Evaluating the biocompatibility of medical devices

Background information 

Evaluating the biocompatibility of medical devices (MDs) is of major importance as it ensures the safety of products with respect to the patient and/or user. It is mainly governed by the ISO 10993 series of international standards – “Biological evaluation of medical devices”.

Biological evaluation of MDs

The ISO 10993 series of international standards consists of several parts, but depending on the type of medical device, the biocompatibility evaluation may be based on other standards (e.g. ISO 18562, ISO 7405, ISO 9394), various specific technical reports (e.g. ISO/TR 37137) or even additional guidelines. These standards are constantly changing in order to take into account scientific and technical advances on the topic.

Standard NF EN ISO 10993-1:2010 “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process” was cancelled on 6 February 2021. It has been replaced by Standard NF EN ISO 10993-1:2020, which has been harmonised for the European market. This version includes the ISO 10993-1:2018 standard as well as the corrected 2018-11 version without any modifications.

The strategy developed in the NF EN ISO 10993-1:2020 standard takes up the 3R principle (“Reduce, Replace, Refine in vivo assays”), introduced in 1959 by W.M.S. Russell as part of scientific research. This principle, widely used in cosmetics, has been greatly developed in all areas of health, including the biocompatibility evaluation of MDs. In vivo biological testing has therefore become a growing concern and the possibility of assessing risks using alternative approaches (in silico, in vitro, chemical or physical) should be considered in order to limit tests on animal or human models. Of course, this strategy does not exclude in vivo testing but it does encourage manufacturers to take a more pragmatic approach.

The publication of Standard ISO 10993-23:2021 “Biological evaluation of medical devices – Part 23: Tests for irritation” has taken this approach a step further. Irritation and sensitisation tests were previously presented in Standard ISO 10993-11:2017 (which is currently being revised to present sensitisation tests only), and the only way to assess the irritation potential of an MD was through in vivo tests on rabbits.

After 70 years of using this animal, the new standard proposes an in vitro alternative, with the use of reconstructed human epidermis (RhE) models. The proposal of alternatives to the use of in vivo tests has therefore become the guiding principle for biological evaluation.

The acceptance and application of the ISO 10993-23:2021 standard has given rise to a number of international reactions, in particular on the part of the European Union for whom this new standard can be considered a “state of the art” concerning medical devices. Since it was only recently published, its implementation cannot be expected immediately and a transition period should be granted. In practice, for existing devices on the market and for devices that are currently or will in the near future be subject to MDD/MDR CE marking, no additional in vitro irritation data are required if in vivo irritation studies are already available.

Also as part of this pragmatic approach to avoid unnecessary animal testing, a draft update to the FDA’s guidance document on biocompatibility was published on 15 October 2020. It deals with the information that must be provided for devices made from polymers and tissues in contact with intact skin. For these frequently used materials, the FDA recommends, among other things, omitting certain biocompatibility tests for medical devices in contact with intact skin. This approach is based on the 3R principle outlined above.

The previous FDA guidance document from 2016, “Use of International Standard ISO 10993-1, ‘Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process’” (2016 Biocompatibility Guidance) will remain in effect in its current form until the new version is finalised. The proposed sections are intended to add to or replace applicable sections of the 2016 biocompatibility guidance document. Sections that are not affected by this selective update will not be changed and will remain in force. The purpose of these guides is to help manufacturers prepare Premarket Applications (PMAs), Humanitarian Device Exceptions (HDEs), Investigational Device Applications (IDEs), Premarket Notifications (510(k)s), and De Novo requests.

As these recent publications show, the biocompatibility of MDs is a constantly changing discipline and the requirements associated with biological/physical/chemical risk assessment are becoming increasingly precise.

For example, several specific points of biological evaluation are discussed below:

• The physical properties of implantable medical devices should be taken into account when evaluating biocompatibility. Standard ISO/TS 10993-19:2020 “Biological evaluation of medical devices – Part 19: Physico-chemical, morphological and topographical characterization of materials” provides a compilation of parameters and test methods that can be useful for the physico‑chemical, morphological and topographical (PMT) characterisation of MD surfaces. These have become major parameters for biocompatibility and clinical efficacy.
• In the context of the biocompatibility of an implantable medical device, particulate contamination is also a risk that should be considered. Particle counting can be one of the solutions to assess this risk.
• The assessment of risks associated with shelf life and storage conditions (e.g. temperature and humidity) is a parameter to be considered when evaluating biocompatibility. Depending on the storage conditions and shelf life, the packaging and also the medical device itself may deteriorate and lead to a biological risk for the patient and/or user.

These biological risks were previously only minimally considered in biological assessments but are now an integral part of assessments by notified bodies.

Our intervention

Biocompatibility is a decisive criterion for the marketing of MDs. Recent changes in the methods used by notified bodies to evaluate technical dossiers have placed this subject at the centre of attention more than ever before. Biological evaluation is indeed a major part of meeting the essential requirements.

In the current context, where demand for compliance is strong and urgent, the Efor Group is providing its customers/MD manufacturers with its expertise and a methodical approach. Our biological evaluation experts will help you better understand changes in the standards governing the biological evaluation of your MDs. In addition, our toxicology experts will be able to assist you with toxicological assessment work according to the ISO 10993-17 standard (toxicological risk assessment (TRA)).

We choose to support you with a team of specialised experts who can monitor your biological and toxicological evaluation project from A to Z, from the implementation of the evaluation strategy to the writing of the report, while engaging in collaborative work based on exchange.