(372s) Alternative Generation and Evaluation Using a Design Framework: Case Study on Drug Substance Manufacturing Processes of Biopharmaceuticals

Drug substance manufacturing of biopharmaceuticals comprises cultivation of host cells to produce active pharmaceutical ingredients (APIs) followed by harvest and purification of the APIs. An important example representing biopharmaceutical APIs is monoclonal antibodies (mAbs). The market size of mAbs is expanding rapidly which raises the need for efficient processes with reduced costs and production time. In order to improve process efficiency, new production methods have been proposed, e.g., continuous operation mode and single-use technology. These new methods generate a large number of process alternatives regarding unit operations and equipment. In previous works, process alternatives of the new continuous operation mode and the conventional batch mode were evaluated and compared through an economic evaluation [1] or a combined economic and environmental assessment [2]. However, the number of investigated alternatives was limited as they were chosen based on heuristics. The whole range of available options was not explored, e.g., the choice of batch or continuous was not applied to all unit operations.

In this work, we present a case study of alternative generation and evaluation for drug substance manufacturing processes of biopharmaceuticals. The basis of the work is the design framework that can systematically generate alternatives at four decision layers that are product specifications, process flowsheet, equipment, and operating conditions [3]. The framework, previously applied to a sterile filling that is a process after drug substance manufacturing, is applied to standard drug substance manufacturing processes of mAbs. If only the choice between batch or continuous operation mode is considered for each of the six unit operations in the involved process, 64 process alternatives can be generated. However, to realize continuous operation, there are further process options available, e.g., alternating tangential flow (ATF) or tangential flow filtration (TFF) system for perfusion, and simulated moving bed (SMB) chromatography or continuous countercurrent tangential chromatography (CCTC) for purification. Combining all of these options generates more than 60,000 process alternatives. A comprehensive set of the alternatives will be automatically generated and evaluated with respect to process production time and costs to select the preferred combination of process alternatives.

The application of the design framework to drug substance manufacturing enables the systematic and comprehensive generation of alternatives to achieve a more holistic approach for process design of biopharmaceuticals.

[1] J. Walther, R. Godawat, C. Hwang, Y. Abe, A. Sinclair, and K. Konstantinov, “The business impact of an integrated continuous biomanufacturing platform for recombinant protein production,” J. Biotechnol., 213, pp. 3–12, 2015.

[2] J. Pollock, J. Coffman, S. V. Ho, and S. S. Farid, “Integrated continuous bioprocessing: economic, operational, and environmental feasibility for clinical and commercial antibody manufacture,” Biotechnol. Prog., 33(4), pp. 854–866, 2017.

[3] H. Shirahata, S. Badr, S. Dakessian, and H. Sugiyama, “Alternative generation and multiobjective evaluation using a design framework: case study on sterile filling processes of biopharmaceuticals,” Comput. Chem. Eng., 123, pp. 286–299, 2019.