Medical Device Packaging Migration Analysis: Extractables and Leachables Evaluation

Medical device packaging migration analysis is a risk-based chemical characterization study that identifies and quantifies substances migrating from packaging materials—plastics, elastomers, adhesives, coatings, and printing inks—into a medical device, its contents, or ultimately the patient. Performed in line with ISO 10993, ISO 11607, and USP <1663>/<1664>, these studies are a core regulatory expectation for biological safety evaluation under the EU MDR 2017/745 and FDA submissions. This article explains the sample types, testing items, analytical methods, toxicological assessment, and typical applications of packaging migration analysis.

Technical Overview

Medical device packaging migration analysis evaluates the transfer of chemical substances from packaging materials into a device or product under manufacturing, sterilization, storage, transport, and end-use conditions. Substances that may migrate include residual monomers, oligomers, plasticizers, antioxidants, slip agents, UV stabilizers and photoinitiators, adhesive components, printing ink components, colorants, catalyst residues, and elemental impurities. Migration is driven by concentration gradients, contact time, temperature, solvent polarity, and the physical condition of the polymer matrix, and it can be significantly accelerated by sterilization processes such as ethylene oxide, gamma, or e-beam irradiation.

The discipline distinguishes between two related concepts. Extractables are compounds that can be released from packaging materials under exaggerated laboratory conditions (aggressive solvents, elevated temperature, extended contact time), and they represent the worst-case inventory of potential migrants. Leachables are compounds that actually migrate into the device or product under normal processing, storage, and clinical-use conditions. Leachables are typically a subset of extractables, although they may also be formed by interaction between the packaging and the product.

The regulatory and scientific framework for packaging migration analysis rests on a risk-based approach articulated in several key standards and guidance documents:

• ISO 10993-1 — Biological evaluation of medical devices: risk management process and evaluation framework
• ISO 10993-12 — Sample preparation and reference materials for extraction studies
• ISO 10993-17 — Toxicological risk assessment and establishment of allowable limits for leachables
• ISO 10993-18 — Chemical characterization of medical device materials within a risk management process
• ISO 10993-7 — Evaluation of ethylene oxide sterilization residuals
• ISO 11607 — Packaging for terminally sterilized medical devices and sterile barrier systems
• USP <1663> and <1664> — Assessment of extractables and leachables associated with pharmaceutical packaging and delivery systems
• EN 1186 and EN 13130 — Migration test methods for plastics in contact with foodstuffs, frequently adapted as reference methodologies
• GB/T 16886 series — The Chinese national adoption of ISO 10993 for biological evaluation
• ICH Q3D (elemental impurities) and ICH Q3E (extractables and leachables) — applicable to drug-device combination products
• EU MDR 2017/745 and corresponding FDA guidance — overarching regulatory requirements for chemical safety documentation

Accredited third-party laboratories typically conduct these studies as part of an overall biological safety evaluation file, integrating analytical chemistry data with toxicological assessment to demonstrate an acceptable margin of safety.

Testing Samples

Sterile Barrier Systems and Flexible Films

Pouches, header bags, and blister laminates constructed from multilayer films such as PET/PE, PA/PE, and PVC/PVDC, as well as porous nonwoven materials such as flash-spun polyethylene and medical paper. These materials are analyzed for monomers, oligomers, plasticizers, adhesive residues, and process aids.

Rigid Containers and Formed Packaging

Thermoformed trays, bottles, vials, cartridges, and tubs produced from PP, HDPE, PET, PETG, PC, or cyclic olefin copolymers. Migration concerns include residual catalysts, antimony, polymer additives, and degradation products generated during thermoforming or sterilization.

Elastomeric Closure Components

Stopper and septum materials, gaskets, O-rings, and cap liners based on butyl rubber, bromobutyl, chlorobutyl, silicone, or thermoplastic elastomers. Typical migrants include vulcanization accelerators, peroxide decomposition products, primary aromatic amines, nitrosamines, and waxes.

Liquid-Contact and Drug-Device Combination Packaging

Intravenous solution bags, prefilled syringes, infusion sets, and primary containers for biologics, ophthalmic, or injectable products. These applications carry the highest sensitivity to leachables such as phthalate plasticizers (DEHP, DINP), bisphenol A, silicone oil, and tungsten or zinc traces from manufacturing.

Secondary Packaging and Printing Materials

Labels, printed inks, varnishes, adhesives, and coated folding cartons that may indirectly transfer substances through volatilization, condensation, or set-off contact, particularly after irradiation sterilization or high-temperature transport.

