The primary goal of the biological evaluation for medical devices is to ensure the safety and biocompatibility of the device for its intended use. This means evaluating potential risks of adverse biological reactions that may occur when the device comes into contact with a patient’s body.
Within the risk management process according to EN ISO 14971; for the biological evaluation process (EN ISO 10993), various factors must be scrutinized to assess the final biocompatibility of the device.
Device material composition and additives, potential contaminations from the manufacturing and manufacturing environment and from cleaning/disinfection/sterilization procedures etc., alongside the definition of the intended use, which determines contact tissues and contact times for the device, have to be considered for the assessment of potential toxicological adverse effects on the patient.
All these mentioned factors define the chemical fingerprint of the device, or more precisely, the set of substances which could interact with the intended use environment (patient tissues and body fluids).
What does the standard ISO 10993-17 address within the context of biological evaluation? This standard can be understood as a tool, which is providing concepts to estimate the potential toxicological impact of those interacting substances.
In 2023, a revision of the highly awaited ISO 10993-17:2002 was released, introducing a number of changes for previously established parameters for toxicological risk evaluation. The first change starts with the revised title for ISO 10993-17:2023, which now is called “Biological Evaluation of Medical Devices — Part 17: Toxicological Risk Assessment of Medical Device Constituents,”.
We would like to discuss further changes to make medical device manufacturers, suppliers and experts aware of the main changes, since the new standard has been already harmonized, thus needs to be considered as the yardstick for using new key concepts and related tools for the evaluation of chemical constituents of medical devices.
Process of toxicological risk evaluation until ISO 10993-17 comes into play
The new revision of ISO 10993-17 develops the idea further to align biological evaluation with the current state-of-the-art practices in the field of toxicology and reflects efforts for further alignment with the other ISO 10993 standards.
It introduces new concepts and parameters and replaces some old parameters.
It is of utmost importance for the toxicological risk analysis to gain information regarding the chemical composition of a medical device. This information is for instance accessible through material data sheets, but most importantly through laboratory testing carried out to determine leachables or extractables (depending on the intended use of the medical device) according to ISO 10993-18.
Analytical data of extracts is being processed accordingly to provide utilizable chemical information of constituents (concentrations). Using concentration data and the guidelines and concepts of ISO 10993-17, toxicological risks can be estimated.
The decision according to ISO 10993-1 to determine if a toxicological risk assessment for compounds/constituents of a medical device is required or not, remains unaffected from the new ISO 10993-17 revision.
If a toxicological risk assessment is required, the assessor collects all relevant toxicological information for the individual constituents.
Search criteria have to be documented, which includes also their justification regarding quality, reliability and suitability for the intended use case.
Toxicological information is usually collected from databases such as ECHA (European Chemicals Agency), PubMed, WHO (World Health Organization), Toxplanet, EPA (Environmental Protection Agency), Carcinogenic Potency Database (CPDB), European Food Safety Authority (EFSA), etc.. Potential harm and toxicity of a chemical can be deduced from records regarding its harms and toxic effects and from toxicological parameters, e.g. DNEL (derived no-effect level), NOAEL (no-observed adverse effect level) or (LOAEL) (lowest observed adverse effect level). Ideally, several databases should be consulted to consider more than one database source for each constituent. In cases where toxicity information is not available, structurally similar substances with sufficient toxicity records can function as an analogue for evaluation. The choice of appropriate analogues, however, requires adequate toxicological knowledge.
Those compounds with relevant biological harms are then further assessed using the ISO 10993-17.
Main changes to ISO 10993-17
Subsequently, according to the previously mentioned research, changes on the new ISO 10993-17 are coming into play.
Two important parameters, to start with, which are replacing the previously calculated “tolerable exposure (TE)”, are the so called TQmax and TSL values.
TQmax reflects the amount of a constituent present in or that can be extracted from a medical device and is the product of TQ (total amount actually extracted) and a scaling factor SF, which is introduced as a factor representing the ratio of the surface area of the medical devices extracted towards the area, which is actually in contact with the patient’s body.
Then there is the Toxicological Screening Limit (TSL), which has been also newly introduced. It contains the well-known TTC value – a further alignment with ISO/TS 21726 – and combines it with the assumed exposure time towards the specific constituent.
TSL value is used to evaluate whether the total amount of an identified chemical constituent is high enough to cause cancer, systemic toxicity, genotoxicity or reproductive toxicity considering a cumulative exposure dose over a specific time period. No toxicological risk assessment is necessary if the total amount of an extracted chemical constituent corrected with the scaling factor (TQmax) is less than the TSL.
