Multi‐criteria manufacturability indices for ranking high‐concentration monoclonal antibody formulations

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 novel frameworks 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 analyzing 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. In this work, three different multi‐criteria data analysis frameworks were investigated to derive manufacturability indices from analysis of the stress maps and the process conditions experienced in the final UF/DF step. Polynomial regression techniques were used to transform the experimental data into a set of stress maps that show viscosity and thermostability as functions of the formulation conditions. A mathematical filtrate flux model was used to capture the time profiles of protein concentration and flux decay behavior during UF/DF. Multi‐criteria decision‐making analysis was used to identify the optimal formulation conditions that minimize the potential for both viscosity and aggregation issues during UF/DF. Biotechnol. Bioeng. 2017;114: 2043–2056. © 2017 The Authors. Biotechnology and Bioengineering Published by Wiley Perodicals, Inc.

Advancing Therapeutic Protein Discovery and Development through Comprehensive Computational and Biophysical Characterization

“…drug-like properties. [8][9][10] Contrary to small molecule drug discovery where some developability rules are widely accepted (e.g. the Lipinski rule of five), 11 guiding principles for selecting proteins with drug-like properties are not yet well established.…”

Understanding the Role of Preferential Exclusion of Sugars and Polyols from Native State IgG1 Monoclonal Antibodies and its Effect on Aggregation and Reversible Self-Association

“…Similarly, reversible self-association of proteins may lead to undesirable solution properties such as liquid-liquid phase separation, opalescence and viscosity which may affect potency or reduce patient compliance (4). Aggregation and reversible self-association of antibodies also complicates manufacturing workstreams for processing steps like ultrafiltration/diafiltration (UF/DF) (5). These instabilities are worsened with the high concentration formulation requirement for subcutaneous route of administration (6).…”

Rational optimization of a monoclonal antibody improves the aggregation propensity and enhances the CMC properties along the entire pharmaceutical process chain

“…45 Notably, the viscosity of a concentrated protein solution represents a major challenge in attaining feasible manufacturing processes such as UF/DF, sterile filtration, as well as during fill and finish, which necessitates a closer link between formulation studies and manufacturing. 61,62 Additionally, current trends lean toward HCLFs to enable subcutaneous and intravitreal administration via thin needles that require low viscosity DPs. 45,61 Our bioinformatic approach guided the modification of another difficult-to-develop mAb, and successfully reduced the viscosity of the HCLF (supplementary Figure S9).…”