Supporting Continuous Manufacturing of Drug Products with Transmission Raman Spectroscopy

Importance of Topic

Transmission Raman Spectroscopy (TRS) emerges as a rapid, non-destructive at-line analytical technique well suited to support continuous manufacturing (CM) of oral solid dosage forms. By providing bulk quantitative analysis, TRS ensures content uniformity (CU) in compliance with regulatory guidelines such as USP <905> and ICH Q13, complementing inline process analytical technology (PAT) sensors and traditional wet chemistry methods.

Objectives and Study Overview

This application note evaluates an Agilent TRS100 system for at-line CU testing in a CM workflow developed by Agilent and equipment manufacturer Fette. The study aims to:

• Assess TRS suitability for rapid, high-throughput API quantification.
• Compare TRS results to inline NIR-based tablet uniformity (TU) measurements and offline HPLC.
• Demonstrate calibration strategies (quick gravimetric and fine-tuned HPLC-corrected PLS models).

Used Instrumentation

The TRS100 system employed a 0.65 W laser, 4 mm spot size, medium optics, and 10 s scan time per sample. Automated trays accommodated up to 100 tablets per sub-lot. Calibration modeling was performed in Solo software, and ContentQC managed data acquisition. Samples from a Fette continuous direct compression (CDC) line were pressed on the FE55 and analyzed inline via Fette ePAT NIR TU sensors.

Methodology

Tablets containing an 85% w/w active pharmaceutical ingredient (API) were analyzed in multiple sets: 61 calibration tablets with varying compositions, 30 first-run samples, and 333 CM tablets. Two PLS models were built:

• Quick method: gravimetric references, two spectral windows (219–823, 1014–1421 cm⁻¹), three latent variables, 91 spectra; R²=0.991, RMSEC=0.727, RMSECV=0.815.
• Fine-tuned method: mixed HPLC and gravimetric references, two spectral windows (170–774, 965–1372 cm⁻¹), three latent variables, 139 spectra; R²=0.968, RMSEC=1.183, RMSECV=1.250.

Main Results and Discussion

Validation of 23 CM tablets against HPLC yielded mean API within specifications for both TRS models, with narrower ranges (quick: RSD=0.45%, fine-tuned: 0.46%) than HPLC (1.33%). Applying both models to 262 additional tablets produced consistent predictions (RSD=0.35–0.36%). Comparison with Fette inline TU data over 24 h showed close alignment, with TRS offering tighter clustering due to bulk sampling and longer acquisition times.

Benefits and Practical Applications

TRS100 provides:

• Rapid, high-throughput CU assessment (real-time deployment possible within three hours).
• Reduced solvent use and cost savings versus HPLC.
• Verification of inline NIR PAT performance and bulk sampling to avoid surface bias.
• Support for process development, validation, and continuous monitoring in CM environments.

Future Trends and Potential Applications

As CM gains broader industry adoption, TRS is poised to integrate with advanced PAT frameworks, offering:

• Automated feedback loops for real-time process control.
• Expanded spectral libraries for diverse formulations.
• Miniaturized probes for on-line measurements.
• Machine learning-enhanced calibration workflows.

Conclusion

The Agilent TRS100 system effectively delivers rapid, precise at-line CU testing, corroborating inline NIR measurements and meeting regulatory requirements. Both quick and fine-tuned calibration approaches yield robust API quantification, supporting the continuous manufacturing of pharmaceuticals with reduced analysis time and increased reliability.

References

• United States Pharmacopeia Chapter <905> Uniformity of Dosage Units, USP, 2011.
• Agilent Technologies. Teva Uses the Agilent TRS100 to Achieve Regulatory Milestone for Content Uniformity Testing with the FDA. Press Release CA22025, Jul 2022.
• Römer M. Transmission Raman Spectroscopy–Implementation in Pharmaceutical Quality Control. In Solid State Development and Processing of Pharmaceutical Molecules; Wiley-VCH GmbH, 2021, pp 165–184.
• Vertex Pharmaceuticals. FDA Approves Orkambi. Press Release, Jul 2, 2015.
• Markarian J. Adopting Continuous Manufacturing for Solid-Dose Drug Products. PharmTech 2021, 45(10), 34–37.
• International Council for Harmonisation. Q13: Continuous Manufacturing of Drug Substances and Drug Products, 2022.
• Everall N. et al. Temporal and Spatial Resolution in Transmission Raman Spectroscopy. Appl. Spectrosc. 2010, 64, 52.
• Fette Compacting. FE CPS Continuous Manufacturing System. 2024.
• Eigenvector Research, Inc. SOLO Chemometrics Software. 2024.