Questions and answers - CHMP Opinion Article 5(3) referral on nitrosamine impurities in human medicinal products - 14 Q&A

Sep 11, 2026

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Guidance in a Q&A format for marketing authorisation holders/applicants on how to respond to the CHMP Opinion under Article 5(3) of Regulation (EC) No 726/2004 for nitrosamine impurities in human medicinal products. Covers scope and the “call for review”, reporting steps to competent authorities, identified risk factors and prioritisation, execution of risk evaluation and confirmatory testing, analytical method requirements, applicable limits, and actions when nitrosamines are detected. Includes mitigation measures, changes to marketing authorisations and regulatory steps by authorities, plus an annex decision tree for products with multiple nitrosamines.

LanguageEnglish

CategoryGeneral

FormatPDF

Pages27

Reading Time9 min

AccessFree to download

Introduction

Revision History

Should the risk of presence of nitrosamines be considered for all human medicinal products?

What is the “call for review”?

What are the currently identified risk factors for presence of nitrosamines?

What to do if new information is identified after step 1 and/or step 2 responses?

What factors should be considered in prioritising the risk evaluation?

How should the risk evaluation be performed?

How should confirmatory tests be conducted by MAHs and manufacturers?

What are the requirements of the analytical method(s)?

Which limits apply for nitrosamines in medicinal products?

What should I do if a nitrosamine is detected in my medicinal product?

Which are the measures to mitigate the risk of presence of nitrosamines?

Which changes would be required for Marketing Authorisations?

What is the approach for new and ongoing marketing authorisation applications (MAA)?

When should a test for nitrosamines be included in the MA dossier?

What are the responsibilities of MAHs for APIs with CEPs or ASMFs?

How does the lessons learnt exercise from presence of nitrosamines in sartans relate to the Article 5(3) Referral Outcome?

What about regulatory requirements in other regions?

How to control the presence of nitrosamines until a substance specific AI is established?

How to control presence of N-nitrosamine exceeding the AI during CAPA implementation?

Annex 1: Decision tree with control options for products containing multiple N-nitrosamines

10 October 2025 EMA/409815/2020 Rev.23 Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products Table of contents Revision History .......................................................................................... 2 Introduction................................................................................................ 4 1. Should the risk of presence of nitrosamines be considered for all human medicinal products? ................................................................................................... 5 2. What is the‘call for review’? ...................................................................... 6 3. For the ‘call for review’ for chemically synthesised and biological medicinal products, when and how should MAHs report steps 1 and 2 to competent authorities? 4. What are the currently identified risk factors for presence of nitrosamines? ....... 9 5. What to do if after submission of step 1 and /or step 2 responses, new information (e.g. related to new potential risk factors or root causes) is identified? ................11 6. What factors should be considered in prioritising the risk evaluation? ..............12 7. How should the risk evaluation be performed? .............................................12 8. How should confirmatory tests be conducted by MAHs and manufacturers? ......13 9. What are the requirements of the analytical method(s)?................................15 10. Which limits apply for nitrosamines in medicinal products? ...........................15 11. What should I do if a nitrosamine is detected in my medicinal product?..........20 12. Which are the measures to mitigate the risk of presence of nitrosamines? ......20 13. Which changes would be required for Marketing Authorisations? ...................21 14. What is the approach for new and ongoing marketing authorisation applications (MAA)? .....................................................................................................21 15. When should a test for nitrosamines be included in the MA dossier? ..............23 16. What are the responsibilities of MAHs for APIs with CEPs or ASMFs? ..............23 17. How does the lessons learnt exercise from presence of nitrosamines in sartans relate to the Article 5(3) Referral Outcome? ....................................................24 18. What about regulatory requirements in other regions? ................................24 19. What is the approach for line extensions and variations applications not linked to changes required as part of article 5(3) recommendation?.................................24 20. What are the regulatory steps taken by authorities following the identification of an N-nitrosamine exceeding the AI? ..............................................................24 21. What is the approach to control the presence of nitrosamines until a substance specific AI is established?.............................................................................25 22. What is the approach to control presence of N-nitrosamine exceeding the AI during CAPA implementation? (Updated) ........................................................25 Annex 1: Decision tree with control options for products containing multiple Nnitrosamines:.............................................................................................27 Revision History Rev. Summary of changes made Date | 0 | Replace obsolete Q&A published in 2019 to support the initial “call for review” with a new version reflecting the main principles agreed as part of the Article 5(3) referral which concluded in July 2020. | 03rd August 2020 | | --- | --- | --- | | 1 | Update to Q&A 3 in order to clarify products in scope of the call for review.
Update to Q&A 4 in order to add the link to the outco

FAQs

Should MAHs consider the risk of nitrosamines for all human medicinal products?

The document addresses whether nitrosamine presence risk assessment is required across human medicinal products and explains how the call for review is applied to products in scope.

What is the “call for review” and how should MAHs report steps 1 and 2 to competent authorities?

It defines the “call for review” and sets expectations for when and how MAHs report risk identified (step 1) and subsequent confirmatory actions (step 2) to competent authorities.

What should be done if new information emerges after submitting step 1 and/or step 2 responses?

The guidance describes how to handle newly identified information, such as new potential risk factors or root causes, after step 1 and/or step 2 have been submitted.

Sep 11, 2026

Upload by Rowan