医疗器械生物学评价和审查指南

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Official Full Text

Guidance on Biological Evaluation and Review of Medical Devices

1. Purpose and Scope

To ensure the correct and effective implementation of GB/T 16886 – ISO 10993 series standards, this guide has been developed.

This guide provides a biological evaluation guide for medical device evaluators and a biological safety review guide for the examination of medical devices.

Note: This guide does not cover biological safety aspects such as microbial contamination, sterilization (e.g., "sterile", "bacterial endotoxin"), disinfection, and the removal and control of viruses from animal-derived medical devices.

2. Terminology

(1) Medical Devices: In accordance with the "Medical Device Management Regulations."

(ii) Manufacturer: The manufacturer of the medical device or the trademark holder/entity.

(iii) Evaluator: The manufacturer of the medical device or a qualified expert acting on their behalf. Note: The manufacturer of the medical device is responsible for the biocompatibility evaluation.

(iv) Reviewer: The administrative department or institution authorized to oversee medical device management, or an institution delegated by such a department to conduct medical device review.

3. Initial Biocompatibility Evaluation of Medical Devices/Materials

(1) Evaluation Basis GB/T 16886 – ISO 10993 "Biological Evaluation of Medical Devices" series of standards.

(2) Evaluator Should have received training and have extensive practical experience in biological evaluation of medical devices.

（Three）Evaluation Requirements

1. Medical devices requiring biological evaluation for human protection purposes shall not enter clinical trials prior to the completion of the biological evaluation (particularly necessary animal studies).
2. When conducting a biological evaluation for a medical device, the evaluation process specified in GB/T 16886.1 – ISO 10993.1 should be followed.
3. During the biological evaluation, the evaluator should focus on utilizing existing information (including materials, literature, in vitro and in vivo test data, and clinical experience), and should not be limited to biological testing.
4. When the biological evaluation determines that biological testing is required, it should be conducted by a testing organization with the appropriate biological testing qualifications.
5. When conducting biological testing, the following should be observed: (1) Conduct in vitro testing prior to animal testing; (2) Fully and reasonably utilize the available animal resources, optimize the testing scheme, and reduce testing costs.
6. The requirements for reporting, as specified in GB/T 16886 – ISO 10993 series standards, should be met by issuing a "Biological Testing Report." Note: The Biological Testing Report does not necessarily need to be issued together with the Type Approval Report.
7. The "Biological Evaluation Report" may consider (but not be limited to) the following aspects: (1) The strategy and procedures for the biological evaluation of the medical device; (2) A description of the selection of materials used in the medical device; (3) Characterization of materials: - Qualitative and quantitative description or analysis of the materials used in the medical device; - Comparison of the materials used in the medical device with commercially available products; (4) The reasons and justification for selecting or abandoning biological testing; (5) Summarization of existing data and test results; (6) Other data required to complete the biological evaluation.

4. Biocompatibility Re-evaluation of Medical Devices

(1) Manufacturers should consider conducting a biocompatibility re-evaluation under the following circumstances:    1. When the source or technical conditions of materials used in the product change;    2. When the product's formulation, process, primary packaging, or sterilization method changes;    3. When the final product changes during its shelf life;    4. When the product's intended use changes;    5. When there is evidence that the product may cause adverse reactions when used on humans.    If a company submits a statement indicating that none of the circumstances specified in paragraph (1) of item 4 have occurred, a biocompatibility evaluation is not required during the re-registration of the product. When the national standards, industry standards, and the series of GB/T 16886-ISO 10993 standards are revised, if a company submits a statement indicating that none of the circumstances specified in paragraph (1) of item 4 have occurred, a supplementary biocompatibility evaluation is not required during the re-registration of the product.

(2) When re-evaluating, it should primarily utilize clinical evaluation information, clinical research information, and clinical adverse event information. Re-evaluation should be conducted based on the documents established in the previous evaluation to avoid unnecessary biological testing. Re-evaluation should be carried out in accordance with the procedures specified in Article 3. Depending on the specific circumstances, re-evaluation can be comprehensive or focused on a particular aspect, but the evaluation content should be documented.

5. Medical Device Biological Safety Evaluation

(1) Evaluators Evaluators should have received training in accordance with GB/T 16886.

(2) Evaluation Basis GB/T 16886 – ISO 10993 "Biological Evaluation of Medical Devices" series standards.

(3) Review Requirements

1. The level of biological safety review should be determined based on the intended use and the magnitude of the biological hazards of the product, as described in the product's instructions for use. Expert opinions should be sought when necessary.
2. The primary subject of the review is the "Biological Evaluation Report for Medical Devices."
3. As an output of the biological safety review, each conclusion should, where possible, cite the relevant clauses of GB/T 16886.1 – ISO 10993.1. Note: For details on the requirements for preparing the "Biological Evaluation Report for Medical Devices," please refer to Annex 2.

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Biological Evaluation Report for Medical Devices: Requirements and Key Points

1. Strategy and Procedures for Biological Evaluation of Medical Devices

The biological evaluation procedure for medical devices should be carried out according to the evaluation flowchart specified in GB/T 16886.1 – ISO 10993.1. Due to the diversity and special nature of medical devices, the actual routes taken by each medical device during the biological evaluation process may differ from the flowchart. Therefore, the specific routes taken should be described in detail.

