Control Strategy Considerations for the Continuous Manufacturing of Low-dose Oral Solid Dosage Formulations.

Abstract

The adoption of Continuous Manufacturing (CM) for Oral Solid Dosages (OSD) is often challenged by the limited sensitivity of traditional Process Analytical Technology (PAT), such as Near-infrared (NIR) and Raman spectroscopy, to provide sufficient accuracy for process monitoring and control of low-dose or fixed-dose formulations. This manuscript explores solutions by highlighting advanced control strategies and alternative manufacturing technologies. These strategies include enhanced spectroscopic methods (e.g., Spatially resolved-NIRS, Light-induced fluorescence) to provide improved accuracy/precision, the use of process data and process models (Residence Time Distribution, Multivariate Statistical Process Control) as soft sensors, hybrid PAT and process models and more traditional at-line/off-line monitoring using NIR, Raman or high-sensitivity liquid chromatography with stratified sampling and bracketing. Alternatively, several technologies inherently ensure high content uniformity, such as semi-Continuous Manufacturing (sCM) with accurate mini-batch dispensing and Dry Coating Technology. For Twin-Screw Hot Melt Extrusion (HME) molecular-level mixing delivers more uniform blends, but current low-dose applications still require pre-blending of the drug substance with suitable excipients. When fed with a uniform powder blend, twin screw wet granulation also ensures compliant content uniformity without the need for PAT monitoring. In conclusion, a successful CM of low dose products may be possible when strategically combining advanced spectral and data approaches, modelling, and innovative platforms to build robust and validated process controls. This has been demonstrated across multiple peer reviewed studies and is now gradually being incorporated into control strategies for the commercial manufacture of pharmaceutical products.