This Perspective explains how the International Conference on Harmonisation's Guidelines on Validation of Analytical Procedures for quantitative methods can be met by near-infrared (NIR) assays of intact pharmaceutical products. Each of the validation characteristics (accuracy, precision, specificity, detection limit, quantification limit, linearity, range, robustness and system suitability testing) is defined, examined for their relevance to quantitative methods and examples given on how they may be used to demonstrate that near-infrared assays are fit for purpose. Methods for preparing samples for calibration are given in detail. The intention is to provide information so that a pharmaceutical manufacturer could validate a method suitable for an application for a variation of a marketing authorisation for an existing product and use a NIR assay instead of the previous method. The perspective is illustrated in detail using a NIR reflectance assay of paracetamol in intact tablets. This proven assay gives results comparable to the British Pharmacopeia ultraviolet assay for paracetamol, the standard errors of calibration and prediction for the NIR method being 0.48% w/w and 0.71% w/w respectively. The method is also precise, the standard deviation and coefficient of variation for six NIR assays on the same day being 0.14% w/w and 0.16% w/w respectively, while measurements over six consecutive days gave 0.31% w/w and 0.36% w/w respectively.

Near-infrared (NIR) reflectance spectroscopy was used to determine rapidly and non-destructively the content of paracetamol in bulk batches of intact Sterwin 500 mg tablets by collecting NIR spectra in the range 1100-2500 nm and using a multiple linear regression calibration method. The developed NIR method gave results comparable to the British Pharmacopoeia 1993 UV assay procedure, the standard errors of calibration and prediction being 0.48% and 0.71% m/m, respectively. The method showed good repeatability, the standard deviation and coefficient of variation for six NIR assays on the same batch on the same day being 0.14 and 0.16% m/m, respectively, while measurements over six consecutive days gave 0.31 and 0.36% m/m, respectively. Applying the calibration to a parallel test set gave a mean bias of -0.22% and a mean accuracy of 0.45%. The developed method illustrates how the full potential of NIR can be utilised and how the ICH guidelines which recommend the validation of linearity, range, accuracy and precision for pharmaceutical registration purposes can be applied. Duplicate determinations on bulk batches could be performed in under 2 min, allowing the potential use of the method on-line for real time monitoring of a running production process.

Production batch samples of paracetamol tablets and specially prepared out-of-specification batches covering the range 90-110% of the stated amount (500 mg) were analysed by the BP official UV assay and by NIR transmittance spectroscopy. NIR measurements were made on 20 intact tablets from each batch, scanned five times each (10 min measurement time per batch) over the spectral range 6000-11,520 cm-1. An average spectrum was calculated for each batch. Partial least squares (PLS) regression models were set up using a calibration set (20 batches) between the NIR response and the reference tablet paracetamol content (UV). Various pre-treatments of the spectra were examined; the smallest relative standard error of prediction (0.73%) was obtained using the first derivative of the absorbance over the full spectrum. Only two principal components were required for the PLS model to give a good relationship between the spectral information and paracetamol content. Applying this model to the validation set (15 batches) gave a mean bias of -0.08% and a mean accuracy of 0.59% with relative standard deviations of 0.75 and 0.44%, respectively. The proposed method is non-destructive and therefore lends itself to on-line/at-line production control purposes. The method is easy to use and does not require a knowledge of the mass of the tablets.

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