Adding trapping agents capable of scavenging adventitious nitrosating agents?

At recent FDA’s Generic Drug Science and Research Initiative Public Workshop, our very own @ASrinivasan introduced the concept of ‘Blocking Nitrosamines formation in Drug Products’

  • Preliminary review of Drug Substances approved by FDA and listed in USP showed that:
  1. ~95 Drugs which are secondary amines
  2. ~65 Drugs with dimethylamino groups (alerts for NDMA formation)
  3. ~135 Drugs which are tertiary amines
  • In order to avoid formation of nitrosamines in drugs, amines and/or nitrites/nitrosating
    agents need to be absent from the formulation
  • It suggests, Thus, the best way to prevent the formation of nitrosamines in finished dosage forms is to cut down the source of nitrite/nitrate
  • It would be worth exploring the feasibility of adding trapping agents capable of scavenging
    adventitious nitrosating agents including nitrites and nitrates in drug product formulations. Potential nitrite scavengers as inhibitors of the formation of nitrosamines may include chemicals like ascorbic acid, caffeic acid, ferulic acid, phenolic acids, resorcinol, glutathione

How can FDA help?
In addition to developing sensitive methods, revisiting the toxicology of nitrosamines, FDA may support research related to the prevention of nitrosation

Any thoughts?

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A problem with the list of scavengers is that they are not commonly recognized as excipients (with the exception of ascorbic acid of course). Does anyone have thoughts about aminoacids as scavengers?

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@GENERAPHARM Allow me to add @ASrinivasan into your reply. I am also sharing her presentation in her behalf. She presented at “FY 2021 Generic Drug Science and Research Initiatives Public Workshop
FDA’s Office of Generic Drugs provided her an opportunity to comment on what they think the Agency should invest in the GDUFA (Generic Drug User fee act). She discussed about the Agency spending on some research related to prevention of formulation nitrosamines in formulation.

FYI. The presentation contains voice over
Watch video here

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Many thanks for this. The subject of nitrite scavenging is one of great interest to me and there are a serious number of possibilities and a serious number of barriers.

I am considering preparing a presentation on this which might be for nitrosamine exchange.

I have to be a little careful because I am currently consulting with Novartis on the nitrosamine story.

Malcolm Ross

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Dear @GENERAPHARM , it is a hot topic! And I’m sure that this new chapter (nitrosamines formation inhibition in the final product) will render a good discussion.

I’m have interest in such presentation.

Lucas Maciel



It seems very interesting to analyze if trapping agents (yet demonstrated effectivity in scavenging adventitiuous nitrosating agents in matrices other than pharmaceutical solid dose forms) , however, I asked myself the following questions:

  1. Which quantity of trapping agent should I include in my finished solid dose form?
  2. How can those trapping agents affect final dose form stability?
    Finally, API-trapping agent interactions should be closely investigated,

Claudio Cerati

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@ccerati Dr. Aloka @ASrinivasan presented this concept to FDA at a recent workshop. I’m sure she can help guide some of your questions.

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Here is the presentation. It is just a five minute talk though to urge FDA to invest some of the user fee money in this research.Nitrosamines- AlokaPresentationMarch18,2021.pptx (3.1 MB)

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All the questions are valid—how much scavenger, will it affect stability etc. and of course the two biggest problems-is it a recognized pharmaceutical additive (vitamin C is but I have seen some really exotic chemicals being suggested-the cure may be worse than the disease) and the need to generate new stability data (will this mean that products that were on the market with say 5 years stability date will need to go back to 2 years based on accelerated testing and then extended)
And an additional thought, some nitrosamines are not that stable—can we rely on accelerated testing to predict extended shelf life.

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Thanks for your answer and point of view.

Without using chemical agents like vitamin C , shoult if be possible to use inert trapping agents (i.e. polymers) with which that issue of #stability threatening # or incompatibility could be avoided?

For the additional thought about nitrosamine stability the correlation between accelerated stability and natural one should probably rely on some kinetic data on continuous nitrosamine generation along these time spaces.

Anyway , the discussion is open !!!