Codeofchina.com is in charge of this English translation. In case of any doubt about the English translation, the Chinese original shall be considered authoritative.
GB/T 16886 Biological Evaluation of Medical Devices consists of the following parts under the general title:
——Part 1: Evaluation and Testing within a Risk Management Process;
——Part 2: Animal Welfare Requirements;
——Part 3: Test for Genotoxicity, Carcinogenicity and Reproductive Toxicity;
——Part 4: Selection of Tests for Interactions with Blood;
——Part 5: Test for In-vitro Cytotoxicity;
——Part 6: Tests for Local Effects after Implantation;
——Part 7: Ethylene Oxide Sterilization Residuals;
——Part 9: Framework for Identification and Quantification of Potential Degradation Products;
——Part 10: Tests for Irritation and Skin Sensitization;
——Part 11: Tests for Systemic Toxicity;
——Part 12: Sample Preparation and Reference Materials;
——Part 13: Identification and Quantification of Degradation Products from Polymeric Medical Devices;
——Part 14: Identification and Quantification of Degradation Products from Ceramics;
——Part 15: Identification and Quantification of Degradation Products from Metals and Alloys;
——Part 16: Toxicokinetic Study Design for Degradation Products and Leachables;
——Part 17: Establishment of Allowable Limits for Leachable Substances;
——Part 18: Chemical Characterization of Materials;
——Part 19: Physico-Chemical Morphological and Topographical Characterization of Materials;
——Part 20: Principles and Methods for Immunotoxicology Testing of Medical Devices.
This is Part 10 of GB/T 16886.
With regards to other biological tests, there will be standards for other parts.
This standard is developed in accordance with the rules given in GB/T 1.1-2009.
This part replaces GB/T 16886.10-2005 Biological Evaluation of Medical Devices - Part 10: Tests for Irritation and Delayed Type Hypersensitivity, compared with which, the following technical changes have been made:
——The standard name is modified;
——Terms and definitions are modified (Chapter 3; Chapter 3 of 2005 edition);
——"Material identification" is cancelled (see 5.4 of 2005 edition);
——Intradermal reaction test is adjusted from annex to text (see 6.4; Annex B of 2005 edition);
——Human skin irritation test method is adjusted from text to annex (see Annex C; 6.4 of 2005 edition);
——Murine local lymph node assay is added in skin sensitization test (see 7.2);
——In vitro tests for skin irritation is added (Annex D);
——Method for the preparation of extracts from polymeric test materials is added (see Annex E).
This part is identical to ISO 10993-10: 2010 Biological Evaluation of Medical Devices - Part 10: Tests for Irritation and Skin Sensitization by means of translation.
Chinese counterparts of the international documents given as normative references in this part are:
GB/T 16886.2-2011 Biological Evaluation of Medical Devices - Part 2: Animal Welfare Requirements (ISO 10993-2: 2006, IDT)
GB/T 16886.9-2017 Biological Evaluation of Medical Devices - Part 9: Framework for Identification and Quantification of Potential Degradation Products (ISO 10993-9: 2009, IDT)
GB/T 16886.12-2017 Biological Evaluation of Medical Devices - Part 12: Sample Preparation and Reference Materials (ISO 10993-12: 2012, 1DT)
GB/T 16886.13-2017 Biological Evaluation of Medical Devices - Part 13: Identification and Quantification of Degradation Products from Polymeric Medical Devices (ISO 10993-13: 2010, IDT)
GB/T 16886.14-2003 Biological Evaluation of Medical Devices - Part 14: Identification and Quantification of Degradation Products from Ceramics (ISO 10993-14: 2001, IDT)
GB/T 16886.15-2003 Biological Evaluation of Medical Devices - Part 15: Identification and Quantification of Degradation Products from Metals and Alloys (ISO 10993-15: 2000, IDT)
GB/T 16886.18-2011 Biological Evaluation of Medical Devices - Part 18: Chemical Characterization of Materials (ISO 10993-18: 2005, IDT)
This part was proposed by China Food and Drug Administration.
