Optimizing bioprocessing efficiency with OptFed: Dynamic nonlinear modeling improves product-to-biomass yield

Abstract

Biotechnological production of recombinant molecules relies heavily on fed-batch processes. However, as the cells' growth, substrate uptake, and production kinetics are often unclear, the fed-batches are frequently operated under sub-optimal conditions. Process design is based on simple feed profiles (e.g., constant or exponential), operator experience, and basic statistical tools (e.g., response surface methodology), which are unable to harvest the full potential of production. To address this challenge, we propose a general modeling framework, OptFed, which utilizes experimental data from non-optimal fed-batch processes to predict an optimal one. In detail, we assume that cell-specific rates depend on several state variables and their derivatives. Using measurements of bioreactor volume, biomass, and product, we fit the kinetic constants of ordinary differential equations. A regression model avoids overfitting by reducing the number of parameters. Thereafter, OptFed predicts optimal process conditions by solving an optimal control problem using orthogonal collocation and nonlinear programming. In a case study, we apply OptFed to a recombinant protein L fed-batch production process. We determine optimal controls for feed rate and reactor temperature to maximize the product-to-biomass yield and successfully validate our predictions experimentally. Notably, our framework outperforms RSM in both simulation and experiments, capturing an optimum previously missed. We improve the experimental product-to-biomass ratio by 19% and showcase OptFed's potential for enhancing process optimization in biotechnology.