EMA and CMDh Expand List of Nitrosamine Limits

The European Medicines Agency (EMA) and the Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh) have revised Appendix 1 of their Questions and Answers document on nitrosamine impurities. Revision 14 adds Acceptable Intakes (AIs) for additional nitrosamines and other N-nitroso compounds.

Background: the Q&A document

The document is aimed at marketing authorisation holders and applicants. It explains the CHMP Opinion on the Article 5(3) referral under Regulation (EC) No 726/2004 concerning nitrosamine impurities in human medicinal products. Appendix 1 refers to the Acceptable Intakes (AI values) set by the Non-clinical Working Party (NcWP).

What Revision 14 brings (as of 1 October 2026)

• Eleven additional nitrosamines with substance-specific AI values:
  o 6,7-Dichloro-4-nitroso-1,3,4,5-tetrahydro-2H-benzo[e][1,4]diazepin-2-one
  o Ethyl N-(2,3-dichloro-6-nitrobenzyl)-N-nitrosoglycinate
  o Ethyl N-(6-amino-2,3-dichlorobenzyl)-N-nitrosoglycinate
  o N,N`-Dinitroso-desmethyl-sumatriptan
  o N-Nitroso-desmethyl-maralixibat
  o N-Nitroso-donepezil Impurity A
  o N-Nitroso-N-methylbenzylamine (NMBzA)
  o N-Nitroso-phenoxybenzamine HCl Impurity A (NDB-A)
  o N-Nitroso-phenoxybenzamine HCl Impurity B (NDB-B)
  o N-Nitroso-torasemide
  o N-Nitroso-tranexamic acid dimer
• One new compound on the "Other N-nitroso structures" tab:
  o N-Nitroso-xylometazoline
• Two compounds without a numerical AI value:
  o N-Nitroso-desmethyl-roxithromycin
  o N-Nitroso-desmethyl-erythromycin

The EMA classifies both as non-mutagenic impurities (NMIs). They can be controlled based on their assessment under ICH Q3A/B, so no AI value has been set.

Context

The expansion mainly affects manufacturers whose active substances or impurity profiles involve one of the new compounds. For them, updating the risk assessment is relevant. The complete overview of all current AI values is available on the EMA website.