ISO/DIS 10993-1:2024-07

ISO/DIS 10993-1:2024-07– What does this standard address?

The first standard in the series of ISO 10993 is the fundamental regulation holistically describing the required workflow for the biological evaluation of medical devices by aligning the biological evaluation process with the principles of the Risk Management of Medical Devices as per ISO 14971.

To mention the most important points, the current draft of the base standard ISO/DIS 10993-1 helps the legal manufucturer to categorize the medical device considering its intended use, foreseeable misuse, duration of contact and contact types with the body of patients and users. It points out ways to evaluate existing data from different sources, to identify gaps in the existing data and how to proceed to close these gaps and obtain additional data, to mitigate remaining risks and finally terminate the biological assessment.

What are the key changes to the current version of ISO 10993-1?  

ISO/DIS 10993-1:2024-07 brings a couple of changes compared to the currently harmonized standard. We will particularly focus on the drastical ones, which will have a serious impact to the device categorization and in the overall assessment process.

·        Device contact categorization for cumulative contact times “concept of total exposure period”: In this regard, a significant change in the counting of cumulated contact times resulted. The days, during which the device is used, are now pivotal for determining the total contact times rather than the exact time ranges of the actual application. To give an example:

if a device is intended to be used for an hour per day within a weeks-period, it means from now on that a 7-day contact duration time needs to be considered rather than 7 x 1hour (7 hours).

Or in other words: any contact time above a minute/per day is to be seen as a 24 hours contact. This change can thus significantly affect device categorization.

·        For medical devices having “very brief contact with the body, typically for less than a minute” the manufucturer can prepare a written justification outlining that there is no potential for biological harm and a biological evaluation can be thus skipped.

·        Bioaccumulation was introduced as a concept which needs to be eyed when cumulative exposure to a medical device takes place. As it is known, some compounds (for instance some representatives from the PFAS family) have potential for bioaccumulation. In such cases the contact duration time is set as long-term regardless of the intended use time, unless otherwise justified.

·        Beyond its intended use, foreseeable misuse scenarios for the medical device with regard to the patient must be considered (for more on this topic, see corresponding section).

·        With medical devices distributed more and more as home-use/point of care devices a broader group of users needs to be taken into account, which might come into contact with device parts.

·        The device category “externally communicating devices” was deleted from the new draft. Devices formerly assigned to this category are now split according to their type of contact into devices having contact to reached or compromised surfaces or internal tissues other than circulating blood on the one hand or devices having direct or indirect contact to blood on the other hand.

·        The application areas for of the endpoints genotoxicity and carcinogenicity was broadened: All prolonged contact medical devices requiring a systemic toxicity evaluation shall now be assessed for genotoxicity. Also this endpoint needs to be evaluated for devices having contact to mucosal, breached or compromised surfaces and additionaly any type of indirect blood contact (which was previously only applicable for prolonged contact). Carcinogenicity has to be evaluated now for devices with long-term mucosal contact and for all other medical devices with long-term contact requiring a chronic toxicity evaluation.

·        Animal welfare is being stressed (chapter 4.3): besides the mentioning of in-silico methods, which is new, and clearly restricting animal tests as such, it is stressed that if animal testing is unavoidable the design of the experiment should be in a way that a minimal number of animals is required with a maximum possible gain of extractable information from these kind of tests. A justification is demanded for all animal tests conducted.   

·        Addition of a credentials for the experts involved in the biological evaluation process is now a must. The CV should demonstrate sufficient expertise (“appropriately qualified”) to perform this kind of assessment.

·        The huge endpoint chart has now been split into individual tables according to the tissue contact types.  

·        Physical and/or chemical information was removed from the Biological effects for consideration, however Chemical characterization in general is more emphasized.

·        Formerly “pyrogenicity” and “reproductive and developmental toxicity” were listed as biological effects in the endpoint charts. These biological effects were moved to the new chapter “other biological effects”. In principal, the scope of these biological effects were more restricted and better defined in this standard. In particular they should be assessed if the medical device contains novel materials. Reproductive and developmental toxicity should also be in particular assessed if sensitive patient populations (e.g. pregnant women) need to be considered and also if the medical device and its constituents could be locally present in the reproductive organs. Other special cases where this biological effect should be assessed are outlined in chapter 6.5.11 (e.g. topical applications of medical devices where substantial absorption through skin or mucosal membranes is intended, etc.). Chemical analysis of leachables and extractables provide useful insights if special attention needs to be devoted to these two biological effects.  

