EU-GMP第六章节质量控制--quality-control-翻译.doc

Chapter 6: Quality Control第1部分第6章：质量控制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.出版详细指南的法律依据：指令2001/83/EC第47条关于人药统一编码和2001/82/EC第51条关于兽药统一编码规定。本文对指令2003/94/EC中人药和91/412/EEC中兽药的药品GMP原则和指南解释提供指南。Status of the document: Revision文件状态：修订Reasons for changes: 变更理由Inclusion of a new section on technical transfer of testing methods and other items such as Out Of Specification results.包括检验方法的技术转移作为新章节，包括其它项目例如OOT结果。Deadline for coming into operation: 1 October 2014生效日期：2014年10月1日Principle 原则This chapter should be read in conjunction with all relevant sections of the GMP guide Quality Control is concerned with sampling, specifications and testing as well as the organisation, documentation and release procedures which ensure that the necessary and relevant tests are carried out, and that materials are not released for use, nor products released for sale or supply, until their quality has been judged satisfactory. Quality Control is not confined to laboratory operations, but must be involved in all decisions which may concern the quality of the product. The independence of Quality Control from Production is considered fundamental to the satisfactory operation of Quality Control.本章应与GMP指南中所有相关章节一起解读。质量控制主要关注取样、质量标准和检测，同时也与组织机构、文件记录和放行程序相关，这些程序保证了必要和相关的测试。只有当产品和物料的质量被判定为可以接受时，物料才可以放行使用，产品才可以放行销售。质量控制不仅局限于化验室操作，还必须包括所有可能与产品质量相关的其它决定。质量控制独立于生产被认为是质量控制可以令人满意地操作的基础。General 通则6.1 Each holder of a manufacturing authorisation should have a Quality Control Department. This department should be independent from other departments, and under the authority of a person with appropriate qualifications and experience, who has one or several control laboratories at his disposal. Adequate resources must be available to ensure that all the Quality Control arrangements are effectively and reliably carried out.每一个生产许可持有人均应具有一个质量控制部门。该部门应独立于其它部门，由一个具有相应资质和经验的人管理，他/她可以管理一个或几个化验室。化验室应具有充分的资源，以保证所有检测要求能有效可靠地实施。6.2 The principal duties of the head of Quality Control are summarised in Chapter 2. The Quality Control Department as a whole will also have other duties, such as to establish, validate and implement all quality control procedures, oversee the control of the reference and/or retention samples of materials and products when applicable, ensure the correct labelling of containers of materials and products, ensure the monitoring of the stability of the products, participate in the investigation of complaints related to the quality of the product, etc. All these operations should be carried out in accordance with written procedures and, where necessary, recorded.质量控制负责人基本职责在第2章里进行了概括。质量控制部门作为一个整体，还具有其它职责，例如建立、验证和实施所有质量控制程序，监督物料和产品的对照和/或留样，保证物料和产品容器上标签正确，保证对产品稳定性进行监控，参与和产品质量相关的客诉的调查等等。所有这些操作均应根据书面程序进行，必要时，应进行记录。6.3 Finished product assessment should embrace all relevant factors, including production conditions, results of in-process testing, a review of manufacturing (including packaging) documentation, compliance with Finished Product Specification and examination of the final finished pack.成品的评估应综合所有相关的因素，包括生产条件、中控检测结果、生产（包括包装）文件审核、成品符合质量标准和最终包装检查。6.4 Quality Control personnel should have access to production areas for sampling and investigation as appropriate.质量控制人员应有权限进入生产区域进行取样，及适当的调查。Good Quality Control Laboratory Practice 优良质量控制化验室规范6.5 Control laboratory premises and equipment should meet the general and specific requirements for Quality Control areas given in Chapter 3. Laboratory equipment should not be routinely moved between high risk areas to avoid accidental cross-contamination. In particular, the microbiological laboratory should be arranged so as to minimize risk of cross-contamination.化验室设施和设备应符合第3章里给出的QC区域通用和特殊要求。为避免交叉污染事故，化验室设备一般不应该设计为需要常常在高风险区域之间移来移去。特别是微生物化验室的布置，应尽可能将交叉污染的风险降至最低。6.6 The personnel, premises, and equipment in the laboratories should be appropriate to the tasks imposed by the nature and the scale of the manufacturing operations. The use of outside laboratories, in conformity with the principles detailed in Chapter 7, Contract Analysis, can be accepted for particular reasons, but this should be stated in the Quality Control records.化验室的人员、设施、设备应与其检验任务和生产规模相当。在有特殊原因情况下，可以使用外部分化验室，但应符合第7章“外包分析”中的原则，并要在质量控制记录上说明。