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本帖最后由 bruce2020 于 2014-9-21 13:06 编辑
Brussels, 13 August 2014 Ares(2014)2674297 EudraLex The Rules Governing Medicinal Products in the European Union
Volume 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use Part 1 Chapter 8: Complaints, Quality Defects and Product Recalls 人兽药EU GMP指南第1部分第8章：客诉、质量缺陷和产品召回 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. 指南制订的法规依据：指令2001/83/EC第47条关于人药规定，及指令2001/82/EC第51条关于兽药规定。本文件提供了对指令2003/94/EC人药和91/412/EEC兽药规定中列出的原则的解释，及药品GMP的指南 Status of the document: Revision 文件状态：修订 Reasons for changes: Extensive changes have been made to this Chapter which now reflect that Quality Risk Management principles should be applied when investigating quality defects or complaints and when making decisions in relation to product recalls or other risk-mitigating actions. It emphasises the need for the cause(s) of quality defects or complaints to be investigated and determined, and that appropriate preventative actions are put in place to guard against a recurrence of the issue and clarifies expectations and responsibilities in relation to the reporting of quality defects to the Competent Authorities. 变更理由：本章改动很大，现在包括了质量风险管理原则。在调查质量缺陷或投诉时，在做出与产品召回相关决定时，及在采取其它转移风险措施时，要应用该原则。本章强调了需要对质量缺陷和投诉的原因进行调查并确认，采取适当的CAPA以防止问题重复发生，说明了向药监当局报告质量缺陷的要求和责任。 Deadline for coming into operation: 1 March 2015. 生效日期：2015年3月1日 Principle总则 In order to protect public and animal health, a system and appropriate procedures should be in place to record, assess, investigate and review complaints including potential quality defects, and if necessary, to effectively and promptly recall medicinal products for human or veterinary use and investigational medicinal products from the distribution network. Quality Risk Management principles should be applied to the investigation and assessment of quality defects and to the decision-making process in relation to product recalls corrective and preventative actions and other risk-reducing actions. Guidance in relation to these principles is provided in Chapter 1. 为了保护公众和动物健康，应制订一个体系和适当的程序来记录、评估、调查和审核客户投诉，包括潜在质量缺陷，必要时及时有效地从销售网络中召回人兽用药和临床试验用药品。应在质量缺陷调查和评估，及与药品召回CAPA和其它降低风险措施的决策过程中使用质量风险管理原则。与这些原则相关的指南在包括在第1章中。 All concerned competent authorities should be informed in a timely manner in case of a confirmed quality defect (faulty manufacture, product deterioration, detection of falsification, non-compliance with the marketing authorisation or product specification file, or any other serious quality problems) with a medicinal or investigational medicinal product which may result in the recall of the product or an abnormal restriction in the supply. In situations where product on the market is found to be non-compliant with the marketing authorisation, there is no requirement to notify concerned competent authorities provided the degree of non-compliance satisfies the Annex 16 restrictions regarding the handling of unplanned deviations. 如果已确认药品或临床试验用药品存在质量缺陷（生产错误、产品腐败、发现假药、不符合上市许可或产品质量标准、或其它任何严重质量问题），可能会导致产品召回或对供应采取异常限制，则应及时通知所有相关药监当局。如果发现已上市产品不符合上市许可，不符合情况满足附录16关于处理计划外偏差的限制，则不需要通知相关药监当局。 In case of outsourced activities, a contract should describe the role and responsibilities of the manufacturer, the marketing authorisation holder and/or sponsor and any other relevant third parties in relation to assessment, decision-making, and dissemination of information and implementation of risk-reducing actions relating to a defective product. Guidance in relation to contracts is provided in Chapter 7. Such contracts should also address how to contact those responsible at each party for the management of quality defect and recall issues. 如有外包活动，合同中应描述生产商、上市许可持有人和/或申报人及其它任何相关第三方在对缺陷产品进行评估、做出决策、传播信息和实施风险降低措施中所承担的角色和责任。与合同外包相关的指南包括在第7章中。合同中还应说明各方管理质量缺陷和召回问题人员的联系方式。 Personnel and Organisation人员和机构 8.1 Appropriately trained and experienced personnel should be responsible for managing complaint and quality defect investigations and for deciding the measures to be taken to manage any potential risk(s) presented by those issues, including recalls. These persons should be independent of the sales and marketing organisation, unless otherwise justified. If these persons do not include the Qualified Person who is involved in the certification for release of the concerned product, the latter should be made formally aware of any investigations, any risk-reducing actions and any recall operations, in a timely manner. 应由经过适当培训和具备经验的人员负责管理投诉和质量缺陷调查，以及决定需要采取的措施（包括召回），以管理这些问题暴露的所有潜在风险。这些人员应独立于市场销售部门组织，否则应另外论述。如果这些人员不包括放行受影响产品的授权人，则该授权人应被及时地正式告知所有调查和降低风险的措施，以及所有召回操作。 8.2 Sufficient trained personnel and resources should be made available for the handling, assessment, investigation and review of complaints and quality defects and for implementing any risk-reducing actions. Sufficient trained personnel and resources should also be available for the management of interactions with competent authorities.
