Production of a high purity therapeutic protein drug substance is critical since aggregates can change protein activity and create potentially undesirable immunological responses in patients. Our protein of interest contained a mixture of acidic and basic charged aggregate species, making it difficult to clear by the traditional bind and elute cation exchange chromatographic method at acceptable loading and yield. A combination of high-throughput screening (HTS) and design of experiment (DoE) methodlogies were utilized to explore design spaces based on the following chromatographic parameters: pH, conductivity, protein loading, and buffer capacity to clear basic and acidic aggregates. Mathematical modeling was employed to predict optimal process operating conditions to obtain a product containing both high monomer purity and step yield. This led to the development of a hydrophobic interaction-based chromatography process, which resulted in over 5-fold increase in productivity and was scaled 1700x to generate multi-kilogram quantities of at least 99.5% monomeric-pure drug substance for clinical use.

Statistical approach to rapidly develop a high-throughput purification process to resolve heterogeneous aggregates

243rd National Meeting (2012)

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