ISO 10993 for biological evaluation of Medical Devices
All medical devices must be subjected to a safety assessment to meet regulatory requirements.
In addition to gain understanding of the device materials and processes of manufacturing and sterilization, manufacturers have to confirm that the device is compatible with biological systems. Therefore, biocompatibility testing is a critical part of the regulatory approval process for medical devices (to assess the interaction between a device and the tissues and physiological system of a patient, and to check whether the use of the device can have any potentially harmful biological reaction in the patient).
For such biocompatibility testing, the ISO 10993 (Biological Evaluation of Medical Devices) standard series are applied. The biological evaluation shall commence with categorization of the device based on the nature and duration of the contact with the body, and, depending on this categorization, the manufacturer should develop a testing strategy.
In order to do so, it is important to know that:
- “The Big Three” tests (cytotoxicity, sensitization and irritation/intracutaneous reactivity) are required for most of the medical devices regardless of nature and duration of the contact with the body, but, as the range of possible biological hazards is wide, many other tests need to be taken into account.
- Some of these tests evaluate short-term effects (acute toxicity, irritation to the skin, eye and mucosal surfaces, haemolysis and thrombogenicity) and some of them long term or specific toxic effects (subchronic and chronic toxic effects, genotoxicity, carcinogenicity and effects on reproduction or development).
- Although the ISO standard specifies that in vitro tests methods shall be considered for use in preference to in vivo tests, nowadays, some of the effects are only evaluable by means of the latter, as no appropriately validated, reasonably and practically available, reliable and reproducible alternative methods exist. In vivo tests are much more time and resources consuming.
Nanotechnology- based Medical Devices
It is now generally accepted that there can be unique properties associated with submicron (<b micron) or nanotechnology components such as aggregation, agglomeration, immunogenicity or toxicity.
For example, various properties of nano-objects can affect their uptake after skin, eye, or mucosa exposure. Larger nano-objects are less likely to have skin penetration, while their smaller counterparts can be able to access the deeper epidermis, dermis and lower cell layers. In addition, shape can also have an effect on skin penetration, with spherical nano-objects showing a higher permeation than elongated nano-objects. All this information, thus, should be considered before starting the testing.
Moreover, nano-objects having a length range from 1nm to 100 nm can be generated during the life cycle of a medical device, so the evaluation of possible adverse effects due to the generation of nano-objects either from preparation, use, wear or degradation of medical devices needs also to be addressed.
It is likely that the various assays as described in the ISO 10993 series are not always appropriate as such in the testing of nanotechnology- based medical devices as nanomaterials pose specific challenges when applying test systems commonly used for medical device evaluation and when interpreting test results.
Therefore, additional considerations (some of them compiled in the ISO/TR 10993-22 published in 2017: Biological evaluation of medical devices- guidance on nanomaterials) should be outlined for the biocompatibility evaluation of medical devices containing nanomaterials, that, may require specialized techniques of characterization and adapted toxicology protocols.
For example, for cytotoxicity testing according to ISO10993-5, cultured cells are exposed to the sample directly or to an extract prepared from it. However, for nano-objects, some of the sample preparation procedures described in ISO 10993-12 might not be applicable. For these cases, considering the ISO19007 standard (Nanotechnologies- In vitro MTS assay for measuring the cytotoxic effect of nanoparticles) could be useful.
The objective of SAFEnmt is to build a platform to offer companies and referent laboratories the capabilities, knowhow, networks and services required for the development, testing, assessment, upscaling and market exploitation of nanotechnology based Medical Devices. This must be done across the whole Life Cycle of nano-enabled Medical Technologies.
The Biomaterials area of the Health Division of Tecnalia has a broad experience in the synthesis and processing/surface modification of biomaterials and biocompatibility and toxicity testing (in vitro and in vivo) of Medical Devices.
Hence, Tecnalia, will provide its experience in offering advice for biocompatibility testing, discussing the common biocompatibility pitfalls and assessing the latest alternatives to animal testing.
Our group will participate in developing testing strategies for different test cases of the project and carrying out in vitro and in vivo studies working together with other partners in this consortium.
Interested in finding out more about TECNALIA, or about the work of the SAFEnmt partners? leave us a comment below!