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GB/T 16886.20-2015: PDF in English (GBT 16886.20-2015)

GB/T 16886.20-2015 Biological evaluation of medical devices - Part 20. Principles and methods for immunotoxicology testing of medical devices ICS 11.100 C30 National Standards of People's Republic of China Medical device biology evaluation Part 20. Medical device immunotoxicology trials Principles and methods Part 20. Principlesandmethodsforimmunotoxicologytestingofmedicaldevices (ISO /T S10993-20.2006, IDT) Released on December 10,.2015 2017-01-01 implementation General Administration of Quality Supervision, Inspection and Quarantine of the People's Republic of China China National Standardization Administration issued Foreword GB/T 16886 "Biology Evaluation of Medical Devices" is divided into the following sections. --- 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 delayed type hypersensitivity test; --- Part 11. Systemic toxicity test; ---Part 12. Sample preparation and reference samples; --- Part 13. Qualitative and quantitative determination of polymer degradation products; --- 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 toxicokinetics of degradation products and solubles; --- 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 20th part of GB/T 16886. This part is drafted in accordance with the rules given in GB/T 1.1-2009. This section uses the translation method equivalent to ISO /T S10993-20.2006 "Medical Device Biology Evaluation Part 20. Medical Devices Principles and Methods of Immunotoxicology Testing. The documents of our country that have a consistent correspondence with the international documents referenced in this part are as follows. GB/T 16886.1-2001 Biological evaluation of medical devices - Part 1. Evaluation and testing (ISO 10993-1..1997, IDT) GB/T 16886.2-2000 Biological evaluation of medical devices - Part 2. Requirements for animal protection (idt ISO 10993-2..1992) GB/T 16886.6-1997 Biological evaluation of medical devices - Part 6. Post-implantation partial response test (idtISO 10993-6. 1994) GB/T 16886.10-2005 Biological evaluation of medical devices - Part 10. Stimulation and delayed hypersensitivity test (ISO 10993-10.2002, IDT) GB/T 16886.11-1997 Biological evaluation of medical devices - Part 11. Systemic toxicity test (idt ISO 10993-11. 1993) YY/T 0316-2008 Medical Device Risk Management for Medical Devices (ISO 14971.2007, IDT) This part is proposed by the State Food and 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. State Food and Drug Administration Jinan Medical Device Quality Supervision and Inspection Center. The main drafters of this section. Hou Li, Yu Shaohua, Huang Jingchun, Liu Chenghu, Zeng Dongming, Zhang Jingping. introduction The main focus of international and European standards is to demonstrate the safety and compatibility of medical devices. Medical device guides in the past few years The potential of the immune system to mutate has attracted more and more attention, so it is necessary to understand how the medical device is bad for the immune system. Use the guide. Since there is currently no standardized trial, this document presents a framework for how to perform immunotoxicity assessments. This document is. --- outlining current cognitive status in the field of immunotoxicology, including information on immunotoxicity assessment methods and their predictive value; --- Identify the problem and how it was handled in the past. Clinical indications for immune variation induced by medical devices, mainly through extensive online medical literature analysis and retrieval systems For review, the key areas of research are. ---Immunosuppressive; ---Immune stimulation; --- Hypersensitivity reaction; ---Chronic inflammation; ---self-immune. These keywords are related to the following materials. ---Plastic products and other polymers; ---metal; ---Ceramics, glass and composites; ---biomaterials. Note. The potential interactions between materials and the immune system are shown in Table 1. Medical device biology evaluation Part 20. Medical device immunotoxicology trials Principles and methods 1 Scope This section of GB/T 16886 gives an overview of the immunotoxicology of the potential immunotoxicity of medical devices. This section also gives A guide to methods for testing the immunotoxicity of different types of medical devices. This section is based on several publications written by different groups of immunotoxicologists over the past few decades, with immunotoxicology as An independent branch within the toxicology category is developing. The current cognitive status of immunotoxicity is described in Appendix A, and Appendix B gives the immunotoxicity associated with medical devices to date. An overview of the clinical experience of science. Note. See reference [11]. 