The Low-pH treatment for virus inactivation unit operation can exhibit a potential risk for in-process product aggregation during downstream processing for a monoclonal antibody.  In this work, a full-factorial experimental design was executed using an automated and well-characterized mixing system to investigate the effect of four process parameters: low pH end point, low pH hold time, low pH titration duration, and neutralization titration duration. The instrument used is a commercially-available automated small-scale workstation, which includes a reactor, dosing units, pH and temperature probes. It enables a well-controlled and automated batch titration as compared to traditional manual pH adjustments carried out in a vessel, significantly streamlining the execution and ensuring the reproducibility of process characterization studies. The automation allows comprehensive data capture that greatly improves our ability to gain process understanding, including data analysis. Factors such as temperature, agitation, pH electrode calibration, which can cause drift in pH measurement were identified and considered for method optimization.  As a result, low end pH point could be controlled within ± 0.05 of target pH, low pH hold time could be accurately defined, low pH titration duration and neutralization titration duration could also be well controlled within ± 10 % of target value. A small-scale model was qualified which can represent clinical trial and commercial manufacturing scale in terms of product quality attributes. The process characterization experimental design consisted of a two level four factor design with three center points providing the desired power to investigate any possible parameter interactions. Statistical analysis of these experiments shows that the two factors – low pH end point and low pH hold time, as well as the interaction of these factors, had a significant effect on key product quality attributes. The remaining two factors – low pH titration duration and neutralization titration duration had no significant effect on any of the product or process attributes.

Multivariate low pH treatment process characterization studies for virus inactivation using an automated mixing platform

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.