Monitoring the concentration of nitrogen oxides in the fluidized bed drying/granulation process and evaluation of reduction methods.

The presence of N-nitrosamine impurities and nitrosamine drug substance-related impurities (NDSRIs) in medicines poses a significant challenge not only for manufacturers of drug substances, drug products, and excipients but also for related industries such as machinery and analytical equipment manufacturers. In addition to the ongoing identification of new NDSRIs, new causes of nitrosamine generation such as atmospheric nitrogen oxides have also been identified. These developments suggest that further discoveries in this area are likely in the future. This study is the first to demonstrate a method for verifying the behavior of nitrogen oxides during the fluidized bed drying/granulation process through real-time monitoring and to clarify their influence on the generation of NDSRIs. The influence of nitrogen oxides concentration in two air sources (inlet air and compressed air) was investigated and it was shown that the concentration can be effectively reduced by installing a suitable chemical filter. Furthermore, it was confirmed that reducing NO2 concentration during the process suppressed NDSRI generation without compromising manufacturability or the physical properties. These findings provide important insights into a previously unknown pathway of NDSRI generation and will contribute to the development of risk mitigation strategies.