Medical plastic extractables and leachables (E&L) testing is a critical chemical characterization process that identifies and quantifies substances migrating from polymer-based medical devices, consumables, and packaging into drugs or patient tissues. Guided by internationally recognized frameworks such as ISO 10993, USP General Chapters, ICH guidelines, and GB/T standards, E&L studies form the scientific basis for biocompatibility evaluation, toxicological risk assessment, and regulatory submission. This article explains the scope, sample types, test items, analytical methods, and practical applications of extractables and leachables testing for medical plastics.
Technical Overview
Medical plastics are widely used in syringes, infusion sets, catheters, dialyzers, implantable components, and primary pharmaceutical packaging. During manufacturing, processing, sterilization, storage, and clinical use, these polymers can release low-molecular-weight chemical species into contacting fluids, drug products, or body tissues. Evaluating these migrants is the purpose of extractables and leachables (E&L) testing, a core element of the chemical characterization required for biological evaluation of medical devices.
Extractables are compounds that can be released from a material under exaggerated laboratory conditions, such as aggressive solvents, elevated temperatures, or extended contact times. Leachables are compounds that actually migrate into the drug product or body fluid under normal conditions of storage and use, and they are generally a subset of the extractables profile. Typical substances of concern include:
- Residual monomers and oligomers, such as vinyl chloride, styrene, acrylonitrile, 1,3-butadiene, caprolactam, methyl methacrylate, and bisphenol A
- Plasticizers, including ortho-phthalates such as DEHP, DINP, and DIDP, as well as citrate and adipate alternatives
- Antioxidants and processing stabilizers, such as BHT, hindered phenolics, and phosphite-type stabilizers
- Slip agents, antiblocking agents, UV absorbers, colorants, fillers, and lubricants including silicone oils
- Sterilization residues and byproducts, such as ethylene oxide, ethylene chlorohydrin, peroxides, and radiolysis products
- Catalyst residues and elemental impurities, such as tin, zinc, titanium, antimony, and heavy metals
Chemical characterization is now the cornerstone of the risk-based biological evaluation framework defined in ISO 10993-1. Combined with toxicological risk assessment under ISO 10993-17 and material characterization under ISO 10993-18, E&L data can often replace certain animal-based biological tests while demonstrating patient safety. Key reference standards and regulations include the ISO 10993 series, USP General Chapters <661.1>, <661.2>, <1663>, and <1664>, the Chinese GB/T 16886 series (adoption of ISO 10993), GB/T 14233.1 for infusion and injection equipment, the YBB national standards for pharmaceutical packaging, the European Pharmacopoeia sections on plastics, EU MDR 2017/745, and ICH Q3C, Q3D, and Q3E guidelines for drug-related applications.
Testing Samples
Infusion, Transfusion, and Injection Devices
Disposable devices with fluid-path contact represent the largest sample category, including syringes, needles, infusion sets, IV catheters, extension tubes, blood bags, blood collection tubes, dialyzers, and oxygenators. Because contacting solutions are administered directly to patients, these products are typically evaluated against the physicochemical panel of GB/T 14233.1 alongside ISO 10993-18 chemical characterization. Common test articles are PVC, polypropylene, polyethylene, polyurethane, and thermoplastic elastomer components, together with their lubricants, adhesives, and inks.
Primary Pharmaceutical Packaging Systems
Bottles, films, blister foils, laminated pouches, closures, and overwraps used for solid oral dosages, injectables, and biologics are tested under USP <661.1> and <661.2>, the YBB standards, and the European Pharmacopoeia. The suitability of a plastic packaging system depends on whether migrants accumulate in the drug product at levels that affect quality, stability, or safety.
Drug-Device Combination Products
Prefilled syringes, autoinjectors, inhalation and nasal delivery devices, and implantable drug pumps require the most rigorous leachables programs. The drug product itself is analyzed over its shelf life for migrants such as silicone oil, tungsten residues, adhesives, and vulcanization accelerators. Study design for these products follows ICH Q3E expectations together with ISO 10993-18.
Implantable and Long-Term Contacting Devices
Implant-grade polymers such as PEEK, UHMWPE, PMMA bone cement, and polyurethane are subjected to exhaustive extraction because of permanent or long-duration tissue contact. Polar and nonpolar extraction solvents are used to characterize the full extractables profile before toxicological evaluation.
Testing Items
Testing programs typically combine a general physicochemical panel with targeted analysis of known additives and non-targeted screening of unknowns. Core test items include:
- Physicochemical indicators: pH variation, acidity and alkalinity, evaporation (non-volatile) residue in aqueous, ethanol, and n-hexane extracts, turbidity, ultraviolet absorbance, and reducing-substance consumption (potassium permanganate demand)
- Elemental impurities: lead, cadmium, mercury, arsenic, and ICH Q3D Class 1 to Class 4 elements measured by ICP-MS or ICP-OES
- Volatile organics: residual monomers and residual solvents controlled under ICH Q3C, analyzed by headspace GC-MS
- Semi-volatile and non-volatile organics: plasticizers, antioxidants, slip agents such as erucamide, UV absorbers, oligomers, and degradation products analyzed by GC-MS, HPLC, and LC-MS/MS
- Specific high-concern migrants: bisphenol A, primary aromatic amines, nitrosamines, and per- and polyfluoroalkyl substances (PFAS)
- Sterilant residues: ethylene oxide and ethylene chlorohydrin controlled under ISO 10993-7
Testing Methods
Sample Preparation and Extraction
Extraction design follows ISO 10993-12 (and GB/T 16886.12). Standardized surface-to-volume ratios, commonly 6 cm²/mL for sheet materials or 0.1 to 0.2 g/mL for irregular shapes, ensure reproducible and comparable results. Extraction conditions range from simulated use, for example 37 °C for 72 hours, to exaggerated conditions such as 50 °C for 72 hours, 70 °C for 24 hours, or 121 °C for 1 hour. Solvent selection covers the polarity spectrum, typically purified water or saline for polar extraction, ethanol-water mixtures for moderately polar extraction, and n-hexane or vegetable oil for lipophilic extraction.
