Preamble ........................

This guideline provides registration applicants/regulators with information on the biocompatibility/toxicological evaluation of medical devices using nanomaterials.

These guidelines are general requirements for the biocompatibility/toxicological evaluation of medical devices using nanomaterials. The applicant for registration should fully explain and refine the content of the registration submission according to the characteristics of the specific product. The applicant for registration should also determine whether the specific content is applicable according to the characteristics of the specific product, and if not, the reasons and corresponding scientific basis should be elaborated in detail.

Scope of application

This guideline applies to the biocompatibility/toxicological evaluation of medical devices that are in direct or indirect contact with the human body and are composed of or contain nanomaterials.

Not applicable:

- In Vitro Diagnosis (IVD) products applying nanomaterials;

- Enabling technologies (e.g. nanorobots) applying nanomaterials;

- Pharmaceutical products using nanomaterials;

- Occupational and environmental risks associated with the manufacture and disposal of medical devices using nanomaterials.

Biocompatibility/Toxicological Evaluation

Evaluation of biocompatibility/toxicology of medical devices applying nanomaterials includes a range of studies such as literature reviews, bioinformatics, in vitro and in vivo tests. For medical devices, the selection strategy for any test is based on its intended use/scope of application. In vivo studies should be conducted using routes of exposure that are relevant to the human exposure pathway of the medical device and/or nanomaterial. All tests should be conducted in accordance with current/valid best laboratory/therapeutic practices and data should be analysed and interpreted by trained and experienced professionals. The biocompatibility/toxicological evaluation of medical devices with nanomaterial applications should be based on the following principles:

1. Principles of conducting multi-level evaluation studies

The biocompatibility/toxicology testing strategy for medical devices with nanomaterials applied is determined by their potential external and internal exposure characteristics. When physicochemical characterisation, exposure assessment, etc. determine that medical devices have the possibility of nanomaterials exposure or relevant surface interface biological effects, in addition to the corresponding tests in accordance with the GB/T 16886 series of national standards, GB/T 42062 general requirements, should also be based on the requirements of nanomaterials risk assessment, with reference to GB/T 37129, GB/Z 16886.22, in accordance with the requirements of risk identification and risk assessment related to nanomaterials The flow chart of hierarchical evaluation methods for risk identification and risk assessment related to nanomaterials should be used to carry out multi-level evaluation studies, and consider whether to add additional indicators of toxicity concern, as well as to carry out in-depth additional toxicity tests.

2. Follow the principle of case-by-case treatment

According to the requirements of GB/T 16886.1, the biological evaluation test strategies of medical devices should all be considered based on the classification of medical devices, the nature of exposure and the duration of exposure. Due to the complexity of medical devices applying nanomaterials, it is impossible for this guideline to cover all the contents of biocompatibility/toxicological evaluation of all medical devices applying nanomaterials. For a specific product, its biocompatibility/toxicological evaluation should follow the principle of case-by-case approach.  

3.Confirmation of the applicability of the test system

The dissolved or dispersed state of nanomaterials, sample preparation method, dosage design, cell line, animal species and other parameters of the test system may affect the reliability of the test results, therefore, it is necessary to confirm whether the test system is suitable for evaluating the application of nanomaterials in medical devices, such as the sample preparation method is not applicable to the application of nanomaterials in medical devices, consider using the end product of the medical device or representative samples directly to carry out the relevant tests. Tests. At present, the exclusive test methods for biological evaluation of medical devices using nanomaterials are still under development, and there are fewer test methods for reference, and the relevant standards that have been published and formally implemented include endotoxin test (YY/T 1295), cytotoxicity test (GB/T 41212, GB/T 41915, YY/T 0993), in vitro haemolysis test (YY/T 1532), and in vitro haemolysis test (YY/T 1532). ). Therefore, the registration applicant should confirm the applicability of the test system and provide biological evaluation information suitable for the characteristics of the declared product. Some in vitro tests may be useful for screening purposes and mechanism of action studies, but the use of these methods must be based on the case-by-case principle. For currently validated in vitro methods see those published by the European Centre for the Validation of Alternative Methods (EURL ECVAM).

4. Principles for characterisation of nanomaterials in biological tissues

The interaction of nanomaterials with biomolecules in biological tissues may lead to the acquisition of new ‘biological features’, i.e. new properties arising from the adsorption of biomolecules, such as proteins, on the surface (protein crowns, biocrowns), which can influence the physiological response of the body as well as the toxicological profile. Therefore, information on the actual form, properties and stability of the nanomaterials under test conditions is essential for the interpretation of any test results. Nanomaterials in biological tissues should be characterised at the beginning and end of the test (if feasible).

5. Principles for determination of toxicokinetic data

Demonstration of exposure to nanomaterials in cells and/or tissues is critical to the interpretation of study results (especially negative results), and the lack of such data may cause considerable uncertainty in drawing final conclusions. Therefore, where technically feasible, it should be determined whether the nanomaterials are distributed in specific regions of tissue or cells, specifying the amount of exposure in the test system.

The purpose of this guideline is to provide trained professionals with a common methodology for biocompatibility/toxicological evaluation of medical devices applying nanomaterials in the context of medical device evaluation, and to discuss how to design a test based on the GB/T 16886 series of standard documents, GB/Z 16886.22, and points of special consideration for medical devices applying nanomaterials in Appendix I. This includes the design of the test, cell/animal model selection, study endpoint selection, and interpretation of results.

This guideline represents the considerations and countermeasures of the regulatory authorities on the endpoints of biocompatibility/toxicological evaluation of medical devices with application of nanomaterials under the existing level of cognition. In the future, as the cognition on toxicology and nano-materials fate grows, more defects of the test methods may be revealed, and the content of this guideline will be improved with the continuous advancement of the research on biocompatibility/toxicological evaluation of nano-materials. Therefore, registration applicants are advised to pay attention to the latest advances in research and take them into account when conducting biocompatibility/toxicological evaluations of medical devices applying nanomaterials, in order to maintain a continuous update of the latest techniques for the biological evaluation of medical devices applying nanomaterials.