(W1030-01-01) Nitrosamine Mitigation Case Study: The Importance of Utilizing a Multi-Pronged Approach to Reduce Impurities

Purpose: Nitrosamine reduction is a top priority for the entire industry, with recent FDA guidance setting ambitious timelines for NDSRI compliance. Each API and drug product formulation is different, a one-size-fits-all additive strategy cannot be applied. In this presentation, we walk through Adare’s experience reducing the presence of nitrosamines in our own products over the last two years and detail our system of best practices in nitrosamine mitigation. This study specifically speaks to reducing the formation of NDSRIs formed from secondary and dimethyl tertiary amines, which the FDA has identified as most problematic. These functional groups can readily react with trace nitrite contamination present in the drug product to form NDSRI impurities. While the new NDSRI guidance specifically applies to marketed products, drugmakers with products in development containing these high-risk functional groups would be well advised to assess and address risks proactively. This minimizes the risk of late-stage reformulation, added costs, and product launch delays.

Methods: Nitrosamine mitigation was studied through the evaluation of nitrite scavengers, amino acids, and pH modification. Materials were chosen due to their chemical properties, inclusion in the FDA Inactive Ingredient Database, and compatibility with the API and formulation. The study was designed to characterize the solid state reactivity and the importance of the API microenvironment. This process utilized a screening process where chemicals were placed in binary mixtures with the API with added sodium nitrite to mimic real world situations. The most promising chemicals, concentrations, and mixtures were used in the subsequent step where they were mixed either with a lab blend or ground drug product at various concentrations. Multiple concentrations were used to gauge the response. The mixtures were dried then placed in a temperature and humidity-controlled environment for 2-4 weeks.

Results: 70-80% reduction in NDSRI formation vs. this control in the API Microenvironment for multiple samples. 84% reduction in NDSRI formation vs. control was achieved in the Solid State Stress Study, including the full formulation. All controls reached 50% to 200% of the regulatory limit, confirming a real-world environment. Traditional nitrite scavengers show the greatest reduction in nitrosamine formation in both the API microenvironment & drug product mixtures. Marked contrast in results from various amino acids.

Conclusion: Mitigation achieved is sufficient for practical use to meet regulatory requirements. An environment simulating real world time on the shelf was achieved. Previously unidentified reaction mechanisms observed in amino acids. Orthogonality was shown, increasing the design space as formulations and processes evolve.


Image 1: N-Nitrosopropranolol Mass Spectra


Image 2: Screening/API Microenvironment Results utilizing traditional nitrite scavengers and diazotization reaction scavengers vs. control (100%)


Image 3: Full formulation Solid State Stress Study Results of traditional nitrite scavengers and diazotization reaction scavengers vs. control (100%)