201502 EMA: 关于GMP的问答(1）--Julia翻译

巴西木

   EMA官网刊载了部分关于GMP的问答，共包括15个方面。由于涉及方面较多，仅翻译并转载部分。

本部分为关于“EU GMP第二部分：原料药基本要求”（问答网页最后更新问题为2014年6月），对应网页目录第二项。由于官方并不提供相关更新通知和预告，参考本文时请随时关注官网更新。


Questions and answers: Good manufacturing practice

This page lists the European Medicines Agency's answers to frequently asked questions, as discussed and agreed by the Good Manufacturing Practice (GMP) / Good Distribution Practice (GDP) Inspectors Working Group.

本页列出了EMA对常见问题的答复，该答复经过GMP/GDP检查工作组讨论后给出。

Further questions and answers are published as the need arises. Individual questions and answers may be removed when the relevant GMP guidelines are updated.

如有必要，会公布更多的问题和答复。如果相关的GMP指南有更新，则可能会移除有关问题和答复。

Code 代码

H: applicable to human medicines 适用于人用药
V: applicable to veterinary medicines 适用于兽用药
Table of contents 目录

European Union (EU) GMP guide part I: Basic requirements for medicinal products: Chapter 5: Qualification of suppliers
EU GMP guide part II: Basic requirements for active substances used as starting materials: GMP compliance for active substances - UPDATED
EU GMP guide part II: Basic requirements for active substances used as starting materials: GMP compliance for active substances in investigational medicinal products (IMPs)
EU GMP guide annexes: Supplementary requirements: Annex 1: Manufacture of sterile medicinal products - UPDATED
EU GMP guide annexes: Supplementary requirements: Annex 6: Manufacture of medicinal gases
EU GMP guide annexes: Supplementary requirements: Annex 8: Sampling of starting and packaging materials: Glycerol
EU GMP guide annexes: Supplementary requirements: Annex 8: Sampling of starting and packaging materials: Use of near-infrared (NIR) technology for container-wise identity testing
EU GMP guide annexes: Supplementary requirements: Annex 11: Computerised systems
EU GMP guide annexes: Supplementary requirements: Annex 13
EU GMP guide annexes: Supplementary requirements: Annex 16
EU GMP guide annexes: Supplementary requirements: Annex 19: Reference and retention samples
General GMP
GMP certificates
Inspection coordination


EU GMP guide part II: Basic requirements for active substances used as starting materials: GMP compliance for active substances – UPDATED

欧洲GMP指南第二部分：用作起始物料的活性物质的基本要求：活性物质GMP符合性---更新

1. How can GMP compliance for active-substance manufacturers be demonstrated? H+V April 2011

活性物质生产商如何证明GMP符合性？H+V 2011年4月

Directive 2001/83/EC as amended (Directive 2001/82/EC for veterinary medicinal products) states that manufacturing-authorisation holders are obliged to use, as starting materials, only active substances that have been manufactured in accordance with the detailed guidelines on GMP for starting materials. Thus the legislation puts the responsibility on the manufacturing-authorisation holders using the active substance and does not foresee mandatory routine inspections of active-substance manufacturers.

法令2001/83/EC及修订内容（法令2001/82/EC兽药）指出生产许可持有人有义务仅使用根据GMP指南生产的活性物质作为起始物料。因此，法律将该责任赋予了使用该活性物质的生产许可持有人，而并没有要求对活性物质生产商进行强制的定期检查。

To provide guidance on how GMP compliance of active-substance manufacturers should be established, guidance documents have been published on this website, including the 'guidance on the occasions when it is appropriate for competent authorities to conduct inspections at the premises of manufacturers of active substances used as starting materials' as part of the Community procedures. This document states that it is expected that manufacturing-authorisation holders will normally gain assurance that the active substances it uses are manufactured in accordance with GMP through audit of the active-substance suppliers.