2 Normative references The following documents are indispensable for the application of this document. For dated references, only the dated version applies to this article. Pieces. For undated references, the latest edition (including all amendments) applies to this document. YY/T 0316-2008 Medical Device Risk Management for Medical Devices (ISO 14971.2007, IDT) 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 10993-10 Biological evaluation of medical devices - Part 10. Stimulation and delayed hypersensitivity test (Biologicalevalua- tionofmedicaldevices-Part 10. Testsforirritationanddelayed-typehypersensitivity) ISO 10993-11 Biological evaluation of medical devices - Part 11. Systemic toxicity test (Biologicalevaluationofmedical devices-Part 11.Testsforsystemictoxicity) 3 Terms and definitions The following terms and definitions apply to this document. 3.1 Immunotoxicology A study of the adverse health effects of foreign bodies directly or indirectly interacting with the immune system. 3.2 Medical device medicaldevice The intended use of the manufacturer is for one or more of the following specific purposes, for humans, whether used alone or in combination, Equipment, appliances, appliances, utensils, implants, in vitro reagents or calibrators, software, materials or other similar or related items. These purposes are. --- Diagnosis, prevention, monitoring, treatment or relief of the disease; ---Diagnosis, monitoring, treatment, mitigation or compensation of injury; --- research, substitution, regulation or support of anatomical or physiological processes; ---Support or sustain life; ---Pregnant control; --- Disinfection of medical devices; --- Provide medical information by in vitro examination of samples taken from the human body. The main design effects on the body surface or in the body are not obtained by pharmacological, immunological or metabolic means, but may have these Means participate and play a certain auxiliary role. Note 1. This definition was developed by the Global Coordination Working Group (GHTF). [YY/T 0287-2003, definition 3.7] Note 2. Products that may be considered medical devices in some jurisdictions, but which do not yet have a coordinated approach are. 1) Supplementary supplies for persons with disabilities/physical defects; 2) Instruments for the treatment/diagnosis of animal diseases and injuries; 3) Medical device accessories (see Note 3); 4) Disinfecting substances; 5) Instruments that meet the above definition requirements but are subject to different controls and contain animal and human tissue. Note 3. The manufacturer specifies that the device used with the “parent” medical device to achieve the intended purpose of the device should be applicable to GB/T 16886/ISO 10993. Note 4. Medical devices differ from drugs/biological products in that their biological evaluation methods are different. Note 5. Medical devices may include dental instruments. 3.3 Foreign body xenobiotic From substances other than the human body or organism. 3.4 Immunogenic immunogenic Cells that stimulate the immune system cause an antigen-specific immune response. 4 Risk assessment and risk management Risk assessment includes hazard identification, dose response assessment, and exposure assessment, along with characterization of risk. Should be based on risk characterization Implement risk management. Since it is difficult to predict the immunotoxicity of new chemicals and new materials, it is necessary to focus on the medical devices. For the assessment and management of the risks associated with known immunotoxic chemicals, medical device risk management should be carried out in accordance with ISO 14971. For medical care The potential immunotoxic hazards of immunotoxic chemicals in devices should first be identified through extensive literature searches. Examples of such hazards are Anaphylactic shock caused by the drug chlorhexidine and latex protein. Then consider the integrated risk management/risk reduction process while taking A variety of measures to reduce residual risk, such as labeling contraindications, product recalls, design changes, and use or application restrictions. 5 Identification of hazards Immune hazards should identify the presence of potential immunotoxicities by assessing the exposure of medical device materials. Can be obtained in many ways Information on the hazard of the epidemic, including but not limited to the following sources. ---Material characterization; ---Residue characterization; --- characterization of leaching materials; --- characterization of drugs and other substances added to medical devices; ---Characterization of contact time and route of exposure; --- Observations of previous exposure to chemicals, drugs or materials; --- Toxicity test. Most of the identified immunological reactions to date have been associated with material additives, so the exposure assessment of these chemicals is The epidemic is important. Table 1 gives the possible immune responses of various materials for different types of medical devices. Table 1 Potential response of the immune system Device classification immune system response Human contact nature contact time Classified contact A-short term (≤24h) B-long term (>24h~30d) C-lasting (>30d) Stimulation/acute Inflammation Chronic inflammatory