Medical Device Materials Chemical Characterization Testing: ISO 10993-18 Extractables and Leachables

Medical device materials chemical characterization testing identifies and quantifies the chemical constituents, extractables, and leachables that may migrate from device materials into patients during clinical use, forming the scientific foundation of biological safety evaluation under the ISO 10993 series. As a risk-based alternative or supplement to traditional biocompatibility testing, it supports regulatory submissions to global authorities while enabling manufacturers to justify material equivalence and control formulation changes. This article explains the technical scope, sample types, testing items, analytical methods, and typical applications of chemical characterization for medical devices.

Technical Overview

Chemical characterization of medical device materials is a systematic analytical process that establishes the chemical identity and composition of a device or its components, and evaluates the compounds that can be extracted from or leach out of those materials under clinically relevant or exaggerated conditions. Within the ISO 10993 framework for biological evaluation, chemical characterization is no longer an optional supplementary study: it is the primary data source for toxicological risk assessment and is explicitly positioned as the starting point of any biological safety evaluation conducted within a risk management process aligned with ISO 14971.

The governing standard, ISO 10993-18:2020, defines the requirements for study design, sample preparation, analytical testing, and reporting of chemical characterization data. Its companion standard, ISO 10993-17, provides the methodology for toxicological risk assessment and the derivation of allowable exposure limits, including the analytical evaluation threshold (AET) that determines whether detected compounds require further evaluation. Additional supporting standards include ISO 10993-1 (evaluation framework), ISO 10993-12 (sample preparation and reference materials), ISO 10993-13, ISO 10993-14, and ISO 10993-15 (degradation products of polymers, ceramics, and metals), as well as ISO 10993-7 for ethylene oxide residuals and pharmacopeial guidance such as USP General Chapters 1663 and 1664 on extractables and leachables studies.

For medical device manufacturers, a well-designed chemical characterization program delivers three key benefits:

• It provides objective evidence of material composition and biological equivalence, allowing a new device or a changed device to leverage existing safety data and potentially reduce or justify the omission of certain biological tests.
• It generates the extractables and leachables data required by regulatory authorities worldwide, including the FDA, notified bodies under the EU MDR, and agencies in China, Japan, and Canada.
• It establishes a chemical fingerprint of qualified materials, enabling effective change control when suppliers, formulations, or manufacturing processes are modified.

Testing Samples

Polymer and Plastic Materials

Polymeric materials are the most frequent subjects of chemical characterization because they typically contain a complex mixture of base polymers, residual monomers, oligomers, plasticizers, stabilizers, antioxidants, slip agents, colorants, and processing aids. Common materials include PVC, polyethylene, polypropylene, polycarbonate, PMMA, ABS, polyurethane, PEEK, and silicone elastomers. Studies typically focus on residual monomers such as styrene, acrylonitrile, vinyl chloride, bisphenol A, and methylene diphenyl diisocyanate (MDI), as well as additive migration such as phthalate and citrate plasticizers and hindered phenolic antioxidants.

Metallic Materials

Metals such as 316L stainless steel, titanium and Ti-6Al-4V alloys, cobalt-chromium alloys, nitinol, and bioresorbable magnesium or zinc alloys are characterized for alloy composition, trace elemental impurities, surface treatment residues, and corrosion or degradation products. Elemental screening verifies compliance with impurity limits and identifies ions such as nickel, cobalt, chromium, aluminum, and vanadium that may be released during patient contact.

Ceramics, Glasses, and Composites

Alumina, zirconia, hydroxyapatite, bioactive glass, and carbon fiber reinforced composites require evaluation of ionic dissolution products, degradation particulates, sintering aids, and resin matrix extractables that may influence both chemical safety and material performance.

Elastomers and Rubber Components

Seals, gaskets, tubing, stoppers, and membranes made from silicone rubber, natural rubber latex, or thermoplastic elastomers are tested for vulcanization accelerators, peroxide decomposition products, siloxane oligomers, nitrosamines, polycyclic aromatic hydrocarbons (PAHs), and primary aromatic amines.

Coatings, Adhesives, Inks, and Processing Aids

Hydrophilic coatings, antimicrobial coatings, parylene coatings, UV-cured adhesives, printing inks, lubricants, mold release agents, cleaning detergents, and sterilization residues such as ethylene oxide and ethylene chlorohydrin are characterized to confirm that process-related compounds remain within safe exposure limits.

Drug-Contacting and Combination Product Materials

Syringe barrels and plungers, IV bags and infusion sets, inhaler and nasal spray components, and catheter delivery systems are studied to assess leachables that may migrate into drug products or body fluids, including tungsten or bismuth fillers used for radiopacity and functional substances intentionally added to the material.

Primary Packaging Materials

Materials in direct contact with the finished device, such as blister foils, tray polymers, and Tyvek-type breathable laminates, are evaluated for extractables that could transfer to the device during storage and sterilization.

Testing Items

Chemical characterization programs are structured around a tiered set of analytical endpoints, tailored to the material type, device category, and nature and duration of body contact:

• Material identification and composition confirmation using FTIR spectroscopy, DSC, TGA, and elemental profiling, verifying that the received material matches the specified grade.
• Extractables screening covering volatile organic compounds (VOCs), semivolatile organic compounds (SVOCs), and nonvolatile organic compounds (NVOCs) under exaggerated extraction conditions.
• Leachables studies under simulated-use or real-time conditions, particularly for fluid-path and drug-contacting devices.
• Elemental analysis and heavy metals screening by ICP-MS or ICP-OES, covering toxic elements such as lead, cadmium, mercury, arsenic, chromium, nickel, and cobalt.
• Target quantification of known compounds of toxicological concern, including phthalate plasticizers, bisphenol A, residual monomers, primary aromatic amines, nitrosamines, PAHs, organotin compounds, per- and polyfluoroalkyl substances (PFAS), and antioxidant additives.
• General extract chemistry parameters, including non-volatile residue (NVR), total organic carbon (TOC), pH, turbidity, buffer capacity, and UV absorbance.
• Polymer molecular weight distribution analysis by gel permeation chromatography (GPC) where oligomer and degradation chemistry is relevant.
• AET-based data evaluation and unknown compound identification with assigned confidence levels, forming the basis of the subsequent toxicological risk assessment.

