The evaluation of the cytotoxicity of a medical device based on ISO 10993 is one of the key milestone for the introduction of new devices on the market, thus it is an essential step during the design control process. Adequate documentation for biocompatibility testing and in general for the biological safety of the device is requested. The evaluation of the biocompatibility can be considered part of the validation activities, along with other activities like electrical safety and electromagnetic compatibilities (only for active medical devices), usability studies, risk management, clinical validation etc. We have also discussed about biocompatibility-related topics such as hemocompatibility for devices in contact with blood and ISO 10993-1.
In this post we will go through the technical aspects of the cytotoxicity evaluation for medical device, with an emphasis of the impact of this type of test on the overall biological safety of the device.
ISO 10993 Cytotoxicity Evaluation
The evaluation of the cytotoxicity of a medical device is one of the mandatory test that always need to be performed, independently from the type of device, the type and duration of contact between the device and human body.
This type of test is regulated by a specific ISO standard
- ISO 10993-5 : Biological evaluation of medical devices — Part 5: Tests for in vitro cytotoxicity
In fact, basically, there are four categories of type of contacts:
- Surface devices, that usually come in contact only with intact skin
- External communicating devices, for example devices that are in contact with blood
- Implant devices, so devices that will be placed inside human body. These are, obviously, the highest risky devices in terms of safety of the users.
How the cytotoxicity test is performed based on ISO 10993 standard?
The cytotoxicity test according to ISO 10993-5 is performed in order to assess the toxicity of a medical device or of the material through which the device is made from.
Usually the test is performed first by an extraction of the device (or components of the device) in a cell culture media; this extraction can be performed under different conditions, however usually the extraction is performed at 37°C for 72 hours.
The volume of culture media to be used for the extraction is determined by the specific applicable standard and it basically depends from the surface and the thickness of the device or of the specific component of the device.
In a second phase of the test, the extraction media is exposed to cell cultures; these cells are allowed to grow in the extract fluid for a specific amount of time. In the last phase, the cells are evaluated in order to determine the level of cytotoxicity.
This evaluation can be performed using qualitative or quantitative method. In the qualitative method, the cells are evaluated under the microscope and scored with a specific cytotoxicity grade (0-4) that depends on an estimated percent lysis (death) and on the morphology (appearance) of the cells.
On the other hand, the quantitative evaluation is using a specific dye in order to assess the metabolic activity of the cells. The results are reported as percent viability (% living cells). Test materials pass the assay if the percent viability if ≥ 70%. Multiple dilutions of the test article extract are generally included with each assay, in case at the high concentration of the extract, a potential cytotoxicity activity is seen.
The type of devices to be tested
It is very important to discuss what type of devices need to be tested in order to evaluate the cytotoxicity of the whole medical devices.
FDA an other competent authorities clearly require that the final fully assembled devices need to be tested for biological safety evaluation. It is important the device under test goes through the whole manufacturing process, including labelling and packaging activities, in order to make sure the device is exposed to all the possible addictive, substances or chemicals with which it may come in contact.
Sometimes, the device cannot be tested entirely due for example of its dimension; in this case it is sometimes accepted to cut the device, in case this activity does not have any adverse effect on biological safety test being performed.
For devices that contain electrical wires or other electrical components that in any case they do not come in contact with patient, user or any other person, it is accepted to take out these parts of the device at the end of the manufacturing process. This is done in order to avoid that these parts could impart a negative effect to the biological evaluation of the device, considering that that will not come in contact in any case with the user.
Failure of cytotoxicity tests
The cytotoxicity tests is an in vitro test, and it is highly sensible. It is not rare that medical devices or specific components of the device show a potential cytotoxicity when tested though the inn-vitro test described above. It is however essential to evaluate the overall tests performed on the device, with a particular emphasis on the in-vivo tests. In fact, tests performed on animal models are more significant and they provide an indication of the safety of the device on living beings.
When a negative cytotoxicity result is highlighted, it is also necessary to identify the source of this potential cytotoxicity effect, for example by testing specific separated components.
Biological Risk Assessment Template
QualityMedDev provides a Biological Risk Assessment Template, a document that will definitely support and facilitate the documentation related to theological safety of medical devices. This document defines the strategy for biological risk assessment, which is, in other words, the application of ISO 14971 requirements into the evaluation of the biological safety of medical devices.
Subscribe to 4EasyReg Newsletter
4EasyReg is an online platform dedicated to Quality & Regulatory matters within the medical device industry. Have a look to all the services that we provide: we are very transparent in the pricing associated to these consulting services.
Within our WebShop, a wide range of procedures, templates, checklists are available, all of them focused on regulatory topics for medical device compliance to applicable regulations. Within the webshop, a dedicated section related to cybersecurity and compliance to ISO 27001 for medical device organizations is also present.
As one of the leading online platforms in the medical device sector, 4EasyReg offers extensive support for regulatory compliance. Our services cover a wide range of topics, from EU MDR & IVDR to ISO 13485, encompassing risk management, biocompatibility, usability, software verification and validation, and assistance in preparing technical documentation for MDR compliance.
Do not hesitate to subscribe to our Newsletter!
