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.
Immunomedics, Inc. 300 American Road, Morris Plains, New Jersey 07950, USA. Jyang@Immunomedics.com
Jeng-Dar
JD
Yang
Canghai
C
Lu
Brad
B
Stasny
Joseph
J
Henley
Woodrow
W
Guinto
Carlos
C
Gonzalez
Joseph
J
Gleason
Monica
M
Fung
Brett
B
Collopy
Michael
M
Benjamino
Jennifer
J
Gangi
Melissa
M
Hanson
Elisabeth
E
Ille
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