应保证有足够的受过训练的人员和资源来处理、评估、调查和审核客诉和质量缺陷，以及实施所有降低风险的措施。管理与药监当局之间沟通也应配备有足够的受过培训的人员和资源。 8.3 The use of inter-disciplinary teams should be considered, including appropriately trained Quality Management personnel. 应考虑使用跨学科团队，包括接受过适当训练的质量管理人员。 8.4 In situations in which complaint and quality defect handling is managed centrally within an organisation, the relative roles and responsibilities of the concerned parties should be documented. Central management should not, however, result in delays in the investigation and management of the issue. 如果客诉和质量缺陷处理是由组织内集中管理，则要记录各相关方所担任的角色和职责。不管如何组织，集中管理都不应该导致问题调查和管理的延迟。 Procedures for handling and investigating complaints including possible quality defects 处理、调查客诉包括可能的质量缺陷的程序 8.5 There should be written procedures describing the actions to be taken upon receipt of a complaint. All complaints should be documented and assessed to establish if they represent a potential quality defect or other issue. 应制订书面程序，描述收到客诉后所采取的措施。所有客诉均应进行记录和评估，以确定其中是否存在的潜在质量缺陷或其它问题。 8.6 Special attention should be given to establishing whether a complaint or suspected quality defect relates to falsification. 要特别注意区分所收到的是真正的客诉还是与假药有关的可疑质量缺陷。 8.7 As not all complaints received by a company may represent actual quality defects, complaints which do not indicate a potential quality defect should be documented appropriately and communicated to the relevant group or person responsible for the investigation and management of complaints of that nature, such as suspected adverse events. 由于公司收到的客诉可能不全是由于实际的质量缺陷引起的，因此那些不存在潜在质量缺陷的客诉，例如可疑不良反应，应适当记录，与负责该类客诉调查和管理的相关部门或人员进行联系， 8.8 There should be procedures in place to facilitate a request to investigate the quality of a batch of a medicinal product in order to support an investigation into a reported suspected adverse event. 应制订程序便于申请对某批药品的质量进行调查，以支持对所报告的可疑不良反应事件进行调查。 8.9 When a quality defect investigation is initiated, procedures should be in place to address at least the following:
在启动一个质量缺陷调查时，应有程序包括至少以下方面： i. The description of the reported quality defect. 所报告的质量缺陷的描述 ii. The determination of the extent of the quality defect. The checking or testing of reference and/or retention samples should be considered as part of this, and in certain cases, a review of the batch production record, the batch certification record and the batch distribution records (especially for temperature-sensitive products) should be performed. 确认质量缺陷程度，应考虑将检查或检测对照品和/或留样作为该调查的一部分，在某些案例中，要审核批生产记录，批检验记录和批销售记录（特别是对于温度敏感的产品）。 iii. The need to request a sample, or the return, of the defective product from the complainant and, where a sample is provided, the need for an appropriate evaluation to be carried out.
