ISO 10993-1:2025: What Changed, Why It Matters, and How to Prepare

The Most Significant Biocompatibility Update in Years

ISO 10993-1:2025, published on November 18, 2025, is the sixth edition of the foundational standard governing biological evaluation of medical devices. It replaces the 2018 edition and introduces changes that are not incremental — they represent a fundamental shift in how manufacturers must approach biocompatibility.

The core message is unambiguous: the era of "Table A.1 checklist" biocompatibility is over. The 2025 revision mandates that biological evaluation be fully embedded within the ISO 14971 risk management framework, driven by scientific justification rather than prescriptive testing matrices. For manufacturers who have relied on simply checking boxes in the old evaluation table, this revision requires a fundamentally different approach.

This guide covers every significant change in ISO 10993-1:2025, explains the practical implications for manufacturers, compares the 2018 and 2025 approaches side by side, and provides a concrete action plan for bringing your biological evaluation documentation into compliance.

The Big Picture: 2018 vs 2025 at a Glance

Aspect	ISO 10993-1:2018	ISO 10993-1:2025
Approach	Test-driven with matrix tables	Risk-based, science-driven, integrated with ISO 14971
Evaluation framework	Single Table A.1 for all device categories	Four separate tables organized by contact type
Risk management	Referenced but loosely applied	Mandatory full alignment with ISO 14971
Chemical characterization	Important but secondary	Core foundation of all biological evaluation
Animal testing	Minimized in principle	Explicitly deprioritized; in vitro methods preferred
Exposure duration	Broad categories (limited, prolonged, long-term)	"Contact days" with cumulative and daily contact calculations
Reasonably foreseeable misuse	Not explicitly addressed	Now in scope for biological evaluation
Documentation (BEP/BER)	Inconsistent expectations	Clearly defined structure and traceability
Endpoint selection	Based on device type and duration	Based on contact type and scientifically justified risk
Genotoxicity	Required for implants and prolonged tissue contact	Expanded to all prolonged-contact devices (except intact skin)

Change 1: From Table A.1 to Four Contact-Specific Tables

The single most visible change in ISO 10993-1:2025 is the restructuring of the evaluation matrix.

What Was Table A.1

In the 2018 edition, Table A.1 in Annex A was the go-to reference for determining which biological endpoints to evaluate. It was a single large matrix organized by device category (surface devices, external communicating devices, implant devices) and contact duration (limited, prolonged, long-term). For each combination, it listed the endpoints to consider: cytotoxicity, sensitization, irritation, systemic toxicity, genotoxicity, implantation, hemocompatibility, and others.

The problem: manufacturers treated Table A.1 as a prescriptive checklist rather than the guidance it was intended to be. If a cell in the table contained an "X," the test was performed — often without considering whether it was scientifically necessary. This led to over-testing, unnecessary animal use, and evaluations that were technically complete but scientifically shallow.

What Replaces It

ISO 10993-1:2025 splits the single matrix into four separate tables, each corresponding to a specific type of body contact:

Table	Contact Type	Examples
Table 1	Intact skin	Electrodes, bandages, compression garments
Table 2	Intact mucosal membranes	Contact lenses, urinary catheters, endotracheal tubes
Table 3	Breached or compromised surfaces, or internal tissues (other than circulating blood)	Surgical wounds, burn dressings, tissue grafts
Table 4	Circulating blood	IV catheters, hemodialysis equipment, blood filters

This reorganization serves multiple purposes:

• It eliminates the old "externally communicating" device category, which was a source of confusion
• It focuses attention on the actual tissue contact rather than device type
• It makes the evaluation more precise — a device contacting intact skin is evaluated differently from one contacting compromised tissue, even if both are "surface devices"
• Each table includes detailed footnotes and guidance specific to that contact type

Key Change: "Biological Endpoints" Become "Biological Effects"

The 2025 revision renames "biological endpoints" to "biological effects." This is not merely semantic — it reflects a shift from "tests to perform" to "biological interactions to evaluate." The evaluation may involve testing, literature review, chemical characterization, or a combination of these approaches, as long as the biological effect is adequately addressed.

