With reaction timescales equal to or shorter than the circulation time, the ideal mixing assumption typically does not hold for large scale bioreactors. As a consequence large scale gradients in extra-cellular conditions such as the substrate concentration exist, which may significantly impact the metabolism of micro-organisms and thereby the process performance. The influence of extra-cellular variations on the organism can be tested using so-called scale-down simulators, laboratory scale setups where deliberate, controlled fluctuations are imposed in the extra-cellular environment.ChemE/Transport PhenomenaBT/Bioprocess Engineerin