Regulatory Deadlines and Supply Chain Challenges Take Center Stage in Nitrosamine Discussion

Nitrosamine analysis comes with many complex analytical, and regulatory challenges. To address these complex issues, the editors of LCGC International organized a peer exchange of experts to discuss the intricate nature of nitrosamine analysis. The panel was moderated by Aloka Srinivasan, principal and managing partner of Raaha, and also featured Mayank Bhanti, senior director of the Compendial Development Laboratory at the United States Pharmacopeia (USP), and Amber Burch, the senior manager of Technical Business Development at Purisys (4).

Nitrosamines are a large group of N-nitroso compounds (NOCs) that bear common functional >N–N=O groups. NOCs can be divided into two classes: N-nitrosamines and N-nitrosamides and related compounds (1). These compounds can be found in various substances, including pharmaceuticals. If humans are exposed to nitrosamines above acceptable levels and over long periods of time, these impurities can increase the risk of cancer (2).

Around the world, drug manufacturers are scrambling to meet the August 1, 2025 deadline set by the U.S. Food and Drug Administration (FDA) to submit nitrosamine drug substance related impurities (NDSRI) confirmatory testing of drug products. The FDA’s guidance is meant to offer details on different types of nitrosamines while providing recommendations on implementing nitrosamine impurity control strategies. But meeting the upcoming FDA deadlines could pose challenging for stakeholders across the supply chain, the panelists noted.

Supply Chain Considerations

The point at which nitrosamines are introduced during drug manufacturing has been a longstanding question among experts. During the manufacturing process, for example, nitrite-containing excipients can introduce nitrosamines into the drug (6). The FDA has indicated these compounds have been found in a range of medicines including heartburn products, diabetes medicines, and antibiotics (5). The best approach is for organizations to work closely with stakeholders throughout the process.

“I think it is really important for companies to take a multi-pronged approach to the problem and working collaboratively with both drug product and drug substance suppliers,” Burch said.

Proper risk assessment can help mitigate problems, and with the right plans, it can ensure that the materials are free of nitrosamines, Bhanti said.

“I think the industry has to adopt a more proactive approach,” Bhanti said. “It’s a responsibility of the product manufacturer, but they have to work collaboratively with active pharmaceutical ingredient (API) manufacturers and to make sure that the product is free from nitrosamines.”

Looming Deadlines

A major concern for drug manufacturers worldwide is the rapidly approaching deadlines set by regulatory agencies—such as the U.S. FDA—regarding confirmatory testing for nitrosamine drug substance-related impurities (NDSRIs) in drug products. These regulations require companies to rigorously assess and, if necessary, reformulate their products to ensure safety and compliance. The complexity and scope of the testing, coupled with the high stakes of non-compliance, have placed significant pressure on manufacturers to act swiftly while navigating scientific, logistical, and regulatory challenges.

"It's a nightmare,” Srinivasan said. “You can’t resolve this. Even for simplest of the simple products, and even if you have five products in the market which are nitrosamine prone.

While Bhanti noted that many industries are now working to catch up and complete their confirmatory and risk assessment testing for nitrosamines, he emphasized that these efforts are only part of a broader set of challenges. “August 1, 2025 is definitely going to be challenging, but I think the industries are now trying to catch up, and they are finalizing the confirmatory testing and risk assessment parts, trying to achieve that date," he reflected (5). "But as you mentioned, it's not that easy, and it is definitely going to be a lot more challenging.”

The panel’s discussion of these complexities not only shed light on the current landscape, but also aimed to spark further dialogue about potential solutions and paths forward for both industry and regulators.

References

(1) Nitrosamines. ScienceDirect 2005. https://www.sciencedirect.com/topics/chemical-engineering/nitrosamines (accessed 2025-4-2)

(2) Information about Nitrosamine Impurities in Medications. FDA 2025. https://www.fda.gov/drugs/drug-safety-and-availability/information-about-nitrosamine-impurities-medications#updates (accessed 2025-4-2)

(3) Eglovitch, J. S. FDA Revises Final Guidance on Nitrosamine Impurities. Regulatory Focus 2024.

(4) Srinivasan, A.; Bhanti, M.; Burch, A. Introducing Our Panel of Experts. LCGC International 2025.https://www.chromatographyonline.com/view/introducing-our-panel-of-experts (accessed 2025-4-2)

(5) Control of Nitrosamine Impurities in Human Drugs: Guidance for Industry. United States Food and Drug Administration 2024. https://www.fda.gov/media/141720/download (accessed 2025-4-10)

(6) Srinivasan, A.; Bhanti, M.; Burch, A. Addressing Sources, Reformulations, and Upcoming Regulatory Deadlines. LCGC International 2025. https://www.chromatographyonline.com/view/addressing-sources-reformulations-and-upcoming-regulatory-deadlines (accessed 2025-4-10)