Pharmaceutical industry standard of the people's Republic of China
 
Test method for sterile medical device package
Part 1 Test guide for accelerated aging
 
Released in 2009-06-16      Implemented in 2010-12-01
Issued by the State Food and Drug Administration
 
Preface
This part of YY/T 0681 revises use ASTM F 1980-02 “Standard guide for sterile medical device package accelerated aging test”. This part is equal with ASTM F 198 2 of equal-02 in the technical content. The main difference lies in deviation between editing differences and reference standard.
This part appendix A is the normative appendix, and appendix B is the descriptive appendix.  
The other parts of YY/T 0681 “Test method for sterile medical device package” will continue to develop¹⁾.
This part is responsible by the National Medical Infusion Appliances Standardization Technical Committee.
Chief development organization: Shandong Medical Equipment Products Quality Inspection Center and Guangdong Province Medical Device Supervision Inspection Institute.
This part main drafters: WuPing, Hong Liangtong, Hu Xianghua, and He Xiaofan.
 
1) The other parts will converse the related test method standard for medical package in ASTM F.
Test method for sterile medical device package
Part I Guide for accelerated aging test
1 Scope
1.1 This part of YY/T 0681 provides information for the compilation of accelerated aging scheme in order to quickly determine the impact of experience of time and environment on the sterile integrity of package and physical characteristics of package materials.
1.2 The information obtained in this part can be used to support effective date given by product package.
1.3 Guide for accelerated aging involves primary package entirety, doesn't involve these aspects that may be involved in the development of new product such as interactions between package and product or compatibility. In the process of material analysis before package design, compatibility and interaction of package and product should be involved.
1.4 This part doesn’t involve aging scheme in real time. However, aging research in real time can be used to testify the results of accelerated aging test with the same evaluation method.
1.5 The methods used to determine the package process include mechanical process, sterilization process, impact of transport and storage don’t involve in the scope of this part.
1.6 This part doesn’t involve all the safety aspects in the usage. Before the usage of this part corresponding safety and health regulation should be established and determine that its complying with the regulations is the responsibility of the user of this part.
2 Normative reference documents
The provisions in following documents become the provisions for this part through quotation of YY/T 0681 this part. For dated reference, subsequent amendments (excluding content of corrigenda) to, or revisions of, any of these publications do not apply to this part. However, parties to agreements based on this part are encouraged to investigate the possibility of applying the most recent editions of the documents indicated below. For all the reference documents not marked with dates, their latest version applies to this part.
GB/T 4857.2 Package   Basic tests for transport packages   Part II: Adjustment of temperature and humidity (GB/T 4857. 2-2005, ISO 2233: 2000, MOD)
GB/T 11605-2005   Method for humidity measurement
GB/T 15171   Test method for leaks in sealed flexible packages
GB/T 19633   Packaging for terminally sterilized medical devices (GB/T 19633-2005, ISO 11607: 2003, IDT)
ASTM D 4169 Performance test specifications for transport container and system
ASTM F 88   Test method for seal strength of flexible barrier materials
ASTM F 1140 Unconstrained and internal-pressure resistance destructive test method for medical flexible package
ASTM F 1585 Test guide for the permeability barrier medical package integrity
ASTM F 1608 Grade test method of microbial barrier for medical packaging air permeability packaging materials
ASTM F 1929 Test method for seal leakage in determination of porous material medical package with the dyeing liquid penetration method
3 Term and definition
3.1 General term
The terms and definition determined in GB/T 19633 apply to this part of YY/T 0681.
3.2 Special term
3.2.1 Accelerated aging AA
Samples are stored in a higher temperature (T_AA) in order to shorten the time to simulate real time aging.
3.2.2 Accelerated aging factor AAF
An estimated or calculated time ratio that attain physical properties changes of the same level with the package stored in real time condition.
3.2.3 Accelerated aging temperature T_AA
T_AA is a higher temperature in aging research. It is base on the estimated storage temperature and estimated usage temperature or both to calculate.
3.2.4 Accelerated aging time AAT
AAT is the length of time for carrying on accelerated aging test.
3.2.5 Ambient temperature T_RT
T_RT represents the storage temperature of real aging time samples in storage condition.
3.2.6 Package shelf life n
It is the length of time for the forecasted storage of packages that can keep its key performance parameters in ambient condition or regulated storage condition.
3.2.7 Real-time aging RT
It is the storage time for the samples in ambient condition.
3.2.8 Real-time equivalent RTE
The estimation of given accelerated aging condition is equivalent to the aging time in real time.
3.2.9 Zero time t₀
It is the starting time of aging research.
3.3 Symbols