immunosuppression immune stimuli hypersensitivity autoimmunity Surface device skin Mucosa Damage surface A × - - × × - B × × - × × - C × × × × × × A × - × × × × B × × × × × × C × × × × × × A × - × × × × B × × × × × × C × × × × × × External access device Blood path, indirect Tissue, bone, and teeth Implanted device A × - - × × × B × × × × × × C × × × × × × A × - × × × × B × × × × × × C × × × × × × Implanted device Tissue, bone and Other body fluids A × - × × × × B × × × × × × C × × × × × × Note. This table is a framework for consideration of the potential interactions between the materials of various types of medical devices and the various parts of the immune system, not a checklist. When an immunocompetent cell meets a toxic foreign substance, it may cause an immune system reaction (immunotoxicity) and kill cells, or foreign substances. Interaction with early products of the immune response results in an immune system response and changes in subsequent responses. The possibility of immunotoxicity is difficult to predict Tested, but can be predicted based on known immunological results. First, the substance that stimulates the immune response must be recognized by the host as a foreign body. The most likely immunogenic substances are proteins, polysaccharides, Nucleic acids and lipids. Small molecular weight substances are generally not immunogenic, however, these substances can bind to host proteins and alter protein knots. The conformation is immunogenic and such substances are commonly referred to as haptens. Leachables, abrasion or degradation products of polymeric materials, ceramics and metallic materials may be combined with host proteins, while biologically derived materials, For example, collagen, natural latex proteins, albumin and animal tissues are known to stimulate immune responses, so measures must be taken to make such materials not Immunogenicity. In order for macromolecular substances (atomic mass > 1000000u) to be immunogenic, such substances must be broken down into smaller ones. substance. The above exemplifies substances and materials having immunogenic potential, and its adverse effects on the immune system should be considered. Physical contact. Every physical contact listed in ISO 10993-1 may have an unsuitable immune response (immunotoxicity), skin and Mucosal membranes may in particular trigger type I and type IV reactions, and other pathways may cause systemic reactions, including type I and type IV reactions. Contact time. Generally speaking, the longer the contact time between the material and the body, the more likely the immunogenic substance is formed. However, some can Chemicals that are immunogenic have a rapid response and produce an immune response within 24 hours of exposure to the body. 6 immunotoxicity assessment method 6.1 General Immunotoxicity assays can be performed in vivo and in vitro. Compared with the in vivo immunotoxicity test, the in vitro method cannot simulate the entire exemption. The complexity of the epidemic system has certain limitations. Because in vitro methods have not been fully studied and standardized, in vitro methods in animal data The value of extrapolation to humans (by clarifying the toxicity mechanism) is further limited. However, in vitro methods can be used as a mechanism for research. Immunotoxicology focuses on the detection and evaluation of adverse effects of substances by rodent tests. Considering animal testing All reasonable and effective alternatives, reductions and optimizations should be identified and implemented in accordance with ISO 10993-2. Although already Confirmed laboratory tests, but in many cases the biological significance and predictive value of immunotoxicity tests need to be carefully considered. Lymphatic Changes in official weight or histology, changes in peripheral white blood cell count or differential count, and lymphoid tissue composition below normal water Leveling, increased susceptibility to opportunistic pathogenic microorganisms or tumors, which can predict potential effects on the immune system. Therefore free The primary task in the field of epidemiology is to identify such changes and assess their importance for human health. Immunotoxicity tests can be divided into two types, non-functional and functional tests. Non-functional tests have descriptive properties in the assay. shape Morphological and/or quantitative terminology, degree of lymphoid tissue change, number of lymphocytes and immunoglobulin levels or other immune function markers Things. In contrast, functional tests measure cell and/or organ activity, such as lymphocyte proliferation of mitogens or specific antigens. Colonization, cytotoxic activity and specific antibody formation (as in response to sheep red blood cells). A new development in this field is the use of "omics" for the detection of changes in gene expression involving immune function. The evaluation of immunotoxicological hazards should be designed in accordance with the flow chart given in Appendix C. Table 2 gives experimental examples and indications of immune response. Although specific materials are known or suspected to be immunotoxic, immunotoxicity tests associated with immunosuppression or immune stimulation are the most Initially it should be limited to the tests in the general toxicity test phase, only those with indications that can lead to immunosuppression or immune stimulation. Further research should be considered. Subacute tests are applicable to the general indication of potential immunosuppression or immune stimuli, such as this Class tests shall be carried out in accordance with ISO 10993-11. 