Data reconciliation in the Quality-by-Design (QbD) implementation of pharmaceutical continuous tablet manufacturing.

ABSTRACT

Data provided by in situ sensors is always affected by some level of impreciseness as well as uncertainty in the measurements due to process operation disturbance or material property variance. In-process data precision and reliability should be considered when implementing active product quality control and real-time process decision making in pharmaceutical continuous manufacturing. Data reconciliation is an important strategy to address such imperfections effectively, and to exploit the data redundancy and data correlation based on process understanding. In this study, a correlation between tablet weight and main compression force in a rotary tablet press was characterized by the classical Kawakita equation. A load cell, situated at the exit of the tablet press chute, was also designed to measure the tablet production rate as well as the tablet weight. A novel data reconciliation strategy was proposed to reconcile the tablet weight measurement subject to the correlation between tablet weight and main compression force, in such, the imperfect tablet weight measurement can be reconciled with the much more precise main compression force measurement. Special features of the Welsch robust estimator to reject the measurement gross errors and the Kawakita model parameter estimation to monitor the material property variance were also discussed. The proposed data reconciliation strategy was first evaluated with process control open-loop and closed-loop experimental data and then integrated into the process control system in a continuous tablet manufacturing line. Specifically, the real-time reconciled tablet weight measurements were independently verified with an at-line Sotax Auto Test 4 tablet weight measurements every five minutes. Promising and reliable performance of the reconciled tablet weight measurement was demonstrated in achieving process automation and quality control of tablet weight in pilot production runs.