Abstract
ABSTRACTThe 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.
Highlights
The dominance of monoclonal antibodies in biopharmaceutical pipelines combined with their success in treating chronic conditions has triggered a shift in their final dosage form and delivery mode to high-concentration formulations
This paper presents a novel concept of manufacturability indices that can be used as predictors in early stage development to rank high-concentration monoclonal antibodies (mAbs) formulation conditions in terms of their ease of manufacture and formulation with respect to minimizing viscosity and aggregation issues during the final UF/DF step
The manufacturability index is a set of numbers which can indicate the ease of manufacture during the final UF/DF step for each formulation candidate
Summary
The dominance of monoclonal antibodies (mAbs) in biopharmaceutical pipelines combined with their success in treating chronic conditions has triggered a shift in their final dosage form and delivery mode to high-concentration formulations. Typical formulation studies explore the responses of the final product to different formulation conditions but do not typically translate these to predicting the ease of manufacture. This becomes important to understand especially with high-concentration formulations that have the potential to pose manufacturing challenges. This paper proposes a novel methodology to predict manufacturability in the final ultrafiltration/diafiltration (UF/DF) step of a mAb process based on biophysical data derived from formulation studies. MAbs have been formulated at low concentrations (e.g., 20 g/L) for intravenous administration in hospitals (see Table I).
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