欧盟GMP附录15：确认与验证(修订版英文 中文)

EUROPEAN COMMISSION ENTERPRISE DIRECTORATE-GENERAL Single market, regulatory environment, industries under vertical legislation Pharmaceuticals and cosmetics Brussels,30 March 2015 EudraLex 欧盟药品管理法 Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal 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 目录 原则    2 概述    3 1.    确认和验证的组织和计划    3 2.    文件，包括验证主计划    5 3.    设备、设施、公用和系统的确认阶段    7 5.    工艺验证    10 6.    运输确认    19 7.    包装验证    20 8.    公用工程的确认    20 9.    检验方法验证    21 10.    清洁验证    21 11.    变更控制    25 12.    词汇    26 Principle 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 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 validATION 1. 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 clarity 1.6. 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 VMP 2. 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-QUALIFICATION 4. 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 validATION 5. 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 process 5.2.1. 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（包括上一次的验证内容）可用。不同之处在于，可以使用界定法决定批量、包装规格、包装容器类型。 5.6. For the site transfer of legacy products, the manufacturing process and controls must comply with the marketing authorisation and meet current standards for marketing authorisation for that product type. If necessary, variations to the marketing authorisation should be submitted. 5.6. 对于老产品的生产地址转移,生产工艺和控制应符合上市监督管理要求，产品类型应符合相应的现行上市标准。必要的时候还应当提交上市许可的变更。 5.7. Process validation should establish whether all quality attributes and process parameters, which are considered important for ensuring the validated state and acceptable product quality, can be consistently met by the process. The basis by which process parameters and quality attributes were identified as being critical or non-critical should be clearly documented, taking into account the results of any risk assessment activities. 5.7. 工艺验证应当证明是否所有的质量属性和工艺参数（被认为可以确保验证状态和产品质量的重要项目）能够与工艺持续相符。应当根据风险评估的结果，在文件中明确哪些工艺参数和质量属性是关键的或者不关键的。 5.8. Normally batches manufactured for process validation should be the same size as the intended commercial scale batches and the use of any other batch sizes should be justified or specified in other sections of EudraLex, Volume 4. 5.8. 工艺验证批次与计划商业化生产的上市批次的批量应保持一致，使用其他批量应按照第四卷其他部分相关的要求进行评估和说明。 5.9. Equipment, facilities, utilities and systems used for process validation should be qualified. Test methods should be validated for their intended use. 5.9. 设备、设施、公用工程和系统在工艺验证前应经过确认，预定用途的检验方法应经过验证。 5.10. For all products irrespective of the approach used, process knowledge from development studies or other sources should be accessible to the manufacturing site, unless otherwise justified, and be the basis for validation activities. 5.10. 与所使用的方法无关，除非经过其他评估，所有产品在研发阶段或者其它来源的工艺知识应当被生产工厂做接收，并作为验证活动开展的基础。 5.11. For process validation batches, production, development, or other site transfer personnel may be involved. Batches should only be manufactured by trained personnel in accordance with GMP using approved documentation. It is expected that production personnel are involved in the manufacture of validation batches to facilitate product understanding. 5.11. 对于工艺验证批而言，生产、研发或者其他现场转移的人员均需要参加。验证批次必须由按照GMP文件规定培训合格的人员进行生产，这样有助于生产人员通过工艺验证批次生产加深对工艺的理解。 5.12. The suppliers of critical starting and packaging materials should be qualified prior to the manufacture of validation batches; otherwise a justification based on the application of quality risk management principles should be documented. 5.12. 在工艺验证开始之前，应审核起始物料、包装材料的供应商，以确定其资质。否则，应当根据风险管理的原则来证明不这样做的理由。 5.13. It is especially important that the underlying process knowledge for the design space justification (if used) and for development of any mathematical models (if used) to confirm a process control strategy should be available. 5.13. 需要特别强调的是，基于设计空间（如有使用）和工艺开发数学模型（如有使用）的基础知识确定的工艺控制策略是可接受的。 