Hunt for NDSRIs: Unveiling Hidden Threats with the Novel 15N-Enriched NAP Test-Pub

New Scientific Knowledge & Development
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https://pubs.acs.org/doi/10.1021/acs.oprd.5c00223

Abstract
Nitrosamine impurities, particularly nitrosamine drug substance-related impurities (NDSRIs), have emerged as a critical concern in pharmaceutical manufacturing due to their potential carcinogenicity. Regulatory agencies now require rigorous risk assessments and confirmatory testing to ensure product safety, considering all nitrogen atom alert groups. In this study, we present a novel strategy that combines the nitrosation assay procedure (NAP) with 15N-enriched nitrosating reagents and 15N NMR spectroscopy to detect and characterize nitrosamine formation. This method enables qualitative analysis of nitrosamines and provides valuable insight into the nitrosation reactivity of pharmaceutical compounds. The diagnostic chemical shift range for N –NO groups was validated, and the method was applied to a series of known nitrosamines and NDSRIs derived from active pharmaceutical ingredients and intermediates. The 15N-enriched NAP test proved effective in identifying nitrosamines, even in complex matrices, and distinguishing between isomeric and degradation products. This integrated approach provides a robust and rapid tool for nitrosamine risk assessment and supports regulatory compliance by confirming or excluding nitrosamine formation under stress conditions.

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very interesting paper, thank you Yosuke!!

the case of Irbesartan is very characteristic of how ‘‘easy’’ is to incorrect conclude that a nitrosamine is formed just from MS and simple 1H-NMR spectrum.

Furthermore, the case of the EDTA and its difficulty to degrade to its two secondary amines, should be flagged in a higher level as the corresponding nitrosamines are included in the list of EMA (appendix 1).

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How had I missed this??

Although the sensitivity may not be as good as required for some nitrosamines this is fascinating stuff.

The EDTA work is particularly interesting, and may help greatly with justifications to regulatory authorities.

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The innovative approach for detecting nitrosamine impurities in APIs addresses limitations of traditional mass-based techniques, research says.

A team of researchers have developed a novel, rapid nuclear magnetic resonance (NMR) spectroscopy-based methodology that can easily confirm or exclude the formation of every predictable nitrosamine for the active pharmaceutical ingredients (APIs) assessed.

The early-stage tool combines the nitrosation assay procedure (NAP) with 15N-enriched nitrosating reagents and 15N NMR spectroscopy. It addresses the limitations of traditional mass-based techniques, according to Simonetto et al.

Enhancing nitrosamine assessment

The authors initiated the study in response to a regulatory requirement for a nitrosamine risk assessment concerning the API dexlansoprazole. Under stress, the API undergoes structural changes, “potentially forming unexpected nitrosamines beyond the scope of standard [nitrosamine drug-substance-related impurities] (NDSRIs).”

As such, they investigated whether the heterocyclic framework of dexlansoprazole could act as a precursor to nitrosamine formation.

Not only did the 15N-enriched NAP test distinguish between isomeric and degradation products, but overall the method acts as a rapid test for derisking “because if there are no 15N-nitroso signals, then the molecule can be considered not prone to nitrosation.”

Gabriele Razzetti, Global Director of R&D at Dipharma Francis S.r.l. said: “Thanks to our innovative approach, we can confirm or exclude nitrosamine formation with exceptional clarity, even in the most complex scenarios”. This includes challenging NDSRIs, added Razzetti.

“This integrated approach provides a robust and rapid tool for nitrosamine risk assessment and supports regulatory compliance by confirming or excluding nitrosamine formation under stress conditions.”

The novel technique offers promise for assessing nitrosamine formation during API development and manufacturing, “supporting impurity profiling, process understanding, and alignment with evolving regulatory expectations”.

The method was developed by Dipharma Francis S.r.l., a contract development and manufacturing organisation (CDMO) and active pharmaceutical ingredient (API) manufacturer. The research is published in Organic Process Research & Development (OPR&D).

Source: Novel NMR-based method could facilitate safer API manufacturing | News | European Pharmaceutical Review

hunt-for-ndsris-unveiling-hidden-threats-with-the-novel-15n-enriched-nap-test.pdf (4.9 MB)

op5c00223_si_001.pdf (1.5 MB)

Thanks & Regards,

Gautam G. Halder

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