Testing Items

A comprehensive packaging migration analysis typically encompasses the following categories of testing:

• Total extractables and non-volatile residue (gravimetric determination)
• Semi-quantitative extractables screening across volatile, semi-volatile, and non-volatile classes (VOC, SVOC, NVOC)
• Targeted quantification of known migrants: phthalates, bisphenol A, phenolic antioxidants (e.g., BHT), phosphate stabilizers, slip agents (erucamide, oleamide), acrylate monomers, styrene, and vinyl chloride monomer
• Primary aromatic amines and nitrosamines derived from polyurethane adhesives and rubber vulcanization systems
• Photoinitiators and UV absorbers (e.g., benzophenone-type compounds) from printing inks and coatings
• Elemental impurities and heavy metals (Pb, Cd, Hg, As, Sb, Ba, Co, etc.) by ICP-MS or ICP-OES
• Ethylene oxide, ethylene chlorohydrin, and ethylene glycol residuals following gas sterilization (ISO 10993-7)
• Per- and polyfluoroalkyl substances (PFAS) from fluoropolymer-coated or barrier materials
• Overall migration into simulated contact media, adapted from EN 1186 methodologies where appropriate
• Aldehydes, ketones, and carboxylic acids generated by polymer oxidation during radiation sterilization

Testing Methods

Study Design and Extraction

Extraction conditions are selected to simulate or deliberately exaggerate clinical use in accordance with ISO 10993-12 and ISO 10993-18. Polar media (water, buffered saline, dilute ethanol) represent aqueous product contact, while non-polar media (hexane or isopropanol mixtures) represent lipophilic contact. Extraction ratios, temperatures, and durations are justified relative to the intended surface-area-to-volume relationship and worst-case exposure scenario. A simulation study, bridging exaggerated extraction to simulated-use leachables, is typically performed for patient-contact products.

Analytical Techniques

Orthogonal chromatographic and spectroscopic platforms are combined because no single technique captures the full extractables profile:

• Headspace GC-MS for volatile organic compounds and residual solvents
• GC-MS (with derivatization where needed) for semi-volatile organic migrants
• LC-MS/MS and HPLC-UV for non-volatile, thermally labile, and polar compounds
• ICP-MS or ICP-OES for elemental impurities and inorganic migrants
• FTIR and NMR for structural confirmation of unknown or tentatively identified compounds
• TOC analysis and gravimetric non-volatile residue for total organic carbon and total extractables

Reporting Thresholds and Toxicological Assessment

Analytical evaluation thresholds (AET) are calculated from the safety concern threshold—commonly applied at 1.5 µg/day—adjusted for the daily patient exposure, dose units, and an uncertainty factor for analytical response variability. All reported extractables and leachables exceeding the AET are identified, semi-quantitated, and subjected to toxicological risk assessment under ISO 10993-17, using tolerable intake values, permitted daily exposures, and margin-of-safety calculations. Where a compound lacks sufficient toxicological data, read-across and structure-based tools such as the threshold of toxicological concern (TTC) are applied. Method validation, system suitability, and mass-balance review ensure the dataset is defensible for regulatory submission.

Applications

Packaging migration analysis supports medical device and combination product manufacturers across the full product lifecycle:

• Regulatory submissions, including FDA 510(k) and PMA chemical characterization packages, EU MDR technical documentation, and NMPA registration dossiers
• Biological safety evaluation files integrating chemical characterization with ISO 10993-1 endpoint assessments
• Drug-device combination products, prefilled syringes, and primary containers for biologics requiring USP <1664> leachables monitoring during stability studies
• Verification of packaging material or supplier changes under change control, including resin substitutions and film redesign
• Impact assessment of sterilization modality changes (ethylene oxide, gamma, e-beam) on leachables profiles
• Shelf-life and accelerated aging studies conducted in conjunction with ISO 11607 and ASTM F1980
• Root-cause investigations of discoloration, odor, turbidity, particulates, or assay interference attributable to packaging interaction
• Vendor qualification and incoming material control programs for critical packaging components

FAQ

What is the difference between extractables and leachables?

Extractables are compounds released from packaging under exaggerated laboratory conditions and represent a worst-case chemical inventory, while leachables are compounds that actually migrate into the device or product under real-world conditions of use. Leachables studies confirm which extractables appear at clinically relevant concentrations.

When is packaging migration analysis required?

It is expected whenever a device or its packaging has direct or indirect patient contact, whenever the product is a liquid, biologic, or drug-device combination contacting primary packaging, when packaging materials or sterilization methods change, and whenever regulatory bodies request chemical characterization under ISO 10993-18 as part of a biological safety evaluation.

Which standards govern these studies?

The core framework consists of ISO 10993-1, -12, -17, and -18, supplemented by ISO 10993-7 for ethylene oxide residuals, ISO 11607 for sterile barrier systems, USP <1663>/<1664> for extractables and leachables methodology, EN 1186 migration methods where adapted, and the GB/T 16886 series for the Chinese market. ICH Q3D and Q3E apply to combination products.

How are results judged to be safe or unsafe?

Each detected migrant is compared against its analytical evaluation threshold and, if exceeded, against health-based exposure limits established through ISO 10993-17 toxicological risk assessment. A margin of safety greater than one, calculated from the worst-case patient exposure, generally indicates acceptable risk.

How long does a migration analysis study take?

Screening extractables studies typically require six to ten weeks, while full simulated-use leachables studies, including method development, toxicological assessment, and report compilation, may extend from three to six months depending on sample complexity and the number of targeted analytes.

Can packaging that complies with food-contact regulations automatically be used for medical devices?

No. Food-contact compliance, such as conformity with EN 1186 or relevant national food-contact regulations, is a useful reference but is not sufficient for medical devices, because exposure routes, contact durations, and vulnerable patient populations differ. Medical-grade packaging must be evaluated against the applicable ISO 10993 and ISO 11607 requirements by accredited third-party laboratories or the manufacturer's own qualified facilities.