The scope of the project is the optimization of downstream processing (DSP) for the production of Biopharmaceuticals. Biopharmaceuticals have been successfully used as efficient therapeutic drugs for many pathophysiological conditions since the first recombinant product, insulin, was approved in 1982. Despite its efficacy, accessibility is still limited due to extremely high costs. In the production chain, capturing and purifying still represents a major bottleneck. Consequently, improvements in this area produce substantial cost reductions and expand patients’ accessibility to highly efficient drugs. Another aim of this action is to cope with the changing manufacturing demands, by lowering its environmental footprint and moving to more sustainable technologies.
The project’s main objective was to implement a fully integrated continuous manufacturing platform based on continuous purification, viral clearance and final Ultrafiltration/Diafiltration (final drug substance formulation) process unit operations, in combination with single-use disposable techniques. All unit operations of monoclonal antibodies DSP sequence on manufacturing scale were integrated together with incorporation of advanced analytical tools (PAT - Process Analytical Technology analytical tools).
In specific work packages we focused on primary separation, where the removal of cells from product takes place. There the aim was substitution of the standard process for primary separation with the utilization of flocculants in combination with filtration or for fully continuous bioprocess (perfusion process) also implementation of tangential flow filtration (TFF). This resulted in substantial reduction of cost and in robust process for removal of cells from the product. In capture step development studies, we focused on continuous chromatography on protein A resin, where the main aim was reduction in size of the columns and reduction of need for expensive resin volume and highly improved productivity. For implementation of such process on manufacturing scale also single use continuous chromatography equipment was developed. Additionally non-chromatographic capture step alternatives, such as continuous precipitation, were explored as a future approaches for purification of biopharmaceuticals. Single-use disposable technology for all downstream processing operations was evaluated and flow-through approaches for polishing steps implemented, to remove impurities in a continuous way. Other options for processing of biopharmaceuticals in a continuous way were also implemented, such as continuous virus inactivation and different continuous UF/DF techniques as part of continuous final DS formulation approach. Best performing technologies were selected and implemented on large scale continuous and integrated process, where we achieved reduction in the size and number of downstream unit operations. In order to monitor and control the established process, advanced analytical tools for measuring impurities, product content and other parameters in real time or close to real time were implemented.
Large scale continuous and integrated process was successfully validated and showed many benefits. Most important ones were more efficient drug production processes, with reduced costs, and greater productivity, flexibility and competitiveness – ultimately leading to greater patient accessibility and lower burdens on healthcare systems. A second aim was to create a more sustainable process, with a reduction in the amount of consumables and water used, leading to reduced environmental footprint of the biopharma industry and reduced investment and operating costs for companies.