5.14. Where validation batches are released to the market, this should be pre-defined. The conditions under which they are produced should fully comply with GMP, with the validation acceptance criteria, with any continuous process verification criteria (if used) and with the marketing authorisation or clinical trial authorisation. 5.14. 验证批上市之前，应确定产品的生产环境应完全符合GMP、验证可接受标准、持续工艺确认标准（如有使用），并获得上市许可或临床许可。 5.15. For the process validation of investigational medicinal products (IMP), please refer to Annex 13. 5.15. 临床试验用药品（IMP）的工艺验证，参见附录13。 Concurrent validation 同步验证 5.16. In exceptional circumstances, where there is a strong benefit-risk ratio for the patient, it may be acceptable not to complete a validation programme before routine production starts and concurrent validation could be used. However, the decision to carry out concurrent validation must be justified, documented in the VMP for visibility and approved by authorised personnel. 5.16. 在特殊情况下，如果对患者利益明显大于风险，允许在常规商业化生产前没有完成验证程序而使用同步验证。然而，进行同步验证的决定必须进行论证，并在验证主计划中明确，且经被授权的人批准。 5.17. Where a concurrent validation approach has been adopted, there should be sufficient data to support a conclusion that any given batch of product is uniform and meets the defined acceptance criteria. The results and conclusion should be formally documented and available to the Qualified Person prior to certification of the batch. 5.17. 当采用同步验证的时候，应有足够数据支持做出“批次间产品是均一的且符合预定可接受标准”的结论。结果和结论应进行正式记录，并在批放行前通过质量授权人审核。 Traditional process validation 传统工艺验证 5.18. In the traditional approach, a number of batches of the finished product are manufactured under routine conditions to confirm reproducibility. 5.18. 在传统方式中，需要在正常条件下生产出很多批成品才能确认其重现性。 5.19. The number of batches manufactured and the number of samples taken should be based on quality risk management principles, allow the normal range of variation and trends to be established and provide sufficient data for evaluation. Each manufacturer must determine and justify the number of batches necessary to demonstrate a high level of assurance that the process is capable of consistently delivering quality product. 5.19. 生产批次数和取样样品数量都应基于质量风险管理的原则，如果能够提供足够的数据进行评估，允许规定变动和趋势的范围。生产商需要确定和交代必须生产多少批次才可以表明工艺能够持续生产出优质产品的高水平保证度。 5.20. Without prejudice to 5.19, it is generally considered acceptable that a minimum of three consecutive batches manufactured under routine conditions could constitute a validation of the process. An alternative number of batches may be justified taking into account whether standard methods of manufacture are used and whether similar products or processes are already used at the site. An initial validation exercise with three batches may need to be supplemented with further data obtained from subsequent batches as part of an on-going process verification exercise. 5.20. 一般来说，在不违背5.19的情况下，正常生产条件下至少连续生产三个批次可被认为满足工艺验证要求。若使用其他批次数，需从该场地是否使用标准操作方法、是否有类似产品或工艺进行评估。初次的三批验证可能需要后续足够批次生产数据来补充，并作为连续工艺确认的一部分。 5.21. A process validation protocol should be prepared which defines the critical process parameters (CPP), critical quality attributes (CQA) and the associated acceptance criteria which should be based on development data or documented process knowledge. 5.21. 应准备工艺验证方案，根据研发数据或工艺知识明确关键工艺参数、关键质量属性和相关的可接受标准。 5.22. Process validation protocols should include, but are not limited to the following: 5.22. 工艺验证方案应包括但不局限以下内容： i. A short description of the process and a reference to the respective Master Batch Record; i. 工艺的简要描述和对应的主批记录的列表； ii. Functions and responsibilities; ii. 功能与职责划分； iii. Summary of the CQAs to be investigated; iii. 将被研究的关键质量属性列表； iv. Summary of CPPs and their associated limits; iv. 关键质量属性及其限度的汇总表； v. Summary of other (non-critical) attributes and parameters which will be investigated or monitored during the validation activity, and the reasons for their inclusion; v. 在验证活动中被研究或监控的其他质量属性（非关键的）和参数一览表，并说明选择它们的理由； vi. List of the equipment/facilities to be used (including measuring/monitoring/recording equipment) together with the calibration status; vi. 将被使用的设备/设施（含测量、监控、记录设备）一览表及其校准状态； vii. List of analytical methods and method validation, as appropriate. vii. 如适用，应有分析方法及其方法验证列表； viii. Proposed in-process controls with acceptance criteria and the reason(s) why each in-process control is selected; viii. 