Manufacturing Process Development for Bioengineered FVIII

描述（由申请人提供）：重组凝血因子VIII的生产是一项复杂的劳动和资本密集型工作。在目前上市的重组蛋白中，凝血因子VIII的生产效率最低，并且是迄今为止单位质量基础上最贵的，每克药价为1000万美元。目前申请的目标是开发一种产品技术和制造工艺，以提高因子VIII生物制剂的产量和药品价格。Expression Therapeutics已经开发了两种技术，一种是生物工程因子VIII转基因，其表达量比标准人因子VIII高100倍，另一种是一种新的幼鼠肾源性（BHK）细胞系，称为BHK- ms，可以在悬浮生物反应器条件下在血清和无血液制品的培养基中以高密度无限期培养和扩增。在目前的申请中，我们建议优化发酵和纯化工艺，并进行规模化生产，以证明生产工艺的概念，并产生大量原料药，用于后续临床前安全性、有效性和稳定性测试，这些测试是在SBIR机制的第二阶段提交新药研究申请所必需的。

DESCRIPTION (provided by applicant): The manufacturing of recombinant coagulation factor VIII is a complex, labor and capital intensive endeavor. Of the recombinant proteins currently marketed, coagulation factor VIII is manufactured with the lowest efficiency and is by far the most expensive on a per unit mass basis with a pharmacy price of $10,000,000 per gram. The goal of the current application is to develop a product technology and a manufacturing process that can improve the production volume and pharmacy price of factor VIII biologics. Expression Therapeutics has developed two technologies, a bioengineered factor VIII transgene that demonstrates 100-fold greater expression than standard human factor VIII, and a new baby hamster kidney-derived (BHK) cell line, designated BHK-MS, that can be cultured and expanded indefinitely and at high density in serum and blood product-free medium under suspension bioreactor conditions. In the current application, we propose to optimize the fermentation and purification processes and conduct a scaled up production run that will demonstrate proof of concept of the manufacturing process and generate a substantial supply of bulk drug substance qualified for subsequent preclinical safety, efficacy and stability testing necessary to submit an Investigational New Drug application during phase II of the SBIR mechanism.