Advanced process control practices for continuous pharmaceutical twin-screw wet granulation

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Model-based optimisation and control strategy for the primary drying phase of a lyophilisation process

The standard operation of a batch freeze-dryer is protocol driven. All freeze-drying phases (i.e., freezing, primary and secondary drying) are programmed sequentially at fixed time points and within each phase critical process parameters (CPPs) are typically kept constant or linearly interpolated between two setpoints. This way of operating batch freeze-dryers is shown to be time consuming and inefficient. A model-based optimisation and real-time control strategy that includes model output uncertainty could help in accelerating the primary drying phase while controlling the risk of failure of the critical quality attributes (CQAs). In each iteration of the real-time control strategy, a design space is computed to select an optimal set of CPPs. The aim of the control strategy is to avoid product structure loss, which occurs when the sublimation interface temperature (Ti) exceeds the the collapse temperature (Tc) common during unexpected disturbances, while preventing the choked flow conditions leading to a loss of pressure control. The proposed methodology was experimentally verified when the chamber pressure and shelf fluid system were intentionally subjected to moderate process disturbances. Moreover, the end of the primary drying phase was predicted using both uncertainty analysis and a comparative pressure measurement technique. Both the prediction of Ti and end of primary drying were in agreement with the experimental data. Hence, it was confirmed that the proposed real-time control strategy is capable of mitigating the effect of moderate disturbances during batch freeze-drying

Supervisory process monitoring, identification and control for continuous pharmaceutical wet granulation

The pharmaceutical industry is facing some major challenges in the 21st century. Most notably are the decrease in research and development productivity and the ever increasing competition because of patent expiration. This triggered the industry and its regulators to rethink the entire business. One particular measure is the aim for faster drug development using flexible manufacturing technologies based on fundamental scientific process understanding. Hence, the aim of this doctoral thesis is to investigate the opportunities of automatic process control in the continuous manufacturing of pharmaceutical tablets. It is illustrated how a combination of real-time chemical and physical product analyzers can be combined with mathematical models to monitor and predict the state of intermediate products in real-time. Moreover, these novel tools were applied in automated control strategies in order to ensure the required drug product quality at all times