Physical/Chemical Characterization Removed from Tables

In the 2018 version, "Physical and/or chemical information" appeared as a row in Table A.1 alongside other endpoints. In the 2025 revision, it has been removed from the tables entirely — not because it is less important, but because it has been elevated. Chemical characterization is now positioned as a prerequisite step that informs all subsequent biological effect evaluations, covered in the risk analysis sections of the standard rather than in a table cell.

Change 2: Mandatory ISO 14971 Integration

The 2025 revision makes explicit what regulators have been pushing toward for years: biological evaluation must be conducted within the ISO 14971 risk management framework.

What This Means in Practice

The standard now adopts ISO 14971 terminology and process flows directly:

1. Identify biological hazards: What biological risks does the device pose?
2. Define biologically hazardous situations: Under what circumstances could these hazards cause harm?
3. Define biological harms: What specific adverse outcomes could result?
4. Perform biological risk estimation and evaluation: How likely and how severe are these harms?
5. Document risk control measures: What will you do to mitigate unacceptable risks?
6. Update throughout the lifecycle: Re-evaluate as new information becomes available

This means your Biological Evaluation Plan (BEP) and Biological Evaluation Report (BER) must be traceable to your risk management file. The biological evaluation is no longer a standalone exercise — it is a component of your overall device risk management.

Why This Matters for Regulatory Submissions

Both the FDA and EU Notified Bodies increasingly expect biocompatibility to be risk-based. The FDA's 2023 guidance on biocompatibility already moved in this direction. EU MDR Article 10 and Annex I require risk management integration. The 2025 revision of ISO 10993-1 makes this expectation explicit in the standard itself.

Submissions that treat biocompatibility as a testing checklist — without risk management traceability — are more likely to receive deficiency letters and requests for additional information.

Change 3: Exposure Duration — The "Contact Day" Concept

The 2025 revision introduces significant changes to how exposure duration is determined, with direct implications for device categorization and the scope of biological evaluation required.

The Old Approach

Under ISO 10993-1:2018, devices were categorized by broad contact duration:

• Limited: Less than 24 hours
• Prolonged: 24 hours to 30 days
• Long-term: More than 30 days

These categories were applied based on the intended duration of a single use or the aggregate contact period, but the methodology for calculating the aggregate was imprecise.

The New Approach: Contact Days

ISO 10993-1:2025 introduces the concept of a "contact day" — any calendar day on which the device has contact with the patient, regardless of how brief the contact is within that day. This has several practical consequences:

1. Daily contact devices: If a device contacts the patient every day (even briefly), each day counts as one contact day. A device used for 15 minutes daily for 30 days = 30 contact days, placing it in the prolonged category.

2. Intermittent contact devices: For devices used with gaps of at least one day between uses, the total exposure period is calculated as the cumulative calendar span from first to last contact.

3. Reusable devices: The total exposure for a single patient is the sum of all contact days across all uses. This may push reusable devices into longer duration categories than they occupied under the 2018 system.

4. Bioaccumulation trigger: If bioaccumulation of device constituents is expected (e.g., the device contains substances known to accumulate in the body), the contact duration shall be classified as long-term unless otherwise justified.

Practical Impact

Many devices will be re-categorized into longer contact duration classes under the 2025 rules. A device that was "limited contact" under 2018 may become "prolonged" under 2025 if it is used on multiple days. This re-categorization can trigger requirements for additional biological effects to be evaluated.

For example:

• A wound contact layer applied during daily dressing changes for 3 weeks: Under 2018, each application might have been considered "limited" (< 24 hours). Under 2025, the 21 contact days place it firmly in the "prolonged" category, potentially requiring evaluation of additional biological effects.

• A reusable surgical instrument sterilized between patients: Each patient's contact is brief, but for a single patient undergoing repeated procedures, the cumulative contact days must be assessed.

Change 4: Expanded Genotoxicity Requirements

The 2025 revision significantly expands the circumstances under which genotoxicity must be evaluated.

What Changed

Under ISO 10993-1:2018, genotoxicity testing was primarily associated with implants and devices in prolonged or long-term contact with tissue. The 2025 revision broadens this requirement:

• Genotoxicity evaluation is now expected for all devices in prolonged contact (not just implants), with the sole exception of devices contacting only intact skin
• If genotoxic constituents are identified, genotoxic carcinogenicity assessment should follow
• Non-genotoxic carcinogenicity evaluation requires long-term contact, as the associated mechanisms require extended exposure to manifest

Why This Matters

This is one of the most practically significant changes for manufacturers. Devices that previously did not require genotoxicity assessment — such as wound contact materials, topical devices in prolonged use, or mucosal-contacting devices — may now need it.

