Use of solvent/detergent virus inactivation in place of low-pH virus inactivation during monoclonal antibody manufacture is often adopted when early screening experiments show signs of aggregation at low pH.  These early screening experiments often expose the antibody to lower pH levels and longer hold times than are required for validating viral clearance. Additionally, when aggregation is observed, it is difficult to assess the process risk or elucidate the cause of the aggregation, as product quality data is typically only collected at the beginning and end of the experiment.<br/><br/>This case study shows that a small number of experiments can be employed to understand the kinetics of aggregation, determine the pH and hold times for large-scale, as well as identify scale-up risks to product quality. This study design provides critical scientific understanding of the process and was successfully used for a monoclonal particularly sensitive to aggregation to scale-up a low pH virus inactivation step, where traditional approaches would have led to the use of solvent/detergent virus inactivation. Further, the Bourne protocol, an experimental protocol employed routinely during small-molecule process development,  was implemented to investigate the impact of micro-, meso-, and macro- scales of mixing on aggregation. The results from these studies demonstrate the complexity associated with achieving a scale-down model to investigate the effects of specific mixing parameters on protein aggregation.

Developing a low pH virus inactivation step for a monoclonal antibody sensitive to aggregation: The importance of sound scientific understanding

ACS Spring 2022

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