Very-high-gravity (VHG) fermentation increases ethanol yield and decreases water use, but it imposes severe osmotic and ethanolic stress on Saccharomyces cerevisiae, which frequently limits overall productivity. In situ ethanol removal through CO2 gas stripping can mitigate this inhibition. However, the optimal timing for stripping onset under different temperature conditions remains not fully characterized. This study examined the effect of stripping initiation timing in VHG fed-batch fermentations at 28, 30, 32, and 34°C. A mechanistic fermentation model based on Monod-type kinetics with ethanol inhibition terms and coupled gas-liquid mass transfer was estimated using differential evolution. Distinct, temperature-specific ethanol concentration thresholds for stripping onset were identified, which maximized ethanol productivity (). Plateau analysis, based on identification of concentration regions where delayed initiation produced negligible changes in , refined these thresholds to within ±0.5 % of the maximum productivity. This resulted in CO2 gas savings equivalent to 1.05 ± 0.06 h per fermentation cycle. Model-based time-varying temperature control optimization predicted an increase in ethanol productivity to 12.32 g L⁻1 h⁻1. The findings provide a simulation and parameter estimation framework for temperature-integrated extractive control strategies to improve ethanol production in high-biomass VHG fermentations.
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