Medical device extractables and leachables | Materials Metric - Materials Metric | Advanced Materials Characterization & Analytical Testing Services and Scientific Consulting

What Are Medical Device Extractables and Leachables — and Why Do They Matter?

Medical device extractables and leachables are chemical compounds that migrate from device materials into a patient’s body or surrounding environment, posing potential safety risks. Understanding and controlling these substances is a core regulatory requirement for any device that contacts patients directly. At Materials Metric, we help device manufacturers meet these requirements with rigorous, science-driven testing.

Regulatory agencies worldwide — including the FDA, EMA, and ISO — require manufacturers to characterize and assess these chemical migrants. Consequently, E&L studies have become a non-negotiable step in medical device development. Furthermore, failures in this area frequently trigger FDA deficiency letters and submission delays.

Moreover, the complexity of modern devices — combining polymers, adhesives, coatings, and metals — makes thorough chemical characterization more challenging than ever. In addition, evolving standards such as ISO 10993-18 Chemical Characterization continue to raise the analytical bar. Therefore, teams need an experienced laboratory partner to navigate this landscape effectively.

Key Takeaways

Extractables are chemicals released under aggressive lab conditions; leachables are those actually migrating during clinical use.

ISO 10993-18 and FDA guidance define the framework for E&L studies in medical devices.

A tiered testing strategy — screening, identification, quantification — keeps costs and timelines manageable.

Analytical methods such as GC-MS Analysis, HPLC Analysis, and ICP techniques are central to E&L workflows.

Toxicological risk assessment determines whether identified leachables are clinically acceptable.

Early-stage planning of E&L studies saves significant time and cost during regulatory review.

Medical device extractables and leachables: Chemical substances that migrate out of device materials — either under exaggerated laboratory extraction conditions (extractables) or during actual patient use (leachables) — and that must be identified, quantified, and toxicologically assessed to confirm patient safety.

Key fact: Chemical leachables from medical device materials are among the leading causes of biocompatibility failures identified during FDA premarket submissions, making E&L testing one of the highest-impact investments a device manufacturer can make.

What Is the Difference Between Extractables and Leachables?

Many engineers use the terms interchangeably, but extractables and leachables represent distinct concepts with different regulatory implications. Understanding this distinction is the first step in designing a compliant testing strategy. For instance, the analytical methods, solvents, and acceptance criteria differ significantly between the two.

Defining Extractables

Extractables are chemical compounds released from a device material when exposed to exaggerated or aggressive laboratory conditions. Specifically, these conditions use solvents, elevated temperatures, or extended contact times not typical of actual clinical use. The purpose is to identify the full universe of chemicals that could migrate — providing a worst-case picture. Consequently, extractables data serve as a screening tool rather than a direct patient safety assessment.

Common extraction solvents include water, ethanol, isopropanol, and hexane. Furthermore, laboratories often use acidic and basic solutions to capture a broader chemical range. By comparison, the conditions used for leachables studies mimic real clinical exposure far more closely.

Defining Leachables

Leachables, by contrast, are compounds that actually migrate into a drug product, biological fluid, or patient tissue during intended use. Therefore, leachables data reflect real clinical risk far more directly than extractables data. In addition, leachables studies typically use clinically relevant solvents and temperatures that match the device’s use environment.

A key principle is that leachables are generally a subset of extractables. However, some leachables can appear that were not identified in the extractables screen — for example, degradation products formed by chemical reactions during long-term storage. Notably, this is why comprehensive analytical coverage at both stages matters so much.

How Extractables Inform Leachables Testing

Regulatory guidance — especially ISO 10993-18 Chemical Characterization — establishes a direct link between extractables and leachables studies. Specifically, the extractables profile sets the analytical scope for leachables testing. Compounds identified during extraction become the target analytes in leachables studies.

This tiered approach is efficient and scientifically defensible. Furthermore, it allows teams to focus expensive and time-consuming leachables work on the chemicals that genuinely matter. As a result, manufacturers save time and resources without compromising on safety. Our Chemical & Analytical Testing team helps clients design both stages cohesively from the outset.

Why Do Regulatory Agencies Require Medical Device Extractables and Leachables Testing?

Regulatory requirements for medical device extractables and leachables exist because device materials contain complex chemistry. Polymers, adhesives, lubricants, colorants, and processing aids all introduce potential migrants. Moreover, patient exposure can be prolonged, systemic, and — in implantable devices — lifelong.

