GB/T 16886.3-2019 English PDF (GBT16886.3-2019)
GB/T 16886.3-2019 English PDF (GBT16886.3-2019)
GB/T 16886.3-2019: Biological evaluation of medical devices -- Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity
Biological evaluation of medical devices--Part 3. Tests for genotoxicity, carcinogenicity and reproductive toxicity ICS 11.100
National Standards of People's Republic of China
Replace GB/T 16886.3-2008
Medical device biology evaluation
Part 3. Genotoxicity, carcinogenicity and
Reproductive toxicity test
(ISO 10993-3..2014, IDT)
State market supervision and administration
China National Standardization Administration issued
GB/T 16886 "Biological Evaluation of Medical Devices" consists of the following parts. --- Part 1. Evaluation and testing in the risk management process;
--- Part 2. Animal welfare requirements;
--- Part 3. Genotoxicity, carcinogenicity and reproductive toxicity test; --- Part 4. Test options for interaction with blood;
---Part 5. In vitro cytotoxicity test;
--- Part 6. Post-implantation local reaction test;
---Part 7. Ethylene oxide sterilization residue;
---Part 9. Qualitative and quantitative frameworks for potential degradation products; --- Part 10. Stimulation and skin sensitization test;
--- Part 11. Systemic toxicity test;
--- Part 12. Sample preparation and reference materials;
--- Part 13. Qualitative and quantitative determination of degradation products of polymer medical devices; --- Part 14. Qualitative and quantitative determination of ceramic degradation products; ---Part 15. Qualitative and quantitative determination of metal and alloy degradation products; ---Part 16. Design of toxicokinetic studies of degradation products and leachables; --- Part 17. The establishment of a limitable amount of leachables;
---Part 18. Chemical characterization of materials;
---Part 19. Physical chemistry, morphological and surface characterization of materials; --- Part 20. Principles and methods for immunological toxicology testing of medical devices. This part is the third part of GB/T 16886.
This part is drafted in accordance with the rules given in GB/T 1.1-2009. This part replaces GB/T 16886.3-2008 "Medical evaluation of medical devices - Part 3. Genotoxicity, carcinogenicity and reproductive toxicity Sex test. Compared with GB/T 16886.3-2008, the main technical changes except editorial changes are as follows. --- Change the test strategy by increasing in vivo testing and subsequent evaluation; --- Add Appendix A "Guidelines for selecting suitable sample preparation procedures in genotoxicity tests"; --- Add further in vitro and in vivo tests to assess the genotoxic potential of medical devices; --- Added Appendix B "Follow-up Evaluation Flow Chart";
--- The original Appendix C was changed to Appendix E, "Implantation studies for consideration of carcinogenicity studies" and developed specifications; --- Added Appendix F "In vitro Embryonic Toxicity Test".
This section uses the translation method equivalent to ISO 10993-3.2014 "Medical Device Biological Evaluation Part 3. Genotoxicity, Carcinogenicity Sexual and reproductive toxicity test.
The documents of our country that have a consistent correspondence with the international documents referenced in this part are as follows. --- GB/T 16886.1-2011 Biological evaluation of medical devices - Part 1. Evaluation and testing in the process of risk management (ISO 10993-1.2009, IDT)
--- GB/T 16886.2-2011 Biological evaluation of medical devices - Part 2. Animal welfare requirements (ISO 10993-2..2006, IDT) --- GB/T 16886.6-2015 Biological evaluation of medical devices - Part 6. Post-implantation partial response test (ISO 10993-6. 2007, IDT)
--- GB/T 16886.12-2017 Medical Device Biology Evaluation Part 12. Sample Preparation and Reference Materials (ISO 10993- 12.2012, IDT)
--- GB/T 16886.18-2011 Biological evaluation of medical devices - Part 18. Chemical characterization of materials (ISO 10993-18.2005) Please note that some of the contents of this document may involve patents. The issuing organization of this document is not responsible for identifying these patents. This part is proposed by the State Drug Administration.
This part is under the jurisdiction of the National Technical Committee for Standardization of Medical Device Biology Evaluation (SAC/TC248). This section drafted by. Shandong Province Medical Device Product Quality Inspection Center, Sichuan University. The main drafters of this section. Hou Li, Sun Xiaoxia, Liang Jie, Yuan Wei, Li Qiu. The previous versions of the standards replaced by this section are.
