Mark Turner, managing director of Medical Engineering Technologies (MET) discusses the new relevance of chemical characterisation in medical device compatibility.
Changes to ISO 10993
In January 2018, seismic changes took place in the world of medical device toxicity assessment.
The new edition of ISO 10993-11 added the requirement for a chemical knowledge of any device, whilst also requiring the driver to use this knowledge to understand the potential toxicity of the device. The potential toxicity then becomes, in its turn, the driver for risk assessment which may finally lead to a testing requirement.
The toxicity end points have not changed, although there are some changes to the biocompatibility matrix. A short term, surface contact device still has the end points of cytotoxicity, sensitisation and irritation for which the risk versus benefit analysis must prove positive. A more invasive, permanent implant still has these end points plus sub-chronic, genotoxic and implant end points with the addition, now, of chronic toxicity and carcinogenicity.
It is not always essential to use biological testing to show that there is acceptable toxicity for each of these end points, and it is stated in the standard that biological testing should not be the first resort. The approach should be data gathering and assessment first.
Extractables and leachables2 along with other materials characterisation3 techniques will be required if all the chemicals and their abundance cannot be defined for a device. This information is not generally known because exactly what chemicals input materials come into contact with cannot be defined. There may be multiple chemicals in the production process and many of the specified materials may contain undeclared additives.
This information is then fed into a toxicity risk analysis. Finally, toxicity testing is applied when the safety of a material or mixture of materials cannot be defined as safe from data available.
Biocompatibility matrix
The ISO 10993-1 biocompatibility matrix provides a guide to the selection of information requirements, with chemical analysis now added to every category.
Material characterisation
It is nearly always the case that it is not known exactly what materials a patient may be exposed to from the device and its supply chain. Because of this an investigation is needed. Material characterisation as described in ISO 10993-184 should be applied.
Characterisation includes consideration of the chemical materials present and also morphology and the nature of the surfaces. The surface investigation may be concerned with features that encourage ingrowth or bacterial colonisation. There might be concerns with particular surface chemistry or catalytic properties of the surface. Methods of investigation could include electron microscopy, elemental analysis, infra-red spectroscopy or other techniques.
The primary study will always be an investigation of materials released from the medical device in use – extractables and leachables, and particulate.
The leachables are described in ISO 10993-175 as ‘released constituents that potentially contact the individual during clinical use’. The extractables include additional entities that can be forced out of the materials of construction, in the ISO 10993-17 definition ‘constituents that can be extracted in the laboratory’. The reason for identifying and quantifying the extractables, in pharmaceutical container studies, is that there is a risk of them transferring into the formulation at some point during its storage. Similarly, the reason for examining extractables in medical devices is that they might become leachable at some point during the device’s lifetime.
ISO 10993-126 gives us the extraction conditions (area to volume ratio, time and temperature, solvent polarity).
The leachables concept transfers quite well to medical devices. This can be considered ‘in use’ or ‘simulated use’ leachables which likely to be delivered to a patient in use.
Leachables can be taken from the device in question much as they have been traditionally in biological tests. The biggest difference in the leaching process is solvent changes between the two methods. Biological tests generally use cotton seed oil as the non-polar extract and water or saline as the polar extract. Whilst chemical analysis is generally carried out using hexane as an example non-polar solvent and water as polar, along with possibly a third solvent or mixed solvents.
Extractables become more important for long term products. There may be substances that are released after a long delay that are not apparent in a 72 hour extract. Testing with more aggressive solvents, higher temperatures and longer soak times may be required.
Here the concept of ‘simulated use’ leachables is introduced. Clearly it is not possible to wait for many years for the extractable to migrate into solution for analysis. Therefore, forced extraction is used, the strength of which (whilst being based in ISO 10993-12) can be adjusted according to the environment and duration of use. Hence, ’simulated use extract’. As we go up the invasiveness scale, we increase the strength of the solvents and consider increasing the extraction times and temperatures. ‘Consider’ because we are only interested in materials that will be present in use not degradation products produced in the extraction process by temperature or other processes not relevant to the ‘in use’ environment. There are specific tests for degradation products detailed in standards such as ISO 10993-137.
Toxicological risk analysis8
The analytical chemistry produces information identifying which materials are present and in what quantities. To be useful this information must be interpreted in terms of the toxicity end points given in the biocompatibility matrix. If no materials of concern are found or the patient contact is transient, then this can be quite a simple assessment. As more materials are identified and the patient contact becomes more intense the requirement for a toxicological risk analysis increases. This analysis is the domain of a registered toxicologist, who takes each material found and calculates the patient dose per 24 hours and over the product lifetime. A variety of information sources are then used to quantify the potential toxicity of the materials individually and combined.
There are several end points which are difficult to assess from published data (as used by the toxicologist), these include haemocompatibility and local effects such as implantation and irritation.
Conclusion
A knowledge of all chemicals released by a device in use is now required in ISO 10993, and this is listed in the testing matrix for every category of device. Although, materials characterisation led by extractables and leachables is not the only route to obtain this information, it is the most likely method to find unexpected materials. The vigour of application of chemical analysis should be tailored to the body contact and risk analysis for the device. Usually the chemical information, through a toxicological risk analysis, can be used to address all the toxicity end points without any need for animal testing.
References
- ISO 10993-1:2018 Biological evaluation of medical devices -- Part 1: Evaluation and testing within a risk management process
- https://www.met.uk.com/4dii-testing-and-analysis-of-extractables-and-leachables
- https://www.met.uk.com/medical-device-testing-services/biocompatibility/chemical-characterisation
- ISO 10993-18:2005 Biological evaluation of medical devices -- Part 18: Chemical characterization of materials (under review)
- ISO 10993-17:2002 Biological evaluation of medical devices -- Part 17: Establishment of allowable limits for leachable substances (under review)
- ISO 10993-12:2012 Biological evaluation of medical devices -- Part 12: Sample preparation and reference materials.
- ISO 10993-13:2010 Biological evaluation of medical devices -- Part 13: Identification and quantification of degradation products from polymeric medical device
- https://www.met.uk.com/medical-device-testing-services/biocompatibility/toxicity-risk-assessment