Detail of GB/T 16886.23-2023

Introduction of GB/T 16886.23-2023

GB/T 16886.23-2023 Biological evaluation of medical devices - Part 23: Tests for irritation 1 Scope This document specifies the procedure for the assessment of medical devices and their constituent materials with regard to their potential to produce irritation. It includes: ——pre-test considerations for irritation, including in silico and in vitro methods for dermal exposure; ——details of in vitro and in vivo irritation test procedures; ——key factors for the interpretation of the results. This document is designed to predict and classify the irritation potential of medical devices, materials or their extracts according to ISO 10993-1 and ISO 10993-2. 2 Normative references The following documents are referred to in the text in such a way that some or all of their content constitutes requirements 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 16886.1-2022 Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process （ISO 10993-1:2018, IDT） 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 Note: GB/T 16886.2-2011, Biological evaluation of medical devices - Part 2: Animal welfare requirements (ISO 10993-2:2006, IDT) ISO 10993-9 Biological evaluation of medical devices - Part 9: Framework for identification and quantification of potential degradation products Note: GB/T 16886.9-2022, Biological evaluation of medical devices - Part 9: Framework for identification and quantification of potential degradation products (ISO 10993-9:2019, IDT) ISO 10993-12 Biological evaluation of medical devices - Part 12: Sample preparation and reference materials Note: GB/T 16886.12-2023, Biological evaluation of medical devices - Part 12: Sample preparation and reference materials (ISO 10993-12:2021, IDT) ISO 10993-13 Biological evaluation of medical devices - Part 13: Identification and quantification of degradation products from polymeric medical devices Note: 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) ISO 10993-14 Biological evaluation of medical devices - Part 14: Identification and quantification of degradation products from ceramics Note: 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) ISO 10993-15 Biological evaluation of medical devices - Part 15: Identification and quantification of degradation products from metals and alloys Note: GB/T 16886.15-2022, Biological evaluation of medical devices - Part 15: Identification and quantification of degradation products from metals and alloys (ISO 10993-15:2019 , IDT) ISO 10993-18 Biological evaluation of medical devices - Part 18: Chemical characterization of medical device materials within a risk management process Note: GB/T 16886.18-2022, Biological evaluation of medical devices - Part 18: Chemical characterization of medical device materials within a risk management process (ISO 10993-18:2020, IDT) ISO 14155 Clinical investigation of medical devices for human subjects - Good clinical practice OECD 404 Acute Dermal Irritation/Corrosion OECD 439 In Vitro Skin Irritation: Reconstructed Human Epidermis Test Method 3 Terms and definitions For the purposes of this document, the following terms and definitions apply. ISO and IEC maintain terminological databases for use in standardization at the following addresses: ——ISO Online browsing platform: available at https://www.iso.org/obp ——IEC Electropedia: available at http://www.electropedia.org/ 3.1 blank solution prepared in the same way as the sample measuring solution but so that it does not contain the analyte to be determined [SOURCE: ISO 10136-1:1993, 3.8, modified] 3.2 dose dosage amount of test sample (3.14) administered (e.g. mass, volume) expressed per unit of body weight or surface area Note: The terms are often used interchangeably (more commonly dosage). 3.3 erythema reddening of the skin or mucous membrane 3.4 eschar scab or discoloured slough of skin 3.5 extract liquid or suspension that results from exposing a test or control material to an extraction vehicle (3.16) under controlled conditions 3.6 irritant agent that produces irritation (3.7) 3.7 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 (3.3) (redness) and swelling [oedema (3.10)] of the skin. 3.8 necrosis cell death as a direct result of irreversible changes caused by injury or disease Note: Tissue repair will occur either resulting in complete functional restoration or resulting in scar formation. 3.9 negative control well-characterized material or substance that, when evaluated by a specific test method, 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 (NC) include blanks (3.1), vehicles (3.16)/solvents and reference materials. 3.10 oedema swelling due to abnormal infiltration of fluid into the tissue 3.11 positive control 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 3.12 skin corrosion production of irreversible damage to the skin, manifested as visible necrosis (3.8) through the epidermis and into the dermis, following application of a test sample (3.14) EXAMPLE: The action of a compound, chemical or a test sample resulting in ulceration of skin (see 3.15). 