2018年7月，药品监管部门首次在含有缬沙坦的产品中发现亚硝胺杂质NDMA。对于该事件，欧洲药品监管网络进行了经验教训总结，在此基础上欧洲药品管理局（EMA）于6月23日发布了针对亚硝胺杂质的总结报告。

往期推荐
EMA百页报告，总结亚硝胺杂质教训

4个月后，10月27日，对于该报告中建议的措施，欧盟监管机构给出了一份具体的行动计划书。该文件名为“实施计划：从沙坦类药物中存在亚硝胺杂质中学到的教训”，共计17页，涉及40个大类的行动项。

如果说，6月份的总结报告是亚硝胺的“偏差调查”报告，这次新发布的文件就是“CAPA计划”了。

让我们看看该CAPA计划的部分内容：

In June 2020, the European Medicines Regulatory Network published a report on lessons learnt from the presence of N-nitrosamines in sartan medicines (also known as angiotensin II receptor antagonists). The report sets out a number of recommendations for strengthening the regulatory framework in order to reduce the potential of N-nitrosamines and other impurities being present in human medicines in the future and to support the regulatory network’s preparedness for managing similar cases of unexpected impurities should they occur in the future.

2020年6月，欧洲药品监管网络发布了一份报告，该报告总结了从沙坦类药品（也称为血管紧张素II受体拮抗剂）中存在N-亚硝胺的经验教训。该报告提出了一些加强监管框架的建议，以减少未来在人药中存在的亚硝胺和其他杂质的可能性，并支持监管网络：为应对类似意外杂质的情况做好准备。

A summary of the recommendations with the assigned responsible party and indicative implementation timelines is provided below.

下面提供了建议摘要，以及实施计划的时间表。

生命周期中，明确责任

1) Clarify responsibilities of MAHs, finished product manufacturers, API manufacturers ASMF Holders and API CEP holders throughout the life cycle of medicinal products, including responsibilities for quality, safety and efficacy. Areas of responsibilities to be clarified include quality management systems, personnel, documentation, supplier qualification, contract and technical agreements, and management of quality defects, complaints and product recalls.

在药品的整个生命周期中，明确MAH、成品制剂生产商、API生产商ASMF持有人和API CEP持有人的责任，包括质量、安全性和功效的责任。需要澄清的责任领域包括：质量管理体系、人员、文件、供应商资质、合同和技术协议，以及质量缺陷、投诉和产品召回的管理。

提醒责任

Section 2.4 (page 42)
Remind MAHs of their responsibilities.
Timeline: Medium (1-3 years)
第2.4节（第42页）
提醒MAH他们的责任。
时间轴：中（1-3年） 

CEP的使用方式
Section 2.4 (page 42)
Review the way CEPs are used and consider how to better address the needs of marketing authorisation holders and regulators with a focus on increased transparency. This should include clarification of regulatory texts on responsibilities of the MAH in cases where API is covered by a CEP and those of CEP holders towards the MAHs regarding availability of dossier information. The information provided to the MAHs should not be less than the applicant’s part of an ASMF on manufacturing process and impurities.
Timeline: Medium (1-3 years)
第2.4节（第42页）
审查CEP的使用方式，并考虑如何以提高透明度为重点，更好地满足MAH和监管机构的需求。需要澄清的法规文本应包括MAH责任（CEP涵盖API情况下），CEP持有人的责任（针对MAH相关档案资料，对于MAHH的可用性）。提供给MAH的信息，应不少：于申请人关于生产工艺和杂质的ASMF。
时间轴：中（1-3年） 

