Nitrosamines Update EMA/409815/2020 Rev.22

What is new?

In the latest EMA Q&A Rev.22 update, the same risk-based approach is now applied across all routes of administration, with the previous allowance for route-specific justifications removed.

A negative result from a well-conducted in vivo transgenic rodent (TGR) mutagenicity study (OECD 488) is now sufficient to classify N-nitrosamines as non-mutagenic impurities (NMIs), allowing control under ICH Q3A(R2)/Q3B(R2) limits.

Additionally, changes to shelf life and storage conditions to comply with interim acceptable intakes (AIs) are to be implemented without delay, following the guideline on variation classification (see Q&A 13).

These updates reflect EMA’s ongoing commitment to science-based, risk-proportionate regulation—and open new opportunities for smarter impurity control strategies.

What does this mean to you?

While this is a relatively minor update, it is particularly useful for Marketing Authorization Holders (MAHs) who were unsure about which in vivo studies to design in order to justify classifying a specific nitrosamine as a non-mutagenic impurity (NMI). It also reinforces the principle that the route of administration should not be considered when setting nitrosamine limits—offering a broader safety margin for patients

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