The Key Laboratory of Carbohydrate Chemistry and Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, China; National Engineering Laboratory for Cereal Fermentation Technology, Jiangnan University, Wuxi 214122, China.
The Key Laboratory of Industrial Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, Wuxi 214122, China; Jiangsu Provincial Research Center for Bioactive Product Processing Technology, Jiangnan University, Wuxi 214122, China.
J Pharm Sci. 2019 Dec;108(12):3785-3791. doi: 10.1016/j.xphs.2019.09.008. Epub 2019 Sep 12.
Owing to the biological activity of the vaccine, the complicated production process, sterility, and uniformity of the product, the producing process of the vaccine is complicated and the product quality hard to control. In recent years, with the development of basic science such as cell biology, molecular biology, and metabolic engineering, bioprocess engineering research has developed rapidly. Therefore, U.S. Food and Drug Administration and European Medicines Agency conduct stringent control over the development of biomedical process engineering and product quality. This case study describes an example of Quality by Design-driven process development for manufacturing a human vaccine produced with Vero cells. Cell density in harvest fermentation broth and antigenic titer were chosen as 2 critical quality attributes. The study through 3 rounds design of experiment revealed that HO and cell boost 4 had a significant effect on antigenic titer. Ethanolamine had significant improvement in the final concentration of cells. Through the Monte Carlo simulation, the design spaces and control space of process parameters were determined. A successful validation in a bioreactor was executed to verify the results of a spinner flask. Our investigation presents a successful case of Quality by Design principle, which encourages other researchers to combine the methodology into other biopharmaceutical manufacturing process.
由于疫苗的生物活性、复杂的生产工艺、产品的无菌性和均一性，疫苗的生产过程复杂，产品质量难以控制。近年来，随着细胞生物学、分子生物学和代谢工程等基础科学的发展，生物工艺工程研究迅速发展。因此，美国食品和药物管理局和欧洲药品管理局对生物医学工艺工程的发展和产品质量进行了严格的控制。本案例研究描述了一个使用 Vero 细胞生产人用疫苗的基于质量源于设计的工艺开发示例。收获发酵液中的细胞密度和抗原效价被选为 2 个关键质量属性。通过三轮实验设计，研究表明 HO 和细胞增强 4 对抗原效价有显著影响。乙醇胺对最终细胞浓度有显著改善。通过蒙特卡罗模拟，确定了工艺参数的设计空间和控制空间。在生物反应器中成功进行了验证实验，以验证摇瓶实验的结果。我们的研究展示了质量源于设计原则的成功案例，鼓励其他研究人员将该方法结合到其他生物制药生产工艺中。