This part is under the jurisdiction of the National Technical Committee on Biological Evaluation on Medical Device of Standardization Administration of China (SAC/TC 248).
The previous editions of the standard replaced by this part are as follows:
——GB/T 16886.10-2000;
——GB/T 16886.10-2005.
Introduction
This part of GB/T 16886 assesses possible contact hazards from chemicals released from medical devices, which may produce skin and mucosal irritation, eye irritation or skin sensitization.
Some materials that are included in medical devices have been tested, and their skin or mucosal irritation or sensitization potential has been documented. Other materials and their chemical components have not been tested and may induce adverse effects when in contact with human tissue. The manufacturer is thus obliged to evaluate each device for potential adverse effects prior to marketing.
Traditionally, small animal tests are performed prior to testing on humans to help predict human response. More recently, in vitro tests as well as human tests have been added as adjuncts or alternatives. Despite progress and considerable effort in this direction, a review of findings suggests that currently no satisfactory in vitro test has been devised to eliminate the requirement for in vivo testing. Where appropriate, the preliminary use of in vitro methods is encouraged for screening purposes prior to animal testing. In order to reduce the number of animals used, this part presents a step-wise approach, with review and analysis of test results at each stage. An animal test is usually required prior to human testing.
It is intended that these studies be conducted using Good Laboratory Practice and comply with regulations related to animal welfare. Statistical analysis of data is recommended and should be used whenever appropriate.
This part is intended for use by professionals, appropriately qualified by training and experience, who are able to interpret its requirements and judge the outcomes of the evaluation for each medical device, taking into consideration all the factors relevant to the device, its intended use and the current knowledge of the medical device provided by review of the scientific literature and previous clinical experience.
The tests included in this part are important tools for the development of safe products, provided that these are executed and interpreted by trained personnel.
This part is based on numerous standards and guidelines, including OECD Guidelines, U.S. Pharmacopoeia and the European Pharmacopoeia. It is intended to be the basic document for the selection and conduct of tests enabling evaluation of irritation and dermal sensitization responses relevant to safety of medical materials and devices.
Biological Evaluation of Medical Devices - Part 10: Tests for Irritation and Skin Sensitization
1 Scope
This part of GB/T 16886 describes the procedure for the assessment of medical devices and their constituent materials with regard to their potential to produce irritation and skin sensitization.
This part includes:
a) pretest considerations for irritation, including in silico and in vitro methods for dermal exposure;
b) details of in vivo (irritation and sensitization) test procedures;
c) key factors for the interpretation of the results.
Instructions are given in Annex A for the preparation of materials specifically in relation to the above tests. In Annex B several special irritation tests are described for application of medical devices in areas other than skin.
2 Normative References
The following referenced documents are indispensable for the application of this document. For dated references, only the edition cited applies. For undated references, the latest edition of the referenced document (including any amendments) applies.
GB/T 16886.1-2011 Biological Evaluation of Medical Devices - Evaluation and Testing Within a Risk Management Process (ISO 10993-1: 2009, IDT)
ISO 10993-2 Biological Evaluation of Medical Devices - Part 2: Animal Welfare Requirements
ISO 10993-9 Biological Evaluation of Medical Devices - Part 9: Framework for Identification and Quantification of Potential Degradation Products)
ISO 10993-12 Biological Evaluation of Medical Devices - Part 12: Sample Preparation and Reference Materials
ISO 10993-13 (Biological Evaluation of Medical Devices - Part 13: Identification and Quantification of Degradation Products from Polymeric Medical Devices)
ISO 10993-14 Biological Evaluation of Medical Devices - Part 14: Identification and Quantification of Degradation Products From Ceramics
ISO 10993-15 Biological Evaluation of Medical Devices - Part 15: Identification and Quantification of Degradation Products from Metals and Alloys
ISO 10993-18 Biological Evaluation of Medical Devices - Part 18: Chemical Characterization of Materials
ISO 14155-1 Clinical Investigation of Medical Devices for Human Subjects - Part 1: General Requirement
ISO 14155-2 Clinical Investigation of Medical Devices for Human Subjects - Part 2: Clinical Investigation Plants
3 Terms and Definitions
For the purposes of this document, the terms and definitions given in GB/T 16886.1-2011 and the following apply.