The ISO 10993 Framework

The ISO 10993 series provides the primary international framework for medical device biocompatibility. Specifically, ISO 10993-18 Chemical Characterization governs chemical characterization of device materials, including E&L testing. It requires manufacturers to identify and quantify chemical constituents and then assess their toxicological risk.

ISO 10993-17 then provides the toxicological risk assessment methodology for identified leachables. Together, these standards form a cohesive chemical safety framework. In addition, ISO 10993-1:2018 introduced a risk-based approach that makes chemical characterization central to biocompatibility evaluation planning.

FDA Guidance on Extractables and Leachables

The FDA’s guidance on biocompatibility aligns closely with ISO 10993 but includes additional expectations specific to the US market. For example, the FDA expects device submissions to include a thorough chemical characterization report as part of the biocompatibility section. Furthermore, FDA reviewers frequently cite inadequate E&L data as a major reason for issuing Additional Information requests.

Our article on FDA biocompatibility deficiencies explores the most common submission gaps in detail. Notably, missing or incomplete extractables data consistently ranks among the top deficiencies. Therefore, early and thorough E&L testing pays dividends at the submission stage.

Device Contact Nature and Duration

The rigor of required E&L testing scales with the device’s contact nature and duration. ISO 10993-1 classifies devices by contact type — surface contact, externally communicating, and implant — and by contact duration: limited (under 24 hours), prolonged (up to 30 days), and permanent (over 30 days).

Consequently, an implantable device requires far more extensive E&L characterization than a skin-contact bandage. Furthermore, blood-contacting and tissue-implanted devices demand the most rigorous analytical and toxicological assessment. By comparison, short-contact surface devices may qualify for a more streamlined approach. For guidance on classification and scope, our Scientific & Technical Consulting team helps manufacturers make defensible decisions early.

How Are Medical Device Extractables and Leachables Studies Designed?

A well-designed E&L study starts with a materials inventory and a clear understanding of device-patient contact. Without this foundation, even the best analytical methods can miss critical migrants. Furthermore, poor study design creates regulatory risk by leaving chemical hazards unidentified.

Step 1 — Building a Material Inventory

The first task is identifying every material component that contacts the patient, drug product, or biological fluid. This inventory includes raw polymers, additives, colorants, adhesives, lubricants, and surface coatings. In addition, manufacturers must consider indirect contact materials — for example, packaging components that may leach into a drug-delivery device.

Each material component requires a supplier-provided formulation disclosure or safety data sheet. However, formulation disclosures are often incomplete due to trade-secret protections. Therefore, laboratory extraction and analysis remain essential even when documentary evidence exists. Our Chemical Purity & Contaminant Screening service helps identify unknowns systematically and efficiently.

Step 2 — Selecting Extraction Conditions

Extraction conditions must reflect both the chemical nature of the materials and the intended use environment. Specifically, ISO 10993-18 recommends a polarity-bracketing solvent approach. This uses at least two solvents — one polar and one nonpolar — to capture the full range of extractable compounds.

Common solvent choices include water and hexane as polarity extremes, with ethanol or isopropanol as intermediate options. Furthermore, acidic and basic solutions help reveal ionic and hydrolytically labile compounds. Temperature and contact duration are also critical variables — elevated temperatures accelerate extraction and capture compounds that appear only under thermal stress. Our team uses Wet Chemistry & Classical Analytical Methods alongside modern instrumentation to ensure complete coverage.

Step 3 — Analytical Method Selection and Validation

Selecting the right analytical methods is arguably the most critical technical decision in an E&L study. No single technique covers all compound classes. Therefore, a combination of complementary methods is always necessary for comprehensive chemical characterization.

Volatile and semivolatile organic compounds are typically analyzed by GC-MS Analysis, which provides both separation and structural identification. Meanwhile, nonvolatile polar compounds require HPLC Analysis with UV, fluorescence, or mass spectrometric detection. Furthermore, elemental impurities — including heavy metals — demand dedicated inorganic techniques aligned with USP General Chapter <232> Elemental Impurities requirements.

All methods must undergo validation — or at minimum rigorous verification — before use in regulatory studies. Specifically, accuracy, precision, linearity, and detection limits must demonstrate fitness for purpose. Our Method Development & Validation team builds defensible, regulatory-ready analytical methods tailored to each device’s chemical profile. Additionally, we reference peer-reviewed methodology from sources such as ScienceDirect – Analytical Methods to ensure our approaches reflect current scientific consensus.

