SBIR Phase I: Novel Compact Cell Settler for Perfusion Cultures of Microbial Cells

SBIR 第一阶段：用于微生物细胞灌注培养的新型紧凑型细胞沉降器

• 批准号: 1519654
• 负责人: Dhinakar Kompala
• 金额: $ 15万
• 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: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1519654&HistoricalAwards=false
• 关键词: SBIR; Phase; Novel; Compact; Cell

The broader impact/commercial potential of this Small Business Innovative Research (SBIR) project is to reduce the manufacturing cost of therapeutic biologics using more efficient production technologies. This will be accomplished by developing novel cell retention technologies for increasing cell concentration and productivity in continuous perfusion bioreactor cultures of recombinant microbial and mammalian cells. Based on the inclined settler technology already proven in large scale mammalian cell cultures, compact and more efficiently scalable cell or particle settlers are being developed to expand its applications to other industrial areas, such as microbial yeast secretory production systems, heterogeneous catalysis, municipal water clarification, wastewater treatment, etc. Following thorough characterization of a novel compact cell settler device for recombinant microbial yeast cells during this Phase I grant, it will be launched commercially for large-scale manufacturing of biologics from recombinant microbial and mammalian cells. As biological manufacturing technology matures from early fed-batch cultures to continuous manufacturing due to increasing market size and more consistent product quality-by-design considerations, these novel compact settlers will enable more efficient production of many therapeutic biologics in large scale high cell density perfusion bioreactors and contribute to a significant reduction in cost of their manufacturing from recombinant mammalian and microbial cell cultures.This SBIR Phase I project proposes to develop a novel method of scaling up the proven inclined settler technology, which has been scaled up rectilinearly in the past as lamellar settlers. While the lamellar settlers have been used successfully to manufacture therapeutic biologics secreted by recombinant mammalian cells in high cell density perfusion bioreactors, they have not yet been adapted for microbial cell cultures. The research objectives of this proposal are to develop more compact and efficient settlers for recombinant yeast cells and characterize the capability of these settlers to remove dead cells selectively in the harvest and recycle the live and productive cells back to the bioreactors. Initial results from the first prototype demonstrate selective removal of the smaller yeast cells, while most of the larger cells are concentrated and recycled back to the bioreactor. Lower cell concentrations and smaller size distributions of the yeast cells leaving in the harvest stream from these compact settlers compared to the those in bioreactors will be measured in steady state continuous cultures and dramatically increasing cell density in the perfusion bioreactor due to the complete recycle of live and productive cells to bioreactor will be characterized for different perfusion harvest rates.

这项小型企业创新研究（SBIR）项目的更广泛的影响/商业潜力是使用更有效的生产技术降低治疗生物制剂的制造成本。这将通过开发新型细胞保留技术来提高重组微生物和哺乳动物细胞的连续灌注生物反应培养物中的细胞浓度和生产力。 基于已经在大规模的哺乳动物细胞培养物中证明的倾斜定居者技术，紧凑型和更有效的可扩展细胞或粒子定居者正在开发以将其应用扩展到其他工业领域，例如微生物酵母分泌生产系统，异质性催化，非均匀催化，城市水澄清，彻底的隔离式型号的隔离型型隔离型型机器人，以彻底的型号的型号的临床，以彻底的型号的型号，以备用新颖的型号的型号，以便在彻底的型号的隔离设备中，以备用新颖的型号的设备。将在商业上推出，用于从重组微生物和哺乳动物细胞中大规模生产生物制剂。 As biological manufacturing technology matures from early fed-batch cultures to continuous manufacturing due to increasing market size and more consistent product quality-by-design considerations, these novel compact settlers will enable more efficient production of many therapeutic biologics in large scale high cell density perfusion bioreactors and contribute to a significant reduction in cost of their manufacturing from recombinant mammalian and microbial cell cultures.This SBIR Phase I project proposes为了开发一种新颖的方法来扩展验证的倾斜定居技术，该技术在过去曾以层状定居者的身份进行直接扩展。 尽管层状定居者已成功地用于生产高细胞密度灌注生物反应器中重组哺乳动物细胞分泌的治疗生物制剂，但它们尚未适用于微生物细胞培养物。该提案的研究目标是为重组酵母细胞开发更紧凑，更有效的定居者，并表征这些定居者在收获中选择性去除死细胞的能力，并将活细胞和生产性细胞回收回生物反应器。第一个原型的初始结果表明，选择性去除较小的酵母菌细胞，而大多数较大的细胞浓缩并回收回生物反应器。 与生物反应器中的酵母细胞的较低细胞浓度和较小的酵母细胞分布相比，这些紧凑型定居者的收获流中，将在稳态连续培养物中测量，并在灌注生物反应器中急剧增加细胞密度，这是由于活性细胞的完全回收和生产性细胞的全部回收率，其对生物反应器的反应率将以不同的灌注速率来表征不同的灌注率。