3.1
allergen
sensitizer
substance or material that is capable of inducing a specific hypersensitivity reaction upon repeated contact with that substance or material
3.2
blank
extraction vehicle not containing the test material, retained in a vessel identical to that which holds the test material and subjected to identical conditions to which the test material is subjected during its extraction
Note: the purpose of the blank control is to evaluate possible confounding effects due to the extraction vessel, vehicle and extraction process.
3.3
challenge
elicitation
process following the induction phase, in which the immunological effects of subsequent exposures in an individual to the inducing material are examined
3.4
dose
dosage
amount of test sample administered (e.g. mass, volume) expressed per unit of body weight or surface area
Note: the terms are often used interchangeably (more commonly dosage).
3.5
erythema
reddening of the skin or mucous membrane
3.6
eschar
scab or discolored slough of skin
3.7
extract
liquid or suspension that results from exposing a test or control material to a solvent under controlled conditions
3.8
induction
process that leads to the de novo generation of an enhanced state of immunological activity in an individual, to a specific material
3.9
irritant
agent that produces irritation
3.10
irritation
localized non-specific inflammatory response to single, repeated or continuous application of a substance/material
Note: skin irritation is a reversible reaction and is mainly characterized by local erythema (redness) of the skin.
3.11
necrosis
cell death as a direct result of irreversible changes caused by injury or disease
Note: one should be aware that tissue repair will occur either resulting in complete functional restoration or resulting in scar formation.
3.12
negative control
any well-characterized material or substance that, when tested by a specific procedure, demonstrates the suitability of the procedure to yield a reproducible, appropriately negative, non-reactive or minimal response in the test system
Note: in practice, negative controls include blanks, vehicles/solvents and reference materials.
3.13
oedema
swelling due to abnormal infiltration of fluid into the tissues
3.14
positive control
any well-characterized material or substance that, when evaluated by a specific test method, demonstrates the suitability of the test system to yield a reproducible, appropriately positive or reactive response in the test system
3.15
skin corrosion
production of irreversible damage to the skin, manifested as visible necrosis through the epidermis and into the dermis, following application of a test sample
Example: the action of a compound/chemical/test sample resulting in ulceration of skin (see 3.19).
3.16
skin sensitization
allergic contact dermatitis
immunologically mediated cutaneous reaction to a substance
Note: in the human, the responses can be characterized by pruritis, erythema, oedema, papules, vesicles, bullae or a combination of these. In other species the reactions can differ and only erythema and oedema can be seen.
3.17
test material
material, device, device portion or component thereof that is sampled for biological or chemical testing
3.18
test sample
material, device, device portion, component, extract or portion thereof that is subjected to biological or chemical testing or evaluation
3.19
ulceration
open sore representing loss of superficial tissue
3.20
vehicle
liquid used to moisten, dilute, suspend, extract or dissolve the test substance/material
4 General Principles - Step-Wise Approach
The available methods for testing irritation and sensitization were developed specifically to detect skin and mucous membrane irritation and skin sensitization potential. Other types of adverse effect are generally not predicted by these tests. For medical devices that are used as implants or external communicating devices, intradermal testing is more relevant in approaching the application and so for detection of irritation activity, intracutaneous testing shall be used as described in 6.4.
