Process analytical technology (PAT) and hot-melt extrusion (HME), commonplace in the food and polymer industries, are becoming increasingly deployed in the pharmaceutical industry. Herein the application of in-line, transmission mode, Fourier-transform near-infrared (FT-NIR) spectroscopy to the HME manufacturing platform for a drug product in development is detailed. NIR spectroscopy and partial least squares (PLS) models were developed for real-time active pharmaceutical ingredient (API) loading (%wt/wt) and surfactant loading predictions. These predictions were used for fault detection, isolation of suspect material, and real-time troubleshooting during HME. Additionally, the NIR/PLS output was used for real-time release of the intermediate drug product.