(M1130-08-54) Mitigation Strategies to Reduce the Risk of the N-nitrosamine Impurity in Drug Products

Purpose: Nitrosamine compounds are carcinogenic and are potential high-risk impurities in drug products. These impurities are labeled ubiquitous as multiple reports outlined the many possible root causes of their formation during the manufacturing process highlighting the complex challenges associated with mitigating their risk. One approach in controlling the levels of these impurities in bumetanide drug products is using antioxidants and pH modifiers in the formulations. The primary objective of this work is to mitigate the risk of formation of N-nitrosamine impurity by evaluating the role of different antioxidant inhibitors in different formulations prepared in-house by OTR formulation scientists using bumetanide as a model drug.

Methods: A multi-factor study design was created, and several model formulations were prepared by wet granulation spiked with sodium nitrite (100 ppm) and different antioxidants (ascorbic acid, ferulic acid and caffeic acid) at three different concentrations (0.1%, 0.5%, and 1% of the total tablet weight). Formulations with acidic and basic pH were also prepared using 0.1N hydrochloric acid and 0.1N sodium bicarbonate, respectively. The formulations were subjected to different temperature and humidity conditions over a 6-month stability study.

Results: Twenty-six formulations were manufactured and tested for N-nitrosamine impurity by a validated mass spectrometric method. The amount of N-nitrosamine impurity formed at Day-0 time point with 1% ascorbic acid was 4-fold lower than the amount of the N-nitrosamine impurity in the sample without antioxidant and added nitrite. At the 6-month data point, samples with 1% of antioxidant showed about a 34% to 41% decrease of N-nitrosamine impurity content as compared to Day-0. A faster decrease of the N-nitrosamine impurity was also observed in sample formulation (with HCl modifier) which showed a ~ 43% decrease at the 6-month time point.

Conclusion: The addition of antioxidants in the formulation of the model drug product showed effective mitigation of the formation of N-nitrosamine impurity. The alkali modifier with sodium bicarbonate had the most effective inhibition of nitrosamine formation in this study. No significant change was observed in the content of the N-nitrosamine impurity in samples with sodium bicarbonate modifier in both accelerated and long-term storage conditions.