Quality by Design Driven Process Development of severe fever with thrombocytopenia syndrome Vaccine

Abstract Due 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, FDA and EMA conduct stringent control over the development of biomedical process engineering and product quality. This case study describes an example of QbD driven process development for manufacturing a human vaccine produced with Vero cells. Cell density in harvest fermentation broth and antigenic titer were chosen as two critical quality attributes (CQAs). The study through three rounds DoE experiment revealed that H2O2 and cell boost 4 (CB4) 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 bioreactor was executed to verify the results of spinner flask. Our investigation presents a successful case of QbD principle, which encourages other researchers to combine the methodology into other biopharmaceutical manufacturing process.