Analytical Workflow for Extractable and Leachable Impurities

Significance of the Topic

Testing extractables and leachables is critical to ensure patient safety and product efficacy in pharmaceutical processing and packaging. Identifying potential contaminants from equipment or contact materials helps mitigate toxicity risks and preserves drug potency.

Objectives and Study Overview

The study evaluated extractable and leachable compounds from four pharmaceutical grade O ring materials exposed to different extraction media under accelerated conditions. Key goals were to profile volatile semi volatile non volatile and elemental impurities and to demonstrate a complete analytical workflow.

Methodology and Instrumentation

Extraction protocol

• O ring samples A red B brown C white D black and blank control in water NaCl 50 percent ethanol 100 percent ethanol polysorbate and acidified media at 40°C for 30 days

Analytical methods

• Gas chromatography high resolution mass spectrometry for volatile and semi volatile organic compounds
• Liquid chromatography high resolution tandem mass spectrometry for non volatile organics
• Inductively coupled plasma mass spectrometry for elemental impurities

Key instruments

• Thermo Scientific Trace 1310 GC and Q Exactive GC mass spectrometer with Orbitrap analyzer
• UltiMate 3000 UHPLC and Q Exactive Plus LC MS MS system
• Thermo Scientific iCAP Q series ICP MS
• Software workflows TraceFinder Compound Discoverer mzCloud library and Qtegra ISDS

Main Results and Discussion

Semi volatile profiling involved deconvolution of 2000 plus peaks and high resolution filtering library matching to identify antioxidants plasticizers and processing aids. Representative compounds included tetraethylene glycol bis2ethylhexanoate Irganox 1076 diphenylcyclopropene carboxylate and di butoxyethyl adipate. Unknowns were assigned molecular formulas such as C20H20O4 and confirmed by MS MS fragmentation within 1 part per million mass accuracy.

Non volatile screening used polarity switching for full scan and data dependent MS MS enabling identification of surface treatments and oligomers via Compound Discoverer and mzCloud searches. Software automation accelerated unknown confirmation across multiple databases.

Elemental analysis demonstrated sub part per trillion detection limits and revealed trace levels of copper zinc cadmium and lead below toxicological thresholds. Rigorous quality checks following USP 233 ensured data validity over extended runs.

Benefits and Practical Applications

The integrated high resolution Orbitrap approach provides superior confidence in identifying unknown extractables while maintaining quantitation performance. Automated workflows reduce analysis time and complexity. Access to high resolution spectral libraries in the cloud enables rapid qualification of new compounds. Combined elemental screening ensures comprehensive control of metal contaminants in pharmaceutical contact materials.

Future Trends and Applications

Advances in unknown structure elucidation software will broaden capability for unanticipated leachables. Wider adoption of high resolution accurate mass data in routine quality control promises improved risk management. Emerging guidelines and standardized protocols will harmonize testing practices. Expansion of public and proprietary databases will enhance screening depth for emerging packaging and process materials.

Conclusion

This complete extractable and leachable workflow from volatiles to elemental impurities demonstrates robust sensitive and high confidence analytical solutions. Integration of GC LC and ICP MS with advanced software enables efficient risk mitigation for pharmaceutical contact materials.