为了提供原料药生产商应如何符合GMP，本网站已公布了指南文件，包括“何时药监局会对用作起始物料的原料药生产商进行现场检查指南”，它是欧盟程序的一部分。本文件指明期望生产许可持有人一般要通过对原料药生产商进行审计来保证其所使用的原料药符合GMP要求。

In addition, a number of questions and answers on audits of active-substance manufacturers on this page provide further guidance.

另外，关于活性物质生产商的审计问答在另一页上可以找到。

2. Do I need to perform an audit of an active substance supplier if it has been inspected by an inspectorate from a European Economic Area (EEA) Member State and a valid GMP certificate is available? H+V July 2006

如果活性物质供应商已接受过EEA成员国的审计，且其GMP证书在有效期内，我是否还需要对其进行审计？

Manufacturing-authorisation holders sometimes confuse the role of inspectorates with their own obligations but nevertheless, when inspection reports or GMP certificates issued by European Economic Area (EEA) mutual-recognition-agreement (MRA) partners or other recognised authorities are available, these can provide useful information to manufacturing-authorisation holders.

上市许可持有人有时会对其在检查义务产生疑惑，不管怎么样，如果具有检查报告，或由EEA互认伙伴及其它互认国家药监局签发的GMP证书，均可以给上市许可持有人提供有用的信息。

However, these alone cannot fulfil the statutory obligations of the manufacturing-authorisation holder or the requirements of section 5.25 of the GMP guideline , but the results of inspections may be used together with other supporting information in a risk-based approach by the manufacturer in establishing priorities for its own audit programme of active-substance suppliers.

但是，这并不能免除GMP指南第5.25部分提出的上市许可持有人的法定义务，但上市许可持有人可以将上述检查结果与其它支持性信息结合，采用基于风险的方法建立其自己对活性物质生产商的审计程序。

3. Is it acceptable to perform a remote assessment based on, for example, questionnaires, review of documents, Internation Organization for Standardization 9000 certification, results of analytical testing and historical experience with the supplier? H+V July 2006

采用远程评估方式，例如，调查问卷，基于对文件、ISO9000证书、分析检测结果和该供应商的历史经验进行评估是否可以接受？ H+V 2006年7月

The EEA inspectorates are not generally in favour of 'paper-based audits' per se as they do not provide the same level of assurance as on-site assessments, but do accept that they have a part to play in a risk-based strategy.

EEA检查官一般不倾向于“纸面审计”，因为这样无法提供与现场评估相同水平的保证，但基于风险策略可以接受将其作为审计的一部分。

They may be particularly applicable when recent positive inspection information is available and where satisfactory audits have been concluded in the past. They cannot replace on-site audits of active-substance suppliers but can be a useful interim and temporary measure within the manufacturer's audit programme.

如果有近期检查信息可以获得时，且过去的现场审计都令人满意时，这种方法可以采用。书面审计不能替代对原料药供应商的现场审计，但可以作为生产商审计计划的中间和临时措施。

4. How do the new requirements affect importers of medicinal products? H+V July 2006

新的要求对制剂的进口商有什么影响？ H+V 2006年7月

Importers are manufacturing-authorisation holders and so the obligations under Article 46f/50f of Directive 2001/83(2) apply to them. For importers, the possibility of a second-party audit performed by the third-country manufacturer that uses the active substance as a starting material may be a further option.

进口商和生产许可持有人承担法令2001/83(2)第46f/50f条赋予其的义务。对于进口商而言，可以由使用活性物质作为起始物料的第三国生产商进行第二方审计。

Importers are already obliged to ensure that the third-country manufacturer complies with standards of GMP equivalent to those of the European Community and should have established arrangements in line with chapter 7 of the GMP guideline . They should therefore be fully satisfied that the third-country manufacturer has adequately demonstrated that the active substances it uses for products destined for the European Community have been manufactured in accordance with GMP.

进口商承担责任来保证第三国生产商符合的GMP等同于欧盟GMP标准，应按GMP指南第7章要求实施。因此他们应该要求第三国生产商充分证明用于销往欧盟的制剂所用的活性物质生产完全符合GMP要求。

Importers may of course choose to verify the standards of GMP at the active-substance suppliers themselves or through a third party. Whichever option is chosen, the questions and answers above are also relevant.

