The Doctor Did Not Prescribe Irgafos: A Solution for Extractables and Leachables Analysis

Importance of the topic

Extractables and leachables (E&L) analysis is a critical component in ensuring the safety, quality, and regulatory compliance of modern products. Chemical impurities migrating from packaging, single-use bioprocess systems, medical devices, and consumer electronics can compromise therapeutic efficacy, pose health risks, and delay product approvals. Comprehensive E&L studies help manufacturers anticipate potential contaminants and support risk assessment and market clearance.

Objectives and Study Overview

This work presents an integrated workflow leveraging Thermo Scientific technologies for efficient characterization of extractable and leachable species, with a focus on Irgafos® 168 and related polymer additives. Key aims include demonstrating accelerated extraction techniques, high-resolution mass spectrometry for identification and quantification, and software-driven data processing to meet stringent regulatory guidelines.

Methodology and Instrumentation

Extraction and sample preparation:

• Accelerated Solvent Extraction (ASE 350): 30-minute automated extraction under pressure and heat, nitrogen-purged to prevent oxidation.
• Comparison to traditional Soxhlet: ASE uses <30 mL solvent vs 160 mL, 30 min vs 24 h, achieving 1.4×–90× higher extractable intensities.

Volatile and semi-volatile analysis:

• TriPlus 300 Headspace sampler and Trace 1310 GC with TG-624SilMS column.
• ISQ Series single-quadrupole and high-resolution Orbitrap GC-MS/MS for deconvolution and empirical formula assignment.

Non-volatile analysis and quantification:

• Vanquish UHPLC coupled to Q Exactive Plus hybrid quadrupole-Orbitrap MS/MS for full-scan and data-dependent MS2.
• Charged Aerosol Detector (CAD) for universal detection without chromophores, enabling relative quantification.
• Targeted quantification of Irganox 1035 at 50 ppt in both positive and negative ion modes.

Elemental impurity profiling:

• iCAP RQ ICP-MS with Qtegra software for fully compliant USP <232>/<233> and ICH Q3D workflows, incorporating in-line autodilution.

Data analysis and structure elucidation:

• TraceFinder for targeted screening and quantitation.
• Compound Discoverer with FISh scoring, custom E&L mass lists, and ChemSpider/MzCloud libraries for de novo elucidation.
• MzCloud and mzVault for high-quality reference spectra and substructure searches.

Main Results and Discussion

The ASE approach dramatically shortened extraction time and reduced solvent usage while maintaining or enhancing recovery of additives, impurities, and degradation products such as irradiated Irgafos 168 derivatives. Headspace GC-MS confidently quantified residual solvents analogous to USP 467 protocols. High-resolution GC-MS delivered limits of detection down to 2 fg on-column with over six orders of linearity. UHPLC-HRMS identified 15–20 non-volatile extractables from IPA/H2O IV bag extracts, supported by MS/MS annotation and FISh scoring. CAD complemented MS by revealing components lacking UV response, streamlining AET (analytical evaluation threshold) assessments. ICP-MS achieved robust multielement profiling for regulatory submission.

Benefits and Practical Applications

• Comprehensive coverage across volatility and polarity scales in a single laboratory setup.
• High throughput and reduced solvent usage accelerate E&L screening in early product development.
• Regulatory compliance demonstrated for USP and ASTM guidelines, facilitating submissions.
• Adaptable to biopharmaceutical single-use systems, medical packaging, food contact materials, and consumer electronics.

Future Trends and Potential Applications

• Enhanced automation integrating extraction, separation, detection, and data processing.
• Expansion of high-resolution spectral libraries and AI-driven structure elucidation tools.
• Advancements in multidimensional chromatography and ion mobility for complex mixtures.
• Broader adoption of universal detectors and orthogonal analytics for comprehensive impurity profiling.
• Evolution of regulatory frameworks to address novel materials and nanotechnology-based systems.

Conclusion

Thermo Scientific’s suite of extraction technologies, chromatography systems, mass spectrometers, detectors, and software provides a robust, end-to-end solution for extractables and leachables analysis. By combining accelerated extraction, high-resolution MS, universal detection, and advanced data workflows, laboratories can achieve rapid, sensitive, and compliant characterization of potential contaminants, ultimately supporting product safety and regulatory approval.

Reference

• Fouyer K et al., Analytical Chemistry, 2012, 84(20):8642–8649.