This part requires a step-wise approach, which shall include one or more of the following:
a) characterization of test material, involving chemical characterization and analysis of the test sample according to the general principles described in ISO 10993-9, ISO 10993-13, ISO 10993-14, ISO 10993-15 and ISO 10993-18;
b) literature review, including an evaluation of chemical and physical properties, and information on the irritation and sensitization potential of any product constituent as well as structurally-related chemicals and materials;
c) in accordance with ISO 10993-2, in vitro tests in preference to in vivo tests shall be considered, and replacement of the latter as new in vitro tests are scientifically validated and become reasonably and practicably available. For the evaluation of skin irritation and corrosion, in vitro alternatives are available for chemicals; there are currently no internationally validated and accepted in vitro tests to detect sensitizers;
d) in vivo animal tests: in order to ensure reproducibility and sensitivity, a test of a positive-control substance for irritation and skin sensitization shall be included in each assay by the testing laboratory in order to validate the test system and demonstrate a positive response; for guinea pig sensitization assays, however, when consistency has been demonstrated over a six month or more extended period, a positive control does not need to be included in every assay, but may be run at regular intervals which shall not exceed six months.
Note 1: sensitization can at the moment only be determined by an in vivo assay. This can be accomplished by using the local lymph node assay (LLNA) in mice, the occluded patch test in guinea pigs or the guinea pig maximization test (GPMT). For single chemicals the LLNA is now the preferred assay for determining the sensitizing potential. See References [69], [88], [90].
Note 2: in vivo animal tests are appropriate when test materials cannot be characterized and risk assessments cannot be undertaken using information obtained by the means set out in a), b) and c).
Note 3: for sensitization assays in guinea pigs, ten animals are normally used for positive control once every six months. Fewer guinea pigs can be used when an assay with a positive control substance is performed more frequently than once every six months. At least five test animals with a positive substance and five control animals should be used.
e) non-invasive human tests/clinical trials; if the material has been demonstrated not to be an irritant, a sensitizer or toxic in animals, studies on skin irritation may then be considered in humans.
Clinical studies in accordance with ISO 14155-1, ISO 14155-2 and to ethics principles shall not be performed before the results of the other evaluations in a) to d) are known.
5 Pretest Considerations
5.1 General
It is important to emphasize that pretest considerations may result in the conclusion that testing for irritation and/or sensitization is not necessary.
The requirements given in Chapter 5 of GB/T 16886-1: 2011 and the following apply.
Non-sterile samples shall be investigated by topical investigation only, as the possibility of microbial contamination of the test sample could confound the final assay interpretation. In cases where the sterility of a test sample cannot be guaranteed, but the sample is still considered to be non-contaminated, intradermal administration may be justified.
5.2 Types of material
5.2.1 Initial considerations
It shall be taken into consideration that, during manufacture and assembly of medical devices, additional chemical components may be used as processing aids, e.g. lubricants or mould-release agents. In addition to the chemical components of the starting material and manufacturing process aids, adhesive/solvent residues from assembly and also sterilant residues or reaction products resulting from the sterilization process may be present in a finished product. Whether these components pose a health hazard/risk depends on the leakage or degradation characteristics of the finished products. These components shall be taken into account for their potential irritation/sensitization activity.
5.2.2 Ceramics, metals and alloys
These materials are normally less complex than polymers and biologically derived materials in terms of the number of chemical constituents.
5.2.3 Polymers
These materials are normally chemically more complex than those in 5.2.2 in terms of composition. A number of reaction products/impurities/additives may be present and the completeness of polymerization may vary.
Foreword i
Introduction iv
1 Scope
2 Normative References
3 Terms and Definitions
4 General Principles - Step-Wise Approach
5 Pretest Considerations
6 Irritation Tests
7 Skin Sensitization Tests
8 Key Factors in Interpretation of Test Results
Annex A (Normative) Preparation of Materials for Irritation/Sensitization Testing
Annex B (Normative) Special Irritation Tests
Annex C (Normative) Human Skin Irritation Test
Annex D (informative) In Vitro Tests for Skin Irritation
Annex E (Informative) Method for the Preparation of Extracts from Polymeric Test Materials
Annex F (Informative) Background Information
Bibliography
Codeofchina.com is in charge of this English translation. In case of any doubt about the English translation, the Chinese original shall be considered authoritative.
