Control limit of Nitrosamines and N-nitroso compounds

Dear Nitrosamines expert,

I have two points making me slight confused regarding setting limits of nitrosamines.

  1. If there are theoretically Potential nitrosamines for example; NDMA and N-nitroso compound for example; N-nitroso Sitagliptin.

My question is; there will be two limits for NDMA and N-nitroso Sitagliptin based on MDD of the API or there will be a Single limit for both nitrosamines where Acceptance daily intake of the most potent nitrosamine will be taken into consideration for calculation of both nitrosamines as Sum limit.

  1. If the drug product has potential risk for nitrosamines formation; an accelerated stability study will be carried where the high temperature can trigger nitrosamines formation which can be risky especially for 6M interval while in long term ; there will be no longer that risk; my Question is; Can Accelerated stability study’s elevated temperature induce nitrosamines formation?.

My regards,

Can Accelerated stability study’s elevated temperature induce nitrosamines formation?
→ In my case, the temperature will accelerate the rate of formulation of Nitrosamine impurity and other factor is water content (For low percentage of water contant, the increasing of Nitrosamine impurity is following the water content).

Dear Heba 94,
first of all you should develop and validate a method(or methods) for the quantification of NDMA and-for example-N-nitroso-sita.
For the limits please consider the Q & A of the EMA doc (EMA/409815/2020 Rev.20) and more specifically question number 10: Which limits apply for nitrosamines in medicinal products?
Regarding the accelarated stability studies, yes they can increase nitrosamines levels and we have seen this in several products we have tested so far.
kind regards

1 Like