Documentation 文件6.7 Laboratory documentation should follow the principles given in Chapter 4. An important part of this documentation deals with Quality Control and the following details should be readily available to the Quality Control Department:化验室文件应符合第4章中给定的原则。这部分文件一个重要部分与质量控制相关，质量控制部门应很容易获得以下详细信息i. Specifications;质量标准ii. Procedures describing sampling, testing, records (including test worksheets and/or laboratory notebooks), recording and verifying;描述取样、检测、记录（包括检测原始记录表和/或化验室笔记本）、记录和确认情况iii. Procedures for and records of the calibration/qualification of instruments and maintenance of equipment;仪器校正/确认，设备维保程序和记录iv. A procedure for the investigation of Out of Specification and Out Of Trend results;OOS和OOT结果调查程序v. Testing reports and/or certificates of analysis;检测报告和/或分析报告vi. Data from environmental (air, water and other utilities) monitoring, where required;环境（空气、水和其它设施）监控数据，必要时vii. Validation records of test methods, where applicable.检验方法的验证记录，必要时6.8 Any Quality Control documentation relating to a batch record should be retained following the principles given in chapter 4 on retention of batch documentation.所有与批记录相关的质量控制文件均应按第4章中关于批文件保留要求的原则留存。6.9 Some kinds of data (e.g. tests results, yields, environmental controls) should be recorded in a manner permitting trend evaluation. Any out of trend or out of specification data should be addressed and subject to investigation.一些类别的数据（例如检测结果、收率、环境控制）记录方式应可以进行趋势评估。所有OOT或OOS数据均应说明，进行调查。6.10 In addition to the information which is part of the batch documentation, other raw data such as laboratory notebooks and/or records should be retained and readily available除了批记录部分的信息外，其它原始数据例如化验室记录本和/或记录均应保留备查。Sampling 取样6.11 The sample taking should be done and recorded in accordance with approved written procedures that describe:取样应根据书面程序进行并记录，书面程序应描述i. The method of sampling;取样方法ii. The equipment to be used;取样工具iii. The amount of the sample to be taken;取样量iv. Instructions for any required sub-division of the sample;分样方法v. The type and condition of the sample container to be used;要使用的样品容器类型和条件 vi. The identification of containers sampled;所取样的容器标识vii. Any special precautions to be observed, especially with regard to the sampling of sterile or noxious materials;观察到的特殊预警情况，尤其是无菌或有毒的物料取样时viii. The storage conditions;存贮条件ix. Instructions for the cleaning and storage of sampling equipment.取样器具清洁和存贮方法6.12 Samples should be representative of the batch of materials or products from which they are taken. Other samples may also be taken to monitor the most stressed part of a process (e.g. beginning or end of a process). The sampling plan used should be appropriately justified and based on a risk management approach.样品应能代表所取批次的物料或产品。也可以取其它样品以监控工艺中最极端的情况（例如在工艺的开始或结束时）。所采用的取样计划应基于风险管理方法进行适当论证。6.13 Sample containers should bear a label indicating the contents, with the batch number, the date of sampling and the containers from which samples have been drawn. They should be managed in a manner to minimize the risk of mix-up and to protect the samples from adverse storage conditions.样品容器应进行标识，指明内容物、批号、取样日期、从哪个包装取样。标签应能最大程度降低混淆风险，保护样品不会被存贮在有负面影响的条件下。6.14 Further guidance on reference and retention on reference and retention samples is given in Annex 19.更多关于对照品及存贮和留样的指南在附录19中给出。Testing 测试6.15 Testing methods should be validated. A laboratory that is using a testing method and which did not perform the original validation, should verify the appropriateness of the testing method. All testing operations described in the marketing authorisation or technical dossier should be carried out according to the approved methods.检验方法应进行验证。如果一个化验室正在使用某一个检测方法，但没有做过初始的验证，则应该确认该方法的适用性。所有在上市批准或技术文件中描述的检测操作均应根据所批准的方法进行。6.16 The results obtained should be recorded. Results of parameters identified as quality attribute or as critical should be trended and checked to make sure that they are consistent with each other. Any calculations should be critically examined.检查所得结果应记录。如果是关键质量参数或质量特性则应进行趋势分析，并检查这些项目间是否具有一致性。所有计算均应进行重点检查。