Optimization of multi flow rate loading strategy for process intensification of Protein A chromatography

Abstract

Monoclonal antibody (mAb) is a widely used therapeutic modality that is being used for treatment of chronic diseases like cancer, psoriasis, and other auto immune diseases. The affordability of these therapeutics is presently low because of their high manufacturing cost. Protein A chromatography step is a major contributor to the cost of manufacturing of mAbs. The proposed study is an attempt to improve process performance of the protein A chromatography step using multi-flow loading strategy. Although continuous chromatography is an efficient tool to improve resin utilization and process productivity, implementation of continuous chromatography warrants additional capital investment. Use of dual flow rate or multi flow rate offers the potential of attaining similar benefit without this additional investment. For optimization of multi flow rate loading strategy, it is necessary to understand the range of operating flow rate, switch time for changing flow rate to next flow rate and the delta change in the flow rate. In the current study, an alternate, industrially feasible and scalable multi flow rate strategy has been developed, which optimizes the switch time for a given set of flow rates. The algorithm uses LDF (linear driving force) model to predict the breakthrough curve. Further, the method optimizes flow trajectory based on simulated breakthrough curves using estimated diffusion coefficients at specific residence times and suggests a switch time strategy leading to a multi-step loading of increasing residence times. It was observed that by operating the process at multiple flow rates, a near maxima of both adsorbent capacity and the productivity can be achieved. Although variable flow rate approaches have been proposed in literature in recent times, our method for multi-step loading is simpler, practical and has been demonstrated both at lab and pilot scales. The results showed that this simple multi-flow loading approach increased loading capacities by ∼20% and resin utilization by ∼15% as compared to regular batch process; with new generation protein A resin, mAb Select PrismATM, as capture chromatography. Approximately 60% reduction in $COGS/g has been demonstrated when compared to constant flow batch process, similar to the benefits obtained with multi-column continuous chromatography.