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GB/T 16886.3-2019 PDF in English

GB/T 16886.3-2019 (GB/T16886.3-2019, GBT 16886.3-2019, GBT16886.3-2019)
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GB/T 16886.3-2019: PDF in English (GBT 16886.3-2019)

GB/T 16886.3-2019
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)
Published on.2019-06-04
2020-01-01 implementation
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
1 Scope
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;
--- Carcinogenicity;
--- 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
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.
Carcinogenicity test
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.
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.
Maximum tolerated amount maximumtolerateddose; MTD
The maximum dose that the test animal can tolerate without any adverse reactions.
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.
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
4.1 General
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)
--- 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
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
5.1 General
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
5.2.1 General
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. [35], 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 following step-by-step procedures should be applied, see also Appendix B.
Step 1. Identification of the influencing factors of the initial test group results of genotoxicity, if possible.
a) Identification of influencing factors (eg non-physiological conditions, interaction between test samples and media, auto-oxidation and cytotoxicity).
b) Identification of metabolic effects (eg characteristics of exogenous metabolic systems, characteristics of metabolism, abnormal metabolites).
c) Identification of impurities by chemical characterization (ie material composition studies or analytical tests).
Step 2. Evidence weight (WOE) assessment and mode of action (MOA) to be considered for each identified factor.
a) Whether it is direct DNA or indirect DNA reaction.
b) Aneuploidy and polyploidy problems. Whether it involves an aneuploidy mechanism.
Step 3. Determine the point.
Determine if the medical device extract or the chemical of interest is a genotoxic substance if.
a) Interpretation of results within the framework of the toxicological risk assessment and WOE/MOA analysis suggest that there is a low/can be available for patients who are expected to use the device
Ignore the risk; or
b) Interpretation of results within the framework of the toxicological risk assessment and WOE/MOA analysis suggest that patients who are expected to use the device may have potential
At risk.
If the result is determined to be a), no additional tests or evaluations are required.
If the result of the determination is b), proceed to step 4.
Step 4. Conduct risk management.
Risk management according to the risk of genotoxicity (source) or selection of appropriate in vitro and/or in vivo follow-up trials.
Step 5. Select and perform additional in vitro and/or in vivo tests.
The corresponding in vivo test should be selected based on the most appropriate endpoint identified in the in vitro test.
Commonly used in vivo tests include.
--- OECD474 gives the rodent in vivo micronucleus test;
--- OECD475 gives an intermediate analysis of rodent bone marrow;
--- OECD488 gives a transgenic gene mutation test.
The selection decisions for the most appropriate test system should be demonstrated and documented.
Note. Recently, the draft OECD 489 guideline has developed a genotoxicity test for the detection of basic single-cell gels of chemicals acting on rodents.
Swimming (comet) test. This test may provide useful information for medical device testing.
An attempt should be made to confirm that the test sample has reached the target organ. For rodent in vivo micronucleus test or rodent bone marrow mid-term analysis
Test, one of the following methods can be used to demonstrate bioavailability.
--- Quantitative analysis of specific extract compounds in blood or serum;
--- Test leachate induces bone marrow cytotoxicity;
--- Intravenous approach (polar medium).
If contact with the target organ cannot be confirmed, the next in vivo test should be performed in another target organ to verify no in vivo genotoxicity.
Step 6. Reinterpret all accumulated data and determine if the test sample is genotoxic.
In some cases, positive results in in vitro tests may not be relevant. The following should be considered to determine the results of all in vitro tests
Relevance. The items listed are not comprehensive but help to judge the process.
a) only one of the first two in vitro tests was positive;
b) that further in vitro studies at the end of a similar mechanism cannot determine positive results;
c) Mechanism of action indicates that positive results in vitro are not related to in vivo conditions (eg high cytotoxicity, osmotic pressure, etc.);
d) In vivo tests with evidence that the test sample reached the target organ showed no genotoxic effects.
All evidence weight (WOE) analysis and interpretation of all data sets should be documented along with their conclusions. In some cases, it may be necessary
Site-specific or genetic endpoint specificity tests were performed. In most cases, these trials do not have an internationally accepted protocol.