阐明相关方对药品的责任

Section 4.2.4 (page 61)
Draft or amend existing guidelines (e.g., EU GMP guideline Part 1, Chapter 7) addressed to MAHs and holders of CEPs and ASMFs (i.e., API manufacturers) clarifying their respective responsibilities with regard to the medicinal product over its lifetime, including its safety, quality and efficacy, covering at least the following areas: quality management system, personnel, documentation, supplier qualification, contract and technical agreements, quality defects, complaints and product recalls. Consideration should be given to the possibility of including some of these aspects in the good manufacturing practice and marketing authorisation holders guidance currently being developed by the GMDP Inspectors Working Group.
Timeline: Medium (1-3 years)
第4.2.4节（第61页）
起草或修订针对MAH以及CEP和ASMF持有人（即API生产商）的现有指南（例如，EU GMP指南第1部分第7章），阐明了他们在整个生命周期内对药品的责任，包括其安全性、质量和功效，至少涵盖以下领域：质量管理体系、人员、文件、供应商资质、合同和技术协议、质量缺陷、投诉和产品召回。应当考虑是否可能将某些方面纳入：GMDP检查员工作组当前正在制定的GMP和MAH指南中。
时间轴：中（1-3年）

起草MAH问答指南

Section 4.2.4 (page 60)
Draft a questions-and-answers document for MAHs and manufacturers to emphasise regulatory authority expectations regarding the information and data provided to the medicinal product manufacturer or MAH by the holder of the CEP or ASMF. This document should ensure that MAHs can take responsibility for quality of the active substance and the medicinal product and cover areas such as:
- clear and comprehensive confidentiality and quality agreements.
- the conduct of investigations and risk assessments and provision of data and information to MAHs and regulatory authorities in case of quality issues.
- the scope and depth of audits of API manufacturers by medicinal product manufacturers.
Timeline: Medium (1-3 years)
第4.2.4节（第60页）
起草针对MAH和生产商的问答文档，就CEP或ASMF持有人提供给药品生产商或MAH的信息和数据方面，强调监管机构的期望。该文件应确保MAH对活性物质和药品的质量负责，并涵盖以下领域：
-明确而全面的保密和质量协议。
-进行调查和风险评估，并在出现质量问题时向MAH和监管机构提供数据和信息。
-药品生产商对原料药生产商的审计范围和深度。
时间轴：中（1-3年） 

MAH，负全责

2) Improve exchange of information between CEP or ASMF holders and marketing authorisation holders regarding impurity formation during the API manufacturing, the manufacturing process and materials used in manufacturing so that marketing authorisation holders can take full responsibility for the quality of their products, including APIs.

就有关API生产、生产工艺和生产中杂质形成方面，改善CEP或ASMF持有人与MAH之间的信息交流，以便MAH对其产品（包括API）的质量承担全部责任。

MAH负全责
Section 2.4 (page 44)
Consider amending the GMP guideline Part 1, chapter 7, to clarify how marketing authorisation holder can take full responsibility for the quality of their products including the API for marketing authorisations granted with reference to a CEP or ASMF.
Timeline: Medium (1-3 years)
第2.4节（第44页）
考虑修订GMP指南第1部分第7章，以阐明MAH对其产品质量负全部责任，包括参考CEP或ASMF而获得上市许可API。
时间轴：中（1-3年）

修改ASMF程序指南
Section 2.4 (page 42)
Consider amending the guideline on the ASMF procedure to provide better transparency on impurities of the process to the MAH including knowledge on materials used in the manufacturing, when an ASMF is used.
Timeline: Medium (1-3 years)
第2.4节（第42页）
考虑修改ASMF程序指南，以提高透明度：当使用ASMF时，有关MAH的工艺杂质的信息，包括有关生产中使用的物料的知识。
时间轴：中（1-3年）。 

API商披露更多信息
Section 4.2.4 (page 61)
Consider a change in the current legislation that would prescribe more information that active substance manufacturers need to disclose to manufacturing and importation authorisations holders and marketing authorisation holders (under confidentiality agreements) as a basis for appropriate GMP audits as well as for robust risk assessment and quality investigations. In addition, consider legal obligations for active substance manufacturers and ASMF/CEP holders located outside the EU.
Timeline: Long (3-5 years)
第4.2.4节（第61页）
考虑当前法规的变更，该变更将规定活性物质生产商需要向生产和进口许可持有人和MAH（根据保密协议）披露的更多信息，作为适当的GMP审计、稳健的风险评估和质量调查的基础。另外，针对活性物质生产商和欧盟以外的ASMF / CEP持有者，考虑法律义务。
时间轴：较长（3-5年）

各方，都要提高意识
3) Raise awareness amongst manufacturing and importation authorisations holders, marketing authorisation holders, and CEP and ASMF holders of the importance of thorough development studies and of process and product knowledge in order to strengthen oversight of the entire supply chain.