进口商也可以选择亲自去原料药生产商那里确认GMP标准，或者通过第三方审计。不管选择哪一种方式，上述问答是等同的。

5. Is it possible to ask for a voluntary inspection of an active-substance manufacturer? H+V June 2014

是否可以自愿申请对活性物质生产商进行检查？ H+V 2006年7月

Responsibility for only using active substances that have been manufactured in accordance with GMP is placed on the holders of a manufacturing authorisation.

只能使用符合GMP要求下生产的原料药是上市许可持有人的责任。

Article 111 of Directive 2001/83/EC (Article 80 of Directive 2001/82/EC for veterinary medicinal products) however makes provision for GMP inspections of active-substance manufacturing sites to be carried out at the request of the manufacturer itself. The request for the inspection should be made to the EEA competent authority where the site is located or, in case of sites located in third countries, to a competent authority where the active substance is used as a starting material in the manufacture of medicinal products. If this is not the case, any EEA authority can be approached.

法令2001/83/EC第111条（兽药法令2001/82/EC第80条）中有规定在活性物质生产商申请下进行GMP检查的条款。检查申请应向工厂所在国EEA合法药监机构提出，如果工厂地址位于第三国，则可以向活性物质用作起始物料的制剂生产国合法药监机构提出。如果不属于上述情况，则可以向任何EEA药监机构提出申请。

There is no guarantee that such a request will be fulfilled, as the competent authorities need to balance such requests with other priorities. When an active substance manufacturer applies for a voluntary inspection, this does not constitute an obligation for the competent authority to trigger an inspection. It should also be borne in mind that an inspection does not replace the responsibility of the manufacturing-authorisation holder using the active substance in question as a starting material and will not be accepted alone as adequate assurance that the manufacturing authorisation holder has fulfilled its responsibilities.

由于药监机构需要权衡其优先性，因此不能保证检查申请一定会被接受。当原料药生产商自愿申请现场检查时，并不表示药监机构有义务来启动一个现场检查。还要知道，即使实施了检查，该检查并不能替代上市许可持有人对于使用该原料药作为起始物料的评估责任，仅具有该检查，也不能证明上市许可持有人完成了其职责。（译者注：上述划线句为2014年更新新增句）

6. The notice to applicants requires the submission of a declaration signed by the qualified person (QP) that the active substance used is manufactured in accordance with GMP. The active substance in my product is widely used, but not normally as a pharmaceutical active substance, and I am having some difficulty in confirming compliance. What should I do to furnish the required declaration? H+V September 2008

申报者须知要求提交一份声明，由QP签字，保证所使用的原料药是根据GMP生产的。我产品里使用的原料药被广泛应用，但通常并不作为原料药来使用，我要确认GMP符合性有点困难。我要怎么来完成所要的声明呢？H+V 2008年9月

Full compliance with GMP for finished products and active substances is a legal obligation for manufacturing-authorisation holders. It is recognised that for a small number of medicinal products, the primary use of the active substance is not in a medicinal product and the producer may therefore not be aiming to meet the specific requirements of pharmaceutical customers that represent an insignificant volume of business.

生产许可持有人有法定责任来保证制剂成品和活性物质完全符合GMP要求。我们也认识到有少量的药品，其原料药的基本用途并不药用，生产商可能因此并不会去追求符合制药行业客户的特定要求，对于他们来说，这些药业用户的业务量非常之少。

Alternative sources should normally be sought, but in exceptional circumstances the manufacturing-authorisation holder should assess and document to which extent GMP is complied with and provide a risk-based justification for the acceptance of any derogation.

一般来说要寻求替代资源，但在例外情况下，生产许可持有人应评估并记录要符合GMP到何种程度，并提供基于风险的评估来对降低要求进行论证。

The declaration provided by the QP should set out in detail the basis for declaring that the standards applied provide the same level of assurance as GMP. The European Medicines Agency will collect experience with this approach, which can be used as a basis for discussion on related amendments to guidelines in the future.

