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.

This paper presents a T-flask based screening platform for evaluating and identifying plant hydrolysates for cell culture processes. The development of this platform was driven by an urgent need of replacing a soy hydrolysate that was no longer available for the fed-batch process of recombinant Sp2/0 cell culture expressing a humanized antibody. Series of small-scale experiments in T-flasks and 3-l bioreactors were designed to gain an insight on how this soy hydrolysate benefits the culture. A comprehensive, function-oriented screening platform then was developed, consisting of three T-flask tests, namely the protection test, the growth promotion test, and the growth inhibition test. The cell growth in these three T-flask tests enabled a good prediction of the cell growth in the fed-batch bioreactor process. Fourteen plant hydrolysate candidates were quickly evaluated by this platform for their ability to exert strong protection, high cell growth promotion, and low cell growth inhibition to the culture. One soy hydrolysate was successfully identified to support the comparable cell growth as the discontinued soy hydrolysate. Because of the advantage of using small-scale batch culture to guide bioreactor fed-batch culture, this proposed platform approach has the potential for other applications, such as the medium and feeding optimization, and the mechanism study of plant hydrolysates, in a high throughput format.