(407f) Monitoring Loss-in-Weight Pharmaceutical Feeders through State Estimation

In recent years the pharmaceutical industry has been putting a lot of effort and resources for operating in a more continuous fashion [1]. Continuous manufacturing of solid oral dosage forms presents many benefits with respect to traditional batch production, and has been encouraged by the U.S. Food and Drug Administration [2]. One important bottleneck for this shift of paradigm is the implementation of an efficient feeding system, as any disturbance coming from the feeders will critically affect the downstream units and the quality of the product, even irreversibly [3,4].

Loss-in-weight feeders are usually resorted to in drug product manufacturing. They are made up of a hopper, where the powder is collected and eventually refilled, an agitator, connected to a motor, and a screws system. Realtime monitoring of the feeder operation is inherently challenging, as the only available process measurement is the net weight of powder in the hopper. The mass flowrate of powder delivered by the feeder can only be obtained indirectly, as a discrete time derivative of the mass measurements in the hopper. The propagation of noise from the measured mass to the inferred mass flowrate can compromise the control of the powder flow and the monitoring of the whole manufacturing line. Commercial feeders tackle the problem by providing the user with a smoothed version of the indirect measurement of the mass flowrate, but this introduces a time delay with respect to the actual mass flowrate fed downstream. In presence of gross errors in the measurement of the mass in the hopper, the inaccuracy in the calculation of the mass flowrate is even greater.

In this study we improve the accuracy of estimation of the mass flowrate coming out of a feeding unit by the implementation of a state estimator [5]. State estimators are widely employed in the process industry, but few contributions in the literature consider their application to continuous pharmaceutical manufacturing [6]. The implemented state estimator is based on a recently developed hybrid model [7] and is tested on experimental data coming from a feeding system. The estimation framework can accurately estimate the states of the system, namely the mass of powder in the hopper (deprived of the measurement noise), the actual mass flowrate provided by the feeder and the effective density in the hopper (an additional variable that cannot be measured online but that is important for process monitoring). The state estimator demonstrates to be robust to the presence of gross measurement errors and faults. The estimated states can be used for detecting faults in the feeding unit and to monitor the downstream operation.

References

[1] Ierapetritou, M., F. Muzzio and G. Reklaitis (2016). Perspectives on the continuous manufacturing of powder‐based pharmaceutical processes. AIChE J., 62, 1846–1862.

[2] Lee, S. L., T. F. O’Connor, X. Yang, C. N. Cruz, S. Chatterjee, R. D. Madurawe, C. M. V. Moore, L. X. Yu and J. Woodcock (2015). Modernizing Pharmaceutical Manufacturing: from Batch to Continuous Production. J. Pharm. Innov., 10, 191–199.

[3] García-Muñoz, S., A. Butterbaugh, I. Leavesley, L. F. Manley, D. Slade and S. Bermingham (2017). A flowsheet model for the development of a continuous process for pharmaceutical tablets: an industrial perspective, AIChE J., 64, 511–525.

[4] Blackshields, C. A. and A. M. Crean (2018). Continuous powder feeding for pharmaceutical solid dosage form manufacture: a short review. Pharm. Dev. Technol., 23, 554–560.

[5] W. H. Ray (1981), Advanced process control, McGraw-Hill, New York (U.S.A.).

[6] Liu, J., Q. Su, M. Moreno, C. Laird, Z. Nagy, G. Reklaitis (2018). Robust state estimation of feeding–blending systems in continuous pharmaceutical manufacturing. Chem. Eng. Res. Des., 134, 140–153.

[7] Bascone, D., F. Galvanin, N. Shah and S. García-Muñoz (2020). A hybrid mechanistic-empirical approach to the modelling of twin screw feeders for continuous tablet manufacturing. Ind. Eng. Chem. Res., in press