Biological evaluation of medical devices -
Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity
1 Scope
This part of GB/T 16886 specifies strategies for risk estimation, selection of hazard (sources) identification tests and risk management, with respect to the possibility of the following potentially irreversible biological effects arising as a result of exposure to medical devices:
- genotoxicity;
- carcinogenicity;
- reproductive and developmental toxicity.
This part is applicable when the need to evaluate a medical device for potential genotoxicity, carcinogenicity, or reproductive toxicity has been established.
Note: Guidance on selection of tests is provided in ISO 10993-1.
2 Normative references
The following documents, in whole or in part, are normatively referenced in this document and are indispensable for its application. For dated references, only the edition cited applies. For undated references, the latest edition of the referenced document (including any amendments) applies.
ISO 10993-1 Biological evaluation of medical devices - Part 1 : Evaluation and testing within a risk management process
ISO 10993-2 Biological evaluation of medical devices - Part 2 : Animal welfare requirements
ISO 10993-6 Biological evaluation of medical devices - Part 6 : Tests for local effects after implantation
ISO 10993-12 Biological evaluation of medical devices - Part 12 : Sample preparation and reference materials
ISO 10993-18 Biological evaluation of medical devices - Part 18 : Chemical characterization of materials
OECD 414 Prenatal Development Toxicity Study)
OECD 415 One-Generation Reproduction Toxicity Study
OECD 416 Two-Generation Reproduction Toxicity
OECD 421 Reproduction/Developmental Toxicity Screening Test
OECD 451 Carcinogenicity Studies
OECD 453 Combined Chronic Toxicity/Carcinogenicity Studies
OECD 471 Bacterial Reverse Mutation Test
OECD 473 In vitro Mammalian Chromosome Aberration Test
OECD 476 In Vitro Mammalian Cell Gene Mutation Tests using the Hprt and Xprt genes
OECD 487 In Vitro Mammalian Cell Micronucleus Test
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 10993-1, ISO 10993-12 and the following apply.
3.1
carcinogenicity test
test to determine the carcinogenic potential of medical devices, materials, and/or extracts using multiple exposures for a major portion of the life span of the test animal
3.2
energy-depositing medical device
device intended to exert its therapeutic or diagnostic effect by the delivery of electromagnetic radiation, ionising radiation or ultrasound
Note: This does not include medical devices that deliver simple electrical current, such as electrocautery medical devices, pacemakers or functional electrical stimulators.
3.3
genotoxicity test
test using mammalian or non-mammalian cells, bacteria, yeasts, fungi or whole animals to determine whether gene mutations, changes in chromosome structure, or other DNA or gene changes are caused by the test samples
3.4
maximum tolerated dose; MTD
maximum dose that a test animal can tolerate without any adverse effects
3.5
reproductive and developmental toxicity test
test to evaluate the potential effects of test samples on reproductive function, embryonic morphology (teratogenicity), and prenatal and early postnatal development
3.6
test sample preparation
residual, extractables, leachables or biodegradable device materials that are resuspended in a vehicle compatible with the test system
4 Requirements for test strategies
4.1 General
ISO 10993-1 indicates circumstances where the potential for genotoxicity, carcinogenicity and reproductive toxicity is a relevant hazard for consideration in an overall biological safety evaluation. Testing to investigate these hazards shall be justified on the basis of a risk assessment. In determining if genotoxicity, carcinogenicity and reproductive toxicity testing of the device is warranted an assessment of risk shall address the following factors
- an analysis of the chemical constituents of the device material(s), including manufacturing process residues and degradation products or metabolites, to identify causes of concern on the basis of structure-activity relationships or previous demonstration of relevant toxicity in the chemical class,
- the mechanistic basis of the toxic response under consideration, if available,
- existing information relevant to the genotoxicity, carcinogenicity and reproductive toxicity evaluation of the medical device,
- the extent of previous use of comparable materials in relevant applications,
- consideration of residuals from the final finished device with respect to how well they are characterized and their potential biological activity (e.g. structure-activity relationships, or previous demonstration of relevant outcomes),
- exposure route,
- patient population,
- extent and duration of localized (at the site of implantation or use) and systemic exposure,
- the anticipated impact of test results (or lack of testing) on risk management judgements, and
- changes in the type or amount of residuals that the patient will be exposed to, either through an increase in device exposure, or an increase in devices size when compared to an equivalent device.
