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GB/T 16886.7-2015 (GB/T16886.7-2015)

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GB/T 16886.7-2015
Biological evaluation of medical devices - Part 7. Ethylene oxide sterilization residuals
ICS 11.100
C30
National Standards of People's Republic of China
Replace GB/T 16886.7-2001
Medical device biology evaluation
Part 7. Ethylene oxide sterilization residues
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 part 7 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 16886.7-2001 "Biology Evaluation of Medical Devices Part 7. Ethylene Oxide Sterilization Residues", and
Compared with GB/T 16886.7-2001, the main technical contents are changed as follows.
--- Modified the introduction;
--- Revised 4.1 overview;
--- Revised 4.3 Allowable Limits. Added overview; modified ethylene oxide (EO) and 2-chloroethanol (ECH) allowable limits; added
Surface contact devices and implants can withstand exposure limits and modify the average daily contact dose of special devices EO and ECH;
--- Modified 4.4.3 product sampling;
--- Modified 4.4.6 product leaching;
--- Modified Appendix A gas chromatographic evaluation;
--- Modified Appendix B for the determination of EO and ECH by gas chromatography. extraction of EO and ECH standard solutions, instruments, reagents and products
The content is integrated into Appendix J and Appendix K; the precision, linearity, method detection limit and quantitative limit are determined;
Table B.2 Recommended gas chromatographic conditions;
--- Added Appendix C application GB/T 16886 series standard This part determines the process of EO and ECH residues in medical devices
Diagram and guide;
--- Revised the original Appendix D (now Appendix E) to determine the leaching conditions of EO residues;
--- Revised the original Appendix E (now Appendix F) Description. The title of the appendix was changed to "Description of the provisions of this part of GB/T 16886"; EO
And the ECH allowable limit determination is integrated into Appendix G and Appendix H respectively; and supplemented and improved;
--- Increased the determination of Appendix G EO Residue Limits;
--- Added the determination of the allowable limit of Appendix H ECH;
--- Increased the determination of the allowable limit of Appendix I EG;
--- Added preparation of Appendix J EO and ECH standards;
--- Added the test method for Appendix K Ethylene Oxide.
This section uses the translation method equivalent to ISO 10993-7.2008 "Medical Evaluation of Medical Devices Part 7. Residues of Cyclohexyl Ester Sterilization".
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 16886.3-2008 Biological evaluation of medical devices - Part 3. Tests for genotoxicity, carcinogenicity and reproductive toxicity
(ISO 10993-3.2003, IDT)
GB/T 16886.10-2005 Biological evaluation of medical devices - Part 10. Stimulation and delayed hypersensitivity test
(ISO 10993-10.2002, IDT)
GB/T 16886.12-2005 Biological evaluation of medical devices - Part 12. Sample preparation and reference samples (ISO 10993-12.2002, IDT)
GB/T 16886.17-2005 Biological evaluation of medical devices - Part 17. Establishment of limits for leaching materials (ISO 10993-17.2002, 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. Luo Hongyu, Shi Yanping, Pan Huaxian, Sun Guangyu, Liu Lili, Shen Yong, Xu Kai.
The previous versions of the standards replaced by this section are.
---GB/T 16886.7-2001.
introduction
The development, validation and routine control requirements for the ethylene oxide sterilization process for medical devices are given in the international standards established by ISO /TC198.
ISO /TC194 has developed a number of international standards that clearly define the biological testing of medical devices, the choice of tests, and the classification of devices.
Specific requirements are imposed on the amount of ethylene oxide and other sterilization process residues. Other international standards describe the specific requirements of specific product biology tests.
As stated in the introduction to ISO 11135-1.2007, when determining the suitability of ethylene oxide (EO) for sterilization of medical devices, it is important that
Ensure that EO, 2-chloroethanol (ECH) and ethylene glycol (EG) levels are present in patients with minimal risk to normal use. therefore,
It is important to consider the use of alternative materials and sterilization processes during the design and development of the product. EO is thought to lead to a series of students
The physical response, including the stimulation, organ damage, mutagenicity and carcinogenicity to humans and animals, and the development of ISO 10993-7
The reproductive effects of animals have been considered. The adverse effects of ECH and EG are also considered. Actually for most instruments
The exposure of EO and ECH is much lower than the maximum specified in ISO 10993-7.
