During the development of manufacturing processes for biologics, changes are often made to improve process performance and/or robustness.  These changes may also impact the product quality profile, which can result in the need for additional studies, up to and including clinical trials.  A case study will be presented which describes the development of an improved bioreactor process for a monoclonal antibody.  The objective was to double the product titer and shortening the bioreactor cycle time, while ensuring that the product quality profile was analytically comparable to the pre-change process.  The initial strategy used to address this challenge was to increase the integrated viable cells in the production reactor, followed by optimization of the current feeding strategy to sustain the higher cell density process. A perfusion process was introduced at the seed bioreactor stage to enable inoculation of the production bioreactor at 2 - 10 times higher cell densities compared to the initial manufacturing process. The current feed medium was found to be nutrient limiting which was addressed by concentrating the current feed and adjusting the feeding intervals. Although the improved feed strategy alleviated most concerns, depletion of certain key nutrients and glucose accumulation were found to impact the titer and product quality.  Replenishing these key nutrients and controlling the glucose concentration successfully enabled a new process using the existing media and feed system which achieved the titer objective with similar product quality.

Process development to increase productivity with minimal impact to product quality

249th National Meeting (2015)

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