In this case I would internally develop my method with 0.8 ng/day but give the proposal of 1.8 ng/day.
So if the limit is changed into what is plausible expected, avoid doubling activities.
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Hi, all.
It is an interesting thread. To understand the topic deeply, I add the figure of N-nitroso betahistine.
When I searched for analogs on LCDB substructure search with the following figure, an appropriate surrogate was not found, except for NMPEA.
That is why I support @Diego_HM’s suggestion. If less than 10% of 8ng/day is confirmed, the betahistine will be free from nitrosamine confidently in most cases. It is a fantastic scenario!!
For other officially used surrogates, please see the following post.
@Yosukemino I beleive the structure @Diego_HM was referring to is N-Nitroso-N-methyl-2-phenylethylamine (CAS 13256-11-6) TD50 0.00797 mg/kg/day, right?
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Hi, @Naiffer_Host.
Yes, you are right. The compound NMPEA looks like the closest for N-nitroso betahistine.
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Is there any correlation between the amount of nitrite present in the excipients and the potential for nitrosation of NDSRI (N-nitroso betahistine) under acidic condition to get some theoretical values of results in ppm. Betahistine contains a tertiary amine and alpha hydrogen and seems queries are more specific towards the potential of nitrosation of the drug substance.
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@Naiffer_Host @Diego_HM @Yosukemino
Here is another one which is one of the probable impurity in betahistine and seems to be the potential source to form N-nitroso N-methyl-2-(pyridin-2-yl)-N-[2-(pyridin-2-yl)ethyl]ethanamine. Not sure whether to consider this under nitrosamine assessment as the same is controlled in the BP monograph with 2% limit.
Any structural analog suggestions for this impurity to apply read across approach?
Thanks, Sumit
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Thank you for asking a good question, @sumitkumarjain. Betahistine contains a secondary amine and it is more reactive than a tertiary amine.
EFPIA workflow describes the risk assessment of the tertiary amine as follows;
- Tertiary amines are significantly less reactive than secondary amines (reports of > 1000 fold lower reactivity) and require an additional de-alkylation step, making their nitrosation in solid state very unlikely. Certain tertiary amines where nitrosation could lead to class 1 low MW nitrosamines could, in certain instances (e.g. where the reactivity towards nitrite is enhanced by particular structural features), lead to an increased propensity towards nitrosation and should be considered as higher risk. Tertiary amines would generally be considered negligible risk given the mild conditions processing conditions would not be expected to lead to a nitrosamine.
And the paper " Potential for the Formation of N -Nitrosamines during the Manufacture of Active Pharmaceutical Ingredients: An Assessment of the Risk Posed by Trace Nitrite in Water" is helpful for the risk assessment. I think you can focus on the N-nitroso betahistine in this situation.
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Hi Sumitkumarjain
99.9% conversion rate after being incubated at 37°C for 4 h with an API concentration of 10 mmol/l in a 40-mol/l sodium nitrite solution at pH 3.5 (with 1 mol/l hydrochloric acid). The pH was adjusted in the sodium nitrite solution, measured (pH 3.5 ± 0.5), and corrected if necessary after the addition of sample material.
https://onlinelibrary.wiley.com/doi/full/10.1002/ardp.202100435
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As above discussion, tertiary amine contained such as impurity/API is low risk for formation of the NDSRIs nitrosamine due to demethylation/ slow reactivity. However, as recently FDA have recall product of Orphenadrine Citrate ER Tablets as (Orphenadrine is contained tertiary amine chemical structure drug substance as mentioned below)
Sandoz, Inc. Issues Nationwide Recall of 13 Lots of Orphenadrine Citrate 100 mg Extended Release Tablets Due to Presence of a Nitrosamine Impurity | FDA.
How to move forward to assessment of nitrosamine (NDSRIs) as contained of tertiary amine in impurity/API OR tertiary amine containing API is considered as low risk for NDSRIs formation.
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Thank you for asking, @sandeep0315. You are right. According to the assessment report by EMA, the following drugs included NDMA.
The original paper is here.
EFPIA mentioned certain tertiary amines where nitrosation could lead to class 1 low MW nitrosamines could, in certain instances (e.g. where the reactivity towards nitrite is enhanced by particular structural features), lead to an increased propensity towards nitrosation. This very common alkyl dimethyl amine may have the potential.
To understand the reactivity of tertiary amines, the NAP test is helpful. I will search for good literature.
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@Yosukemino : the question is still there, "how to conclude the risk when there is tertiary amine in structure? what justification will suffice the requirement for not to perform confirmatory testing?
or Should we opt for performing confirmatory testing regardless secondary or tertiary amine?
Thank you for asking, @Chirag. I think it depends on the possible risk of nitrosamines contamination. You can take the AI limits of nitrosamines, the MDD of the products, manufacturing processes, the amounts of nitrite in excipients, pKa of amines, and other mitigating factors such as pH into consideration. The example demonstrated by Dr. Urquhart is helpful.
Back to N-Nitroso-Betahistine closest surrogate, wouldnt be possible to think of this one?:
This compound called NNK was already used as point of departure for nitroso duloxetine and fluoxetine both published in Q&A.
Compared to above mentioned NMPEA surrogate it has pyridine heterocycle, same as betahistine has:
It is also a possibility. However, at the end it depends on the health authority to accept. Nevertheless, the idea to use a lower limit (10% of 8 ng/day) is about the analytical method developed and the LOQ, in case the BoH goes for NMPEA not do an addendum to the validation for example.
We have seen crazy surrogates in the past.
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I am sorry to say that no, it would not be a valid surrogate. Betahistine has a methyl substituent, and an aromatic ring attached to the beta position. NNK fulfills those two characteristics, but the surrogate you are proposing, while having the methyl group has a carbonyl group attached to the gamma position, and then there is the aromatic ring. It is different enough to not be comparable, even more when you have a suitable analogue.
At the moment I would not expect betahistine getting and AI over 8 ng/day
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Hi thank you for your opinion, but I do not agree. Similar argumentation of non-appropriate surrogate selection can be applied while comparing betahistine with N-Nitroso-N-methyl-2-phenylethylamine (phenyl aromatic ring in NMPEA surrogate instead of pyridine which is the part of N-Nitroso betahistine is presenting huge difference from electronic point of view, and compounds characteristics as basicity, polarity…)
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Sure, you are right, but it is important to see the approach EMA is taking. Nortryptiline has nothing to do with NMPEA, but it has two carbon atoms before the double bond which has electronic comunication with the phenyl rings. So basically, two carbon atoms and then aromaticity. There are other big differences between nortryptiline and NMPEA that are not taken into account, such as it is going to be the polarity, or even the molecular weight of the molecule. That is the basic feature they are using in this case to establish the 8 ng/day
Sure, unfortunatelly I dont see EMA apprach as good benchmark since many controversial SAR/Read Across they made so far…As a good example of that is the case of 1-Methyl-4-nitrosopiperazine, MeNP (16339-07-4), where the Limit was derived using NDEA as point of departure even there is plenty tox data available on similar nitrosopiperazines. See papers below where they discuss it in detail:
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