Proactive-residence time distribution method for determining low-risk setpoints of critical material attributes in...

In recent years, the pharmaceutical manufacturing industry has been working towards adopting continuous manufacturing of drug product to improve productivity. However, the complexity of integrated processes makes quality assurance difficult. In pharmaceutical manufacturing, the required product quality is achieved by maintaining the critical material attributes (CMAs) within a region called the design space (DS). To keep the CMAs within the DS, their feedback control plays a critical role, and proper determination of their setpoints is crucial. In the present work, we propose the proactive-residence time distribution (P-RTD) method, which determines setpoints based on the prediction of the effective CMAs calculated using RTD functions. We compared the performance of the P-RTD method and those of the other three methods through control simulations of realistic continuous dry granulation lines. Besides, we conducted simulations under various conditions varying the relationships among CMAs and the lag times of the processes. The results showed that only the P-RTD method kept the CMAs within the DS under all conditions.