For device materials requiring surface or structural characterization alongside chemical analysis, techniques such as FTIR Analysis and Raman Spectroscopy provide valuable complementary data. These methods identify polymer types, degradation products, and surface chemistry changes that may correlate with leachable generation. In addition, our Chemical & Elemental Characterization capabilities cover both organic and inorganic analytes within a single integrated workflow.

For a deeper look at how extractables and leachables testing relates to other device qualification activities, see our companion article on extractables vs leachables. Furthermore, manufacturers assessing material changes should also review our guidance on device material equivalency, since material substitutions trigger new E&L requirements. Understanding these interconnections early prevents costly late-stage surprises.

Advanced Analytical Techniques for Medical Device Extractables and Leachables

Modern E&L studies demand a broad analytical toolkit. No single instrument captures every chemical class, so laboratories combine complementary techniques to achieve comprehensive coverage. Furthermore, method selection must align with regulatory expectations and the specific chemistry of each device material.

Elemental Analysis — ICP-MS, ICP-OES, and AAS

Elemental impurities represent a critical subset of medical device extractables and leachables. Heavy metals such as lead, arsenic, cadmium, and chromium can leach from metal components, pigments, and processing aids. Consequently, inorganic analysis is mandatory for most device categories.

Inductively coupled plasma mass spectrometry (ICP-MS) offers the lowest detection limits — often in the sub-parts-per-trillion range — making it the preferred choice for permanent implants and blood-contacting devices. Meanwhile, ICP optical emission spectrometry (ICP-OES) handles higher-concentration matrices efficiently and provides excellent multi-element throughput. By contrast, atomic absorption spectrometry (AAS) suits single-element confirmation workflows where ICP instruments are unavailable.

All three techniques align with USP Elemental Impurities requirements and ISO 10993-18 guidance on inorganic characterization. Our Chemical & Elemental Characterization service integrates all three modalities for complete inorganic coverage.

Surface and Structural Characterization Techniques

Chemical migrants often originate at material surfaces. Therefore, surface-sensitive techniques add important mechanistic insight to E&L investigations. They help teams identify which surface chemistries or defects are driving leachable generation.

XPS Analysis quantifies elemental composition and chemical bonding states at the outermost material surface — typically the top 5–10 nm. This technique is particularly valuable for coated metals, surface-treated polymers, and oxide layers. In addition, XRF Analysis provides rapid semi-quantitative elemental screening across bulk and surface layers without sample destruction.

For structural identification of particulates or inorganic residues found in extracts, XRD Analysis determines crystalline phase composition. Moreover, NMR Spectroscopy provides definitive structural elucidation for unknown organic leachables — especially oligomers, degradation products, and polar nonvolatile compounds that GC-MS cannot resolve effectively.

Hyphenated and High-Resolution Mass Spectrometry

High-resolution mass spectrometry (HRMS) techniques — such as quadrupole time-of-flight (Q-TOF) and Orbitrap platforms — are increasingly central to E&L workflows. Specifically, HRMS enables confident structural assignment of unknown compounds at trace levels without requiring reference standards. This capability is invaluable when screening complex polymer extracts that contain dozens of unexpected migrants.

Liquid chromatography coupled with HRMS (LC-HRMS) handles nonvolatile, polar, and thermally labile compounds that GC-MS cannot address. Furthermore, this combination supports non-targeted screening — an approach that regulatory agencies increasingly expect for novel or complex devices. As a result, laboratories investing in HRMS capability deliver significantly more comprehensive analytical reports. Our Chemical & Analytical Testing team applies these advanced platforms to the most complex E&L challenges.

Research published through ScienceDirect continues to advance best practices in hyphenated MS techniques for pharmaceutical and medical device extractables work, providing the scientific community with evolving method frameworks.

Toxicological Risk Assessment of Identified Leachables

Identifying and quantifying leachables is only half the work. Ultimately, regulators require a toxicological risk assessment (TRA) that determines whether each identified compound poses an acceptable risk to patients. This assessment is where analytical chemistry and toxicology intersect.

Establishing Tolerable Intake and Safety Thresholds

ISO 10993-17 provides the methodology for deriving tolerable intake (TI) values for individual leachables. For compounds with existing toxicological databases, TI values come from no-observed-adverse-effect levels (NOAELs) and appropriate uncertainty factors. In addition, compounds with carcinogenic or genotoxic potential require more conservative threshold calculations.

The analytical evaluation threshold (AET) is a critical concept in this framework. Specifically, the AET is the analytical detection limit that must be achieved to ensure no clinically relevant leachable goes undetected. Compounds detected above the AET require full toxicological characterization; those below it may be excluded from further assessment. Our Biocompatibility & Toxicity Testing service integrates AET calculations directly into study design.

