Hand-Held Raman Spectroscopy for Paracetamol Assay in Solution for Infusion: Expanding the Capabilities of Process Analytical Technologies.

Currently, the manufacture of injectable drug products relies on a quality-by-test approach, where product quality is evaluated at fixed manufacturing steps. The introduction of the quality-by-design approach, supported on process analytical technologies (PAT) is changing this paradigm. The US Food and Drug Administration established the foundations for the application of PAT in real-time control of the drug manufacturing process. One of the most versatile PAT tools is the Raman spectroscopy. Nevertheless, the application of this technique to injectables is still underexplored. This work intends to expand the use of Raman spectroscopy as a PAT tool for injectable drug products. A Raman spectroscopy method was developed for the assay of paracetamol in paracetamol infusion solutions, using a PLS (partial least squares) algorithm. The method is specific, with a root mean square error of calibration (RMSEC), cross-validation (RMSECV) and prediction (RMSEP) of 1.067%, 2.591%, and 2.601%, respectively, with R2 of 0.999 and Q2 of 0.992. The method was developed with a hand-held Raman spectrometer and was tested as an at-line PAT tool, rendering similar error levels to the ones found for the validation, with results readily available in ca. 1 min. This work presents a further extension of PAT applied to injectable drug products, specifically with the development of an at-line paracetamol assay method. This approach enables flexible sampling in several manufacturing steps with a single instrument and without adaptation of the manufacturing line. This work marks a significant step towards a comprehensive monitorization and control of the injectable manufacturing process.