SBIR Phase I: Novel compact cell settlers for high cell density perfusion cultures of mammalian cells

SBIR 第一期：用于哺乳动物细胞高密度灌注培养的新型紧凑型细胞定居器

• 批准号: 1648370
• 负责人: Dhinakar Kompala
• 金额: $ 22.5万
• 依托单位: Sudhin Biopharma Company
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-01 至 2017-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1648370&HistoricalAwards=false
• 关键词: SBIR; Phase; Novel; compact; cell

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.

该小企业创新研究 (SBIR) 项目的更广泛影响/商业潜力是开发一种新型紧凑型细胞沉降器，它可以选择性地从细胞培养液中去除死细胞和细胞碎片，并将所有活细胞和生产细胞完全回收回连续灌注生物反应器。 由于这种无膜装置不像竞争的基于膜的细胞保留装置那样容易堵塞，因此单个灌注生物反应器培养不需要在3或4周后提前终止（由于死细胞和细胞碎片的积累导致产品质量下降和当前装置中的膜堵塞）。 与其他细胞保留装置相比，新型紧凑型细胞沉降器的尺寸和占地面积较小，增加了更多生物制造公司更广泛采用该技术的可能性，并降低了治疗性生物制剂的制造成本。 由于预计即将结束专利保护的成功产品将面临生物仿制药的价格竞争，因此使用先进的细胞培养技术降低其制造成本将使更广泛的患者群体能够更负担得起这些药物。该 SBIR 第一阶段项目建议开发一种新型紧凑且更有效的方法来扩大倾斜沉降器技术，该技术作为直线层状沉降器扩大规模效率低下。 虽然一些生物制造商已成功采用突出的层状沉降器，以在高细胞密度灌注生物反应器中从重组哺乳动物细胞制造治疗性生物制品，但预计所提出的新型紧凑型细胞沉降器将实现从高细胞密度灌注生物反应器中分离死细胞和细胞碎片所需的效果，与原始倾斜层状沉降器相比，占地面积要小得多 设计。该研究的三个关键目标是：1）证明新型紧凑型细胞沉降器可以无限期地实现并维持高活细胞密度，2）确定两种不同尺寸的较小沉降器无限期地保持高活细胞密度的最大灌注速率，3）开发新的缩放法则，可以预测较大商业规模生物反应器沉降器的尺寸要求。 这些目标将通过系统的实验计划来实现，以研究两种不同尺寸和两种不同哺乳动物细胞类型的新型定居者的性能。