The Low pH treatment for virus inactivation unit operation presents a potential risk for in-process product aggregation during downstream processing for a monoclonal antibody. This presentation discusses a full-factorial experimental design to investigate the effect of four process parameters:
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.
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With over years of experience in downstream process development, CMC, and process scale up, Hiren Ardeshna is a Scientific Leader at GlaxoSmithKline. Hiren leads a team of development scientists responsible for scale-up and technology transfer for various GSK assets to clinical and commercial manufacturing sites, including the required process development and characterizations support. Hiren earned a Masters in Chemical Engineering from the University of Massachusetts with focus on biotechnology process development and Harvest/clarification, normal flow filtration, and process economic evaluations.