Extractables and leachables (E&L) analysis is a critical component of medical device chemical characterization and biological safety evaluation, required under the ISO 10993 series of standards and by major regulatory authorities worldwide. This technical article explains E&L study design, applicable device sample types, target analytes, analytical methods such as GC-MS, LC-MS and ICP-MS, and the toxicological risk assessment framework used to demonstrate patient safety.
Technical Overview
Extractables and leachables (E&L) analysis is a laboratory-based discipline that identifies and quantifies chemical compounds that may migrate from medical device materials into patients during clinical use. Extractables are compounds that can be released from device materials, components, or packaging under exaggerated laboratory conditions, such as aggressive extraction solvents, elevated temperatures, or extended contact durations. Leachables are the subset of compounds that actually migrate from the device into the patient contact medium, such as body fluids, infusion solutions, or drug products, under real-world use and storage conditions.
Leachable substances originate from a wide range of material components, including polymer additives (plasticizers, antioxidants, UV stabilizers, slip agents, and pigments), residual monomers and oligomers, catalyst residues, processing aids, adhesives, coating components, sterilant residues, and material degradation products. Because patient exposure to these compounds cannot be predicted from material specifications alone, regulatory frameworks including the EU Medical Device Regulation (MDR) and FDA biocompatibility guidance require chemical characterization as a foundational element of the biological evaluation described in ISO 10993-1.
The E&L evaluation follows a risk-based, tiered approach. ISO 10993-18 governs the chemical characterization of device materials, ISO 10993-12 defines sample preparation and extraction conditions, and ISO 10993-17 provides the methodology for toxicological risk assessment of identified constituents. Complementary guidance includes USP General Chapters <1663> and <1664> on extractables and leachables associated with pharmaceutical packaging and delivery systems, as well as the Chinese national standard series GB/T 16886, which adopts the ISO 10993 framework. Analytical results are compared against thresholds such as the analytical evaluation threshold (AET) and the safety concern threshold (SCT), enabling manufacturers to justify whether further toxicological assessment or biological testing is needed.
Testing Samples
Blood-Contact and Extracorporeal Circulation Devices
Devices with direct circulating blood contact represent the highest exposure concern category. Typical samples include intravenous catheters, blood bags and donor tubing sets, hemodialyzers and dialysis tubing, blood oxygenators, extracorporeal membrane oxygenation (ECMO) circuits, transfusion filters, and heart-lung bypass components. These devices are evaluated under dynamic flow conditions where appropriate, because fluid movement can significantly increase the migration of plasticizers and other additives.
Infusion and Administration Devices
This category covers syringes, infusion sets and administration lines, intravenous solution containers (flexible bags and rigid bottles), stopcocks, extension tubes, syringe pump cassettes, and needle-free connectors. Because infusion devices deliver compounds directly into the bloodstream over extended periods, both polar leachables (such as metal ions and water-soluble organics) and lipophilic leachables (such as phthalate plasticizers) are characterized.
Implantable Devices
Implantable samples include orthopedic implants and fixation hardware, cardiovascular stents and their delivery systems, pacemakers and leads, dental materials, intraocular lenses, absorbable sutures, and tissue scaffolds. For permanent implants, exhaustive extraction studies are often performed to establish the total releasable burden of constituents, while long-duration simulated extractions model chronic exposure.
Respiratory and Anesthesia Devices
Breathing circuits, face masks, endotracheal tubes, tracheostomy tubes, humidifier chambers, and anesthesia breathing bags are evaluated for volatile and semi-volatile organic compounds, since gas-path contact can transport vapor-phase leachables such as residual monomers, lubricants, and sterilant byproducts directly to the patient airway.
Drug-Device Combination Products and Device Packaging
Testing Items
A comprehensive E&L study targets the full spectrum of compound classes that may be released from polymeric, metallic, ceramic, and elastomeric device materials. Core testing items include the following:
- Volatile organic compounds (VOCs), including residual solvents, residual monomers such as styrene and acrylamide, and volatile degradation products.
- Semi-volatile organic compounds (SVOCs), including phthalate plasticizers (DEHP, DINP, DIDP), citrate and adipate plasticizers, hindered phenol antioxidants (such as Irganox-type phenols), phosphite antioxidant degradants (such as 2,4-di-tert-butylphenol), slip agents (erucamide, oleamide), and oligomeric species.
- Non-volatile organic compounds (NVOCs), including high-molecular-weight oligomers, waxes, curing agents, and polymeric additives analyzed by LC-based methods.
- Elemental impurities and heavy metals, including lead, cadmium, mercury, arsenic, chromium, nickel, cobalt, tin, zinc, titanium, and barium, evaluated against ISO 10993-18 limits and regional elemental impurity requirements.
- Inorganic anions and cations, such as chloride, sulfate, nitrate, ammonium, and silicates, measured by ion chromatography.
- N-nitrosamines and nitrosatable precursors in elastomeric and latex components, commonly screened per ASTM F2126.
- Polycyclic aromatic hydrocarbons (PAHs) in carbon-black-containing rubbers and elastomers.
- Bisphenol A, bisphenol S, and related phenolic compounds from polycarbonate and epoxy-based materials.
- Ethylene oxide, ethylene chlorohydrin, and ethylene glycol residuals following gas sterilization, per ISO 10993-7.
