Introduction Biologics are known to be rather complex products. Apparently small changes in the manufacturing processes can cause significant differences in their clinical properties. Hence, production processes for biologics are approved by authorities only with clearly defined constraints on their manufacturing procedures. Consequently, reproducibility is of utmost importance. Additionally, reproducibility is very important as it affects the downstream processing and thus quality of the final product. From the engineering point of view there are two challenges in guaranteeing batch-to-batch reproducibility. First of all, within the given constraints, the operational procedure, most robust with respect to typically appearing process fluctuations, must be found. And, secondly, while running the process along this robust path, the remaining randomly appearing disturbances must be eliminated by means of feedback control. 1 Fig. 1 open circles open triangles  2 1 8 m P t P 1 \documentclass[12pt]{minimal}
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$$ m_{{\text{P}}} = {\int\limits_0^{t_{{\text{P}}} } {\pi x\,{\text{d}}t} }, $$\end{document} π x μ 12 μ 10 μ 5 7 11 13 14 16 18 μ μ x μ x μ 2 \documentclass[12pt]{minimal}
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$$ \frac{{{\text{d}}x}} {{{\text{d}}t}} = \mu _{{{\text{set}}}} x. $$\end{document} x set t μ x μ set t x x μ x μ 4 x Materials and methods Escherichia coli 1 Table 1 Composition of the mineral medium Mineral salt solution Trace element solution Component Concentration (g/kg) Component Concentration (g/kg) 2 4 14.60 2 20.10 2 4 2 3.60 3 2 16.70 4 2 4 2.46 2 2 0.74 2 4 2.00 2 2 0.21 4 2 1.20 4 2 0.18 4 2 1.00 4 2 0.10 4 0.50 4 2 0.10 Kanamycin 0.10   Thiamin 0.10   Trace element solution 2 mL/kg   ® 2 Fig. 2 Experimental setup of the cultivation equipment  3 −1 K s x μ x F ref 2 2 2 ® 2 ® ® ® Results x t X t x est t 4 x x est x set 3 \documentclass[12pt]{minimal}
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$$ \Delta x = x_{{{\text{set}}}} - x_{{{\text{est}}}} . $$\end{document} x x Y xs 4 \documentclass[12pt]{minimal}
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$$ F = \frac{{\mu _{{{\text{set}}}} x_{{{\text{est}}}} }} {{{\left( {Y_{{{\text{xs}}}} - \alpha } \right)}S_{{\text{f}}} }}\quad {\text{with}}\;0.7F_{{{\text{ref}}}} \le F \le 1.3F_{{{\text{ref}}}} . $$\end{document} F α x 5 \documentclass[12pt]{minimal}
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$$ \alpha = k_{1} \Delta x + k_{2} {\int\limits_{t_{S} }^t {\Delta x\,{\text{d}}t\quad } }{\text{with}} - 0.15 \le \alpha \le 0.15. $$\end{document} k 1 k 2 k 1  −1 2 −1 −1 3 Fig. 3 Total biomass signals from five fermentations performed sequentially using the same setpoint profile  4 Fig. 4 t ind   5 t F t 6 Fig. 5 Relative deviations of the total biomass from the mean. The controller was switched on 7 h after the cultivation was inoculated  Fig. 6 x  There is one exception. In the last experiment (S330) feed pump was switched off from 3 to 5 h in order to test the controller performance under process conditions with an extremely hard disturbance. The controller appeared to be robust enough to cope with this disturbance. Again in the end the relative deviation from the mean remained in the 2% interval. μ 6 \documentclass[12pt]{minimal}
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$$ {\text{OUR}} = Y_{{{\text{OX}}}} \mu X + m_{{\text{O}}} X, $$\end{document} 7 \documentclass[12pt]{minimal}
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$$ {\text{CPR}} = Y_{{{\text{CX}}}} \mu X + m_{{\text{C}}} X. $$\end{document} μ t t μ 7 μ t μ t 7 Fig. 7 X t  8 Fig. 8 Product concentration profiles for the cultivation processes already mentioned. All protein data stay within the error bar ranges representing the confidential interval of the protein analysis method  x Discussion 9 15 12 μ μ set t 5 7 11 13 16 18 6 We wished to extend the work on fermentation control towards quality assurance of process and thus product formation. This first of all requires improving the batch-to-batch reproducibility of the processes. There are two motivations for this. First, the product quality in recombinant protein manufacturing processes can be affected by changes in the fermentation operational procedure, hence the authorities link process approval with tight constraints on the process trajectories. Thus, good reproducibility increases product quality. Secondly the downstream processing can work much more efficiently when the cultivation results are highly reproducible. Therefore, having the same culture each time should be beneficial to the overall product yield as well. 4 x x x μ μ F t x t F t F 2 x μ x μ x