Characterization of Technically Unavoidable Particles in Bulk Excipients

In the bulk of excipients, a few particles having different size, shape, color, etc., than the rest of the particles are permissible, if they are arising out of normal processing conditions and if they are investigated sufficiently. Regulatory guidance is limited in this area and as a result, materials may be rejected unnecessarily by the excipient users. For example, consider the situation for cellulosic excipients, like microcrystalline cellulose MCC which chars at temperature greater than 230°C. When this material is manufactured by processes such as spray drying, a few discolored or charred particles may be generated because of overheating of particles at certain locations in the processing equipment. In fact, such particles are inherent to the bulk of excipients in many of these materials being used for pharmaceutical product development and production. In pharmaceutical excipient manufacturing, some level of physical change of particles is often technically unavoidable due to the nature of the manufacturing process itself. The resulting particles are referred to as “Technically Unavoidable Particles” (TUPs). Excipient manufacturers are generally aware of the origin, type, and quantity of such unusual visible particles in their products; however, their identity is often not investigated to demonstrate that they present no risk to the product’s purity. This article aims to provide a brief outline for ways to demonstrate the purity of pharmaceutical excipients containing visibly different particles. Digital and scanning electron microscope images of white and discolored particles of MCC were used to establish morphological similarity. Differential scanning calorimetry and powder X-ray diffraction tools demonstrated polymorphic nature of batches. In addition, analytical tools such as: FT-IR, SEM-energy dispersive spectroscopy, and solid-state 13C NMR were employed to confirm chemical similarity. The combination of these techniques represents a possible testing framework for the identification and characteriza