由QP提供的声明应详细说明所实施的标准可以提供与GMP相同程度的保证。欧洲药品管理局将收集这方面的经验，用作对将来指南相关修订的讨论。

7. What kind of GMP documentation is needed for an active-substance manufacturer that performs sterilisation of an active substance? July 2010

无菌原料药生产商要提交什么样的GMP文件？2010年7月

The GMP basic requirements for active substances used as starting materials (EU GMP guideline part II) only applies to the manufacture of sterile active substances up to the point immediately prior to the active substance being rendered sterile. The sterilisation and aseptic processing of sterile active substances are not covered by this guideline and should be performed in accordance with GMP for medicinal products (Commission Directive 2003/94/EC as interpreted in the basic requirements for medicinal products including annex 1 of the EU GMP guideline part I). This implies that for any active-substance manufacturer that performs sterilisation and subsequent aseptic handling of the active substance, a valid manufacturing authorisation or GMP certificate from an EEA authority or from an authority of countries where MRA or other Community arrangements apply has to be submitted.

用作起始物料的活性物质的基本GMP要求（EU GMP指南第二部分）仅适用于无菌原料药中灭菌前的步骤。该指南不包括无菌原料药的灭菌和无菌操作，而应实施药品GMP的要求（法令2003/94/EC药品基本要求中说明，包括EU GMP指南第一部分附录1）。这也就是说，所有实施无菌和灭菌操作及其后操作的活性物质生产商，需要提交有效的生产许可，或EEA药监局，或MRA国家药监局颁发的GMP证书。

The active-substance manufacturer also has to submit data on the sterilisation process of the active substance (including validation data) to the marketing-authorisation applicant or holder for inclusion in the dossier submitted for the finished product and approval by the licensing authorities.

活性物质生产商还必须提交活性物质（包括验证数据）灭菌工艺的数据给上市许可的申请人或持有人，并将其包括在制剂申报资料中，由许可机构进行批准。

8. During inspections, why do inspectors sometimes ask to see reports of audits of active substance manufacturers carried out by the medicinal product manufacturer? H+V May 2013

在检查中，为什么检查官有时会要求查看制剂生产商对活性物质生产商的审计报告？ H+V 2013年5月

Inspectors may need to see audit reports during inspections as part of the assessment of the manufacturing-authorisation holder’s systems for confirming GMP compliance of active substance manufacturers or suppliers. Inspectors will expect to see the full details of these reports upon request, including responses received from the audited site, indication of closure of deficiencies raised or commitments made.

在检查过程中，作为对上市许可持有人体系的评估的一部分，检查可能需要查看这些审计报告以确认活性物质生产商或供应商的GMP符合性。检查官希望看到这些报告的所有细节，包括收到的审计回复，缺陷关闭证据或所做的承诺等。

9. What expectations do inspectors have for the content of reports of audits of active substance manufacturers carried out by the medicinal-product manufacturer? H+V May 2013

检查官期望制剂生产商对活性物质生产商审计的报告中有什么内容？H+V  2013年5月

As a minimum, the following is expected to be included in the report:

至少以下内容应该包括在报告中

l  The full postal address of the site. The auditors must be identified by full name and their employer recorded. If the audit is conducted on behalf of other parties this should be clear in the report. Where an audit report is obtained through a third party, the manufacturing-authorisation holder is responsible for ensuring the validity and impartiality of the audit report. The identity of key staff participating in the audit should be recorded along with their roles. The full contact details of the person through which the audit was arranged should be recorded including contact details (e-mail address, telephone number). The dates of the audit should be recorded, with the full-day equivalents clarified if full days were not spent on site. A justification should be recorded for the duration of the audit. If, in exceptional circumstances, the audit had to be restricted to fewer days on site than required by the scope of the audit, the reasons should be explained and the conclusions with respect to the GMP status of the site should be justified. And ground information on the active substance manufacturer should be recorded; this should include the company ownership, the age of the site, the number of staff employed in total and for the specific products being audited. The role of the site in manufacture of the active substances being audited should also be clarified for each of the active substances being audited, e.g. if the site performs the full manufacture or only part of the manufacture.