In addition, when EO sterilization is selected, even if the provisions of this part of GB/T 16886 are not considered, the contact of EO residues should be reduced.
lowest. The requirements in this section are in addition to the biological evaluation and testing requirements for various types of medical devices described in GB/T 16886.1. For EO
The acceptability of sterilized instruments is demonstrated in conjunction with biological evaluation and testing requirements as well as EO sterilization process residue limits. When using EO
When ECH is present in a medical device for bacteria, the maximum allowable residue of ECH is also clearly defined. This part has taken into account the local effects (such as
Stimulate) and integrate into the EO given in 4.3.5.2 and Appendix G, and the tolerable exposure limit of ECH given in 4.3.5.3 and Appendix H
Among the quantities (TCL).
Medical device biology evaluation
Part 7. Ethylene oxide sterilization residues
1 Scope
This part of GB/T 16886 specifies EO and 2-chloroethanol (ECH) residues on a single piece of medical device sterilized by ethylene oxide (EO).
The allowable limit of retention, the EO and ECH detection steps, and the method of determining whether the device can be shipped. Also provided in the informative appendix
Other background information, including guidelines and application flow diagrams in this section.
This section does not include EO-sterilized instruments (such as in vitro diagnostic equipment) that are not in contact with the patient.
Note. The limit for ethylene glycol (EG) is not specified in this section.
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 10993-1 Biological evaluation of medical devices - Part 1. Evaluation and testing in the process of risk management (Biologicalevalua-
tionofmedicaldevices-Part 1.Evaluationandtestingwithinariskmanagementprocess)
ISO 10993-3 Biological evaluation of medical devices - Part 3. Tests for genotoxicity, carcinogenicity and reproductive toxicity (Biologicale-
valuationofmedicaldevices-Part 3.Testsforgenotoxicity,carcinogenicityandreproductivetoxicity)
ISO 10993-10 Biological evaluation of medical devices - Part 10. Stimulation and delayed hypersensitivity test (Biologicalevalua-
tionofmedicaldevices-Part 10.Testsforirritationanddelayed-typehypersensitivity)
ISO 10993-12 Biological evaluation of medical devices - Part 12. Sample preparation and reference samples (Biologicalevaluationof
medicaldevices-Part 12. Samplepreparationandreferencematerials)
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 defined by ISO 10993-1 and ISO 10993-17 apply to this document.
3.1
Simulated using leaching simulated-useextraction
Water leaching to simulate product use, by evaluating the level of residue that the patient or user is exposed to in the daily use of the device,
Leaching in accordance with the requirements of this part of ISO 10993.
3.2
Limit extraction exhaustiveextraction
Subsequent leaching to the extract is less than the amount of EO or ECH in the first extract, or the dip is measured.
There was no significant increase in cumulative residue.
Note. The definition of the above limit leaching is used because complete recovery of the residue is not possible.
4 requirements
4.1 Overview
Note. Information on determining the limit values and other important background information related to the use of this document are given in the informative appendix to this part of ISO 10993.
Information and guidelines.
This chapter specifies the maximum allowable residue of EO on a unit product after sterilization of ethylene oxide (EO) in medical devices. Such as ISO 11135-
As described in the introduction in.2007, when determining the suitability of EO for medical device sterilization, it is important to ensure EO, 2-chloroethanol (ECH) and
The residual level of ethylene glycol (EG) poses the least risk to patients who normally use the product. Moreover, when EO sterilization is selected, even if it is not considered
In this section, contact with EO residues should also be minimized. When there is an ECH in a medical device that uses EO sterilization,
Specifies the maximum allowable residual amount of ECH. Local effects (such as stimuli) have been considered and integrated into the recommendations given in 4.3.5.2 and Appendix G.
EO, and the tolerable contact limit (TCL) of ECH given in 4.3.5.3 and Appendix H. This section does not specify the EG of the device
Limited, because the risk assessment data (Appendix I) indicates that the calculated allowable limit level is higher than the possible residual amount in the medical device. however,
Acute hemodynamic and hemolysis reactions may occur after rapid intravenous injection of EG hypertonic compounds. Ethylene oxide sterilized
Medical devices are not expected to produce hypertonic solutions. The method for determining EO and ECH is given in 4.4.
The requirements of this part of ISO 10993 are in addition to the requirements for the biological evaluation and testing of medical devices in ISO 10993-1. For use
For EO-sterilized instruments, special attention should be paid to the requirements of ISO 10993-3 and ISO 10993-10. All applicable requirements in ISO 10993-1
The level of EO residue at the time of shipment of various medical devices should be considered.
