Multi-criteria manufacturability indices for ranking high-concentration monoclonal antibody formulations
File(s)
Author(s)
Yang, Y
Velayudhan, A
Thornhill, NF
Farid, SS
Type
Journal Article
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 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. 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 behaviour 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.
Date Issued
2017-05-26
Date Acceptance
2017-05-02
Citation
Biotechnology and Bioengineering, 2017, 114 (9), pp.2043-2056
ISSN
1097-0290
Publisher
Wiley
Start Page
2043
End Page
2056
Journal / Book Title
Biotechnology and Bioengineering
Volume
114
Issue
9
Copyright Statement
© 2016 The Authors. Biotechnology and Bioengineering Published by Wiley Perodicals, Inc. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
License URL
Sponsor
Engineering & Physical Science Research Council (E
Grant Number
EGKW
Subjects
data mining
high-concentration protein formulation
manufacturability index
viscosity
aggregation,
Publication Status
Published