EMA/CMDh: Nitrosamine Q&A Document revised

The EMA/CMDh nitrosamine Q&A document "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" was updated again in January 2024 and is now available in revision 20. Like the three appenices, the Q&A document is published on the EMA website and can be viewed under "Questions and answers".

In the latest version, three questions and the corresponding answers have been revised and supplemented. These include the following points:

  • 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? 
  • 9. What are the requirements of the analytical method(s)? 
  • 10. Which limits apply for nitrosamines in medicinal products?

Information on the handling of non-mutagenic nitrosamine impurities (NMI) has been added to the texts of questions 3 and 10. The acceptability timelines for the Ames test were also included in the answer to question 10. The answer to question 9 now shows even more clearly in the new version that the sensitivity of the analytical methods is decisive for the detection of nitrosamine impurities.

Appendix 1 was also revised in January and the following substances were added:

  • 1-(2,3-dichlorophenyl)-4-nitrosopiperazine
  • N-nitroso-azacyclonol
  • N-nitroso-betaxolol
  • N-nitroso-dabigatran etexilate
  • N-nitroso-desmethyl-sildenafil
  • N-nitroso-desmethyl-sumatriptan
  • N-nitroso-desmethyl-terbinafine
  • N-nitroso-dorzolamide
  • N-nitroso-mirtazapine
  • N-nitroso-ranolazine impurity 1
  • N-nitroso-ribociclib impurity 1
  • N-nitroso-rivaroxaban amide
  • N-nitroso-rivaroxaban open-ring acid
  • N-nitroso-terbinafine degradant
  • N-nitroso-terbinafine impurity A
  • N-nitroso-urapidil

The complete Q&A catalogue for nitrosamines can be found on the EMA website in the "Questions and answers" section.

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