Improving the sigma level of a pharmaceutical process leads to increased overall efficiency and quality, which, in turn, reduces cycle times. These objectives can be achieved using an approach involving: (a) process analytical technologies (PAT), for data extraction; (b) Six-sigma methodology, which serves as the driving force for continuous improvement by identifying the root cause or causes of low process yield; (c) process modeling, which is based on system biology and first principles models; and (d) advanced process control (APC) and statistical process control (SPC). This methodology is demonstrated on a simplified process for the production of penicillin, including a fermentor and the first of the downstream processing steps. We show that a combination of improved process control in the downstream processing section, as well as a modified substrate feeding profile in the fermentor, can together achieve a 40% reduction in batch time while, at the same time, significantly increasing throughput yield and decreasing impurities concentration. Evidently, this systematic approach can make a substantial impact in the pharmaceutical industry, through improved overall process yield, quality, and return on investment.