---GB/T 16886.3-1997, GB/T 16886.3-2008.
Medical device biology evaluations are usually based on experience, and attention to human safety is the driving force behind their development. Such as cancer The risk of serious and irreversible effects such as the second-generation malformation is particularly noticeable to the public. In the process of providing safe medical devices, Such risks are minimized to the minimum. Assessment of mutagenic, carcinogenic and reproductive risks (sources) is an essential component of such risk control section. At present, the test methods for genotoxicity, carcinogenicity or reproductive toxicity assessment have not been well developed, and in medical devices The effectiveness of the mechanical test has also not been fully confirmed. Due to the controversy in the size and preparation of the test sample, the scientific understanding of the disease process and the confirmation of the test, the existing The method has limitations. For example, little is known about the biological significance of solid carcinogenicity, and it is expected that with advances in science and medical technology, It will change the understanding and understanding of these important toxicological effects. In the development of this document, the recommended test method is in many ways. Most acceptable. Other alternative tests are acceptable as long as they are scientifically relevant for safety assessment. When it is necessary to evaluate a specific medical device and choose a test, it can only be used between the intended human application and the device and various biological systems. A detailed assessment of potential interactions is particularly important in the field of reproductive and developmental toxicology. This part of GB/T 16886 gives test methods for testing specific biological hazards (sources) and test selection strategies. In some cases it helps to identify hazards (sources). Testing is not always necessary for the management of toxicological risks in contact with medical device materials. Or useful, but when appropriate, it is important to achieve maximum test sensitivity. There are many factors that may occur and many important factors affecting the results, such as the degree of contact with the test sample, species differences, and machinery. Or physical factors, so the results need to be assessed according to the specific situation. Medical device biology evaluation
Part 3. Genotoxicity, carcinogenicity and
Reproductive toxicity test
This part of GB/T 16886 specifies risk estimation, selection of hazard (source) identification tests and risk management strategies, as well as The possibility of touching the following potentially irreversible biological effects caused by medical devices. ---Genetic toxicity;
--- Reproductive and developmental toxicity.
This section applies to the evaluation of medical devices that have been identified as having potential genotoxic, carcinogenic or reproductive toxicity. Note. A test selection guide is given in ISO 10993-1.
2 Normative references
The following documents are indispensable for the application of this document. For dated references, only dated versions apply to this article. Pieces. For undated references, the latest edition (including all amendments) applies to this document. ISO 10993-1 Biological evaluation of medical devices - Part 1. Evaluation and testing in the process of risk management (Biologicalevalua- tionofmedicaldevices-Part 1.Evaluationandtestingwithinariskmanagementprocess) ISO 10993-2 Medical Device Biology Evaluation Part 2. Animal welfare requirements (Biologicalevaluationofmedical devices-Part 2.Animalwelfarerequirements)
ISO 10993-6 Biological evaluation of medical devices - Part 6. Post-implantation partial response test (Biologicalevaluationof medicaldevices-Part 6.Testsforlocaleffectsafterimplantation)
ISO 10993-12 Biological evaluation of medical devices - Part 12. Sample preparation and reference materials (Biologicalevaluationof medicaldevices-Part 12. Samplepreparationandreferencematerials)
ISO 10993-18 Biological evaluation of medical devices - Part 18. Chemical characterization of materials (Biologicalevaluationofmedical devices-Part 18.Chemical characterizationofmaterials)
OECD414 Embryonic Developmental Toxicity Study (PrenatalDevelopmentToxicityStudy) OECD415 Generation Reproductive Toxicity Study (One-GenerationReproductionToxicityStudy) OECD416 Second Generation Reproductive Toxicity Study (Two-GenerationReproductionToxicity) OECD421 Reproduction/DevelopmentalToxicityScreeningTest
OECD451 Carcinogenicity Studies (CarcinogenicityStudies)
OECD453 Comprehensive Chronic Toxicity, Carcinogenicity Studies (CombinedChronicToxicity/CarcinogenicityStudies) OECD471 Bacterial Reverse Mutation Test (BacterialReverseMutationTest)
OECD473 In vitro mammalian chromosome aberration test (InvitroMammalianChromosomeAberrationTest) OECD476 In vitro mammalian cell gene mutation assay using Hprt and Xprt genes (InVitroMammalian CelGeneMutationTestsusingtheHprtandXprtgenes)
OECD487 in vitro mammalian cell micronucleus test (InVitroMammalianCel MicronucleusTest) 3 Terms and definitions
The following terms and definitions defined by ISO 10993-1 and ISO 10993-12 apply to this document. 3.1
At the main stage of the life cycle of the experimental animal, the medical device, material and/or extract are repeatedly exposed to the test animal to determine its carcinogenicity. Potential test.
