Medical Device Extractables and Leachables (E&L) Testing: Methods, Standards, and Applications

Extractables and leachables (E&L) testing is a cornerstone of the chemical characterization and biological safety evaluation of medical devices, as mandated by ISO 10993-1 and ISO 10993-18. This technical article explains E&L study design, extraction strategies, analytical techniques, target analytes, and toxicological risk assessment, providing manufacturers with the knowledge needed to support compliant regulatory submissions and patient-safe product development.

Technical Overview

Medical device extractables and leachables (E&L) testing, also known as chemical characterization, is the systematic process of identifying and quantifying chemical substances that can migrate from device materials, components, or packaging into a patient during clinical use. Extractables are compounds released from a device under exaggerated laboratory conditions, such as aggressive solvents, elevated temperatures, or extended extraction times. Leachables are the subset of those compounds that actually migrate into the patient-contacting fluid or tissue under normal processing, storage, and use conditions.

Modern biocompatibility frameworks place chemical characterization at the center of the risk management process. ISO 10993-1 requires that chemical constituents be evaluated as part of the overall biological evaluation, while ISO 10993-18 specifies the methodology for characterizing materials, and ISO 10993-17 provides the framework for converting analytical results into a toxicological risk assessment. Robust E&L data can often justify a reduction in animal testing by demonstrating that patient exposure to released chemicals remains below safety thresholds.

• ISO 10993-1 – Biological evaluation of medical devices within a risk management process
• ISO 10993-12 – Sample preparation and reference materials
• ISO 10993-17 – Toxicological risk assessment of medical device constituents
• ISO 10993-18 – Chemical characterization of medical device materials
• USP General Chapters <1663> and <1664> – Best-practice guidance for extractables and leachables studies
• GB/T 16886 series – Chinese national standards harmonized with ISO 10993
• ICH Q3D and ICH Q3E – Elemental impurities and E&L guideline frameworks for combination products

Testing Samples

Polymer-Based Devices and Fluid Path Components

This category includes catheters, syringes, infusion sets, intravenous containers, extension tubing, stopcocks, dialyzers, oxygenators, breathing circuits, and wound dressings. Common materials include PVC, polyurethane, silicone elastomers, polyolefins, polycarbonate, and TPE, all of which may contain plasticizers, antioxidants, lubricants, and residual monomers that can leach into contacting fluids.

Drug-Delivery and Combination Products

Prefilled syringes, autoinjectors, metered-dose inhalers, implantable pumps, transdermal patches, and drug-eluting devices require rigorous E&L evaluation because the contact time between the drug product and the polymer or elastomer components can be long, and leachables may accumulate to significant concentrations over the shelf life.

Coated and Surface-Treated Devices

Hydrophilic lubricious coatings, antimicrobial coatings, antithrombogenic layers, and surface-modified devices are tested for coating degradation products, residual reagents, and substances released from the coating matrix during use.

Metallic and Ceramic Implants

Although often evaluated through ion-release testing, implants made of titanium alloys, cobalt-chromium alloys, and stainless steel are assessed for the release of metal ions such as Ni, Co, Cr, and V into surrounding tissue under simulated physiological conditions.

Primary Packaging and Accessories

Elastomeric closures, films, blister materials, adhesives, inks, labels, and secondary packaging that contact the device or drug product are included in E&L evaluation, particularly for sterile barrier systems and long-term storage configurations.

Testing Items

The scope of analytes is defined by the device materials, manufacturing process, sterilization method, and intended clinical use. Typical target categories include:

• Volatile organic compounds (VOCs): residual solvents, monomers, and volatile degradation products such as styrene, methyl methacrylate, toluene, and chlorinated hydrocarbons
• Semivolatile organic compounds (SVOCs): plasticizers and phthalates (DEHP, DINP, DIDP), citrate and adipate esters, hindered phenolic antioxidants (e.g., Irganox 1010, Irganox 1076), phosphite processing stabilizers (e.g., Irgafos 168), slip agents (erucamide, oleamide), and lubricants
• Nonvolatile organic compounds: oligomers, waxes, polymeric additives, and dye or pigment-related species
• Elemental impurities and metals: Pb, Cd, Hg, As, Cr, Ni, Co, V, Al, Sn, Zn, Ti, Cu, and catalyst residues, consistent with ICH Q3D principles
• Inorganic ions: chloride, sulfate, nitrate, phosphate, ammonium, and sodium, determined by ion chromatography
• Sterilant residues: ethylene oxide (EtO), ethylene chlorohydrin (ECH), and ethylene glycol (EG) per ISO 10993-7
• Emerging contaminants: nitrosamines, bisphenol A, polycyclic aromatic hydrocarbons (PAHs), and per- and polyfluoroalkyl substances (PFAS)
• Bulk screening parameters: nonvolatile residue (NVR), total organic carbon (TOC), pH, UV absorbance, turbidity, and Fourier-transform infrared (FTIR) extract profiles

Testing Methods

Extraction Study Design

Extraction conditions are selected according to ISO 10993-12 and ISO 10993-18 to be both exaggerated relative to clinical exposure and scientifically justified. Three general strategies are applied:

• Simulated-use extraction: replicates actual clinical contact conditions to estimate realistic patient exposure (leachables study)
• Accelerated or exaggerated extraction: uses elevated temperature and solvents of matching polarity to maximize release (extractables screening)
• Exhaustive extraction: repeated extractions until the released quantity falls below a defined fraction of the initial extraction, used to establish the total available pool

Solvents are chosen to represent polar (water, buffered saline), intermediate (ethanol-water mixtures), and nonpolar (hexane or similar) contact scenarios. Standard extraction conditions include 37 °C for 72 hours, 50 °C for 72 hours, 70 °C for 24 hours, or 121 °C for 1 hour, with surface-area-to-volume ratios (e.g., 6 cm²/mL) applied as specified in ISO 10993-12. Devices should be tested in their final, sterilized, and packaged condition whenever possible.

