I attended a recent Nitrosamines event, and it really caught me by surprise the level of aggressiveness in the discussion from some attendance and industry group representatives on the whole discussion about the role of excipients in NDSRIs. The discussion sent me down a rabbit hole of information research to truly understand the background and arguments to finally build my own opinion.
I wanted to share with you some of the raised points during that discussion (somewhat paraphrased):
Other forms of Nitrosamine exposure are much higher than in Pharmaceutical, it’s not ‘fair’ to our industry this level of rigurocity
Excipients are not (historically demonstrated in the food space) are not responsible for formation of nitrosamines, so how big of a problem is this for excipient manufacturers? Furthermore, additional controls and industrial changes will impact the supply chain and cost of this materials
Scientists need to understand and differentiate between Nitrates and Nitrites, nitrates are not nitrosamines precursors. There is no data that confirm the opposite.
These are my own views, from my reading of nitrosamines.
Personally, I believe that the food argument is a bit misleading, from my reading to date. The investigations into food were mainly dealing with the formation of a small number of specific nitrosamines, whereas the issue now for the pharmaceutical industry is the formation of NDSRIs from many different drug substances and impurities. Nitrites levels within excipients have been shown to impact the levels of nitrosamines formed in the finished drug product, and control over excipient nitrite levels can provide one route for the reduction of nitrosamines in the finished product, but not the complete elimination. More than happy to be proven wrong from the food industry on this, I have by no means read everything that is available. The recently published European Food Safety Authority document only talks about certain nitrosamines, they are not talking about any and all nitrosamines present, which we are doing as the pharmaceutical industry.
Nitrites versus nitrates, and nitrosamine formation. This is trickier. In terms of nitrosamine formation in the drug substance or drug product prior to it entering the body, then nitrite is the number one (only?) culprit of these 2, though there are other routes e.g. atmosphere. Once within the body, and subject to biological processes, enzymes and conditions, then it may be that nitrates come more into the equation and are capable of effectively being precursors for nitrosamine formation. But at this point, the source of nitrates and nitrites is not just the drug that has been received, but food and drink consumed, bacterial activity and other potential mechanisms. Which is the greater source of nitrosamines, formation within the product or within the body, is a question that has yet to be answered fully and may go some way to determining whether nitrates are important or not. It is also where nitrosamines fundamentally diverge from issues like ICH Q3d and Elemental Impurities – there is no formation of heavy metals for a product on stability or once within the body, and so it is a finite number from fixed sources to be measured and controlled in the manufacturing process, nitrosamines can be present or formed through various mechanisms and can continue to increase throughout the life cycle of the product. Understanding and controlling the level of nitrosamine formed in every stage from API manufacture through to absorption within the body, especially to the current daily limits for any drug that doesn’t have individually prescribed higher levels, is going to be a timely and expensive process. As an industry we are still only just starting to understand the scale of the problem and identify potential control measures within finished products. Biological formation is not even really on the radar and would be a completely different problem.
I would like to highlight the last part of your comment. Endogenous nitrosamine formation would be the real deal in the years to come. I remember an FDA workshop in 2021, where this point was mentioned.
However, I wonder if there is the technology available to determine this endogenous formation, as bio-tracers, etc. are missing.