Request for risk assessment and confirmatory testing for nortriptyline containing products

Dear all,

Have you heard about the request of “Request for risk assessment and confirmatory testing for nortriptyline containing products” in the EU?

In particular it has been asked among others the following:

  • Perform a risk assessment on potential presence of N-nitrosonortriptyline for all nortriptyline containing medicinal products (regardless of the outcome of the risk evaluation / step 1 response in the general call for review).

  • Regardless of risk assessment outcome, perform a confirmatory testing on a representative number of finished product batches (10% of annual batches, or 3 per year, whichever is highest).

  • Further testing has to be conducted when nitrosamines are found >30% AI in selective testing. Testing results should be provided by 1 July 2024 to all national competent authorities

It is always interesting when this request come, as my 1st thought is why? It reminds me the Azithromycin case times ago. Finally, I always wondered about the 8 ng/day limit for this molecule, considered the used surrogate NMPEA has debatible data regarding fit for purpose of the TD50 linear extrapolation model, the most senstive tissue selection, etc.


Or the “Request for risk assessment and confirmatory testing for sitagliptin containing products” sent by the EMA on 8 July 2022.


After presenting a case for 41 ng/day for NMPEA to EMA, NcWP, NS OEG on 17 October 2022 Industry hasn’t heard back on this AI assignment I believe. However as already indicated on that occasion, the complexity was also that a consistent approach would be preferably implemented by the EMA, thus requiring that also for NDMA (145 ng/day) and NNK (180 ng/day) the ICH M7 (most sensitive species and tumor site) approach would be used.

Next to this there is however the discussion on extrapolating the 41 ng/day to for example 100 ng/day based on MW arguments, especially considering the MW > 200 Da.

At the moment however I believe indeed HC, EMA and TGA stick to the 8 ng/day based on NMPEA readacross, but FDA uses CPCA Category 1- 26.5 ng/day.

Note that when applying the Fine 2023 MW correction rule (163 pmol/day x MW nitrosamine (ng/pmol) = AI (ng/day)), an AI close to 50 ng/day would be obtainable, thus again supporting the 41 ng/day proposal.

Would be interesting to see new biological data and mechanistic studying of the NMPEA analogue class.



Could you please clarify if there is any official publication from EMA or other authority?

Kind regards,


The information was forwarded to the pharma industry associations by EMA official email including a CMDh letter. I infer you could ask EPFIA for the official communication as it is my understanding for the time being it is not publicly available (therefore, cant share the document as of now apart from the very brief summary shared at the beggining).

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