GB/T 16886 Biological Evaluation of Medical Devices consists of the following parts under the general title:
——Part 1: Evaluation and Testing within a Risk Management Process;
——Part 2: Animal Welfare Requirements;
——Part 3: Test for Genotoxicity, Carcinogenicity and Reproductive Toxicity;
——Part 4: Selection of Tests for Interactions with Blood;
——Part 5: Test for In-vitro Cytotoxicity;
——Part 6: Tests for Local Effects after Implantation;
——Part 7: Ethylene Oxide Sterilization Residuals;
——Part 9: Framework for Identification and Quantification of Potential Degradation Products;
——Part 10: Tests for Irritation and Skin Sensitization;
——Part 11: Tests for Systemic Toxicity;
——Part 12: Sample Preparation and Reference Materials;
——Part 13: Identification and Quantification of Degradation Products from Polymeric Medical Devices;
——Part 14: Identification and Quantification of Degradation Products from Ceramics;
——Part 15: Identification and Quantification of Degradation Products from Metals and Alloys;
——Part 16: Toxicokinetic Study Design for Degradation Products and Leachables;
——Part 17: Establishment of Allowable Limits for Leachable Substances;
——Part 18: Chemical Characterization of Materials;
——Part 19: Physico-Chemical Morphological and Topographical Characterization of Materials;
——Part 20: Principles and Methods for Immunotoxicology Testing of Medical Devices.
This is Part 10 of GB/T 16886.
With regards to other biological tests, there will be standards for other parts.
This standard is developed in accordance with the rules given in GB/T 1.1-2009.
This part replaces GB/T 16886.10-2005 Biological Evaluation of Medical Devices - Part 10: Tests for Irritation and Delayed Type Hypersensitivity, compared with which, the following technical changes have been made:
——The standard name is modified;
——Terms and definitions are modified (Chapter 3; Chapter 3 of 2005 edition);
——"Material identification" is cancelled (see 5.4 of 2005 edition);
——Intradermal reaction test is adjusted from annex to text (see 6.4; Annex B of 2005 edition);
——Human skin irritation test method is adjusted from text to annex (see Annex C; 6.4 of 2005 edition);
——Murine local lymph node assay is added in skin sensitization test (see 7.2);
——In vitro tests for skin irritation is added (Annex D);
——Method for the preparation of extracts from polymeric test materials is added (see Annex E).
This part is identical to ISO 10993-10: 2010 Biological Evaluation of Medical Devices - Part 10: Tests for Irritation and Skin Sensitization by means of translation.
Chinese counterparts of the international documents given as normative references in this part are:
GB/T 16886.2-2011 Biological Evaluation of Medical Devices - Part 2: Animal Welfare Requirements (ISO 10993-2: 2006, IDT)
GB/T 16886.9-2017 Biological Evaluation of Medical Devices - Part 9: Framework for Identification and Quantification of Potential Degradation Products (ISO 10993-9: 2009, IDT)
GB/T 16886.12-2017 Biological Evaluation of Medical Devices - Part 12: Sample Preparation and Reference Materials (ISO 10993-12: 2012, 1DT)
GB/T 16886.13-2017 Biological Evaluation of Medical Devices - Part 13: Identification and Quantification of Degradation Products from Polymeric Medical Devices (ISO 10993-13: 2010, IDT)
GB/T 16886.14-2003 Biological Evaluation of Medical Devices - Part 14: Identification and Quantification of Degradation Products from Ceramics (ISO 10993-14: 2001, IDT)
GB/T 16886.15-2003 Biological Evaluation of Medical Devices - Part 15: Identification and Quantification of Degradation Products from Metals and Alloys (ISO 10993-15: 2000, IDT)
GB/T 16886.18-2011 Biological Evaluation of Medical Devices - Part 18: Chemical Characterization of Materials (ISO 10993-18: 2005, IDT)
This part was proposed by China Food and Drug Administration.