是否需要从投诉者要求样品、或退回缺陷产品，如果提供了样品，则应进行适当的评估 iv. The assessment of the risk(s) posed by the quality defect, based on the severity and extent of the quality defect. 根据质量缺陷的严重性和程度，评估质量缺陷所带来的风险
v. The decision making process that is to be used concerning the potential need for risk-reducing actions to be taken in the distribution network, such as batch or product recalls, or other actions.
决定在分销网络中是否需要采取降低风险行为时所用的流程，例如批召回还是产品召回，或是其它行为 vi. The assessment of the impact that any recall action may have on the availability of the medicinal product to patients/animals in any affected market, and the need to notify the relevant authorities of such impact.
评估召回行为对受影响的市场中患者/动物的产品供应是否有影响，评估是否需要将该影响通知有关药监机构 vii. The internal and external communications that should be made in relation to a quality defect and its investigation.所需做的与质量缺陷和其调查有关的内外沟通工作 viii. The identification of the potential root cause(s) of the quality defect.
识别质量缺陷的可能根本原因 ix. The need for appropriate Corrective and Preventative Actions (CAPAs) to be identified and implemented for the issue, and for the assessment of the effectiveness of those CAPAs.
应识别是否需要制订并实施适当的针对该问题的CAPA，以及对这些CAPA有效性进行评估。 Investigation and Decision Making 调查和做出决策 8.10 The information reported in relation to possible quality defects should be recorded, including all the original details. The validity and extent of all reported quality defects should be documented and assessed in accordance with quality risk management principles in order to support decisions regarding the degree of investigation and action taken. 与可能的质量缺陷有关的报告信息应记录，包括所有原始细节。所有被报告的质量缺陷的有效性和程度应根据质量风险管理原则进行记录和评估，以支持关于调查深度和所采取措施的决策。 8.11 If a quality defect is discovered or suspected in a batch, consideration should be given to checking other batches and in some cases other products, in order to determine whether they are also affected. In particular, other batches which may contain portions of the defective batch or defective components should be investigated. 如果发现某批产品有质量缺陷或疑似质量缺陷，应考虑检查其它批次相同产品，有些案例下可能还要考虑其它产品，以确定这些批次和产品是否也受到影响。特别是其它批次可能会包括缺陷批次的一部分，或其它产品中可能含有被调查的成分。 8.12 Quality defect investigations should include a review of previous quality defect reports or any other relevant information for any indication of specific or recurring problems requiring attention and possibly further regulatory action. 质量缺陷调查应包括对以前质量缺陷报告及其它需要引起注意，可能需要采取进一步法规措施的相关特定或重复发生问题的信息。 8.13 The decisions that are made during and following quality defect investigations should reflect the level of risk that is presented by the quality defect as well as the seriousness of any non-compliance with respect to the requirements of the marketing authorisation/ product specification file or GMP. Such decisions should be timely ensure that patient and animal safety is maintained, in a way that is commensurate with the level of risk that is presented by those issues. 在以下质量缺陷调查中做出的决定应反映质量缺陷，以及与上市许可/产品标准文件或GMP要求相关的所有不符合事件严重性所代表的风险水平。这样的决策应及时做出，以保证维护患者和动物安全，并与这些问题所代表的风险水平相当。 8.14 As comprehensive information on the nature and extent of the quality defect may not always be available at the early stages of an investigation, the decision-making processes should still ensure that appropriate risk-reducing actions are taken at an appropriate time-point during such investigations. All the decisions and measures taken as a result of a quality defect should be documented.