Handling Compounds Without Established Toxicology Data

Many extractables identified in device materials lack established toxicological data. Consequently, toxicologists must apply computational tools — such as quantitative structure-activity relationship (QSAR) modeling — to predict hazard potential. Furthermore, structure-activity relationship (SAR) analysis identifies structural alerts for genotoxicity, sensitization, and endocrine disruption.

For compounds with structural alerts or insufficient data, a conservative worst-case approach protects patient safety. Notably, this is an area where experienced toxicological expertise makes a decisive difference in achieving regulatory acceptance. Our Scientific & Technical Consulting team supports TRA development for compounds at every level of data availability.

E&L Testing Across Device Categories — Key Considerations

Different device categories present distinct E&L challenges. The materials involved, exposure routes, patient populations, and regulatory pathways all influence study design. Therefore, a one-size-fits-all approach rarely serves manufacturers well.

Implantable and Long-Term Contact Devices

Implantable devices — orthopedic implants, cardiovascular stents, neural interfaces — demand the most rigorous extractables and leachables characterization. Permanent patient contact means even low-level chronic exposures require careful evaluation. Furthermore, biomaterial degradation over implant lifetime can generate leachables that do not appear in short-term extraction studies.

Additionally, implantable devices often combine multiple materials — metals, polymers, ceramics, and biologic coatings — each contributing its own chemical profile. Our teams routinely conduct multi-material, multi-solvent extraction protocols for these complex assemblies. For context on reprocessed implants and reusable devices, our article on reusable medical device testing explores additional qualification requirements that intersect with E&L programs.

Drug-Device Combination Products

Drug-delivery systems — prefilled syringes, autoinjectors, inhaled drug-device combinations — face dual regulatory oversight from both drug and device perspectives. In these products, leachables can directly contaminate the drug formulation and affect both efficacy and patient safety. Consequently, the FDA and EMA impose especially stringent E&L requirements on combination products.

Leachables studies for combination products must use the actual drug formulation as the extraction medium where possible. Moreover, the analytical evaluation threshold for injectable and inhalation routes is far lower than for skin-contact devices — reflecting the direct systemic exposure these routes create. Our Method Development & Validation team designs formulation-compatible methods that meet both drug and device agency expectations.

Comparison of E&L Requirements by Device Category

Device Category	Contact Duration	Key Analytical Focus	Typical AET Range
Skin-contact surface device	Limited (<24 h)	Organic migrants, allergens	Relatively high
Externally communicating (blood path)	Prolonged (up to 30 days)	Organics, metals, degradants	Moderate
Implantable device	Permanent (>30 days)	Full chemical characterization	Very low
Drug-device combination (injectable)	Repeated systemic dosing	Organics, metals, particles	Lowest (ppb–ppt)

Quality Assurance and Best Practices in E&L Programs

Analytical quality is the foundation of a defensible E&L program. Regulators scrutinize laboratory data closely, and any gap in quality can invalidate an otherwise thorough study. Therefore, best-practice quality systems are non-negotiable for E&L work intended for regulatory submission.

GLP Compliance and Laboratory Standards

Good Laboratory Practice (GLP) regulations govern non-clinical safety studies submitted to regulatory agencies. Specifically, GLP requires documented study protocols, calibrated instrumentation, traceable reference standards, and thorough raw data retention. Furthermore, GLP-compliant E&L studies carry significantly more regulatory weight than non-GLP work.

Even when full GLP compliance is not required, laboratories should follow ISO/IEC 17025 accreditation principles. Notably, accredited laboratories demonstrate documented competency, method validation, and external audit readiness. In addition, proficiency testing and inter-laboratory comparisons strengthen the defensibility of analytical results under regulatory scrutiny.

Documentation, Reporting, and Regulatory Submission Readiness

Complete documentation separates a regulatory-ready E&L report from a purely scientific exercise. Consequently, every study decision — solvent selection, extraction conditions, method validation parameters, and AET justification — must appear in the final report with clear scientific rationale. Reviewers expect to trace each analytical result back to raw data without ambiguity.

Furthermore, the report must clearly map leachables findings to the toxicological risk assessment conclusions. Presenting data in isolation — without toxicological context — is a common submission deficiency. Our article on FDA biocompatibility deficiencies highlights exactly how incomplete reporting triggers additional information requests. Ultimately, a well-structured, fully integrated E&L report is the most powerful tool a manufacturer has at the submission stage.

