A Rational Analysis of Uniformity Risk for Agglomerated Drug Substance Using NIR Chemical Imaging

Early risk detection and quick diagnosis of manufacturing challenges are necessary to support the accelerated development pace of drug product in the current competitive environment. Analytical tools, such as near-infrared (NIR) chemical imaging (CI), can be employed for alerting drug substance uniformity risks in intermediates and the final product of solid dosage forms. In this particular study, the ability to characterize the behavior of agglomerated drug substance throughout process development was enabled by NIR CI to identify uniformity risks with small sample sizes and short turnaround time. Using NIR chemical imaging, the drug substance distribution and cluster size in all intermediates were visualized throughout the drug product process. NIR CI enabled rapid identification of the key unit operations that produced the greatest reduction in cluster size for enhanced distribution of the drug substance. The comil acted as a high shear mixing step to disperse soft lumps prior to roller compaction. Shear forces or pressure during roller compaction was sufficient to break down and disperse the agglomerates further. Ultimately, the process was robust against a range of drug substance input properties such that the uniformity of the final blend was consistently achieved and the agglomerated drug substance had no risks to the drug product process.