6.17 The tests performed should be recorded and the records should include at least the following data:所进行的检测均应记录，记录应至少包括以下数据i. Name of the material or product and, where applicable, dosage form;物料名称或产品名称，以及剂型（适用时）ii. Batch number and, where appropriate, the manufacturer and/or supplier;批号，生产商和/或供应商名称（适用时）iii. References to the relevant specifications and testing procedures;所参照的相关质量标准和检验方法iv. Test results, including observations and calculations, and reference to any certificates of analysis;检测结果，包括观察现象和计算，所参照的检验报告v. Dates of testing;检测日期vi. Initials of the persons who performed the testing;测试人的姓名首字母vii. Initials of the persons who verified the testing and the calculations, where appropriate;对检测和计算进行复核的人员的姓名首字母（适用时）viii. A clear statement of approval or rejection (or other status decision) and the dated signature of the designated responsible person;对结果批准或拒绝的清楚结论（或其它状态决定），受任命的责任人的签名和日期ix. Reference to the equipment used.设备所用的对照品6.18 All the in-process controls, including those made in the production area by production personnel, should be performed according to methods approved by Quality Control and the results recorded.所有中控检测，包括在生产场所由生产人员所实施的检测均应按照质量控制部门批准的检测方法进行，结果应记录。 6.19 Special attention should be given to the quality of laboratory reagents, solutions, glassware, reference standards and culture media. They should be prepared and controlled in accordance with written procedures. The level of controls should be commensurate to their use and to the available stability data.要特别注意化验室试剂、溶液、玻璃器皿、对照品和培养基的质量。这些物品应根据书面程序进行准备和控制，控制水平应与其用途及稳定性数据相当。6.20 Reference standards should be established as suitable for their intended use. Their qualification and certification as such should be clearly stated and documented. Whenever compendial reference standards from an officially recognised source exist, these should preferably be used as primary reference standards unless fully justified (the use of secondary standards is permitted once their traceability to primary standards has been demonstrated and is documented). These compendial materials should be used for the purpose described in the appropriate monograph unless otherwise authorised by the National Competent Authority.对照品应适合其用途，应该清楚说明和记录其确认情况及证书。如果有官方认可的来源，则应优先采用作为基本对照品，否则应有完整的证明（采用第二对照品也是可以的，只要证明其可追溯至基本对照品并有相关记录）。除非经过国家药监部门的批准，这些药典物质只能用于其在相应药典各论中所指明的用途。6.21 Laboratory reagents, solutions, reference standards and culture media should be marked with the preparation and opening date and the signature of the person who prepared them. The expiry date of reagents and culture media should be indicated on the label, together with specific storage conditions. In addition, for volumetric solutions, the last date of standardisation and the last current factor should be indicated.化验室试剂、溶剂、对照品和培养基均应标识制备和开瓶日期，以及制备人签名。试剂和培养基有效期应在标签上标明，上次标化日期和上次标化所得浓度因子应在标签上注明。6.22 Where necessary, the date of receipt of any substance used for testing operations (e.g. reagents, solutions and reference standards) should be indicated on the container. Instructions for use and storage should be followed. In certain cases it may be necessary to carry out an identification test and/or other testing of reagent materials upon receipt or before use.必要时，用于检测操作的所有物质的接收日期（例如，试剂、溶液和对照品）应在容器上标识。要遵守使用和存贮规范。在某些情况下，可能需要在接受时，或使用前对试剂物料进行鉴别测试和/或其它测试。6.23 Culture media should be prepared in accordance with the media manufacturers requirements unless scientifically justified. The performance of all culture media should be verified prior to use.除非另有科学判定，否则培养基应根据培养基生产厂家的要求进行制备。所有培养基的性能均应在使用前进行确认。6.24 Used microbiological media and strains should be decontaminated according to a standard procedure and disposed of in a manner to prevent the cross-contamination and retention of residues. The in-use shelf life of microbiological media should be established, documented and scientifically justified.使用过的微生物培养基和菌种应根据标准程序避免污染，其处理方式应能防止交叉污染和残留。应建立、记录并科学判定微生物培养基的使用寿命。6.25 Animals used for testing components, materials or products, should, where appropriate, be quarantined before use. They should be maintained and controlled in a manner that assures their suitability for the intended use. They should be identified, and adequate records should be maintained, showing the history of their use.用于测试成分、物料或产品的动物，适当时，在使用前应进行隔离。其维护和控制方式应能保证适用于其用途。应对其进行标识，保留充分的记录显示其使用历史。