Chromatographic and Spectrometric Techniques
A complementary analytical battery is applied because no single instrument can detect all migrant classes:
- Headspace GC-MS and GC-FID for volatile compounds and residual solvents
- GC-MS in scan and SIM modes for semi-volatile organics, with confirmation against spectral libraries
- HPLC with UV/DAD detection for phenolic antioxidants and UV absorbers
- LC-MS/MS and LC-QTOF for polar, thermolabile, and high-molecular-weight migrants and non-targeted screening
- ICP-MS or ICP-OES for elemental impurities and catalyst residues
- Ion chromatography for inorganic anions and cations
- FTIR for polymer identification and structural elucidation of isolated unknowns
- Total organic carbon (TOC) as a rapid screening indicator of overall organic migration
Targeted and Non-Targeted Analytical Strategies
Targeted methods quantify known additives and degradation products against reference standards with full validation of specificity, linearity, accuracy, precision, and limits of detection and quantitation. Non-targeted screening captures unexpected migrants using high-resolution mass spectrometry and mass-balance approaches. Method sensitivity must be demonstrated below the analytical evaluation threshold (AET) derived from the study, and results are reported with identification confidence levels for each compound.
Toxicological Risk Assessment and Reporting
Under ISO 10993-17 and USP <1663> and <1664>, detected compounds are evaluated against health-based exposure limits. For drug-related applications, the safety concern threshold of 1.5 µg/day is commonly used to derive the AET, while permitted daily exposure (PDE) values are applied where compound-specific toxicology exists. The final report consolidates extraction conditions, chromatographic data, identified and quantified migrants, comparison to thresholds, and margins of safety.
Applications
Extractables and leachables testing by accredited third-party laboratories and in-house analytical teams supports the entire product lifecycle:
- Regulatory submissions, including NMPA registration in China, FDA 510(k) and PMA applications in the United States, and CE technical documentation under EU MDR
- Material selection and design verification during development of devices and packaging systems
- Supplier qualification and incoming raw material control programs
- Change management, including assessment of new resin grades, colors, adhesives, or sterilization modes
- Drug-container compatibility and shelf-life stability studies for combination products
- Risk management documentation under ISO 14971 and biological evaluation plans under ISO 10993-1
FAQ
What is the difference between extractables and leachables?
Extractables are compounds forced out of a plastic material under exaggerated laboratory conditions, while leachables are the compounds that actually migrate into a drug product or body fluid during real-world storage and use. Leachables are usually a subset of the extractables profile, and confirming this relationship is a key objective of a well-designed study.
Which standards govern medical plastic extractables and leachables testing?
The primary framework is the ISO 10993 series, especially ISO 10993-12 for sample preparation, ISO 10993-17 for toxicological risk assessment, and ISO 10993-18 for chemical characterization. In China, the GB/T 16886 series and GB/T 14233.1 apply, along with YBB standards for pharmaceutical packaging. For drug products and combination products, USP General Chapters 661.1, 661.2, 1663, and 1664, plus ICH Q3C, Q3D, and Q3E, are the key references.
How are extraction conditions selected?
Conditions are chosen to bracket or simulate actual clinical use while remaining analytically practical. Simulated-use extraction at 37 °C for 72 hours approximates patient contact, whereas exaggerated conditions such as 50 °C for 72 hours or 70 °C for 24 hours accelerate migration to build worst-case safety margins. Solvent polarity is matched to the contacting medium, from water and saline to ethanol mixtures and n-hexane.
What is the analytical evaluation threshold (AET)?
The AET is the concentration in an extract above which a detected compound must be reported and toxicologically evaluated. It is derived from the safety concern threshold of 1.5 µg/day, the dosing or exposure scenario, and the dilution and concentration factors of the analytical method. Methods must be validated to quantify reliably at or below the AET.
When is a leachables study required in addition to extractables testing?
A leachables study is generally required when a plastic contacts a drug product over extended storage, such as prefilled syringes, IV bags, and inhalation products, or when the extractables assessment identifies potentially toxic migrants. Leachables data are collected on the actual product at relevant time points through its shelf life.
How long does a complete E&L project take?
An extractables characterization with subsequent toxicological assessment typically requires eight to twelve weeks, depending on sample complexity and the number of analytical techniques needed. Leachables studies run in parallel with stability programs and conclude at the end of the intended shelf life. Early planning with an accredited third-party laboratory helps align study design with the intended regulatory pathway and avoid repeat testing.