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GB/T 16886.13-2017 (GB/T16886.13-2017, GBT 16886.13-2017, GBT16886.13-2017)
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GB/T 16886.13-2017: PDF in English (GBT 16886.13-2017)

GB/T 16886.13-2017
Biological evaluation of medical devices--Part 13. Identification and quantification of degradation products from polymeric medical devices
ICS 11.100.20
C30
National Standards of People's Republic of China
Replace GB/T 16886.13-2001
Medical device biology evaluation
Part 13. Degradation products of polymer medical devices
Qualitative and quantitative
Biologicalevaluationofmedicaldevices-Part 13.Identificationand
(ISO 10993-13.2010, IDT)
Released on.2017-12-29
2018-07-01 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 "Biological Evaluation of Medical Devices" consists of the following parts.
--- 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 skin sensitization test;
--- Part 11. Systemic toxicity test;
--- Part 12. Sample preparation and reference materials;
--- Part 13. Qualitative and quantitative determination of degradation products of polymer medical devices;
--- 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 13th part of GB/T 16886.
This part is drafted in accordance with the rules given in GB/T 1.1-2009.
This part replaces GB/T 16886.13-2001 "Medical evaluation of medical devices - Part 13. Degradation products of polymer medical devices
Qualitative and quantitative. The main technical changes compared with GB/T 16886.13-2001 are as follows.
--- Revised scope (see Chapter 1);
--- Modified "4 degradation test method";
--- Modified "5 test steps";
--- Added Appendix B polymer environmental stress cracking.
This section uses the translation method equivalent to ISO 10993-13.2010 "Medical Device Biology Evaluation Part 13. Polymer Medical Devices
Qualitative and Quantitative Analysis of Mechanical Degradation Products.
The documents of our country that have a consistent correspondence with the international documents referenced in this part are as follows.
---GB/T 6682-2008 Analytical laboratory water specifications and test methods (ISO 3696.1987, MOD);
--- GB/T 16886.1-2011 Biological evaluation of medical devices - Part 1. Evaluation and testing in the process of risk management
(ISO 10993-1.2009, IDT);
--- GB/T 16886.9-2017 Biological evaluation of medical devices - Part 9. Qualitative and quantitative framework for potential degradation products
(ISO 10993-9.2009, IDT);
--- GB/T 16886.12-2017 Medical Device Biology Evaluation Part 12. Sample Preparation and Reference Samples (ISO 10993-
12.2012, IDT);
--- GB/T 16886.16-2003 Biological evaluation of medical devices - Part 16. The toxic kinetics of degradation products and solubles
Research design (ISO 10993-16.1997, IDT);
--- GB/T 16886.17-2005 Biological evaluation of medical devices - Part 17. Establishment of leaching allowances
(ISO 10993-17.2005, IDT).
Please note that some of the contents of this document may involve patents. The issuing organization of this document is not responsible for identifying these patents.
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, National Food and Drug Administration
Bureau of Peking University Medical Device Quality Supervision and Inspection Center.
The main drafters of this section. Luo Hongyu, Xu Kai, Xu Yongxiang.
The previous versions of the standards replaced by this section are.
---GB/T 16886.13-2001.
introduction
The degradation products included in this part of GB/T 16886 mainly refer to hydrolysis and/or oxidation in aqueous environments (such as humans).
The process leads to degradation products formed by chemical bond cleavage. It is generally believed that other biological factors such as enzymes, proteins and cellular activities may change.
Degradation rate and degradation properties.
It should be noted that polymer devices may contain residues such as monomers, oligomers, solvents, catalysts, additives, fillers and processing aids.
Residues and leachables. If these ingredients are present, they may interfere with the characterization and quantification of the degradation products, which need to be considered and explained. Want
It is recognized that the residual monomer may be the same as the degradation product produced by the polymer itself. Readers only pay attention to further biological evaluation
The results of the degradation test are used in the test, and no distinction is made between the leachables and the degradation products. If this is the case, it may not be necessary to produce from degradation.
The leachables were separated from the material.
Due to the general characteristics of this part of GB/T 16886, there are product standards that describe degradation products under more relevant conditions of use.
When forming, consider replacing this part. This section applies to screening new polymer materials and/or improvements with unknown degradation behavior after contact with in vivo.
Polymer material. This section does not involve degradation caused by in vivo testing. Users of this section may consider other in vivo degradation monographs.
Degradation test described.
Long-term implants may not degrade within the test time range given in this section. The purpose of this section is to assist in the identification of medical devices.
