SBIR Phase I: Determine Performance Characteristics During Cultivation of Living Organisms in a Novel Single-Use Horizontal Modular and Pressurizable Microbial Fermentor

这一小型企业创新研究(SBIR)第一阶段项目的更广泛影响/商业潜力是显著提高生产生物药物的能力。生物制药行业正在努力培育特定的基因工程微生物细胞，这些细胞将生产疫苗、可注射蛋白质或其他产品。迫切需要培养独特的微生物，从小规模的批次开始，迅速扩大到具有商业可行性的批次大小，并提高产品产量。加压卧式发酵罐支持行业向微生物发酵的一次性袋子发展，因为一次性使用的发酵罐降低了运营成本，并减少了可能导致整批损失的交叉污染。这种可扩展的一次性发酵罐应该可以实现更高的产量，并使制药商能够以更具成本效益的方式生产千克量的蛋白质。这种创新的、灵活的、可加压的水平模块化设计将缩短疫苗、治疗性蛋白质或其他微生物制造产品的上市时间，无论是小型还是大型生物制品生产商，以降低运营成本和挽救生命，对抗全球传染病和其他疾病。拟议的项目将促进对微生物细胞如何在水平、加压一次性袋式发酵罐中培养的了解。所获得的知识将使用模块化设计来验证微生物生产，这种设计提供了调整系统容量的灵活性，而不需要重大的设施修改或成本。最初的原型在快速混合时间、适当的可扩展功率输入和出色的氧气传质方面显示出非常令人鼓舞的结果。这里要改进的设计有可能通过影响产生高细胞密度和降低微生物制造成本的能力来改变生物制品制造业。研究目标是展示：一种完全开发的设计，具有高细胞密度发酵所需的散热能力(目前使用现有的工业立式一次性发酵罐设计无法实现)；一种能够实现高密度培养所需氧气传输速率的加压袋式系统；以及一种允许快速扩展到3000升的可扩展格式。将使用计算流体力学分析和培养条件的实验室测试来建造和评估一个功能齐全的测试发酵罐。实验工作将评估高搅动叶轮、高气体流量、气体喷射器设计和系统结构元素。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase I project is to significantly improve the ability to generate biological pharmaceuticals. The biopharmaceutical industry is working to grow specific genetically engineered microbial cells that will produce a vaccine, injectable protein, or other products. There is a pressing need to culture unique microbes, starting from small scale batches, that rapidly scale to commercially viable batch sizes with high product output. A pressurized horizontal fermentor supports the industry’s drive towards single-use bags for microbial fermentation, as single-use fermentors lower operating costs and reduce cross-contamination that can result in loss of an entire batch. This scalable, single-use fermentor should achieve higher yields and allow drug producers to produce kilogram quantities of protein in a more cost-effective manner. This innovative, flexible, pressurizable, horizontal modular design will decrease time-to-market for vaccines, therapeutic proteins or other microbially manufactured products, from both small and large biologics producers, to combat global infectious, and other diseases, at reduced operating costs, saving lives.The proposed project will advance the knowledge of how microbial cells are cultivated in a horizontal, pressurized single-use bag fermentor. The knowledge gained will validate microbial production using a modular design that provides flexibility to adjust the capacity of the system, without significant facility modifications or cost. An initial prototype demonstrated highly encouraging results regarding fast mixing times, proper scalable power input, and excellent oxygen mass transfer. The design to be refined here has the potential to transform the biologics manufacturing industry by impacting the ability to generate high cell densities and reduce the cost of microbial manufacturing. Research objectives are to demonstrate: a fully developed design with the heat removal capacity required of high cell density fermentation (currently unachievable using existing industry vertical single-use fermentor designs); a pressurized bag system that can achieve oxygen transfer rates needed for high density cultures; and a scalable format that allows for rapid scaling to 3000 liters. A fully functioning test fermentor will be built and evaluated using both computational fluid dynamics analysis and laboratory testing of culture conditions. Experimental work will evaluate high agitation impellers, high gas flows, gas sparger designs, and system structural elements.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.