5.3 Sample preparation
Unless the sample is soluble in a solvent compatible with the test system, the concentration of genotoxic residues in the material or medical device should be sufficient
Select a suitable extraction solvent based on the maximum leaching capacity level of the positive reaction in the test system, but no instrument or test sample
Degradation of the product. The extraction medium of the test system should be selected on the basis of compatibility with the genotoxicity test. Respond to the final product (including sterilization, such as
a solution, suspension of a chemical component of the device material, instrument component or device (eg Method A in Appendix A), extract (eg Appendix A)
The method C) or the rigorous extract (as in Method B in Appendix A) is tested.
Unless otherwise demonstrated, the device material should include all final formulations and processing. It is usually not suitable to test with raw materials.
Because the formulation and processing may change the potential toxicity of the final product of the device.
The rationale for selecting a chemical component for testing should be demonstrated and documented. Reasons should include consideration of interactions and synergies.
If applicable, the test material should be leached with two solvents in accordance with ISO 10993-12 or Appendix A.
Any decision to use only one solvent to reduce the test should be justified and documented.
6 carcinogenicity test
6.1 General
The requirements of ISO 10993-1 should be considered before determining the carcinogenicity test. Should cause cancer in the evaluation of medical device use
On the basis of the risk, the decision to conduct the test is demonstrated. If the new carcinogenicity test data is not generated, if the risk can be charged
If assessed or managed, no carcinogenicity test should be performed.
The carcinogenicity test can be designed to detect both chronic toxicity and carcinogenicity in a single study. When evaluating slow in a single study
In the case of sexual toxicity and carcinogenicity, special care must be taken during the study design phase to ensure that the dosage group is appropriate. This helps prevent the whole from being chronic/accumulated
Unexpired death due to physical toxicity or minimizing mortality, ensuring that surviving animals are obtained by the end of the study (ie normal life)
The level of statistical evaluation of the data.
Note. A suitable in vitro cell transformation system can be used for carcinogenic pre-screening, such as the Syrian Hamster Embryo (SHE) cell transformation test given by OECD214.
And Balb3T3 cell transformation test. A description of the test system is given in Appendix C, and additional information on the cell transformation test system is given in Appendix D.
6.2 Evaluation Strategy
Scientific demonstration of the carcinogenicity test of genotoxic materials should be carried out. For genotoxic materials, most cases can be presumed to be
Cancer risk (source) and risk management.
In the absence of evidence to rule out the risk of carcinogenicity of non-genotoxic materials, consideration should be given to the conduct of carcinogenicity tests, which may include
the following.
--- Materials with a degradation time of more than 30d;
--- Materials that have entered the human body and/or body cavity for more than 30 days.
The circumstances in which no test is required after the argument include.
--- Materials with a large and sufficient body application or contact data;
--- Materials expected to cause solid carcinogenicity (as specified in Appendix E);
--- Other circumstances that are limited by methodological studies or that are predictive of low value.
In order to determine whether a device has a large history of human use, the assessment should include whether the device undergoes a similar processing process,
Evaluations for similar patient populations, for similar sites of action, and for shorter or similar cumulative action times. Human history
Documented to indicate whether the information was obtained from the monitoring of adverse events and specific cancer risk in the use group.
When considering whether a carcinogenicity study should be conducted, the role of the study in assessing human risk should be explained and the need for the study should be addressed.
Demonstration of sexuality and research design. The argument should consider the uncertainty of implanted carcinogenicity studies in biological safety assessments,
And you need to use a lot of animals.
If chronic toxicity and carcinogenicity are considered in accordance with ISO 10993-1 and it is determined that testing is necessary, if feasible,
OECD453 was tested.
If it is only necessary to consider the carcinogenicity study according to ISO 10993-1 and determine that the test is required, it should be carried out in accordance with OECD451.
An animal species is sufficient to test the carcinogenicity of a medical device. Animal species should be selected and documented in accordance with ISO 10993-2.
6.3 Sample preparation
When a carcinogenicity test is required as part of a biological safety assessment, materials, definitive chemicals or chara......
Source: Above contents are excerpted from the PDF -- translated/reviewed by: www.chinesestandard.net / Wayne Zheng et al.