Monitoring Pharmaceutical Uniformity During Manufacture Using FT-NIR Spectroscopy

Pharmaceutical manufacturers are required to enhance their critical quality performances. This is being encouraged by the FDA which is pushing towards using modern process analytical technologies (PATS) to ensure the quality of the final product.

A large number of applications in the Process Analytical Technology (PAT) initiative can be addressed using NIR spectroscopy. For drug product sites for instance, NIR spectroscopy can be used at almost each step of tablet manufacture from raw material control to content uniformity analysis of the dosage unit. Bruker Optics has seized the PAT initiative by introducing products specifically designed for the needs of the Pharmaceutical Industry.

Figure 1. FT-NIR 1. Derivative spectra (9000-8700 cm^-1) of tablets with the following concentrations of the active drug: 0.1, 0.25, 0.5, 1 and 2%.

Along with Pfizer, Bruker Optics has developed the TANDEM system that integrates on-line NIR content uniformity with traditional tablet testing on weight, thickness, hardness and diameter. Traditionally, content uniformity analysis has been performed by HPLC. This high volume, time-consuming, labour-intensive process needs test samples to be taken from the production area to the QC/QA laboratory where they are prepared and analyzed. Pharmaceutical companies are trying to implement new process analytical technologies that can help to enhance product quality and minimize manufacturing costs. Near-infrared spectroscopy is a quick, cost- and time-effective, convenient and non-destructive alternative for routine content uniformity analysis.

TANDEM offers comprehensive solutions for the pharmaceutical industry. It provides a full set of tablet characterization parameters including weight, size, thickness, hardness, diameter, and NIR content uniformity in a single analyzer. TANDEM can be integrated with existing tablet pressing systems for automated analysis.

Additionally, the analysis information can be utilized immediately to adjust production parameters and improve product uniformity. Methods can be developed on the TANDEM or they can be transferred from a Bruker Optics MPA FT-NIR spectrometer.

Instrumentation

The TANDEM system comprises the Pharmatron 10X conventional tablet tester and a Bruker Optics MATRIX FT-NIR spectrometer. The system is controlled from a fast PC; a communication link to the tablet press is provided.

Figure 2. Cross validation results of PLS based models for the prediction of active drug showing excellent correlation.

The TabStat/TandemSK software offers a convenient interface for operators. The software package is fully 21CFRpart11 compliant. Software wizards are provided to make OQ/PQ testing an easy task.

Tablet Manufacture - Compression

During compression, tablets are delivered from the tablet press to the TANDEM system automatically. The TANDEM system then performs weight and thickness analysis on each tablet. Based on the pre-configured analysis sequence, tablets are either taken to the diameter and hardness station for the completion of the testing or they are taken to the NIR reading head. During a batch, 30 locations of 7 tablets are typically sampled for NIR analysis. For each location, the identity of a tablet is kept and tablets are stacked in vials in a 30-station carousel.

Real Time Date

The process control window of the TabStat/TandemSK software offers a precise overview of the positions of all tablets delivered from the tablet press. In addition all results produced by the TANDEM on the current run are displayed on the screen. For NIR results, a graphical display of the potency of each tablet as well as the average over 7 tablets and their %RSD is shown. The same information is given in a table format. After completion of the batch, a full report is available.

Experimental

In order to monitor the potency of a batch using FT-NIR spectroscopy, spectra are taken in transmission in the spectral range 12000-7500 cm^{- 1} (833-1330 nm). The addition of 16 scans per spectra at a resolution of 8 cm^-1 allows a fast data acquisition of less than 10 seconds per spectrum. The increase of active drug concentration is shown in the spectra, allowing the development of a calibration model with an excellent Standard Error of Cross Validation (RMSECV) of 0.015 mg/Tab and a correlation coefficient R² of 99.95%. The unique self-optimization function in the OPUS software was used to develop the model. The calibration range covered a concentration of 0.1 to 2% of the active drug.

Quantitative Analysis

Near-infrared spectra result from combination and overtone bands of C-H, N-H, O-H, etc. vibration. Since most actives and excipients contain at least one of these bonds, they are suitable for near-infrared analysis. The OPUS/QUANT quantitative analysis software package uses partial least squares (PLS) to develop quantitative models. Calibration model development requires measuring the FT-NIR spectra of multiple samples containing a range of concentrations of the components of interest. The unique Quant self-optimization routine is then applied to develop the calibration model.

Measurement Sequence

Throughout a batch, 30 locations of 7 tablets are typically sampled for NIR analysis. The measurement sequence can be performed so that the sampling rate is intensified at the start and end of a batch, where abnormalities in tablet manufacture are more likely to happen. All tablets analyzed by NIR are stored in a 30-vial carousel, retaining the identity of each individual tablet.

Implementation

The TANDEM has been developed for use in a process environment next to a tablet press. The system has a robust design with a built-in FT-NIR spectrometer, which is insensitive to vibrations from the tablet press. The TANDEM comes in an IP 65 rated stainless steel enclosure and is sealed against dust and sprayed water. The TANDEM has an open architecture for cleaning and product changeover.

Cross validation results of PLS based models for the prediction of active drug shows excellent correlation.

This information has been sourced, reviewed and adapted from materials provided by Bruker Optics.

For more information on this source, please visit Bruker Optics.