Nitrosamine Impurities: Further Update of EMA's Question and Answer Document

The Q&A document developed by EMA and CMDh is updated at irregular intervals to reflect the latest knowledge. On 12 October 2022, the EMA published on its "What's new" website a new update of the 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 nitrosamin impurities in human medicinal products" - now the 14th revision.

The document contains the following innovations:

Question 10: Which limits apply for nitrosamines in medicinal products?

The two nitrosamine compounds 4-(methylnitrosoamino)-1-(3-pyridinyl)-1-butanone (NKK) and N-nitrosoduloxetine were newly included in the table with corresponding limits (100 ng/day). The limit for nitrosoduloxetine was derived from structure-activity relationships. The value for NKK is based on the TD50 dataset of a database on carcinogenic potencies of numerous compounds (carcinogenic potency database; CPDB).

New question 21: What is the approach to control the presence of nitrosamines until a substance specific AI is established?

If new types of nitrosamine contaminants occur for which an acceptable intake (AI) has not yet been established due to a lack of toxicological data, a temporary limit, t-AI, of 178 ng/day (as the value for the sum of all nitrosamines present) can be applied. The validity of this t-AI value is 12 months, i.e. within this period no intervention (recall etc.) is required from the regulatory side for batches with a nitrosamine content up to 178 ng/day. If this period is exceeded, a special agreement with the authorities is required.

The t-AI value cannot be used automatically; a case-by-case assessment by the authority is required in each case.

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