(T1430-02-11) Monitoring of NO_X Concentration on Fluidized Bed Dryer and Evaluation of Its Reduction Method

Purpose: In recent years, trace amounts of nitrosamines compounds has been detected in pharmaceuticals drug products both domestically (in Japan) and internationally resulting in various numbers of undesired drug recalls. In 2021, Ministry of Health, Labor and Welfare of Japan has issued a notice regarding risk management of nitrosamine contamination in pharmaceuticals¹. In 2024, CDER issued the “Control of Nitrosamine Impurities in Human Drugs” guidance², which indicated that “certain manufacturing processes using forced air, such as fluid bed drying at elevated temperature and jet milling, can create favorable conditions for nitrosamine formation in at-risk APIs when nitrogen oxides in the air react with the APIs”. As the importance of this risk reduction measure increases, both authors’ affiliates (pharmaceutical machinery manufacturer and analytical instrument manufacturers) have received an increasing number of inquiries and questions regarding fluidized bed drying and nitrosamine formation regarding the indication. In this study, we have evaluated the impact of the fluidized bed drying process against generation of nitrogen oxides (NO_X, which is stated as the source of nitrosamines generation in the environment), the methods to reduce NO_X concentration during the process and the influence of reduction against a model compound.

Methods: For the evaluation of this research, R&D type tumbling fluidized bed granulator dryer/coater system FD-MP-01E (Powrex Corporation, JAPAN) (Fig. 1) was selected.  FD-MP-01E was modified so that NO_X Monitor APNA-380 (Horiba, Ltd., JAPAN) can be suitably connected and enable real-time monitoring of NO_X concentrations in ppb orders. To evaluate the possibility of NO_X generation inside FD-MP-01E, both inlet air flow and inlet temperature were appropriately changed, and internal monitoring was performed. To reduce the NO_X concentration inside the system, we have developed a dedicated apparatus equipped with a special filter, which can measure NO_X concentration by connecting APNA-380 and can directly connect to the FD-MP-01E’s inlet air supply port. The performance was evaluated by calculating the removal rate [%] of NO_X with and without the apparatus by monitoring various points of FD-MP-01E using APNA-380. Effect of the reduction of NO_X exposure was evaluated by using a model compound (low molecular weight secondary amine which easily reacts with NO₂ in the atmosphere) after layering for 7 hours in FD-MP-01E with and without the dedicated apparatus and measured the trend of nitrosation from the collected granules after severe testing at 60 degrees using LC-MS/MS method.

Results: By monitoring the NO_X concentration inside the fluid bed chamber and changing the operation conditions of inlet air flow and inlet temperature, it was confirmed that there are no changes in the value of NO_X indicating that the NO_X concentration does not increase nor decrease within the FD-MP-01E and depends on the concentration in the supplied air (inlet air flow [m³/min] / NO_X concentration [ppb]: 0.75/5.7, 1.0/5.4, 1.25/5.3, 1.50/5.1) (inlet temperature [deg] / NO_X concentration [ppb]: 40/4.6, 60/5.0, 80/4.4, 100/5.1) (Fig. 2). By connecting the developed dedicated apparatus, NO_X concentration from the inlet air has been successfully reduced (removal rate from inlet air: 84%) which leads to a reduction in the concentration inside the fluid bed drying / granulation system (removal rate inside FD-MP-01E: 78%). It would be noteworthy that the measured NO_X by APNA-380 is the sum of NO and NO₂, and the reduced amount for each were for inlet air were 43% and 94%, respectively, indicating that this method is more effective on reducing the NO₂.Also, since the FD-MP-01E is a tumbling fluid bed granulator dryer/coater system which can change its configuration from dryer to granulator by alternating its chamber, that the NO_X reduction using the measure was also confirmed to be possible for other configurations (removal rate inside FD-MP-01E (tumbling fluid bed granulation configuration): 87%). Additionally, experiment using model compound confirmed that appropriate measures using the dedicated apparatus resulted in successful reduction of nitrosation of the model compound after severe testing (NDSRI [ppm] / week: (w/ apparatus) 0.23/0, 0.68/1, 0.99/3, (w/o apparatus) 0.36/0, 1.4/1, 1.33/3) (Fig. 3), and reduction of NO_X can become an effective measure for the prevention of nitrosation.

Conclusion: The result of this research suggests that NO_X concentration does not increase in the fluidized bed drying or granulation process and the concentration in the inlet air or the environment has the direct impact on the generation of nitrosamines. Also, the developed dedicated apparatus can contribute to both monitoring of NO_X concentration and the reduction of the nitrosamine generation from amine compounds. Therefore, to reduce and suppress the risk for generation of nitrosamines during the fluidized bed drying or granulation process overall, we would like to propose the importance of reducing the amount of nitrosating agents not only from raw materials (API, excipient, water/solvent, etc.) but also from the manufacturing process environment including inlet air.

References: 1. Inspections regarding the risk of nitrosamines in pharmaceuticals (in Japanese, title: direct translation of Japanese), PMDA, October 2021.
2. Control of Nitrosamine Impurities in Human Drugs Guidance for Industry, CDER, September 2024.


Fig. 1 R&D type tumbling fluidized bed granulator dryer/coater system FD-MP-01E.


Fig. 2 Confirmation of inlet temperature influence against NOX generation inside FD-MP-01E.


Fig. 3 Transition of model compound’s nitrosation (generation of NDSRI) after severe testing with and without dedicated apparatus during layering.