6.2 inflammation Foreign bodies can interact with non-specific components of the immune system (ie, granulocytes, macrophages, and other cell types that produce and release inflammatory mediators). Type) interaction. It should be noted that after the foreign body is implanted, the local inflammatory reaction is very common, and the time and extent of the reaction can be determined whether or not Show some kind of adverse effect. The most direct and appropriate method for evaluating the degree of inflammatory response after implantation of a foreign body is to inject or implant a foreign body. The site was observed for histopathology. Different from the foreign body reaction of macrophages and foreign body giant cells with tissue/material interface, and immunity Chronic inflammation associated with toxicity is a lymphocyte-based lesion. The initial local inflammation test is given in ISO 10993-6. Other suitable test methods include serum assays for C-reactive protein and acute phase proteins. 6.3 Immunosuppression Immunosuppression is detected in a multi-layered manner to reflect the complexity of the immune system and its various functions and components. This multi-layer The formula includes a non-functional test for the first layer of immunosuppression test and a functional test for the second layer. This multi-layer approach does not provide the most Sensitive methods available because functional tests are more sensitive than non-functional tests. For the first layer, including less sensitive indications, and second The layer includes reasons for more sensitive indications, not because it best assesses the immune system, but because it reduces the number of additional experimental animals. Demand. In the first layer, the resulting immunosuppressive indications are, immune organ weight, cell number and/or cell population, and immunoglobulin Variety. In the second layer, a more specific immunological function test can be used, such as determining the natural killing (NK) of the active substance during active immunization. Effects on cell viability and/or immune function, for example, detection of antigen-specific antibody production after sensitization. Some tests in this category The method has been included in the first layer (antibody reaction to T cell-dependent antigens such as sheep red blood cells). By assessing the anti-bacterial, viral and/or parasitic animal model of infection, and/or anti-tumor effects, it may be best to determine immunosuppression The true result of the system. The importance of this type of test is to assess the immune system as a complete and functional entity. However, since a single toxicity or immunosuppression study cannot be used to evaluate all immune-related parameters, it is necessary to identify the most important fingers. Parameters are shown and a practical approach is chosen to assess immunosuppression of a particular agent. Since the general discomfort of the individual also affects the immune system, immunity is detected at dose levels that do not produce significant systemic toxicity. Consider immunosuppression when mutating. Therefore, it is best to perform an immunosuppressive test in combination with a systemic toxicity test because the systemic toxicity test is used. Serial doses of the agent and evaluate all major organ systems. For the general toxicity test after subacute exposure of chemical substances, the recently adopted OECD407 [1] includes several immunotoxicological parameters. Number, for the determination of the immunotoxic effects of the compounds studied. Table 2 Test examples and indications for evaluation of immune response Immune response functional test Non-functional test Soluble medium phenotype other a Tissue/inflammation Implantation/whole body ISO 10993-6 and ISO 10993-11 Not applicable to cell surface marker organ weight analysis Humoral response Immunoassay (eg ELISA) for anti-antibody Body response to antigen plus adjuvant b Plaque forming cell Lymphocyte proliferation Antibody-dependent cytotoxicity Passive skin allergic reaction Direct allergic reaction Complement (including C3a and C5a anaphylatoxin) Immune complex Cell surface marker Cell response Table 2 (continued) Immune response functional test Non-functional test Soluble medium phenotype other a T cell NK cell Macrophages and others Monocyte Dendritic Cells Vascular endothelial cell Granulocyte Cell, eosinophilic Cellulose, neutrophil Cell) Guinea pig maximum dose test Mouse partial