The 6th version of ISO 10993 – Biological evaluation of medical devices — Part 1: Requirements and general principles for the evaluation of biological safety within a risk management process has been released!
With the entry into force of Medical Devices Regulation (EU) 2017/745 (MDR), the approach to safety has become even more stringent, especially for substance-based medical devices (MDs). Manufacturers of medical devices must ensure the safety of their devices and minimize potential biological risks. The assessment of MDs’ biological safety is conducted to determine the potential toxicity resulting from the device’s materials contacting the body.
In this scenario, the ISO 10993-1 standard is an essential point of reference for a proper biological evaluation (Fig.1). It addresses the assessment of the biological response to medical devices, providing general guidelines rather than specific details for each device type. ISO 10993-1 standard is not mandatory, but is the recognized preferred method for assessing the biocompatibility of a medical device. It aims to develop a device-specific testing strategy, avoiding the use of animals whenever possible, in line with the 3Rs principles (Replacement, Reduction, Refinement) and other unnecessary tests.
ISO 10993-1 6th edition has been reshaped with a stronger focus on risk estimation in alignment with ISO 14971- Application of risk management to medical devices. The standard aims now to evaluate the medical device within its life cycle, and to further analyze all the device’s exposure scenarios, taking into account the worst-case scenario as part of the overall risk management process.
Risk estimation for MDs can present challenges. The evaluation should account for the sequences of events that can be misused compared to what the manufacturers claim in the Instructions For Use (IFUs). This leads to the need to include more defined terminology when investigating a device’s utilization. It’s important to define who can use a specific MD, what the potential sources of hazard are, under what circumstances one may be exposed to it, and what harm can result from it.
New medical device categories based on body contact
MDs are categorized based on type and duration of body contact. Body contact can be either direct contact or indirect contact.
Direct contact can occur with physical contact in or on the body (e.g., a hip implant or wound dressing), or ex vivo (e.g., a blood oxygenating circuit). Indirect contact can occur by means of transport of constituents within a fluid (gas or liquid) that passes from the medical device to the tissues (e.g., infusion equipment, ventilators).
Based on the type of body contact, MDs are no longer classified in 8 contacting typologies but just in 5 categories:
- Non-contacting MDs
- Medical Devices in contact with intact skin
- Medical devices in contact with intact mucosal membrane
- Medical devices in contact with either breached or compromised surfaces (skin or mucosal membrane) or internal tissue, other than circulating blood.
- Medical devices in contact with circulating blood
It’s important to notice that externally communicating MDs are no longer a separate contact category.
New calculation of the exposure period
Contact duration categories have changed from the previous ISO 10993-1 edition. Contact duration categories, Limited exposure, Prolonged exposure, and Long-term exposure, shall be based on the total exposure period of a single patient to the MD. Total exposure period is defined as the number of calendar days between the first and last use of MD or a replacement of the same device on a single patient. Therefore, any calendar day that a MD comes into contact with the patient, regardless of the portion of time, is entirely taken into account.
This means an MD, which IFUs claimed to be used for 5 min a day for 28 days only by adults, is no longer considered to be a 140 min contact duration (limited exposure A < 24h) as for EN ISO 10993-1:2020, but it’s a 28-day contact as EN ISO 10993-1:2025 (prolonged exposure B > 1 day). Or for example, intermittent contact medical devices used a 2 times a year for maximum 5 years would be categorized as prolonged (10 days contact) unless otherwise justified.
Moreover, devices containing a constituent expected to bioaccumulate in the body shall be long-term unless properly justified. That’s because the key to the application of risk management to medical devices is to always consider the worst-case scenario.
This new exposure definition is important to take into consideration for manufacturers since it shifts lots of devices, which were previously categorized into an exposure category, to the upper one, and this can lead to a different testing strategy.
However, for MDs that have very brief contact with the body, (e.g less than one minute) and for MDs in contact only with intact skin during normal use and with components made from materials with a history of safe use in consumer products or MDs with a similar type and similar or longer duration of contact, it could be possible to prepare a written justification regarding the negligible potential for biological harm.
