ISO 10993-18 | Materials Metric

What Is ISO 10993-18 and Why Does It Matter for Medical Devices?

ISO 10993-18 is the internationally recognized standard that defines how to chemically characterize materials used in medical devices, helping manufacturers identify and assess potentially harmful substances before those devices reach patients. At Materials Metric, we help device manufacturers navigate this standard efficiently, from extractables studies through full toxicological risk assessment.

Chemical characterization is one of the most demanding steps in the ISO 10993-18 Chemical Characterization compliance pathway. Consequently, many teams underestimate the analytical depth required. Furthermore, regulatory agencies such as the FDA and EU notified bodies now scrutinize chemical characterization data more closely than ever. Therefore, understanding the standard’s scope, framework, and testing requirements is essential for any team preparing a biocompatibility submission.

In this guide, we break down ISO 10993-18 in plain language. Specifically, we cover its structure, analytical thresholds, method requirements, and how the standard integrates with the broader ISO 10993 series. Moreover, we explain how a well-planned study can reduce costly delays and support a faster regulatory review.

Key Takeaways

ISO 10993-18 governs the chemical characterization of medical device materials, including extractables and leachables studies.

The standard requires a risk-based approach, not just a list of analytical tests.

Analytical Evaluation Thresholds (AET) drive method selection and sensitivity requirements.

Qualification Threshold (QT) and Reporting Threshold (RT) determine which chemicals require toxicological follow-up.

A Chemical Characterization Report must document all decisions, methods, and results transparently.

ISO 10993-18 works alongside ISO 10993-1 (biological evaluation), ISO 10993-17 (toxicological risk assessment), and other parts of the series.

ISO 10993-18: An internationally adopted standard that specifies a risk-based framework for chemically characterizing medical device materials — identifying, quantifying, and assessing extractable and leachable chemical substances to support biocompatibility and patient safety evaluations.

Key fact: ISO 10993-18 (2020 revision) significantly expanded the analytical requirements compared to the 2005 edition, introducing formal Analytical Evaluation Thresholds and a structured risk-based justification for every testing decision — making thorough chemical characterization a non-negotiable part of regulatory submissions worldwide.

What Is the Scope of ISO 10993-18?

ISO 10993-18 applies to all medical devices that contact patients directly or indirectly. Specifically, it covers devices with body contact — whether surface contact, externally communicating, or implantable — as defined under ISO 10993-1. Furthermore, the standard applies to both the bulk materials and any processing residues, additives, or colorants present in those materials.

Importantly, the standard does not prescribe a single fixed set of tests. Instead, it requires manufacturers to design a study that is appropriate for their device’s contact type, duration, and patient population. Consequently, the scope is broad, and the analytical program must be scientifically justified at every step.

Which Devices and Materials Fall Under ISO 10993-18?

In general, ISO 10993-18 applies to any device component that could release chemical substances into a patient. For example, polymer tubing, adhesives, coatings, metal alloys, ceramics, and biological materials all fall within scope. Moreover, devices that contact blood, tissue, or mucous membranes receive the highest level of scrutiny.

By contrast, devices with no patient contact — such as external imaging equipment that never touches the body — typically fall outside the standard’s scope. However, even indirect-contact devices may require assessment if leachable substances could migrate through a fluid pathway. Therefore, manufacturers should always evaluate contact pathways carefully before scoping their study.

How ISO 10993-18 Fits Within the ISO 10993 Series

The ISO 10993 series contains more than 20 parts, each addressing a different aspect of biocompatibility. Specifically, ISO 10993-18 focuses on chemical characterization, while ISO 10993-1 sets the overall biological evaluation framework. Furthermore, chemical characterization data feeds directly into the toxicological risk assessment conducted under ISO 10993-17.

In addition, the standard links closely with ISO 10993-12, which governs sample preparation and reference materials for biological testing. Overall, these parts work together as an integrated system. Consequently, a gap in chemical characterization often creates downstream problems in the toxicological risk assessment and the overall biological evaluation plan.