l  工厂完整地址。审计员必须识别全名和其所有者。如果审计是代表其它方进行，则应在报告中清楚写明。如果审计报告是通过第三方获得，则生产许可持有人有责任保证审计报告的有效性和公正性。应记录参与审计人员的姓名及其职位。要记录审计联系人的详细信息，包括联系信息（EMAIL地址、电话号码）。审计日期要记录，如果在工厂时间不足整天，要说明是否等同整天。审计时长是否合适要进行论证。如果，在例外情况下，审计不得不限于较少的时间，短于审计范围所要求的时长，则要结合工厂的GMP状态解释其原因，并对结论进行论证。活性物质生产商的背景信息要记录，这包括公司所有权、工厂建立时间、员工数量及所审计活性物质相关员工数量。工厂在活性物质生产中的所扮演的角色也要说明，例如，工厂进行全部的生产活动，还是只进行部分生产。

l  The scope of the audit should be clearly stated e.g. what activities (against European Union GMP part II / International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Q7 chapters) were covered. The activities which were not covered by the audit should also be clearly recorded. Auditors should identify the high risk areas for audit specific to the site or products being audited. For example, these could include but not be limited to:

l  审计范围应清楚说明，例如，所涵盖的活动范围（相对于欧盟GMP第二部分/ICH指南Q7）。审计所未包括的活动也要清楚地记录。审计人员应识别所审计场所或所审计产品的高风险区域，例如，它们可以包括但不限于：

l  process, cleaning or validation;

l  工艺，清洁或验证

l  risk of cross-contamination with other active substances or other substances;

l  与其它活性物质或其它物质的交叉污染的风险

l  potential for generation of unknown impurities;

l  未知杂质生成的可能性

l  risk of mix-up of materials and products through materials handling or packing;

l  在物料处理或包装过程中混料的风险

l  change control;

l  变更控制

l  deviation recording or management;

l  偏差记录或管理

l  security sealing of active substance containers and security or temperature control of shipments.

l  活性物质容器的保安封签，运输过程中温度控制和保安

l  Subsequent audits conducted as part of the ongoing supplier audit program may have a reduced scope focusing on the highest risk areas. In such cases the highest risk areas should be identified and justified.

l  作为在用供应商审计程序的一部分，后续审计可能会缩小审计范围，只着重于高风险部分。在这种情况下，需要对高风险部分进行识别和论述。

l  A list should be recorded of all active substances directly included in the audit scope plus other active substances or intermediates (or other products) manufactured at the site.

l  应该有一份清单记录所有包括在审计范围内的活性物质，加上其它在该工厂厂址内生产的活性物质或中间体（或其它产品）。

There should be a clear record of the products, the stages of manufacture and the buildings audited. If access was denied to any relevant areas of the site this should be recorded and explained. The list should clarify which of the active substances in the scope of the audit are manufactured in multi-purpose equipment or buildings as either final product or any of the intermediate stages.

对于在所审计的建筑内生产的产品和步骤应该有清楚的记录。如果审计中有一部分相关区域未被许可进入，则应该记录并解释。清单应说明在多功能设备或建筑中，所生产的哪个活性物质包括在审计范围内，是最终成品还是其它中间体步骤。

l  Dates of any previous audit conducted by or on behalf of the same manufacturing-authorisation holder should be recorded. If any of the audits did not conclude with a positive GMP compliance status, a brief summary of the reasons for this should be recorded.