Biological hazards of degradation products of mechanical polymer parts. As noted above, those degradation products may result from various degradation mechanisms. This section does not
A comprehensive analysis of the degradation of medical devices and their performance, users can refer to the relevant product standards. Qualitative degradation products
And quantification, which is the basis for biological evaluation according to GB/T 16886.1, and is based on GB/T 16886.17 for risk assessment and appropriate time.
Basis for toxicokinetic studies in accordance with GB/T 16886.16.
Medical device biology evaluation
Part 13. Degradation products of polymer medical devices
Qualitative and quantitative
1 Scope
This part of GB/T 16886 is a qualitative and quantitative test for the degradation products of the simulated polymer medical device simulation environment prepared for clinical use.
The design provides general requirements.
This section describes two test methods for the formation of degradation products, one for accelerated degradation testing as a screening method and the other for simulation.
Real-time degradation testing of the environment. For materials that are polymerized in situ during use, the cured polymer is used in the test. Test data were used
Biological evaluation of polymers. This section applies only to non-absorbent polymers, and similar but suitably adjusted test procedures may also apply.
For absorbable polymers.
This section only applies to degradation products produced by chemical changes in finished polymer devices, not applicable to the intended use of the device.
Mechanical stress, wear, electromagnetic radiation or degradation of the device caused by biological factors such as enzymes, other proteins and cellular activities.
Note. This section presents an informative text discussing polymer environmental stress cracking (ESC), which is helpful for degradation research design (see Appendix B).
This section does not cover the biological activity of debris and soluble degradation products, which should be in accordance with GB/T 16886.1, GB/T 16886.16 and
The principle of GB/T 16886.17 was evaluated.
Due to the wide range of polymeric materials used in medical devices, no specific analytical techniques have been specified or specified. This section is not degraded
The acceptable level of product specifies specific requirements.
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.
ISO 3696 Analytical Laboratory Water Specifications and Test Methods (Waterforanalyticallaboratoryuse-Specification)
Andtestmethods)
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 10993-9 Biological evaluation of medical devices - Part 9. Qualitative and quantitative framework for potential degradation products (Biologicaleval-
uationofmedicaldevices-Part 9. Frameworkforidentificationandquantificationofpotentialdegra-
Dationproducts)
ISO 10993-12 Biological evaluation of medical devices - Part 12. Sample preparation and reference samples (Biologicalevaluationof
medicaldevices-Part 12. Samplepreparationandreferencematerials)
ISO 10993-16 Biological evaluation of medical devices - Part 16. Design and analysis of toxic kinetics of degradation products and solubles
(Biologicalevaluationofmedicaldevices-Part 16. Toxicokineticstudydesignfordegradationproducts
Andleachables)
ISO 10993-17 Biological evaluation of medical devices - Part 17. Establishment of leaching allowances (Biological
evaluationofmedicaldevices-Part 17.Establishmentofalowablelimitsforleachablesubstances)
3 Terms and definitions
The following terms and definitions apply to this document.
3.1
Residual monomer residualmonomer
A chemical component that constitutes a polymer chain that is still present in the final polymer material but does not react.
3.2
Degradation product
Chemical composition due to cracking of the polymer material, including any chemical components produced in a continuous chemical reaction.
3.3
Polymer material
A material consisting of long chains and/or crosslinked molecules composed of units called monomers.
3.4
Hydrolytic degradation hydrolytic degradation
The cleavage of the chemical bonds of the polymer under the action of water.
Note. The pH of water can be neutral, acidic or alkaline, and it can contain other chemical components or ions.
3.5
Oxidative degradation oxidativedegradation
The cleavage of a chemical bond of a polymer under the action of one or more oxidants.
3.6
Debris debris
Particulate matter produced by degradation of polymer materials.
4 degradation test method
4.1 General steps
4.1.1 Test design
According to ISO 10993-9, degradation tests are applied to the production, qualitative and/or quantitative degradation products. If degradation is observed in the accelerated test
Occurrence, qualitative and quantitative degradation products can provide sufficient information for risk analysis. When accelerated testing does not provide adequate risk analysis
For qualitative and quantitative information on degradation products, real-time degradation tests should be performed. The test is described in detail in this part of GB/T 16886.
The order of the steps.
Note. Accelerated degradation tests can be used as screening tests. If no degradation is observed in the accelerated test, no real-time degradation test is required.
4.1.2 Sample preparation
Sample preparation should generally be consistent with ISO 10993-12 unless otherwise specified.
