Application of process analytical technology (PAT) in real-time monitoring of pharmaceutical cleaning process: Unveiling the cleaning mechanisms governing the cleaning-in-place (CIP)

Abstract

We report for the first time the combination of inline process analytical technology and optical imaging to track and understand different cleaning mechanisms governing the cleaning process of Olanzapine. Clean-in-Place process parameters were studied through simultaneous inline process analytical technology and image analysis in a film flow apparatus. Methanol and water were compared as cleaning agents, and the effect of flow (0.5—1 L.min−1) and temperature (20–40 °C, and 60 °C for water) was investigated. The cleaning process was assessed in terms of cleaning time, volumetric efficiency, surface residue and governing phenomena. Raman spectroscopy was used to prove no degradation occurred during cleaning. Temperature increase improves the efficiency even when solubility is negligible. High variability was observed when detachment behaviour is dominant, and it is then advisable to prioritize dissolution in the final clean-in-place steps to improve repeatability. Results show that the cleaning process is governed by an interplay of dissolution and mechanical shear phenomena and is more efficient when solubility is significant. The combination of in-situ process analytical technology and optical imaging analysis during process development allows for the determination of the most efficient and repeatable conditions, which in turn significantly reduces solvent usage in pharmaceutical cleaning.