Industrial fermentation involves the use of a living cell culture to produce desired chemical products. Through screening, directed evolution or recombinant methods, the cell culture is typically optimized to maximize production of the desired enzyme, protein or small molecule metabolite.
Control of operating variables such as nutrient and dissolved oxygen concentration, pH, and temperature are used to promote cell growth or production of the desired chemical at the appropriate time. However, because it is a living system with many complex processes occurring simultaneously or concurrently, there is a tendency for significant batch to batch variability in production yield and quality.
Due to the vital importance of avoiding contamination of the cell population, there has been little progress in implementing advanced Process Analytical Technology for fermentation processes. Fermentation progress is typically inferred from cell growth models and fairly simple measurements of turbidity and other indirect measurements – along with periodic off-line sampling and analysis to verify operation within acceptable limits. Recently, more advanced measurement technologies with the ability to directly measure complex cellular systems and multiple dissolved chemicals – including both substrates and products – in the fermenter broth.
Real-time reaction monitoring of critical substrate concentration – and even product concentration when the product metabolite is expressed from the cell into the fermenter broth – are both easily achievable with in situ ReactIR measurements.
Direct in situ monitoring of the cell population is also now possible with FBRM - providing real-time information of relative cell count, cell dimension, and detection of aggregation and flocculation – has been shown to provide valuable insight into cell growth kinetics that can be used for batch optimization or even real-time control of fermentation.