Biocompatibility evaluation of a medical devices include chemical toxicity, unacceptable biological response to the medical device or changes in the device’s physicochemical characteristics due to any aspects of the manufacturing process.
In addition to the International Standard ISO 10993-1, “Biological evaluation of medical devices – Part 1: Evaluation and testing within a risk management process”, the U.S. Food and Drug Administration (US FDA) has also a published guidance document to assist the industry in preparing submissions for Premarket Applications (PMAs), Humanitarian Device Exceptions (HDEs), Investigational Device Exemption (IDE) Applications, Premarket Notifications (510(k)s) and De Novo request for medical devices. This FDA guidance document provides further clarification on how to use the ISO-10993-1 for biocompatibility compliance.
Which device requires biocompatibility testing?
To determine whether a medical device requires biocompatibility testing, the FDA’s biocompatibility evaluation flow chart is a good reference. It outlines how one might proceed to evaluate risks factor in device biocompatibility. The key determining factors depend on the body parts that come into contact with the device, the contact duration, and the anticipated biological effects.
The guidance document also recommends consultations with a toxicologist or other qualified individuals (such as a clinical investigator) to determine the best approach to fulfil the test requirement of the ISO Material Biocompatibility Matrix.
A device manufacturer can reduce the number of tests required if there is sufficient evidence to ascertain the biological safety of the device. This includes results from relevant studies that have been conducted previously, or any existing pre-clinical and clinical data that meet the requirements of biological evaluation.
Steps to complete biocompatibility testing
Generally, biocompatibility testing will be completed in various stages. The first stage is to evaluate the composition and material that made up the medical device, assess any expected risks to the users, and determine which tests are required to address these risks.
Based on the initial evaluation plan, the manufacturer will have to conduct tests and assessments identified in accordance with the recommendation outlined in the ISO 10993-1 document. The results will be curated into a capstone biological evaluation report to be submitted to the FDA.
In general, when the risk assessment process concludes that testing is warranted, there are different approaches that a manufacturer can undertake to complete these tests. While there are many different biocompatibility endpoints, some commonly used approaches are outlined below.
- Cytotoxicity: This refers to the toxicity of the material toward living cells. Generally, cytotoxicity can be tested by exposing cell samples to the device materials in the laboratory (in vivo) and checking for cell damage or malformation. There are three commonly performed cytotoxicity tests, including the direct contact procedure, agar diffusion assay and the MEM elution assay.
- Sensitization: The test helps to determine if the device material can cause local or systemic adverse effects after repeated or prolonged exposures – allergic responses that arise from activating the immune system. Sensitization tests can be performed using the medical device itself or chemical compounds extracted from the device. Specific procedures included the Guinea Pig Maximization Test, Closed Patch Test, and the Murine Local Lymph Node Assay.
- Irritation: This aims to evaluate whether the device material induces local irritation, and typically will employ exaggerated exposure conditions compared to the real-world scenario. Irritation tests can be achieved via intracutaneous tests, primary skin irritation tests, and mucous membrane irritation tests.
- Acute system toxicity: The test seeks to identify whether there are leachable substances from the device that could cause harmful systemic toxic effects. All blood contact devices are recommended to undergo acute system toxicity tests.
- Sub-chronic toxicity: The test is used to determine whether the device can cause long-term harmful effects from multiple exposures. Sub-chronic toxicity tests are complicated and there are multiple approaches to completing them. The manufacturer should determine the appropriate animal models for testing based on the unique physicochemical properties of the device.
- Genotoxicity: Materials that damage or alter the structure of DNA are harmful to the users. A genotoxicity test aims to determine whether the material from a device or the whole device could cause genotoxicity. The Ames test is most used in this case.
- Implantation test: The test is used to determine whether an implantable medical device or materials that come into direct contact with living tissues other than the skin (such as a pacemaker) is biocompatible.
- Hemocompatibility: The test aims to examine whether the device is compatible with blood. The test is essential for medical devices that are used intravenously, including catheters and blood transfusion equipment.
At Synergy Bioscience, our scientists specialize in designing and performing biocompatibility studies that can support your regulatory submissions.