l  记录同一个上市许可持有人之前实施，或代表该上市许可持有人实施的检查的日期。如果这些审计GMP符合结论为不符合，则应该有一份记录决定采用该供应商的简要说明

l  Each of the applicable sections of EU GMP part II should form sections of the report with a summary of what was examined, the key findings and compliance with the requirements of each section. The report should clearly state findings against each activity audited with particular focus on the high risk areas. Any GMP deficiency identified during the audit must be clearly recorded with its criticality defined. An explanation should be given, in the report or in a supporting standard operating procedure, of the categorisation system used to classify deficiencies, e.g. critical, major or minor.

l  EU GMP第二部分的每个适用部分均应成为报告的一部分，并应有总结，说明检查的内容、主要缺陷、是否符合各部分的要求。报告应清楚说明针对高风险领域所审计的各项活动。所有在审计过程中辨别出的GMP缺陷均应清楚记录，并按关键程度进行分类。在报告中或在支持性SOP中，应解释用于缺陷分类的分类系统，例如，关键、主要或次要。

l  Responses to the audit by the active-substance manufacturer should be reviewed by the auditors. Corrective and preventative actions and timescales for completion should be assessed by the auditors to establish whether these are appropriate to the findings. Further clarification or evidence of completion should be requested, commensurate to the risk.

l  活性物质生产商对审计所做的回复应由审计员进行审核。审计员应对CAPA和完成时间表进行评估，以确认CAPA是否适合于这些缺陷。应要求生产商提供与风险相对称的CAPA完成的申明或提交证据。

l  A summary assessment of the status of corrective and preventive actions should be recorded by the auditors once these have been received and assessed. An overall recommendation should be made in the final report. The summary should include whether the auditor regards the actions as satisfactory. The responsible QP should ensure that he or she, or someone to whom it is delegated, is in agreement with the overall recommendation of the final report. The QP must not release the relevant medicinal products without knowledge of a positive recommendation from the auditors. This recommendation should include the GMP compliance status of the site and whether any reduced controls on materials receipt at the finished product manufacturing site are supported by the auditors.

l  一旦收到CAPA回复，审计官应立即进行评估总结并记录。在最终报告中要给出一份全面建议。总结应包括审计官是否认为该措施令人满意。负责的QP应保证他/她或受权人同意最终报告中的全面建议。在审计官未能作出肯定的结论前，QP不能放行相关的药品。该结论应包括工厂的GMP符合状态，检查官是否支持减少该物料接受控制

l  A proposed re-assessment period should be recommended.

l  建议一个再评估周期

l  The final report should be signed and dated by, at least, the lead auditor.

l  最终报告应由，至少是主审员签字并日期

10. How should active substance auditors be qualified? H + V May 2013

活性物质审计人员要怎么样进行资质确认？ H+V 2013年5月

Auditors should have sufficient scientific, technical and other experience to enable them to perform an adequate and thorough audit of the active substance manufacturer, as related to the planned scope of the audit. Where a proposed auditor lacks an appropriate level of direct experience in the field of active substance manufacture, he or she should undergo a documented training and assessment programme in the areas that are relevant to the audit, taking into account the auditor’s anticipated role in the audit and the technologies that are likely to be encountered during the audit. Auditors must also be trained and assessed in their knowledge and understanding of EU GMP part II and in auditing techniques in general. The training and assessment should be fully documented.

审计员应具有充分的科学技术和其它经验，能够根据所计划的审计范围，对活性物质生产商实施充分完整的审计。如果提议的审计官缺乏该活性物质生产领域内适当的直接经验，他/她应接受一定的培训，培训要有书面记录，并接受在与审计领域相关的评估，同时考虑审计官在审计中的角色，以及其在审计过程中可能牵涉的技术。审计官还必须接受对EU GMP第二部分，以及审计通用技巧的知识和理解性培训和评估。培训和评估均要进行书面记录。

The qualification and experience of contracted auditors are the same as the requirements for the manufacturing-authorisation holder’s own auditors.