Testing Methods

Extraction Study Design

Extraction conditions are selected according to ISO 10993-12 and the intended use of the device. Extraction media typically include a polar solvent (water, saline), a semipolar solvent (ethanol or ethanol-water mixtures), and a nonpolar solvent (n-hexane or n-heptane) to cover the range of compounds that may be released. Extraction conditions may range from simulated-use extractions at 37°C for 72 hours to exaggerated or exhaustive conditions such as 50°C for 72 hours, 70°C for 24 hours, 121°C for 1 hour, or Soxhlet and reflux extraction. The surface-area-to-solvent-volume ratio is standardized to represent a worst-case patient exposure scenario.

Chromatographic Screening and Quantification

Volatile compounds are analyzed by headspace GC-MS, while semivolatile compounds are assessed by GC-MS and GC-FID, often after concentration or derivatization. Nonvolatile and thermally labile compounds are analyzed by HPLC with UV or diode array detection and by LC-MS/MS or high-resolution accurate-mass LC-MS, which enables structural elucidation of unknown extractables. Ion chromatography is used for inorganic anions and cations. Where accurate quantification is needed for risk assessment, targeted methods are developed and validated for specificity, sensitivity, linearity, accuracy, precision, and recovery.

Elemental and Surface Analysis

ICP-MS and ICP-OES provide sensitive quantification of elemental impurities and metal ion release, with XRF and SEM-EDX used for rapid screening and surface-layer characterization. These techniques support both compositional verification and degradation product assessment.

Material and Structural Identification

FTIR and Raman spectroscopy identify base polymers and functional groups, NMR confirms molecular structures of isolated extractables, and GPC, DSC, and TGA characterize molecular weight distribution, thermal transitions, and filler content.

Data Evaluation and AET Calculation

The analytical evaluation threshold is calculated for each analysis from the safety concern threshold (SCT), the clinical exposure dose, the extract or leachate volume, and an analytical uncertainty factor accounting for method variability. Detected compounds above the AET are identified to an assigned confidence level, quantified, and passed to toxicological evaluation under ISO 10993-17, where margins of safety are derived from established health-based exposure limits.

Applications

Chemical characterization data are used across the entire medical device lifecycle:

• Regulatory submissions, including FDA 510(k), De Novo, and PMA applications, EU MDR technical documentation and CE marking files, and registration dossiers in China, Japan, Canada, and other jurisdictions.
• Biological equivalence justifications that leverage material and formulation data to reduce or omit specific biological endpoint testing, consistent with ISO 10993-1:2018 and current FDA biocompatibility guidance.
• Change control and equivalence re-evaluation following material supplier changes, formulation adjustments, manufacturing process modifications, or site transfers.
• Extractables and leachables studies for combination products, drug delivery systems, and fluid-path components in contact with pharmaceuticals or infused fluids.
• Supplier qualification, incoming material verification, and long-term material fingerprinting programs.
• Support for sterilization validation, including ethylene oxide and ethylene chlorohydrin residual testing per ISO 10993-7.
• Investigation of field complaints, adverse events, and failure analyses involving suspected chemical release.

FAQ

What is chemical characterization testing for medical devices?

It is a structured set of analytical tests that identify the chemical composition of device materials and the compounds that can be extracted from them, so that patient exposure can be evaluated through toxicological risk assessment rather than relying solely on biological endpoint testing.

Which standards govern chemical characterization testing?

The core standards are ISO 10993-18 for the characterization framework, ISO 10993-17 for toxicological risk assessment, ISO 10993-12 for sample preparation, and ISO 10993-1 for the overall evaluation strategy, complemented by degradation product standards (ISO 10993-13, -14, -15), ISO 10993-7 for EO residuals, and pharmacopeial guidance on extractables and leachables.

Can chemical characterization replace biocompatibility testing?

It can justify the reduction or omission of certain biological tests when a robust biological equivalence argument is demonstrated, particularly for cytotoxicity, systemic toxicity, and genotoxicity endpoints. However, the final testing strategy must be justified within the risk management file, and some endpoints, such as sensitization or irritation, may still require data or a documented literature-based rationale.

What is the analytical evaluation threshold (AET)?

The AET is a concentration threshold in an extract or leachate, derived from a safety concern threshold and the clinical exposure scenario. Compounds detected above the AET must be identified and toxicologically evaluated, while compounds below it are considered adequately controlled.

How are extraction solvents and conditions selected?

Selection is based on the polarity of expected extractables, the nature and duration of body contact, and the device geometry. A combination of polar, semipolar, and nonpolar solvents under both simulated-use and exaggerated conditions is typically applied to achieve comprehensive coverage.

How much sample is required and how long does testing take?

Screening studies generally require one to several grams of material or a defined surface area per extraction condition, and take approximately four to eight weeks. Full programs including method validation, leachables simulation, and toxicological risk assessment typically span three to six months, depending on material complexity and regulatory scope.

Should testing be performed in-house or externally?

Manufacturers may perform screening in-house, but accredited third-party laboratories with validated instrumentation, ISO 17025-aligned quality systems, and experienced chemists and toxicologists are commonly engaged for submission-grade studies, since regulators expect robust method validation and traceable data packages.