Optimal Process Synthesis for the Production of Multiple Recombinant Proteins

This paper presents a novel solution strategy for the synthesis of multiproduct and multihost protein production processes. There are several possible hosts that may express each of the products, and different downstream processing separation and purification tasks are needed, which in part depend on the host selection. Moreover, alternative unit operations may be available for some of these separation tasks. Finally, these processing units may be arranged in different configurations. A single mixed-integer optimization model represents the different decisions involved in synthesizing a plant for producing multiple proteins. The mathematical model optimizes the profit of the multiproduct plant and allows the decisions to be made simultaneously, namely, the choice of hosts, downstream operations, the configuration and size of units, as well as their scheduling. An example is solved for a plant that must produce four proteins for which there are alternative hosts for their expression (Escherichia coli, Chinese hamster ovary cells, and yeast that, depending on the product, may express it as an extracellular or intracellular protein) that require 15 stages with choices of unit operations as well as in or out of phase operations. Given the very large quantity of novel recombinant proteins for a number of novel therapeutic uses presently being approved or "in the pipeline", multiproduct and multihost recombinant protein production plants have recently been or are being built for the manufacture of these products. The strategy presented in this paper is of crucial value for the optimal utilization of such plants.