ISO 10993 Part	Primary Focus	Relationship to Part 18
ISO 10993-1	Biological evaluation framework	Sets overall strategy; Part 18 data feeds the BEP
ISO 10993-12	Sample preparation	Defines extraction conditions used in Part 18 studies
ISO 10993-17	Toxicological risk assessment	Uses chemical identities and quantities from Part 18
ISO 10993-18	Chemical characterization	Core subject of this article
ISO 10993-9 / 10 / 13	Degradation products	Part 18 may incorporate degradation data as leachables

Understanding Extractables and Leachables Under ISO 10993-18

Two terms appear throughout ISO 10993-18 and are central to understanding the standard: extractables and leachables. Extractables are chemical compounds released from a device or material under exaggerated or controlled laboratory conditions. Leachables, by contrast, are the subset of those compounds that actually migrate into a patient under realistic clinical use conditions.

Therefore, an extractables study serves as a worst-case screen, while a leachables study reflects real-world patient exposure. Importantly, ISO 10993-18 requires manufacturers to assess both, and to justify the relationship between them using a scientifically sound correlation argument.

Extractables Studies: Purpose and Design

Extractables studies use aggressive solvents, elevated temperatures, and extended contact times to force the release of all possible chemical migrants from a material. For example, polar solvents such as water or ethanol and non-polar solvents such as hexane or isopropyl alcohol are commonly used together. Furthermore, the choice of solvents must reflect the polarity range of substances likely to be present.

Consequently, a well-designed extractables study gives regulators confidence that no significant chemical migrant has been overlooked. The resulting data — chemical identities and estimated quantities — then drives the selection of analytical methods for leachables testing. In addition, these results inform the Analytical Evaluation Threshold calculation, which is a key concept under ISO 10993-18.

Leachables Studies: Simulating Real Patient Exposure

Leachables studies use clinically relevant conditions: realistic contact fluids, physiological temperatures, and contact durations that match actual device use. For instance, a catheter tested in saline at 37°C for the labeled dwell time is a typical leachables simulation. By contrast, an extractables study might use the same catheter in ethanol at 70°C for 72 hours.

Moreover, leachables data must be expressed in terms of patient dose — not just concentration in the extract. Specifically, the standard requires manufacturers to calculate daily patient intake of each leachable, using patient exposure scenarios tied to device contact type and duration. Consequently, the Chemical & Analytical Testing program must be designed with the end-use toxicological assessment clearly in mind from the start.

Quick note: ISO 10993-18 distinguishes clearly between extractables (lab-generated, worst-case) and leachables (clinically realistic). Many regulatory deficiency letters arise from teams that conflate these two concepts or fail to justify the extractables-to-leachables correlation adequately.

The Risk-Based Framework: AET, Reporting Thresholds, and Qualification Thresholds

One of the most significant contributions of the 2020 revision of ISO 10993-18 is a formal, tiered threshold framework. This framework gives manufacturers a structured, defensible method to prioritize which chemical substances require full toxicological characterization. Importantly, it replaces older, less systematic approaches with a rigorous risk-based process.

Furthermore, the framework aligns closely with similar threshold systems used in pharmaceutical sciences, such as the USP General Chapter <232> Elemental Impurities framework, making it easier for teams with pharmaceutical backgrounds to apply the concepts. However, the specific calculations and toxicological inputs differ from pharmaceutical contexts, so direct translation requires care.

What Is the Analytical Evaluation Threshold (AET)?

The Analytical Evaluation Threshold — commonly abbreviated as AET — is the minimum concentration a method must be capable of detecting and reporting. Specifically, the AET defines the analytical sensitivity floor for a given study. Any compound present at or above the AET must be identified and quantified.

