Evaluation of Analytical and Sampling Errors in the Prediction of the Active Pharmaceutical Ingredient Concentration in Blends From a Continuous Manufacturing Process

Abstract

Purpose A near-infrared (NIR) spectroscopic method was developed for real time analysis of the active pharmaceutical ingredient (API) in blends from a continuous manufacturing process. The sampling and analytical errors of these determinations were estimated through variographic analysis. Methods Thirty-three calibration blends were prepared in laboratory scale equipment with a concentration range spanning from 70 to 130% of API target concentration. The NIR calibration model was validated using three independent validation sets (prepared in laboratory and pilot plant facilities and in the CM equipment). Real-time NIR spectra were obtained with an interface where three NIR spectrometers monitored the CM process. A variographic study was performed with the NIR predictions of drug concentration in blends. Results A total of 1800 NIR spectra were obtained throughout a CM run that lasted 2.5 h. Two NIR spectrometers (M1 and M2) monitored the CM run while located in positions b-1 and b-3 of the sensing interface. These two positions yielded very similar results. The average NIR predictions for blends were 101.67% LC for the first run using spectrometer M1 and 103.60% LC with M2. The second run provided an average NIR prediction of 101.19% LC with M1 and 103.16% LC with M2. The average drug concentration in tablets was 100.63% LC for the first run and 100.42% LC for the second run. Variograms showed a low sill and a flat, stable variogram demonstrating good mixing of the blend. Conclusion The CM process provided tablets with excellent content uniformity. The sampling and analytical errors and the true process variation were easily discerned through variographic analysis.

Real-Time Monitoring of Crystallization Processes Using a Novel Compact Composite Sensor Array

“…PAT monitoring is governed by the same principles as those defined by the theory of sampling. ,, Although the literature shedding light on the impact of the position of PAT probes used to monitor liquids is limited, it is well-recognized that the lack of mixing and poor choice of probe angle and depth might lead to spatial heterogeneity of suspended particles in stirred crystallizers/tanks. ,,− Particularly, it has been demonstrated that the signal quality for probe designs with flow-through gaps/slids/cells, as employed in the CCSA (Figure S3 in the Supporting Information), , strongly depends on the hydrodynamic conditions influenced by the probe orientation, angle, and immersion depth. , Arbitrary placement of PAT probes can lead to stagnant liquid accumulating in the probe gaps/slids/cells resulting in nonrepresentative and fluctuating measurements of the bulk properties . In the present work, it was attempted to align the cell of the CCSA probe along the liquid motion in the crystallizer (Figure S3 in the Supporting Information) to permit unrestricted flow through the measuring cell without claiming to have achieved optimized conditions.…”

“…PAT monitoring is governed by the same principles as those defined by the theory of sampling. 2,69,72 Although the literature shedding light on the impact of the position of PAT probes used to monitor liquids is limited, 73 it is well-recognized that the lack of mixing and poor choice of probe angle and depth might lead to spatial heterogeneity of suspended particles in stirred crystallizers/ tanks. 23,37,74−76 Particularly, it has been demonstrated that the signal quality for probe designs with flow-through gaps/slids/ cells, as employed in the CCSA (Figure S3 in the Supporting Information), 37,38 strongly depends on the hydrodynamic conditions influenced by the probe orientation, angle, and immersion depth.…”

Development of an In-Line Near-Infrared Method for Blend Content Uniformity Assessment in a Tablet Feed Frame

“…Adapting an in-line PAT method, such as a NIR spectroscopic method, for analyzing content uniformity of powder in the feed frame provides opportunities to assure the quality of tablets in the late stages of tablet manufacturing. Near-infrared spectroscopy has been used in-line for blend uniformity determination at locations before compression, such as at the exit of blenders, 6 mixers 7 and twin screw granulators, 8 or inside feed chutes 9,10 and feed frames. 11–15 The feed frames have been identified as a reliable location to achieve representative sampling of blends.…”