合同审计官的资质和经验要求与上市许可持有人自己的审计官的要求相同。

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罗伊鲱

EU GMP问答-4：制剂部分 第8章：投诉、质量缺陷和产品召回 2问[color=rgba(0, 0, 0, 0.3)]

原创：julia

Julia法规翻译
2018-03-05

European Union (EU) GMP guide part I: Basic requirements for medicinal products: Chapter 8: Complaints, Quality Defects and Product Recalls

EU GMP指南第一部分：药品的基本要求：第8章：投诉、质量缺陷和产品召回 2问

1. What are the quality defect reporting requirements of EU GMP?

EU GMP的质量缺陷报告要求是什么？

Suspected product quality defects (e.g. product deterioration, packaging mix-up, among others) should be reported to the competent authority with responsibility for the manufacturing site (or importer where the manufacturer is located outside the EEA), and to the competent authority in each EEA market supplied. In case of impact to EU centrally authorised products, the EMA must also be notified. This notification should be prior to taking any market action, unless, as per paragraph 8.26 of Chapter 8, the need for market action is so serious as to warrant immediate action to protect patient or animal health.

疑似药品质量缺陷（例如，药品变质、包法混淆等）应向负责生产场所监管的药监当局报告（如生产商位于EEA境外，则由进口商报告），或报告给各EEA上市国的药监当局。如果对欧盟集中审评药品产生影响，则必须通知EMA。除令第8章第8.26段需要采取市场措施特别严重从而必须立即执行以保护患者或动物健康外，采取市场措施之前即应通知当局。

Confirmation of a quality defect does not require completion of the investigation. Reporting should be initiated when available information supports the detection of the issue and when the initial assessment of the potential risks presented to patients/animals indicates that it could result in market action. Notification to competent authorities should typically take place within one working day of confirmation that reporting is required.

对质量缺陷的确认并不需要调查全部完成。如已获得的信息足以证明所发现的问题时，并且对患者/动物潜在风险的初步评估显示可能会导致市场措施时，即应启动报告程序。一般应在确认有通知必要之后，在一个工作日内通知药监当局。

In cases where asuspected quality defect involves multiple manufacturing sites, reportingresponsibilities should be defined in a technical agreement. It is normalexpectation that the MAH and site of final EU batch certification should takethe lead on reporting, unless otherwise justified.

如果疑似质量缺陷牵涉多个生产场所，则应在技术协议中指定报告职责。一般期望MAH和最终EU批次认证的场所承担主要报告职责，另有论证者除外。

Manufacturers areencouraged to notify their national competent authority (or EU SupervisoryAuthority for sites located outside the EEA) of confirmed serious GMP issueswith the potential to lead to a suspected product defect requiring marketaction (e.g. media fill failure, serious equipment failure, etc.). Confirmationof a serious GMP issue does not require completion of the investigation;reporting should be initiated when available information confirms the detectionof the issue.

鼓励生产商通知其国家药监机构（如在EEA境外则为EU监管机构），确认其严重的GMP问题，以及导致疑似药品缺陷需要采取市场措施的可能性（例如，培养基灌装失败、严重设备故障等）。确认严重的GMP问题并不需要调查完成，只要有足够的信息确认所发现的问题即应启动报告程序。

Serious GMP issues whichmay result in an abnormal restriction in supply should be notified to the MAHand relevant competent authorities in accordance with legal obligations givenin Art 23(2) of Directive 2001/83/EC, Art 27 of Directive 2001/82/EC,Regulation 726/2004 and EMA guidance1:

应依指令2001/83/EC第23（2）条、指令2001/82/EC第27条、法规726/2004和EMA指南中指定的法律义务通知MAH和相关药监机构可能导致供应异常限制的严重GMP问题。

EMA指南链接：http://www.ema.europa.eu/ema/ind ... =WC0b01ac0580024593

In the event that a medicinalproduct which is the subject of a marketing authorisation issued by an EEAauthority, and which is marketed in another third country (or countries) then themarketing authorisation holder shall forthwith inform the relevant EU competentauthority of any prohibition or restriction imposed by the competentauthorities of any country in which the medicinal product is marketed and ofany other new information which might influence the evaluation of the benefitsand risks of the medicinal product concerned (e.g recalls or serious GMPissues). This is even if the particular batch subject to the prohibition orrestriction is not marketed in the EEA.