提高生产和进口许可持有人、MAH以及CEP和ASMF持有人的意识，以进行深入的开发研究，认识到工艺和产品知识的重要性，以加强对整个供应链的监督。

起草针对行业的特定指南
Section 4.2.4 (page 61)
Draft specific guidelines for industry in order to raise awareness amongst holders of MIAs, marketing authorisations, CEPs and ASMFs of the importance of thorough development studies and of process and product knowledge. These guidelines should also aim to increase awareness of the importance of strengthening oversight of the entire supply chain, including the development phases.
Timeline: Medium (1-3 years)
第4.2.4节（第61页）
起草针对行业的特定指南，以提高MIA、MAH、CEP和ASMF持有者对深入开发研究、及工艺和产品知识的重要性的认识。这些指南还应旨在提高人们对加强整个供应链（包括发展阶段）监督重要性的认识。
时间轴：中（1-3年）

MAH，对原料药的监督
4) Strengthen quality agreements between marketing authorisation holders and API and intermediate manufacturers; require more effective audits of API manufacturers; improve the reliability of the qualified person declaration system so that marketing authorisation holders can exercise effective oversight of API and intermediate manufacturers; and improve supply chain traceability of API in finished products.

加强MAH与原料药及中间生产商之间的质量协议；需要对API生产商进行更有效的审计；提高质量授权人声明系统的可靠性，以便MAH可以对API和中间生产商进行有效的监督；并提高成品中API的供应链可追溯性。

改进质量协议
Section 2.4 (page 42)
Encourage improved quality agreements between MAHs and API manufacturers. These should be technical quality agreement rather than just purchasing agreements.
Timeline: Medium (1-3 years)
第2.4节（第42页）
鼓励MAH和API生产商之间改进质量协议。这些应该是技术质量协议，而不仅仅是采购协议。
时间轴：中（1-3年）

质量审计
Section 2.4 (page 42)
Require better quality audits of API manufacturers by MAHs and improve the QP declaration system to ensure it is reliable.
Timeline: Medium (1-3 years)
第2.4节（第42页）
要求MAH对API生产商进行更好的质量审计，并改善QP声明系统以确保其可靠性。
时间轴：中（1-3年） 

审核：欧盟变更指南
5) Review requirements in the EU variations guideline for conditions/documentation for variations associated with adding or changing API manufacturers and manufacturing processes (including those documented in ASMFs and CEPs).

审核欧盟变更指南中：就有关与添加或更改API生产商和生产工艺（包括ASMF和CEP中记录的变更），相关的变更条件/文档的要求。

评估API相关变更指南
Section 2.4 (page 44)
With regard to the EU variations guideline, the lessons learnt group recommends that the network convene a dedicated group to assess the need to update the classification guideline in terms of conditions/documentation for indents associated with adding or changing API manufacturers and manufacturing processes (including those documented in ASMFs and CEPs) to avoid misclassification or to better appraise impact of such changes in relation to the drug product quality. It is recommended to strengthen requirements for introducing a new source of API covered by a CEP to ensure the MAH has adequate knowledge of the quality of the active substance.
Timeline: Medium (1-3 years)
第2.4节（第44页）
关于欧盟变更指南，经验教训小组建议该网络召集一个专门小组，以评估与添加或更改API生产商和生产工艺有关的分类指南，以避免分类错误、或更好地评估此类变更对药品质量的影响。建议加强对引入CEP涵盖的API的新来源的要求，以确保MAH对活性物质的质量有足够的了解。
时间轴：中（1-3年）

MAH，提交更多数据
6) Require marketing authorisation holders to include data on impurities and information from the API manufacturer in their dossier, irrespective of how the active substance documentation is submitted (e.g. via ASMFs or CEPs).