This part is under the jurisdiction of the National Technical Committee on Biological Evaluation on Medical Device of Standardization Administration of China (SAC/TC 248).
The previous editions of the standard replaced by this part are as follows:
——GB/T 16886.10-2000;
——GB/T 16886.10-2005.
Introduction
This part of GB/T 16886 assesses possible contact hazards from chemicals released from medical devices, which may produce skin and mucosal irritation, eye irritation or skin sensitization.
Some materials that are included in medical devices have been tested, and their skin or mucosal irritation or sensitization potential has been documented. Other materials and their chemical components have not been tested and may induce adverse effects when in contact with human tissue. The manufacturer is thus obliged to evaluate each device for potential adverse effects prior to marketing.
Traditionally, small animal tests are performed prior to testing on humans to help predict human response. More recently, in vitro tests as well as human tests have been added as adjuncts or alternatives. Despite progress and considerable effort in this direction, a review of findings suggests that currently no satisfactory in vitro test has been devised to eliminate the requirement for in vivo testing. Where appropriate, the preliminary use of in vitro methods is encouraged for screening purposes prior to animal testing. In order to reduce the number of animals used, this part presents a step-wise approach, with review and analysis of test results at each stage. An animal test is usually required prior to human testing.
It is intended that these studies be conducted using Good Laboratory Practice and comply with regulations related to animal welfare. Statistical analysis of data is recommended and should be used whenever appropriate.
This part is intended for use by professionals, appropriately qualified by training and experience, who are able to interpret its requirements and judge the outcomes of the evaluation for each medical device, taking into consideration all the factors relevant to the device, its intended use and the current knowledge of the medical device provided by review of the scientific literature and previous clinical experience.
The tests included in this part are important tools for the development of safe products, provided that these are executed and interpreted by trained personnel.
This part is based on numerous standards and guidelines, including OECD Guidelines, U.S. Pharmacopoeia and the European Pharmacopoeia. It is intended to be the basic document for the selection and conduct of tests enabling evaluation of irritation and dermal sensitization responses relevant to safety of medical materials and devices.
Biological Evaluation of Medical Devices - Part 10: Tests for Irritation and Skin Sensitization
1 Scope
This part of GB/T 16886 describes the procedure for the assessment of medical devices and their constituent materials with regard to their potential to produce irritation and skin sensitization.
This part includes:
a) pretest considerations for irritation, including in silico and in vitro methods for dermal exposure;
b) details of in vivo (irritation and sensitization) test procedures;
c) key factors for the interpretation of the results.
Instructions are given in Annex A for the preparation of materials specifically in relation to the above tests. In Annex B several special irritation tests are described for application of medical devices in areas other than skin.
2 Normative References
The following referenced documents are indispensable for the application of this document. For dated references, only the edition cited applies. For undated references, the latest edition of the referenced document (including any amendments) applies.
GB/T 16886.1-2011 Biological Evaluation of Medical Devices - Evaluation and Testing Within a Risk Management Process (ISO 10993-1: 2009, IDT)
ISO 10993-2 Biological Evaluation of Medical Devices - Part 2: Animal Welfare Requirements
ISO 10993-9 Biological Evaluation of Medical Devices - Part 9: Framework for Identification and Quantification of Potential Degradation Products)
ISO 10993-12 Biological Evaluation of Medical Devices - Part 12: Sample Preparation and Reference Materials
ISO 10993-13 (Biological Evaluation of Medical Devices - Part 13: Identification and Quantification of Degradation Products from Polymeric Medical Devices)
ISO 10993-14 Biological Evaluation of Medical Devices - Part 14: Identification and Quantification of Degradation Products From Ceramics
ISO 10993-15 Biological Evaluation of Medical Devices - Part 15: Identification and Quantification of Degradation Products from Metals and Alloys
ISO 10993-18 Biological Evaluation of Medical Devices - Part 18: Chemical Characterization of Materials
ISO 14155-1 Clinical Investigation of Medical Devices for Human Subjects - Part 1: General Requirement
ISO 14155-2 Clinical Investigation of Medical Devices for Human Subjects - Part 2: Clinical Investigation Plants
3 Terms and Definitions
For the purposes of this document, the terms and definitions given in GB/T 16886.1-2011 and the following apply.
