Scale-down models are widely used in the biopharmaceutical industry as tools to support large-scale manufacturing processes. For example, in industrial groups such as Manufacturing Sciences & Technology, scale-down models are used to evaluate and qualify manufacturing process changes. In this report, we detail strategies that were used to develop a robust scale-down model to support the technical transfer of a unique mammalian cell culture process from one facility with 5,000-L fed-batch production bioreactors to a second facility with 25,000-L fed-batch production bioreactors. One of the major challenges associated with this technical transfer was the development of a process capable of handling an inoculum expansion with a relatively low final VCD required for each stage while maintaining enough volume to inoculate the production bioreactor. To develop scale-down models of multiple seed bioreactors and a fed-batch production bioreactor, the P/V approach was used to determine agitation rates and linear VVM scaling was used to determine gas flow rates. Single and dual impeller arrangements as well as the effects of sintered versus drilled hole spargers were investigated. In addition, manual base addition was used to match large scale osmolality and pCO<sub>2</sub> profiles. An accurate scale down model was developed to statistically match manufacturing process characteristics such as peak VCD, peak osmolality, final viability, and specific productivity. In addition, product quality attributes such as charge variants, presence of high molecular weight species, and glycosylation profiles are compared between the large and small scale bioreactors. For the seed bioreactors, top-off and draw-down/rebatch strategies were evaluated to support robust inoculum expansion. Lastly, to investigate final VCD limitations in shake flasks and cell bags, growth curve experiments were conducted to collect peak VCD and media nutrient information (i.e. amino acids and vitamins). The information gained with respect the final VCD inoculum expansion limitations can be used for future applications to improve process robustness.

Development of a NS0 monoclonal antibody producing scale-down model for support of a technical transfer

249th National Meeting (2015)

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