Yesterday EMA published the Rev.12 of the Nitrosamines Q&A guideline. Nitrosamines EMEA-H-A5(3)-1490 - QA Art. 5(3) Implementation_ for October PROM (QA10 and 21) (europa.eu)
In summary, the list of changes includes the following points:
- Update of Q&A 10 to add 2 new N-nitrosamines to the list and
- Addition of a new Q&A 21 on approach to control presence of nitrosamine while the AI is being established.
In detail, newly added to Q&As 10 and the list of potential N-nitrosamines is
- 4-(Methylnitrosoamino)-1-(3-pyridinyl)-1-butanone (NNK) with a limit of 100 ng/day and
- N-nitrosoduloxetine using a limit of 100 ng/day.
Furthermore, the footnotes for N-nitrosoduloxetine was added clarifying that the limit derived using structure-activity-relationship (SAR) /read-across approach using the TD50 of NNK as point of departure. In accordance with Health Canada evaluation for example.
The new Q&As 21 is clear in the statement that the Non-clinical Working Party (NcWP) and the CHMP are the final instances to decide on control options for the nitrosamine in the finished product.
The application of a temporary AI limit for a max of 12 month would be acceptable for avoiding shortages.
In practice, this means that when competent authorities are notified about a product containing a new N-nitrosamine exceeding the TTC limit of 18 ng/day, no market actions may be required for batches with N-nitrosamine levels ≤178 ng/day at the MDD pending the agreement of the AI. The adoption of the t-AI is not automatic and is evaluated by the relevant authorities at the time of notification. Use of the t-AI beyond 12 months will require additional consultation with competent authorities.
The t-AI should not be used as a target for development of validated analytical methods to quantify new nitrosamines since the long-term limits adopted by CHMP might ultimately be lower than the t-AI.
This is I think a great step into looking for pragmatic solutions for the NA issue.