如果某药品的上市许可是由一个EEA药监机构签发的，并且在另一个（或多个）第三国上市，则上市许可持有人应通知相关EU药监机构其在任何其它药品上市地国家药监机构要求采取的禁止或限制措施，以及可能影响相关药品受益/风险评估的任何其它新信息（例如，召回或严重的GMP问题）。即使被禁止或受限的特定批次并未在EEA销售亦应遵守。

In cases where nationalcompetent authorities set additional national expectations regarding whatquality defects should be reported and the timelines for reporting, theseshould be complied with.

如果有某个国家药监机构设定了其它的需要报告质量缺陷的国家要求和报告时间限，则同时亦应遵守国家要求。

2. For the purposes of product recall, at what stage inthe supply chain is a product considered to be 'placed on the market' (ref:Chapter 8 paragraph 8.21)?

产品召回中，供应链中哪个阶段的产品是作为“上市销售”的（参见第8章第8.21段）？

Abatch recall is defined in the Compilation of Community Procedures as "Theaction of withdrawing a batch from the distribution chain and users. A batchrecall may be partial, in that the batch is only withdrawn from selecteddistributors or users". This definition covers the entire distributionchain from all points following manufacture through to the end user, thepatient. Also, it is possible that the MAH or its subsidiaries are actors inthe supply chain, acting as the distributor in certain cases. In such cases,the MAH or its subsidiaries should be regarded as also being part of thedistribution chain.

批次召回在欧共体程序汇编中定义为“从分销链和用户手中取回一个批次的行动。批次召回可以是部分的，此时只从指定的分销商或用户手中取回该批次药品。”此定义覆盖了整个销售链，从生产后的所有点直到最终用户、患者。同时，有可能MAH或其分支机构也是供应链中的行动方，在特定情形下扮演分销商角色。在此情形下，该MAH或其分支机构也应作为是销售链的一部分。

Abatch of medicinal product is considered to have been 'placed on the market'when one of the following takes place:

一批药品在以下情形发生时即被认为是“上市销售”：

l  A batch has been Qualified Person (QP) certified and has been madeavailable for sale on the stock management system of the pre-wholesaler/primarywholesaler, etc.

l  该批次已由QP认证，在预批发商/总批发商等的库存管理系统中作为可销售批次。

l  A batch has been QP certified and supplied to a facility where themanufacturer has no further control over when the product is transferred tosaleable stock. This applies even if within the pre-wholesaler/primarywholesaler network.

l  该批次已由QP认证，已发至某个生产商无法进一步控制其转移至可销售库存的场所。即使在预批发商/总批发商网络内也适用此条。

l  In the case of supply chain models where the manufacturer or primarywholesaler supplies direct to the customer (e.g. pharmacy), the batch has beenplaced on the market from the time of the first customer supply of product fromthe batch.

l  如果供应链模式中，生产商或总批发商直接向客户发货（例如，药房），该批次在向首个客户供应起即认为已上市销售。

Nationalcompetent authorities should be notified of all recall action proposed afterthe product has been placed on the market. In situations where the MAH candemonstrate that the batch is reconciled without issuing a recall notice, the nationalcompetent authority may agree that public recall communication throughout thedistribution network is not necessary.

在药品上市后，即应将所有召回措施通知给国家药监机构。如果MAH可以证明该批次数量可以平衡，不需要签发召回矣，则国家药监机构可以同意不需要通过销售网络进行公众召回沟通。

Itis acknowledged that certain short expiry products (e.g. radiopharmaceuticals, advancedtherapy medicinal products, etc.) may be shipped under quarantine prior tocertification. Retrieval of batches during this quarantine period may bemanaged within the pharmaceutical quality system.

要了解特定的短效期药品（例如，放射性药品、前沿治疗药品等）可能会在认证之前即在待验状态下发货。在此待验期间收回批次可以在药物质量体系内进行管理。

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