Manufacturing Process Development for Bioengineered FVIII

描述(申请人提供)：重组凝血因子VIII的制造是一项复杂的、劳动和资本密集型的工作。在目前市场上销售的重组蛋白中，凝血因子VIII的生产效率最低，是迄今为止单位质量基础上最昂贵的，药价为每克10,000,000美元。目前应用的目标是开发一种能够提高因子生物制品的生产量和药价的产品技术和制造工艺。Expression Treeutics已经开发了两项技术，一种是生物工程第八因子转基因，其表达水平是标准人类第八因子的100倍；另一种是新的幼年仓鼠肾脏(BHK)细胞系，名为BHK-MS，可以在悬浮生物反应器条件下，在无血清和血液产品的培养液中以高密度无限培养和扩增。在目前的申请中，我们建议优化发酵和提纯工艺，并进行扩大的生产运行，这将证明制造工艺的概念证明，并产生大量符合后续临床前安全性、有效性和稳定性测试要求的原料药，以便在SBIR机制的第二阶段提交研究性新药申请。

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.