The results of the device biology assessment may require more stringent limits than those specified in 4.3. The limits specified in 4.3 are intended to prevent
Set by systemic reaction.
4.2 Device classification
In determining the maximum daily dose of EO and ECH that a medical device is allowed to release to a patient, the device should be classified by contact time.
According to 5.3 of ISO 10993-1, the device should belong to one of the following three contact types.
a) short-term exposure. equipment that is used, accessed or contacted once, repeatedly or repeatedly within 24 hours;
b) long-term exposure. equipment that has been used or contacted for a long time, multiple times or repeatedly within 24 hours and 30 days;
c) Prolonged contact. A device that has been used or contacted for more than 30 days, once or repeatedly.
If the material or device is part of more than one time classification, more rigorous testing and/or evaluation considerations should be used. For multiple connections
The device that is touched should consider the potential cumulative effect and total contact time when deciding which classification the device belongs to.
Note. “Multiple use” in this part of ISO 10993 refers to the repeated use of the same device. For example. dialyzer.
4.3 Allowable limit
4.3.1 Overview
For each medical device classified under 4.2, the maximum allowable dose of EO and ECH released to the patient should not exceed the values given below.
The limits for long-lasting exposure and long-term exposure to the device are expressed in terms of the maximum average daily dose. Also follow the additional limit of the first 24h contact period
And, for permanent contact devices, the additional limit of the first 30 days of contact is to be followed. These limits define the EO and early release to the patient.
ECH limited. If there is suitable data available, if multiple instruments containing residues are used at the same time, it should be considered to reduce the limit proportionally, or when
When the device is used only for part of the contact period, it should be considered to increase the limit proportionally. These multiple device contacts are given in ISO 10993-17
Factor (CEF) and proportional contact factor (PEF). Appendix G describes the method used to determine the EO allowable limit, which is described in Appendix H.
The method of determining the ECH allowable limit, Appendix I describes the basic principle of determining the EG allowable limit.
4.3.2 Permanent contact devices
The average daily dose of EO to the patient should not exceed 0.1 mg/d, in addition to the maximum dose.
--- should not exceed 4mg in the first 24h;
--- The first 30d should not exceed 60mg;
--- should not exceed 2.5g in a lifetime.
The average daily dose of ECH to the patient should not exceed 0.4 mg/d, in addition to the maximum dose.
--- should not exceed 9mg in the first 24h;
--- The first 30d should not exceed 60mg;
--- should not exceed 10g in a lifetime.
4.3.3 Long-term contact devices
The average daily dose of EO to the patient should not exceed 2 mg/d, in addition to the maximum dose.
--- should not exceed 4mg in the first 24h;
--- The first 30d should not exceed 60mg.
The average daily dose of ECH to the patient should not exceed 2 mg/d, in addition to the maximum dose.
--- should not exceed 9mg in the first 24h;
--- The first 30d should not exceed 60mg.
4.3.4 Short-term contact devices
The average daily dose of EO to the patient should not exceed 4 mg.
The average daily dose of ECH to patients should not exceed 9 mg.
4.3.5 Surface contact devices and implants can withstand exposure limits
4.3.5.1 Overview
The unit of EO tolerance to exposure (TCL) is micrograms per square centimeter, and the unit of ECH tolerance to contact (TCL) is milligrams.
Each square centimeter, square centimeter is the patient-device contact area.
Note. The purpose of this clause is to prevent local irritative reactions from EO or ECH released by the device.
4.3.5.2 EO tolerable contact limits
The EO tolerance tolerance for surface contact devices and implants should not exceed 10 μg/cm2, or should be shown as ISO 10993-
Very mild irritating response as specified in 10.
4.3.5.3 ECH can withstand exposure limits
The contact tolerance of surface contact devices and implants ECH should not exceed 5 mg/cm2, or should be shown as ISO 10993-
Very mild irritating response as specified in 10.
4.3.6 Special circumstances
For multi-instrument systems, the limits for the instruments that each patient is exposed to should be specified.
The residual EO of each intraocular lens should not exceed 0.5 μg per day, or should not exceed 1.25 μg per lens. Single artificial crystal
The body mass is calculated as 20mg, and other intraocular instruments are calculated according to their masses in proportion to the limit. Due to the level of ECH that produces ophthalmia
Four times higher than the corresponding EO level, the acceptable level of ECH for intraocular devices made of chlorine-containing viscoelastic materials may need to be evaluated.
For blood cell separators used by patients and blood donors, the maximum allowable dose of EO is 10 mg, and the maximum allowable dose of ECH should not be
More than 22mg.
