Solutions for pharmaceutical, medical device extractables and leachables analysis

Significance of the topic

Extractables and leachables (E&L) testing is critical for ensuring the safety and regulatory compliance of pharmaceuticals, biologics, medical devices and their packaging. Migration of volatile, semi-volatile, non-volatile organic compounds, PFAS and elemental impurities from contact materials into drug products or biological interfaces can present toxicological risks and lead to product recalls. Modern E&L workflows emphasize sensitive, high-confidence identification and quantification, minimized sample preparation artifacts, higher throughput, and regulatory traceability.

Objectives and overview

This document presents an integrated approach and product ecosystem for E&L investigations across pharmaceutical container-closure systems, single-use manufacturing components and medical devices. The primary goals are to (1) provide faster, solvent-sparing extraction and sample preparation; (2) implement complementary targeted and non-targeted analytical platforms for volatiles, semi-volatiles, non-volatiles, PFAS and elemental impurities; and (3) deliver compliant data acquisition, processing and reporting to support risk assessment and regulatory submissions.

Methodology and workflow

• Extraction and concentration: Accelerated Solvent Extraction (ASE) is recommended as an automated alternative to Soxhlet, enabling extractions in ~0.5 h and using <30 mL solvent per sample versus >24 h and >150 mL for classical methods. Automated evaporation concentrates extracts up to ~200×.
• Volatile analysis: Headspace sampling with automated TriPlus 500 autosamplers coupled to GC or HS-GC and single-quadrupole or GC-MS systems for residual solvent and low molecular weight volatiles.
• Semi-volatile analysis: GC-MS/MS and HRAM GC (Orbitrap Exploris GC) workflows provide targeted quantitation and untargeted discovery with high mass accuracy for semi-volatiles; derivatization is used when needed.
• Non-volatile analysis: UHPLC–HRAM MS (Vanquish + Orbitrap Exploris 120) with complementary detectors (DAD, charged aerosol) and advanced software for structure elucidation and library searching.
• PFAS analysis: A combined targeted and non‑targeted LC‑HRAM MS approach (polarity-switched Full Scan-ddMS2) using PFAS-specific kits and a delay column to suppress background. Achieved limits of quantitation down to ~0.1 ppb for a panel of PFAS while enabling discovery of unknowns.
• Elemental impurities: Trace and ultra-trace metals analysis by ICP-MS (iCAP MX series) and ICP-OES/AA as complementary techniques, following ICH Q3D and USP <232>/<233> guidance.
• Data management and compliance: Chromeleon CDS, Qtegra and Compound Discoverer software enable 21 CFR Part 11–capable acquisition, automated QC checks, unified reporting and high-resolution spectral library searching (mzCloud).

Used instrumentation

• Dionex ASE 350 Accelerated Solvent Extractor and automated evaporators (Rocket Evaporator)
• Thermo Scientific TriPlus 500 and TriPlus RSH autosamplers for headspace and liquid injection
• TRACE 1600 GC and TRACE 1610 GC
• ISQ 7610 single-quadrupole GC-MS; TSQ 9610 GC-MS/MS
• Orbitrap Exploris GC 240 (GC‑HRAM) and Orbitrap Exploris 120 (LC‑HRAM)
• Vanquish UHPLC systems with Charged Aerosol Detector
• Chromeleon CDS and Compound Discoverer software; mzCloud spectral library
• iCAP MX series ICP‑MS, ICP‑OES and AA systems
• Consumables: SureSTART and MS Certified vials, TraceGOLD and other GC/LC columns, PFAS analysis kit and delay column

Main results and discussion

• ASE provides comparable or improved extraction efficiency versus traditional Soxhlet while reducing extraction time from days to under an hour and lowering solvent consumption by a factor of ~5 or more.
• HRAM Orbitrap systems deliver sub-ppm mass accuracy across concentrations, improving confidence in elemental formula assignment and structural elucidation for unknowns; this capability supports robust deconvolution and reduced false positives.
• PFAS workflow combining targeted quantitation and non-targeted screening from a single LC‑MS injection enables reliable detection at sub-ppb LOQs for multiple PFAS analytes and supports discovery of unknown fluorinated species while minimizing background using dedicated kits and hardware.
• Integrated software and cloud spectral libraries (mzCloud) accelerate unknown identification by combining multiple search strategies and detectors (MSn, DAD, CAD), producing unified reports suitable for regulatory review.
• ICP-MS solutions provide the sensitivity and throughput needed to meet ICH Q3D and USP elemental impurity limits with automated routines and QA/QC logging.

Benefits and practical applications

• Higher throughput and lower cost-per-sample via automated ASE extraction, fast evaporation and autosampling.
• Reduced solvent use and improved laboratory sustainability without compromising extraction performance.
• Comprehensive coverage across analyte classes (volatiles to metals) in harmonized workflows supports a single-vendor approach to method development and troubleshooting.
• Improved confidence in unknown identification through HRAM MS, spectral libraries and combined detector data.
• Regulatory readiness: software and workflows designed to support 21 CFR Part 11, GMP/GLP environments and ICH/USP guidance for E&L and elemental impurities.
• PFAS-specific capability helps organizations proactively address regulatory scrutiny on fluorinated chemistries in manufacturing and packaging.

Future trends and potential applications

• Intensifying regulatory focus on PFAS and other emerging contaminants will drive broader adoption of sensitive LC‑HRAM PFAS workflows and passive monitoring across supply chains.
• Greater automation of sample preparation, instrument setup and QC will reduce hands-on time and variability while enabling higher throughput in regulated labs.
• Expansion of cloud-based, annotated HRAM spectral libraries and AI-driven algorithms will accelerate unknown structural elucidation and reduce manual interpretation time.
• Integration of orthogonal detectors and multi-technique data fusion (GC, LC, HRAM MS, CAD, DAD, ICP-MS) will become standard for comprehensive E&L characterization.
• Sustainability-driven method optimisation (lower solvent volumes, greener extraction chemistries) will continue to be an operational priority.

Conclusion

A modern E&L program couples optimized sample preparation (e.g., ASE), complementary analytical platforms (GC/HS-GC, GC‑MS/MS, GC‑HRAM, UHPLC‑HRAM, ICP‑MS) and compliance-ready data systems to deliver rapid, sensitive and defensible characterization of extractables and leachables. Implementation of PFAS-aware workflows and comprehensive elemental impurity testing aligns analytical capability with evolving regulatory expectations and reduces product risk throughout development and manufacturing.

References

1. United States Pharmacopeia (USP) chapters cited: USP <381>, <660>, <661>, <665>, <1663>, <1664>, <1665>.
2. PQRI and BPOG guidelines on extractables and leachables.
3. ASTM F1980-07 (accelerated aging of packaging).
4. ISO 10993 series, including ISO 10993-18 for extractables and leachables.
5. International Council for Harmonisation (ICH) guidance Q3 and Q3D on impurities and elemental impurities.
6. USP <232>, <233> and <2232> for elemental impurities and related methods.