Early-Stage Planning Pays Off

Engaging E&L testing early — ideally during design and material selection — prevents the most costly problems. Specifically, discovering a high-risk leachable late in development may force material changes, redesign, or additional toxicology studies. By contrast, early screening identifies material risks when changes are still straightforward and inexpensive.

Additionally, manufacturers assessing material substitutions or suppliers should consult our guidance on device material equivalency, since even minor formulation changes can alter the extractables profile significantly. Our Scientific & Technical Consulting team helps manufacturers build proactive E&L strategies that align testing investment with actual regulatory risk.

Quick note: Regulators do not simply want analytical data — they want a coherent story linking material chemistry, analytical findings, and toxicological conclusions. Building that narrative from day one of your E&L program is the single most effective way to accelerate regulatory review and avoid deficiency letters.

Frequently Asked Questions About Medical Device E&L

What is the difference between extractables and leachables in medical devices?

Extractables are chemicals released from device materials under aggressive laboratory conditions designed to capture the worst-case chemical profile. Leachables, by contrast, are compounds that actually migrate into the patient or drug product during normal clinical use. In practice, leachables are typically a subset of extractables, though degradation products can sometimes appear only during real-world use. Both require identification, quantification, and toxicological assessment under ISO 10993-18.

Which analytical methods are most commonly used in E&L studies?

GC-MS is the primary tool for volatile and semivolatile organic compounds, while HPLC with mass spectrometric detection addresses nonvolatile polar compounds. ICP-MS and ICP-OES handle elemental impurities. Furthermore, FTIR, Raman, NMR, and XPS provide structural and surface characterization support. Comprehensive studies routinely deploy five or more complementary techniques to achieve full chemical coverage.

How does the analytical evaluation threshold (AET) work?

The AET is the minimum concentration that analytical methods must reliably detect in an E&L study. Specifically, it is calculated from the patient’s tolerable intake for a given compound, the device’s dose or contact parameters, and appropriate safety factors. Compounds detected above the AET require full toxicological evaluation. Those consistently below the AET may be excluded from further characterization, simplifying the overall assessment.

Do all medical devices require extractables and leachables testing?

Not all devices require the same depth of E&L testing, but most devices with direct patient contact require at least some chemical characterization under ISO 10993-18. Device contact nature and duration determine the rigor required. Consequently, permanent implants and drug-contacting devices face the most extensive requirements. By contrast, limited-contact skin devices may qualify for abbreviated assessments supported by material documentation.

When should manufacturers start E&L testing in the development timeline?

Manufacturers should initiate extractables screening as early as material selection — ideally before design freeze. Early testing identifies chemical risks while design changes remain practical and cost-effective. Furthermore, regulatory agencies expect E&L data to be available well before submission, since generating it under time pressure often leads to incomplete studies and deficiency letters. Building E&L into the design verification plan from day one is strongly recommended.

How do material changes affect an existing E&L program?

Any change in material formulation, supplier, or processing conditions can alter the extractables profile of a device component. Therefore, manufacturers must reassess E&L data whenever material changes occur. In some cases, a comparative extractables study may demonstrate equivalency. However, significant formulation changes typically require a new full characterization. Our guidance on device material equivalency outlines the decision framework for evaluating these changes systematically.

Conclusion

Medical device extractables and leachables testing sits at the intersection of analytical chemistry, toxicology, and regulatory science. Consequently, it demands rigorous planning, expert technique selection, and thorough documentation to produce results that satisfy regulators and protect patients. Shortcuts at any stage create compounding risk that surfaces — expensively — at the submission or post-market stage.

Furthermore, the analytical landscape continues to evolve. High-resolution mass spectrometry, non-targeted screening, and advanced computational toxicology are raising the standard for what comprehensive E&L characterization looks like. Manufacturers who invest in these capabilities now build a stronger regulatory position for current and future submissions.

At Materials Metric, our integrated Chemical & Analytical Testing and Biocompatibility & Toxicity Testing services provide end-to-end E&L support — from material inventory and extraction design through analytical execution, toxicological risk assessment, and regulatory report preparation. In addition, our Method Development & Validation team ensures every analytical method meets regulatory fitness-for-purpose requirements before a single sample is processed.

Whether you are preparing a first-in-class submission, managing a material change, or responding to an FDA deficiency, our team brings the scientific depth and regulatory experience your program needs. Contact Materials Metric today to discuss your E&L testing requirements and build a strategy that protects both your patients and your development timeline.