A high antibiotic expression level was obtained in a pilot-scale fermentation process with Streptomyces. With a new supervisory computer control algorithm, the agitation, aeration rate, vessel pressure, and culture temperature were automatically changed sequentially during the process, avoiding the dissolved oxygen (DO) limitation. A unique pH control strategy was also used in the process, and cells grew and produced the secondary metabolite product, rapamycin, over a wider pH range. The quantity of acid addition was very small when the pH reached the higher limit, 6.8, and then the pH was dropped and adjusted gradually by the culture itself towards the lower limit, 6.2. Due to the optimized culture environment the entire fermentation time was reduced, and the productivity was simultaneously increased. The harvested dry cell weight was over 25 g/l and intracellular rapamycin was over 110 mg/l.