Solutions for pharmaceutical, medical device extractables and leachables analysis

Importance of the topic

Extractables and leachables (E&L) analysis is essential for ensuring the chemical safety and regulatory compliance of pharmaceuticals, biologics and medical devices. E&L testing identifies and quantifies compounds that can migrate from container-closure systems, single-use manufacturing components, medical devices and packaging into drug products. Growing regulatory scrutiny (FDA, EMA, ICH, USP, ISO) and emerging concerns such as PFAS contamination and elemental impurities make robust, high-confidence analytical workflows critical for product safety, supply-chain control and avoidance of costly recalls or delays.

Objectives and overview of the material

This brochure describes integrated laboratory workflows, instrumentation and consumables supporting comprehensive E&L programs across volatiles, semi-volatiles, non-volatiles, PFAS and elemental impurities. Key goals presented are: maximize sensitivity and throughput, minimize sample preparation time and background contamination, enable untargeted and targeted screening, and deliver regulatory-compliant data management for risk assessment and release decisions.

Methodology and analytical workflows

• Extraction: Accelerated solvent extraction (ASE) is proposed as an automated alternative to traditional Soxhlet/reflux methods. ASE reduces extraction time to <0.5 h/sample and solvent consumption to <30 mL/sample while maintaining controlled temperature and pressure to avoid sample deformation.
• Volatiles: Headspace sampling followed by GC or GC–MS (including HS-GC and single quadrupole GC-MS) for residual solvents and low molecular weight VOCs. Emphasis on automated headspace autosamplers to improve throughput and reduce manual sample prep.
• Semi-volatiles: Liquid injection (with optional derivatization) followed by GC–MS/MS or HRAM GC-MS for confident qualitative and quantitative analysis. Targeted and untargeted approaches are recommended for frequent E&L semi-volatiles.
• Non-volatiles: UHPLC–HRAM MS workflows with orthogonal detectors (DAD, CAD, HRAM MS) and spectral library searching for complex, high molecular weight migrants, oligomers and polymer additives.
• PFAS: Combined targeted quantitation and non-targeted screening in a single LC-MS injection using polarity switching Full Scan-ddMS2 HRAM Orbitrap detection, PFAS-specific kits and delay columns to reduce background and achieve LOQs to ~0.1 ppb for a panel of PFAS.
• Elemental impurities: ICP-MS and ICP-OES approaches aligned with ICH Q3D and USP <232>/<233> requirements for trace metals; emphasis on compliant software-controlled workflows and automation for routine performance checks and calibration.
• Data handling: Use of 21 CFR Part 11-compliant chromatography and MS data systems, plus specialized software for unknown identification (Compound Discoverer, mzCloud spectral searching) and unified reporting across detectors.

Instrumentation used

• Accelerated Solvent Extraction: Dionex ASE 350 system.
• Evaporation / Concentration: Automated fast evaporators (Rocket Evaporator) to achieve up to ~200× concentration.
• Volatiles: TriPlus 500 Headspace Autosampler, TRACE 1600 GC, ISQ 7610 single-quadrupole GC-MS.
• Semi-volatiles (GC): Orbitrap Exploris GC 240 Mass Spectrometer, TSQ 9610 GC-MS/MS, TRACE 1610 GC.
• Non-volatiles (LC): Vanquish UHPLC systems coupled to Orbitrap Exploris 120/Orbitrap MS platforms; Charged Aerosol Detector (CAD); DAD detectors.
• PFAS workflow: Vanquish UHPLC with Orbitrap Exploris 120 HRAM LC-MS; PFAS-specific kits and delay columns; Chromeleon CDS for compliant acquisition.
• Elemental impurities: iCAP MX Series ICP-MS, ICP-OES and AA as fit-for-purpose alternatives; Qtegra and AutoTune/QC LabBook software for automated workflows and 21 CFR Part 11 readiness.
• Consumables: Low-background autosampler vials (SureSTART, MS Certified), TraceGOLD and other GC/LC columns, certified vial kits and septa.

Main findings and discussion

The material synthesizes an end-to-end strategy for E&L that balances speed, sensitivity and confidence: ASE plus automated concentration substantially reduces sample-preparation time and solvent use compared with Soxhlet/reflux while delivering equivalent extraction efficiency. HRAM Orbitrap MS applied to both GC and LC enables sub-ppm mass accuracy (<1 ppm stated) across concentrations, greatly improving unknown identification and deconvolution. For PFAS, the combined targeted and non-targeted LC–HRAM method attains LOQs near 0.1 ppb for 17 PFAS, with reduced background using PFAS-specific consumables. ICP-MS systems are positioned to meet ICH Q3D and USP elemental impurity thresholds with compliant software and automated checks to facilitate routine laboratory operation. The brochure stresses the importance of low-background consumables and validated data systems to minimize false positives and ensure defensible results.

Benefits and practical applications

• Regulatory readiness: Workflows align with industry standards and regulatory chapters (ICH, USP, ISO), supporting risk assessments and submission needs.
• Higher confidence in unknown identification: HRAM MS and integrated spectral libraries increase the certainty of structural assignments for non-targets.
• Operational efficiency: Automation in extraction, concentration and sampling reduces analyst time, throughput bottlenecks and solvent consumption.
• Lower detection limits for critical analytes: PFAS sub-ppb LOQs and trace elemental capability address emerging regulatory pressures.
• Modular and unified reporting: Integrated software ecosystems offer 21 CFR Part 11-compliant data management and streamlined reporting across platforms.

Future trends and potential applications

• Increased regulatory specificity for PFAS and other persistent contaminants will drive routine PFAS monitoring and method standardization in pharma supply chains.
• Greater adoption of HRAM MS for GC workflows will expand non-target discovery capabilities for semi-volatile and volatile migrants.
• Automation and cloud-enabled spectral libraries will accelerate cross-laboratory identification and reduce turnaround for investigations.
• Miniaturized and greener extraction techniques will continue to reduce solvent usage and laboratory waste while maintaining extraction efficiency.
• Integration of orthogonal detectors and multi-omics-style data fusion will improve structural elucidation for complex polymer-derived leachables.

Conclusion

A robust E&L program combines automated, efficient extraction and concentration, sensitive targeted assays and comprehensive HRAM-based untargeted screening, supported by low-background consumables and compliant data systems. Together these elements enable pharmaceutical and medical device manufacturers to detect, identify and quantify a broad range of leachables and extractables—volatile to non-volatile and metals—thereby supporting safety assessments, regulatory compliance and supply-chain assurance.

References

• International Council for Harmonisation (ICH) Q3D Guideline for Elemental Impurities.
• United States Pharmacopeia (USP) chapters: <1113?> (note: USP references in the source include <381>, <1663>, <660>, <1664>, <661>, <1665>, <665>—refer to actual USP chapter texts for details).
• PQRI and BPOG guidance documents on extractables and leachables.
• ISO 10993-18: Biological evaluation of medical devices — Chemical characterization of materials.
• ASTM F1980: Accelerated aging of sterile medical device packaging.