4.1.3 Initial material characterization
The analytical method used for the initial material characterization should be suitable for the polymer material being studied. The analytical techniques used should be reported and demonstrated.
The analytical methods for the characterization of polymer materials and their scope of application are given in Appendix A.
4.1.4 Test solutions and equipment
4.1.4.1 Test solution
4.1.4.1.1 General
All test solutions should be described and demonstrated in the test report.
The test solution selected should be as similar as possible to the intended application environment of the polymer medical device.
If the environment cannot be simulated, the test solutions given in 4.1.4.1.2 and 4.1.4.1.3 can be used as the first screening for degradation. These solutions
The expected degradation mechanism for polymeric materials may be higher or less challenging than the in vivo environment.
Other test solutions can be selected for specific polymers or special use environments.
Note. If bioassays are to be performed on debris or degradation solutions, the use of antibacterial or antifungal agents will interfere with these analyses, throughout the real-time degradation test.
A sterile environment may be required.
4.1.4.1.2 Test solution for hydrolytic degradation
The following solutions are recommended for hydrolytic degradation.
a) Analytical laboratory water, in accordance with ISO 3696 secondary water;
b) Buffer.
Note. See examples of buffers for hydrolytic degradation studies in ISO 13781.
4.1.4.1.3 Test solution for oxidative degradation
The following solutions are recommended for oxidative degradation.
a) Water and hydrogen peroxide, such as Pharmacopoeia grade 3% hydrogen peroxide solution.
b) Fenton's reagent [a mixture of a dilute hydrogen peroxide solution and an iron (II) salt, such as 100 μmol Fe 2 and 1 mmol H 2 O 2 ].
These oxidizing solutions may be unstable at elevated temperatures or after prolonged periods of time, so the oxidizing power should be maintained within an appropriate range.
The scope of stability should be clarified and demonstrated and reported.
4.1.4.2 Container
Chemical grade glass containers, Teflon or polypropylene containers should be used in closed systems depending on the test solution. Should use pair
The container is evaluated for contaminants and the container should be certified to not interfere with the analysis.
4.1.4.3 Balance
The balance used to determine the mass loss should be able to weigh the original sample to the required accuracy. Determination of absorbable materials, balance accuracy 1%
It is appropriate. The material designed to be resistant to degradation shall have a balance accuracy of at least 0.1%. Determination of the final sample quality of the absorbable polymer
The accuracy of the balance should be 0.1% of the mass of the final sample. Determine the final sample quality of the stabilized polymer. The accuracy of the balance should be
0.01% of the total mass of the sample.
The accuracy and standard deviation of the mass loss measurement method should be described in the test report.
4.1.4.4 Dryer
A device that can dry the test sample to constant weight without causing contamination or loss of volatile degradation products should be used.
The device should be described and detailed in the test report.
4.1.4.5 Vacuum source
A device that achieves a sufficient degree of vacuum (< 0.5 kPa) in the dryer.
The device should be described and detailed in the test report.
4.1.4.6 Separation device
Means can be used to separate debris generated during the degradation study. The device includes an inert filter and a temperature controlled centrifuge or both
Combined equipment.
The device is described and detailed in the test report.
4.1.5 Number of test samples
At least 3 test samples should be made for each test period. Sample recommendations include the finished product itself or a representative sample. Each sample should
Use a single container. A blank control sample should be made for each test period.
For effective statistical analysis, more samples should be used as appropriate during each trial period.
4.1.6 Shape and size of the test sample
The tester should recognize that the size and shape of the sample plays a key role in the amount of degradation products produced. If part of the finished device
Used as a test sample, the part of the device that is not in contact with the biological environment should be avoided or reduced as much as possible.
The size, shape and surface area of the sample should be chosen to be compatible with the degradation solution and to achieve a constant mass in the mass balance determination.
Within acceptable limits.
If the medical device consists of more than one material, a joint action should be considered. It is recommended that the device not tested in this section be planned
A representative portion of the material is also added to the test solution.
Note 1. In some cases, the preparation of samples may require the preparation of test samples in the same processing, cleaning, and sterilization methods used in the manufacture of the device.
Note 2. For absorbable polymers, it is not required to reach equilibrium with the degradation solution.
4.1.7 mass/volume ratio
The ratio of the mass of the test sample to the volume of the test solution is preferably at least 1 g. 10 mL. The sample should be completely immersed in the test solution.
Report and demonstrate the selection ratio in the test report.
