Managing risk for medical devices
What is so special about the biological risk estimate?
Good comparisons: the key to estimating biological risk
Typically, there is very little we need to know from the biological risk estimate. In most cases, all we need to know is that the risk is OK because it’s just the same as another risk that we already know is OK. That’s all!
However, identifying the right comparison can be challenging.
This idea is not an oversimplification; it is a valid truth that we hold to be self-evident. It’s in line with ISO 14971, which does not specify any particular level of risk, or how it should be estimated. In fact, there are several examples of the use of comparisons for risk estimation in ISO 10993.
This blog looks into the logical basis for the use of comparisons in biological risk estimation. The same basic principle has been used for over 50 years. A comparative approach, presented as guidance in ISO 10993-18:2005, has now been transformed into a key element of ISO 10993-1:2025.
Prior use as a measure of acceptability
The early development of biological evaluation methods is touched upon in the ICON Biological evaluation – the past, the present and the future. This described a systematic approach based on commonly established toxicological risk assessment principles, comprising a review of formulation data (plus any available residue data), a comparison with materials known to have been used in similar situations in the past and a review of the results of biological tests. 50 years later, ISO 10993-1:2025 describes exactly the same process in rather more detail, noting that gathering data to characterise medical device materials remains “a crucial first step in the biological evaluation”.
What are these data on material characterisation used for? They have two uses:
- They are a direct entry into the risk management process as the way to identify biological hazards – both toxicological hazards and those arising from other material properties. Hazard Identification is arguably the most important step in a biological evaluation. If you know about a hazard you will do something about it. Most market withdrawals due to biological safety issues happened because the hazard had not been appreciated.
- We accept that, if a material has been used before and there is no reason to suspect a problem, it is all right to use it again. This is a very nebulous concept compared to quantitative toxicological risk estimation but, when backed up by evidence, it introduces a valuable comparative approach. As with any risk estimate, the estimate of uncertainty is critical. Post-market surveillance is about as insensitive as you can get as a toxicological technique but, when meaningful data are collected, they score highly for relevance.
So, with proper attention to the inherent uncertainties, comparisons based on prior use improve the overall level of confidence in a biological risk estimate, and it is worthwhile maximising the evidential value of post-market data and seeking valid comparisons from market surveillance.
Comparative toxicological risk estimation
The ISO Working Group on toxicological risk assessment, responsible for ISO 10993 Parts 7 and 17, has documented several useful ways to use comparisons to estimate risk when the identity of a compound of interest is unclear or when toxicological data are absent or unreliable.
The basic approach is to establish a safe level of exposure based on the worst-case assumption that the compound of interest is highly toxic. This “threshold of toxicological concern” concept is also used to determine reporting thresholds for analytical chemistry studies.
To improve the dependability of the risk estimate when this concept is applied to medical devices, the ISO Working Group is developing more appropriate, device-specific thresholds. The Working Group is also looking into techniques such as read-across or QSAR (quantitative structure-activity relationship) that predict toxicological hazard by comparison with well-researched compounds that share key structural similarities.
The development of biological equivalence
Judging similarity between medical device materials, based on their composition and manufacturing processes, has always been at the heart of biological evaluation. This is typified by the general principle stated 20 years ago in ISO 10993-18 that “consideration of the chemical characterisation of the materials from which a medical device is made is a necessary first step in assessing the biological safety of the device. It is also important in judging equivalence of a proposed material to a clinically established material, and a prototype device to a final device”.
At that time, ISO 10993-18 contained an informative annex covering principles for judging toxicological equivalence. The key principle applied in making this judgment was that a proposed material should demonstrate toxicological or biological safety no worse than that of a clinically established material. Examples of toxicologically equivalent situations were provided and while this was sensible guidance to assist the risk assessment process outlined in the body of the standard, it could not easily be used for conformity assessment purposes – but that didn’t really matter in 2005.
The process of chemical characterisation has since become more complex as our ability to obtain independent verification of composition from analytical chemistry has increased, and with this, our expectations for such analyses to be conducted. However, the requirement for chemical characterisation to be a stepwise process remains. If you can demonstrate equivalence, or safety, without resorting to analytical chemistry, or biological testing, that is fine.
Focus on equivalence sharpened considerably in 2016, with the publication of the European Commission guidance MEDDEV 2.7/1 rev4. European Competent Authorities had been appalled to see some clinical evaluation reports where assurances of safety and performance were based on unsupportable claims of equivalence, which had not been challenged by Notified Bodies.
As a result, they were determined to stamp out this practice by highlighting the criteria for determining equivalence (which had previously been relegated to a footnote in an annex).
Since then, the basis for claims of equivalence has been given prominence, first in the clinical evaluation guidance and then in the EU Medical Devices Regulation. However, the basis for biological equivalence was never adequately explained in these documents. The MEDDEV specified the use of “the same materials or substances” but referred to ISO 10993, rather than explaining what the word “same” meant. It remains impossible to decipher what biological equivalence actually means from these European regulatory documents alone.
ISO/TC 194’s Working Group on material characterisation rose to the challenge of defining biological equivalence in a way that would be scientifically valid and meaningful for both clinical and biological evaluation. Annex C of ISO 10993-18:2020 was the result, and this is now the basis for the key specification of “sufficient similarity” in Clause 6.7 of ISO 10993-1:2025.
The value of comparison
We know from experience that, in the vast majority of cases, materials used in medical devices are biocompatible and constituent chemicals present in them are non-hazardous. Comparison with existing materials or devices can be a simple way of estimating the biological risk of a device under evaluation as being the same as that of the comparator. When there is confidence in the validity of the comparison and the safety of the comparator, there is confidence in the risk estimate and thus in the conclusion that the biological risk is acceptable and in line with the state of the art.
Nothing more is needed.
Author
Jeremy Tinkler, ERT
Chair of the Technical Committee responsible for ISO standards on biological and clinical evaluation of medical devices and member of the Joint ISO/IEC Working Group responsible for ISO 14971.
References
Standards and guidance, old, new and in the pipeline
- ISO 14971:2019 Medical devices - Application of risk management to medical devices (current)
- ISO 10993-1:2018 Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process (withdrawn – transition period recommended)
- ISO 10993-1:2025 Biological Evaluation of Medical Devices – Part 1: Requirements and general principles for the evaluation of biological safety within a risk management process (current)
- ISO 10993-18:2005 Biological Evaluation of Medical Devices – Chemical characterization of materials (withdrawn)
- ISO 10993-18:2020 Biological Evaluation of Medical Devices – Chemical characterization of materials within a risk management process (current)
- ISO 10993-7:2008 Biological evaluation of medical devices - Part 7: Ethylene oxide sterilization residuals (to be replaced soon)
- SO 10993-17:2023 Biological evaluation of medical devices - Part 17: Toxicological risk assessment of medical device constituents (current)
- MEDDEV 2.7/1 rev4, Clinical evaluation: A guide for manufacturers and notified bodies under directives 93/42/EEC and 90/385/EEC, 2016 (to be replaced soon by MDCG guidance)
- ISO/TS 21726:2019 Biological evaluation of medical devices - Application of the threshold of toxicological concern (TTC) for assessing biocompatibility of medical device constituents (revision under development)
- ISO/TS 24830 - (Q)SAR/Read Across: Best Practices for Medical Device Extractables (under development)