Integration of the upstream and downstream processes and conversion to continuous manufacturing allows increasing productivity, decreasing equipment size, and reducing the manufacturing cost, at the same time as the product quality increases due to a steadier operation and a lower residence time in the bioreactor. It is important to have an integrated and continuous process from the very first stages of the process development, not only due to the easier and safer scalability of the process, but also because the small scale production of drug candidates is currently very labor demanding, with a lot of manual and inefficient steps, which an integrated and automated approach could address. Some research on integrated and continuous biomanufacturing has been reported, showing the advantages of integrating a biopharmaceutical process and converting it to continuous mode. But the scale at which these processes are implemented (with bioreactor volumes from 1.5 L to 12 L) are not the most suitable for the earliest stages of the process development, like the discovery and pre-clinical tests, and much equipment is required to perform all the steps of the process. In this work, an end-to-end mAb platform at small scale was implemented in a compact design with minimal equipment required: a 200 mL ATF perfusion bioreactor, and a single chromatography system for all downstream steps. The upstream and the downstream were integrated and run continuously with a periodical process using a twin-column capture where a column is loaded while the rest of the downstream process is carried out. In addition, to avoid any manual interaction, the process was automated and controlled from an external software called Orbit, developed at the department of Chemical Engineering at Lund University (Lund, Sweden), and several control strategies were applied to be able to deal with variable perfusion rates and concentrations from the bioreactor. The different steps in the purification chain were integrated based on the concept Integrated Column Sequence (ICS), where all steps are implemented in a single chromatography system and the eluate of a column gets directly loaded into the next one. A productivity up to 43 mg ml-1 day-1, based on the capture column volume, and a total recovery yield up to 60%, were achieved.

Small scale end-to-end mAb platform with a continuous, integrated and compact process

2019 Spring National Meeting

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