Complete or periodic continuity in continuous manufacturing platforms for production of monoclonal antibodies?

BACKGROUND: Monoclonal antibodies (mAbs) currently dominate the biotherapeutic market. This has resulted in significant efforts towards the development of a continuous integrated platform for the manufacturing of mAbs. MAIN METHODS AND MAJOR RESULTS: In this study, a continuous mAb platform has been developed consisting of an Acoustic Wave Separator, a Cadence BioSMB PD system, a customized coiled flow reactor, a modular single-pass TFF kit, an in-line diafiltration module, and a continuous dead-end filtration skid. A three-step chromatographic purification was performed in the platform consisting of Protein A capture chromatography followed by an anion exchange membrane directly coupled to a cation exchange chromatography. Two operational case studies have been executed on the platform, namely complete continuous ("CC") and periodic continuous ("PC") modes of operation. The CC mode was designed to ensure that each unit operation had completely continuous inflow and outflow by increasing the number of columns, filtration modules and tanks, while the PC mode operated in periodic pulses with scheduled flow and hold steps. Both modes were designed to handle the same flow rate and titers from the upstream bioreactor or fed-batch harvest tank, and were compared in terms of productivity and operational complexity. Both modes offer viable options for continuous processing of mAbs and result in achievement of target critical quality attribute profiles of the final drug product over 24 h of operation. CONCLUSIONS AND IMPLICATIONS: It was found that the CC mode was superior in terms of specific productivity (20-50% higher) and consumable utilization (20% lower resin utilization), while the PC mode was operationally simpler and had lower facility costs due to significant reductions in the number of auxiliary equipment (pumps, columns, tanks, and valves). The work successfully highlighted the pros and cons of both approaches, and demonstrates that while several groups have amply shown the superiority of continuous processing over batch mode, there are intermediate variants which may be optimal in a given situation.