461837 Dynamic Optimization of Continuous Manufacturing of Pharmaceuticals

Tuesday, November 15, 2016: 5:05 PM
Continental 4 (Hilton San Francisco Union Square)
Michael Shoham Patrascu and Paul I. Barton, Process Systems Engineering Laboratory, Massachusetts Institute of Technology, Cambridge, MA

Continuous manufacturing (CM) of pharmaceuticals is being explored as an alternative to traditional batch-wise production. This shift holds great promise to increase production efficiency, enable smaller production facilities, minimize waste, energy consumption, and raw material use and to enable drug quality monitoring on a continuous basis. However, implementing CM in the pharmaceuticals industry implies short operational campaigns, with significant transient phases (start-up and shutdown), constituting up to 30% of the entire time horizon. This significantly hampers the plant's economic feasibility. Efforts to optimize the overall production process involve mathematical modeling and solution of hybrid (discrete-continuous) systems embedding differential-algebraic equations (DAEs), along with the associated parametric sensitivity trajectories to be used in rigorous gradient-based optimization algorithms.

In this contribution, these efforts will be described, addressing the numerical issues related to the hybrid and non-smooth nature of the mathematical model. A case-study pilot plant model incorporating several synthesis, separation and purification steps to produce final tablets [1] is used for demonstration. The dynamic optimization approach that is employed maximizes the accumulated on-spec production directly over the entire time horizon (so-called Economic-Optimization), while guaranteeing differentiability with respect to the controls [2]. Optimization results will be presented followed by a discussion on the process design and formulation and the intelligent choice of the open-loop control decision variables.

[1] S. Mascia et al., "End-to-End Continuous Manufacturing of Pharmaceuticals: Integrated Synthesis, Purification, and Final Dosage Formation", Angew Chem. Int. Ed. Engl., 2013, 52(47), 12359-63

[2] A. Sahlodin and P.I. Barton, "Optimal Campaign Continuous Manufacturing", Ind. Eng. Chem. Res., 2015, 54(45), 11344-59.

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