When developing a new medical device, the biocompatibility must always be considered when the product comes directly or indirectly in contact with the patient.
A biomaterial is any non-vital material used in medical devices intended to interact with biological systems, resulting in an appropriate response from the human tissue. A material that acts this way is considered biocompatible,
Biocompatibility is not absolute, it is the interaction of the material properties, the host and the function of the material. A band-aid is biocompatible when placed on a cut on your finger but not biocompatible when placed on your heart. The below graph shows this correlation.
The ISO norm
Biocompatibility testing checks if your medical device is compatible with living tissue and systems. The medical device supplier should do these tests before clinical evaluation. ISO10993 describes most of the biocompatibility testing that can be done, Additional testing might be required, depending on your device and materials. The norm consists of 23 parts.
I would advise reading the first part, the ISO 10993-1 and not just the tables in Appendix A with the testing requirements. In this article, I’ll explain the process on a relatively high level, which may improve understanding of the ISO10993-1 norm. Hiring professional consultants is advised if you do a biocompatibility study of a (new) device. This article does not detail specific considerations of sampling and testing and leaves out details (which might be important for you) to improve readability.
Often heard question
The first question you might have is, do I need to do a biocompatibility study? You may find the answer in figure 1 of ISO10993-1. When there is direct or indirect contact with the patient, a toxicological evaluation is required.
THe supplier of my raw material states that it is biocompatible, so do I need to do these testing?
The answer is yes, except for some applications like dental. You need to evaluate the risk for biocompatibility, even when you use biocompatible or FDA-approved materials or did initial testing during R&D and all was fine. Also, arguments like the product only come in contact with the patient for 5 minutes are not a reason for not evaluating the risk. You cannot rely on the cytotoxicity testing your supplier did unless the material did not undergo any change. Examples of changes are heating steps, chemical reactions, or sterilization. The extent of testing depends on risk, available literature/data, and use.
Risk Analysis for Biocompatibility
Like all activities when developing Medical Devices, we start with a risk analysis. The risk of biocompatibility follows the steps of risk management described in ISO14971. For more details on risk management, read my previously published article. In summary, there are three steps: Risk Management Plan – Risk Analysis/evaluation – Risk Management Report. This does not differ from the biocompatibility risk analysis: Biological evaluation plan – Testing and risk assessment – Biological Evaluation Report.
Collecting existing information
The risk management process generally begins with an assessment of the device, including the material components, the manufacturing processes, and the clinical use of the device” With this in mind, the potential risks from a biocompatibility perspective can be identified.
Sources of potential risks and mitigation can be found in previous experience with the same/similar material or device / in preferably same/similar anatomical location, information from master files, suppliers, in vivo test data, chemical or surface analysis of the device in final form, published literature, and clinical experience. The data’s applicability depends on the relation of the new device compared to the previously tested device.
The biocompatibility plan
Secondly, a plan should be developed, considering the potential biological impact. This plan contains either
(biocompatibility) testing or other evaluations that appropriately address the risks (literature data). To reduce the number of tests, it is advised to use as much relevant information as possible.
The biocompatibility testing
The testing starts (when applicable) with a chemical analysis and a review of the results. This review should be done by a knowledgeable person, such as a toxicologist. Doing chemical analyses is extensive, costly, and time-consuming.
As a result of the literature, search, and chemical analysis, you now know which information is missing and which tests should be conducted. These gaps are covered with the testing as described in ISO10993-1.
The biocompatibility testing can only be selected with the final design and intended use. Also, the production process must be pretty straightforward. If one starts too early with the biocompatibility testing, there is a risk that design or process changes might affect the biocompatibility, and retests must be performed. Starting earlier with the risk analysis is a good idea. You cannot refer to the tests your supplier did unless the material did not undergo any change. Examples of changes are heating steps, chemical reactions, or sterilization.
If you need to do full-blown biocompatibility testing, be aware that the process is expensive (over €150k) and time-consuming (about a year, of which the in-vitro and in-vivo testing take about six months.
The biocompatibility report
The process is still not finished when the tests are finished, and you have received the reports from the testing labs. A summary report, including all literature searches, justifications of why some tests were or were not done, risk mitigations, residual risk evaluation and risk-benefit analysis (when appropriate) and a conclusion must be written.
The biocompatibility records are part of the technical file and will be reviewed by the notified body.
About Sandra de Vos
Sandra de Vos has 20+ years of experience in polymer and 15+ years in medical devices. She has experience in product and process development, including DHF files, Risk analysis, biocompatibility, and process validation. In her career, Sandra has set up twice a complete ISO13485 Quality Management Systems from scratch and is a certified Lead Auditor.
Currently, Sandra is the founder and CEO of Vosfox Medical. Vosfox Medical offers a contract manufacturing organization specializing in the low-volume production of medical devices.
3D medical printing is a typical low-production method, but we do more than that. Soon we will have low-volume injection moulding and assembly of electrical devices. Our CMO services include process and packaging development, packaging, transport, sterilization validation and shelf life studies. In our facilities, we can produce your device in a validated ISO Class 7 cleanroom or a clean but not controlled production room. Upon request, you can have your dedicated space. The facilities are always welcoming you for testing or training colleagues.
In conclusion, you can stay as involved as you wish and outsource what you want with us.
Please get in touch with Vosfox Medical or directly to me. (email@example.com). You can also comment on the article and help me improve this and future articles.