Why is NMEA associated with Amphotericin B? (Appendix 1 March 2026 Update)

N-nitrosamines Chemistry
1

In the March 2026 update of the EMA Appendix 1 (Acceptable Intakes for N‑nitrosamines), N‑nitroso‑methylethylamine (NMEA) is listed as a potential impurity associated with Amphotericin B.

However, based on a comparison of the chemical structure of Amphotericin B (a complex polyene macrolide) and NMEA (a simple low molecular weight dialkyl nitrosamine), there does not appear to be an obvious structural relationship or common secondary/tertiary amine precursor within the API itself.

Could anyone provide insight into the mechanistic rationale for this association? For example:

  • Is the proposed origin linked to specific synthetic steps, degradation pathways, or manufacturing reagents/solvents rather than the API structure itself?

  • Or could this be an example where the listed “source” reflects a potential risk scenario (e.g., external amine/nitrosating agent combination) rather than a structure-derived impurity?

I would appreciate any clarification on whether this linkage is chemically justified or if it might reflect a conservative or generic assignment in the EMA table.

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