N-nitroso-deucravacitinib

Confirmatory Testing & Analytical Challenges
1

I would like to seek your guidance regarding the available options for testing N-nitroso-deucravacitinib in the drug product.
Despite our efforts to procure this NDSRI, we have been unable to obtain it. We engaged with multiple vendors, including API manufacturers, to explore the possibility of synthesizing the impurity; however, they have confirmed that synthesis is not feasible.
Given these constraints, I kindly request expert input on how best to represent this limitation and the associated testing strategy in dossier with the FDA.
Looking forward to your valuable suggestions.

2

dear Pramod,
EMA Guideline for nitrosamines recommends:
During development of an analytical method, a reference standard of the relevant nitrosamine impurity is generally needed. If, despite extensive efforts, it becomes apparent that the relevant nitrosamine impurity cannot be synthesised, then this could be an indication that the nitrosamine either does not exist or that there is no risk of it being formed. In such cases, it may not be necessary to conduct confirmatory testing. This should be justified thoroughly on a case-by-case basis according to appropriate scientific principles. The justification could include relevant literature, information on structural/stereoelectronic features and reactivity of the parent amine, stability of the nitrosamine and experimental data to illustrate the efforts made to synthesise and to analyse the impurity. The justification should be documented in the risk assessment in the MAH’s pharmaceutical quality system.

i dont know if this could help you in any way

2 Likes
3

Thank for your response, sure this will help me

4

you can also see:
How to justify the absence of NDSRIs in finished product if the custom synthesis of the same NDSRIs is not possible? - Confirmatory Testing & Analytical Challenges - Nitrosamines Exchange
and
Synthesis Attempts and Failure Report :face_with_monocle: - Confirmatory Testing & Analytical Challenges - Nitrosamines Exchange

2 Likes
5

Dear Pramod Patil,
in addition to Eleni’s input, you should ask from the impurities manufacturers and vendors who have failed to synthesize it, an analytical report with their trials, experimental data (like NMR and MS spectra) and an explanation for their failure.
best regards
Christos

2 Likes
6

however I am curious…
is this approach along with the failure report supported also by FDA?
i couldn’t find anything specific in the FDA Guidance, except I miss it.

7

Dear Eleni,
A failure report is also accepted by the FDA provided all the relevant data corresponding to the failure of impurity synthesis is provided along with the theoretical explanation. Generally the demand is for more exhaustive which includes attempts using different nitrosating agents (t-butyl nitrite, n-butyl nitrite) in different conditions etc.
N-Nitroso Amlodipine is an example where such a justification is generally accepted.

4 Likes
8

Thank you Amit for your guidance

9

Based on the structure of deucravacitinib, the formation of N-nitroso-deucravacitinib seems chemically unlikely. The aniline nitrogen is a weak nucleophile due to electron-withdrawing groups, and the molecule is also sterically hindered, which makes nitrosation even less feasible. I’ve seen a similar case with ticagrelor, where several attempts to synthesize the N-nitroso impurity failed, and it was concluded that the compound does not form. Given these limitations, it is reasonable to include a scientific justification in the dossier stating that this NDSRI is not expected to form and cannot be tested; this can be supported by in silico analysis and an expert statement.

1 Like