- Emerging contaminants of concern, including per- and polyfluoroalkyl substances (PFAS) from fluoropolymer coatings and tubing, and terephthalate oligomers from polyester materials.
Testing Methods
Extraction Study Design
Extraction conditions are selected based on the device's clinical use duration and contact category, following ISO 10993-12 principles. Three general extraction strategies are applied: simulated-use extraction, which replicates actual clinical exposure; exaggerated extraction, which uses elevated temperature, extended duration, or stronger solvents to provide a safety margin; and exhaustive extraction, which repeats extraction until no additional analyte is released, typically reserved for permanent implants. Extraction media span the polarity range, commonly including water or saline for polar compounds, ethanol-water mixtures for semi-polar compounds, and hexane or isopropanol for non-polar compounds. Temperature conditions typically range from 37°C for physiological simulation up to 70°C for exaggerated studies, with extraction durations from 24 hours to 72 hours or longer as justified by the risk assessment.
Analytical Techniques
No single instrument can detect the full E&L chemical space, so studies combine complementary chromatographic and spectrometric platforms. Headspace GC-MS is used for volatile organic compounds, direct-injection GC-MS with EI ionization for semi-volatile organics, and pyrolysis-GC-MS for insoluble polymeric materials. LC-MS/MS and high-resolution LC-QTOF-MS provide detection of thermally labile and non-volatile compounds with accurate-mass identification. ICP-MS or ICP-OES quantifies elemental impurities, and ion chromatography measures ionic species. FTIR spectroscopy supports material and extract screening, NMR provides structural elucidation for unknowns, and size-exclusion chromatography characterizes oligomer distributions. Quantitation is typically performed using structurally representative internal standards, with relative response factors applied across each compound class.
Data Interpretation and Toxicological Assessment
Unknown compounds are identified using mass spectral libraries, accurate mass data, and where necessary, authentic standards, with identification confidence levels documented. The analytical evaluation threshold is calculated from the safety concern threshold, the dose or exposure basis, and uncertainty factors accounting for method response variability. Constituents detected above the AET are carried forward to toxicological evaluation per ISO 10993-17, in which estimated patient exposures are compared with health-based exposure limits to calculate margins of safety. Where a compound lacks compound-specific toxicological data, the threshold of toxicological concern (TTC) framework is applied. This structured workflow allows manufacturers to close biological evaluation endpoints chemically, reducing unnecessary animal testing in accordance with ISO 10993-2.
Applications
Extractables and leachables studies support medical device manufacturers, material suppliers, and contract developers across the complete product lifecycle. Key applications include:
- Regulatory submissions, including FDA 510(k) and PMA filings, CE technical documentation under the EU MDR, NMPA registration dossiers, and submissions to other national authorities.
- Chemical characterization within ISO 10993-1 biological evaluation plans, providing the data required to justify the selection or waiver of biological endpoint tests.
- Material selection, vendor qualification, and incoming material control programs during design and development.
- Change control and material equivalency assessments when suppliers, formulations, or manufacturing processes are modified.
- Evaluation of sterilization method impact, including ethylene oxide residual determination and assessment of radiation-induced degradation products.
- Support of stability and shelf-life studies for drug-device combination products and solution-contacting devices.
- Complaint investigation, adverse event root cause analysis, and post-market surveillance activities.
Accredited third-party laboratories with validated E&L platforms are frequently engaged to perform these studies, providing ISO/IEC 17025-aligned data packages that withstand regulatory scrutiny in multiple jurisdictions simultaneously.
FAQ
What is the difference between extractables and leachables?
Extractables are compounds released under forced laboratory conditions such as aggressive solvents, elevated temperature, and extended time, representing the maximum possible release from a material. Leachables are the compounds that actually migrate into the patient or drug product under normal clinical use and storage conditions. Leachables are typically a subset of the extractables profile, although they may include reaction or degradation products formed under real conditions.
Which medical devices require E&L testing?
Any device with patient-contacting materials can benefit from chemical characterization, but E&L studies are most critical for blood-contacting devices, long-term contacting devices, implants, infusion and administration sets, respiratory gas-path devices, and drug-device combination products. The required depth of study is determined by contact duration, contact category, and the risk analysis described in ISO 10993-1.
What is the Analytical Evaluation Threshold (AET)?
The AET is the concentration above which an extracted compound must be reported and toxicologically evaluated. It is derived from the safety concern threshold, the patient exposure basis, the volume or mass of extract, and an uncertainty factor accounting for analytical response variability. Compounds reported below the AET are considered toxicologically negligible without further assessment.
How long does an E&L study take?
Typical timelines range from eight to sixteen weeks, depending on the number of extraction conditions, the complexity of the extract profile, the extent of unknown identification work, and whether a full toxicological risk assessment report is included. Exhaustive extraction studies for implants and combination-product leachables studies tied to stability programs may require longer durations.
Can E&L data replace biological testing?
Chemical characterization alone does not replace all biological endpoints, but robust E&L data combined with a toxicological risk assessment per ISO 10993-17 and ISO 10993-18 can be used to justify waiving specific biological tests, such as certain systemic toxicity or genotoxicity endpoints. This chemical-based waiver approach must be scientifically documented and is increasingly accepted by regulatory authorities as part of a risk management file.
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