tA novel control concept was developed for a two phase biocatalytic oxidoreduction system. Thehydrophobic substrate acetophenone dissolved in n-heptane is reduced to (S)-1-phenylethanol by Can-dida parapsilosis carbonyl reductase 2, immobilized in a polyvinyl alcohol hydrogel. The cofactor NADHis regenerated via formic acid oxidation using likewise immobilized Candida boidinii formate dehydro-genase, increasing the pH-value of the aqueous phase. Therefore, the measured amount of CO2leavingthe reactor is used to calculate the amount of formic acid to be replaced.Experiments lead to unexpectedly poor conversions motivating the development of a holistic processmodel, which was exclusively based on literature data and did not require parameter fitting. Simula-tion studies identified the CO2-solubility in n-heptane as the root cause for the time-lag in co-substratefeed and the resulting pH-shifts leading to poor conversions. They also indicated enzyme activity andstability as improvement targets, and the choice of an organic phase with low CO2-solubility. Exemplar-ily, increased buffer concentration to stabilize the pH within the hydrogel resulted in a predicted 13%productivity improvement, which could be validated experimentally, thus highlighting the potential ofprocess models for complex biocatalytic process evaluation.