Project Portugal 2030

Summary

The main objective of this project is to propose and demonstrate significant improvements to the monoclonal antibody’s purification process, resulting in a more sustainable processes with lower manufacturing costs and higher productivity while maintaining or improving quality standards; ultimately leading to a more widespread availability of these increasingly sought biopharmaceuticals. Currently, purification is the limiting step in mAbs bioprocessing, since it has not kept up with the developments in upstream processing that allowed the increase in product concentration. Antibodies purification is conducted over a series of batch chromatography steps which suffer from low productivity and mass transfer limitations that cause significant underutilization of the stationary phases, particularly relevant in the case of the expensive Protein A chromatography. Often this leads biomanufacturing facilities to compromise on production rate in order to control operational costs, limiting their production capabilities and thus the accessibility of these products. Acknowledging these issues, regulatory agencies have urged the adoption of continuous manufacturing. This project proposes the use of multicolumn continuous chromatography (MCC) to overcome these problems, potentially leading to lower operational costs, increased efficiency and flexibility, streamlined processes, reduced process footprint, and improved product consistency and quality. These technologies include simulated moving bed, Periodic Countercurrent Chromatography, and Multicolumn Countercurrent Solvent Gradient Purification and allow a more intensive adsorbent utilization as they catch the breakthrough of a column into the next. They can be combined to deal with the several requirements of the purification process: mAb capture from the cell-culture fluid, removal of viral contaminants at low pH, and removal of negatively charged impurities. Although the Protein A purification step is the most significant and where improvements are most impactful, the successful design of new a MCC process requires its harmonious incorporation in the purification pipeline, namely the previous clarification stage and the following virus inactivation and polishing steps. These additional chromatography steps are also prone to the implementation of MCC technologies or for their integration into a combined strategy which aims to conduct mAbs capture, virus clearance, and polishing over the multiple columns of one or more continuous chromatography units. This is akin to the SMB Reactor that combines the principles of chromatographic separation and chemical reaction in a single, continuous multicolumn operation. This technology is currently used in the chemical industry for the efficient and selective production of high-value products [1]. The pharmaceutical industry is naturally conservative in the application of new production and purification techniques mainly due to regulatory and product safety concerns. Although continuous operation bioreactors have recently been implemented to produce mAbs (e.g., perfusion cell culture bioreactors), no fully continuous purification processes are implemented commercially, creating a significant technological gap and a process bottleneck. Therefore, there is still opportunity to innovate as the manufacture of affordable drugs is still far from attaining maximum efficiency.