·        The concept of neurotoxicity is introduced, which is missing in the current ISO 10993-1 standard. Neurotoxicity should be evaluated for devices having direct contact with tissues of the central or peripheral nervous system or indirect contact with nervous tissue or cerebrospinal fluid.

·        Biological equivalence is inserted as an own chapter (chapter 6.7). Using data for cross-comparison with existing/predicate devices having similar/comparable properties is emphasized in the reorganized standard. These compartable properties can be a

o   chemical,

o   physical,

o   contact and

o   material

equivalence. This concept holds true in particular devices with an established extensive clinical use history in the relevant contact category.

It should be pointed out again, that the above-presented list is not complete. Further changes in definitions and wordings within the reorganized standard need to be considered. But the changes, we believe pose the greatest challenges for the biological evaluation are definitely listed.

In general, it can be stated that the interlinking/harmonization between the base standard for the biological evaluation and the standard for risk management is being emphasized more strongly in the new draft ISO/DIS 10993-1:2024.07, thus shifting the scope of the evaluation from a prescribed to-do-checklist to a more-risk based approach. Risk control measures applied in the following order and derived from ISO 14971 are emphasized:

1.      safe design and manufacturing,

2.      protective measures to be implemented and

3.      training and information to users.

Once these risk mitigating controls have been conducted, the overall residual risk needs to be re-evaluated.

Foreseeable misuse – a new “obstacle”, which must be considered in your biological evaluation 

The new ISO 10993-1 draft underlines that manufucturers are not only obliged to evaluate their device according to its intended use.

Foreseeable misuse, already described elsewhere in other standards (e.g. ISO 14971 –as reasonably foreseeable misuse) or guidances (e.g. MDCG 2019-16 – EC) has now also been uptaken by the new draft.

·        reasonably foreseeable misuse:

use of a medical device (3.25) in a way not intended by the manufacturer (3.23), but which can result from readily predictable human behaviour

Note 1 to entry: Readily predictable human behaviour includes the behaviour of all types of users (3.36), e.g. lay and

professional users (3.36).

Note 2 to entry: Reasonably foreseeable misuse can be intentional or unintentional.

By definition foreseeable misuse occurs if a medical device is being (mis)used in a way that may be considered reasonable, or to phrase it in other words, result from readily predictable human behaviour but which is not intended by the manufacturer. Foreseeable misuse can happen intentionally or unintentionally.

To give an example for these options let us consider an endoscope for urethroscopy. While it is intended to be used in the urological field and its intended use is also described as such within the related Instructions for Use for this device, a possible foreseeable misuse scenario could be, when a healthcare professional uses this endoscope for gynecological examinations to save for instance costs on an actual uretherescope. The attributes of the endoscope designed for urological applications (length and diameter of the endoscope shaft) will most probably allow its use for gynecogical application since entry into the womb through wider cavities such as the cervix can be easier realized compared to the entry through the urether. Possible foreseeable misuse scenarios could also derive from manipulations on the device design to extend their scope of use.

Staying with the endoscope example, an aggressive use of an endoscope causing its deeper entry into the intended body cavities than is intended by the manufucturer, results in an unintentional foreseeable misuse scenario.

How can these foreseeable misuse scenarios affect your biological evaluation?

To start with, parts/materials of the device previously assigned as non-contacting parts (to patient and/or user) might come into focus creating a dilemma if they need to be considered in the biological testing/chemical characterization (later more on this aspect).

A very important aspect is also that the formerly assigned biological endpoints to be assessed when solely the intended use was within the scope, might need to be revised according to the possible foreseeable misuse scenarios. Even the categorization of the medical device could be altered by options of foreseeable misuse as different types of skin and body fluids might come into contact with the device. 

Foreseeable misuse can also lead to a different duration of device use and the use of the medical device on patient populations other than prescribed by the device manufucturer.

