Hi!
In my experience… they will always ask you for batch analysis to verify with “facts”. Then you can apply 10% or 30% of the specification if you are below this limit.
Any theoretical justification is welcome but insufficient by regulatory agencies.
I have no experience as to whether the nitrosation process is favored , but if it is a low-dose medication, the daily limit of nitrosamine will go up quite a bit.
Cheer up.
NDSRIs are rarely formed during the API manufacturing process. This is normally formed in the drug product on stability.
I would advise specific evaluation of every secondary and dimethyl tertiary amine, which you are doing. The first real step of this in the lab should be confirming that the nitrosamine can be formed. If you find an FDA limit and a standard from a reputable source, one can presume that it can be formed. Neither are the case here. Additionally, this paper ( Risk assessment for nitrosated pharmaceuticals: A future perspective in drug development - Schmidtsdorff - 2022 - Archiv der Pharmazie - Wiley Online Library) shows another lab that has tried to form the resulting nitrosamine without success. This work can be done in the lab or in-silico.
If and only if you prove that the nitrosamine can be formed will you proceed to confirmatory testing of old stability/retain samples.
First of all, thank you so much for sharing this publication. very fruitful
I have worries to be formed in our FP.
I have checked this publication and concluded that no success for determing N-nitroso torasemide, but the fact is when i purchase working standard ,what limit can i go for it to control or decide whether its below 10% or 30% of limit?
My assessment is: depending on the attached route of synthesis purified water _nitrite content in presence of acidic conditions favored by acetic acid and 2ry amino group on p-tolyl ring favor its formation.
I need to exclude my worries to predict what we will do in our labs.
So, the problem you’re running into is that there are a number of companies trying to sell all kinds of nitrosamine standards, even though they cannot make that nitrosamine.
You need to determine if the nitrosamine can be formed. There are a number of resources in the forum to perform the NAP test or a modified NAP test. Don’t just presume that since someone wants to sell you N-nitroso-torasemide that it can actually form. They will take your money and will not provide you anything you need to help your cause.
If you don’t have an LC-MS or the in-silico tools, you will need to contract out this work.
Hello.
If you are their client, ask them for information about it. They will already be working on this issue. I work at API and ours clients constantly ask us for MS analysis and risks evaluations.
What Mr. Brown tells you is true. But the bureaucracy is not scientific and they ask you for evidence beyond paper data. At least in my experience… or is it that we have very bad luck
Another thing that Mr. Brown says is the issue of impurities… Well here you need someone serious. There are many Jack Sparrows. Ideally, you have an experienced MS lab and an experienced synthesis company. Another option is to look for a university in your area if they work in chemical synthesis and analysis…
Good luck.
Totally agree with you!. From my humble experience as an analytical chemist:
The issue of impurities is drawing the attention of many pirates . But the fault also lies with the authorities. They ALWAYS ask for proof. It’s up to me to search (LC MS analysis) even though it is materially impossible.
I also meet a lot with MS method developers (external lab )… there is nothing like homemade.
Only one comment though, although NDSRI are not usually formed during synthesis of API, beware of the stability of the API!
We have observed OOS just in APIs - which also leads to, we are always very focused on nitrite levels on excipients, but sometimes we should not forget that the API itself can have low ppm nitrites
I got the idea of performing N-nitrosation of the API and to be injected in the LC-MS against our Torasemide product and see if there detectable or not in our FPP.
But concerning the limits; we got the issue of not establishing yet by any regulatory authorities.
Is this idea can be helpful and alternative to expensive in-silico assessment?
For LC-MS we have it in our labs, we can go on an organic chemistry journey Nitrosation of the API and regarded it as secondary standard and injected against our FPP and see what the result reveals, but we will have the issue for the control limit to see if the results are below detection limits or not?.
Don’t forget the lessons learned from Valsartan, nitrites salts are sometime used in the synthesis or the reagents can bring nitrites impurities as well.
Limits-wise, there’s only one secondary amine in torasemide, between the aromatic rings. Assuming this is the site of nitrosation rather than the sulphonylurea, the nitrosamine formed is a clear cat 5 by CPCA (1500 ng/day) and even a good substrate for read-across to nitrosodiphenylamine (limit 78000 ng/day based on the lower confidence interval of available carcinogenicity studies) as has been performed for mefenamic acid by the EMA…
If you do do the nitrosation studies, please properly characterise the product; I would guess it will be on the amine but it would be good to confirm it is not on the urea. All N-nitroso compounds are cohort of concern, including nitrosoureas, but the CPCA does not apply to them so additional work may be needed if it is there!
Hi,
just for information, anyone purchased and/or synthetized a valid standard of N-nitroso Torasemide? We received from a contract lab a report with detailed sinthesis tentatives. They never obtained N-nitroso Torasemide, but always other products.
Good morning to everyone
Just for the information of the group.
A vendor which previously was not able to synthesize N-Nitrosotorasemide for us, before some days informed us that now they found a specific synthetic route and they could prepare it.
I suggest to approach this with extreme caution. We continue increasingly to hear about suppliers providing materials where the accompanying documentation (NMR, MS, etc) match perfectly. However when testing in the lab, the MS fragmentation confirms a completely different structure.
It was largely believed that NDSRIs formed from nitrite in excipients in drug product and not in API. However since there is no control on quality of water during API synthesis, there is possibility of formation of NDSRIs in API itself. Most API vendor underestimated quality of water in their risk assessment and conclude that since no direct nitrosating agent used in synthesis, risk is low which is not the case.
I think when there is structural based risk identified in API, nitrosation study should be conducted. If NDSRI formed , then synthesis & characterize the impurity . Test the API and based on result of testing, control strategy can be decided. Results obtained shall be communicated to vendor for control and mitigation.
of course you are right. We have recently a similar ‘‘experience’’ with a ‘‘fake’’ N-nitrosoticagrelor and fortunately our API manufacturers guide us very targeted and we avoid to cause ‘‘false alarm’’.
It was the case where even with MS fragmentation was not possible to distinguished the difference between the structures. Only 2D NMR could prove it!!!
In the case of N-nitrosotorasemide, as the producer is the one who failed in the N-nitrosoticagrelor, we consider that they would be very confident to say that they managed to produce it.
We will see
. But the fault also lies with the authorities. They ALWAYS ask for proof. It’s up to me to search (LC MS analysis) even though it is materially impossible.
)… there is nothing like homemade. 
