S150: The CHO platform process development tool kit: accelerating understanding using metabolomic based experimental design

Global metabolomic profiling was used as a basis to improve the average productivity from the in house CHO upstream platform for the production of therapeutic proteins.  As a base for development, comprehensive metabolomic analysis was conducted using five cloned cell lines from the Merck pipeline.  Each cell line expressed a different therapeutic protein and was the result of a separate yet identical screening procedure.  From this diverse background, common metabolic issues such as membrane stress, oxidative stress, and osmoregulatory stress were detected.  In addition, clone specific items such as nutrient depletion and metabolic pathway blockages were found.  Acting on these observations, an iterative experimental plan involving process alterations and subsequent metabolomic profiling was put into place.  This plan utilized both small scale bioreactors as well as shake flasks to evaluate the interaction of the nutritional environment as well as the operating ranges of the production process on the ability of the cell line to produce the desired product.  Impact to product quality attributes such as glycan profile and molecule assembly was also monitored.  Using this approach, the developmental experimentation was intended modulate a specific metabolomic phenotype across a collection of cloned cell lines; with the goal of advancing the productivity of the platform as a whole.