The ratio of 1g.10mL is indeed feasible, but it is also recommended to consider the release of degradation products to interfere with degradation.
The process itself affects the rate of degradation and the balance of the degradation reaction.
4.1.8 Sample Pretreatment
To achieve mass balance, the sample should be dried to constant weight. If the device contains volatile components, the appropriate drying method should be chosen.
In this case, the drying method and conditions should be explained and demonstrated in the test report.
4.1.9 pH range
If the pH of the test solution is involved, the pH should be maintained within an appropriate range. Should be based on the site of use of the device (eg acidic stomach)
Choose the pH. Changes in pH due to physiological phenomena such as inflammatory reactions should be considered.
The selected pH should be explained and demonstrated in the test report.
Note. An increase in temperature can change the pH.
It will be appreciated that if the pH is not maintained within an appropriate range, the degradation products produced by the test may be produced under biological conditions.
Inconsistent in life.
4.1.10 Determination of mass balance
After taking the sample from the test solution, rinse it with a sufficient amount of analytical water. The rinse solution and the washed debris are collected into the test solution. will
Finally, the samples and fragments separated from the liquid by filtration or centrifugation are dried to constant weight, and then the mass balance is determined.
Note. Due to the dilution of a large amount of rinsing liquid, it is not conducive to the liquid phase analysis of leachables.
4.1.11 Final material characterization
Characterize the final material using the method of initial material characterization (see 4.1.3).
4.2 Accelerated degradation test
4.2.1 Temperature
The temperature selected should be above 37 ° C but below the temperature range at which the polymer melts or softens. If applicable, (70 ± 2) °C should be used.
The selected temperature is reported and demonstrated in the test report.
Note 1. Higher temperatures can cause changes in side reactions and additive solubility, which may not occur at lower temperatures. It is recommended to consider polymer materials
The thermodynamic properties of the additive.
Note 2. The melting point range information can be obtained by differential scanning calorimetry.
4.2.2 Test period
For instruments intended for more than 30 days, a test period of 2d and 60d should be used. For instruments using less than 30d, 2d should be used
And the test period of 7d. Other test periods can also be selected based on the intended use of the polymer or device under study.
If the selected temperature is not 70 ° C, it may be necessary to adjust the test period.
The test period should be reported and demonstrated.
Note. For instruments made of absorbable polymers, the test period can last until the instrument loses its integrity (refers to a single material).
4.3 Real-time degradation test in simulated environment
4.3.1 Temperature
The test was carried out at (37 ± 1) °C.
4.3.2 Test period
For devices that are expected to be used for more than 30 days, the test period of 1 month, 3 months, 6 months and 12 months should be used for less than 30 days.
For the device, choose the other 4 trial periods, but should include 30d. Others may also be selected depending on the intended use of the polymer or device being studied
Test period.
The test period should be reported and demonstrated.
Note. For instruments made of absorbable polymers, the test period can last until the instrument loses its integrity (refers to a single material).
5 test steps
5.1 General
The test procedure is described in 5.2, 5.3 and Figure 1.
Note. For the evaluation of crosslinked polymers, the next test will be based on mass balance and determination of polymer crosslink density, rather than molecular weight/molecular weight distribution.
Determination.
5.2 Initial material characterization
Initial material characterization should include the host polymer in the finished device as well as the residual materials and additives present. Because relying on analysis to get
This information is difficult, so it is best to get this information from the supplier or manufacturer of the material. The purity of the polymer and the formula
It is very important to fully characterize the additives used (see 4.1.3).
5.3 accelerated degradation test
5.3.1 Initial mass measurement
The test sample is dried to constant weight and the mass of the test sample is determined.
The drying methods and conditions should be stated and demonstrated in the test report.
5.3.2 Separation of samples, fragments and solutions
5.3.2.1 Filter separation
The filter was dried to constant weight at room temperature under vacuum to determine the mass of the filter. Use a constant weight filter to make the sample and possibly exist
The fragments are separated from the degradation solution. If necessary, vacuum or pressure filtration can be used, and the filtrate is washed 3 times with analytical water.
5.3.2.2 Centrifugal separation
After measuring the quality of the dried and cleaned centrifuge tube, the degradation test sample solution is transferred to the centrifuge tube, and the centrifuge tube is closed before centrifugation. will
The centrifuge tube is rotated on the centrifuge to obtain solid debris particles, and the supernatant in the centrifuge tube is gently transferred to a container, and then the analysis water is used.