3.13 test material material, device, device portion or component thereof that is sampled for biological or chemical testing 3.14 test sample material, device, device portion, component, extract (3.5) or portion thereof that is subjected to biological or chemical testing or evaluation 3.15 ulceration open sore representing loss of superficial tissue 3.16 vehicle liquid used to moisten, dilute, suspend, extract or dissolve the test substance/material 3.17 vehicle control extraction vehicle (3.16) not containing the test material (3.13), 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 4 General principles - Step-wise approach The available methods for testing irritation were developed specifically to detect skin and mucous membrane irritation potential. Other types of adverse effects, such as sensitization, are generally not predicted by these tests. Historically irritation testing was done on rabbits. 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 is indicated as described in 7.2. Preference for in vitro tests instead of in vivo tests in accordance with ISO 10993-2, shall be considered, with replacement of the latter as new in vitro tests are scientifically validated and qualified for use with medical devices and become reasonably and practicably available. The results of a large contrast test that tested two types of RhE models showed that these models can also be used to detect the presence of irritant chemicals extracted from polymeric materials [polyvinylchloride (PVC) and silicone] commonly used in the manufacture of medical devices. This method was found equally sensitive to detect low concentrations of some strong irritant compounds when compared to the human patch testing and intracutaneous rabbit test. Therefore, the in vitro irritation test shall be performed before animal testing or human patch test is considered. Note 1: It can be relevant to provide detailed information of the applicability of the RhE model for the specific medical device being tested. This document describes a stepwise approach, which shall include one or more of the following: a) chemical characterization, supplemented where needed with chemical testing of samples in accordance with the general principles specified in ISO 10993-9, ISO 10993-13, ISO 10993-14, ISO 10993-15 and ISO 10993-18; b) literature review, as indicated in ISO 10993-1, including an evaluation of chemical and physical properties, and information on the irritation potential of any product constituent as well as structurally-related chemicals and materials; Note 2: In silico methods, such as structure activity relationship, QSAR, read across can indicate potential irritant activity. c) in vitro alternative test using validated RhE per the methods in 6.2 to 6.12; Note 3: For special irritation tests relevant for medical devices intended to be applied to a specific area (Annex D), i.e. mucosal or eye epithelia, the RhE models are not adapted and it is recommended to explore the use of other in vitro models with relevant cells or tissues if qualified for use with medical devices. d) in vivo animal tests: Note 4: 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). e) clinical studies according to ISO 14155 and ethics principles governing human clinical research, shall not be performed before the irritancy potential of a device has been established through one or more of the evaluations described in a) to d). 5 Pre-test considerations 5.1 General It is important to emphasize that pre-test considerations can result in the conclusion that testing for irritation is not necessary. For example, if the pH of the test sample is ≤2.0 or ≥11.5 the material shall be considered an irritant and no further irritant testing is required according to OECD 404. The requirements specified in GB/T 16886.1-2022, Clause 5 on the categorization of medical devices and the following apply Non-sterile samples shall be investigated in vivo 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 shall 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 can be used as processing aids,for example, lubricants or mould-release agents. In addition to the chemical components of the starting material and manufacturing process aids, adhesive/solvent residues from assembly,sterilant residues or reaction products resulting from the sterilization process can be present in a finished product. Whether these components pose a health hazard/risk depends on the leaching or degradation characteristics of the finished products. These components shall be taken into account for their potential irritation activity.The following types of materials are often used in medical devices and could introduce risks for irritation. 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 ceramics, metals and alloys in terms of composition. A number of reaction products, impurities, and additives can be present and the completeness of polymerization can vary. 5.2.4 Biologically derived materials These materials are inherently complex in their composition. They often also contain process residues, for example, cross-linkers and anti-microbial agents. Biological materials can be inconsistent from sample to sample. 