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:
~95 Drugs which are secondary amines
~65 Drugs with dimethylamino groups (alerts for NDMA formation)
~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
@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.
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:
Which quantity of trapping agent should I include in my finished solid dose form?
How can those trapping agents affect final dose form stability?
Finally, API-trapping agent interactions should be closely investigated,
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.
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.