On-going stability programme 持续稳定性试验方案6.26 After marketing, the stability of the medicinal product should be monitored according to a continuous appropriate programme that will permit the detection of any stability issue (e.g. changes in levels of impurities or dissolution profile) associated with the formulation in the marketed package.上市后，药品的稳定性应根据适当的持续方案进行监控，这样可以发现所有与上市包装配方有关的稳定性问题（例如，杂质水平变化、溶出度概况变化）。6.27 The purpose of the on-going stability programme is to monitor the product over its shelf life and to determine that the product remains, and can be expected to remain, within specifications under the labelled storage conditions.持续稳定性考察的目的是在货架期内对产品进行监控，确认产品在标识的存贮条件下能，或预期能符合质量标准。6.28 This mainly applies to the medicinal product in the package in which it is sold, but consideration should also be given to the inclusion in the programme of bulk product. For example, when the bulk product is stored for a long period before being packaged and/or shipped from a manufacturing site to a packaging site, the impact on the stability of the packaged product should be evaluated and studied under ambient conditions. In addition, consideration should be given to intermediates that are stored and used over prolonged periods. Stability studies on reconstituted product are performed during product development and need not be monitored on an on-going basis. However, when relevant, the stability of reconstituted product can also be monitored.这主要适用于市售包装的药品，但也要考虑散装产品。例如，如果散装产品在包装和/或从生产场所发运至包装场所前存贮了相当长时间，则包装后产品稳定性受到的影响需要进行评估，并在室温条件下进行考察。另外，还要考虑存贮并在延长的时间内使用的中间体。再生产品的稳定性研究已经在研发期间做过了，不需要持续考察。但如果需要，也应该监控再生产品的稳定性。6.29 The on-going stability programme should be described in a written protocol following the general rules of Chapter 4 and results formalised as a report. The equipment used for the ongoing stability programme (stability chambers among others) should be qualified and maintained following the general rules of Chapter 3 and Annex 15.持续稳定性试验应在一份书面方案中描述，应符合第4章的一般规则，试验结果应汇总作为一份报告。持续稳定性试验所用设备（稳定性考察箱）应根据第3章和附录15的一般要求进行确认和维护。6.30 The protocol for an on-going stability programme should extend to the end of the shelf life period and should include, but not be limited to, the following parameters:持续稳定性计划方案应延长至产品的货架期，方案应包括，但不仅限于以下项目：i. Number of batch(es) per strength and different batch sizes, if applicable;适用时，每个剂量和不同批量的批数ii. Relevant physical, chemical, microbiological and biological test methods;相关物理、化学、微生物和生物检测方法iii. Acceptance criteria;可接受标准iv. Reference to test methods;检验方法引用标准v. Description of the container closure system(s);容器密闭系统的描述vi. Testing intervals (time points);检测间隔（时间点）vii. Description of the conditions of storage (standardised ICH/VICH conditions for long term testing, consistent with the product labelling, should be used);存贮条件的描述（ICH/VICH长期稳定性标准条件，应与产品标签一致）viii. Other applicable parameters specific to the medicinal product.药品特定的其它适用参数6.31 The protocol for the on-going stability programme can be different from that of the initial longterm stability study as submitted in the marketing authorisation dossier provided that this is justified and documented in the protocol (for example the frequency of testing, or when updating to ICH/VICH recommendations).如果经过证明，并记录在方案中（例如，检测频次，或根据ICH/VICH建议更新），则在检的稳定性方案可以与初始提交申报上市许可的长期稳定性试验方案不同。6.32 The number of batches and frequency of testing should provide a sufficient amount of data to allow for trend analysis. Unless otherwise justified, at least one batch per year of product manufactured in every strength and every primary packaging type, if relevant, should be included in the stability programme (unless none are produced during that year). For products where on-going stability monitoring would normally require testing using animals and no appropriate alternative, validated techniques are available, the frequency of testing may take account of a risk-benefit approach. The principle of bracketing and matrixing designs may be applied if scientifically justified in the protocol.批数和检测频次应能提供足够量的数据来进行趋势分析。除非另有说明，在生产品种每个剂量、每个内包形式，如果对稳定性有影响的话，至少每年增加一批至稳定性试验中（除非该年度未生产该品种）。对于正常需要用动物进行检测，且并没有适当的可以替代的、经过验证的技术的情况，其测试频次可以采用风险-利益权衡方法决定。如果在方案中经过科学论证，也可以采用括号法和矩阵法设计原则。6.33 In certain situations, additional batches should be included in the on-going stability programme.在特定情形下，要增加批次到持续稳定性试验中。For example, an on-going stability study