For blood oxygenators and blood separators, the maximum allowable dose of EO to the patient is 60 mg, and the maximum allowable dose of ECH to the patient
Should not exceed 45mg.
For instruments used in cardiopulmonary bypass procedures, the maximum allowable limit for EO should be 20 mg and the maximum allowable limit for ECH should be 9 mg.
For extracorporeal blood purification equipment, the EO and ECH limits for each device should be 4.6 mg, but may exceed EO lifetime.
Dosage.
For surgical orders that are expected to be in contact with intact skin only, the maximum allowable limit for EO is 10 μg/cm2 of tolerable contact limit, ECH
A 5 mg/cm2, or surgical list should show a very mild irritating response as specified in ISO 10993-10.
Note. Appendix F gives a description of certain instruments whose specified EO limits are inconsistent with general requirements.
Appendix C gives a flow chart and guidance for applying this part of ISO 10993 to determine the amount of EO residues in medical devices.
4.4 Determination of EO and ECH residues
4.4.1 Overview
4.4.1.1 Steps
The step of determining compliance with 4.3 includes extracting the residue from the sample, determining the amount of the residue, and measuring the contact surface of the device to
And analyze and interpret the data.
Danger. All work performed by the analyst and other personnel preparing the sample, including the use of chemicals and solvents, should be ventilated
Carry out the appropriate protective clothing in the closet and review the material safety data before using each chemical. According to occupation
Health and safety regulations, health care workers using ethylene oxide sterilized medical devices should take appropriate precautions.
4.4.1.2 Ethylene oxide
Ethylene oxide is a flammable gas that irritates the body and causes a strong reaction. In many cases, ethylene oxide has mutagenic
Sexual, fetal toxicity and teratogenic properties have adverse effects on testicular function and can cause damage to multiple organ systems in the body. In animals
In cancer studies, inhaled EO can produce several tumorigenic changes, including leukemia, brain tumors, and breast tumors, while ingestion or subcutaneous injection of EO is only
A tumor is formed at the contact site. One investigator reported that workers exposed to EO had higher cancer and mortality rates. However, in the near future
The results of the study did not match the findings, see references [177], [178] and [181]. In.1994, the International Agency for Research on Cancer (IARC)
The mechanism of action of EO is reclassified as a human carcinogen (category), see reference [75].
4.4.1.3 2-chloroethanol
2-Chloroethanol is a flammable liquid that irritates the body, is acutely toxic, and is rapidly absorbed through the skin at toxic doses. ECH
It has mild mutagenicity, has the potential to produce fetal toxicity and teratogenic changes, and causes damage to several organ systems in the body.
Includes the lungs, kidneys, central nervous system, and cardiovascular system. ECH was negative in animal carcinogenicity tests.
4.4.2 Determination of residual amount
The amount of EO and ECH (if necessary) accepted by the patient should be determined using a confirmed leaching and measurement method.
If the ECH is not detected by the method given in K.4.2 or K.4.7, there is no need to further monitor the ECH.
Note. Many gas chromatography (GC) methods use a capillary column instead of a packed column to measure EO, ECH, and EG results in a single injection.
In selecting the appropriate method for quantitative determination of EO and ECH (if necessary) (4.4.6), the guiding principle is to evaluate the patient's recipient
Quantity to meet the requirements of 4.3.
The limit leaching measurement shows that the residual amount is within the product requirements and meets all applicable limits in 4.3.
It is intended to use the extraction method to test the instrument. When using the limit extraction method, special attention should be paid to the limits of the first 24h and the first 30d as described in 4.3.
A variety of methods for determining the amount of EO residues are described and evaluated in the references. However, due to the manufacture of materials and sterile medical devices
There are big differences in the law. In some cases, it may still be possible to determine the amount of EO and ECH residues using the methods given in the references.
question. Therefore, any method that demonstrates that its analysis is reliable (ie, has certain accuracy, precision, linearity, sensitivity, and selectivity) is only
Can be used. The general validation requirements for gas chromatography are given in Appendix A.
4.4.3 Product sampling and “blank” samples
4.4.3.1 Product sampling
Samples used for residue analysis should be representative of the product. When selecting samples, you should be aware of the many factors mentioned in Appendix D.
Because these factors not only affect the initial level of residuals on the instrument components, but also affect the rate of residue dissipation. When the test sample is sterilized
These factors should also be taken into consideration when taking the batch for analysis in the laboratory. Take samples from the sterilization batch that has just completed the sterilization cycle and transport it to the far
The laboratory from the sterilization site or stored in the laboratory for later analysis will cause the residual amount on the sample to not reflect the other in the sterilization batch.
