Patent ID: 8722374

Claim:
A method of producing secondary metabolites under oxygen-limited or anaerobic culture conditions in a bioreactor, the method comprising: providing a bioreactor comprising: a reactor housing defining an extracapillary space; a porous tubular hollow fiber substrate having a first external surface side and a second inner lumen side, the porous tubular hollow fiber substrate being configured to allow the passage of secondary metabolites therethrough and to prevent the passage of microorganism cells therethrough; and a feeding arrangement supplying a nutrient solution to the extracapillary space under pressurized conditions; inoculating the bioreactor extracapillary space with microorganisms to establish a biofilm of microorganisms attached to the first external surface side of the substrate, the biofilm of microorganisms having a membrane/substrate interface between the substrate and the biofilm of microorganisms; and causing a nutrient solution to flow under pressure through the biofilm and the substrate in direction from the first external surface side thereof to the second inner lumen side thereof under anaerobic culture conditions, at a rate which is sufficiently low for a nutrient gradient to be established across the biofilm such that the nutrient concentration is high at an outer surface of the biofilm and sufficiently high to support exponential growth of the microorganisms, and wherein the nutrient concentration is low closer to the substrate and sufficiently low to induce and sustain a stationary phase of the microorganisms and thereby cause the microorganisms to produce at least one secondary metabolite, the flow of the nutrient solution through the substrate carrying said secondary metabolite through the substrate to the second inner lumen side thereof where secreted secondary metabolite can be collected, with the microorganism cells from the biofilm being retained at the external surface first side thereof, wherein the pressure at which the nutrient solution is caused to flow through the biofilm and the substrate is increased over time from 5 to 100 kPa to sustain and maintain the stationary phase of the microorganisms at the membrane/substrate interface between the substrate and the biofilm of microorganisms.