Analytical Techniques

• Headspace GC-MS: identification and quantification of volatile organic compounds
• GC-MS and GC-FID: semivolatile organics, phthalates, antioxidants, PAHs, and residual solvents, with derivatization where required
• LC-MS/MS and LC-QTOF-MS: nonvolatile, polar, and thermally labile compounds, oligomers, and accurate-mass identification of unknowns
• ICP-MS / ICP-OES: trace elements and heavy metals with ppb-level sensitivity
• Ion chromatography (IC): inorganic anions and cations
• Quantitative NMR (qNMR) and FTIR: structural confirmation and absolute quantitation of extractables
• SEC/GPC: molecular weight distribution of polymeric extractables and oligomers
• TOC, NVR, UV-Vis, and pH: complementary bulk measurements supporting mass balance

Data Evaluation and Toxicological Risk Assessment

Detected compounds are reported with an assigned identification confidence level (confirmed, probable, or tentative identifications) as described in ISO 10993-18. Results are compared against health-based thresholds: a Safety Concern Threshold (SCT), commonly set at 1.5 µg/day based on the threshold of toxicological concern, is converted into a device-specific Analytical Evaluation Threshold (AET) that accounts for product dilution volumes, extraction uncertainty factors, and the number of devices a patient may contact daily. Compounds exceeding the AET are carried forward for toxicological risk assessment under ISO 10993-17, in which tolerable intake (TI) values and margins of safety (MOS) are derived. Accredited third-party laboratories routinely perform these integrated chemistry and toxicology evaluations and deliver study reports suitable for regulatory submission.

Applications

• Regulatory submissions: supporting documentation for FDA 510(k), PMA, and De Novo submissions, EU MDR technical files, and NMPA registrations under GB/T 16886
• Biocompatibility assessment: providing weight-of-evidence justification to reduce or replace certain biological endpoint tests in line with ISO 10993-1 and ISO 10993-2
• Change control: demonstrating chemical equivalence after material, supplier, formulation, or manufacturing process changes
• Sterilization support: verification of ethylene oxide residual levels against ISO 10993-7 limits, and assessment of radiation-induced degradation products
• Stability and shelf-life studies: migration studies conducted across the product expiry period to characterize leachables growth over time
• Vendor qualification and incoming material control: screening raw polymers, elastomers, and components before production release
• Complaint and failure investigation: root-cause analysis of adverse events linked to chemical release

FAQ

What is the difference between extractables and leachables?

Extractables are compounds forced out of a material under aggressive laboratory conditions designed to reveal the full range of potential migrants. Leachables are the compounds that actually migrate into the patient-contacting medium under real conditions of storage and use. Leachables are typically a subset of extractables, though they can include reaction products formed between the device and the drug product or fluid.

Which standards govern E&L testing for medical devices?

The primary framework is the ISO 10993 series, in particular ISO 10993-1 (evaluation strategy), ISO 10993-12 (sample preparation), ISO 10993-17 (toxicological risk assessment), and ISO 10993-18 (chemical characterization). USP General Chapters <1663> and <1664> provide complementary methodological guidance, while the GB/T 16886 series applies in China. For combination products, ICH Q3D and ICH Q3E considerations may also apply.

How are extraction solvents and conditions selected?

Solvent selection mirrors the polarity of the clinically contacting medium: aqueous or buffered saline for blood and tissue contact, ethanol-water mixtures for intermediate polarity, and nonpolar solvents for lipid-contacting or long-duration exposures. Temperature and duration are chosen to be exaggerated yet chemically realistic, following the validated conditions listed in ISO 10993-12, and must be justified in the study report.

What is the Analytical Evaluation Threshold (AET)?

The AET is a device-specific reporting threshold derived from the Safety Concern Threshold (SCT). It incorporates the patient dose, dilution volume, number of devices used per day, and an uncertainty factor that accounts for analytical and extraction variability. Compounds detected above the AET require identification and toxicological evaluation, whereas those below it can generally be excluded from further assessment.

Can E&L data replace biological testing?

Chemical characterization alone does not automatically replace all biological endpoint tests, but comprehensive E&L data combined with a documented toxicological risk assessment can provide a scientific rationale for omitting certain in vivo tests, consistent with the risk-based approach of ISO 10993-1 and the animal welfare principles of ISO 10993-2. The final judgment is always made in the context of the complete biological evaluation file.

How long does a typical E&L study take?

A full extractables screening, confirmatory quantification, and toxicological risk assessment typically requires eight to sixteen weeks, depending on device complexity, the number of extraction conditions, the extent of unknown identification work, and the depth of the toxicological evaluation. Simulated-use leachables studies aligned to stability programs may run in parallel with the product shelf-life timeline.