Population balance model development, validation, and prediction of CQAs of a high-shear wet granulation process: Towards QbD in drug product pharmaceutical manufacturing

This paper focuses on the predictive model development for a pharmaceutically relevant model granulation process. A population balance modeling (PBM) framework has been employed for modeling purposes which is then utilized to obtain accurate predictions of the process. The model is aligned to adequately describe the high-shear mode of granulation operation in a batch process. The model is calibrated using the particle swarm algorithm (PSA) in the form of a multiobjective optimization problem. The multiobjective optimization problem was implemented based on the ε-constraint method which involves the handling of multiple cost functions in the form of constraints with the minimization of one primary objective function from the entire set of cost functions. The resultant solutions obtained from the model are Pareto optimal. The effects of the impeller speed, liquid-to-solid ratio, and wet massing time on the particle size distributions were characterized, and predicted size distributions were in agreement with experimental results. The predictive model framework lends itself to the quality by design (QbD) initiative undertaken by the US Food and Drug Administration (US FDA).