Shift to high-intensity, low-volume perfusion cell culture enabling a continuous, integrated bioprocess.

In order to address the increasing demand for biologics, cell culture intensification using perfusion offers significantly higher productivities while also reducing manufacturing costs, especially when part of an integrated, continuous bioprocess. An initial study of a long-duration perfusion process using a cell-bleed to maintain a target cell density observed a 2.1-fold higher cell-specific productivity and a gradual decline in the culture growth rate when perfused at an overall lower rate. Subsequent studies sought an alternative process that largely reduced the overall volume of media needed by first perfusing at a high cell-specific perfusion rate (CSPR) to support a high cell density followed by continued perfusion at a low CSPR to promote a more productive stationary phase. This high intensity, low-volume perfusion (HILVOP) process achieved cumulative volumetric productivities of 1.5-1.6 g/L/day with two CHO cell lines. When compared to each cell line's respective commercial-ready, fed-batch process, a 3.1-3.8-fold productivity increase was demonstrated while yielding similar product quality. Furthermore, the higher productivity achieved with HILVOP used 6.6-12.3-fold less media than a similarly productive long-duration process. © 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:1472-1481, 2018.