Medical Device Extractables and Leachables (E&L) Testing: Technical Overview, Methods, and Regulator

Medical device extractables and leachables (E&L) testing is a core element of chemical characterization and biological safety evaluation required under the ISO 10993 framework and by regulatory authorities worldwide. This technical guide explains E&L study design, extraction conditions, analytical techniques, and toxicological risk assessment approaches to help manufacturers build compliant, science-based safety dossiers for product registration and material change control.

Technical Overview

Extractables and leachables (E&L) testing, often referred to as extractables/leachables characterization or chemical extraction testing, is the systematic process of identifying and quantifying chemical substances that migrate from medical device materials, components, or packaging into patients or contact media during clinical use. As part of the biological evaluation of medical devices defined by ISO 10993-1, chemical characterization has become the preferred first step in toxicity assessment because it replaces or reduces the need for animal testing and provides quantitative, analyte-specific safety data.

The key technical principles include:

• Extractables are compounds released from device materials under exaggerated or aggressive laboratory conditions (elevated temperature, extended duration, strong solvents) designed to reveal the full inventory of potential migrants.
• Leachables are compounds that actually migrate under real or simulated clinical use conditions, such as during infusion, dialysis, storage of a drug product, or long-term implantation.
• Correlation between extractables and leachables studies allows targeted quantitation of clinically relevant analytes and demonstrates that the exaggerated extraction covers worst-case patient exposure.

The primary governing standards and references include ISO 10993-18 (chemical characterization of medical device materials), ISO 10993-12 (sample preparation and reference materials), ISO 10993-17 (toxicological risk assessment and allowable limits), USP General Chapters <1663> and <1664> for extractables and leachables assessment, USP <661.1> and <661.2> for plastic materials and systems, the Chinese GB/T 16886 series (harmonized with ISO 10993), the emerging ICH Q3E guideline, and FDA guidance on biocompatibility and chemical assessment of medical devices.

Testing Samples

Direct and Indirect Blood-Contact Devices

Devices with circulatory contact carry the highest exposure risk per unit time. Typical test articles include intravenous infusion sets, syringes and needles, extension lines, stopcocks, blood bags, hemodialyzers, extracorporeal circuit tubing, oxygenators, and cell separation sets. Extraction is generally performed with polar media (water or saline) and, where lipid-contacting drugs are administered, with mixed solvent systems.

Implantable and Long-Term Contact Devices

Implants release substances over months or years, requiring exhaustive or accelerated extraction to estimate cumulative exposure. Examples include vascular stents and delivery systems, orthopedic implants and bone cements, cardiac pacemakers and leads, hernia meshes, occluders, absorbable scaffolds, and intraocular lenses.

Drug-Device and Biologic-Device Combination Products

Prefilled syringes, autoinjectors, inhalation devices, infusion pumps, drug-eluting stents, and dual-chamber containers require leachables profiling of the actual drug product or simulated formulation under real-time and accelerated storage conditions, because the drug vehicle can act as a powerful extracting medium.

Device Packaging and Labeling Components

Blister films, thermoformed trays, pouches, closures, laminates, inks, adhesives, and secondary labels may transfer substances into the device surface or drug product. Container-closure systems for sterile devices and pharmaceutical packaging are evaluated under USP <661> concepts and USP <1663>/<1664>.

Raw Materials and Processing Aids

Polymers, thermoplastic elastomers, silicone tubing, adhesives, coatings, colorants, masterbatches, sterilization residues (ethylene oxide and its reaction products), and cleaning agents can be characterized at the resin or component level to support vendor qualification and material selection.

Testing Items

The scope of E&L testing is driven by the material composition and the intended clinical use. Common analyte classes include:

• Plasticizers: DEHP, DINP, DINCH, TOTM, ATBC, acetyl tributyl citrate, and adipates.
• Antioxidants and stabilizers: hindered phenols (e.g., Irganox-type 1010/1076), phosphite process stabilizers (e.g., Irgafos-type 168), BHT, benzophenone, and UV absorbers.
• Slip agents and lubricants: erucamide, oleamide, stearamide, silicone oils, and fatty acid esters.
• Monomers, oligomers, and starting materials: styrene, bisphenol A, caprolactam, methyl methacrylate, terephthalate species, and cyclic siloxanes (D3–D20).
• Elemental impurities and heavy metals: lead, cadmium, mercury, arsenic, chromium, nickel, cobalt, vanadium, tin, zinc, barium, and catalyst residues.
• Volatile and semi-volatile species: residual solvents, aldehydes, ketones, low-molecular-weight hydrocarbons, and sterilant residues.
• Emerging high-concern classes: nitrosamines, per- and polyfluoroalkyl substances (PFAS), polycyclic aromatic hydrocarbons (PAHs), and azo/colorant degradation products.
• Anions and cations: chloride, sulfate, nitrate, ammonium, and small organic acids by ion chromatography.
• Screening endpoints: non-volatile residue (NVR), total organic carbon (TOC), pH change, ultraviolet absorbance, and infrared (FTIR) fingerprinting for material identification.

