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.

Keywords: Continuous manufacturing; Data reconciliation; Pharmaceutical; Quality by Design; Tablet press.

Fig. 1.

Scope and connections of data reconciliation with other related approaches.

Fig. 2.

Major steps in Natoli BLP-16 rotary tablet press.

Fig. 3.

A hierarchical three-level process control for direct compaction.

Fig. 4.

Tablet weight measurement for real-time monitoring and control.

Fig. 5.

Comparisons between Kawakita model prediction and experimental measurements: main compression force vs. relative density (top) and main compression force vs. tablet weight (bottom).

Fig. 6.

Offline data reconciliation with open-loop experiment with at-line Sotax AT4 sampling. (a) Soft sensor predictions of tablet weight with original Kawakita model subjects to model uncertainties; (b) Measurements of tablet weight with a balance subject to noise and gross errors; (c) Reconciled measurement of tablet weight; (d) Kawakita model parameter updates with data reconciliation.

Fig. 7.

Offline data reconciliation with open-loop experiment without at-line Sotax AT4 sampling.

Fig. 8.

Offline data reconciliation with closed-loop experiment without at-line Sotax AT4 sampling.

Fig. 9.

Measurement error and parameter estimation by offline data reconciliation with closed-loop experiment without at-line Sotax AT4 sampling.

Fig. 10.

The hierarchical Level 1 (top) and Level 2 (bottom) control for continuous tablet press.

Fig. 11.

Online integrated data reconciliation and process control for continuous tablet press.