GB/T 16886 consists of the following parts under the general titleBiological Evaluation of Medical Devices:
——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 Polymerical 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 12 of GB/T 16886.
This standard is developed in accordance with the rules given in GB/T 1.1-2009.
This part replaces GB/T 16886.12-2005Biological Evaluation of Medical Devices - Part 12: Sample Preparation and Reference Materials, compared with which, the following technical changes have been made:
——The Chinese name “医疗器械生物学评价第12部分：样品制备与参照样品” is modified as “医疗器械生物学评价第12部分：样品制备与参照材料”;
——The terms of “accelerated extraction”, “extractables” and “ leachables” are added; (See Clause 3)
——The content of general requirements is added; (See Clause 4);
——The extraction conditions and methods are modified; (See Article 10.3, 10.3 in 2009 edition)
——The relative content of principles of test sample extraction is modified (See Annex C, Annex C in 2009 edition)
——The content of exhaustive extraction of polymeric materials for biological evaluation is added (See Annex D)
This part is identical to GB/T 16886.12-2005 Biological Evaluation of Medical Devices - Part 12: Sample Preparation and Reference Materials by means of translation.
Chinese counterparts of the international documents given as normative references in this part are:
GB/T 16886.1-2011 Biological Evaluation of Medical Devices - Part 1:Evaluation and Testing within a Risk Management Process (ISO 10993-1:2009, IDT)
GB/T 16886.2-2011 Biological Evaluation of Medical Devices - Part 2: Animal Welfare Requirements (ISO 10993-2: 2006, IDT)
GB/T 16886.3-2008 Biological Evaluation of Medical Devices - Part 3: Tests for Genotoxicity, Carcinogenicity and Reproductive Toxicity (ISO 10993-3:2003, IDT)
GB/T 16886.4-2003 Biological Evaluation of Medical Devices--Part 4: Selection of Tests for Interactions with Blood (ISO 10993-4:2002, IDT)
GB/T 16886.5-2017 Biological Evaluation of Medical Devices-Part 5: Tests for in Vitro Cytotoxicity (ISO 10993-5:2009, IDT)
GB/T 16886.6-1997 Biological Evaluation of Medical Devices-Part 6: Tests for Local Effects after Implantation (ISO 10993-6:1994, IDT)
GB/T 16886.7-2001 Biological Evaluation of Medical Devices-Part 7: Ethylene oxide sterilization residuals (ISO 10993-7: 1995, 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 16886.10-2017 Biological evaluation of medical devices- Part 10: Tests for irritation and skin sensitization (ISO 10993-10: 2010, IDT)
GB/T 16886.11-2011 Biological evaluation of medical devices-Part 11: Tests for systemic toxicity (ISO 10993-11: 2006, 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 16886.16-2013 Biological evaluation of medical devices―Part 16: Toxicokinetic Study Design for Degradation Products and Leachables(ISO 10993-16: 2010, IDT)
GB/T 16886.17-2005 Biological evaluation of medical devices -- Part 17: Establishment of allowable limits for leachable substances(ISO 10993-17: 2002, IDT)
GB/T 16886.18-2011 Biological Evaluation of Medical Devices - Part 18: Chemical Characterization of Materials (ISO 10993-18: 2005, IDT)
GB/T 16886.19-2011 Biological Evaluation of Medical Devices - Part 19: Physico-chemical, Morphological and Topographical Characterization of Materials (ISO 10993-19: 2006, IDT)
YY/T 0316-2008 Medical devices—Application of Risk Management to Medical Devices ( ISO 14971:2007,IDT)
Attention is drawn to the possibility that some of the elements of this document may be the subject of patent rights. The issuing body of this document shall not be held responsible for identifying any or all such patent rights.
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 16886.12-2005.
Introduction
This part of GB/T 16886 specifies methods of sample preparation and provides requirements and guidance for the selection of reference materials for the biological evaluation of medical devices. It is important that sample preparation methods be appropriate for both the biological evaluation methods and the materials being evaluated. Each biological test method requires the selection of materials, extraction solvents and conditions.
This part of GB/T 16886 is based on existing national and international specifications, regulations and standards wherever possible. It is periodically reviewed and revised.
Biological Evaluation of Medical Devices –
Part 12: Sample Preparation and Reference Materials
1 Scope
This part of GB/T 16886 specifies requirements and gives guidance on the procedures to be followed in the preparation of samples and the selection of reference materials for medical device testing in biological systems in accordance with one or more parts of GB/T 16886.