Returning back to biological testing: there could be a significant impact on the previously calculated Analytical Evaluation Threshold (AET) value. Foreseeable misuse might lead to consider changes in the numbers of daily used devices, or the times a device is used over a specific time period and/or contact duration and repeated exposure times. Particulary the C-term of the AET calculation might need to be modified. Moreover, even so ISO 10993-12 states that non-contacting parts should be excluded from biological testing, as above-mentioned, non-contacting parts can turn into contacting parts – when foreseeable misuse scenarios are also considered.

In such cases compromise might be rational: those “foreseeable misuse-contact parts” – which are still non-contacting parts per definition – might be extracted alongside with the “intended use-contact parts”. However, the areas of those “foreseeable misuse-contact parts” could be ignored in the toxicological risk assessment calculations. This concept would support a worst-case scenario by bringing in the possibility of additional contaminant released into the extracts but by avoiding “dilution” of concentrations due to the exclusion of the “foreseeable misuse-contact parts” surface area.

Foreseeable misuse has gained an increased focus in regulatory applications and the question arises how it will be enforced by the notified bodies.

So how could the assessor cover and address all possible foreseeable misuse scenarios to avoid and reduce questions from reviewers, respectively?

Principally misuse is a quite broad term, which can include any device misuse considering even extreme scenarios, which cannot be anymore rationally covered and which clearly do not fall under the foreseeable misuse concept. However the difficulty lies in borderline scenarios where distinguishing between general misuse and foreseeable misuse is not straightforward and where the analysis of possible foreseeable misuse scenarios is incomplete.

Also the question arises if it is not sufficient to state clearly the intended use of the device within the IFU alongside with notifications which foreseeable misuses sceanarios are to be avoided by the device users.

The new draft does unfortunately not – and this could be its weakest point, which might lead to a new revision on this topic in the future – address these questions satisfactorily and also does not provide a clear guidance for the assessors on how to proceed in the analysis of foreseeable misuse scenarios. 

A conceivable way to cover a broad range of possible foreseeable misuse applications could lie in collecting information from clinicians/users on comparable/predicate devices on the market. If a device is still in the development stage possible foreseeable misuse scenarios could be found out by conducting suitable tests, e.g. such as mechanical stress tests to monitor changes on the device in extreme-use scenarios.

Biological risk estimation as an essential part of the biological evaluation plan

Biological risk estimation, though also mentioned as a concept in the current ISO 10993-1, is emphasized stronger in the draft ISO/DIS 10993-1. It should be now an integral part of the biological evaluation plan. Annex C provides a guideline for the biological risk estimation. The manufucturer should identify adequately the biological risks, if they are present. Qualitative or quantitative values should be assigned to the severity and probability of occurrence of biological harm. These values, either obtained through qualitative judgement or quantitative calculation are then combined to reach the biological risk estimate. If the resulting risks cannot be deemed as negligible, those risks should be treated as residual risk and should be considered as input to benefit-risk assessment.   

Biological evaluation is no more a single-time point assessment for market clearance – rather a process that applies to the whole device life cycle

All phases in the life of a medical device, from the initial conception to final decommissioning and disposal have to be considered for biological safety evaluation.

Reprocessing cycles (cleaning, disinfection and sterilization) for re-usable devices, transport and storage according to the defined shelf-life until use might affect biocompatibility. Particularly polymers, but also ceramics, metals and alloys might be subjected to degradations due to wear, storage and reprocessing procedures. Degradations can be of physical or chemical nature.

Previously, the consideration of the biocompatibility throughout the life-cycle was only mentioned in a short paragraph in the currently active standard. This has changed in the new draft. Guidance on material selection regarding material fitness for whole life cycle of products is being provided in Annex A.2., also with clear references on processing methods during the product life cycle.

Also active data collection by the device manufucturer during device life cycle is clearly demanded in ISO/DIS 10993-1. That means, post-market surveillance data gains significantly more importance for the process of biological safety evaluation.

Look out for the published standard!

The underlying draft of the ISO 10993-1 standard is under publication since September 2025. This means that the standard will be published by the end of the year at the latest. Hence, publication of the EN ISO Version can be expected for 2026. You need support to stay compliant also in 2026? Competent experts in the field of biocompatibility will support you in assessing toxicological parameters harmonized with the new revised standard. Get in touch with us!

Please note that all details and listings do not claim to be complete, are without guarantee and are for information purposes only.