Importantly, the AET calculation begins with a Tolerable Intake (TI) value for the most toxic compound realistically expected in the device. Manufacturers then work backward through patient exposure assumptions to establish the minimum detectable concentration in the extract. Consequently, the AET drives the method development requirements — laboratories must validate that their techniques achieve the required sensitivity before the study begins. For more on this topic, see our article on the Analytical Evaluation Threshold and how it shapes study design.

Reporting Threshold and Qualification Threshold Explained

Above the AET, ISO 10993-18 establishes two further decision points: the Reporting Threshold (RT) and the Qualification Threshold (QT). The Reporting Threshold defines the minimum level at which a detected compound must be formally reported and identified. Meanwhile, the Qualification Threshold marks the concentration above which a compound requires full toxicological evaluation.

By contrast, compounds detected between the AET and the RT need only be reported as detected, without full structural identification. Additionally, compounds above the QT must be characterized to a level sufficient to allow a meaningful risk assessment. Consequently, the tiered system focuses analytical and toxicological resources where patient risk is actually highest, rather than requiring exhaustive assessment of every trace signal.

Threshold	Abbreviation	Action Required
Analytical Evaluation Threshold	AET	Minimum detection sensitivity; all compounds at/above must be reported
Reporting Threshold	RT	Compounds must be identified and reported with quantities
Qualification Threshold	QT	Full toxicological characterization and risk assessment required

How Method Sensitivity Ties to Threshold Calculations

Method sensitivity is not an afterthought in ISO 10993-18 — it is a foundational requirement. Specifically, the analytical methods used in a chemical characterization study must demonstrate that they can reliably detect and quantify compounds at or below the AET. Therefore, Method Development & Validation becomes a critical pre-study activity, not an administrative checkbox.

Furthermore, the standard requires that method validation data be included in the Chemical Characterization Report. Reviewers expect to see documented evidence — such as limits of detection (LOD) and limits of quantification (LOQ) — that the chosen methods meet the AET requirements. Consequently, laboratories that skip or abbreviate this step frequently receive deficiency letters requesting additional analytical justification. For insight into how regulators evaluate this data package, see our overview of the FDA chemical characterization review process.

What Analytical Techniques Does ISO 10993-18 Require?

ISO 10993-18 does not mandate a single analytical method. Instead, it requires manufacturers to select techniques appropriate for the chemical classes likely present in their device materials. Consequently, most compliant studies use a multi-technique approach, combining chromatographic, spectroscopic, and elemental methods to achieve comprehensive coverage.

Furthermore, the analytical program must demonstrate sufficient sensitivity to meet AET requirements for each chemical class. Therefore, method selection is a scientific decision — not simply a matter of laboratory availability or cost. A well-chosen technique suite significantly reduces the risk of missing a toxicologically relevant compound.

Chromatographic Methods: GC-MS and HPLC

Gas chromatography–mass spectrometry (GC-MS) is one of the most widely used techniques in ISO 10993-18 studies. Specifically, it excels at identifying and quantifying volatile and semi-volatile organic compounds. Moreover, GC-MS provides library-searchable mass spectra, enabling confident structural identification of unknown extractables. Our GC-MS Analysis service supports both screening and quantitative leachables studies.

High-performance liquid chromatography (HPLC) complements GC-MS by covering non-volatile and thermally labile compounds that would degrade during gas-phase analysis. For example, antioxidants, UV stabilizers, and certain polymer additives are best analyzed by HPLC Analysis. Furthermore, coupling HPLC with mass spectrometry detection — forming LC-MS — greatly expands structural identification capability for complex extracts.

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

Elemental impurities represent a critical subset of chemical characterization under ISO 10993-18. Inductively coupled plasma–mass spectrometry (ICP-MS) delivers the lowest detection limits of any elemental technique, making it essential for trace-level metal screening. Consequently, ICP-MS dominates elemental characterization in medical device studies where metals such as lead, cadmium, arsenic, and nickel must be quantified at parts-per-billion levels.

