Evaluation of Optimization Metrics for Continuous Fermentation of Plasmid DNA

An evaluation of cumulative productivity metrics for optimizing the continuous fermentation of plasmid DNA (pDNA) is carried out in this work. DNA plasmids provide a good illustrative example for comparison because of the plasmid instability issues associated with their production. However, the analysis presented in this work can also be applied to other intracellular bioproduct continuous fermentation systems. The productivity metrics considered are cumulative product mass per time, profit, and cost objective functions. These metrics are used to determine the optimal continuous fermentation run time at a given dilution rate, during the dynamic period associated with switching from batch to continuous fermentation. The results of this study indicate that different optimum continuous fermentation run times are predicted based upon the choice of the continuous fermentation operating conditions and optimization metric. In particular, the dilution rate must be larger than the inverse of a characteristic time, that is a function of the initial batch operating and plasmid stability times before continuous operation becomes optimal. Provided that this condition is met, different optimal continuous operation run times are obtained depending on the cumulative productivity metric, or operating objective, that is employed.