(166c) Tracking the Fate of Agglomerated API in the Drug Product Process with NIR Chemical Imaging

With the accelerated pace of drug product development due to fast changes in the pharmaceutical industry, the quality of the final product and the commercial process relies on the capability of detecting risks early in development and quickly diagnosing issues in routine commercial manufacture. In this particular study, the ability to characterize the behavior of agglomerated API throughout drug product development was enabled by efficient analytical tools to quickly identify risks. Agglomerated API was selected for use over large single particles because the agglomerate manufacturing process offered several advantages such as shorter cycle times and higher yield. However, the use of agglomerated API in the drug product process poses risks to blend uniformity and content uniformity of the final dosage form given that agglomerate properties such as size and strength may vary batch to batch.

One such analytical tool that was employed for understanding risk and found to be critical to monitor agglomerate behavior throughout the process was Near Infrared (NIR) chemical imaging. Near Infrared (NIR) chemical imaging facilitates visualization of the API and excipient distribution based on quantitative estimates of the concentration of the ingredients throughout the sample. The method requires minimal resources and is nondestructive to the sample. More importantly, the turnaround time is short, a much needed element assuring quick but informed decision making.

Embedding NIR chemical imaging throughout development enabled a qualitative understanding of both formulation and process robustness in response to changes in agglomerate size and strength. Using NIR chemical imaging, we can extract the agglomerate distribution and size in all intermediates throughout the drug product process. The visualization of agglomerate size is an advantage of this method in understanding the survivability of agglomerates that cannot be achieved with online NIR monitoring or HPLC based methods for blend uniformity. The NIR images enabled the team to identify the key unit operations and process parameters that produced the size change and further enhanced distribution of the API. This size reduction also provides insight into the agglomerate strength. Given agglomerates of very high strength, little to no size reduction would be observed across the process. However, we demonstrate that the shear forces to which the agglomerates are subjected to during roller compaction are great enough to break down the agglomerates.

Regardless of differences in initial agglomerate size or strength, the final granulation was reproducibly shown to have acceptable uniformity. Thus, we demonstrate that the process is robust against a range of agglomerate properties and there is no risk to content uniformity of the final dosage form.