The debris particles were suspended, centrifuged again, and the supernatant was gently transferred to a container. Repeat this step 2 times or more.
5.3.3 Analysis
5.3.3.1 Determination of mass balance
Dry the filter and its filtrate or centrifuge tube and its contents to constant weight at room temperature under vacuum, then measure the filter and its filtrate or
Calculate the mass loss of the sample by measuring the mass of the tube and its contents.
5.3.3.2 Final material characterization (samples and fragments)
The molecular weight and molecular weight distribution were determined using an appropriate method (see 4.1.11).
5.3.4 Evaluation
5.3.4.1 General
Figure 1 shows the flow chart of the test procedure.
5.3.4.2 First case (none/none)
There was no change in mass balance and molecular weight/molecular weight distribution.
No degradation was observed and the test was terminated; no real-time degradation tests were required.
Note. In some cases, it is necessary to conduct further research in accordance with ISO 10993-9 to confirm the results.
5.3.4.3 The second case (none/yes)
There is no change in mass balance, but the molecular weight/molecular weight distribution has changed. Check the subject sample and debris to see if there are degradation products. must
The real-time degradation test was started when necessary.
5.3.4.4 Third case (with/without)
The mass balance changed, but the molecular weight/molecular weight distribution did not change.
The polymer is not degraded and the leachables present in the liquid should be evaluated in accordance with other relevant part of ISO 10993. Start when necessary
Real-time degradation test.
Note. Leachables may not be produced under low temperature conditions, and real-time degradation tests in simulated environments may be considered based on the risk assessment of leachables.
Figure 1 Test procedure flow chart
5.3.4.5 Fourth case (with/with)
Both mass balance and molecular weight/molecular weight distribution change.
Characterize and quantify the leachables and polymer degradation products in the liquid and check the host sample and debris for degradation products.
Start the real-time degradation test if necessary.
Note. Degradation and leachables may not occur under low temperature conditions, and may be considered in a simulated environment based on the risk assessment of leachables and polymer degradation products.
Real-time degradation test.
5.4 Real-time degradation test in simulated environment
5.4.1 Initial mass measurement
Dry the test sample to constant weight. The quality of the test sample was determined.
5.4.2 Separation of samples, fragments and solutions
5.4.2.1 Filter separation
The filter was dried to constant weight at room temperature under vacuum to determine the mass of the filter. Use a constant weight filter to make the sample and possibly exist
The fragments are separated from the degradation solution. If necessary, vacuum or pressure filtration can be used, and the filtrate is washed 3 times with analytical water.
5.4.2.2 Centrifugal separation
After measuring the quality of the dried and cleaned centrifuge tube, the degradation test sample solution is transferred to the centrifuge tube, and the centrifuge tube is closed before centrifugation. will
The centrifuge tube is rotated on the centrifuge to obtain solid debris particles, and the supernatant in the centrifuge tube is gently transferred to a container, and then the analysis water is used.
The debris particles were suspended, centrifuged again, and the supernatant was gently transferred to a container. This step is repeated twice more.
5.4.3 Analysis
5.4.3.1 Determination of mass balance
Dry the filter and its filtrate or centrifuge tube and its contents to constant weight at room temperature under vacuum, then measure the filter and its filtrate or
Calculate the mass loss of the sample by measuring the mass of the tube and its contents.
5.4.3.2 Final material characterization (samples and fragments)
The molecular weight and molecular weight distribution were determined using an appropriate method (see 4.1.11).
5.4.4 Evaluation
5.4.4.1 General
Figure 1 shows the flow chart of the test procedure.
5.4.4.2 First case (none/none)
There was no change in mass balance and molecular weight/molecular weight distribution.
No degradation was observed and the test was terminated.
Note. In some cases, it is necessary to further study the results in accordance with ISO 10993-9.
5.4.4.3 The second case (none/yes)
There is no change in mass balance, but the molecular weight/molecular weight distribution has changed.
Check the subject sample and debris to see if there are degradation products.
5.4.4.4 Third case (with/without)
The mass balance changed, but the molecular weight/molecular weight distribution did not change.
The polymer is not degraded and the leachables present in the liquid should be evaluated in accordance with the relevant other part of GB/T 16886.
5.4.4.5 Fourth case (with/with)
Both mass balance and molecular weight/molecular weight distribution change. Qualitative and quantitative determination of leachables and polymer degradation products in liquids,
Also check whether the main sample and debris have degradation products, and then perform ISO 10993-1 and/or ISO 10993-17 as app......
 
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