Manufacturability Indices for High-Concentration Monoclonal Antibody Formulations

Abstract

Abstract The need for high-concentration formulations for subcutaneous delivery of therapeutic monoclonal antibodies (mAbs) can present manufacturability challenges for the final ultrafiltration/diafiltration (UF/DF) step. Viscosity levels and the propensity to aggregate are key considerations for high-concentration formulations. This work presents a novel framework for deriving a set of manufacturability indices related to viscosity and thermostability to rank high-concentration mAb formulation conditions in terms of their ease of manufacture. This is illustrated by analysing published high-throughput biophysical screening data that explores the influence of different formulation conditions (pH, ions and excipients) on the solution viscosity and product thermostability. A decision tree classification method, CART (Classification and Regression Tree) is used to identify the critical formulation conditions that influence the viscosity and thermostability. Polynomial regression techniques combined with the impact of protein concentration-time profiles and flux decay behaviour during UF/DF are used to transform the experimental data into a set of stress maps which show viscosity and thermostability as functions of the formulation conditions and time profiles during UF/DF. Manufacturability indices are derived from analysis of the stress maps and the process conditions experienced in the final UF/DF step. The indices are used to identify the optimal formulation conditions that minimize the potential for both viscosity and aggregation issues during UF/DF.