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.
Microbial cells are more readily rendered nonviable by the combined action of air sparging and mechanical agitation than by either action along. A. bubble breakup/coalescence model that incorporates the cell-bubble encounter rate, bubble breakup rate, and death probability is proposed to describe cell inactivation in the presence of bubbles maintained through the joint action of agitation and air, which is continually fed into the impeller stream region via passive vortex entrainment from the surface above or via active sparging from below. Experimental results obtained from a fragile algal (Ochromonas malhamensis) culture are consistent with the model prediction. In particular, the specific cell death rate is linearly related to the specific bubble interfacial surface area. It is shown that cells exhibit sparging-sensitive characteristics when agitation is mild, but become sensitive to surface vortexing when agitation turns vigorous enough to introduce air entrainment. Experimental data obtained from different stirrer sizes are in good agreement with the model.
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