LOW CELL DENSITY FERMENTATION PROCESS FOR THE PRODUCTION OF HETEROLOGOUS RECOMBINANT PROTEINS IN MICROORGANISMS

A low cell density fermentation process for the production of heterologous proteins in microorganisms. The cell culture obtained by cultivating host microorganisms transformed with a vector carrying genetic material for the said proteins and an inducible promoter under batch fermentation conditions is fed with a feed medium after an OD600 of 0.16 to 8 has been achieved or after 0 to 4 hrs from the start of the fermentation process. The feed medium comprises 5 to 30% of carbon source and 1 to 30% of nitrogen source and 0 mg to 400 mg antibiotics and 2.5 to 4.25% inorganic phosphates and trace elements. The concentration of the carbon source in the feed medium is 10 to 30 and the amino acid content in nitrogen source is 45 to 95%. The initial feed rate is in the range of 0 ml/hr to 12 ml/hr and is raised exponentially by an exponent in the range of 0.1 to 0.4 and/or linearly with the slope of the curve in the range of 0.5 to 3. The production of the heterologous proteins is induced with 0.01-4% inducer at a cell density of OD600 0.1-OD600 50. The feeding of the cell culture with the feed medium and the feed rate described above is continued after production has been induced. The pO2 is adjusted between 10% to 60% by passing sterile air into the fermentation broth and the temperature and pH of the fermentation broth are maintained at 33° C.-41° C. and 6.9-8.5, respectively during the entire fermentation.