3.1
allergen
sensitizer
substance or material that is capable of inducing a specific hypersensitivity reaction upon repeated contact with that substance or material
3.2
blank
extraction vehicle not containing the test material, retained in a vessel identical to that which holds the test material and subjected to identical conditions to which the test material is subjected during its extraction
Note: the purpose of the blank control is to evaluate possible confounding effects due to the extraction vessel, vehicle and extraction process.
3.3
challenge
elicitation
process following the induction phase, in which the immunological effects of subsequent exposures in an individual to the inducing material are examined
3.4
dose
dosage
amount of test sample administered (e.g. mass, volume) expressed per unit of body weight or surface area
Note: the terms are often used interchangeably (more commonly dosage).
3.5
erythema
reddening of the skin or mucous membrane
3.6
eschar
scab or discolored slough of skin
3.7
extract
liquid or suspension that results from exposing a test or control material to a solvent under controlled conditions
3.8
induction
process that leads to the de novo generation of an enhanced state of immunological activity in an individual, to a specific material
3.9
irritant
agent that produces irritation
3.10
irritation
localized non-specific inflammatory response to single, repeated or continuous application of a substance/material
Note: skin irritation is a reversible reaction and is mainly characterized by local erythema (redness) of the skin.
3.11
necrosis
cell death as a direct result of irreversible changes caused by injury or disease
Note: one should be aware that tissue repair will occur either resulting in complete functional restoration or resulting in scar formation.
3.12
negative control
any well-characterized material or substance that, when tested by a specific procedure, demonstrates the suitability of the procedure to yield a reproducible, appropriately negative, non-reactive or minimal response in the test system
Note: in practice, negative controls include blanks, vehicles/solvents and reference materials.
3.13
oedema
swelling due to abnormal infiltration of fluid into the tissues
3.14
positive control
any well-characterized material or substance that, when evaluated by a specific test method, demonstrates the suitability of the test system to yield a reproducible, appropriately positive or reactive response in the test system
3.15
skin corrosion
production of irreversible damage to the skin, manifested as visible necrosis through the epidermis and into the dermis, following application of a test sample
Example: the action of a compound/chemical/test sample resulting in ulceration of skin (see 3.19).
3.16
skin sensitization
allergic contact dermatitis
immunologically mediated cutaneous reaction to a substance
Note: in the human, the responses can be characterized by pruritis, erythema, oedema, papules, vesicles, bullae or a combination of these. In other species the reactions can differ and only erythema and oedema can be seen.
3.17
test material
material, device, device portion or component thereof that is sampled for biological or chemical testing
3.18
test sample
material, device, device portion, component, extract or portion thereof that is subjected to biological or chemical testing or evaluation
3.19
ulceration
open sore representing loss of superficial tissue
3.20
vehicle
liquid used to moisten, dilute, suspend, extract or dissolve the test substance/material
4 General Principles - Step-Wise Approach
The available methods for testing irritation and sensitization were developed specifically to detect skin and mucous membrane irritation and skin sensitization potential. Other types of adverse effect are generally not predicted by these tests. For medical devices that are used as implants or external communicating devices, intradermal testing is more relevant in approaching the application and so for detection of irritation activity, intracutaneous testing shall be used as described in 6.4.
