BACKGROUND Design principles of a fed‐batch bioreactor system to fine‐tune bioreactor performance by increasing production and productivity are investigated. To enhance the production and productivity in fed‐batch fermentation of recombinant human growth hormone (rhGH) by Bacillus subtilis, this work develops a continuous feed stream (CFS) design method with the parameters, cultivation time to switch batch‐ to fed‐batch operation, so called transition time, tT, and specific growth rate, μ. RESULTS Based on batch‐bioreactor data for rhGH production by recombinant B. subtilis (scoC−) carrying pMK4::pre(subC)::hGH, three components of the defined medium were determined for continuous feeding. Theoretical analysis and modelling of the fed‐batch reactor lead to CFS design, to be applied starting at tT, which is a function of specific growth rate, μ. Transition time tT was optimised experimentally using the batch operation μ value, 0.100 h−1; and the highest rhGH concentration was obtained at tT=4 h. rhGH concentration increased further to 127 mg dm−3, when the CFS flow rate applied was calculated using μ = 0.125 h−1. CONCLUSION The performance of the fermentation process was enhanced by 36% and 8 h shortened cultivation time of t = 16 h, increased the rhGH productivity 2.4‐fold compared with batch‐fermentation. © 2015 Society of Chemical Industry
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