The broader impact/commercial potential of this Small Business Innovation Research (SBIR) project is the development of a novel compact cell settler that can selectively remove dead cells and cell debris from the cell culture broth and completely recycle all the live and productive cells back to the continuous perfusion bioreactor. As this membrane-free device is not prone to clogging like the competing membrane-based cell retention devices, a single perfusion bioreactor culture does not need to be terminated prematurely after 3 or 4 weeks (due to accumulation of dead cells and cell debris resulting in reduced product quality and clogged membranes in current devices). The novel compact cell settler has a small size and footprint compared with other cell retention devices, and increases the likelihood of wider adaptation of the technology by a larger number of biomanufacturing companies and reduces the cost of manufacture of therapeutic biologics. As biosimilar price competition is expected for successful products that are coming off patent protection, reducing the cost of their manufacture using superior cell culture techniques will enable increased affordability of these drugs to a wider patient population. This SBIR Phase I project proposes to develop a novel compact and more efficient method of scaling up inclined settler technology, which has been scaled up inefficiently as rectilinear lamellar settlers. While a few biological manufacturers have successfully adapted the protruding lamellar settlers to manufacture therapeutic biologics from recombinant mammalian cells in high cell density perfusion bioreactors, the proposed novel compact cell settler is predicted to achieve the required separation of dead cells and cell debris from a high cell density perfusion bioreactor with a much smaller footprint compared to the original inclined lamellar settler design. Three key objectives for the research are to 1) demonstrate that the novel compact cell settler can achieve and maintain high viable cell densities indefinitely, 2) determine the maximum perfusion rate that maintain the high viable cell density indefinitely for smaller settlers of two different sizes, and 3) develop new scaling laws that can predict the size requirements of the settlers for larger commercial-scale bioreactors. These objectives will be accomplished by a systematic experimental plan to investigate the performance of the novel settlers at two different sizes and for two different mammalian cell types.