拟定有可接受标准的中控措施及为何选择它们作为中控的理由； ix. Additional testing to be carried out with acceptance criteria; ix. 含有可接受标准的其它将要进行的附加测试； x. Sampling plan and the rationale behind it; x. 取样计划及其合理性； xi. Methods for recording and evaluating results; xi. 结果的记录和评价方法； xii. Process for release and certification of batches (if applicable). xii. 放行流程及批合格证的发放（适用时）。 Continuous process verification  持续工艺确认 5.23. For products developed by a quality by design approach, where it has been scientifically established during development that the established control strategy provides a high degree of assurance of product quality, then continuous process verification can be used as an alternative to traditional process validation. 5.23. 对于采用质量源于设计的理念开发出来的药品，由于其工艺在研发期间已被科学地建立，所建立的控制策略提供了高水平的产品质量保证，那么持续性工艺确认可以作为传统工艺验证的替代性选择。 5.24. The method by which the process will be verified should be defined. There should be a science based control strategy for the required attributes for incoming materials, critical quality attributes and critical process parameters to confirm product realisation. This should also include regular evaluation of the control strategy. Process Analytical Technology and multivariate statistical process control may be used as tools. Each manufacturer must determine and justify the number of batches necessary to demonstrate a high level of assurance that the process is capable of consistently delivering quality product. 5.24. 应当明确过程采用哪种方法进行验证，应该有针对原辅料、关键质量属性和关键工艺参数的基于科学基础的控制策略以确保产品实现要求的质量标准，这也包括对控制策略的定期评估。过程分析技术和多变量的统计学手段可以作为工具使用。生产商需要确定和交代必须生产多少批次才可以表明工艺能够持续生产出优质产品的高水平保证度。 5.25. The general principles laid down in 5.1 – 5.14 above still apply. 5.25. 上述5.1~5.14的基本原则仍然适用。 Hybrid approach 混合型方法 5.26. A hybrid of the traditional approach and continuous process verification could be used where there is a substantial amount of product and process knowledge and understanding which has been gained from manufacturing experience and historical batch data. 5.26. 在有大量的产品与工艺知识和基于生产经验及历史批生产数据支持，对工艺有良好认识的基础上，可以使用传统方法和持续性工艺确认组成的混合型方法。 5.27. This approach may also be used for any validation activities after changes or during ongoing process verification even though the product was initially validated using a traditional approach. 5.27. 这种方法也适用于变更后或首次使用了传统的验证方法并正在进行持续性工艺确认期间的任何验证活动。 Ongoing Process Verification during Lifecycle  生命周期中的连续工艺确认 5.28. Paragraphs 5.28-5.32 are applicable to all three approaches to process validation mentioned above, i.e. traditional, continuous and hybrid. 5.28. 本文5.28~5.32款适用于传统、持续性、混合型的工艺验证方法。 5.29. Manufacturers should monitor product quality to ensure that a state of control is maintained throughout the product lifecycle with the relevant process trends evaluated. 5.29. 生产商应通过评估相关的工艺趋势来监控产品质量以确保其在整个生命周期中始终处于受控状态。 5.30. The extent and frequency of ongoing process verification should be reviewed periodically. At any point throughout the product lifecycle, it may be appropriate to modify the requirements taking into account the current level of process understanding and process performance. 5.30. 应定期审核连续性工艺确认的程度和频率，考虑到对现有工艺的理解程度和工艺性能，允许在产品生命周期的任何一点上对工艺要求进行修改。 5.31. Ongoing process verification should be conducted under an approved protocol or equivalent documents and a corresponding report should be prepared to document the results obtained. Statistical tools should be used, where appropriate, to support any conclusions with regard to the variability and capability of a given process and ensure a state of control. 5.31. 持续性工艺确认应在应批准的方案或等同文件的指导下进行，同时应当准备一个相应的报告来将获取的结果文件化。如果需要的话，可以使用统计学工具来对既有工艺的变化和性能做出判断，以确保工艺处于受控状态。 5.32. Ongoing process verification should be used throughout the product lifecycle to support the validated status of the product as documented in the Product Quality Review. Incremental changes over time should also be considered and the need for any additional actions, e.g. enhanced sampling, should be assessed. 5.32. 连续工艺确认应在产品生命周期中进行，充分考虑随着时间递增的变化情况，评估采取附加措施的必要性（如增加取样），以证明工艺处在产品质量回顾中所述的验证状态。 6. VERIFICATION OF TRANSPORTATION 6. 