(624c) Resonant Acoustic Mixing for the Preparation of Impurity Spiked GLP Toxicological Batches of API

Resonant acoustic mixing (RAM) has emerged as a valuable tool in the pharmaceutical industry for homogenizing solid-solid mixtures. Gilead process chemistry has recently adopted RAM to produce impurity-spiked Good Laboratory Practice (GLP) toxicology batches of active pharmaceutical ingredients (APIs). This study highlights RAM's operational simplicity, reproducibility, solvent-free mixing, ability to maintain API crystalline form, and reduced worker exposure to powdered API.

We compare the method of creating a GLP toxicology batch for API 1 with the RAM method used to creating a GLP toxicology batch for API 2. The method for API 1 involves dissolving the API with impurities, removing the solvent to obtain heterogeneous particles, and manually grinding and sieving the material to achieve homogeneity. In contrast, the RAM method for API 2 utilizes solid-solid mixing of API and isolated impurities, with yttria stabilized zirconia milling beads used to reduce particle size when necessary. This process is straightforward, solvent-free, and can be performed on several grams up to 1 kg in as little as 2–3 hours.

Although each API has unique physical properties requiring specific RAM methods, general guidelines have been developed to ensure robust processes and reduced development time. These guidelines facilitate the efficient production of GLP toxicology lots, underscoring RAM's potential to streamline pharmaceutical manufacturing.