Pharma workflow solutions

Significance of the Topic

Controlling impurities and residues in pharmaceuticals is critical for patient safety and regulatory compliance. Robust analytical workflows enable sensitive detection of genotoxic impurities, active pharmaceutical ingredients and residual solvents, ensuring consistent product quality across discovery, development and QA/QC stages.

Objectives and Overview of the Study

This collection of workflows from Thermo Fisher Scientific illustrates complete solutions for four common pharmaceutical analyses:

• Nitrosamine impurity quantitation in ranitidine products
• Ibuprofen assay with improved peak symmetry
• Cephalosporin antibiotic profiling with enhanced resolution
• Residual solvent determination meeting USP <467> requirements

Additionally, a guide for modernizing older HPLC methods is provided to reduce run times and solvent consumption.

Methodology and Instrumentation

The workflows combine optimized sample preparation, chromatography and detection platforms:

• Nitrosamines: protein precipitation plates, Acclaim PA2 UHPLC column, Vanquish Horizon UHPLC and Orbitrap Exploris 120 MS for high-resolution mass analysis.
• Ibuprofen: Accucore C18 column on Vanquish Core HPLC with UV detection to minimize peak tailing and meet USP monograph criteria.
• Cephalosporins: Hypersil GOLD columns with Vanquish Core HPLC and UV detection to achieve symmetrical peaks and robust quantitation at low levels.
• Residual Solvents: Headspace autosampler coupled to TRACE 1600 GC system with TraceGOLD TG-624 and TG-WaxMS columns to separate Class 2A solvents with Rs ≥ 1.0.
• Method Modernization: Equations for adjusting flow rate and gradient times when migrating from 5 µm, 4.6 mm ID HPLC columns to sub-2 µm, narrow-bore UHPLC columns.

Instrumentation details:

• Vanquish Horizon and Core HPLC/UHPLC systems
• Orbitrap Exploris 120 mass spectrometer
• TRACE 1600 GC with TriPlus headspace autosampler
• Thermo Scientific solid-core and sub-2 µm columns (Accucore, Hypersil GOLD, Acclaim PA2, TraceGOLD)
• Thermo Scientific consumables: protein precipitation plates, SPE cartridges, syringes, vials, caps, guard cartridges

Main Results and Discussion

Each workflow demonstrated high sensitivity, reproducibility and compliance with pharmacopeial standards:

• Nitrosamine analysis achieved sub-ppb quantitation of nine genotoxic impurities with mass accuracy <1 ppm and peak capacity supporting FDA limits.
• Ibuprofen and valerophenone assays exhibited minimal tailing and excellent run-to-run consistency, exceeding USP specifications.
• Cephalosporin antibiotics showed enhanced peak symmetry and higher sensitivity, reducing risk of quantitation errors for low‐level impurities.
• Residual solvent separation on TraceGOLD columns met or exceeded USP <467> resolution requirements across 16 common solvents.
• Method modernization examples demonstrated run time reductions up to 60% and solvent savings up to 65% by transitioning to narrower columns and optimized flows.

Benefits and Practical Applications

These integrated workflows deliver:

• Regulatory compliance through validated impurity and residue analysis
• Time and solvent savings with modernized chromatographic methods
• Robust and reproducible separations across multiple compound classes
• Flexibility for discovery, pre-clinical, clinical and QA/QC environments
• Reduced operational costs by minimizing method transfer risks

Future Trends and Applications

Emerging directions in pharmaceutical analytics include:

• Automation and robotics for high-throughput sample preparation
• AI-driven method development and predictive chromatography
• Advanced stationary phases for challenging polar or isomeric compounds
• Hyphenated techniques combining LC, GC and high-resolution MS for comprehensive impurity profiling
• Green analytical chemistry initiatives to further reduce solvent use and waste

Conclusion

This summary highlights complete, end-to-end workflows for critical pharmaceutical analyses. By leveraging modern columns, instrumentation and method-migration strategies, laboratories can achieve superior sensitivity, regulatory compliance and operational efficiency.

References

• Thermo Fisher Scientific Application Note: HRAM LC-MS method for nitrosamine impurities in drugs
• Thermo Fisher Scientific AppsLab: Ibuprofen and valerophenone analysis
• Thermo Fisher Scientific Brochure: Hypersil GOLD HPLC columns
• Thermo Fisher Scientific Application Note: USP <467> residual solvent analysis