Automatic system dynamics characterization of a pharmaceutical continuous production line

Continuous Manufacturing (CM) of drug products is a new approach in the pharmaceutical industry. In the presented paper, a GMP continuous wet granulation line for production of solid oral dosage forms was investigated in order to assess the system dynamics of the line and to define the best control and diversion strategy. The following steps were involved in the continuous process: dosing/feeding, blending, twin-screw wet granulation, fluid-bed drying, sieving and tableting. Two drug products with two different drug substances were compared during this study: one drug substance as model drug compound and one formulation of a currently evaluated commercial drug product. Several step tests in API concentration were performed in order to characterize the process flow and assess the process dynamics. API content was monitored in real time by Process Analytical Technologies (PAT) thanks to three Near Infrared (NIR) probes located along the process and measuring the API content after blender, after dryer and in the tablet press feed frame. The process parameter values were changed during production in order to detect the impact on the quality of the final product. An automatic residence time distribution (RTD) computation method has been developed in order automate the RTD calculation on the basis of process data to further define and monitor the system dynamics with the final aim of out of specification material diversion during the continuous production. The RTD has been seen as a process fingerprint: a change in the RTD values implies a change in the process.