Commonly used risk assessment tools [e.g. TTC[) TTC is short for Threshold toxicological concern.])] may be helpful in evaluating these factors.
Where an analysis of the composition of device materials reveals the presence of chemical constituents that are of concern but for which inadequate toxicity data are available, consideration shall be given to testing individual chemical. Individual chemicals shall be tested in preference to compounded materials or extracts, where this would improve the risk estimate. Where testing of a device material is indicated testing shall be conducted on the final product (including sterilization if applicable), or representatives from the final products, or materials processed in the same manner as the final product (including sterilization if applicable). The decision to test, and the nature of the test sample, shall be justified and documented.
Testing may be warranted for additional states of the device such as, wear debris generated from the device or materials that cure in situ (e.g. cements, adhesives and pre-polymer mixtures) unless toxicological risk assessment determines no cause for concern from additional device/material states. For guidance on in situ curing devices see ISO 10993-12.
4.2 Additional requirements for carcinogenicity testing
For carcinogenicity testing, in addition to 4.1, the following factors shall be addressed:
- physical characteristics (e.g. particle size and shape, pore size, surface continuity, surface condition, device thickness);
- results from genotoxicity, implantation and other studies.
4.3 Additional requirements for reproductive toxicity testing
For reproductive testing, in addition to 4.1, the total direct or indirect cumulative contact duration with reproductive tissue, the embryo/foetus or the germ cells shall be addressed.
Any information from published literature on the effect of device materials on male/female reproductive organs or from subacute/chronic study on the histopathology of reproductive system should also form the basis before a full scale reproductive toxicity testing is performed.
Biological evaluation of medical devices -
Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity
1 Scope
This part of GB/T 16886 specifies strategies for risk estimation, selection of hazard (sources) identification tests and risk management, with respect to the possibility of the following potentially irreversible biological effects arising as a result of exposure to medical devices:
- genotoxicity;
- carcinogenicity;
- reproductive and developmental toxicity.
This part is applicable when the need to evaluate a medical device for potential genotoxicity, carcinogenicity, or reproductive toxicity has been established.
Note: Guidance on selection of tests is provided in ISO 10993-1.
2 Normative references
The following documents, in whole or in part, are normatively referenced in this document and are indispensable for its application. For dated references, only the edition cited applies. For undated references, the latest edition of the referenced document (including any amendments) applies.
ISO 10993-1 Biological evaluation of medical devices - Part 1 : Evaluation and testing within a risk management process
ISO 10993-2 Biological evaluation of medical devices - Part 2 : Animal welfare requirements
ISO 10993-6 Biological evaluation of medical devices - Part 6 : Tests for local effects after implantation
ISO 10993-12 Biological evaluation of medical devices - Part 12 : Sample preparation and reference materials
ISO 10993-18 Biological evaluation of medical devices - Part 18 : Chemical characterization of materials
OECD 414 Prenatal Development Toxicity Study)
OECD 415 One-Generation Reproduction Toxicity Study
OECD 416 Two-Generation Reproduction Toxicity
OECD 421 Reproduction/Developmental Toxicity Screening Test
OECD 451 Carcinogenicity Studies
OECD 453 Combined Chronic Toxicity/Carcinogenicity Studies
OECD 471 Bacterial Reverse Mutation Test
OECD 473 In vitro Mammalian Chromosome Aberration Test
OECD 476 In Vitro Mammalian Cell Gene Mutation Tests using the Hprt and Xprt genes
OECD 487 In Vitro Mammalian Cell Micronucleus Test
3 Terms and definitions
For the purposes of this document, the terms and definitions given in ISO 10993-1, ISO 10993-12 and the following apply.
