The basic framework of the biological safety assessment of medical devices in Japan is based on the guidance of the Ministry of Health, Labor and Welfare issued in January 2020, “Basic principles of biological safety evaluation for application for approval of the manufacture and sale of medical devices.” (Yakuseikishinhatsu 0106 No. 1). Although there is no major change in the biological safety assessment system based on the conventional risk management method, physical and chemical information of the medical devices is required and should be evaluated in the evaluation items to be considered Endpoints are increasing. This guidance document summarizes the latest requirements of the Ministry of Health, Labor and Welfare, and is basically harmonized with ISO 10993-1: 2018.
Assessment of irritation is an essential item of the biological evaluation of medical devices that has direct or indirect contacted with the body. Skin irritation test has typically been performed using in vivo models. Recently, alternative in vitro test method for assessing skin irritation potential in medical device extracts have been developed using a Reconstructed Human Epidermis (RhE) models to reduce in vivo test. The results of the in vitro method international round robin study show that it can be useful for correctly estimating the irritation potency of medical device extracts. Based on these results, the latest of MHLW Notification, an attachment “Guidance on test methods for biological safty evaluation of medical devices”, Part 5 “Irritation Test” has adopted the new in vitro test method for skin irritation test. It is an alternative to the primary skin irritation test. However, it is desired that the in vitro test will be improved to detect irritation response quantitatively, as the same with in vivo tests.
Guidance on hemocompatibility testing for Biological Safety Evaluation of Medical Devices in Japan was revised to make it more practical. Due to the characteristics of hemocompatibility testing for medical devices, there are no testing methods and protocols applicable to almost all medical devices, except material-induced hemolysis testing. There was also little information on the testing in Japan. They would make harder for the users in Japan to understand what testing should be conducted as hemocompatibility testing. Therefore, the revised guidance puts the highlight on providing the information so that the users can understand the risk related to the hemocompatibility of medical devices and design the testing according to it appropriately. This paper provides the explanation on the major modified points in the guidance. These information would be helpful to design the hemocompatibility testing for each medical device as well as to understand the guidance.
Medical devices that come into contact with human body need to be evaluated for the biological safety according to ISO 10993 series. Although the ISO 10993 series defines several biological safety tests including cytotoxicity, irritation and sensitization tests, ISO 10993-1 “Evaluation and testing within a risk management process” requires that information on the chemical properties of biomaterials must be collected before conducting tests. The scheme for chemical characterization of biomaterials and the concept of toxicological threshold of concern (TTC) that may be able to promote animal welfare and reduce the testing costs are newly specified in ISO 10993-18 and ISO/TS 21736, respectively, and hence, chemical analysis for biological safety assessment is expected to be increasingly used in the near future. Chemical analysis is very useful for assessing elution amounts from medical devices and the exposure amounts to human when the target chemical is known. On the other hand, since raw material suppliers do not disclose all compositions including impurities, available information for chemical analysis is limited. Therefore, TTC approach is used for comprehensive qualitative and quantitative analyses for medical devices, but there are several and critical problems in current extractables and leachables (E & L) analysis using for the approach. In this section, the problems of the current E & L analysis are introduced, such as the concept of hazard analysis, sensitivity for detection, analysis method and so on. In addition, we propose a strategic analysis package that is different from current E & L analysis and available as alternative for genotoxicity and sensitization tests, according to TTC approach and the novel concept for dermal sensitization threshold (DST).
The Pharmaceuticals and Medical Devices Agency (PMDA) is regulatory agency in Japan and reviews for marketing approval of pharmaceuticals and medical devices. In accordance with the Pharmaceutical Affairs Act, PMDA evaluates the efficacy, safety, and quality of drugs and medical devices for which applications have been submitted for regulatory approval, based on the current scientific and technological standards. The biological evaluation of any material or medical device intended for use in humans should part of a structured biological evaluation plan within a risk management process. When assessing new medical devices, the sponsor should evaluate the biological responses that are regarded as adverse, caused by materials in one application. This paper described how the sponsor should approach to the biological evaluation on medical devices.