From adhesive bandages to audiometers, container-closure systems to catheters, and stethoscopes to scalpels – medical devices cover an impressive range of healthcare products.

Of course, different types of medical device have varying levels of human health risk associated with them. For example, examination gloves worn by a healthcare professional are less likely to cause a potentially-adverse impact on the health of a patient than a replacement heart valve. The impact on patient health generally depends on the chemical composition of the device, as well as the type and duration of contact that it has with the body. These various levels of risk are reflected in the legal frameworks of regulatory authorities around the globe – in the EU, for example, there are essentially four classifications of medical devices (Class I, Class IIa, Class IIb and Class III), ranging from low to high risk.

All medical devices must demonstrate biological safety and biocompatibility. However, depending on the type of device, different biological endpoints must be evaluated to satisfy the regulatory authority.


How do we know what biological endpoints the regulator will expect to have been addressed?

Fortunately, ISO 10993-1 provides an excellent framework on which to base your biological safety evaluation. The nature of the body contact (e.g. surface device intended for contact with breached or compromised skin) and the contact duration (limited, prolonged or long-term) influence the battery of toxicological/biological endpoints that should be considered as part of the assessment.

The ISO 10993-1 guideline has recently been updated, and the “endpoints to be addressed” have been revised. Before conducting the biological evaluation of your device, two key points must be understood:

1)    “Chemical characterisation” of the device can provide invaluable information regarding the chemical constituents and potential leachables from the device

2)    Although the specified endpoints must be “addressed”, this does not mean that laboratory testing is mandatory. Biological testing, particularly in vivo, should be considered as a last resort.


A guideline for chemically characterising the device has been published as Part 18 of ISO 10993.

Extractables testing usually consists of extracting the device in appropriate solvents at elevated temperatures. The extracts are then analysed using techniques such as GC-MS, LC-UV-MS and ICP-MS or ICP-OES, and a profile of potential leachables is established. These leachables are compounds that the patient could possibly be exposed to during actual use of the medical device.

The ISO 10993-1 guideline indicates that the chemical characterisation should be followed by a toxicological evaluation and risk assessment of the identified components of the device.


ISO 10993 Part 17 guidance on the risk assessment of leachables

As outlined in ISO 10993-17, risks associated with exposure to identified leachables are managed by quantifying the associated risks and limiting exposure within tolerable levels. The process of establishing these tolerable levels can be broken down into the following key steps:

  • Conduct comprehensive literature searches
  • Identify the critical health endpoint
  • Determine a point-of-departure (usually a NOAEL)
  • Derive a Tolerable Intake (TI), specific for the route of entry and duration of exposure
  • Calculate the Tolerable Exposure (TE) for the target patient subgroups
  • If appropriate, modify the initial TE to account for utilisation, benefit etc
  • Compare the final TE with the estimated worst-case exposure of the potential leachable and calculate a Margin of Safety (MOS).

By conducting a comprehensive toxicological risk assessment of the extractables identified by the chemical characterisation, and assuming that adequate datasets exist for the extractables under evaluation, then the critical health risks posed by exposure to the medical device have been addressed. As such, it may be unnecessary to conduct further testing in laboratory animals for endpoints such as (sub)chronic systemic toxicity, genotoxicity, carcinogenicity and reproductive/developmental toxicity.

Bibra has many years of experience in deriving such TE, TI and MOS values for chemically-characterised substances in human health risk assessments. In addition, bibra scientists are able to evaluate the health risks of exposure to certain unidentified extractables (i.e. “unknowns”) using concepts derived from the Threshold of Toxicological Concern (TTC) approach.

If your device requires a toxicological risk assessment, or you would like more information regarding toxicological evaluations, chemical characterisation or biocompatibility, then please get in touch.



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