Energy storage medical device energy-depositingmedicaldevice
A device that relies on the release of electromagnetic radiation, ionizing radiation, or ultrasound for therapeutic or diagnostic purposes. Note. Instruments that deliver simple currents, such as electric moxibustion devices, pacemakers, or functional electrical stimulators, are not included. 3.3
Genotoxicity test genotoxicitytest
Whether mammalian or non-mammalian cells, bacteria, yeast, fungi, or whole animals are used to determine whether a test sample causes a gene mutation Experiments with changes in chromosome structure and other DNA or genetic changes. 3.4
Maximum tolerated amount maximumtolerateddose; MTD
The maximum dose that the test animal can tolerate without any adverse reactions. 3.5
Reproductive and developmental toxicity test
Tests for the potential effects of test samples on reproductive function, embryo morphology (teratogenicity), and fetal and early postnatal development were evaluated. 3.6
Test sample preparation testsamplepreparation
The residue, leachables, leachables or biodegradable device material is resuspended in a medium compatible with the test system. 4 test strategy requirements
The possible considerations for genotoxicity, carcinogenicity and the need to be considered throughout the biological safety assessment process are given in ISO 10993-1. The situation of the risk (source) of reproductive toxicity. The tests for studying these hazards (sources) should be demonstrated on the basis of risk assessment. In the determiner The following factors should be included in the risk assessment of whether the device is tested for genotoxicity, carcinogenicity and reproductive toxicity. --- Analysis of the chemical composition of the device material, including process residues and degradation products or metabolites, according to its structure - live Sexual relationships or related toxicity previously demonstrated in chemical classification to identify the cause of concern; --- If possible, consider the mechanism of toxicity;
--- There is information about the genotoxicity, carcinogenicity and reproductive toxicity of the medical device; --- The extent of prior use of comparable materials in related applications; --- Consider the degree of characterization of the final product residues of the device and their potential biological activity (eg, structure-activity relationship, or related results) Pre-argument)
--- Contact route;
--- patient group;
--- Partial (implantation or use of the site) and the degree of contact and contact cycle of the whole body; --- the expected impact of the test results (or no test) on risk management judgment; and --- The type and magnitude of the expected contact residue caused by the increase in the degree of contact with the device or the size of the device when compared to an equivalent device Change.
Commonly used risk assessment tools [eg TTC1) may be helpful in evaluating these factors. 1) TTC is an abbreviation for "Threshold toxicityological threshold".
When the compositional analysis of the material of the device indicates the presence of a chemical component of interest but lacks sufficient toxicological data, consideration should be given to each chemical. The test was carried out. Testing for each chemical should take precedence over composite or leachate testing, which will help to improve risk estimates. When a device When determining the test, the final product of the device (including sterilization, if applicable) or a representative portion of the final product, or the final product (including extinction) The bacteria, if applicable, the materials of the same processing method, the decision to conduct the test and the characteristics of the test sample shall be demonstrated and documented. The test may also be performed in other states of the instrument, such as friction debris generated from the instrument or in situ cured material (eg bone water) Mud, binder and pre-polymerization mixture, unless the toxicological risk assessment indicates that there is no need to pay attention to other conditions of the device/material. ISO 10993-12 A guide to in-situ curing instruments is given.
4.2 Additional requirements for carcinogenicity test
For carcinogenicity tests, in addition to 4.1, the following factors should be stated. ---Physical properties (such as particle size and shape, pore size, surface continuity, surface state, instrument thickness); --- Genotoxicity, implantation and other research results.
