Fully integrated downstream process to enable next‐generation manufacturing

Abstract

Next-generation manufacturing (NGM) has evolved over the past decade to a point where large biopharmaceutical organizations are making large investments in the technology and considering implementation in clinical and commercial processes.There are many well-considered reasons to implement NGM. For the most part, organizations will not fund NGM unless the implementation benefits the funding organization by providing reduced costs, reduced time, or additional needed capabilities. Productivity improvements gained from continuous purification are shown in this work, which used a new system that fully integrates and automates several downstream unit operations of a biopharmaceutical process to provide flexibility and easy implementation of NGM. The equipment and automation needed to support NGM can be complicated and expensive. Biopharmaceutical Process Development considered two options as follows: (1) design its own NGM system or (2) buy a prebuilt system. PAK BioSolutions offers a turn-key automated and integrated system that can operate up to four continuous purification stages simultaneously, while maintaining a small footprint in the manufacturing plant. The system provides significant cost benefits (~10× lower) compared with the alternative-integration of many different pieces of equipment through a Distributed Control System that would require significant engineering time for design, automation, and integration. Integrated and Continuous Biomanufacturing can lead to significant reductions in facility size, reduced manufacturing costs, and enhanced product quality when compared with the traditional batch mode of operation. The system uses new automation strategies that robustly link unit operations. We present the optimized process fit, sterility and bioburden control strategy, and automation features (such as pH feedback control and in-line detergent addition), which enabled continuous operation of a 14-day end-to-end monoclonal antibody purification process at the clinical manufacturing scale.

Reviewing the process intensification landscape through the introduction of a novel, multitiered classification for downstream processing

“…Examples include process intensification of the capture step by multicolumn chromatography (Coolbaugh et al, 2021; Kateja et al, 2021; Shi et al, 2021), the inclusion of a multicolumn chromatography capture step followed by connected polishing steps with ion exchange membrane adsorbers (Gjoka et al, 2017), continuous viral inactivation (Gillespie et al, 2019; Martins et al, 2020) and single‐pass TFF (Clutterbuck et al, 2017; Ding et al, 2022; Elich et al, 2019). Processes have more recently developed even further towards that of a fully integrated continuous downstream approach (Coolbaugh et al, 2021; Ramos et al, 2023). While these recent processes are not fully optimized, they do provide an excellent framework and proof of concept that has brought us ever closer to the end goal of true integrated continuous biomanufacturing.…”

Current challenges and recent advances on the path towards continuous biomanufacturing

“…This strategy enabled achieving a constant concentration downstream of the capture step, regardless of the variability in titer during the run. 176 Karst et al demonstrated a feedback control system that modulates the capture step operating parameters of a countercurrent two-column capture based on at-line HPLC titer measurements. 177 Another key factor to consider when integrating upstream and downstream is the amount and composition of impurities generated during the upstream process.…”