Scale-down and parallel operation of a riboflavin production process with Bacillus subtilis

Bettina Knorr, doctoral thesis Technische Universität München, 2005

Novel parallel bioreactor systems at a milliliter scale were recently developed for the design and improvement of biological cultivations. The objective of this work was to identify the reaction parameters that were necessary for a representative scale-down of an industrial manufacturing process to be carried out with the new technology. The process for the production of riboflavin with Bacillus subtilis, operated in a controlled fed-batch mode, served as an example for investigations in stirred-tank reactors at a 3 liter scale and at a 10 milliliter scale. Automated at-line analyses were established for 48 parallel milliliter vessels to be controlled by a laboratory robot. Despite an intermittent process operation – eight needles of the pipetting robot served 48 milliliter bioreactors – the transfer of the complex riboflavin production process into the milliliter system was achieved for the first time. In the future, this may allow a fast evaluation of process strategies, for example the application of new bacterial strains, for the biotechnological manufacturing of riboflavin under technically relevant conditions.


  • Knorr B, Schlieker H, Hohmann H-P, Weuster-Botz D (2006): Scale-down and parallel operation of the riboflavin production process with Bacillus subtilis. Biochem Eng J 33: 263-274.