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Several factors influence the precision of laser-induced breakdown spectroscopy (LIBS) measurements. This paper reports on the effect of emission signal temporal development, sample translational velocity, number of spectra accumulated, laser pulse stability, detector gate delay, surface roughness, and use of background correction on LIBS precision. The results are presented in two formats: within measurement/shot-to-shot precision (intra-measurement) and between measurement precision (inter-measurement). The data indicate that intra- and inter-measurement precision are optimized under different conditions. The best precision obtained was 0.03%.

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A near-infrared (NIR) calibration was developed using an efficient offline approach to enable a quantitative partial least-squares (PLS) chemometric model to measure and monitor the concentration of active pharmaceutical ingredients (API) in powder blends in the feed frame (FF) of a tablet press. The approach leveraged an offline "feed frame table," which was designed to mimic the full process from a NIR measurement perspective, thereby facilitating a more robust model by allowing more sources of variability to be included in the calibration by minimizing the consumption of API and other raw materials. The design of experiment (DOE) for the calibration was established by an initial risk assessment and included anticipated variability from factors related to formulation, process, environment, and instrumentation. A test set collected on the feed frame table was used to refine the PLS model. Additional fully independent test sets collected from the continuous drug product manufacturing process not only demonstrated the accuracy and precision of the model but also illustrated its robustness to material variability and process variability including mass flow rate and feed frame paddle speed. Further, it demonstrated that a calibration can be generated on the offline feed frame table and then successfully implemented on the full process equipment in a robust manner. Additional benefits of using the feed frame table include streamline model monitoring and maintenance activities in a manufacturing setting. The real-time monitoring enabled by this offline calibration approach can be useful as a key component of the control strategy for continuous manufacturing processes for drug products, including detecting special cause variations such as transient disturbances and enabling product collection/rejection based upon predetermined concentration limits, and may play an important role in enabling real-time release testing (RTRt) for manufactured pharmaceutical products.

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Two-dimensional images of the distribution in space and time of the chemical species associated with the spectral emission from a laser-induced breakdown (LIB) plasma on a solid sample were captured. The time-dependent spatial shape and size of the plasma, viewed simultaneously from two orthogonal directions, were measured in terms of the emission from a lead ionic line and a set of lead atomic lines. The temporal and spatial behavior are characteristically different for the different spectral lines. The ionic emission (220 nm) is confined to a smaller, more concentrated central part of the LIB plasma, whereas the atomic emission (280 nm) is more evenly dispersed over the entire plasma. A protrusion of the plasma was observed where there was no significant emission at 220 or 280 nm. Time-resolved spectral imaging has the potential to considerably improve analytical LIB spectroscopy (LIBS) results and lead to a better fundamental understanding of its behavior.

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