The evaluation does not necessarily require testing. A well-documented chemical characterization showing the absence of genotoxic constituents, supported by toxicological risk assessment, may be sufficient. But the burden of justification has shifted: you must now actively justify why genotoxicity is not a concern, rather than simply not testing because it was not on the checklist.

Change 5: Chemical Characterization as the Foundation

The 2025 revision elevates chemical characterization from an important consideration to the core foundation of biological evaluation.

The New Expectation

Chemical characterization — the systematic identification and quantification of chemical constituents, leachables, and degradation products from device materials — is now expected to be the first step in biological evaluation. This aligns with the increased reliance on:

• ISO 10993-18: Chemical characterization of materials
• ISO 10993-17: Toxicological risk assessment of leachable substances

The standard expects manufacturers to:

1. Identify all materials of construction
2. Characterize the chemical composition, including additives, processing aids, and potential contaminants
3. Evaluate leachables and extractables under clinically relevant conditions
4. Perform toxicological risk assessment on identified chemical constituents
5. Use the results to determine which biological effects need further evaluation through testing

What This Means for Testing Strategy

A robust chemical characterization can sometimes reduce the need for biological testing. If you can demonstrate through chemical analysis that no concerning leachables are present at clinically relevant levels, you may be able to justify omitting certain in vivo tests. This is the core of the risk-based approach: test when scientifically necessary, not when a table tells you to.

Conversely, if chemical characterization reveals potentially concerning constituents, it guides targeted testing rather than blanket testing.

Change 6: "Reasonably Foreseeable Misuse" Now In Scope

The 2025 revision explicitly includes reasonably foreseeable misuse as a factor in biological evaluation. This means manufacturers must consider not only the intended use of the device but also plausible ways the device could be used incorrectly.

Examples of Foreseeable Misuse Affecting Biocompatibility

• A device intended for single use that is reprocessed and reused by a healthcare facility
• A topical device applied to compromised skin when it is intended for intact skin only
• A device used for a longer duration than recommended in the instructions for use
• A device used on a patient population not included in the intended use (e.g., pediatric use of a device designed for adults)

Each of these scenarios may change the contact type, contact duration, or chemical exposure profile, potentially triggering evaluation of additional biological effects.

Change 7: "Implantation Effects" Become "Local Effects After Tissue Contact"

The biological effect formerly known as "implantation effects" has been renamed to "local effects after tissue contact" in the 2025 revision.

This change broadens the applicability of this evaluation:

• Under the 2018 standard, "implantation effects" were primarily associated with permanently implanted devices
• Under the 2025 revision, "local effects after tissue contact" explicitly applies to any device in prolonged or long-term contact with tissues, not just implants
• This includes wound wash solutions, prolonged-use wound dressings, mucosal-contacting devices, and other non-implanted devices that maintain tissue contact

For manufacturers of non-implant devices in prolonged tissue contact, this represents an expanded evaluation requirement.

Change 8: Strengthened Documentation Requirements (BEP and BER)

The 2025 revision provides clear expectations for the structure and content of the Biological Evaluation Plan (BEP) and Biological Evaluation Report (BER).

BEP Expectations

The Biological Evaluation Plan should document:

• Device description and intended use
• Materials of construction and their characterization
• Contact type and duration (using the new contact day methodology)
• Identification of biological hazards and hazardous situations
• Planned approach for evaluating each biological effect
• Justification for any testing that is not performed
• Integration with the ISO 14971 risk management file

BER Expectations

The Biological Evaluation Report should document:

• Results of all evaluations (chemical characterization, testing, literature reviews)
• Traceability to the risk management file
• Conclusions on biological safety for each evaluated effect
• Overall assessment of biological safety
• Any residual risks and how they are managed
• Recommendations for post-market surveillance related to biocompatibility

Traceability

The key word is traceability. Every conclusion in the BER must be traceable to data, and every data element must be traceable to the BEP and the risk management file. This is the documentation standard that regulators and Notified Bodies will expect.

