Fed-batch bioreactor process scale-up from 3-L to 2,500-L scale for monoclonal antibody production from cell culture.
This case study focuses on the scale-up of a Sp2/0 mouse myeloma cell line based fed-batch bioreactor process, from the initial 3-L bench scale to the 2,500-L scale. A stepwise scale-up strategy that involved several intermediate steps in increasing the bioreactor volume was adopted to minimize the risks associated with scale-up processes. Careful selection of several available mixing models from literature, and appropriately applying the calculated results to our settings, resulted in successful scale-up of agitation speed for the large bioreactors. Consideration was also given to scale-up of the nutrient feeding, inoculation, and the set-points of operational parameters such as temperature, pH, dissolved oxygen, dissolved carbon dioxide, and aeration in an integrated manner. It has been demonstrated through the qualitative and the quantitative side-by-side comparison of bioreactor performance as well as through a panel of biochemical characterization tests that the comparability of the process and the product was well controlled and maintained during the process scale-up. The 2,500-L process is currently in use for the routine clinical production of Epratuzumab in support of two global Phase III clinical trials in patients with lupus. Today, the 2,500 L, fed-batch production process for Epratuzumab has met all scheduled batch releases, and the quality of the antibody is consistent and reproducible, meeting all specifications, thus confirming the robustness of the process.
Yang
Jeng-Dar
JD
Immunomedics, Inc. 300 American Road, Morris Plains, New Jersey 07950, USA. Jyang@Immunomedics.com
Lu
Canghai
C
Stasny
Brad
B
Henley
Joseph
J
Guinto
Woodrow
W
Gonzalez
Carlos
C
Gleason
Joseph
J
Fung
Monica
M
Collopy
Brett
B
Benjamino
Michael
M
Gangi
Jennifer
J
Hanson
Melissa
M
Ille
Elisabeth
E
D000818:Animals; D000911:Antibodies, Monoclonal / Q000096:biosynthesis*; D061067:Antibodies, Monoclonal, Humanized; D019149:Bioreactors / Q000382:microbiology*; D018929:Cell Culture Techniques / Q000295:instrumentation* / Q000379:methods; D045744:Cell Line, Tumor; D003198:Computer Simulation; D004867:Equipment Design; D019544:Equipment Failure Analysis; D051379:Mice; D008954:Models, Biological; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism*; D010865:Pilot Projects; D015202:Protein Engineering / Q000295:instrumentation* / Q000379:methods
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C448700:epratuzumab