Purpose: Nitrosamines are carcinogenic impurities that have been found in drug products containing a susceptible amine and nitrite/nitrate. The purpose of this work was to implement a validated ion chromatography method to monitor the concentration of nitrogen-based precursors (nitrite, nitrate and dimethylamine) following the addition of antioxidants to develop procedures to mitigate nitrosamine formation in drug products. Methods: Three ion chromatography (IC) methods were developed and validated according to ICH Q2 (R1) regulatory guidelines to evaluate nitrite, nitrate, and dimethylamine in pharmaceutical drug products using conductivity and UV as detection methods. Nitrite and nitrate were evaluated using an AS19 column with a potassium hydroxide eluent generator cartridge with a concentration gradient. Dimethylamine was evaluated using a CS19 column with a methane sulfonic acid eluent generator cartridge with a concentration gradient. The final method was validated for linearity, range, accuracy, precision, selectivity, specificity, limit of detection, and robustness. Stability studies were also conducted. The analytes were also evaluated for spike recovery in the drug products at three concentrations. Results: The linearity of the nitrite, nitrate, and dimethylamine methods met specifications with r2 ≥ 0.99. The accuracy over four concentrations tested ranged from 88-105% for nitrite, 98-107% for nitrate, and 95-108% for dimethylamine. The precision over four concentrations was ≤ 5%RSD for nitrite, ≤ 3%RSD for nitrate, and ≤ 4%RSD for dimethylamine. The method was applied to test nitrite, nitrate, and dimethylamine levels in marketed and formulated model drug products. Multiple formulations of the products were manufactured in-house with some containing 100 ppm of nitrite, 100 ppm of dimethylamine, 0.1-1% of antioxidant, or a combination of the three. The results over a 3-month stability study at elevated temperatures and humidity demonstrated that certain antioxidants could provide better mitigation of nitrosamine formation relative to the study controls. Conclusions: The validated ion chromatography analytical methods were successfully applied for the evaluation of nitrite, nitrate, and dimethylamine in drug products. Monitoring nitrite, nitrate, and dimethylamine during the manufacturing of drug products can provide valuable information to assess nitrosamine mitigation approaches in drug.

Development and validation of ion chromatography methods for the evaluation of nitrosamine precursors (nitrite, nitrate, and dimethylamine) in pharmaceutical drug products

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