This part of GB/T 16886addresses the following:
—— test sample selection;
—— selection of representative portions from a device;
———test sample preparation;
——experimental controls;
—— selection of, and requirements, for reference materials;
—— preparation of extracts.
This part of GB/T 16886 is not applicable to live cells, but can be relevant to the material or device components of combination products containing live cells.
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.
ISO 10993(All parts) Biological Evaluation of Medical Devices
ISO 14971 Medical devices—Application of Risk Management to Medical Devices
3 Terms and Definitions
For the purposes of this document, the following terms and definitions apply.
3.1
accelerated extraction
extraction that provides a measure of the leachable or extractable materials of the device or material, using conditions that shorten the time for leaching of the substances into the extraction vehicle but do not result in a chemical change of the substances being extracted
EXAMPLE:Elevated temperature, agitation, changing of the extraction vehicle.
3.2
blank
extraction vehicle not containing the test material, which is retained in a vessel identical to that holding the test sample and subjected to conditions identical to the ones the test sample is subjected to during its extraction
NOTE: The purpose of the blank is to evaluate possible confounding effects due to the extraction vessel, extraction vehicle and extraction process.
3.3
CRM
certified reference material; CRM
reference material, accompanied by a certificate, one or more of whose property values are certified by a procedure which establishes its traceability to an accurate realization of the unit in which the property values are expressed, and for which each certified value is accompanied by an uncertainty at a stated level of confidence
[ISO Guide 30:1992, definition 2.2]
3.4
exaggerated extraction
extraction that is intended to result in a greater amount of a chemical constituent being released as compared to the amount generated under the simulated conditions of use
NOTE: It is important to ensure that the exaggerated extraction does not result in a chemical change of the material.
3.5
exhaustive extraction
extraction conducted until the amount of extractable material in a subsequent extraction is less than 10 % by gravimetric analysis of that detected in the initial extraction
NOTE: As it is not possible to demonstrate the exhaustive nature of residual recovery, the definition of exhaustive extraction adopted is as above. See also Annex C.
3.6
experimental control
substance with well-characterized responses, which is used in a specific test system to assist in evaluating if the test system has responded in a reproducible and appropriate manner
3.7
extract
liquid that results from extraction of the test sample or control
3.8
extractables
substances that can be released from a medical device or material using extraction solvents and/or extraction conditions that are expected to be at least as aggressive as the conditions of clinical use
3.9
homogeneous
property of a material and its relationship to a biological endpoint, meaning that it is of uniform structure or composition, thereby consistently rendering, or not, a specific biological response
NOTE: A reference material is said to be homogeneous if the biological response to a specific test is found to lie within the specified uncertainty limits of the test, irrespective of the batch or lot of material from which the test sample is extracted.
3.10
leachables
substances that can be released from a medical device or material during clinical use
3.11
negative control
any well-characterized material and/or substance, which, 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 are reference materials but can include blanks and extraction vehicles/solvents.
3.12
positive control
any well-characterized material and/or substance, which, 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
3.13
reference material; RM
material with one or more property values that are sufficiently reproducible and well established to enable use of the material or substance for the calibration of an apparatus, the assessment of a measurement method, or for the assignment of values to materials
NOTE 1: Adapted from ISO Guide 30:1992, definition 2.1.
NOTE 2: For the purpose of this part of GB/T 16886, an RM is any well-characterized material or substance, which, when tested by the procedure described, demonstrates the suitability of the procedure to yield a reproducible, predictable response. The response may be negative or positive.
3.14
simulated-use extraction
extraction conducted to demonstrate compliance with the requirements of this part of GB/T 16886 by evaluating leachable material levels available to the patient or user from devices during the routine use of a device, using an extraction method that simulates product use
NOTE:The burden of validation on the analytical laboratory is to demonstrate that the simulated-use extraction is carried out under conditions that provide the greatest challenge to the intended use. Product-use simulation is carried out assuming the device is assigned to the most stringent category possible for the duration of exposure and takes into consideration both the tissue(s) exposed and the temperature of exposure.
Foreword i
Introduction v
1 Scope
2 Normative References
3 Terms and Definitions
4 General requirements
5 Reference materials (RMs)
6 Use of RMs as experimental controls
7 Test sample selection
8 Test sample and RM preparation
9 Selection of representative portions from a device
10 Preparation of extracts of samples
11 Records
Annex A (Informative) Experimental Controls
Annex B (Informative) General Principles on, and Practices of, Test Sample Preparation and Sample Selection
Annex C (Informative) Principles of Test Sample Extraction
Annex D (Informative) Exhaustive Extraction of Polymeric Materials for Biological Evaluation
Bibliography
GB/T 16886 consists of the following parts under the general titleBiological Evaluation of Medical Devices:
——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 Polymerical 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 12 of GB/T 16886.
