Nitrosamines - Elastomers perspective (PDA publication)

@BettineBoltres Thanks for sharing the article with our community. I have a couple of questions:

  • In the regulatory framework, it mentions “Currently, no limits exist for any pharmaceutical packaging components or elastomer components. Other industries, such as cosmetic, food and nutrition and general rubber industry either have limits for nitrosamines and/or their precursors or recommendations for their limitation”. Do you see elastomeric industry (Pharma) moving in that direction? Do you anticipate the creation of a similar Questionnaire for Excipient Nitrosamines Risk Evaluation” but for packaging manufacturers?

  • When discussing Nitrosamines in Rubber, it says “Knowing the compositions of the rubber components, the specific nitrosamine species that could potentially be formed from these ingredients can be targeted in the analytical evaluation. Both the FDA and EMA have seven specific nitrosamines in scope for risk assessment” As you mention in the article, the chemistry of ‘rubbers’ is quite complex, a simple screening of nitrosamines is not the answer, Do you see the industry moving into a comprehensive assessment of their processes and sharing information with their stakeholders? Do you see manufacturers limiting their assessment to only those ‘seven specific nitrosamines’?


We have already had one major elastomer manufacturer start testing their products; they have provided us with the Nitrosamine results for 4-6 of their products already; 3 of which have some detected level of nitrosamines. They did not limit their assessment to the “seven specific nitrosamines”. There were 1 or 2 additional nitrosamines included in their analysis, so it does appear at least this one manufacturer is evaluating which nitrosamines would result from their specific process.


@ejdowse Thanks for the report and insight. It’s wonderful to hear that elastomeric manufacturers are taking early actions related to Nitrosamines. As a side note, please feel free to invite them to join the community in case they would like to share more about their challenges and learns. Kudos to @BettineBoltres that got our discussion going.

@KB_nelson @areumer @Ward most likely you are also doing some work with stakeholders in that area. Anything you would like to highlight?

It’s also my understanding that USP’s packaging expert committee is collecting information and discussing the potential needs to address this topic from the compendial point of view.

@davidetartaglione @celine.martin003 @Elodie are you supporting work on elastomer related to nitrosamine from one of your technical hubs?

Yes, we have also done nitrosamine testing on several of our products.
And we also added some nitrosamines to our testing and skipped some others, because not all of the NAs listed by FDA and EMA are relevant to elastomers. And as I explained in my article, other NAs could be relevant based on the compositional knowledge.
But then also you can’t measure every elastomer composition using an individual set of NAs. That would be much too much work. So we agree on a general set of NAs that could potentially built in the usual elastomer compositions, even if there are no precursors present in that particular elastomer that you are measuring. So, mostly, it is more a checkbox exercise, except for when you actually know about precursors in the formulation.

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I don’t think as of now that it would make sense to set limits on elastomeric closures, as there are still too many open points. The analytics for NA measurements on elastomers is quite complicated, so this is really nothing that can be done on a batch-release basis. And if you set limits, you have to put them into specification, then you also have to measure for them. And this is absolutely not feasible now.
Also, the NAs listed by FDA and EMA are partly not relevant for elastomers. So why would we need to measure them then on a regular basis? And if we agree on a different set, what basis would we have for this set? And would it be individual for each composition? Or general?
And if there are no NA precursors in the elastomer composition and no nitrosating agents within the processing (or at least very low risk; I know there is no “no” :-)) then again why would we have to measure it?
Sorry that I have answered your question by posing even more new questions :slight_smile:
But this just shows that there indeed still are a lot of open questions


Thank you for sharing and running this discussion, evaluating the elastomer alone will not be sufficient as some rubber material used in Pharam may contain catalyzers of secondary amines and upon contact with drug solution, or under manufacturing conditions such as sterilisation, new NA can be generated and released into the drug product. Thus testing the rubber is important to set a benchmark for NA contribution from the rubber to the total NA level in the drug product.

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Regarding secondary amines as present in elastomers-we have conducted a very through literature search and find that nitrosamine precursors used in elastomers is extremely rare and the one or two cases we have found are no longer used in the polymer industry. It seems that the plastics industry (probably because of the issues with natural rubber vulcanisation) has been much more aware of the nitrosamine issue than the pharma industry

Yes, I fully agree with you. The decisive measurement can only be done in the final drug product, as only then all contributing factors come together.

It is correct that many NA precursors can only still be found in legacy formulations, but then again, many pharma companies still use these formulations because they don’t want to “upgrade” to more modern formulations; we all know how much work it is to change the filing, so it is understandable from their perspective.
Also, I wanted to point out that not all secondary amines are really forming carcinogenic NAs. We have seen communication in that direction from EMA and FDA. And there is a really good paper on structure-activity by K.P. Cross and D.J. Ponting:
Developing Structure-Activity Relationships for N-Nitrosamine Activity, Computational Toxicology (2021), doi: Redirecting. This nicely shows how a change on just one single atom can make a change between carcinogenic and non-carcinogenic. That is really nice reasearch!