Inductively coupled plasma–optical emission spectrometry (ICP-OES) offers excellent multi-element capability at slightly higher detection limits than ICP-MS. Meanwhile, atomic absorption spectrometry (AAS) provides a cost-effective, single-element option for targeted quantification. All three techniques appear in ISO 10993-18 compliant programs, and the choice depends on the analyte list and required sensitivity. Our Chemical & Elemental Characterization team routinely combines these methods for comprehensive coverage, aligning with guidance from the USP Elemental Impurities framework.

Spectroscopic and Surface Techniques

Spectroscopic techniques play a supporting role in ISO 10993-18 studies, particularly for material identification and surface characterization. For instance, FTIR Analysis rapidly confirms polymer identity and detects bulk additives, providing a first-pass screen before more targeted testing. Similarly, Raman Spectroscopy characterizes coatings, thin films, and surface residues that are difficult to extract into solution.

Additionally, XPS Analysis and XRF Analysis reveal surface elemental composition and oxidation states — information that supports both chemical characterization and understanding of potential degradation pathways. Moreover, published analytical research cited in sources such as ScienceDirect continues to advance multi-technique strategies for complex medical device extracts. Our Chemical & Analytical Testing team integrates these tools into a coherent, ISO 10993-18 aligned study plan.

Technique	Chemical Classes Covered	Key Strength
GC-MS	Volatile and semi-volatile organics	Library-matched structural identification
HPLC / LC-MS	Non-volatile organics, additives	Covers thermally labile compounds
ICP-MS	Elemental impurities (metals)	Ultra-trace detection (ppt–ppb range)
ICP-OES	Multi-element metals screening	High-throughput multi-element analysis
FTIR	Polymers, bulk additives	Rapid material identification
XPS / XRF	Surface elemental composition	Surface-specific chemical state analysis

How Does ISO 10993-18 Apply Across Different Device Categories?

ISO 10993-18 applies broadly, yet the practical demands vary considerably across device categories. Specifically, contact type, contact duration, and the vulnerable patient population all shape what a compliant chemical characterization program must include. Therefore, manufacturers benefit from understanding how the standard’s requirements translate into their specific device context.

Implantable and Long-Term Contact Devices

Implantable devices face the most stringent requirements under ISO 10993-18. For example, permanent implants such as orthopedic components, vascular stents, and cardiac rhythm management devices can expose patients to leachable substances for a lifetime. Consequently, the tolerable intake values used to calculate AETs for implantable devices are typically the most conservative, and method sensitivity requirements are correspondingly demanding.

Furthermore, degradation products — not just processing residues and additives — must be considered for implantable materials. Polymer hydrolysis, metal corrosion, and coating delamination can all generate chemical migrants over time. In addition, our Biocompatibility & Toxicity Testing service works alongside chemical characterization to provide the integrated data package these submissions require.

Short-Term and Surface-Contact Devices

Short-term contact devices — those used for fewer than 24 hours — and surface-contacting devices generally permit somewhat less conservative AET calculations. However, this does not eliminate the need for rigorous chemical characterization. Moreover, single-use devices manufactured at high volumes create systemic patient exposure risks if leachables are present even at low concentrations per device.

By contrast, devices with intact skin contact only face a lower risk profile than those contacting mucous membranes or breached skin. Nevertheless, the standard still requires a documented, scientifically justified assessment for all contact categories. Therefore, manufacturers should not assume that a short contact duration or limited contact surface automatically simplifies the study design.

Drug–Device Combination Products

Drug–device combination products present a particularly complex chemical characterization challenge. Specifically, leachables from the device component may interact with the drug formulation, potentially altering drug stability or patient safety. Consequently, ISO 10993-18 studies for combination products must address both device-derived leachables and their potential impact on the drug product.