Testing Methods

Sample Preparation and Extraction Design

Extraction follows ISO 10993-12 using standardized surface-area-to-volume ratios, typically 6 cm²/mL for thin-walled materials (thickness below 0.5 mm), 3 cm²/mL for thicker sections, or gravimetric ratios such as 0.1–0.2 g/mL for irregular solids. Polar (water, saline), semi-polar (ethanol–water mixtures), and non-polar (e.g., hexane) media bracket the polarity range of clinically relevant contact fluids. Extraction modes include simulated-use extraction, exaggerated extraction at elevated temperatures (e.g., 37 °C, 50 °C, 70 °C), and accelerated or exhaustive extraction for implants, with duration and agitation defined by the study rationale.

Chromatographic Screening for Organic Extractables

A complementary multi-technique approach ensures broad chemical space coverage:

• Headspace GC-MS for highly volatile compounds and residual solvents.
• GC-MS and GC-FID for semi-volatile organics after liquid–liquid extraction or direct injection.
• LC-MS/MS (and high-resolution LC-MS) for non-volatile, polar, and thermally labile organics.
• LC-UV/DAD and LC-ELSD/CAD as orthogonal detectors for compounds with weak ionization.

Inorganic and Elemental Analysis

Inductively coupled plasma mass spectrometry (ICP-MS) provides trace-level quantitation of elemental impurities with multielement capability, while ICP-OES is used for higher-concentration metals. Ion chromatography with conductivity detection addresses inorganic anions, organic acids, and cations.

Identification, Quantitation, and the Analytical Evaluation Threshold

Unknown peaks are identified using mass spectral libraries, reference standards, and accurate-mass data, reporting confidence levels. Quantitation applies response-factor assumptions, and the analytical evaluation threshold (AET) is derived from the safety concern threshold (typically 1.5 µg/day), dose, dilution, and uncertainty factors per ISO 10993-17 and USP <1663>. Targeted confirmatory methods with validated accuracy, precision, linearity, and detection limits are then developed for leachables that approach or exceed thresholds.

Toxicological Risk Assessment

Reported leachable levels are converted to patient exposure (µg/day) using device contact volume and duration, then compared against health-based exposure limits derived from ISO 10993-17 allowable limits, the threshold of toxicological concern (TTC), ICH M7 principles for potentially mutagenic impurities, or compound-specific toxicology. A margin-of-safety calculation closes the assessment and supports the overall biological evaluation conclusion.

Applications

E&L testing data support a wide range of regulatory and engineering objectives:

• Registration submissions in major markets, including premarket notifications and approvals, EU MDR technical documentation, and NMPA dossiers under GB/T 16886 requirements.
• Biological safety evaluation as an alternative or supplement to chemical-screening-based animal tests, consistent with ISO 10993-1 and FDA expectations.
• Biological equivalence justification when comparing a new device to a predicate device, or when evaluating changes in materials, suppliers, processing, sterilization, or packaging.
• Chemical characterization for combination products, where leachables must be controlled within the drug product stability program.
• Supplier qualification, raw material incoming control, and establishment of material specifications and extractables profiles.
• Root-cause investigation of field complaints, discoloration, odor, haze, precipitation, or unexpected toxicity findings.

Accredited third-party laboratories with validated instrumentation and toxicology expertise are commonly engaged to ensure data quality and regulatory acceptance across jurisdictions.

FAQ

What is the difference between extractables and leachables? Extractables are compounds forced out under aggressive laboratory conditions, generating a worst-case inventory; leachables are the subset that actually migrates under real clinical or storage conditions and represents actual patient exposure.

Which standards govern medical device E&L testing? ISO 10993-18 defines chemical characterization, ISO 10993-12 defines sample preparation and extraction, ISO 10993-17 defines toxicological risk assessment, USP <1663>/<1664> provide extraction and study design principles, and the GB/T 16886 series is the corresponding Chinese national framework.

When is E&L testing required? It is expected for devices with blood or tissue contact, implantable devices, devices contacting drug products, following material or supplier changes, and whenever biological equivalence to a predicate cannot be demonstrated without chemical data.

How are extraction solvents and conditions selected? Solvents are chosen to bracket the polarity of clinical contact media (polar, semi-polar, non-polar), while temperature and duration are selected to achieve simulated-use, exaggerated, or exhaustive extraction depending on device contact duration and the safety question being addressed.

What is the analytical evaluation threshold (AET)? The AET is the mass of an individual analyte below which reporting is not required; it is calculated from the safety concern threshold, daily dose or contact volume, dilution factors, and an analytical uncertainty factor, and it defines the required method sensitivity.

How long does a complete E&L study take? A typical screening, correlation, targeted quantitation, and toxicological assessment program spans several weeks to a few months, depending on device complexity, the number of extraction conditions, analyte confirmation requirements, and the depth of risk assessment needed for submission.