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Ajit NarangAjit Narang, Ph.d., works for the Drug Product Science & Technology Department of Bristol-Myers Squibb Co. in New Brunswick, N.J. on oral solid dosage forms after receiving his doctorate from the University of Tennessee, Memphis.

Pharmaceutical processes for oral solid dosage forms have long occupied the realm of direct compression, dry granulation, and wet granulation (WG). WG can be either a low or a high shear process, including fluid bed granulation. Traditionally, WG is a batch process that is controlled based on process parameters. The effect of changes in the equipment, scale, or formulation are typically assessed on the attributes of dried granules or compressed tablets.

This approach increases the required experimentation, provides indirect controls, and the results on the measured attributes may be confounded with the role of unit operations such as drying, milling, and compaction. Such a drug product development work stream presents challenges for building quality by design into the processes and delineating interactions of process parameters used for different unit operations on product attributes.

Significant efforts have been invested in the recent years in developing the process analytical technology (PAT) tools for real-time measurement of relevant granule attributes in the granulator itself during processing. These measurements have included the indirect measures such as impeller power, torque, or the wet mass density. Direct measurements of attributes have utilized techniques such as focused beam reflectance measurement to measure granule chord length distribution during granulation, which can be correlated to the particle size distribution (PSD) of granules.

The most important question to these efforts, however, remains—What should we measure, and why? The end goal should always be kept in mind!

Traditionally, granule PSD has been the key parameter that is assessed through and across the unit operations. PSD has significant implications on the manufacturability parameters of the dosage form such as flow, density, and fines content. The chosen attributes for PAT development, of course, depend on the attributes specific to a drug product and processes. The critical quality attribute for several drug products is drug release—which usually correlates better with granule porosity or density rather than size.

These recent developments indicate an urgent need for the WG PATs to evolve with this paradigm shift or addition of focus to include granule densification.

Note: The author’s papers will be available during the 2013 AAPS Annual Meeting and Exposition.