由于在调查的初期，并不一定能获得质量缺陷特性的全面信息，因此做出决策的过程还应保证在调查过程中在适当的时间点采取适当的降低风险的措施。所有这些决定及由于质量缺陷引发所采取的措施均应记录。 8.15 Quality defects should be reported in a timely manner by the manufacturer to the Marketing Authorisation Holder/Sponsor and all concerned Competent Authorities in cases where the quality defect may result in the recall of the product or in an abnormal restriction in the supply of the product. 如果质量缺陷可能会导致产品召回或产品销售受到异常的限制，生产商应及时报告给生产许可持有人/申报人及所有相关药监机构。 Root Cause Analysis and Corrective and Preventative Actions根本原因分析和纠正预防措施 8.16 An appropriate level of root cause analysis work should be applied during the investigation ofquality defects. In cases where the true root cause(s) of the quality defect cannot be determined, consideration should be given to identifying the most likely root cause(s) and to addressing those. 在对质量缺陷进行调查过程中，应对根本原因进行适当程度的分析。如果导致质量缺陷真正的根本原因无法找到，则应考虑识别最可能的根本原因，并对其进行说明。 8.17 Where human error is suspected or identified as the cause of a quality defect, this should be formally justified and care should be exercised so as to ensure that process, procedural or system-based errors or problems are not overlooked, if present. 如果怀疑有人为差错，或识别人为差错是质量缺陷的根本原因，则应该进行正式的论述，并要小心处理，以保证其过程、程序或系统误差或问题不会被忽略。 8.18 Appropriate CAPAs should be identified and taken in response to a quality defect. The effectiveness of such actions should be monitored and assessed. 质量缺陷回复中应识别并执行适当的CAPA。这些措施的有效性应进行监控和评估。 8.19 Quality defect records should be reviewed and trend analyses should be performed regularly for any indication of specific or recurring problems requiring attention. 应对质量缺陷记录进行审核，并定期进行趋势分析，以发现需要引起注意的特定的或重复发生问题指标。 Product Recalls and other potential risk-reducing actions产品召回和其它潜在的降低风险的措施 8.20 There should be established written procedures, regularly reviewed and updated when necessary, in order to undertake any recall activity or implement any other risk-reducing actions. 应建立书面程序，并对程序进行定期审核，必要时进行更新，以实施所有召回活动，或实施其它降低风险的行为。 8.21 After a product has been placed on the market, any retrieval of it from the distribution network as a result of a quality defect should be regarded and managed as a recall. (This provision does not apply to the retrieval (or return) of samples of the product from the distribution network to facilitate an investigation into a quality defect issue/report.) 有产品上市销售后，所以因质量缺陷从分销网络收回的产品均应作为召回管理。（本条款不适用于从分销网络中收回（或退回）样品便于质量缺陷问题/报告调查） 8.22 Recall operations should be capable of being initiated promptly and at any time. In certain cases recall operations may need to be initiated to protect public or animal health prior to establishing the root cause(s) and full extent of the quality defect 召回操作应可以在任何时间及时启动。在特定情形下，召回操作可能需要在找到根本原因和全面质量缺陷前即行启动以保护公众或动物健康。 8.23 The batch/product distribution records should be readily available to the persons responsible for recalls, and should contain sufficient information on wholesalers and directly supplied customers (with addresses, phone and/or fax numbers inside and outside working hours, batches and amounts delivered), including those for exported products and medical samples. 负责产品召回的人员应可以方便地调取批/产品分销记录，记录中应包括有关于批发商和直接供应客户的充分信息（地址、24小时电话和/或传真号、发运的批数和数量），包括出口产品和药用样品。 8.24 In the case of investigational medicinal products, all trial sites should be identified and the countries of destination should be indicated. In the case of an investigational medicinal product for which a marketing authorisation has been issued, the manufacturer of the investigational medicinal product should, in cooperation with the sponsor, inform the marketing authorisation holder of any quality defect that could be related to the authorised medicinal product. The sponsor should implement a procedure for the rapid unblinding of blinded products, where this is necessary for a prompt recall. The sponsor should ensure that the procedure discloses the identity of the blinded product only in so far as is necessary. 对于临床试验用药品，所有试验场所均应进行识别，说明目的地国家。如果临床试验用药品已拥有上市许可，临床试验用药品的生产商应与申报人合作，将可能与许可药品相关的所有质量缺陷通知上市许可持有人。