3.1
carcinogenicity test
test to determine the carcinogenic potential of medical devices, materials, and/or extracts using multiple exposures for a major portion of the life span of the test animal
3.2
energy-depositing medical device
device intended to exert its therapeutic or diagnostic effect by the delivery of electromagnetic radiation, ionising radiation or ultrasound
Note: This does not include medical devices that deliver simple electrical current, such as electrocautery medical devices, pacemakers or functional electrical stimulators.
3.3
genotoxicity test
test using mammalian or non-mammalian cells, bacteria, yeasts, fungi or whole animals to determine whether gene mutations, changes in chromosome structure, or other DNA or gene changes are caused by the test samples
3.4
maximum tolerated dose; MTD
maximum dose that a test animal can tolerate without any adverse effects
3.5
reproductive and developmental toxicity test
test to evaluate the potential effects of test samples on reproductive function, embryonic morphology (teratogenicity), and prenatal and early postnatal development
3.6
test sample preparation
residual, extractables, leachables or biodegradable device materials that are resuspended in a vehicle compatible with the test system
4 Requirements for test strategies
4.1 General
ISO 10993-1 indicates circumstances where the potential for genotoxicity, carcinogenicity and reproductive toxicity is a relevant hazard for consideration in an overall biological safety evaluation. Testing to investigate these hazards shall be justified on the basis of a risk assessment. In determining if genotoxicity, carcinogenicity and reproductive toxicity testing of the device is warranted an assessment of risk shall address the following factors
- an analysis of the chemical constituents of the device material(s), including manufacturing process residues and degradation products or metabolites, to identify causes of concern on the basis of structure-activity relationships or previous demonstration of relevant toxicity in the chemical class,
- the mechanistic basis of the toxic response under consideration, if available,
- existing information relevant to the genotoxicity, carcinogenicity and reproductive toxicity evaluation of the medical device,
- the extent of previous use of comparable materials in relevant applications,
- consideration of residuals from the final finished device with respect to how well they are characterized and their potential biological activity (e.g. structure-activity relationships, or previous demonstration of relevant outcomes),
- exposure route,
- patient population,
- extent and duration of localized (at the site of implantation or use) and systemic exposure,
- the anticipated impact of test results (or lack of testing) on risk management judgements, and
- changes in the type or amount of residuals that the patient will be exposed to, either through an increase in device exposure, or an increase in devices size when compared to an equivalent device.
Commonly used risk assessment tools [e.g. TTC[) TTC is short for Threshold toxicological concern.])] may be helpful in evaluating these factors.
Where an analysis of the composition of device materials reveals the presence of chemical constituents that are of concern but for which inadequate toxicity data are available, consideration shall be given to testing individual chemical. Individual chemicals shall be tested in preference to compounded materials or extracts, where this would improve the risk estimate. Where testing of a device material is indicated testing shall be conducted on the final product (including sterilization if applicable), or representatives from the final products, or materials processed in the same manner as the final product (including sterilization if applicable). The decision to test, and the nature of the test sample, shall be justified and documented.
Testing may be warranted for additional states of the device such as, wear debris generated from the device or materials that cure in situ (e.g. cements, adhesives and pre-polymer mixtures) unless toxicological risk assessment determines no cause for concern from additional device/material states. For guidance on in situ curing devices see ISO 10993-12.
4.2 Additional requirements for carcinogenicity testing
For carcinogenicity testing, in addition to 4.1, the following factors shall be addressed:
- physical characteristics (e.g. particle size and shape, pore size, surface continuity, surface condition, device thickness);
- results from genotoxicity, implantation and other studies.
4.3 Additional requirements for reproductive toxicity testing
For reproductive testing, in addition to 4.1, the total direct or indirect cumulative contact duration with reproductive tissue, the embryo/foetus or the germ cells shall be addressed.
Any information from published literature on the effect of device materials on male/female reproductive organs or from subacute/chronic study on the histopathology of reproductive system should also form the basis before a full scale reproductive toxicity testing is performed.
