A newly published review article titled “Impact of Antioxidant Excipients on N-nitrosamine Formation and Bioequivalence in Metformin Formulations” explores the role of antioxidants in mitigating N-nitrosamine formation. This article provides valuable insights for pharmaceutical scientists focusing on risk assessment, formulation strategies, and regulatory considerations.
Article open access until March 28, 2025:
Summary
The discovery of N-nitrosamine impurities in pharmaceutical products has raised serious quality concerns, particularly in metformin products, which are widely used in the treatment of type 2 diabetes mellitus. The detection of N-nitrosodimethylamine (NDMA) in metformin products has led to global recalls and increased regulatory investigations. Generic manufacturers face the challenge of balancing stringent bioequivalence requirements for Biopharmaceutical Classification System (BCS) Class III drugs, which require strict control of excipient composition while ensuring N-nitrosamine control and therapeutic equivalence. The use of antioxidants as a strategy to reduce N-nitrosamine formation requires careful consideration to maintain both bioequivalence and product safety. This article evaluates the use of antioxidants for the prevention of N-nitrosamine formation in metformin formulations, addressing the implications of this strategy on bioequivalence and its relationship with the regulatory framework.
Very comprehensive, and has raised a few questions in my mind, and not just around nitrosamines, but also other issues potentially facing the pharmaceutical universe.
One though that I had was that it was my memory that the FDA had limited the level of scavenger to 10mg/dose in all products, irrespective of the BCS of the API. The data is for Class III drugs, where the permeability across the membranes is low, and so could be impacted by changes. Is this limit really applicable to Class I and II substances, where there is a high permeability? Are the FDA being overly cautious?
Thank you so much for your feedback. I’m truly pleased that my publication has sparked such questions.
Although the high permeability of these drugs may suggest that the impact of excipients, such as scavengers, on bioavailability is minimal, the FDA appears to have adopted this limit as a precautionary measure to mitigate potential risks associated with nitrosamine formation. This approach may be due to the limited data differentiating risk levels across different BCS classes.
However, the practical implications are significant. Exceeding this limit could potentially trigger additional in vivo bioequivalence (BE) studies, adding more complexity, time, and cost to the process.
Furthermore, considering the limited data on how large amounts of antioxidants might affect formulation performance, there could be potential risks beyond nitrosamine formation. For example, high doses of antioxidants might theoretically trigger drug-drug interactions by affecting metabolic enzymes or membrane transporters. While these excipients may not directly alter solubility, their potential effects on membrane permeability and transport systems warrant further investigation. Additionally, some antioxidants may cause allergic reactions in sensitive individuals, adding another layer of complexity to safety assessments.
Is the FDA being overly cautious? Perhaps. However, as more data becomes available, this approach could evolve into a more flexible, case-by-case strategy.
Article open access until March 28, 2025: