Mechanistic model of pH and excipient concentration during ultrafiltration and diafiltration processes of therapeutic antibodies.

Abstract

Ultrafiltration and diafiltration (UF/DF) unit operations are widely used for the manufacture of therapeutic antibodies to control drug substance protein concentration, pH, and excipient properties. During UF/DF, molecular interactions and volume exclusion effects often lead to substantial differences in pH and excipient concentrations between the diafiltration buffer and final UF/DF pool. These differences complicate the design process beyond simply specifying a buffer with the desired drug substance pH and excipient conditions. This article describes a UF/DF process model which dynamically and accurately simulates UF/DF retentate pool pH and excipient conditions throughout the UF/DF process. This multiscale model accounts for microscopic descriptions of ion-protein charge interactions using the Poisson-Boltzmann equation as well as macroscopic descriptions of volume exclusion and mass transfer. Model predictions of the final UF/DF pool properties were experimentally verified through comparisons to design of experiment (DoE) data from four monoclonal antibody (mAb) processes, each with differing formulations and UF/DF operating conditions. Additionally, model simulations of the retentate pool properties throughout the UF/DF process were verified for two mAb processes through comparisons to experimental data collected at intermediate process points. Model results were qualified, using statistical equivalence tests, against the outputs from large-scale GMP runs which confirmed that the model accurately captures large-scale process performance. Finally, the model was applied toward the simulation of process scenarios beyond those examined experimentally. These in-silico experiments demonstrate the model's capability as a tool for augmented process design and it is potential to reduce the extent of UF/DF laboratory experiments.