Biological safety evaluations are designed to assess whether a product is safe for its intended use depending on its composition. For example, an evaluation of a cardiovascular implantable device would need to assess potential risks associated with long term contact with blood and vascular tissue.
ISO 10993-1:2018, and the associated guidance document from the Food and Drug Administration (FDA), provides a framework for biological safety evaluations using biological endpoint assessments for new or modified medical devices.1 Devices are categorized by their type of contact with the body – whether surface, externally communicating, or implantable devices. Additionally, they are categorized by their duration of contact – whether they have limited, prolonged or long term contact.
These documents help to guide the necessary steps in biological endpoint testing and assessments in biocompatibility evaluations.2 As part of this process, it is necessary to consider the safety of all the materials involved in the processing and construction of the device, as well as potential contaminants.
The types of testing that might form part of a biocompatibility evaluation include chemical characterization in a study designed to simulate or exaggerate the clinical use case, or in vitro and in vivo biological testing.
The biological endpoints which are required to be evaluated are depending on the nature and duration of exposure. These endpoints can include cytotoxicity, irritation, sensitization, systemic toxicity, pyrogenicity, hemocompatibility, implantation, genotoxicity, carcinogenicity, and reproductive and development toxicity. These endpoints may be addressed through existing data, through justification regarding their relevance to the clinical use case, or through new testing of the device.
Localized endpoints, such as cytotoxicity, irritation, or hemocompatibility, are those which correspond to a localized tissue response. Such endpoints typically require in vitro or in vivo biological testing. In contrast, systemic endpoints, such as genotoxicity, systemic toxicity, and carcinogenicity, may be addressed through chemical characterization and toxicological risk assessment. Certain endpoints, such as sensitization and pyrogenicity, result from a systemic physiological response, but are commonly addressed through biological testing. These endpoints may require a combination of in vitro testing and chemical characterization with predictive toxicological assessments in order to avoid in vivo testing for regulatory or ethical reasons.
As part of a biocompatibility assessment, it is also essential to consider whether information on the individual, isolated material will truly represent the material in the finished device. Changes in material properties might occur due to exposure to different environments or processing. Furthermore, the presence of multiple material types within a device may result in “mixture effects” which should be accounted for in a robust biocompatibility assessment.
In vitro and in vivo biological test methods to address required endpoints are outlined in the various sub-parts of the ISO 10993 series of standards, as well as OECD guidelines, USP chapters, and ASTM methods. The involvement of expert guidance is recommended for evaluate biological safety endpoints, particularly in selection of tests and justifications for leveraging of existing safety data.
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- FDA (2022) Biocompatibility Evaluation Endpoints by Device Category, https://www.fda.gov/medical-devices/biocompatibility-assessment-resource-center/biocompatibility-evaluation-endpoints-device-category, accessed May 2022
- FDA (2022) ISO 10993-1, https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-international-standard-iso-10993-1-biological-evaluation-medical-devices-part-1-evaluation-and, accessed May 2022