Design of a process development workflow and control strategy for single-pass tangential flow filtration and implementation for integrated and continuous biomanufacturing

Integrated and continuous biomanufacturing (ICB) offers several advantages compared to traditional batch methods, prompting the development of novel technologies and infrastructure for the implementation of ICB in the biopharmaceutical sector. However, most of the advancements have been in the early stages of the purification process, with relatively fewer advancements in the final filtration steps. This work focuses on some of the last major unit operations of a traditional bioprocess: ultrafiltration and diafiltration. Our proposed technological solution involves robust control algorithms for (1) precisely maintaining consistent protein concentration in single-pass ultrafiltration (SP-UF) and (2) achieving the targeted buffer exchange in single-pass diafiltration (SP-DF). Specifically, we adopted an integrated experimental, modeling, and simulation approach to develop a robust process understanding of SP-UF/SP-DF operations via semi-empirical maximum permeate flux models. These models were employed in the optimization of key design variables such as the filter area and the development of control strategies. Finally, we demonstrate the applicability of our proposed solution by operating a single-pass tangential flow filtration (SP-TFF) system in an integrated and continuous manner for six days. We believe that this work is instrumental for the successful realization of SP-UF/SP-DF operations in both batch and ICB processes. [Display omitted] •Systematic workflow for the design and development of SP-TFF operations•Semi-empirical models developed for maximum permeate flux as a function of feed parameters•Models used to estimate optimal filter sizing within operating space•Robust control strategies developed for concentrating in SP-UF, and maintaining concentration and buffer exchange in SP-DF•Demonstration of integrated and continuous SP-TFF operations with robust process control at a commercial scale for 6 days