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GB/T 16886.20-2015 English PDF (GBT16886.20-2015)

GB/T 16886.20-2015 English PDF (GBT16886.20-2015)

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GB/T 16886.20-2015: Biological evaluation of medical devices -- Part 20: Principles and methods for immunotoxicology testing of medical devices

GB/T 16886.20-2015
Biological evaluation of medical devices - Part 20. Principles and methods for immunotoxicology testing of medical devices ICS 11.100
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
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.
---Immune stimulation;
--- Hypersensitivity reaction;
---Chronic inflammation;
These keywords are related to the following materials.
---Plastic products and other polymers;
---Ceramics, glass and composites;
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.
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.
Foreign body xenobiotic
From substances other than the human body or organism.
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
B-long term
Chronic inflammatory immunosuppression immune stimuli hypersensitivity autoimmunity Surface device
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 a...

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