Increasing bioreactor titers have necessitated companies to address bottlenecks in their downstream processes, in order to improve productivity and keep up with the upstream production rate. Much of this work has been focused on the chromatography unit operations, with the goal of improving yield and process efficiency wherever possible, while still achieving the desired impurity clearance and product quality. The amount of mass exiting the final chromatography step has forced us to explore higher concentration drug substance formulations to mitigate storage limitations and improve patient convenience. However, the combination of higher mass and higher concentration has forced us to reevaluate our UFDF processes.<br/><br/>We will present a case study in which we leverage Monte Carlo simulations, in combination with mechanistic models, to assess facility fit challenges and screen process configurations for their impact on yield and process performance within the facility constraints. These simulations led us to a two-stage process: a traditional fed-batch UFDF coupled with a single pass concentration to achieve 200 g/L drug substance with higher yield and better filterability than purely recirculation based UFDF processes.

Leveraging Monte Carlo simulations and mechanistic models to optimize a high concentration UFDF process within facility constraints

251st National Meeting (2016)

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