申请人应在需要进行快速召回时，对盲样药品实施快速揭盲程序。申请人应保证该程序只有在必要时才会揭露盲样药品。 8.25 Consideration should be given following consultation with the concerned Competent Authorities, as to how far into the distribution network a recall action should extend, taking into account the potential risk to public or animal health and any impact that the proposed recall action may have. The Competent Authority should also be informed in situations in which no recall action is being proposed for a defective batch because the batch has expired (such as with short shelf-life products.) 考虑对公众或动物健康潜在风险及所拟召回行为可能的影响，在决定召回行为需涉及分销网络的深度时，应听取相关药监当局的意见。如果由于批次已过效期（例如短效期药品），因而不召回缺陷批次，则相关情况也需要通知药监当局。 8.26 All concerned Competent Authorities should be informed in advance in cases where products areintended to be recalled. For very serious issue (i.e. those with the potential to seriously impact upon patient or animal health), rapid risk-reducing actions (such as a product recall) may have to be taken in advance of notifying the Competent Authorities. Wherever possible, attempts should be made to agree these in advance of their execution with the concerned Competent Authorities 如果准备召回产品，则应提前通知所有相关的药监当局。如果问题严重（即对患者或动物健康存在潜在严重影响时），可能在通知药监当局前即必须采取快速风险降低措施（例如产品召回）。 8.27 It should also be considered whether the proposed recall action may affect different markets in different ways, and if this is the case, appropriate market-specific risk-reducing actions should be developed and discussed with the concerned competent authorities. Taking account of its therapeutic use the risk of shortage of a medicinal product which has no authorised alternative should be considered before deciding on a risk-reducing action such as a recall. Any decisions not to execute a risk-reducing action which would otherwise be required should be agreed with the competent authority in advance. 还要考虑所拟的召回行为可能对不同的市场有不同的影响，如果是这样，那么要研究对适当的市场采取特定的风险降低措施，与相关的药监机构进行讨论。要考虑其治疗使用 8.28 Recalled products should be identified and stored separately in a secure area while awaiting a decision on their fate. A formal disposition of all recalled batches should be made and documented. The rationale for any decision to rework recalled products should be documented and discussed with the relevant competent authority. The extent of shelf-life remaining for any reworked batches that are being considered for placement onto the market should also be considered. 召回的产品应进行标识，在等待最终处理决定期间，单独存贮在一个有安保措施的区域。对所有召回批次应做出正式处理决定并记录。如对召回产品进行返工，则其合理性应进行记录，并与相关药监当局讨论。返工批次在上市销售时应考虑其剩余的货架期。 8.29 The progress of the recall process should be recorded until closure and a final report issued, including a reconciliation between the delivered and recovered quantities of the concerned products/batches.
召回过程的进度应记录直到关闭，及签发最终报告，包括相关产品/批次发出和收回数量平衡。 8.30 The effectiveness of the arrangements in place for recalls should be periodically evaluated to confirm that they remain robust and fit for use. Such evaluations should extend to both within office-hour situations as well as out-of-office hour situations and, when performing such evaluations, consideration should be given as to whether mock-recall actions should be performed. This evaluation should be documented and justified.
已有召回安排的有效性应进行周期性评估，以确认其它耐用性且与其用途相适合。该评估应延伸至办公时间情形和非办公时间情形，在进行评估时，应考虑是否需要进行模拟召回演习。该评估应进行记录并论述。 8.31 In addition to recalls, there are other potential risk-reducing actions that may be considered in order to manage the risks presented by quality defects. Such actions may include the issuance of cautionary communications to healthcare professionals in relation to their use of a batch that is potentially defective. These should be considered on a case-by-case basis and discussed with the concerned competent authorities.
除召回以外，还可以考虑其它潜在的降低风险的措施，以管理质量缺陷代表的风险。这类措施可以包括向使用其可能会具有潜在缺陷的批次的卫生专业机构签发警告书。这些需要根据个案考虑，并与相关药监当局讨论。 | 
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发表于 2014-9-21 11:08:44
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