This part requires a step-wise approach, which shall include one or more of the following:
a) characterization of test material, involving chemical characterization and analysis of the test sample according to the general principles described in ISO 10993-9, ISO 10993-13, ISO 10993-14, ISO 10993-15 and ISO 10993-18;
b) literature review, including an evaluation of chemical and physical properties, and information on the irritation and sensitization potential of any product constituent as well as structurally-related chemicals and materials;
c) in accordance with ISO 10993-2, in vitro tests in preference to in vivo tests shall be considered, and replacement of the latter as new in vitro tests are scientifically validated and become reasonably and practicably available. For the evaluation of skin irritation and corrosion, in vitro alternatives are available for chemicals; there are currently no internationally validated and accepted in vitro tests to detect sensitizers;
d) in vivo animal tests: in order to ensure reproducibility and sensitivity, a test of a positive-control substance for irritation and skin sensitization shall be included in each assay by the testing laboratory in order to validate the test system and demonstrate a positive response; for guinea pig sensitization assays, however, when consistency has been demonstrated over a six month or more extended period, a positive control does not need to be included in every assay, but may be run at regular intervals which shall not exceed six months.
Note 1: sensitization can at the moment only be determined by an in vivo assay. This can be accomplished by using the local lymph node assay (LLNA) in mice, the occluded patch test in guinea pigs or the guinea pig maximization test (GPMT). For single chemicals the LLNA is now the preferred assay for determining the sensitizing potential. See References [69], [88], [90].
Note 2: in vivo animal tests are appropriate when test materials cannot be characterized and risk assessments cannot be undertaken using information obtained by the means set out in a), b) and c).
Note 3: for sensitization assays in guinea pigs, ten animals are normally used for positive control once every six months. Fewer guinea pigs can be used when an assay with a positive control substance is performed more frequently than once every six months. At least five test animals with a positive substance and five control animals should be used.
e) non-invasive human tests/clinical trials; if the material has been demonstrated not to be an irritant, a sensitizer or toxic in animals, studies on skin irritation may then be considered in humans.
Clinical studies in accordance with ISO 14155-1, ISO 14155-2 and to ethics principles shall not be performed before the results of the other evaluations in a) to d) are known.
5 Pretest Considerations
5.1 General
It is important to emphasize that pretest considerations may result in the conclusion that testing for irritation and/or sensitization is not necessary.
The requirements given in Chapter 5 of GB/T 16886-1: 2011 and the following apply.
Non-sterile samples shall be investigated by topical investigation only, as the possibility of microbial contamination of the test sample could confound the final assay interpretation. In cases where the sterility of a test sample cannot be guaranteed, but the sample is still considered to be non-contaminated, intradermal administration may be justified.
5.2 Types of material
5.2.1 Initial considerations
It shall be taken into consideration that, during manufacture and assembly of medical devices, additional chemical components may be used as processing aids, e.g. lubricants or mould-release agents. In addition to the chemical components of the starting material and manufacturing process aids, adhesive/solvent residues from assembly and also sterilant residues or reaction products resulting from the sterilization process may be present in a finished product. Whether these components pose a health hazard/risk depends on the leakage or degradation characteristics of the finished products. These components shall be taken into account for their potential irritation/sensitization activity.
5.2.2 Ceramics, metals and alloys
These materials are normally less complex than polymers and biologically derived materials in terms of the number of chemical constituents.
5.2.3 Polymers
These materials are normally chemically more complex than those in 5.2.2 in terms of composition. A number of reaction products/impurities/additives may be present and the completeness of polymerization may vary.
Contents of GB/T 16886.10-2017
Foreword i
Introduction iv
1 Scope
2 Normative References
3 Terms and Definitions
4 General Principles - Step-Wise Approach
5 Pretest Considerations
6 Irritation Tests
7 Skin Sensitization Tests
8 Key Factors in Interpretation of Test Results
Annex A (Normative) Preparation of Materials for Irritation/Sensitization Testing
Annex B (Normative) Special Irritation Tests
Annex C (Normative) Human Skin Irritation Test
Annex D (informative) In Vitro Tests for Skin Irritation
Annex E (Informative) Method for the Preparation of Extracts from Polymeric Test Materials
Annex F (Informative) Background Information
Bibliography
