Advantages and limitations of the inclusion of ascorbic acid on nitrosamine mitigation in pharmaceutical drug products.

Nitrite scavenging is an effective strategy to control nitrosamine formation during the shelf-life of pharmaceutical drug products, particularly when other interventions are insufficient. Here, we showed that the addition of a specific nitrite scavenger, ascorbic acid, decreased nitrosamine formation in tablets. It was found that a homogeneous distribution of ascorbic acid in the excipient blend achieved through wet blending was critical to minimizing nitrosamine formation. As an antioxidant, the use of ascorbic acid requires a validated analytical method and established acceptance limits for regulatory compliance, which is complicated by our observation that ascorbic acid was unstable during routine tablet production and on stability. Additionally, new API related substances were seen and attributed to the reaction with ascorbic acid, which necessitates structure elucidation and toxicological qualification. With these limitations in mind, implementing a nitrite scavenging system for nitrosamine control requires well-defined workflows for the data package, analytical methods, and regulatory filing strategy throughout the product lifecycle.