Some developments in the application of process systems engineering techniques to biochemical processes are reviewed, particularly with regard to operation, focusing on both fermentation and downstream. As in chemical plants it is necessary to consider the whole system to ensure that a globally optimal solution is obtained. This is particularly true in process operations where some variation between batches can be expected but simulation techniques can help guide operating strategies to ensure optimal recovery of valuable product. Because advances in yields and recovery are made constantly resulting from developments of the micro-organism, strain data must play a more central role in the simulation systems allowing new data to be entered efficiently to obtain rapid appraisals of the current process system in use. Some significant on-line measurement developments which play an important role in optimising operations are discussed. The developments are discussed with reference to recent work involving protein production within Escherichia coil and Saccharomyces cerevisiae.