Model-based analysis on the extractability of information from data in dynamic fed-batch experiments

Dynamic changes of physiological bioprocess parameters, e.g. a change in the specific growth rate μ, are frequently observed during industrial manufacturing as well as bioprocess development. A quantitative description of these variations is of great interest, since it can bring elucidation to the physiological state of the culture. The goal of this contribution was to show limitations and issues for the calculation of rates with regard to temporal resolution for dynamic fed-batch experiments. The impact of measurement errors, temporal resolution and the physiological activity on the signal to noise ratio (SNR) of the calculated rates was evaluated using an in-silico approach. To make use of that in practice, a generally applicable rule of thumb equation for the estimation of the SNR of specific rates was presented. The SNR calculated by this rule of thumb equation helps with definition of sampling intervals and making a decision whether an observed change is statistically significant or should be attributed to random error. Furthermore, a generic reconciliation approach to remove random as well as systematic error from data was presented. This reconciliation technique requires only little prior knowledge. The validity of the proposed tools was checked with real data from a fed-batch culture of E. coli with dynamic variations due to feed profile.