Process Synthesis of Continuous Downstream Bioprocessing of Recombinant Intracellular Products

Though continuous manufacturing has been implemented in almost every other industry, but biopharmaceutical industry has been reluctant to change from the archaic batch processing model. In the past, the main concern of the biopharmaceutical industry was the regulatory authorities’ definition of a batch, but the FDA and European Medical Agency (EMEA) has defined a batch as a specific quantity of a drug that is intended to have uniform character and quality within specified limits, putting more emphasis on drugs meeting specific quality standards and less emphasis on the means of production¹. Therefore, biopharmaceutical companies should be pursuing integrated continuous biomanufacturing platforms as these methods have been shown to reduce costs (net present value) by 55% relative to conventional batch processing². However, biopharmaceutical companies are still reluctant to pursue integrated continuous biomanufacturing platforms for intracellular products because intracellular cell culture is difficult to achieve continuously, specifically due to the bottlenecks of the downstream processing.

In this research, we explore the development of continuous downstream bioprocessing using process synthesis for recombinant intracellular products. The case study that we are conducting uses the extraction of beta-carotene from recombinant Saccharomyces cerevisiae. The separation and extraction pathway consists of five sections, 1) cell harvesting, 2) cell disruption, 3) cell extraction and recovery, 4) drying and tablet formulation and 5) recovery of media to be reused in the bioreactor. The superstructure is formulated as a mixed-integer nonlinear programming (MINLP) mode using profitability as the objective function based on that the cost of production for a 10% beta-carotene tablet found in literature³. The optimal topology for the downstream processing will be integrated with a continuous bioreactor model to give an optimal, continuous production implementation for intracellular product for comparison with traditional batch processes.

1. Jungbauer, Alois. “Continuous Downstream Processing of Biopharmaceuticals.” Trends in Biotechnology 31.8 (2013): 479–492.
2. Andrew L Zydney, Perspectives on integrated continuous bioprocessing — opportunities and challenges, Current Opinion in Chemical Engineering, Volume 10, November 2015, Pages 8-13, ISSN 2211-3398, http://dx.doi.org/10.1016/j.coche.2015.07.005.
3. Marz, Ulrich. The Global Market for Carotenoids. BCC Research, 2015.