2. Description of Materials Used in Medical Devices

3. Material Characterization

(1) Qualitative and Quantitative Description or Analysis of Medical Device Materials

The reviewer must have access to information regarding the composition of the materials used in the medical device. The manufacturer is obligated to provide detailed information about the formulation and/or source of the materials selected for the medical device. Information regarding the materials must be obtained from at least one of the following sources:

1. Accepted chemical name of the material;
2. Physicochemical properties of the material;
3. Information regarding the composition of the material obtained from the material supplier;
4. Information regarding the composition of processing aids obtained from the manufacturer of the medical device;
5. Chemical analysis;
6. Relevant standards.

Note: The use of materials that have been approved by the relevant authority and have corresponding standards provides a greater assurance of biocompatibility compared to materials that have not been approved.

(二) Comparison of Medical Devices/Materials with Marketed Products

The purpose of comparing a device/material with a marketed product is to demonstrate that the device/material has the same biological safety as the marketed product, thereby establishing whether the biological evaluation and/or testing of the device/material can be reduced or waived.

The comparison of a device/material with a marketed product is primarily divided into two aspects. First, it involves comparing whether the materials and uses of the device/material are the same. Since the materials and uses of medical devices play a decisive role in their biological safety, if it can be proven that the materials and uses of the device under registration are equivalent to those of the marketed product, it indicates that the device under registration has the most basic biological safety guarantee. However, this is not sufficient to prove that the device under registration is completely equivalent to the marketed product. It is also necessary to demonstrate that the manufacturing processes (processing, sterilization, packaging, etc.) of the two are the same, because the manufacturing process may also introduce new harmful substances (residual sterilants, processing aids, demolding agents, etc.).

Comparing a device/material with similar products, materials, and manufacturing processes involves comparing not only whether the two materials are completely equivalent, but also from a toxicological perspective. The principle of comparing materials with similar products is that the materials and manufacturing processes used should have a biological safety level that is no lower than that of the biological safety of the clinically acceptable materials of the same type. To demonstrate that a medical device and/or material under registration is equivalent to a marketed medical device and/or material, appropriate evidence must be provided. The following examples, as provided in ISO 10993-18, can demonstrate biological equivalence:

1. The components and leachables of the proposed material are equivalent to those of clinically established materials;
2. The proposed material is consistent with the materials specified in the current standards, and the proposed material meets the uses, contact times, and levels specified in the current standards;
3. The proposed material has a clinical application history with a higher contact level than its proposed contact method;
4. The limit of leachables in the proposed material does not exceed the limits specified in GB/T 16886.17 – ISO 10993.17;
5. The chemical substances or residues in the proposed material are more toxicologically safe than the clinically established materials it replaces (

4. Reasons and Justification for Selecting or Abandoning Biological Testing

Evaluation may include information from prior studies and actual testing. If the materials used in the medical device design have a documented history of use in specific applications, the results of such evaluation may not require further testing.

Due to the diversity of medical devices, not all of the tests recommended in GB/T 16886.1 – ISO 10993.1 Tables 1 and 2 may be necessary or feasible for any particular medical device. It is important to consider which tests are appropriate based on the specific characteristics of the medical device. Other tests not mentioned in the table may also be necessary.

Documentation should be maintained regarding the tests considered, the reasons for selecting or rejecting them. Historical data from previous studies and materials can be used as justification for rejecting tests, but this data must be included.

5. Summary of Existing Data and Test Results

(1) Retrieval and Review of Relevant Domestic and International Literature

The retrieval and review of relevant literature is a crucial prerequisite for ensuring the quality of the evaluation. Based on the retrieval and review of relevant materials, the efficiency of biological evaluation of medical devices, conducted by biological experts with theoretical knowledge and experimental experience, is the highest. Therefore, the quantity of relevant biological documents retrieved is an important aspect that reflects the reliability and correctness of the biological evaluation conclusions for medical devices.

(ii) Reports on previously conducted biological testing and newly conducted biological testing (if any) Biological testing shall be conducted by an organization with the necessary biological testing qualifications, in accordance with GB/T 16886 – ISO 10993 series standards, and a report shall be issued.

6. Additional data required for the biological evaluation.

(1) Test data performed according to standards: This includes type testing and routine testing data that demonstrate material consistency through chemical analysis data (quantitative and qualitative) and physical characterization data (such as density, hardness, tensile strength, etc.).

(ii) Relevant clinical use information and/or clinical study conclusions

Currently, biological testing relies on animal models. The tissue reactions observed in animals may not necessarily occur in humans. Even materials that have been proven to be the best may cause adverse reactions in some individuals due to differences between humans. Therefore, after a medical device has undergone biological evaluation, it is necessary to further validate its safety for human use through clinical trials. Therefore, when clinical evaluation data is available for a medical device, fully utilizing clinical data for biological safety evaluation is an important way to improve the evaluation quality. When evaluating a medical device that already has clinical data, it is important to fully utilize the available clinical information for evaluation, rather than requiring animal testing.

Clinical data for medical devices/materials are primarily obtained from:

1. Published clinical research reports for the relevant medical device/material, both domestically and internationally;
2. Clinical research on the medical device conducted in accordance with the "Regulations for Clinical Trials of Medical Devices" prior to market approval;
3. Data obtained from clinical use of the medical device after market approval, including reports and records of adverse events.