The Ministry of Health, Labour and Welfare of Japan (MHLW), the Japanese regulating authority responsible for medical device circulation, issued updated guidance dedicated to biocompatibility testing of medical devices.
Biocompatibility Testing Standards
According to the document, biocompatibility testing should be performed in accordance with the requirements provided by the appropriate national standard JIS T 0993-1:2020 which actually constitutes an ISO 10993-1 standard being translated in Japanese. At the same time, all requirements provided by the Japanese standard are exactly the same as the ones stated in the initial standard. The authority takes all the steps necessary to keep the national standard in compliance with the initial document by implementing the appropriate amendments.
It is also important to mention that the authority has previously issued two other documents dedicated to the requirements applicable to the biocompatibility data provided in the course of pre-market approval procedure and pre-market certification.
The document covers the standards that should be used when confirming compliance with biocompatibility requirements for the purpose of applying for the approval for manufacturing or marketing medical devices, an application on certification and change notifications. The document describes the way the biocompatibility testing should be performed and the particular testing methods to be applied for the results to be reliable and acceptable for the intended purpose. The new regulation partially implements the requirements set forth in ISO 14971, describing the risk management regarding medical devices.
First of all, the document highlights the most important definitions, such as:
- Raw materials – materials the device is composed of, or any material used in the manufacturing process, including synthetic or natural polymer compounds, metals, alloys, ceramics or other chemical substances;
- The final product – the device or its component regarding which all manufacturing processes had been finished, including packaging and sterilization (if applicable), that is ready for use;
- Hazard – any factor that could impact negatively the health of a human;
- Risk – a probability of the negative impact caused by the hazard to occur.
Biocompatibility testing, in general, is based on the Japanese national standard JIS T 0993-1 “The biology of medical devices”. Each particular assessment element is based on the appropriate ISO 10993 series. It is required to choose the appropriate testing method and to assess safety. The safety assessment should be performed properly for each testing method. Thus, it should be replaced with the assessment using the method based on other public standards (e.g. the initial ISO standard). It is required to describe the testing methods and the way they are applied to particular medical devices. Each of the devices should be assessed on the basis of testing results. Since it is necessary to choose the testing methods depending on the situation and the device subject to evaluation, the document highlights the main aspects to be taken into account when assessing the biocompatibility and safety.
The authority also warns that national and international standards could be subject to review as the development of science and technologies. Thus, the manufacturers shall refer to the newest standards available at the moment of testing and choose the appropriate testing method.
Principles of the Biocompatibility Assessment
According to the document, the general approach to biological safety is described in JIS T 14971 or in the ISO 14971 respectively. In particular, the document describes the following principles:
- The assessment should be performed using the approved risk analysis method. First of all, it is necessary to define the intended purpose of a medical device and its safety characteristics. Then, it is necessary to identify potential hazards and the risk of harm caused by each particular hazard. “Positive” approach means that each safety issue should be detected and identified, while it does not directly lead to the disqualification of the device itself, and it remains compliant with the safety requirements. At the same time, each new revision of the standards does not require an additional assessment.
- Biological safety assessments should be based on information collected through testing appropriate for the particular medical device due to its type and features. In general, it should be based on information from scientific literature, data from non-clinical trials, clinical experience (including post-marketing surveillance), etc. It is necessary to assess the safety of any and all components directly or indirectly contacting the tissues of the human body, the remains or waste resulting from the manufacturing process, packaging materials (chemical substances contacting directly or indirectly with the medical devices), derivative products, components and its interaction, features and characteristics of the final product, and physical characteristics of the final product.
- Biological safety assessments should be performed by skilled and experienced professionals.
- It is necessary to perform additional biological risk assessment in case of any changes to the supplier or specification of the materials used to manufacture the devices, to components or combinations of the products, processing methods, initial packaging and sterilization, changes to the shelf life and transportation requirements, intended purpose of the final product, the information indicating that the product could cause harmful impact when used by people.
- In case of devices intended by the manufacturer to be used multiple times, the assessment should be performed with regard to the last cycle available.
- For the purpose of the document, the classification of the device should be based on its surface contact with the human body. If the device could not directly be assigned to any of the categories, it should be assigned to the one that is closest due to its features. In particular, the classification would depend on the contact type (contactless, surface-contacting device, wound contacting device, etc.), contact length (temporary contact, short- and long-term contact).
Biological Safety Assessment Performance
The assessment of the biocompatibility includes several steps. First of all, it is necessary to collect all physical and chemical information, as well as the information regarding raw materials used, manufacturing and sterilization methods, design, physical features, contact with the human body, etc. All chemical components should be duly identified. Chemical assessment should be based on the ISO 10993-18. In some cases, the information collected on this step would be sufficient to perform the assessment and mare reliable conclusions on the biocompatibility of the device.
It is also allowed to use references to the equivalence to the approved/certified medical device already present on the market to confirm compliance with the applicable safety requirements.
The document also describes the particular testing methods to be used depending on the device itself and also on the objectives of testing. The manufacturer must use the appropriate testing methods explicitly approved by the authority.
Summarizing the information provided above, the new document issued by the Japanese regulating authority provides the requirements related to biocompatibility testing and the information to be used to confirm the compliance with such requirements.
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