Robust factor selection in early cell culture process development for the production of a biosimilar monoclonal antibody.
This work presents a multivariate methodology combining principal component analysis, the Mahalanobis distance and decision trees for the selection of process factors and their levels in early process development of generic molecules. It is applied to a high throughput study testing more than 200 conditions for the production of a biosimilar monoclonal antibody at microliter scale. The methodology provides the most important selection criteria for the process design in order to improve product quality towards the quality attributes of the originator molecule. Robustness of the selections is ensured by cross-validation of each analysis step. The concluded selections are then successfully validated with an external data set. Finally, the results are compared to those obtained with a widely used software revealing similarities and clear advantages of the presented methodology. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 33:181-191, 2017.
Institute of Chemical and Bioengineering, ETH Zurich, Zurich, Switzerland.
Michael
M
Sokolov
Institute of Chemical and Bioengineering, ETH Zurich, Zurich, Switzerland.
Jonathan
J
Ritscher
Merck Serono S.A, Biotech Process Sciences, Corsier-sur-Vevey, Switzerland.
Nicola
N
MacKinnon
Merck Serono S.A, Biotech Process Sciences, Corsier-sur-Vevey, Switzerland.
Jean-Marc
JM
Bielser
Merck Serono S.A, Biotech Process Sciences, Corsier-sur-Vevey, Switzerland.
David
D
Brühlmann
Seminar for Statistics, Department of Mathematics, ETH Zurich, Zurich, Switzerland.
Dominik
D
Rothenhäusler
Seminar for Statistics, Department of Mathematics, ETH Zurich, Zurich, Switzerland.
Gian
G
Thanei
Bioengineering and Advanced Functional Materials Laboratory, UCT Prague, Czech Republic.
Miroslav
M
Soos
Merck Serono S.A, Biotech Process Sciences, Corsier-sur-Vevey, Switzerland.
Matthieu
M
Stettler
Merck Serono S.A, Biotech Process Sciences, Corsier-sur-Vevey, Switzerland.
Jonathan
J
Souquet
Merck Serono S.A, Biotech Process Sciences, Corsier-sur-Vevey, Switzerland.
Hervé
H
Broly
Institute of Chemical and Bioengineering, ETH Zurich, Zurich, Switzerland.
Massimo
M
Morbidelli
Institute of Chemical and Bioengineering, ETH Zurich, Zurich, Switzerland.
Alessandro
A
Butté
D000911:Antibodies, Monoclonal / Q000096:biosynthesis* / Q000737:chemistry; D059451:Biosimilar Pharmaceuticals / Q000737:chemistry*; D018929:Cell Culture Techniques / Q000379:methods*; D057166:High-Throughput Screening Assays / Q000379:methods*
D000911:Antibodies, Monoclonal; D059451:Biosimilar Pharmaceuticals
biosimilars; decision trees; high-throughput process development; multivariate data analysis; principal component analysis; process screening