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

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.