is DQ where the compliance of the design with GMP should be demonstrated and documented. The requirements of the user requirements specification should also be verified during the design qualification. 新设施、系统或设备验证的下个要素是设计确认，应该证明并记录设计的GMP合规性。设计确认过程中应符合URS的要求。Factory acceptance testing (FAT) /Site acceptance testing (SAT) 工厂验收测试/现场验收测试3.4 Equipment, especially if incorporating novel or complex technology, should be evaluated at the vendor prior to delivery. 设备特别是有新颖或复杂技术的，在交付之前应该队供应商评估。3.5 Prior to installation, equipment should be confirmed to comply with the URS/ functional specification at the vendor site unless otherwise justified. 安装之前，在供应商生产场所确认设备符合URS要求或者功能说明的要求，另有规定除外。3.6 Where appropriate and justified, documentation review and some tests could be performed at the FAT stage without the need to repeat on site if it can be shown that the functionality is not affected by the transport and installation. 必要和合适条件下，在工厂验收阶段应进行文件审核及相关测试，如果可以证明设备在运输和安装时功能不受影响，在厂区可以不必重复操作。3.7 FAT may be supplemented by the execution of a SAT following the receipt of equipment at the manufacturing site. 设备接收时在生产现场进行的现场验收测试可作为工厂验收测试的补充。Installation qualification (IQ) 安装确认3.8 IQ should be performed on new or modified facilities, systems and equipment. 安装确认是针对新的或者修改的设施、系统和设备。3.9 IQ could include, but is not be limited to the following: 安装确认包括但不限于以下内容：a) Installation of equipment, pipe work, services and instrumentation as detailed in the design and confirmation of current engineering regarding drawings and specifications. 按照现行确认的图纸规格对设备、管道、服务和仪器进行安装。b) Verification of the correct installation against pre-defined criteria. 正确安装与既定标准确认。c) Collection and collation of supplier operating and working instructions and maintenance requirements. 收集整理供应商操作和工作说明以及维护要求。d) Calibration of instrumentation. 仪器校验e) Verification of the materials of construction. 材质确认Operational qualification (OQ) 运行确认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). 运行确认一般是安装确认之后进行，但是根据设备的复杂性，运行确认可以与安装/运行确认结合。OQ could include but is not be limited to the following: 运行确认包括但不限于以下：a) Tests that have been developed from the knowledge of processes, systems and equipment. 从工艺、系统和设备知识中开发的测试b) Tests to confirm upper and lower operating limits, and/or “worst case” conditions.测试确认运行上下限度以及最坏条件3.11 The completion of a successful OQ should allow the finalisation of maintenance plans, standard operating and cleaning procedures, operator training and preventative maintenance requirements. 一份完整的成功的运行确认应该包括维护计划的确定、标准操作和清洁规程，操作人员培训和 预防性维护要求。 Performance qualification (PQ) 性能确认3.12 PQ should follow the successful completion of IQ and OQ.性能确认应在成功完成安装确认和运行确认之后进行。3.13 Although PQ is described as a separate activity, it may in some cases be appropriate to perform it in conjunction with OQ or Process Validation. 尽管讲性能确认描述为一个单独的活动，但有些情况下需要与运行确认或工艺验证结合进行。3.14 PQ could include, but is not be limited to the following: 性能确认包括但不限于以下内容：a) 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. 使用生产材料，经确认的代替品或者模拟产品的在正常生产条件下采用最坏条件的批量进行等效测试。 应该确认在测试过程中所需的取样频率。b) Tests should cover the operating range of the intended process, unless documented evidence from the development phases which confirm the operational ranges are available. 测试要涵盖预期的工艺操作范围，除非研发阶段有书面证据证明操作范围有可选择性。4 PROCESS VALIDATION 工艺验证General 通则4.1 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. 本部分规定的要求和原则适用于药品制剂的生产。涵盖了新工艺的首次验证，之后工艺修订，生产场所转移以及进行中的工艺确认的后续验证。4.2 This section should be used in conjunction with the current EMA guideline on Process Validation. Note: It should be taken into account that the guideline on Process Validation is intended to provide guidance on the information and data to be provided in the regulatory submission and GMP requirements extend beyond this. It should also be noted that a lifecycle approach is applied linking product and process development, validation of the commercial manufacturing process and maintenance of the process in a state of control during routine commercial production. 本部分请结合EMA工艺验证指南使用。需要注意的是EMA工艺验证目的是为法规提交的信息和数据提供指南，GMP 要求超出了本文件的要求。同时要注意的是生命周期方法时结合产品和工艺开发，在日常商业化生产中对生产工艺进行验证和保持工艺验证状态。4.3 Medicinal products 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 should undergo a prospective validation programme wherever possible prior to marketing of the product. 药品研发可能使用传统方法或者持续确认方法，但是不管哪种方法，放行上市之前必须都能证明工艺的稳定性并确保能持续符合产品质量。可能的情况下，产品上市之前生产工艺要进行预验证。4.4 Process validation for new products should cover all intended marketed strengths and sites of manufacture, however for products which are transferred from one site to another or within the same site, and where there is existing product knowledge, including the content of the previous validation, the number of validation batches could be reduced by the use of a bracketing approach. This approach could be acceptable for different strengths, batch sizes and pack sizes/ container types if justified. 新产品的工艺验证要涵盖所有打算上市的产品规格以及生产线，但是对于产品生产场所转移的，比如一个场所到另一个场所或者同场所之内转移的，根据已经存在产品知识的，包括先前验证内容，采用对不同规格、产品批量和包装批量和包装形式综合评估的方式减少验证次数。4.5 For the site transfer of legacy products, the manufacturing process and controls should comply with the