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The Extended Iterative Optimization Technology (EIOT) method is proposed as an extension to Muteki's [I&ECR 2013;52 (35):12258-12268] Iterative Optimization Technology to address deviations from Beer-Lambert's law in powders. The new method estimates the apparent spectrum for the pure species, rather than using the measured spectrum and augments Beer-Lambert's law with a bilinear term to capture the signature and strength of the nonchemical interferences. The proposed method has exhibited acceptable performance in spite of using a lean data set to estimate its parameters. The method provides robust and coherent estimates within the physical boundaries of the system and exhibits robustness to instrument transfer. The lean effort needed to build the EIOT method positions it as an attractive option in early stages of pharmaceutical drug product development. Its robustness to distinguish chemical from nonchemical signals implies a potential to lower the total cost of ownership for an EIOT-based solution in manufacturing.

No abstract

An on-line analytical method based on transmission near-infrared spectroscopy (NIRS) for the quantitative determination of water concentrations (in parts per million) was developed and applied to the manufacture of a pharmaceutical intermediate. Calibration models for water analysis, built at the development site and applied at the manufacturing site, were successfully demonstrated during six manufacturing runs at a 250-gallon scale. The water measurements will be used as a forward-processing control point following distillation of a toluene product solution prior to use in a Grignard reaction. The most significant impact of using this NIRS-based process analytical technology (PAT) to replace off-line measurements is the significant reduction in the risk of operator exposure through the elimination of sampling of a severely lachrymatory and mutagenic compound. The work described in this report illustrates the development effort from proof-of-concept phase to manufacturing implementation.