New contact category approach
MD’s categorization can change when the new ISO 10993-1 standard is applied; this does not stand only on the changes in the distribution of the devices in the 5 categories or in the new exposure period calculation. MD’s categorization should now take into consideration the reasonably foreseeable misuse. This new approach depends on the merger between ISO 10993-1 and ISO 14971, which gives more relevance to risk estimation in biological safety evaluations.
Reasonably foreseeable misuse is defined as the use of a product in a way not intended by the manufacturer, but which can result from readily predictable human behaviour. Therefore, it is now more relevant to evaluate the probability of the systematic intentional or unintentional application of the medical device outside its intended use.
Biological safety can be adequately assessed only when the evaluation considers all populations that may come into contact with the medical device. Device users are not limited to patients or healthcare professionals. For certain medical devices, particularly those intended for home use, the range of potential users may be broader and include individuals other than trained clinicians. In fact, the updated ISO 10993-1 emphasizes the need to evaluate biological risks not only for the intended target population but also for other reasonably foreseeable users, such as children or elderly individuals. This approach reflects the broader requirement to consider realistic use scenarios and potential variability in user characteristics as part of the overall biological risk assessment.
Moreover, the biological evaluation shall address the medical device life cycle from design and development through initial use to final decommissioning or withdrawal from use. Thus, the categorization should account for the foreseeable misuse in terms of the life cycle of the medical device, from its material selection to disposal. If a medical device is intended to change during its clinical use, such as materials that polymerize or degrade in situ, the evaluation shall take into account all the different device states.
Furthermore, in this scenario, the new EUDAMED database provides a living picture of the lifecycle of medical devices made available in the European Union (EU).
Manufacturers need to define in the IFU the intended use of their MD, how long the device application lasts, and how many applications are needed to achieve its effect. For the evaluation of biological safety, any available information regarding unintentional use or use beyond the intended duration shall be carefully considered. The risks associated with such scenarios need to be taken into account as part of the overall biological risk assessment. This situation may occur, for example, when a single-use medical device is reused. In such cases, the potential chemical and physical degradation of the components should be evaluated. Material deterioration may lead to exposure to new substances, such as degradation products resulting from polymer breakdown.
Cumulative use of a medical device plays a significant role in the EN ISO 10993-1:2025 framework. The resulting biological safety profile may differ from what was originally anticipated during device development. As a consequence, it may be necessary to identify and assess alternative chemical exposure scenarios.
Post Market Surveillance (PMS) data can provide valuable support in this assessment. These data are continuously collected and updated based on manufacturing and post-market experience. They may reveal adverse reactions related to device misuse, extended duration of use beyond that specified in the IFUs, or exposure of more sensitive populations. PMS, therefore, provides manufacturers with essential information on how their MDs perform in real-world conditions and supports the continuous evaluation of biological safety over time. That’s in accordance with the principle of ongoing risk management described in ISO 14971.
New Biological Effects specifications
Taking into account the reasonably foreseeable misuse for the recategorization of the MD according to EN ISO 10993-1:2025, it may lead manufacturers to different testing choices for their medical devices. According to the new ISO 10993-1 standard version, for each category, different biological effects are identified that shall be addressed for a proper biological evaluation:
- Cytotoxicity
- Sensitization
- Irritation
- Systemic toxicity
- Local effects after tissue contact
- Genotoxicity
- Carcinogenicity
- Hemocompatibility
Other biological effects, if relevant, should be considered as immunotoxicity, neurotoxicity, reproductive and developmental toxicity, and material-mediated pyrogenicity.
Testing is required only if data retrieved from literature research are insufficient for the biological effect. If it’s necessary, based on the total exposure period approach, a device with only 2 days of contact and a device of the same category type with 29 days of contact are both categorized as prolonged exposure MDs, but the systemic toxicity study duration will look very different.
If performed, testing shall be carried out in accordance with appropriate laboratory quality assurance controls [e.g., ISO/IEC 17025, OECD Principles of Good Laboratory Practice (GLP)]. Where test methods not detailed in the ISO 10993 series are used in the biological evaluation, these tests shall be sensitive, precise, and accurate. Prior testing can be considered during initial data gathering for the evaluation, but any differences relative to the applicable standards shall be justified and documented.
