Process analytical technologies (PAT) are increasingly being explored and adopted by pharmaceutical and industrial biotechnology companies for enhanced process understanding, Quality by Design (QbD) and Real Time Release (RTR). To achieve these aspirations there is a critical need to extract the most information, and hence understanding, from complex and often 'messy' spectroscopic data. This contribution reviews a number of new approaches that have been shown to overcome the limitations of existing calibration/modelling methodologies and describes a practical system which would enhance robustness of the closed loop process control system and overall 'control strategy'. Application studies are described of the use of on-line spectroscopy for the monitoring and control of a downstream solvent recovery column, batch cooling crystallization and pharmaceutical fermentation. Crown Copyright (C) 2011 Published by Elsevier Ltd. All rights reserved.