This standard is developed in accordance with the rules given in GB/T 1.1-2009.
This part replaces GB/T 16886.12-2005Biological Evaluation of Medical Devices - Part 12: Sample Preparation and Reference Materials, compared with which, the following technical changes have been made:
——The Chinese name “医疗器械生物学评价第12部分：样品制备与参照样品” is modified as “医疗器械生物学评价第12部分：样品制备与参照材料”;
——The terms of “accelerated extraction”, “extractables” and “ leachables” are added; (See Clause 3)
——The content of general requirements is added; (See Clause 4);
——The extraction conditions and methods are modified; (See Article 10.3, 10.3 in 2009 edition)
——The relative content of principles of test sample extraction is modified (See Annex C, Annex C in 2009 edition)
——The content of exhaustive extraction of polymeric materials for biological evaluation is added (See Annex D)
This part is identical to GB/T 16886.12-2005 Biological Evaluation of Medical Devices - Part 12: Sample Preparation and Reference Materials by means of translation.
Chinese counterparts of the international documents given as normative references in this part are:
GB/T 16886.1-2011 Biological Evaluation of Medical Devices - Part 1:Evaluation and Testing within a Risk Management Process (ISO 10993-1:2009, IDT)
GB/T 16886.2-2011 Biological Evaluation of Medical Devices - Part 2: Animal Welfare Requirements (ISO 10993-2: 2006, IDT)
GB/T 16886.3-2008 Biological Evaluation of Medical Devices - Part 3: Tests for Genotoxicity, Carcinogenicity and Reproductive Toxicity (ISO 10993-3:2003, IDT)
GB/T 16886.4-2003 Biological Evaluation of Medical Devices--Part 4: Selection of Tests for Interactions with Blood (ISO 10993-4:2002, IDT)
GB/T 16886.5-2017 Biological Evaluation of Medical Devices-Part 5: Tests for in Vitro Cytotoxicity (ISO 10993-5:2009, IDT)
GB/T 16886.6-1997 Biological Evaluation of Medical Devices-Part 6: Tests for Local Effects after Implantation (ISO 10993-6:1994, IDT)
GB/T 16886.7-2001 Biological Evaluation of Medical Devices-Part 7: Ethylene oxide sterilization residuals (ISO 10993-7: 1995, 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 16886.10-2017 Biological evaluation of medical devices- Part 10: Tests for irritation and skin sensitization (ISO 10993-10: 2010, IDT)
GB/T 16886.11-2011 Biological evaluation of medical devices-Part 11: Tests for systemic toxicity (ISO 10993-11: 2006, 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 16886.16-2013 Biological evaluation of medical devices―Part 16: Toxicokinetic Study Design for Degradation Products and Leachables(ISO 10993-16: 2010, IDT)
GB/T 16886.17-2005 Biological evaluation of medical devices -- Part 17: Establishment of allowable limits for leachable substances(ISO 10993-17: 2002, IDT)
GB/T 16886.18-2011 Biological Evaluation of Medical Devices - Part 18: Chemical Characterization of Materials (ISO 10993-18: 2005, IDT)
GB/T 16886.19-2011 Biological Evaluation of Medical Devices - Part 19: Physico-chemical, Morphological and Topographical Characterization of Materials (ISO 10993-19: 2006, IDT)
YY/T 0316-2008 Medical devices—Application of Risk Management to Medical Devices ( ISO 14971:2007,IDT)
Attention is drawn to the possibility that some of the elements of this document may be the subject of patent rights. The issuing body of this document shall not be held responsible for identifying any or all such patent rights.
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 16886.12-2005.
Introduction
This part of GB/T 16886 specifies methods of sample preparation and provides requirements and guidance for the selection of reference materials for the biological evaluation of medical devices. It is important that sample preparation methods be appropriate for both the biological evaluation methods and the materials being evaluated. Each biological test method requires the selection of materials, extraction solvents and conditions.
This part of GB/T 16886 is based on existing national and international specifications, regulations and standards wherever possible. It is periodically reviewed and revised.
Biological Evaluation of Medical Devices –
Part 12: Sample Preparation and Reference Materials
1 Scope
This part of GB/T 16886 specifies requirements and gives guidance on the procedures to be followed in the preparation of samples and the selection of reference materials for medical device testing in biological systems in accordance with one or more parts of GB/T 16886.
This part of GB/T 16886addresses the following:
—— test sample selection;
—— selection of representative portions from a device;
———test sample preparation;
——experimental controls;
—— selection of, and requirements, for reference materials;
—— preparation of extracts.
