A PAT approach to improve process understanding of high shear wet granulation through in-line particle measurement using FBRM C35.

This article summarizes the investigation of in-line particle characterization during high shear wet granulation (HSWG) using focused beam reflectance measurement (FBRM) for enhanced process understanding, which is part of an effort to develop this drug product within the framework of quality by design (QbD) and process analytical technology (PAT). Traditionally, the effectiveness of in-line monitoring of HSWG processes is hindered by wet and sticky material fouling the probe resulting in inconsistent and erroneous data collection. For this study, a FBRM C35 probe was used which incorporates a scraping mechanism to maintain a clean probe window ensuring consistent measurements throughout each batch. The evaluations were conducted on nine scale-up DOE development batches and eight clinical sub-lots. In the DOE campaign, the purpose of FBRM was used to study the impact of varying water amount and wet massing time on granule dimension and count during granulation, while batch-to-batch variation or batch reproducibility was evaluated under the same process conditions for the clinical batches. In addition, a preliminary investigation of the most optimal probe position was conducted. The results indicate that FBRM is capable of monitoring the rate and degree of change to granule dimension/count during HSWG, and could be a potential technique for granulation endpoint determination. (c) 2010 Wiley-Liss, Inc. and the American Pharmacists Association