lymph node test Mouse ear swelling test Lymphocyte proliferation Mixed lymphocyte reaction T cell subset (Th1 Cytokines of Th2) Type indication Cell surface marker Help and cytotoxicity T cell) Tumor cytotoxicity does not apply to cell surface markers Phagocytosis Antigen presentation Cytokine (IL1) TNFα, IL6, TGFβ, IL10, γ-interferon) MHC logo Antigen presentation to T cells does not apply to cell surface markers Activation Threshing Phagocytosis Chemokines, biological activities Amine, inflammatory cell Sub-enzyme Not applicable to cytochemistry Host resistance against bacteria, viruses and anti-tumor is not applicable Clinical symptoms are not applicable, not applicable, not applicable Allergies, rash, Rubella, edema, lymph Disease, inflammation a Animal models of some people's autoimmune diseases are available, but it is not recommended to use materials/instruments to induce autoimmune diseases as routine tests. b The most commonly used test. Functional testing is generally more important than soluble media or phenotypic testing. 6.4 Immunostimulation In most cases, immune stimuli do not cause less resistance to infectious diseases, but instead can exacerbate existing allergies or themselves. Immune symptoms. Test methods for immunosuppression are also generally applicable to the detection of immunostimulation. Those that can non-specifically stimulate the immune system Preferably, an animal model that has induced sensitization or autoimmunity is used for evaluation studies. For host tolerance models, allergies and self-elimination The epidemic model is quite cumbersome, and there is currently no effective way to test allergies and autoimmunity by extrapolating animal data to humans. Animal model. In addition to the immunostimulatory properties of the material itself, the immunostimulatory activity of the contaminant should also be considered, as in ISO 10993-11 Appendix F. Specified pyrogen. 6.5 Hypersensitivity The substrates are recognized by the immune system based on their antigenic properties, and similarly, these agents can induce hypersensitivity as an allergen. Most common The hypersensitivity reaction forms are delayed-type hypersensitivity (type IV) and immediate hypersensitivity (type I), and there is no good pre-sensitivity for type I hypersensitivity. Testability test. Delayed hypersensitivity reactions include antigen-specific cellular inflammatory responses, and such assays are given in ISO 10993-10. IgE mediates immediate hypersensitivity, and can be used to test the production of specific IgE in several ways. The classic immediate hypersensitivity response induces The method includes a passive allergy test. 6.6 Autoimmune Exogenous substrates alter the composition of the host and are recognized as "non-self" by the immune system. In this case, the substrate and the substrate are generally required. High specific binding between hosts; animal studies show that autoimmune diseases are largely due to hereditary factors, so common toxicology The screening test is unlikely to detect the evoked potential of autoimmunity. There is currently no effective animal model for testing allergies and autoimmunity that can extrapolate animal data to humans. An autoimmune predictive test model, an improved method of axillary lymph node test, has been proposed. Proliferation of draining lymph nodes in this trial The response is thought to be an indication of sensitization-induced induction, including autoimmunity. Expanded T cell-dependent antigen And non-T cell-dependent antigens (reporter antigens) increase the value of the assay and detect new antigen-induced responses, but this approach also requires Further confirmation. 7 Extrapolation of data provided by preclinical trials Because of the immunodeposition and/or reserve characteristics of the immune system, in vitro and animal experiments are very complex for humans. Free The physiology of epidemics does not necessarily affect health, and specific tests are required due to differences in location (eg, systemic, lung, skin). Immunopathology is also different (such as hypersensitivity, immune regulation, autoimmunity, and inflammation). These phenomena cannot be tested by traditional general toxicity tests. Distinguished. An increasingly deep understanding of the cellular, molecular, and genetic factors that produce a suitable immune response, as well as the immune mediators involved in these factors, has been We offer opportunities to take advantage of easier and more informative experiments. Appendix A (informative appendix) Current cognitive state A.1 Immunology The immune system protects human health and resists various factors that threaten human health, especially the infectious agents that cause disease, including other rings. Circumstances and tumor formation. The immune system works through immunosurveillance mechanisms and the production of immunoglobulins, cytokines, and interleukins...... ......
 
Source: Above contents are excerpted from the PDF -- translated/reviewed by: www.chinesestandard.net / Wayne Zheng et al.