2018年7月，藥品監管部門首次在含有纈沙坦的產品中發現亞硝胺雜質NDMA。對于該事件，歐洲藥品監管網絡進行了經驗教訓總結，在此基礎上歐洲藥品管理局（EMA）于6月23日發布了針對亞硝胺雜質的總結報告。
往期推薦
EMA百頁報告，總結亞硝胺雜質教訓
4個月后，10月27日，對于該報告中建議的措施，歐盟監管機構給出了一份具體的行動計劃書。該文件名為“實施計劃：從沙坦類藥物中存在亞硝胺雜質中學到的教訓”，共計17頁，涉及40個大類的行動項。
如果說，6月份的總結報告是亞硝胺的“偏差調查”報告，這次新發布的文件就是“CAPA計劃”了。
讓我們看看該CAPA計劃的部分內容：
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，歐洲藥品監管網絡發布了一份報告，該報告總結了從沙坦類藥品（也稱為血管緊張素II受體拮抗劑）中存在N-亞硝胺的經驗教訓。該報告提出了一些加強監管框架的建議，以減少未來在人藥中存在的亞硝胺和其他雜質的可能性，并支持監管網絡：為應對類似意外雜質的情況做好準備。
A summary of the recommendations with the assigned responsible party and indicative implementation timelines is provided below.
下面提供了建議摘要，以及實施計劃的時間表。
生命周期中，明確責任
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.
在藥品的整個生命周期中，明確MAH、成品制劑生產商、API生產商ASMF持有人和API CEP持有人的責任，包括質量、安全性和功效的責任。需要澄清的責任領域包括：質量管理體系、人員、文件、供應商資質、合同和技術協議，以及質量缺陷、投訴和產品召回的管理。
提醒責任
Section 2.4 (page 42)
Remind MAHs of their responsibilities.
Timeline: Medium (1-3 years)
第2.4節（第42頁）
提醒MAH他們的責任。
時間軸：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節（第42頁）
審查CEP的使用方式，并考慮如何以提高透明度為重點，更好地滿足MAH和監管機構的需求。需要澄清的法規文本應包括MAH責任（CEP涵蓋API情況下），CEP持有人的責任（針對MAH相關檔案資料，對于MAHH的可用性）。提供給MAH的信息，應不少：于申請人關于生產工藝和雜質的ASMF。
時間軸：中（1-3年）
闡明相關方對藥品的責任
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節（第61頁）
起草或修訂針對MAH以及CEP和ASMF持有人（即API生產商）的現有指南（例如，EU GMP指南第1部分第7章），闡明了他們在整個生命周期內對藥品的責任，包括其安全性、質量和功效，至少涵蓋以下領域：質量管理體系、人員、文件、供應商資質、合同和技術協議、質量缺陷、投訴和產品召回。應當考慮是否可能將某些方面納入：GMDP檢查員工作組當前正在制定的GMP和MAH指南中。
時間軸：中（1-3年）
起草MAH問答指南
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節（第60頁）
起草針對MAH和生產商的問答文檔，就CEP或ASMF持有人提供給藥品生產商或MAH的信息和數據方面，強調監管機構的期望。該文件應確保MAH對活性物質和藥品的質量負責，并涵蓋以下領域：
-明確而全面的保密和質量協議。
-進行調查和風險評估，并在出現質量問題時向MAH和監管機構提供數據和信息。
-藥品生產商對原料藥生產商的審計范圍和深度。
時間軸：中（1-3年）
MAH，負全責
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.
就有關API生產、生產工藝和生產中雜質形成方面，改善CEP或ASMF持有人與MAH之間的信息交流，以便MAH對其產品（包括API）的質量承擔全部責任。
MAH負全責
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節（第44頁）
考慮修訂GMP指南第1部分第7章，以闡明MAH對其產品質量負全部責任，包括參考CEP或ASMF而獲得上市許可API。
時間軸：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節（第42頁）
考慮修改ASMF程序指南，以提高透明度：當使用ASMF時，有關MAH的工藝雜質的信息，包括有關生產中使用的物料的知識。
時間軸：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節（第61頁）
考慮當前法規的變更，該變更將規定活性物質生產商需要向生產和進口許可持有人和MAH（根據保密協議）披露的更多信息，作為適當的GMP審計、穩健的風險評估和質量調查的基礎。另外，針對活性物質生產商和歐盟以外的ASMF / CEP持有者，考慮法律義務。
時間軸：較長（3-5年）
各方，都要提高意識
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.