The ISO 10993-1 6th edition includes different recommendations for genotoxicity and carcinogenicity evaluation for medical device categories with the same contact duration.
Exposure to a genotoxic chemical increases the risk of cancer development. When exposure is systemic, a genotoxic chemical can reach multiple tissues, increasing the risk, more medical devices will require genotoxicity assessment. A genotoxicity evaluation has been added for medical devices contacting mucosal membranes (Fig 2.), breached or compromised surfaces, and in direct contact with circulating blood. Now, if a prolonged contact MD presents systemic toxicity, then it must be addressed as genotoxicity. Regardless of duration, this could affect any device in contact with circulating blood. A carcinogenicity evaluation should be performed for all long-term contact medical devices requiring a chronic toxicity evaluation.
Biological evaluation shall take all available relevant information into account, including intended use, reasonably foreseeable misuse, physical and chemical information, preclinical tests, clinical investigations, post-market experience, and any other relevant information.
It’s important to highlight that physical and/or chemical information is not identified as a biological effect in the table, as in the previous version of ISO 10993-1, but remains an essential part of the biological evaluation.
The evaluation shall take into account knowledge regarding a finished medical device (or material), including the geometric, chemical, and physical properties and the supplier’s identity (EN ISO 10993-1:2025 Annex A). Relevant information should be gathered by literature review or generated by chemical testing. Therefore, chemical characterization shall be conducted in accordance with ISO 10993-18 and relevant physical attributes shall be characterized because they’re useful to identify a potential biological risk (EN ISO 10993-1:2025 A3.2.).
Moreover, it’s important to identify the MD characteristics related to biological safety arising from the potential availability of toxic constituents or hazardous physical characteristics. Hazard should be identified regardless of the guidance of the table and the probability of leading to biological harm.
Chemical information and subsequent toxicological risk assessment can provide a basis for the evaluation of carcinogenicity and of the presence of potential reproductive or developmental toxicants. If the MD contains constituents known to cause such effects, the potential for these harms should be considered in the biological risk assessment, irrespective of the type or duration of body contact.
What if an MD has an already assessed and consolidated safety profile?
These products should be re-evaluated, considering the available information to determine whether any differences may affect the previous conclusion regarding the biological safety of the medical device. An update of the documentation may not be required, but such a decision must always be justified and documented.
New biological evaluation key concept
For a MD biological evaluation, a description of its chemical-physical characterization, manufacturing process, and contact categorization is required. If it is possible to compare materials of construction, configurations, production processes, contact location with the body, patient population of a medical device with others, a medical device family may be identified.
Medical device families share performance characteristics related to safety, intended use, and function with each other. Therefore, a representative sample may be the worst case taken from a medical device family.
Moreover, it can be useful to find a medical device’s biological equivalence to perform the gap analysis. This is possible in circumstance where the chemical and physical characteristics and manufacturing process of a MD is sufficiently similar to a comparator MD in a relevant type and duration of body contact (Fig.3). If no new or increased biological risks are identified for the medical device under evaluation compared to the biological equivalent one, according to EN ISO 10993-1:2025 biological safety could be established.
New specification of the evaluator’s qualifications
The strong overlap between ISO 10993-1 and ISO 14971 can pose challenges for MDs’ biological evaluations. To take into account the foreseeable reasonable misuse requires transversal skills and/or collaboration among experts such as toxicologists, clinicians, and engineers.
The evaluation of biological safety “shall be planned, conducted, and reported upon by knowledgeable and experienced professionals, appropriately qualified by education, training, skill, and experience, capable of making informed decisions based upon scientific data and a knowledge of medical devices. Qualification of evaluators shall be documented“.
ToxHub comprises a specialized team dedicated to ensuring the safety and regulatory compliance of medical devices. Our toxicologists possess extensive experience in medical devices’ toxicological risk assessments. They offer the required expertise in regulatory compliance and are available to provide technical and specialized consultancies to ensure the success of MD product development.
Issued by Eleonora Pace