Furthermore, regulatory expectations for combination products often draw simultaneously on ISO 10993-18, ICH Q3B (impurities in drug products), and container closure system guidance. In addition, the ISO 10993-18 framework must integrate with the pharmaceutical regulatory pathway, requiring close coordination between device and pharmaceutical teams. Our Scientific & Technical Consulting team regularly guides combination product developers through this cross-regulatory landscape.

Best Practices for ISO 10993-18 Compliance and Study Quality

A technically sound ISO 10993-18 study requires more than running the right instruments. Specifically, it demands careful planning, clear scientific rationale at every decision point, and a structured documentation approach that anticipates regulatory review. Moreover, experience consistently shows that the studies generating fewest deficiency letters share several common characteristics.

Planning the Chemical Characterization Report Early

The Chemical Characterization Report (CCR) is the primary deliverable of an ISO 10993-18 study. Importantly, teams that outline the CCR structure before testing begins produce more coherent, defensible documents. For instance, mapping each analytical result back to a specific threshold calculation — and documenting the rationale — prevents gaps that reviewers frequently flag.

Furthermore, the CCR must describe the device, its materials, contact conditions, the extraction study design, method validation data, analytical results, and any toxicological conclusions. Consequently, it functions as both a technical record and a regulatory argument. Our Method Development & Validation service ensures that method performance data integrates cleanly into this document structure from the outset.

Selecting the Right Extraction Conditions

Extraction condition selection is one of the most consequential decisions in the entire ISO 10993-18 process. Specifically, solvents, temperatures, and extraction times must be aggressive enough to be a credible worst case, yet scientifically justified rather than arbitrarily severe. For example, using an extraction temperature far above the device’s processing or use temperature adds little scientific value and may generate artifactual degradation products.

Moreover, ISO 10993-12 provides detailed guidance on extraction vehicles and conditions that map to device contact type and duration. Therefore, teams should anchor extraction condition selection firmly in ISO 10993-12 before beginning any ISO 10993-18 extractables study. Additionally, documenting the rationale for every extraction condition choice greatly strengthens the CCR during regulatory review.

Avoiding Common Deficiency Letter Triggers

Regulatory deficiency letters for chemical characterization submissions cluster around a predictable set of issues. Understanding these common pitfalls helps teams avoid them proactively. The following are the most frequently cited problems:

Insufficient method sensitivity: LOD and LOQ values exceed the AET, leaving a detection gap.
Incomplete chemical identification: Compounds detected above the RT are not structurally identified.
Missing extractables-to-leachables correlation: No scientific justification links the two study types.
Inadequate solvent coverage: Only aqueous extraction performed, missing non-polar migrants.
Unsupported threshold calculations: AET values lack documented toxicological inputs or exposure assumptions.
No method validation data: The CCR references methods without performance qualification evidence.

In addition, teams that engage Scientific & Technical Consulting support early in study planning consistently reduce the frequency and severity of these issues. Furthermore, a pre-submission meeting with the regulatory agency — where available — can surface agency-specific expectations before the study begins.

Quick note: The most effective ISO 10993-18 studies treat the Chemical Characterization Report as a live scientific argument — not a post-hoc summary. Writing the report structure first, then filling in data as testing progresses, consistently produces stronger regulatory submissions.

Frequently Asked Questions About ISO 10993-18

What is the difference between ISO 10993-18 and ISO 10993-17?

ISO 10993-18 governs chemical characterization — the analytical identification and quantification of extractable and leachable substances from a medical device. By contrast, ISO 10993-17 covers toxicological risk assessment — the evaluation of whether the identified chemicals pose an unacceptable risk to patients. Consequently, Part 18 generates the chemical data that Part 17 evaluates. Both parts are required for a complete biocompatibility submission, and the output of Part 18 directly feeds into the toxicological risk assessment under Part 17.

When was ISO 10993-18 last updated, and what changed?

