Solutions for pharmaceutical, medical device extractables and leachables analysis

Importance of the topic

Extractables and leachables (E&L) analysis is critical for ensuring safety and regulatory compliance of pharmaceutical and biopharmaceutical products, medical devices, and their packaging and manufacturing consumables. Migrating organic compounds, high molecular weight additives, PFAS, and elemental impurities can compromise product quality or pose toxicological risk. Effective E&L workflows protect patients, reduce risk of recalls, and support lifecycle management as regulatory scrutiny increases globally.

Objectives and overview of the document

• Provide a comprehensive workflow for detection, identification and quantitation of volatiles, semi-volatiles, non-volatiles, PFAS and elemental impurities originating from container-closure systems, single-use systems, medical devices and related consumables.
• Present strategies to accelerate and automize extraction and sample preparation while maintaining analytical confidence and regulatory compliance (e.g., 21 CFR Part 11, ICH Q3D/USP chapters).
• Recommend instrumental platforms and software that support untargeted screening and targeted quantitation across compound classes and matrices.

Methodology and workflow

The recommended E&L workflow is modular and tailored to analyte volatility and chemistry: volatiles (headspace GC-MS), semi-volatiles (GC‑MS or LC‑HRAM), non-volatiles (UHPLC‑HRAM MS), PFAS (targeted LC‑MS with HRAM screening), and elemental impurities (ICP‑MS/ICP‑OES/AA). Key methodological features include:

• Sample extraction: use Accelerated Solvent Extraction (ASE) to replace Soxhlet/reflux approaches—ASE reduces extraction time (<0.5 h per sample), solvent use (<30 mL/sample) and risk of thermal degradation while providing reproducible, controlled extractions.
• Concentration and cleanup: automated evaporation and concentration workflows to achieve necessary enrichment (up to ~200×) while minimizing contamination and losses.
• Volatile analysis: headspace autosampling for residual solvents and low molecular weight volatiles followed by GC-MS or HS‑GC-FID/GC‑MS/MS for qualitative and quantitative determinations.
• Semi-volatile and non-volatile screening: combination of targeted MS/MS (triple quadrupole) for sensitive quantitation and HRAM (Orbitrap) full-scan with data-dependent MS2 for unknown identification and formula confirmation.
• PFAS analysis: combined targeted quantitation and non-targeted screening in a single LC‑MS injection using polarity-switching Full Scan-ddMS2 HRAM acquisition, PFAS-specific kits and delay columns to minimize background contamination and reach sub‑ppb LOQs.
• Elemental impurities: compliant trace elemental quantitation using ICP‑MS (for lowest limits) with QC workflows and software for automation of tuning, calibration and LabBook QC reporting per pharmacopeial guidance.
• Data processing: integrate spectral library searching (mzCloud and cloud HRAM libraries), advanced unknown-ID software (e.g., Compound Discoverer), and compliant CDS (Chromeleon, Qtegra) to streamline identification, quantitation and audit-ready reporting.

Used instrumentation

The document highlights a suite of analytical platforms that together address the breadth of E&L challenges:

• Accelerated Solvent Extractor (Dionex ASE 350) and automated evaporators for extraction and concentration.
• Headspace autosampler (TriPlus 500) coupled to GC systems (TRACE 1600/1610) and ISQ/TSQ GC‑MS and GC‑MS/MS instruments for volatiles/semi-volatiles.
• Orbitrap Exploris GC and Orbitrap Exploris/Orbitrap 120 HRAM MS for high-resolution GC and LC analysis enabling <1 ppm mass accuracy for confident elemental composition and structural elucidation.
• Vanquish UHPLC and Vanquish Core HPLC systems with Charged Aerosol Detector for non-volatile separations and near-universal detection.
• TSQ 9610 GC‑MS/MS and other triple quadrupole systems for targeted sensitive quantitation.
• iCAP MX series ICP‑MS for trace elemental impurity analysis compliant with ICH Q3D and USP <232>/<233> requirements; ICP‑OES and AA offered for fit-for-purpose alternatives.
• Chromeleon CDS, Qtegra ISDS, Compound Discoverer and mzCloud spectral resources for data acquisition, processing, unknown identification and regulatory-compliant reporting.

Main results and discussion

Although the document is a solutions brochure rather than a single study, it synthesizes best practices and performance claims relevant to E&L testing:

• ASE extraction provides comparable or improved recoveries versus Soxhlet with dramatically reduced time and solvent consumption, enabling higher throughput and lower environmental impact.
• Combining targeted MS/MS with HRAM full-scan allows both sub‑ppb quantitation (for regulatory targets like PFAS) and discovery of unknowns with high mass accuracy (<1 ppm), improving confidence in structural assignments and reducing false positives.
• Use of PFAS-specific consumables (kits and delay columns) substantially reduces background PFAS contamination, which is critical to reach low limits of quantitation and avoid artifactual detections.
• Integrated software ecosystems (CDS + unknown-ID + spectral libraries) streamline workflows from instrument control through data review and compliant reporting, reducing manual intervention and increasing reproducibility.

Benefits and practical applications

• Robust detection and identification across volatility classes enable comprehensive risk assessment for container-closure systems, single-use manufacturing components, and medical devices used in drug handling and delivery.
• Higher throughput extraction and automated sample handling reduce turnaround time and cost per sample while maintaining analytical rigor required for regulatory submissions.
• Capability to detect trace PFAS and elemental impurities supports proactive monitoring in supply chains and helps avoid recalls or regulatory non-compliance.
• HRAM workflows facilitate dereplication and structural elucidation of unknown extractables, supporting formulation and material selection decisions early in development.

Future trends and possibilities for use

• Broader adoption of HRAM spectrometry and integrated library-driven identification will further reduce uncertainty in unknown identification and enable harmonized reporting across laboratories.
• Continued development of PFAS‑free consumables and more sensitive PFAS workflows will become standard as regulatory limits tighten and environmental persistence concerns grow.
• Automation in sample preparation, instrument setup and QC reporting—coupled with AI-driven spectral interpretation—will increase throughput and reduce subjective decision‑making in E&L assessments.
• Cloud-based spectral libraries and collaborative data-sharing initiatives will improve cross-industry identification of novel extractables and speed risk assessments.

Conclusion

A comprehensive, multi-platform analytical strategy combining accelerated extraction, headspace GC, targeted MS/MS and HRAM LC/GC analysis, plus robust trace elemental techniques, provides the breadth and depth required for modern extractables and leachables programs. Adoption of automated, contamination‑aware workflows and integrated data software improves efficiency and regulatory confidence, enabling proactive material selection and risk mitigation across pharmaceutical and medical device supply chains.

Reference

• Regulatory and guidance documents referenced: ICH Q3/Q3D, USP chapters <381>, <660>, <661>, <665>, <1663>, <1664>, <1665>, USP <232>/<233>/<2232>, PQRI and BPOG guidelines, ASTM F1980-07, ISO 10993 series.
• Key analytical platforms and software noted: Accelerated Solvent Extractor (ASE 350), TriPlus 500 Headspace Autosampler, TRACE series GC, ISQ/TSQ GC-MS/MS, Orbitrap Exploris GC and LC mass spectrometers, Vanquish UHPLC systems, iCAP MX ICP‑MS, Chromeleon CDS, Qtegra ISDS, Compound Discoverer, mzCloud library.