The transition from batch to continuous processes in the pharmaceutical industry has been driven by the potential improvement in process controllability, product quality homogeneity, and reduction of material inventory. A quality-by-control (QbC) approach has been implemented in a variety of pharmaceutical product manufacturing modalities to increase product quality through a three-level hierarchical control structure. In the implementation of the QbC approach it is common practice to simplify control algorithms by utilizing linearized models with constant model parameters. Nonlinear model predictive control (NMPC) can effectively deliver control functionality for highly sensitive variations and nonlinear multiple-input-multiple-output (MIMO) systems, which is essential for the highly regulated pharmaceutical manufacturing industry. This work focuses on developing and implementing NMPC in continuous manufacturing of solid dosage forms. To mitigate control degradation caused by plant-model mismatch, careful monitoring and continuous improvement strategies are studied. When moving horizon estimation (MHE) is integrated with NMPC, historical data in the past time window together with real-time data from the sensor network enable state estimation and accurate tracking of the highly sensitive model parameters. The adaptive model used in the NMPC strategy can compensate for process uncertainties, further reducing plant-model mismatch effects. The nonlinear mechanistic model used in both MHE and NMPC can predict the essential but complex powder properties and provide physical interpretation of abnormal events. The adaptive NMPC implementation and its real-time control performance analysis and practical applicability are demonstrated through a series of illustrative examples that highlight the effectiveness of the proposed approach for different scenarios of plant-model mismatch, while also incorporating glidant effects.


This article is published under a CC-BY license.

Huang, Y.-S.; Sheriff, M.Z.; Bachawala, S.; Gonzalez, M.; Nagy, Z.K.; Reklaitis, G.V. Evaluation of a Combined MHE-NMPC Approach to Handle Plant-Model Mismatch in a Rotary Tablet Press. Processes 2021, 9, 1612. https://doi.org/10.3390/pr9091612


Continuous pharmaceutical manufacturing; model predictive control; state estimation; quality-by-control (QbC); glidant effects; plant-model mismatch

Date of this Version