The most recent edition of ISO 10993-18 was published in 2020, replacing the 2005 version. Importantly, the 2020 revision introduced formal Analytical Evaluation Thresholds (AETs), a structured risk-based decision framework, and significantly expanded requirements for method validation and documentation. Furthermore, the new edition aligned more closely with pharmaceutical leachables science and established clearer expectations for the Chemical Characterization Report. Submissions based on the 2005 edition are no longer considered sufficient by most regulatory agencies.

Do I need a full extractables and leachables study for every device?

Not necessarily. ISO 10993-18 permits a risk-based scoping approach. Specifically, manufacturers may use material composition data, supplier information, and existing literature to justify a reduced or desk-based chemical characterization for certain low-risk devices or materials with well-established safety profiles. However, this justification must be documented thoroughly. Moreover, regulatory reviewers scrutinize scoping arguments carefully, so unsupported claims of low risk are a frequent deficiency trigger. Our Biocompatibility & Toxicity Testing team can help determine the appropriate study scope for your device.

How does ISO 10993-18 relate to FDA expectations for chemical characterization?

The FDA’s guidance on biocompatibility, most recently updated in 2016 and supplemented by subsequent Q&A documents, aligns closely with ISO 10993-18. Specifically, FDA reviewers expect submissions to follow the ISO 10993-18 framework for chemical characterization, including AET calculations, threshold-based reporting, and method validation documentation. Furthermore, the FDA has explicitly stated that chemical characterization is often the most critical component of a biocompatibility submission. For a detailed review of FDA-specific expectations, see our article on the FDA chemical characterization review process.

What is the role of the Analytical Evaluation Threshold in study design?

The AET defines the minimum detection sensitivity that analytical methods must achieve before a study begins. Specifically, it ensures that no compound present at a toxicologically relevant level escapes detection due to insufficient method sensitivity. Consequently, AET calculation is one of the first activities in study design — it directly determines which analytical instruments and validation parameters are required. For a deeper explanation of how the AET is calculated and applied, our dedicated article on the Analytical Evaluation Threshold covers the topic comprehensively.

Which analytical techniques are most commonly used in ISO 10993-18 studies?

Most ISO 10993-18 studies rely on a combination of GC-MS for volatile organics, HPLC or LC-MS for non-volatile organics, and ICP-MS or ICP-OES for elemental impurities. Additionally, FTIR provides rapid material identification, while XPS and XRF support surface characterization. The specific technique mix depends on the device materials, expected chemical classes, and AET requirements. Our Chemical & Analytical Testing team designs multi-technique programs tailored to each device’s characterization needs.

Conclusion

ISO 10993-18 sets the global standard for chemical characterization of medical devices, and compliance demands far more than a list of analytical tests. Specifically, it requires a scientifically rigorous, risk-based program — from AET calculation and extraction study design through method validation, leachables quantification, and a fully documented Chemical Characterization Report.

Furthermore, the 2020 revision raised the bar considerably. Regulatory agencies worldwide now expect submissions to reflect the formal threshold framework, comprehensive analytical coverage, and transparent scientific justification that the standard demands. Moreover, gaps in chemical characterization remain one of the leading causes of regulatory deficiency letters and submission delays.

Ultimately, a well-executed ISO 10993-18 study protects patients, accelerates regulatory review, and demonstrates the scientific rigor that regulators and notified bodies expect. By contrast, an underprepared chemical characterization package creates costly cycles of deficiency responses that delay market entry and consume development resources.

At Materials Metric, we combine deep ISO 10993-18 expertise with a full suite of analytical capabilities — including GC-MS, HPLC, ICP-MS, FTIR, XPS, and more — to deliver compliant, defensible chemical characterization studies. In addition, our consulting team supports study design, AET calculations, method validation, and CCR preparation at every stage. Therefore, whether you are characterizing a simple polymer component or a complex multi-material implant, we have the expertise to support your program efficiently and thoroughly.

Ready to discuss your ISO 10993-18 chemical characterization needs? Contact Materials Metric today to speak with our team and learn how we can support your device’s regulatory pathway from study design through final submission.