要求MAH将有关杂质的数据和来自API生产商的信息包括在其注册档案中，而不论活性物质文档如何提交（例如通过ASMF或CEP）。

MAH自己提交杂志信息
Section 2.4 (page 42)
Consider requiring MAHs to generate and submit their own information on impurities rather than just relying on information provided by their API suppliers.
Timeline: Medium (1-3 years)
第2.4节（第42页）
考虑要求MAH自己生成并提交有关杂质的信息，而不仅仅是依靠其API供应商提供的信息。
时间轴：中（1-3年） 

修改ASMF程序指南
Section 2.4 (page 43)
Consider amending the guideline on the ASMF procedure to provide better transparency on impurities of the process to the MAH including knowledge on materials used in the manufacturing, when an ASMF is used.
Timeline: Medium (1-3 years)
第2.4节（第43页）
考虑使用ASMF时，修改ASMF程序指南，以向MAH提供更好的工艺杂质透明度，包括有关生产中所用物料的知识。
时间轴：中（1-3年）

MAH：处罚
7) Ensure that marketing authorisation holders as well as manufacturing and importation authorisation holders are subject to effective, proportionate and dissuasive penalties (in accordance with Article 111 (8) of Directive 2001/83/EC) if product quality is not appropriately ensured.

当产品质量不能适当保证时，确保MAH以及生产和进口许可持有人受到有效、相称和劝阻性的处罚（根据2001/83 / EC指令第111条第8款）。

有效、相称和劝阻性的处罚
Section 4.2.4 (page 62)
Consider taking necessary measures to ensure that MAHs as well as manufacturing and importation authorisation holders are subject to effective, proportionate and dissuasive penalties (in accordance with Article 111 (8) of Directive 2001/83/EC) if product quality is not appropriately ensured.
Timeline: Long (3-5 years)
第4.2.4节（第62页）
考虑采取必要措施，当产品质量不能适当保证时，确保MAH以及生产和进口许可持有人受到有效、相称和劝阻性的处罚（根据2001/83 / EC指令第111条第8款）。
时间轴：较长（3-5年） 

亚硝胺来源，详细信息
8) The network publishes detailed information about potential sources of N-nitrosamine impurities and other cohort-of-concern compounds.

欧洲监管网络将发布：有关N-亚硝胺杂质和其他相关化合物的潜在来源的详细信息。

杂质来源问答指南
Section 2.4 (page 42)
The network may publish a detailed questions-and-answers document with information on potential sources of N-nitrosamine impurities and of other cohort-of-concern compounds (e.g. azoxy compounds), including the conditions under which they can form.
Timeline: Short (<1 year)
第2.4节（第42页）
该网络可能会发布详细的问答文件，其中包含有关N-亚硝胺杂质和其他相关化合物（例如叠氮化合物）的潜在来源的信息，包括其形成条件。
时间轴：短（<1年）

欧洲药典，下一步
9) The Ph.Eur. Commission pursue its ongoing revision of the general monograph on substances for pharmaceutical use with the intention to include new requirements in order to mitigate the risks of N- nitrosamines.

欧洲药典委员会正在继续修订有关药用物质的一般专着，以期包括新的要求，以减轻N-亚硝胺的风险。

修订欧洲药典
Section 2.4 (page 42)
The group suggested that the European Pharmacopoeia Commission consider additional recommendations for all active substances to avoid the risk of deliberate or inadvertent introduction of cohort-of-concern compounds in general in substances used in medicinal products along with appropriate control strategies. The group noted that the European Pharmacopoeia Commission has already started the revision process for the general monograph Substances for Pharmaceutical Use (2034) with the intention of including new requirements to mitigate the risk of N-nitrosamines.
Timeline: Medium (1-3 years)
第2.4节（第42页）
该小组建议欧洲药典委员会考虑所有活性物质的其他建议，以避免在药物产品中有意或无意引入风险化合物的风险，以及采取适当的控制策略。该小组指出，欧洲药典委员会已经开始对通则《药用物质》（2034）进行修订，目的是加入新的要求，以减轻N-亚硝胺的风险。
时间轴：中（1-3年） 

原文链接：

Lessons learnt from presence of N-nitrosamine impurities in sartan medicines- Implementation Plan. 27 October 2020. HMA, EMA.
https://www.ema.europa.eu/en/documents/other/lessons-learnt-presence-n-nitrosamine-impurities-sartan-medicines-implementation-plan_en.pdf