Medical devices play a critical role in improving and maintaining human health. So why is biocompatibility important?
Manufacturers must be able to demonstrate that a device will not result in avoidable or unacceptable health risks to patients or other end-users (such as medical staff). All devices must be subjected to an assessment of their biocompatibility, a term that refers to the ability of a medical device to perform its intended function without causing harm. Medical devices can make contact with the body directly (such as implants or wound dressings) or indirectly (such as nebulisers). Here’s an insight into everything you need to know about biocompatibility testing for medical devices.
Do I need a biocompatibility assessment for my medical device?
Yes. A biocompatibility assessment is a critical aspect of medical device development. The assessment is best done within a risk management process. A biocompatibility assessment should address the materials that are used, the manufacturing processing and the final finished form. Degradation products and possible leachables/extractables should be considered.
There are, in essence, three phases to an assessment:
- Develop a Biological Evaluation Plan (BEP). The plan should review the device and its materials, identify potential risks and suggest an evaluation/testing strategy to address those risks.
- Device evaluation and testing. This could include ISO 10993-compliant biological tests (for effects) and analytical tests (for extractables), in-house or at your chosen contract laboratories.
- Produce a Biological Evaluation Report (BER). This should include much of a and b, as well as a review of the biological test results, their interpretation, and the results of any Toxicological Risk Assessment (TRA) of the extractables, which should be conducted in compliance with ISO 10993-17. [Note that a new 10993-17 is now in draft form and will soon replace the 2002 version.] Finally, the BER should record a conclusion on the device’s biocompatibility status.
It is sensible to involve your favourite toxicologist throughout these phases, to ensure that you select the best strategy, commission the right tests, and that any TRA is performed by suitably-qualified toxicologists. ISO 10993-1 states that “The biological evaluation shall be planned, carried out, and documented by knowledgeable and experienced professionals”. The bibra scientists are experienced in the evaluation of medical devices, are professionally registered under both the RSB/BTS and Eurotox schemes, and would be delighted to support you throughout the entire process.
Is medical device evaluation and testing essential?
It depends. While a biocompatibility assessment is always required, the laboratory testing effort needed can vary considerably and is driven by factors such as the device composition, intended function and the nature of the contact. Key questions might be:
- Is the device identical in composition, morphology and intended use, to a marketed device?
- Is the device essentially the same as a marketed device but a component has been replaced by one that has a similar or lower-concern hazard profile?
- Is the combination of materials known to be biocompatible and have good evidence of safety?
- Does a change in the manufacturing processes (including the risk of contamination) change the safety profile?
- Does the device have only very brief contact with the body (e.g., hypodermic needles, capillary tubes that are used for <1 minute)? [Note that manufacturers should consider cumulative use and residual coatings or lubricants that could be left in contact with the body after the medical device is removed.]
- Can biocompatibility testing for medical devices be waived using toxicity information from the published literature?
Bibra scientists can advise on the extent of testing required to complete the assessment successfully. The toxicologists are also skilled in searching the published literature, and experienced in the generation of data waivers as well as in test interpretation.
What biocompatibility studies do I need to consider conducting?
ISO provides excellent guidance in this respect. The ISO 10993 standards [1] provide a framework for evaluating the potential biological risks associated with medical devices that come into direct or indirect contact with a tissue or body fluid. In addition to ISO 10993, breathing gas pathway devices such as ventilation masks, breathing circuits, and nebulisers are assessed under ISO 18562 [2]. Biocompatibility testing for medical devices that comply with ISO 10993 are acceptable in Europe and Asia. The US FDA has also adopted many parts of ISO 10993, and has issued specific guidelines for its use [3]. By adhering to these standards, manufacturers can ensure that their devices are safe and reliable for use by clinicians and patients.
The tests (or actually endpoints) proposed by ISO 10993 standards vary, and take into account the duration of contact with the device and the types of exposed tissues. Not surprisingly, a permanently implanted device will require more rigorous testing than a device that contacts the intact skin only for a short period.
Broadly, the types and duration of body contact as outlined in ISO 10993 are as follows:
Type of body contact
- Surface-contacting devices make direct contact with the skin (e.g., medical tape, bandages, electrodes), mucosal membranes (e.g., contact lenses, urinary catheters, orthodontic devices) or compromised surfaces (e.g., burn/ulcer dressings).
- Externally-communicating devices contact tissue/bone/dentin or circulating blood directly, or act as a conduit to deliver substances to the blood.
- Implant devices are categorised according to their contact with tissue/bone or blood.
Duration of contact
- Limited exposure – up to 24 hours
- Prolonged exposure – >24 hours up to 30 days
- Long-term exposure – >30 days
The duration of contact is determined as the cumulative sum of single, multiple or repeated exposures to the medical device.
Based on the type and duration of contact, ISO 10993 provides a framework for the types of biocompatibility endpoints that should be assessed. The full list of endpoints is as follows:
- Chemical/physical properties
- Cytotoxicity
- Irritation/intracutaneous reactivity
- Sensitisation
- Pyrogenicity
- Systemic toxicity (acute, subacute, subchronic and/or chronic)
- Implantation effects
- Haemocompatibility
- Genotoxicity
- Carcinogenicity
- Reproductive/developmental toxicity
- Degradation
- Toxicokinetics
- Immunotoxicology
Only the chemical/physical properties element is listed as compulsory for all medical devices. The type of contact and tissue define the others that should be addressed (as a minimum).
Bibra toxicologists can advise on the selection of endpoints that need evaluation. The selection should be recorded within the BEP, addressed in the evaluation and testing phase, and the results and interpretation be summarised in the BER.
Summary
ISOs 10993 and 18562 provide very helpful guidance on the biocompatibility assessment of medical devices. Involving your partners (biological test contract houses, chemical analysts and toxicologists) from the start will maximise the probability that your BEP is robust, the commissioned tests are selected optimally, any ensuing TRA is conducted properly, the BER is scientifically sound, and your device can be submitted for approval and safely marketed.
If you would like to find out more about biocompatibility testing for medical devices, please get in touch with our experts today.
References
[1] ISO (2018). International Organization for Standardization. ISO 10993-1:2018 Biological evaluation of medical devices Part 1: Evaluation and testing within a risk management process.
[2] ISO (2017). International Organization for Standardization. ISO 18562-1:2017. Biocompatibility evaluation of breathing gas pathways in healthcare applications — Part 1: Evaluation and testing within a risk management process.
[3] US FDA (2020). Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process". Guidance for Industry and Food and Drug Administration Staff. Document issued on: September 4, 2020. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-international-standard-iso-10993-1-biological-evaluation-medical-devices-part-1-evaluation-and