4.3 Additional requirements for reproductive toxicity testing
For reproductive toxicity tests, in addition to 4.1, the total direct or indirect relationship between the device and the reproductive tissue, embryo/fetal or germ cells should also be stated. Accumulate the contact period.
Conducting a comprehensive reproductive toxicity test should also be based on published literature on the effects of device materials on male/female reproductive organs or from emergency Sexual/chronic studies of any information obtained in histopathological studies of the reproductive system. 5 Genetic toxicity test
The requirements of ISO 10993-1 should be considered before deciding to perform a genotoxicity test. Considering the given points in 4.1~4.3 After relevant factors, the principles of the test procedure should be demonstrated and documented. The genotoxicity test is used to detect two major types of genetic damage. ---Gene mutation (point mutation);
---Chromosomal damage [structural aberrations such as translocations, small or large deletions and insertions, chromosome number aberrations (aneuploidy)]. 5.2 Test strategy
A single test could not detect all relevant genotoxic substances. Therefore, a set of in vitro tests is usually performed, under certain conditions. Perform an in vivo test.
Bacterial reverse mutation assays detect the relevant genetic toxicities produced by most genotoxic carcinogens detected in rodent trials Sexual changes, but not certain specific classes of genotoxic substances, such as halocarbons, are detected. Test materials that produce potential DNA damage in bacterial systems may not be relevant to their role in eukaryotic cells, as Therefore, unless an argument is made, the test should be carried out in a mammalian cell test system. Several commonly used mammalian cell systems include. A system for determining total chromosomal damage (in vitro assays for chromosome structure and number abnormalities), a system for determining genetic mutations (HPRT mutation assay), and a system for determining gene mutations and framing effects [mouse lymphoma thymidine kinase (tk) assay, including colony counts And size determination]. In vitro chromosomal damage and in vitro mouse lymphoma tk test yielded consistent results. Consistently recognized in the two test results A negative result was obtained in the bacterial back mutation test for genotoxic compounds. Therefore, in the standard genotoxicity test combination Among them, any combination of the chromosomal aberration test and the mouse lymphoma tk test with the bacterial back mutation test is currently considered acceptable. 5.2.2 Test combination
When performing a genotoxicity test, the test combination should include. a) The bacterial back-mutation test given in OECD471 has been modified to apply to medical devices, such as testing with instrument extracts, ISO /T R10993-33. Chapter 6 of.2015, and any of the following;
b) cytogenetic evaluation test of in vitro mammalian chromosome damage given by OECD473, modified to apply to medical devices, ISO /T R10993-33. Chapter 7 of.2015; or
c) OECD490 in vitro mouse lymphoma tk assay, including detection of small clones (slow proliferation) and large clones, modified For medical devices, according to Chapter 9 of ISO /T R10993-33.2015; or d) In vitro mammalian cell micronucleus test given by OECD487 for the detection of chromosomal damage and aneuploidy, modified For medical devices, press Chapter 8 of ISO /T R10993-33.2015.
When other relevant factors (such as genotoxic mechanisms and pharmacokinetics) may affect the genotoxic effects of a compound, In vivo testing needs to be considered after the card. In vivo chromosomal damage testing in rodent hematopoietic cells may include OECD475 Given bone marrow cell analysis of chromosomal mutations or analysis of micronuclei with bone marrow cells or peripheral blood red blood cells given in OECD474 (by ISO /T R10993-33. Chapter 10 or Chapter 11 of.2015).
Where applicable, two extracts should be used in rodent hematopoietic cells as required by ISO 10993-12 or by reference to Appendix A. In vivo chromosomal damage test. The polar medium is preferred for the intravenous route, and the non-polar medium is preferred for the abdominal route. If the user can confirm that the amount of extractables obtained from the test sample is less than fully characterized, it can cause yang in the in vivo micronucleus test. The amount of genetic toxin that is sexually responsive does not require in vivo testing. An example of cisplatin (CAS number. 15663-27-1) is given in Ref. , which shows that it causes micronuclear genetic toxicity in vivo. The positive reaction dose was 0.3 mg/kg.
5.2.3 Follow-up evaluation
If the genotoxicity test is carried out in accordance with 5.2.2 and the results of the two in vitro tests are negative, no further animal remains are required. Transmission toxicity test.
If any of the in vitro genotoxicity tests are positive, the ...