Novel Applications of at-line Near-infrared Spectroscopy as Process Analytical Technology for Solid Dosage Form Pharmaceutical Analysis

The principal aim of this research was to assess at-line Near Infrared Spectroscopy (NIRS) to support Process Analytical Technology (PAT) applications within solid dosage form manufacturing. The history of PAT was traced from implementation of process analytical applications prior to the 2003 United States, Food and Drug Administration PAT initiative through to current time. The use of NIRS within the PAT context was reviewed, highlighting two areas in solid dosage manufacturing where further research of at-line NIRS is warranted; material testing and finished dosage form analysis. Novel applications of at-line NIRS were investigated and developed aligned with the PAT philosophy, to establish an innovative system of analysis that combined chemometrics and spectral analysis with statistical process control (SPC). In particular, various chemometric algorithms were explored to enable rapid monitoring of global spectral quality as well as the quality of specific critical-to-process material attributes within a SPC framework. Novel approaches to within and between batch SPC for tablet quality conformance were also developed including the adaption of distribution profile control charts typically applied to particle size measurement. These were quick to develop with greatly reduced reliance on reference analysis. It provided an opportunity for extensive process monitoring and in-depth process understanding. The work highlighted gaps in currently available chemometric and SPC capabilities within NIR instrument control software and provided insight into a new direction for NIRS analysis in the future. The new conformance methodology was demonstrated to provide business value and critical science based understanding of the pharmaceutical formulation and processes with successful application of the methodology at a commercial Pfizer facility. This methodology is in the process of rolling out worldwide. The approach was found to be approachable for plant operators through to quality analysts, and is broadly applicable with the potential to extend beyond the solid dosage form studied