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Adding to the number of recalls during 2024 for NDSRIs, Ascend (Alkem) is recalling the anticoagulant drug Dabigatran Etexilate for the presence of Nitrosamine Drug Substance Related Impurity (NDSRI) N-nitroso-Dabigatran (NDAB) above acceptable limits. Alkem is recalling 8 lots of Dabigatran Etexilate capsules across multiple strengths of 75 and 150 mg.

In a separate recall incident, Aurobindo is recalling two lots of the blood pressure drug Nebivolol for the presence of NDSRI N-Nitroso Nebivolol.

Year 2024 has seen several recalls of drug products for NDSRIs including Duloxetine (Aurobindo, Iowa), Cinacalcet (Aurobindo, Dr.Reddys, Accord, Intas), , Rizatriptan (Glenmark), Desloratadine (Lupin),  Diltiazem (Glenmark) among others. This shows a significant increase in drug recalls due to NDSRI from year 2022 and 2023.

There are several generics approved in US for Dabigatran Etexilate, including from major generic manufacturers  like Alembic, Apotex, Hetero, and MSN. Nebivolol also has several generics in US including those from Glenmark, Cadila, MSN, Mankind, Indchemie, and Torrent. Alkem (Ascend) had recalled several lots of Dabigatran Etexilate in 2023 also for presence of NDAB, while no other recall of Dabigatran is reported for NDSRIs. However for Nebivolol, above recall of the drug product for NDSRI is a first.

Nitrosamines and NDSRI impurities in pharmaceutical products are a cause for concern as they could be carcinogenic, so called “Cohort-of Concern”. NDSRIs are API-derived complex nitrosamines, formed due to the nitrosation reaction of an amine functional group (typically secondary amines) in the API in the presence of nitrite impurities. NDSRIs may be formed during the manufacture of the API, the manufacture and/or packaging of the formulation product, or during storage. One reason for formation of NDSRIs in drug products containing actives with a facilitating structure for formation of nitrosamines (vulnerable amine functional group) is presence of Nitrite impurities in excipients (inactive substances).

NDSRI Impurity N-Nitroso-Dabigatran in Dabigatran

The daily Acceptable Intake (AI) limit for N-Nitroso-Dabigatran is 400 ng/day as per the FDA’s CDER Nitrosamine Impurity Acceptable Intake Limits (the EMA has prescribed a limit of 1500 ng/day). Dabigatran has a secondary amine functional group. The general route of synthesis (ROS) for Dabigatran involves the condensation reaction of methylamino nitrobenzoic acid with an ethylpyridylamino propionate to form an amine intermediate, followed by nitro group reduction to form the amine intermediate and cyclization with phenylamino acetic acid (e.g., 2-(4-cyanoanilino)acetic acid). The ROS does not involve any nitrite salts, making nitrosation reactions leading to NDSRI impurities highly unlikely in the synthesis of Dabigatran. However, NDSRI N-Nitroso-Dabigatran may be generated during drug product manufacture or storage due to the presence of nitrite/nitrate salts from pharmaceutical excipients interacting with the amine functional group.

NDSRI Impurity N-Nitroso Nebivolol in Nebivolol

The NDSR N-nitroso-nebivolol has a maximum daily acceptable intake of 1500 ng as per both the FDA and EMA lists for Acceptable Intakes of nitrosamine impurities. The general route of synthesis for Nebivolol involves a condensation reaction between an epoxide intermediate (e.g., 6-fluoro-3,4-dihydro-2-oxiranyl-2h-1-benzopyran) and benzylamine. Nebivolol has a secondary amine functional group. However, the ROS does not involve any nitrite salts, making the generation of the nitrosamine impurity N-Nitroso Nebivolol very remote during synthesis of the API. As discussed with Dabigatran, the presence of nitrite impurities in excipients can trigger the generation of nitrosamine impurities in Nebivolol too.

Control of NDSRI Formation in Drug Products.

With the increasing number of NDSRI-related recalls, a robust risk assessment and control strategy for excipients becomes critical. The control strategies should include a supplier qualification program involving potential nitrite impurities across excipient suppliers and excipient lots. For actives vulnerable to NDSRI formation, selecting excipient sources and controlling nitrites in excipients are critical.

Conclusion
As per USFDAs RAIL guidance and Nitrosamine Guidance, drug product manufacturers and applicants must complete their risk assessment of products for NDSRI formation, conclude confirmatory testing, implement necessary changes, and submit required changes to the FDA by August 2025. Manufacturers should identify potential sources of nitrosating agents and amines, assess the effectiveness of current mitigation strategies, and make changes if warranted, including employing alternate manufacturing processes, reformulating products, implementing stricter manufacturing controls, and exploring alternate ingredients. The FDA may not object to the distribution of products containing nitrosamines and NDSRIs at or below recommended interim levels until the estimated duration. However, if shortage risks are alleviated, the FDA can revise the interim control limits. As excipients are a key risk factor contributing to the formation of NDSRIs, it is imperative for manufacturers to comprehensively assess the risk of nitrosating agents from excipients and implement control strategies not only to comply to current interim limits but to minimise the potential for formation of the nitrosamine impurities to the maximum extent possible.  

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