Change 9: Biological Equivalence Tightened

The 2025 revision raises the bar for claiming biological equivalence between devices. Previously, if a manufacturer could demonstrate that a new device used the same material, manufacturing process, physical properties, body contact, and clinical use as a predicate device, a toxicological risk assessment could be sufficient to conclude the biological evaluation.

Under ISO 10993-1:2025, biological equivalence requires a more thorough assessment:

1. Chemical equivalence: Demonstrated through chemical characterization (ISO 10993-18) showing comparable extractables and leachables profiles
2. Physical equivalence: Comparable physical properties that could affect biological interactions (surface morphology, porosity, degradation behavior)
3. Contact equivalence: The same type and duration of body contact as the predicate device
4. Manufacturing equivalence: The same manufacturing processes, including sterilization method, surface treatments, and processing aids

The increased depth of assessment means manufacturers must be more specific in defining biological harms — whether they relate to the application of the device or to the specific biological effects requiring evaluation. This makes the equivalence argument more rigorous but also more scientifically defensible.

Impact on Existing Predicate-Based Evaluations

If you have previously claimed biological equivalence to support a device's biocompatibility without conducting a full chemical characterization, the 2025 revision may require you to strengthen that claim. This does not necessarily mean re-testing — but it does mean providing more detailed scientific justification, including chemical characterization data where appropriate.

Change 10: Lifecycle and Animal Welfare

Lifecycle Approach

ISO 10993-1:2025 emphasizes that biological evaluation is not a one-time event but a lifecycle activity. Manufacturers must consider:

• Changes in device characteristics during transport, storage, and use
• Effects of reprocessing on reusable devices (each processing cycle may alter material properties)
• End-of-life evaluation: biocompatibility at the end of the device's useful life
• Post-market surveillance for biological safety signals

Animal Welfare

The 2025 revision strengthens the requirement to minimize animal testing:

• In vitro methods must be given preference over in vivo methods whenever they provide equally relevant information
• Animal testing must not be performed unless essential and no suitable alternative exists
• The principle applies throughout the evaluation, from initial screening to confirmatory testing
• This aligns with the global trend toward reducing animal use in medical device testing

Connection to EU MDR and FDA Requirements

EU MDR GSPR Requirements

The EU MDR's General Safety and Performance Requirements (GSPRs) in Annex I include several provisions directly related to biocompatibility:

• GSPR 10.1: Devices must be designed and manufactured to eliminate or reduce risks from substances leaking from the device
• GSPR 10.2: Devices intended to contact the patient must be designed to minimize risks from substance leakage
• GSPR 10.3: Devices must not contain carcinogenic, mutagenic, or toxic reproductive (CMR) substances above specified thresholds
• GSPR 10.4: Where devices contain CMR or endocrine-disrupting substances, justification must be provided

ISO 10993-1:2025 provides the evaluation framework for demonstrating compliance with these GSPRs. The shift from checklist testing to risk-based evaluation aligns with the MDR's emphasis on risk management throughout the product lifecycle. Your biological evaluation report should explicitly reference the relevant GSPRs and demonstrate how the evaluation addresses each requirement.

FDA Expectations

The FDA's approach to biocompatibility has been moving in the same direction as ISO 10993-1:2025 for several years. Key FDA expectations that align with the 2025 revision:

• The FDA's 2023 guidance on biocompatibility already emphasizes chemical characterization and toxicological risk assessment
• FDA reviewers expect manufacturers to justify why specific tests are performed — and why others are omitted
• The FDA's Recognized Consensus Standards database will eventually include ISO 10993-1:2025, but even before formal recognition, the principles are consistent with FDA expectations
• Pre-submission meetings are an opportunity to discuss biocompatibility strategy with FDA reviewers, particularly for novel materials or devices with complex contact scenarios

Regional Adoption Timelines

The adoption of ISO 10993-1:2025 varies by region:

European Union

Quick adoption is expected. The revision is likely to be recognized as "state of the art" under the EU MDR relatively quickly. Notified Bodies conducting conformity assessments will reference the 2025 version as the current standard, and manufacturers will be expected to align their evaluations accordingly.

