ISO 10993-1:2025: Key Changes in Biological Evaluation of Medical Devices

The Core Standard for Biological Evaluation

ISO 10993-1 is the core standard for the biological evaluation of medical devices. With the release of the 6th edition ISO 10993-1:2025, the standard has undergone significant revisions which clarify the conduction of a biological evaluation within a risk management framework and enable a more intuitive process. The aim is a risk-based, scientifically sound and lifecycle-oriented approach. In response, manufacturers must review their evaluation strategies accordingly. What are the key changes?

Clear Integration Into a Risk Management Framework According to ISO 14971

As the new title of the ISO 10993-1:2025 “Requirements and general principles for the evaluation of biological safety within a risk management process” indicates, the standard provides detailed guidance on conducting a biological evaluation within a risk management system aligned with ISO 14971. Activities required under ISO 10993 are now clearly linked to the elements of risk management (i.e. hazard identification, estimation of the associated risk, determination of their acceptability, risk control) and a summarising flow-chart assists evaluators in their strategic conduction. 

A biological evaluation within a risk management system brings the advantage of a risk-based approach. This implies that the rigor and detail of the evaluation align with the risk profile of the device under evaluation. For example, for low-risk devices like a well-established medical device in limited contact with the intact skin made from state-of-the-art materials, data gaps may be acceptable. On the other hand, high-risk devices, like an implant, require detailed information to enable a meaningful risk assessment. However, if the implant is made from materials standardised for its intended purpose (e.g. ISO 5832 series), focus on chemical characterisation of residues from manufacturing, sterilisation and cleaning processes may be sufficient. 

In relation to the risk management process, the committee included the consideration of reasonably foreseeable misuse. Accordingly, unintended use of the medical device, which can result from readily predictable human behaviour shall be evaluated. Examples might include extended contact duration, improper remanufacturing, use in an unintended biological environment (e.g. unintended tissues or unintended clinical environment) or the use in unintended patient populations. Reasonably foreseeable misuse is, however, not about abstract scenarios which are unlikely to occur but to literally consider “readily predictable” behaviour. 

Revised Contact Categorisation May Change Update Priorities

Another key change is the modified determination rules for the contact duration. Accordingly, repeated short-term contacts are no longer clustered in a specific category (i.e. limited, prolonged or long-term). Instead, each contact is considered as one “contact day”, irrespective of its actual duration within that day. In consequence, the categorisation of medical devices used repeatedly on the same patient may shift towards a longer contact duration. Similarly, indicators of bioaccumulation trigger long-term categorisation. As a result, more biological effects, formerly known as biological endpoints, would need to be addressed which may change update priorities. According to Clause 6.6.2 of the standard, the biological evaluations of devices requiring the assessment of additional biological effects need to be updated in the short term. All other biological evaluations, for which no additional biological effects are applicable, may not need an update for now. However, a related review process should justify the decision and document the outcome.

Restructuring of the Categorisation Table Simplifies the Overview of Categorisation Rules

The change refers to the comprehensive Table A.1 in Annex A of the ISO 10993-1:2018 which is used to categorise the devices under evaluation and retrieve the endpoints to be addressed in a biological risk assessment. It was restructured and is now distributed across the relevant chapters addressing the general contact types. There are four tables for medical devices in contact with:

• intact skin
• intact mucosal membranes
• breached or compromised surfaces (skin or mucosal membranes) or internal tissues other than circulating blood
• circulating blood

In the process, the much-debated contact category “externally communicating medical device” was removed and the focus shifted on biological effects to specific tissues, which makes the evaluation more intuitive. 

Changes of Biological Effects to be Addressed in a Biological Risk Assessment

The most obvious change in relation to the endpoints is their renaming “biological effects”. In addition, the evaluation of the effects was revised, which enables a more flexible device-specific evaluation. 

Systemic toxicity became a general category leaving the request to evaluate acute, subacute, subchronic or chronic toxicity out of the categorisation tables. Instead, the evaluation shall represent the duration of use. Similarly, material-mediated pyrogenicity was removed from the tables and should only be evaluated if constituents have previously elicited a pyrogenic response or if the pyrogenic potential is unknown. Otherwise, it is well accepted that material-mediated pyrogenicity is very rare, and a related response is mostly elicited by endotoxins. A list of non-endotoxin pyrogenic substances is included in Annex G of the current ISO 10993-11:2017, a standard which is currently revised as well. A third change to the biological effects is the renaming of the implantation effects, which are now “local effects after tissue contact”. This change enables a more intuitive evaluation of medical devices which are not implanted (e.g. wound wash solutions or devices in contact with intact mucosa for longer than 24 hours). Finally, the evaluation of genotoxicity is more broadly required for all devices in at least prolonged contact with the patient, except for contact with intact skin. Related assessment of genotoxic carcinogenicity should follow if genotoxic constituents are present. The evaluation of non-genotoxic carcinogenicity requires long-term contact as the associated mechanisms need time to be activated. 

Requirements Directed Into Focus

Finally, certain requirements receive more emphasis in comparison to previous revisions. These include the evaluation of a medical device over its entire life-cycle as well as the inclusion of clinical data. If clinical data is used to support the biological safety profile of a device, its relevance to the biological effects, the quality and the type of clinical data shall be discussed. Further, the evaluation of novel materials requires more rigor and, finally, the evaluators shall consider sensitive populations such as young infants, chronically ill or immunocompromised patients. 

Global Acceptance of ISO 10993-1:2025

Following the ISO 10993 series is globally generally well accepted, though regional differences remain:

• European notified bodies follow the most recent ISO standards and already expect a gap-analysis of existent biological evaluations against ISO 10993-1:2025.
• Japan’s written requirements still correspond to ISO 10993-1:2018 however, like in the EU, state-of-the-art is expected.
• The FDA has not yet added ISO 10993-1:2025 to its list of recognised consensus standards and related guidance is not anticipated soon.
• China is ahead and drafted the national standard GB/T 16886.1-2025 aligned with ISO/FDIS 10993-1:2025. A final version corresponding to ISO 10993-1:2025 is expected by December 2026

ISO 10993-1:2025 is More Than an Update

ISO 10993-1:2025 makes the evaluation more intuitive, considers the complete life-cycle and enables greater flexibility for the demonstration of device-specific biological safety. 

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