Dear colleagues, I received this rationale from one of my CMOs. Have you ever used this kind of justification, and is it acceptable?
Timolol Hemihydrate contains one secondary and one tertiary amine. The corresponding NSDRI is category 5 (according to CPCA approach) which results in an acceptable daily intake of 1500 ng/day. Considering the MDD of Timolol of 800 µg, the corresponding acceptable level of N-Nitroso-Timolol in the drug product is 0.1875% (AI / MDD: 1500 nd/d / 800 µg/day)
The drug product is well controlled by the release specification limit for unknown degradation products, i.e. 0.1%. This specification ensure to have a total amount of NTIM below its AI
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It seems well justified to me. Given the very low MDD and high AI, its limit is >0.1%, therefore it can be controlled along with regular impurities.
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i will agree with Mircea,
we have used similar approaches for inhaled products, where the MDD is in μg…
High AI and very low MDD is the best scenario for nitrosamines. Of course, the reference standard of the NDSRI, should be tested in the method for the related substances, for specificity reasons.
kind regards
Christos
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Exactly, the reasoning is perfect but you need to show authorities that your methods of related substances are able to detect the nitrosamine
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Hi HGranel,
I have used this similar argumentation during submission with regard to API-related impurities which could react to form a nitrosoamine. In this specific matter only one secondary amine is very unlikely but hypothetically possible to be formed which could theoretically react with nitrite, if present.
However I argued that the specification limit for any unspecified impurity is <0.5% keeping a theoretical “NDSRIRI” (a Nitrosamine drug substance related impurity related impurity 
) at around 30% AI with regard to CPCA and MDD.
I am still waiting for an answer to that. As soon as I get feedback I can share that knowledge.
From a general Point of view, It does make sense that if you control unspecified impurities to a certain amount which would then end up being below AI.
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Bonjour Georg,
Merci beaucoup pour votre retour et pour le partage de l’information, c’est très précieux !
Henri
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One thing to clarify – is 800 ug/day the exposure to the drug product, or the exposure to the API? The math (and acceptable level as a % in the drug product) is only correct if 800 ug is the patient exposure to the formulated drug product, not the API.
Hi,
If its MDD is the drug, then the justification is justified provided you demonstrate the detection of this impurity with LOD and LOQ levels in the said method.
MDD always refers to API and % impurities also reported to API
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Does your current method able to detect the nitrosamine?
In most of the cases answer is “NO”.
dear vbongade,
in three similar cases, where the spec. limit of the tested nitrosamine was at level of 0.1% w/w and more), the RS method was capable to identify this in all cases.
To be honest, i think that the determination of the nitroso-derivatives in those levels is anticipated to be feasible with LC method as they are less polar molecules than the corresponding amine and will eluted after this one.
kind regards
Christos
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