This part of GB/T 16886 is not applicable to live cells, but can be relevant to the material or device components of combination products containing live cells.
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.
ISO 10993(All parts) Biological Evaluation of Medical Devices
ISO 14971 Medical devices—Application of Risk Management to Medical Devices
3 Terms and Definitions
For the purposes of this document, the following terms and definitions apply.
3.1
accelerated extraction
extraction that provides a measure of the leachable or extractable materials of the device or material, using conditions that shorten the time for leaching of the substances into the extraction vehicle but do not result in a chemical change of the substances being extracted
EXAMPLE:Elevated temperature, agitation, changing of the extraction vehicle.
3.2
blank
extraction vehicle not containing the test material, which is retained in a vessel identical to that holding the test sample and subjected to conditions identical to the ones the test sample is subjected to during its extraction
NOTE: The purpose of the blank is to evaluate possible confounding effects due to the extraction vessel, extraction vehicle and extraction process.
3.3
CRM
certified reference material; CRM
reference material, accompanied by a certificate, one or more of whose property values are certified by a procedure which establishes its traceability to an accurate realization of the unit in which the property values are expressed, and for which each certified value is accompanied by an uncertainty at a stated level of confidence
[ISO Guide 30:1992, definition 2.2]
3.4
exaggerated extraction
extraction that is intended to result in a greater amount of a chemical constituent being released as compared to the amount generated under the simulated conditions of use
NOTE: It is important to ensure that the exaggerated extraction does not result in a chemical change of the material.
3.5
exhaustive extraction
extraction conducted until the amount of extractable material in a subsequent extraction is less than 10 % by gravimetric analysis of that detected in the initial extraction
NOTE: As it is not possible to demonstrate the exhaustive nature of residual recovery, the definition of exhaustive extraction adopted is as above. See also Annex C.
3.6
experimental control
substance with well-characterized responses, which is used in a specific test system to assist in evaluating if the test system has responded in a reproducible and appropriate manner
3.7
extract
liquid that results from extraction of the test sample or control
3.8
extractables
substances that can be released from a medical device or material using extraction solvents and/or extraction conditions that are expected to be at least as aggressive as the conditions of clinical use
3.9
homogeneous
property of a material and its relationship to a biological endpoint, meaning that it is of uniform structure or composition, thereby consistently rendering, or not, a specific biological response
NOTE: A reference material is said to be homogeneous if the biological response to a specific test is found to lie within the specified uncertainty limits of the test, irrespective of the batch or lot of material from which the test sample is extracted.
3.10
leachables
substances that can be released from a medical device or material during clinical use
3.11
negative control
any well-characterized material and/or substance, which, 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 are reference materials but can include blanks and extraction vehicles/solvents.
3.12
positive control
any well-characterized material and/or substance, which, 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
3.13
reference material; RM
material with one or more property values that are sufficiently reproducible and well established to enable use of the material or substance for the calibration of an apparatus, the assessment of a measurement method, or for the assignment of values to materials
NOTE 1: Adapted from ISO Guide 30:1992, definition 2.1.
NOTE 2: For the purpose of this part of GB/T 16886, an RM is any well-characterized material or substance, which, when tested by the procedure described, demonstrates the suitability of the procedure to yield a reproducible, predictable response. The response may be negative or positive.
3.14
simulated-use extraction
extraction conducted to demonstrate compliance with the requirements of this part of GB/T 16886 by evaluating leachable material levels available to the patient or user from devices during the routine use of a device, using an extraction method that simulates product use
NOTE:The burden of validation on the analytical laboratory is to demonstrate that the simulated-use extraction is carried out under conditions that provide the greatest challenge to the intended use. Product-use simulation is carried out assuming the device is assigned to the most stringent category possible for the duration of exposure and takes into consideration both the tissue(s) exposed and the temperature of exposure.
Contents of GB/T 16886.12-2017
Foreword i
Introduction v
1 Scope
2 Normative References
3 Terms and Definitions
4 General requirements
5 Reference materials (RMs)
6 Use of RMs as experimental controls
7 Test sample selection
8 Test sample and RM preparation
9 Selection of representative portions from a device
10 Preparation of extracts of samples
11 Records
Annex A (Informative) Experimental Controls
Annex B (Informative) General Principles on, and Practices of, Test Sample Preparation and Sample Selection
Annex C (Informative) Principles of Test Sample Extraction
Annex D (Informative) Exhaustive Extraction of Polymeric Materials for Biological Evaluation
Bibliography