The consideration behind the introduction of the TSL is to decrease the workload on assessors for the toxicological risk assessment.
Of rather higher importance is the assessment of the potentially harmful chemical constituents.
The TSL concept is, however, not applicable for use in the following cases: Cohort of Concern chemicals, volatile organic compounds extracted from patient airway systems having indirect contact to patients (ISO 18562), irritation-related harm, devices categorized as long-term contact devices being used from neonates to young infants and not characterized (unknown) compounds.
Hence, TSL can – if the assessed substances do not fall under the above-mentioned criteria – be used for eliminating substances fulfilling the TQmax < TSL criteria, but which were detected at higher concentrations than the analytically established analytical evaluation threshold (AET) level derived from ISO 10993-18, which is specific for the selected analytical-technical methodology.
The concept of TI (tolerable intake) is kept within ISO 10993-17.
Toxicologically relevant parameters (e.g. LOAEL) are named point of departure (POD), and for this, the clinically most relevant parameter must be selected, while TI is calculated as the ratio between POD and the modifying factor (MF), which is the product of uncertainty factors as was also described in the older version of the standard.
Note that the selection criteria and levels for uncertainty factors are further refined in this standard, particularly, the bioavailability of a substance has been added as a new important criterion. The selection of adequate uncertainty factors for extrapolations between PODs, different exposure routes and durations, physical states of chemicals and data quality and reliability, and also of patient population specific factors, is being better guided in the revised version.
For irritating substances, if sufficient information is available with regard to irritating levels, the assessment route via the tolerable contact level (TCL) can be chosen, as also described in the older standard, but also with consideration on the new refinements of the uncertainty factors.
In the event of a lack of reported threshold parameters, the threshold of toxicological concern (TTC) approach can be used. Depending on the toxicity of a compound – if cancerogenic/mutagenic/reproduction/developmental toxic, or not – a suitable TTC can be taken. Cramer Classes provide the correct TTC levels for non-CMR compounds, while CMRs need to undergo a more stringent evaluation via the CMR compounds specific TTCs. The risk of potential harm of constituents is deemed acceptable, if the worst-case exposure dose lies below the perceived TTC levels.
For the other cases, if TI and TCL values could be obtained, a margin of safety (MOS) is calculated to finally assess the toxicological risk of these individual substances. The MOS value is compared with the toxicological risk acceptance criteria (ISO 10993-1/ISO 14971) to decide if a substance is deemed acceptable or if risk mitigation procedures need to be implemented.
To calculate the MOS another parameter is introduced: the worst-case exposure dose (EEDmax). The EEDmax approach represents a more clinically relevant exposure and includes the known or assumed release kinetics of a compound over the period of use time. Basically, it provides information on the worst-case exposure per day for a chemical constituent that is in contact with the patient’s body and is released from the device. Several ways are described within the standard to access release kinetics of a compound. This can be the simulated extraction method (devices having less than 24 hours of patient contact) or performing a release kinetics study, in which data is collected within defined time periods. Real release kinetics studies can be also circumvented using calculation methods, described in the standard, over the defined periods when acute, sub-acute, sub-chronic and chronic toxicity occurs. A scaling factor has to be also considered, which considers the maximum number of devices utilized clinically.
Additionally, a cancer risk-specific dose (CRSD) has been introduced to evaluate human and suspected human carcinogens. It considers an acceptable lifetime cancer risk of 1 in 100000 (10-5). This value is primarily accessible either via using the cancer slope factor or the TD50 approach, but also other approaches are permitted, if justified and documented.
Last but not least, some minor changes should not be concealed:
Regarding weights and categories of patients the reference weight value was raised from 58 kg to 60 kg for adult women, while for children and newborns the weights which need to be referred to are as follows: 1.5 kg (very low-weight) and 0.5 kg (premature babies). This is also an alignment with the reference weights described in ISO 18562.
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These summarized changes in the standard will impact toxicologists and manufacturers preparing toxicological risk assessment reports. We recommend attending expert-led training sessions to fully comprehend the new requirements in the updated ISO 10993-17 standard. These changes will reduce the turnaround time for preparing toxicological risk assessment reports. Simply get in touch with us!
Please note that all details and listings are not intended to be exhaustive, are without guarantee and are for information purposes only.