5.3 Information on chemical composition 5.3.1 General A description of the medical device chemical constituents shall be established according to ISO 10993-18. As described in ISO 10993-1, the extent of physical and/or chemical characterization required depends on what is known about the material formulation and on the nature and duration of body contact with the medical device. At a minimum, the characterization shall address the constituent chemicals of the medical device and possible residual process aids or additives used in its manufacture. The rigour necessary in the characterization of the chemical constituents is principally determined by the nature, degree, frequency and duration of the exposure and the hazards identified for the medical device or material. Where relevant to biological safety, quantitative data shall also be obtained. If quantitative data are not obtained, the rationale shall be documented and justified. 5.3.2 Existing data sources Qualitative and quantitative information on the composition shall be obtained where possible from the supplier of the starting material. For polymers, this often requires access to proprietary information; provision should be made for the transfer and use of such confidential information. Qualitative information about any additional processing additives (e.g. mould-release agents) shall also be obtained from appropriate members of the manufacturing chain, including converters and component manufacturers. In the absence of any data on composition, a literature search is recommended to establish the likely nature of the starting material(s) and any additives, so as to assist in the selection of the most appropriate methods of analysis for the material concerned. The chemical characterization of a medical device shall be conducted in accordance with ISO 10993-18. Note: The composition of ceramics, metals and alloys can be specified in accordance with ISO or American Society of Testing Materials (ASTM) standards or it can be specified by the user, or both. However, in order to obtain full qualitative and quantitative details on composition, it can be necessary to request these from the supplier or manufacturer of the starting material and also from component manufacturers to ensure that processing aids are also identified. Material master files held by regulatory authorities are another source of data, where they are accessible. 6 In vitro irritation tests 6.1 General The in vitro method with RhE models for testing irritation was developed specifically to detect skin irritation potential for neat chemicals (see OECD 439). The method was adapted and validated with two RhE models for detection of irritant chemicals in medical device extracts. This method was found equally sensitive to detect low concentrations of some strong irritants in extracts from polymeric medical materials (PVC and silicone) when compared to the human patch testing and intracutaneous rabbit test. Hence, the RhE test as described in this document can replace the in vivo rabbit test for irritation by skin exposure and by intracutaneous (intradermal) administration.

Contents of GB/T 16886.23-2023

Foreword I Introduction III 1 Scope 2 Normative references 3 Terms and definitions 4 General principles - Step-wise approach 5 Pre-test considerations 5.1 General 5.2 Types of material 5.2.1 Initial considerations 5.2.2 Ceramics, metals and alloys 5.2.3 Polymers 5.2.4 Biologically derived materials 5.3 Information on chemical composition 5.3.1 General 5.3.2 Existing data sources 6 In vitro irritation tests 6.1 General 6.2 In vitro reconstructed human epidermis model 6.2.1 Test system - Reconstructed human epidermis model 6.2.2 Principle of the test 6.2.3 Prediction model 6.3 Materials 6.3.1 Reconstructed human epidermis models - Product description 6.3.2 Preparation of medical device extracts 6.4 Methods 6.4.1 General 6.4.2 Test procedure 6.4.3 Media and end point solutions 6.4.4 Test sample and control preparation 6.5 Considerations for test performance 6.5.1 Receipt of the reconstructed human epidermis tissues 6.5.2 Preparation and pre-incubation 6.6 Application of the test sample and rinsing 6.6.1 General 6.6.2 Preparation 6.6.3 Test extract and controls exposure 6.7 MTT test for determination of RhE tissue viability after the exposure period 6.7.1 MTT incubation and Isopropanol extraction 6.7.2 Absorbance measurements 6.8 Test acceptance criteria 6.9 Data calculation steps 6.9.1 General 6.9.2 Isopropanol background control for OD in RhE assay 6.9.3 Negative DPBS or PBS treated controls 6.9.4 Positive control 6.9.5 Tested extract and VC samples (TTs) 6.10 Data interpretation - Prediction model 6.11 Method documentation sheet 7 In vivo irritation tests 7.1 General 7.2 Animal irritation test by skin exposure 7.2.1 Principle 7.2.2 Test materials 7.2.3 Animals and husbandry 7.2.4 Test procedure 7.2.5 Observation of animals 7.2.6 Evaluation of results 7.2.7 Test report 7.3 Animal irritation test by intracutaneous (intradermal) administration 7.3.1 Introduction 7.3.2 Exclusion from test 7.3.3 Test sample 7.3.4 Animals and husbandry 7.3.5 Test procedure 7.3.6 Observation of animals 7.3.7 Evaluation of results 7.3.8 Test report 8 Human skin irritation test 8.1 General 8.2 Initial considerations Annex A (Normative) Preparation of materials for irritation testing Annex B (Informative) Test method check list for in vitro irritation testing using reconstructed human epidermis models Annex C (Informative) Example of method documentation sheet for reconstructed human epidermis models Annex D (Normative) Special irritation tests Annex E (Normative) Human skin irritation test Annex F (Informative) Background information on irritation tests Bibliography