A simple log-normal function was developed for on-line prediction of Toyocamycin (TM) titer of 12,000 dm3 production fermentations based on the oxygen uptake rates (OUR) (see NOTE below) and QTM behavior observed at the 120 dm3 scale at constant TV :
f(t)=A exp(B [ ln t - C ]2 ), where A, B, C, represent QTM and OUR curve scale, shape and location of maxima, respectively, determined on the 120 dm3 scale (Fig. 22) (73, 86).
NOTE: OUR DETERMINED CONTINUOUSLY, ON-LINE WITH CO2 AND O2 ANALYZERS AND COMPUTER USING THE EQUATION :
OUR = FN / VL (( PO[ in] / Pt - PO[in] - PW[ in] - PC[ in] ) _ ( PO[out] / Pt - PO[out] - PW[out] - PC[out] ))
This technique allowed for simple on-line prediction of QTM time course and TM titer during the 12,000 dm3 batch production process. The predicted TM titer could be rapidly (<15 min) confirmed by off-line HPLC determinations from samples from each fermentation to assess the reproducibility of the productivity of each 12,000 dm3 batch. The comparison of the predicted and observed QTM and OUR values for scale-up to the 12,000 dm3 scale with the model whose coefficients were determined on the 120 dm3 scale is shown in Fig. 23.
The Tm final titer on the 12,000 dm3 scale was found to be reasonably predicted (p<0.001) from the log-normal scale factor (A) from 120 dm3 scale data at a constant value of TV. This simple model was very useful, as 12,000 dm3 batches were not pH controlled and pH correlated with final TM titer. A reproducible QTM and OUR time course predicted with log-normal 120 dm3 scale coefficients served as a guide for intermittent pH adjustment of the 12,000 dm3 scale vessel to maintain predicted OUR or QTM values (86, 87).
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