(T1530-12-81) Evaluating the Impact of Excipient Selection on Nitrosamine Formation in Drug Products

Purpose: The challenge of controlling nitrosamine impurities in drug products poses a significant risk in the industry. Nitrosamines can form when nitrites react with amine-containing APIs or impurities during drug product manufacturing and storage. The level of nitrites in excipients and the reaction rate play a crucial role in nitrosamine accumulation. However, the systematic investigation of the impact of excipient selection with varying nitrite levels on nitrosamine formation has been lacking. In this study, we calculate the theoretical nitrosamine content in model formulations based on realistic conversion percentages and average nitrite content from literature sources. We then assess the potential changes in nitrosamine content by replacing either the excipient supplier or type in the formulation.

Methods: To assess nitrosamine formation in tablets, a series of case studies was conducted. These studies involved calculating the theoretical formation of nitrosamines based on known values, including the nitrite levels in each excipient ¹, the molecular weight of the expected nitrosamine, tablet dose weight, expected conversion percentage of nitrite to nitrosamine ², and the composition of the dosage form. For each case study, the potential nitrosamine formation per excipient (in ppm) was determined by considering the nitrite levels and conversion rate. Subsequently, the contribution of each excipient to the overall nitrosamine content in the tablet was calculated, taking into account the tablet composition. The impact of average, maximal, and minimal nitrite levels in selected excipients on the total formation of nitrosamines was then compared.

Results: The first case study involved a 200 mg immediate release tablet with various excipients. Changing the MCC supplier had a significant impact on nitrosamine formation. Using MCC with the highest nitrite level increased nitrosamine levels by +151%, surpassing the acceptable daily intake (ADI). Conversely, using MCC with the lowest nitrite level reduced nitrosamine formation by -59% compared to the average. Figure 1 illustrates the mitigation of risk through switching to a low-nitrite MCC supplier. A limitation is that the conversion percentage is based on a specific formulation and API, as reported in a case study in the literature ². Other APIs or formulations could have different percentages of conversion. However, the relative increase and decrease in nitrosamine formation for the worst and best-case MCC scenarios compared to the average scenario hold true. In the second case study, a 200 mg wet granulated (WG) immediate release tablet formulation was examined. It contained 10% of a secondary amine API in the salt form, with lactose being the main component. Figure 2 demonstrates that both the average and worst-case formulations, where lactose has the highest nitrite content, exceed the ADI limit. Replacing lactose with a supplier having minimal nitrite levels reduced nitrosamine formation by -53% compared to the average formulation, ensuring compliance with the ADI limit. Both case study 1 and case study 2 illustrate nitrosamine risk mitigation by qualifying different excipient suppliers for the main filler excipient. Another strategy involves re-formulating a product using excipient types with lower nitrite levels. Figure 3 showcases the impact of changing the superdisintegrant on nitrosamine formation. The original product contains crospovidone (average nitrite levels: 6.5 ppm¹), while the re-formulated product uses croscarmellose sodium (average nitrite levels: 0.42 ppm¹). This reformulation strategy reduces nitrosamine formation by -36%. Although the superdisintegrant represents only 5% of the tablet content, replacing it can significantly reduce theoretical nitrosamine content due to higher nitrites per unit weight in crospovidone compared to other excipients. However, in this specific case study, replacing the superdisintegrant alone did not fully de-risk the formulation below the ADI limit. Consequently, in Figure 4 (not shown), the cumulative impact of (i) selecting MCC and lactose suppliers with the lowest nitrite levels and (ii) replacing crospovidone with croscarmellose sodium was evaluated. This complete reformulation strategy achieved an -89% reduction in nitrosamine formation (from 422 to 45 ng per dose), effectively de-risking the product ADI limit

Conclusion: This study demonstrates the impact of excipient supplier selection and superdisintegrant reformulation on nitrosamine formation in drug products. Changing suppliers and critical excipients significantly reduces theoretical nitrosamine formation. Selecting excipients with the lowest nitrite levels can reduce nitrosamines by nearly 10-fold compared to average nitrite levels. However, this reduction may not always be sufficient to meet the 18 ng/day ADI limit. Additional strategies such as using dry manufacturing methods or adding nitrite scavengers may be necessary in such cases. Overall, reducing nitrosamines through low-nitrite excipient selection is a valuable approach.

References: 1. Boetzel R, Schlingemann J, Hickert S, et al. A Nitrite Excipient Database: A useful Tool to Support N-Nitrosamine Risk Assessments for Drug Products. J Pharm Sci. Published online 2022.
2. Moser J, Ashworth IW, Harris L, Hillier MC, Nanda KK, Scrivens G. N-Nitrosamine Formation in Pharmaceutical Solid Drug Products: Experimental Observations. J Pharm Sci. Published online 2023.

Figure 1. Risk mitigation of nitrosamines formation through the adoption of an alternative low-nitrite MCC.

Figure 2. Risk mitigation of nitrosamines formation through the adoption of an alternative low-nitrite lactose.

Figure 3. Risk mitigation of nitrosamines formation through changing the superdisintegrant type in the formulation (re-designed uses croscarmellose sodium).