United States (FDA)

The FDA maintains a database of Recognized Consensus Standards and can choose to recognize all, part, or none of a revised standard. The FDA's recognition of ISO 10993-1:2025 is expected, but the timeline is uncertain — it may take 12-18 months from publication for formal recognition. However, even before formal recognition, FDA reviewers are aware of the revision and may reference risk-based evaluation principles in their reviews.

The FDA's own guidance on biocompatibility (the 2023 update to the 2020 guidance) already emphasizes risk-based approaches and chemical characterization, so the 2025 revision is well-aligned with FDA expectations.

Other Markets

Most global regulators reference ISO 10993 as the standard for biological evaluation. The 2025 revision will be adopted through each jurisdiction's standards recognition process.

What Manufacturers Must Do Now

Immediate Actions (Next 30 Days)

1. Inventory your biocompatibility documentation: Identify which devices have evaluations based on the 2018 standard and which evaluations rely heavily on Table A.1 checklist approaches.

2. Assess exposure duration: Review the contact duration assumptions for each device. Apply the "contact day" methodology to determine if any devices would be re-categorized into longer duration classes.

3. Evaluate genotoxicity coverage: Determine if any devices in prolonged contact (other than intact skin) lack genotoxicity assessment. Plan to address gaps.

Short-Term Actions (3-6 Months)

4. Conduct gap assessments: Compare your current biological evaluations against the 2025 requirements. Document gaps and create remediation plans.

5. Strengthen chemical characterization: For devices where chemical characterization is weak or absent, plan and execute appropriate chemical analysis (ISO 10993-18) and toxicological risk assessment (ISO 10993-17).

6. Update BEP and BER documentation: Restructure your Biological Evaluation Plans and Reports to align with the 2025 documentation expectations, including traceability to your ISO 14971 risk management file.

Medium-Term Actions (6-12 Months)

7. Integrate with risk management: Ensure your biological evaluation is fully integrated into your ISO 14971 risk management process. Every biological hazard should be traceable from identification through risk control to post-market monitoring.

8. Address foreseeable misuse: For each device, document the reasonably foreseeable misuse scenarios and assess their impact on biological evaluation.

9. Plan for lifecycle evaluation: Establish processes for re-evaluating biocompatibility at design changes, process changes, supplier changes, and at end of useful life.

10. Engage toxicology expertise: The 2025 revision demands deeper toxicological knowledge than the checklist approach. If your team lacks in-house toxicology expertise, engage external specialists to support your biological evaluation strategy.

Common Mistakes to Avoid

1. Waiting for FDA recognition: Even before the FDA formally recognizes ISO 10993-1:2025, the principles it embodies (risk-based evaluation, chemical characterization, ISO 14971 integration) are already expected by regulators. Waiting puts you behind.

2. Treating the four tables as the new checklist: The tables in the 2025 revision guide your thinking — they do not replace it. Scientific justification is still required for every evaluation decision.

3. Ignoring re-categorization: Devices may shift into longer contact duration categories under the contact day methodology. Ignoring this can leave gaps in your biological evaluation.

4. Minimizing chemical characterization: Chemical characterization is now the foundation, not an optional supplement. Skipping it and going straight to biological testing is inconsistent with the 2025 approach.

5. Separating biocompatibility from risk management: The biological evaluation must be traceable to the risk management file. Maintaining them as separate documents creates compliance risk.

6. Assuming existing evaluations are automatically valid: The 2025 revision does not require re-testing of all existing devices, but manufacturers are expected to review previous evaluations and document that they remain valid under the updated framework. Gaps must be addressed.

Cost and Timeline Implications

The transition to ISO 10993-1:2025 will have different cost impacts depending on where your current biological evaluation stands:

Scenario	Impact	Estimated Cost
Strong existing evaluation with chemical characterization and risk management integration	Low — primarily documentation updates	$5,000 - $15,000 per device
Moderate evaluation with some gaps in chemical characterization	Moderate — gap assessment, some additional testing	$15,000 - $50,000 per device
Checklist-based evaluation with no chemical characterization	High — full reassessment likely needed	$30,000 - $100,000+ per device

The cost of early compliance is significantly lower than the cost of regulatory delays, deficiency letters, or market access issues. Manufacturers who proactively transition will have a competitive advantage as regulators and Notified Bodies begin expecting 2025-aligned evaluations.