The level of residue in the product. Moreover, if the sample cannot be extracted and disposed of from the sterilization batch, it is not necessary to consider the effect of ventilation on the sample.
Tests should be conducted during each season of the year to establish the relationship between sample ventilation and sterilization batch ventilation.
Precautions should be taken to minimize the effects of laboratory conditions on the extraction of test samples from product sterilization batches in terms of ventilation speed
Or control this effect (see D.1.5). In addition, the safety of operators and analysts should be ensured. Immediately before the date of analysis or when the sample is retrieved
Samples should be placed with the sterile batch before freezing. It is advisable to minimize the removal of the sample from a controlled ventilation area to the start of the extraction.
The time between the products. If the analysis time is to be postponed, the sample should be frozen, sealed, transported and stored. Samples should be stored in dry ice when delivered overnight.
In the container, the container should always have dry ice throughout the transportation process until the package is opened in the laboratory. Can also be used during the required ventilation time
At intervals, samples were taken directly from the sterile batch and immediately placed in a headspace vial, sealed and sent to the laboratory for analysis. Or you can leach samples
The extract is sent to an analytical laboratory for analysis. If the extract is water, the leachate should always be kept cold during transport.
(< 10 ° C). It is advisable to test to determine the EG hydrolyzed by EO.
The sample for analysis should be placed in a fume hood and opened and removed from the package. Should follow any applicable instructions in the product label
Prepare samples. Sample leaching should be performed as soon as possible after removal of the device from the package or preparation for use.
4.4.3.2 "Blank" sample
In the same retention time, in order to ensure the absence of other sample components in the determination of the residue, it should be evaluated whether there is this in the "blank" sample.
Interference occurs by leaching the unsterilized sample using the same leaching process as the EO sterilized sample. In gas chromatography analysis,
If the substance extracted from the “blank” conflicts or overlaps with the residue retention time, the chromatographic conditions should be changed to separate the interference peak.
Separation in the peak, or other analytical steps should be used.
4.4.4 Sample/Liquid Ratio
The volume of liquid used to leach the residue on a representative part of the instrument or instrument should be sufficient for maximum extraction efficiency while maintaining
Detection sensitivity. The optimum volume of the extract depends on the nature and size of the instrument sample, so it should be based on the extraction method and sample size.
The minimum amount of extract reaches the maximum analytical sensitivity. An apparatus made of a highly absorbent material or a method of injecting an extract to extract a residue
The ratio of the instrument, sample/leaching solution may need to reflect the volume of liquid added. In either case, the ratio of sample to extract should not be
Reduce detection sensitivity.
4.4.5 Leaching time and conditions
The purpose of product leaching is to indicate the worst-case magnitude of the device that may be released to the patient in actual use. one-day exposure period
Short-term exposure limits, long-term exposure limits from one day to one month, and long-term exposure limits from one day to one month or even a lifetime. As Appendix E
As described in Appendix F, the limit leaching described below, if it is ensured that this short-term leaching method is reliable, for long-lasting contact devices
May be a useful way of leaching.
4.4.6 Product extraction
4.4.6.1 Overview
There are two basic extraction methods for determining the EO sterilization residue of medical devices. simulating the use of extraction as the standard method;
Reference is an acceptable alternative in some cases. The extraction method should be selected according to the intended use of the device. The push is given in Appendix K.
An example of a recommended extraction method.
The selected extraction method should represent the greatest risk to the patient in the intended use of the product, not just the efficiency of the analysis or the residual
The apparent concentration was minimized.
The leaching temperature and time should be determined according to the nature of the device acting on the patient and the time of contact, as described in 4.2 and 4.3. Leaching temperature
See ISO 10993-12.
Analysts should note that some instruments using simulated leaching may result in a relatively large elution volume, in which case
It may be necessary to greatly increase the detection limit for residue determination to meet the requirements of this part of ISO 10993.
Small instruments should be placed in a suitable container for leaching. When the instrument is too large to be fully leached, you may want to choose several representative ones.
The instrument components are leached to ensure data reliability.
To select a representative part of the device, either of the following two methods can be used. If there are several different materials, each group
The proportion of the total ma......
 
Source: Above contents are excerpted from the PDF -- translated/reviewed by: www.chinesestandard.net / Wayne Zheng et al.