Real-Time Adaptive Inline Acidification Enhances Continuous pH Control for Viral Inactivation

Abstract

Existing low pH viral inactivation methods for continuous downstream processing of biologics typically rely on predictive models to estimate the necessary pH adjustments. However, these methods are of limited use during the process development stage due to the dynamic nature of capture chromatography, where batch variations can alter the eluted protein titer. This study introduces an inline viral inactivation system (IVIS) that utilizes real-time adaptive control and inline sensor readings to precisely regulate the pH manipulation for inline acidification and continuous viral inactivation. The IVIS, which includes a coiled flow inversion reactor (CFIR), is integrated with a multicolumn capture chromatography system to demonstrate a fully continuous process from protein capture chromatography to inline pH manipulation. The system achieved precise inline pH manipulation within ±0.15 and a narrow residence time distribution of 13.5 min with a relative width of 0.7. The introduction of real-time inline pH manipulation with the IVIS signifies a notable advancement in managing critical process parameters (CPPs) and ensuring consistent product quality across varied production environments for continuous downstream bioprocessing.