Supporting Continuous Manufacturing of Drug Products with Transmission Raman Spectroscopy

Significance of the Topic

The shift toward continuous manufacturing (CM) of oral solid dosage forms is transforming the pharmaceutical industry by improving efficiency, quality, and supply chain resilience. Robust analytical methods are essential to monitor drug content and uniformity in real time, ensuring patient safety and regulatory compliance. Transmission Raman spectroscopy (TRS) emerges as a powerful at-line tool to complement in-line process sensors and traditional off-line assays.

Objectives and Study Overview

This study evaluates the Agilent TRS100 system as an at-line analytical technique for supporting CM of tablets. In collaboration with Fette Compacting, the work compares TRS performance to Fette’s in-line near-infrared (NIR) probes and off-line high-performance liquid chromatography (HPLC). Key goals include:

• Assessing the ability of TRS to quantify active pharmaceutical ingredient (API) content and tablet uniformity (TU).
• Developing rapid chemometric models for real-time prediction.
• Validating TRS results against in-line NIR data and HPLC reference methods over a full 24-hour CM run.

Methodology

An Agilent TRS100 system was configured for non-destructive, high-throughput analysis of up to 100 tablets per tray. Partial least squares (PLS) models were built using spectra from calibration tablets (varying API concentration), first-run samples, and continuously manufactured (CM) tablets. Two calibration strategies were developed:

• Quick method: gravimetric API values, model built within three hours, using 91 spectra.
• Fine-tuned method: combination of gravimetric and HPLC-corrected values, using 139 spectra for enhanced accuracy.

Used Instrumentation

The following instruments and settings were employed:

• Agilent TRS100 Transmission Raman Spectrometer: 0.65 W laser power, 4 mm spot size, medium optics, 10 s total scan time (10 × 1 s exposures).
• Fette FE CPS Continuous Direct Compression (CDC) system with in-line NIR sensors for blend and tablet uniformity.
• HPLC system for reference API quantification on selected samples.
• Solo chemometric software (Eigenvector Research) for PLS model development and Agilent ContentQC for data acquisition.

Main Results and Discussion

Validation against 23 HPLC-analyzed CM tablets demonstrated that both TRS models achieved mean API recovery within 0.15 w/w% of target and relative standard deviations below 0.5%. The quick model delivered real-time predictions during the two-day run, while the fine-tuned model offered slightly improved accuracy. Application to the remaining 262 tablets showed tight API distributions (RSD ≈ 0.35%). Direct comparison with Fette’s in-line NIR TU data over 24 hours revealed close agreement and lower sample-to-sample variability in the TRS measurements, attributable to bulk sampling.

Practical Benefits and Applications

At-line TRS100 analysis offers several advantages:

• Rapid throughput and near real-time feedback compatible with CM process controls.
• Bulk sampling avoids surface-bias inherent to backscatter probes, enhancing representativity.
• Reduced reliance on solvents and consumables compared to wet-chemistry assays.
• Facilitates method development and process validation by providing quantitative data within hours.

Future Trends and Applications

As CM adoption expands, at-line TRS can be integrated into advanced process analytical technology (PAT) frameworks alongside in-line NIR, Raman, and other spectroscopic sensors. Emerging trends include:

• Automated chemometric model updating using machine learning to adapt to formulation changes.
• Miniaturized TRS probes for true in-line bulk monitoring.
• Integration with digital twins for predictive process control.
• Extension to other dosage forms such as granules and pellets.

Conclusion

This study demonstrates that the Agilent TRS100 provides reliable, high-precision at-line analysis of API content and tablet uniformity in a continuous manufacturing environment. Rapid chemometric calibration, coupled with bulk sampling advantages, positions TRS as an essential complement to in-line PAT and traditional off-line assays, supporting quality assurance and process optimization.

Reference

• United States Pharmacopeia Chapter <905> Uniformity of Dosage Units, Stage 6, 2011.
• Teva Uses the Agilent TRS100 to Achieve Regulatory Milestone for Content Uniformity Testing with the FDA, Agilent Technologies press release, 2022.
• Römer M. Transmission Raman Spectroscopy–Implementation in Pharmaceutical Quality Control. In Solid State Development and Processing of Pharmaceutical Molecules, Wiley-VCH, 2021, pp. 165–184.
• Vertex Pharmaceuticals, FDA Approves Orkambi, Press Release, July 2, 2015.
• Markarian J. Adopting Continuous Manufacturing for Solid-Dose Drug Products. Pharmaceutical Technology, 2021; 45(10): 34–37.
• ICH Q13 Continuous Manufacturing of Drug Substances and Drug Products, ICH, 2022.
• Everall N. et al. Temporal and Spatial Resolution in Transmission Raman Spectroscopy. Applied Spectroscopy, 2010; 64: 52.
• Fette Compacting FE CPS Continuous Manufacturing System, Fette Compacting product information.
• Eigenvector Research Solo Chemometric Software, Eigenvector Research, Inc.