AAM’s GRx+Biosims "Nitrosamines In Pharmaceuticals: Where the Industry and Agency Stands"

On November 9, AAM’s GRx+Biosims meeting had a session titled, “Nitrosamines in Pharmaceuticals: Where the Industry and Agency Stands”. The presenters included representatives from the Agency and the Industry, and the moderator was Aloka Srinivasan @ASrinivasan . The presentations were meaningful, and the discussions were vibrant. The issue that loomed large was how Agency would like the industry to address the API like larger nitrosamine impurities, which have very little or no information available in the literature. Currently, industry is observing these nitrosamines in many drugs which are themselves secondary and tertiary amines. It was pointed out that about 35% of the FDA approved drugs in the US market are secondary amines, capable of forming nitrosamines. Presenters acknowledged that the excipients are the “wild west” of pharmaceuticals, many of them containing significant levels of nitrosating agents. The role of Ames Test in determining the mutagenic potential of the large, and API-specific nitrosamines was discussed at length; also discussed was the feasibility of developing sensitive analytical methods for detection of the incredibly low levels of nitrosamines. There were questions from the audience regarding possible extension of the dates related to confirmatory testing and reporting of nitrosamine related controls to FDA, to which the FDA speakers did not comment. Overall, it seemed that we have only seen the tip of the iceberg, when it comes to the larger, API like nitrosamines and Industry as well as the Agency will need to invest a lot of resources to understand how the carcinogenicity of these larger nitrosamines may impact the currently marketed drug products.

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@ASrinivasan Thank you for sharing the helpful information. I understood nitrite in excipient is now focused on the nitrosamine contamination problem. As NDSRI was found in losartan, the aromatic heterocyclic amines like indole are not free from this problem. Therefore 35% looks realistic. To solve this problem, several ways are considerable, to measure and reduce the amount of nitrite in an excipient, to develop and apply new formulation with scavenger, to perform Ames tests and further tests for NDSRI, and to perform confirmatory tests highly sensitive for NDSRI. I think any of them is not the easy way. Besides confirmatory tests may be required to confirm the safety of drug products.

Anyway industries, agencies and regulatory should be cooperative and enthusiastic about this problem furthermore. I appreciate your help.

I agree with your conclusions. We should also move beyond sartans to the larger nitrosamines. I had proposed in an FDA public meeting that scavengers should be considered. But we need to understand that it is not a trivial task. Not all scavengers will work for all products. They could give rise to new unwanted impurities. Also, many are new and never used in pharmaceuticals and thus by regulations will need a battery of safety testing. However, if the Agencies are ready to accept these with less than usual qualification based on use, we may be in a better place.

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@ASrinivasan Do you know if there is a list of medication available from those “35% of the FDA approved drugs in the US market” ?

Naiffer, I have made such lists for some organizations, but not at liberty to share it with public. Again, 35% is an approximation.