运输确认 6.1. Finished medicinal products, investigational medicinal products, bulk product and samples should be transported from manufacturing sites in accordance with the conditions defined in the marketing authorisation, the approved label, product specification file or as justified by the manufacturer. 6.1. 成品药物、临床研究用药、大宗原料药及样品应从生产商按照上市许可规定的条件、批准的标签、质量标准或生产合格证进行发运。 6.2. It is recognised that verification of transportation may be challenging due to the variable factors involved however, transportation routes should be clearly defined. Seasonal and other variations should also be considered during verification of transport 6.2. 由于各种变化性因素，对运输确认进行挑战性试验已成为共识，并且明确运输线路。在运输确认中，应当考虑季节和其他变化因素对运输的影响。 6.3. A risk assessment should be performed to consider the impact of variables in the transportation process other than those conditions which are continuously controlled or monitored, e.g. delays during transportation, failure of monitoring devices, topping up liquid nitrogen, product susceptibility and any other relevant factors. 6.3. 应当对运输过程中除了持续受控或监测的条件以外的变量因素的影响进行风险评估，比如：运输延迟、监控设备失效、液氮补充、产品敏感性和其他相关因素。 6.4. Due to the variable conditions expected during transportation, continuous monitoring and recording of any critical environmental conditions to which the product may be subjected should be performed, unless otherwise justified. 6.4. 对于运输过程中已知的环境变化，产品可能面对的任何关键环境因素都应持续受控并记录，否则应说明理由。 7. validATION OF PACKAGING 7. 包装验证 7.1. Variation in equipment processing parameters especially during primary packaging may have a significant impact on the integrity and correct functioning of the pack, e.g. blister strips, sachets and sterile components, therefore primary and secondary packaging equipment for finished and bulk products should be qualified. 7.1. 由于设备参数的变化对基础包装的完整性和正确性有重要影响，比如铝塑条形包装、小袋和无菌部件，因此用于最终产品和中间产品的初级和次级包装设备需要进行确认。 7.2. Qualification of the equipment used for primary packing should be carried out at the minimum and maximum operating ranges defined for the critical process parameters such as temperature, machine speed and sealing pressure or for any other factors. 7.2. 初级包装设备的确认应包含关键工艺参数操作范围的上下限，比如温度、转速、密封压力及其他相关因素。 8. QUALIFICATION OF UTILITIES 8. 公用工程的确认 8.1. The quality of steam, water, air, other gases etc. should be confirmed following installation using the qualification steps described in section 3 above. 8.1. 蒸汽、制药用水、空气及其他气体等，应按照本文第3节所述的步骤进行确认。 8.2. The period and extent of qualification should reflect any seasonal variations, if applicable, and the intended use of the utility. 8.2. 如果适用的话，确认的周期和程度应当反映任何季节性变化和公用工程的预期用途。 8.3. A risk assessment should be carried out where there may be direct contact with the product, e.g. heating, ventilation and air-conditioning (HVAC) systems, or indirect contact such as through heat exchangers to mitigate any risks of failure. 8.3. 应当对加热、通风、空调系统等与产品直接接触的介质或换热器等不直接接触产品的介质进行风险评估以降低失败的风险。 9. validATION OF TEST METHODS 9. 检验方法验证 9.1. All analytical test methods used in qualification, validation or cleaning exercises should be validated with an appropriate detection and quantification limit, where necessary, as defined in Chapter 6 of the EudraLex, Volume 4, Part I. 9.1. 用于确认、验证或清洁活动中的任何检验方法应当按照第四卷第一部分第六章规定进行包括检测限和定量限在内的分析方法验证。 9.2. Where microbial testing of product is carried out, the method should be validated to confirm that the product does not influence the recovery of microorganisms. 9.2. 如果产品需要做微生物测试，那么检验方法需要进行验证以确保产品不会影响微生物的回收率。 9.3. Where microbial testing of surfaces in clean rooms is carried out, validation should be performed on the test method to confirm that sanitising agents do not influence the recovery of microorganisms. 9.3. 当洁净区做表面微生物检测时，检验方法需要进行验证以确保消毒剂不会影响微生物回收率。 10. CLEANING VALIDATION 10. 清洁验证 10.1. Cleaning validation should be performed in order to confirm the effectiveness of any cleaning procedure for all product contact equipment. Simulating agents may be used with appropriate scientific justification. Where similar types of equipment are grouped together, a justification of the specific equipment selected for cleaning validation is expected. 10.1. 