Biocompatibility testing questions

What is biocompatibility testing for medical devices?

According to the MDR and FDA regulations biocompatibility must be demonstrated for all medical devices. If a device is biocompatible if performs its function without adverse effects on adjacent tissue or the organism. Biocompatibility testing follows a review of component materials and a biological safety risk analysis. This process is described in ISO 10993. In the standard the safety requirement is defined according body contact and duration. Chemical characterisation can be used to define the majority of these requirements.

Is biological testing still required for medical devices?

The 2018 version of ISO 10993 emphasises risk assessment and chemical understanding. This means that if the combination of chemicals and materials in a device are known and their toxicity is known, this information can be combined to with knowledge of the product's use to eliminate biological testing when appropriate. It is still a good idea to conduct cytotoxicity testing and in some cases an investigation of local effects.

Is chemical extract testing required for medical devices?

ISO 10993 has chemical characterisation as the first requirement in the testing matrix. It encourages the use of this chemical analysis when insufficient information is available to define all the required toxicity end points. It is only required if the material review and risk assessment conclude that this information is not available.

What are biocompatibility end points?

There are many ways in which a material can be toxic. In medical device regulations these are described as end points. A substance could damage DNA and be mutagenic or carcinogenic; it could cause inflammation after the immune system has been primed and be sensitizing; it might irritate the tissues which it contacts. These end points must be considered in the risk analysis for a medical device. The relationship between end points and body contact is defined in the ISO 10993 matrix. In conjunction with this standard the risk analysis could conclude that: sufficient information is available and no testing is required; or that chemical analysis of leachables is required; and /or that biological testing is required

How do I calculate sample requirements for medical device biocompatibility testing?

Part 12 of ISO 10993 details the ratio of extract solvent volume to device surface required to produce the test fluids. This ratio can be applied to devices and pharmaceutical containers. Your testing supplier will be able to advise you on what volume of fluid is required for each test. In the case materials characterisation, and leachables and extractables the required volume is often 50 to 100ml.

What is the testing biocompatibility matrix?

The biological evaluation matrix in ISO 10993 lists end points for toxicity assessment for medical devices. The end points required are defined according to the invasiveness of the device's use and its duration of contact. An end point is a toxicological risk that must be discussed and evaluated with the object of showing that the risk from a device is insignificant when compared to the benefit. Examples are cytotoxicty, geneotoxicity and mutagenicity.

What is ISO 10993-18?

Chemical characterisation of materials has become one of the most important components of assessing medical device biocompatibility. Chemical analysis is not compulsory. A knowledge of the substances associated with a device is necessary. It is listed in the biocompatibility matrix for every category of human contact.

ISO 10993-18 explains a variety of ways of obtaining the required information.

It suggests research methods based on gathering information on input materials and known uses of the materials. The most obvious example is if you have two devices with the same input materials and processes and with the same patient contact, then toxicity data may be passed from one to the other.

When chemical analysis is required the standard discusses a variety of methods of conducting that analysis.

More information.

What is chemical characterisation?

Chemical characterisation is a combination of information obtained by reviewing information sources including:

the input materials (specification, MSDS, safety testing)
processing (heating, contact with other materials, other stresses)
the storage conditions,
sources of contamination,
the effects of sterilisation,
any information obtained from chemical testing.

This is the information that a Toxicologist can use to weigh up the risks of using the device. This Toxicological Risk Analysis can conclude whether or not the device is safe to use or if biological testing is required to confirm some aspect of safety. Hence, biological testing is the ‘gold standard’ but also the ‘last resort’.

How does ISO 18562 relate to ISO 10993?

ISO 18562 describes specific biocompatibility requirements for internal air paths in breathing components. Whilst ISO 10993 is general for many different medical devices, ISO 18562 has additional end points. The air path requirements, for testing, are: particulate release, vapour (VOC) release and leachate (usually in condensed water) transmission to the patient. The ISO 18563-4 leachate test includes analytical chemistry, sensitization and cytotoxicity from ISO 10993. The particulate and gas quantification are specific tests for inspired air. There can be additional to ISO 10993 tests external surfaces of components. However, any of these components will have only transitory contact with skin and therefore do not always need testing, but they do need to be included in an ISO 10993 Biological Evaluation Report. The chemical characterisation combined with toxicological assessment can replace the sensitization test.

Are carbon monoxide and ozone testing required in ISO 18562 studies?

For certain products and jurisdictions yes.

Note 3 in section 4.5 of ISO 18562-1 states that certain substances that could be in the respired gas stream are not covered by the standard but that some authorities may require their evaluation.

The most significant example is the variety of air quality requirements in the USA which are applicable at least to a gas pathway medical device with an electronic componentry.

These include:

US EPA 40CFR Part 60, Append A, Compendium Method 3C
US EPA National Ambient Air Quality Standards (Carbon Monoxide)
US OSHA Test Method # ID-214 (Ozone)
US OSHA Personal Exposure Level (PEL) Database (Carbon dioxide)
US EPA NAAQS CO (ppm) - Max CO concentration of 09ppm
US FDA Max Ozone Safety Limit - Max O3 concentration of 0.050ppm
US OSHA PEL – Max CO2 concentration of 10,000ppm

Which devices should be tested according to ISO 18562?

Medical Engineering Technologies defines the requirement for VOC and particulate testing as applying if inspired air can pass over your device. If gas, liquid or solid material from your device could get into the patient then is should be tested.

There is a tension between some standards and the evaluation of breathing gas pathways. For example EN 14683 Medical face masks, refers biocompatibility testing to ISO 10993. Whilst section 3.5 of the gas pathway standard describes its target as the interior surfaces bounded by ports over which gases flow or interior surfaces of enclosures over which inspired gases could flow. The definition goes on to give examples of items that are and are not covered, but they are presented in way that causes the examples to contradict the definition. Masks (without defining which type) are given as an example, but it is not if this is an example of what to test or what not to test.

Logic dictates that if you can breathe in air across or through the device you should be worried about particles and VOCs.

What biocompatibility tests are required for IVF products?

The European Commission Guidance document MEDEV 2.2/4, January 2012 advises that the requirements of ISO 10993 Biological Evaluation of Medical Devices are followed. Guidelines for conformity assessment of In Vitro Fertilisation (IVF) and Assisted Reproduction Technologies (ART) products lists parts 1, 3, 5, 10 and 16 of the biocompatibility standard. This means that the end points which must be considered are: genotoxicity, carcinogenicity and reproductive toxicity, cytotoxicity, irritation and skin sensitization and toxicokinetic studies for degradation products and leachables.

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