APPLICATION NOTEBOOK - IMPURITIES - Developing Safe and Effective Drugs

Significance of the Topic

Extractables and leachables analysis is critical to ensuring the safety and efficacy of pharmaceutical and food packaging. Investigations of material–compound interactions help prevent contamination of drugs and food products by compounds migrating from packaging or processing materials. Recent regulatory guidances demand comprehensive profiles of extractables to safeguard consumer health and meet compliance requirements.

Aims and Study Overview

This compilation reports advances in sample extraction and analysis of extractable compounds using two complementary techniques: supercritical fluid extraction (SFE) enabled by the Waters MV-10 ASFE system and UltraPerformance Convergence Chromatography (UPC™2) on the ACQUITY UPC2 System. The goals are to simplify workflows, reduce solvent consumption, increase throughput, and maintain broad chemical coverage from non-polar to polar analytes.

Methodology and Instrumentation

• Sample Preparation: Extraction of polymer and packaging materials via SFE using CO₂ and a cosolvent (methanol or isopropanol), compared to conventional Soxhlet extraction.
• Chromatography: Analysis on the ACQUITY UPC2 System with BEH 2-EP columns, employing CO₂ with organic modifier gradients to separate extractable components.
• Detection: Ultra-violet detection with the ACQUITY UPC2 PDA and mass detection using the ACQUITY QDa Mass Detector or Xevo TQ for targeted screening.
• Software: Data acquisition and processing with Empower Chromatography Data Software and MassLynx software; method development guided by Fusion QbD software for related studies.

Key Results and Discussion

• SFE versus Soxhlet: SFE achieved equivalent or better recoveries of non-polar and moderately polar extractables in minutes instead of hours, reducing solvent use by >90% and run times by 75%.
• Workflow Integration: Direct injection of SFE extracts into the UPC2 system provided streamlined sample-to-data workflows, eliminating intermediate concentration and cleanup steps.
• UPC2 Selectivity: Convergence chromatography separated a broad range of extractables—from hydrophobic antioxidants to polar leachables—using optimized gradients within 5–8 minutes.
• UV Sensitivity Enhancement: Implementing PDA reference-wavelength compensation improved S/N by 3–5×, enabling detection limits down to sub-ng levels for trace extractables.
• QbD Method Development: Design-of-experiments using Fusion software on UPLC accelerated impurity method creation for vancomycin and ziprasidone, delivering robust methods amenable to future adjustments.

Benefits and Practical Applications

• Substantial time and solvent savings in extractables sample prep and analysis, lowering operational costs and environmental impact.
• High throughput and flexible analysis for diverse extractable classes—with broad polarity range—using a single chromatography platform.
• Improved sensitivity and robustness for trace-level extractable detection via consolidation of extraction and analysis techniques.
• Streamlined method transfer from UPLC to HPLC ensures that optimized methods are deployable in quality-control laboratories without UPLC equipment.

Future Trends and Opportunities

• Expansion of SFE–UPC2 workflows to cover highly polar and ionic leachables through novel cosolvent systems or inline derivatization.
• Further integration of automated method development and QbD principles to accelerate compliance-driven extractables testing.
• Coupling UPC2 with high-resolution MS/MS for untargeted screening and structural elucidation of unknown migrating compounds.
• Implementation of data-management platforms with predictive analytics to correlate extractables profiles with material formulations and long-term stability.

Conclusion

Combining supercritical fluid extraction with UltraPerformance Convergence Chromatography offers a powerful, streamlined approach to extractables analysis. This workflow delivers rapid, sensitive, and robust detection of a wide chemical space, while dramatically reducing time, solvent consumption, and complexity. The integration of modern software for method development and data processing further enhances productivity and compliance readiness for pharmaceutical and packaging industries.

Reference

• ICH Q3E: Assessment of Extractables and Leachables in Pharmaceutical Development Guidance, 2018.
• Flick, E.W. Microwave Assisted Sample Preparation in Analytical Chemistry. ACS Symposium Series 960, 2007.
• Ganster, J., et al. Supercritical Fluid Extraction and Chromatography. CRC Press, 2005.
• Waters Application Notes: Streamlining Extractables Analysis Using MV-10 ASFE and UPC2, 2014; Enhanced UV Sensitivity in SFC, 2010.