清洁验证的目的是为了确认清洁程序对产品接触设备的清洁效果。根据科学合理的评判，可以使用模拟试剂。如果相同类型的设备作为一组进行验证时，应当说明选择特定设备开展清洁验证的原因。 10.2. A visual check for cleanliness is an important part of the acceptance criteria for cleaning validation. It is not generally acceptable for this criterion alone to be used. Repeated cleaning and retesting until acceptable residue results are obtained is not considered an acceptable approach. 10.2. 清洁验证中的目测检查干净与否是可接受标准的重要评判指标，但只进行目检的话则是不充分的，一般不被接受。重复清洁和重复测试至残留物达到合格标准也被认为是不能接受的。 10.3. It is recognised that a cleaning validation programme may take some time to complete and validation with verification after each batch may be required for some products, e.g. investigational medicinal products. There should be sufficient data from the verification to support a conclusion that the equipment is clean and available for further use. 10.3. 完成一个清洁验证程序需要一定的时间是取得共识的，可能部分产品（如临床试验用产品）在每批生产结束后需要对验证进行确认。应从确认中获得足够的数据以支持“设备已被清洁干净并且满足后续使用”的结论。 10.4. validation should consider the level of automation in the cleaning process. Where an automatic process is used, the specified normal operating range of the utilities and equipment should be validated. 10.4. 清洁验证应考虑清洁程序的自动化应用水平，当采用自动化程序时，应当验证公用系统和设备指明的正常操作范围。 10.5. For all cleaning processes an assessment should be performed to determine the variable factors which influence cleaning effectiveness and performance, e.g. operators, the level of detail in procedures such as rinsing times etc. If variable factors have been identified, the worst case situations should be used as the basis for cleaning validation studies. 10.5. 应当对清洁工艺有哪些影响清洁效果和清洁性能的变量进行评估，例如操作员、程序中的细节像淋洗时间等，若变量经过证实，那么应考虑将最差条件作为清洁验证研究的基础。 10.6. Limits for the carryover of product residues should be based on a toxicological evaluation. The justification for the selected limits should be documented in a risk assessment which includes all the supporting references. Limits should be established for the removal of any cleaning agents used. Acceptance criteria should consider the potential cumulative effect of multiple items of equipment in the process equipment train. 10.6. 产品残留的携带限度应根据毒理学评价，限度选择的依据应在包含参考文件的风险评估中写明，还应当给出所使用清洁剂残留的限度，可接受标准制定时还应当考虑工艺设备清单中多个设备潜在的累积效应。 10.6.1.Therapeutic macromolecules and peptides are known to degrade and denature when exposed to pH extremes and/or heat, and may become pharmacologically inactive. A toxicological evaluation may therefore not be applicable in these circumstances. 10.6.1. 已知治疗性大分子和肽链在pH超过限制或加热的情况下会发生降解和变性，有可能失去药理学活性，基于毒理学的评价在这种情况下有可能不适用。 10.6.2.If it is not feasible to test for specific product residues, other representative parameters may be selected, e.g. total organic carbon (TOC) and conductivity. 10.6.2. 如果没有办法可以检测特定的产品残留，可以使用其他代表性参数，比如总有机碳（TOC）和电导率。 10.7. The risk presented by microbial and endotoxin contamination should be considered during the development of cleaning validation protocols. 10.7. 在制定清洁验证方案时，应考虑可能出现的微生物和细菌内毒素风险。 10.8. The influence of the time between manufacture and cleaning and the time between cleaning and use should be taken into account to define dirty and clean hold times for the cleaning process. 10.8. 清洁工艺中，应考虑生产完成至清洁开始以及清洁后至再次使用的时间间隔，以明确脏设备和干净设备的存放时间。 10.9. Where campaign manufacture is carried out, the impact on the ease of cleaning at the end of the campaign should be considered and the maximum length of a campaign (in time and/or number of batches) should be the basis for cleaning validation exercises. 10.9. 采用连续性生产时，应考虑在生产结束后进行清洁的难易程度，并将最长连续生产的时间（以时间和/或生产批次计）作为清洁验证的基础。 10.10. Where a worst case product approach is used as a cleaning validation model, a scientific rationale should be provided for the selection of the worst case product and the impact of new products to the site assessed. Criteria for determining the worst case may include solubility, cleanability, toxicity and potency. 10.10. 当采用最差条件产品的方法作为清洁验证模式时，应从溶解性、可清洁性、毒性和效价等方面科学合理的解释为什么选择该产品作为最差条件的产品，并在有新产品引入时应评估其影响。 10.11. Cleaning validation protocols should specify or reference the locations to be sampled, the rationale for the selection of these locations and define the acceptance criteria.