What level of testing and controls for nitrosamines are expected for components of container closure systems, for example rubber stoppers?
As far as I’m aware, nitrosamine testing is only included on ad-hoc basis in the scope of E&L studies. This might be the result of a risk assessment of the sponsor, or on own suggestion when we learn the materials of construction. If there would appear a clear framework, guideline or recommendation whether or not to include nitrosamine testing in E&L studies, I would be happy to take notice.
For sure, the low limits for nitrosamines require targeted methods so unfortunately nitrosamines will likely not be detected with the chromatography - mass spectrometry screening methods. But it might be interesting to screen for possible precursors like secondary or tertiary amines in the GC/MS or LC/MS screening analysis. Since these precursors might lead to nitrosamine formation under the appropriate conditions, this might be a trigger for further targeted nitrosamine analysis.
Nitrosamines in relation to certain vulcanisation accelerators used in rubber closures have been known for decades. Due to this, suppliers for parenteral drug product rubber closures are not using those vulcanisation accelerators anymore and will provide the pharmaceutical company with statements that they are not used. I highly recommend that those statements will be used in the nitrosamine risk assessment and not to do testing for those nitrosamines in which the source has been removed for a long time.
Carsten, nice to “see” you here
So, one way you are right. Nitrosamines (NAs) from vulcanization or any other additives in the rubber formulation are known since decades. However, many of these old rubber components are still out there and in use. This is simply due to the fact that pharma companies are quite reluctant to change anything in their registered products. Also, NA analytics is very challenging and not done on a regular basis. And the chemical reaction between NA precursors and nitrosating agents is very complex. Not all NA precursors have to react into NAs. That is why I am generally skeptical if supplier issue such a “blank” statement. Happy to discuss
Thanks for the Insights into this topic.
@Naiffer_Host This is another area that requires attention. Have been trying to understand impact of Nitrosamines wrt Primary Packaging Materials
In the PF 45 (6) Stimuli Article “Elastomeric components for inhalation packaging/delivery systems”, a method using GC-TEA was included for N-nitrosamines and PAHs analysis in these components.
In the scope of E&L studies, I agree with @Ward about giving a focus on a screening analysis of precursor compounds (e.g.: 2ry/3ry amine) which could be extracted/leached into the product and likely to lead to the formation of nitrosamines (under appropriate conditions) in presence of nitrosating agents (coming from excipients or whatever is the source). @Naiffer_Host , thoughts?
Note-1 manufacturer has reported nitrosamines being formed in blister packs where nitrocellulose layer (a nitrosating agent) reacts during the heat sealing of the blister with amines that are present in the printing ink, This produced a nitrosamine vapour which could transmit to the drug product
Just as an fyi and for those who are interested:
My paper on nitrosamines from elastomers has been accepted by PDA Journal of Pharm Science & Technology:
Evaluating Nitrosamines from Elastomers in Pharmaceutical Primary Packaging | PDA Journal of Pharmaceutical Science and Technology
Maybe this also helps a little bit to understand the background of nitrosamines from elastomers.
@BettineBoltres Congrats! Thank you for sharing the article with our community. If you do not mind I will move your post to its own thread. I believe this is the first publication we see dedicated to Nitrosamines and closure systems.
Sure, and yes you right, there is no publication that I know of that deals with nitrosamines from pharma closures.
We are currently writing a paper on nitrocellulose and printing ink in blister packs where we have demonstrated that nitrosamines can be created during the sealing process and can be transmitted to the product.
@GENERAPHARM Thank you for sharing information. I am sure it will be definitely helpful for our risk assessment. I appreciate your help.
Thanks for the heads up… I have hear in several forums about this work. I’m extremely curious about the experimental details to capture/enclose/absorb the nitrosamines in-situ during the blistering process. Please let us know when you have mode details… we have host a #JournalClub session to discuss the details of the article.
That’s an interesting read @BettineBoltres
Thanks for sharing
Thanks @GENERAPHARM for updating us on this development.
Looking forward to more learnings on the outcome of your work on Primary pkg materials👍
@BettineBoltres I’m quite late with my reaction but thank you for sharing your publication. Very interesting! There is not many literature out there discussing nitrosamines originating from primary packaging
In a recent investigation, we found both the precursor amine and corresponding nitrosamine in an extract of a rubber stopper. First we detected the nitrosamine in a DP of the sponsor, and could link it to the rubber stopper as root cause. The whole case supports my opinion that a lot of information about NA leaching from packaging is still ‘hidden’ or goes undetected. And I see a couple of arguments for that:
- Nitrosamine analysis is not standard included in E&L studies. And if it would become standard practice → which nitrosamines to screen for? Luckily, we see an increased awareness of material suppliers that ask for a targeted nitrosamine screening.
- The amine precursors should be screened in the extractables study as well, because they can possibly further react to NA when they potentially leach in the DP and the DP would contain traces of a nitrosating agent. But there are pitfalls to the screening of amines with GC/MS or LC/MS: (1) the reporting limit is usually set at the AET, based on the TTC and maximum daily dose. However, in the context of nitrosamines, the TTC is not applicable. As a consequence, amines that would be present below the AET are neglected, so that information remains hidden, while it should raise attention at any concentration. (2) amines are usually not so sensitive in GC/MS or LC/MS screenings because they easily interact with non-inert surfaces in the sample path. Or in other words, their detection limits are already higher compared to other compounds in the screening process. (3) a liquid/liquid extraction is a killer for the screening of amines, because they have a very poor extraction recovery in the organic solvent. But liquid/liquid extraction is still very common to aqueous or mixed aqueous/alcohol solvents for a better amenability to GC/MS or LC/APCI-MS (ESI is less of a problem). Many extractables studies do not even include a 100% organic solvent that is directly injected in GC or LC, so amines go undetected this way as well.
I hope to keep seeing updates from your side! Ward
thank you very much for your thoughts. I fully agree with you. Let me expand on this with my own words:
- That is one challenge: Which NAs to screen for? You cannot possibly screen for “all” NAs on a regular basis. And also it doesn’t make a lot of sense, just work. Some NAs that can build from NA precursors from rubber are not listed in the EMA/FDA guidances. Others that are listed are not very likely to come from rubber to begin with. So you need to come up with your own reasonable list anyway.
I think the assessment should start with a theoretical evaluation of the rubber raw materials. Is there any potential NA precursors in the formulation? Based on this knowledge a targeted screening for the potential NA can be performed.
- And yes, then this targeted Extr screening should include the know NA precursor. And yes, the extraction already is a challenge. If you want to extract considerable amounts from rubber, you have to use more organic solvents as you wont find a lot in purely aqueous solutions.
It is definitely a challenge for the analytical labs to include this into their testing routine.