提高生產和進口許可持有人、MAH以及CEP和ASMF持有人的意識，以進行深入的開發研究，認識到工藝和產品知識的重要性，以加強對整個供應鏈的監督。
起草針對行業的特定指南
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節（第61頁）
起草針對行業的特定指南，以提高MIA、MAH、CEP和ASMF持有者對深入開發研究、及工藝和產品知識的重要性的認識。這些指南還應旨在提高人們對加強整個供應鏈（包括發展階段）監督重要性的認識。
時間軸：中（1-3年）
MAH，對原料藥的監督
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.
加強MAH與原料藥及中間生產商之間的質量協議；需要對API生產商進行更有效的審計；提高質量授權人聲明系統的可靠性，以便MAH可以對API和中間生產商進行有效的監督；并提高成品中API的供應鏈可追溯性。
改進質量協議
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節（第42頁）
鼓勵MAH和API生產商之間改進質量協議。這些應該是技術質量協議，而不僅僅是采購協議。
時間軸：中（1-3年）
質量審計
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節（第42頁）
要求MAH對API生產商進行更好的質量審計，并改善QP聲明系統以確保其可靠性。
時間軸：中（1-3年）
審核：歐盟變更指南
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).
審核歐盟變更指南中：就有關與添加或更改API生產商和生產工藝（包括ASMF和CEP中記錄的變更），相關的變更條件/文檔的要求。
評估API相關變更指南
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節（第44頁）
關于歐盟變更指南，經驗教訓小組建議該網絡召集一個專門小組，以評估與添加或更改API生產商和生產工藝有關的分類指南，以避免分類錯誤、或更好地評估此類變更對藥品質量的影響。建議加強對引入CEP涵蓋的API的新來源的要求，以確保MAH對活性物質的質量有足夠的了解。
時間軸：中（1-3年）
MAH，提交更多數據
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將有關雜質的數據和來自API生產商的信息包括在其注冊檔案中，而不論活性物質文檔如何提交（例如通過ASMF或CEP）。
MAH自己提交雜志信息
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節（第42頁）
考慮要求MAH自己生成并提交有關雜質的信息，而不僅僅是依靠其API供應商提供的信息。
時間軸：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節（第43頁）
考慮使用ASMF時，修改ASMF程序指南，以向MAH提供更好的工藝雜質透明度，包括有關生產中所用物料的知識。
時間軸：中（1-3年）
MAH：處罰
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.
當產品質量不能適當保證時，確保MAH以及生產和進口許可持有人受到有效、相稱和勸阻性的處罰（根據2001/83 / EC指令第111條第8款）。
有效、相稱和勸阻性的處罰
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節（第62頁）
考慮采取必要措施，當產品質量不能適當保證時，確保MAH以及生產和進口許可持有人受到有效、相稱和勸阻性的處罰（根據2001/83 / EC指令第111條第8款）。
時間軸：較長（3-5年）
亞硝胺來源，詳細信息
8) The network publishes detailed information about potential sources of N-nitrosamine impurities and other cohort-of-concern compounds.
歐洲監管網絡將發布：有關N-亞硝胺雜質和其他相關化合物的潛在來源的詳細信息。
雜質來源問答指南
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節（第42頁）
該網絡可能會發布詳細的問答文件，其中包含有關N-亞硝胺雜質和其他相關化合物（例如疊氮化合物）的潛在來源的信息，包括其形成條件。
時間軸：短（<1年）
歐洲藥典，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.
歐洲藥典委員會正在繼續修訂有關藥用物質的一般專著，以期包括新的要求，以減輕N-亞硝胺的風險。
修訂歐洲藥典
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節（第42頁）
該小組建議歐洲藥典委員會考慮所有活性物質的其他建議，以避免在藥物產品中有意或無意引入風險化合物的風險，以及采取適當的控制策略。該小組指出，歐洲藥典委員會已經開始對通則《藥用物質》（2034）進行修訂，目的是加入新的要求，以減輕N-亞硝胺的風險。
時間軸：中（1-3年）
原文鏈接：
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
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