Nitrosamine in Varenicline particularly Nitroso-varenicline

Dear Colleagues and Experts,

I would like to understand from experts regarding the Nitrosamine Impurities in Varenicline particularly Nitroso-varenicline. FDA has published information on Nitroso-Varenicline and recently we have seen that Chantix (RLD) by Pfizer has to make recall for some lots. However other generic layers such as Apotex and Par could control this impurity. In my opinion and FDA’s discussion this impurity forms due to use of nitrating agent in ROS, I would like to understand from experts that is only API responsible form getting this impurity in finished product or excipient also has role, particularly Nitroso-varenicline impurity. Please comment based on your expertise and knowledge. Thank you.

The API varnecline is very prone to nitrosation. So, it may not be enough that nitrite is not present based on the synthetic route. It would be important to test your excipients for nitrite/nitrate.

Has anybody done quantitation of Nitroso-Varenicline by using GCMS/MS ? Can any anyone share experience on the results obtained by GCMS/MS?

I’m sorry for my delayed response. In the following post, possible root cause of N-nitroso-varenicline is illustrated by Johnson.

KSM and nitric acid may be the root cause of nitrosamine.

@nitish461990 in the thread below we share the method that FDA published for determination of Nitroso-Varenicline. Have you & team been challenged with this product?

Thank you for the information. It is well explained in PPT , I already gone through this information. My experience is that API does not have Nitroso-varenicline impurity it means API colleagues have taken precaution for the same, however it increases in formulation. I would like to understand the mechanism/responsible factor for increasing Nitroso-Varenicline in formulation in presence of excipient. Best to my knowledge analytical method is very crucial in testing since there is interference of other impurities at Nitroso-varenicline RT.

I would like to request analytical experts and those practically working on this method need to comment on suitability of methods, it seems there is interference of other impurities (which exists in keto-enol form), experts with analytical and chemistry knowledge can discuss more. Since I am not directly working with method (being formulation expert), I am not challenging the method but sharing some thought process and little experience on this issue. Working on this area hence learning through these discussions.

Perfectly agree, we did analysis for nitrite content in excipients but did not find any significant values, may be more investigation needed.
Here I would like to request all colleagues that we (formulation expert) always request for nitrosamine declaration from API and excipient supplier, I think we should request nitrate/nitrite content in API/excipient along with nitrosamine declaration. In most of the cases ( even in Metformin), nitrate/nitrite content has major role in forming the NDMEA impurity.
Thank you all colleagues for sharing the knowledge, it will help to achieve safer drug products.

That is why Nitrosamines Risk Assessment for formulation needs to be done to assess potential sources of Nitrosamines formation. Analytical methods are crucial , at the same time these methods need to be evaluated wrt matrix components of formulation under study and API process related Impurities. Assessing specificity of an Analytical method is important prior to adopting these methods.