Q₁₀: the aging factor when the temperature is increased or decreased 10℃
T_m: melting temperature of materials
T_g: glass transition temperature
T_a: alfa temperature; heat distortion temperature
4. Significance and Application
4.1 The physical properties of materials and the adhesive may degrade over time. Dynamic events in the storage and transportation may lead to loss of integrity of package.
4.2 GB/T 19633 describes, the manufacturer shall confirm the final package is at least in the shelf life within the medical device claims. In the harsh sale, storage, transport and aging conditions, and storage conditions regulated by manufacturer keep its integrity and package should not be damaged and opened.
4.3 Aging procedure in real time provides the optimum data for assuring package materials and package integrity not degrade over time. But in the market conditions that products being updated rapidly, the new products need to be put into the market in the shortest possible time. The aging research in real time can not meet this demand. Accelerated aging research provides another alternative method for us. In order to assure accelerated aging research can represent actually the real time effect, the real time aging research should be implemented synchronously with accelerated aging research. The real time research must implement up to the shelf life of product.
4.4 If lack of knowledge of evaluated package material, the conservative accelerated aging factor must be used. And it must illustrate the relationship between real time aging and accelerated aging by testimony of formation of documents.
Note: The determination of AAF is not in the scope of this guide.
5 Instruments
5.1 Chamber（or box）, its size can make the sample containers or packages be independent of exposure to a selected temperature and relative humidity circulating air.
5.1.1 Controlling instruments, can keep the room temperature in tolerance limits under atmospheric conditions required.
5.2 Humidity meter, is used to indicate relative humidity, the accuracy is ±2% relative humidity. Use psychrometer to directly measure the relative humidity or to check humidity meter. (Test method is described in GB/T 11605)
5.3 Thermometer, can use any instrument that can indicate temperature and accuracy is 1℃. Dry bulb thermometer of psychrometer can be used to directly measure temperature or check instruments with temperature indicator.
6. Accelerated aging theory
6.1 Accelerated aging of material refers to performance changes accelerated with time. Performance here refers to those that are related to safety and function of materials and packages.
6.2 In an aging research, make material or package’s exterior suffer a harsher and more frequent stress in a relative short time.
6.3 Accelerated aging technology is based on such assumption that the chemical reaction contained in material deterioration should follow Arrhenius reaction rate function. This function describes the same process as the temperature increases or decreases about 10℃, the chemical reaction rate doubling or halving (Q₁₀)^[2].
6.4 Determination of Q₁₀ includes the products were tested at various temperatures and determined diversity of reaction rate for temperature changing 10℃. To simulate the material deterioration under dynamic conditions is very complex and difficult, so it is not covered by this guide ^[3].
7. Accelerated aging scheme
7.1 Characterization of materials
Accelerated aging (AA) theory and its application are directly related to the constitution of packaging materials. Aspects to be considered are:
7.1.1 Constitution
7.1.2 Morphology (glass state, amorphous, semi-crystal, high crystal, % crystal, etc.)
7.1.3 Thermal conversion point (T_m, T_g, T_a)
7.1.4 Additive, process agent, catalyzer, lubricant, residual solvent and stuffing.
7.2 Accelerated aging scheme----design guide
7.2.1 Must consider temperature limit on basis of instruments and packaging materials characterization in order to assure proper conservative aging factor. According to the expectant storage conditions and packaging material characterization to determine the temperature of the test. Materials characterization and constitution are the important factors for establishing accelerated aging temperature limit. Selection of temperature is advised to avoid material to perform any physical transformation.
7.2.2 Room temperature or ambient temperature (T_RT) --- select the temperature that can represent storage and usage conditions of actual product.
Note: The temperature is often at the range of 20~25℃. 25℃ is considered to be conservative value.
7.2.3 Accelerated aging temperature (TAA) --- Combined consideration about material characterization in research, selects a temperature for accelerated aging test. The more the accelerated temperature is, the more the AAF is. Hence, the shorter for the time of accelerated aging. Must pay attention to, not only depends on the improvement of accelerated aging temperature to shorten the time of accelerated aging. Once the temperature is too high then material may react. While this can not happen at actual time temperature or room temperature. (See appendix A) Select aging temperature according to the following guide.
7.2.3.1 Select T_AA considering researching the thermal transition temperature of the material. It is advised to select any transition temperature below material or below temperature that make material distorted. For example, it is advised to select temperature that is below T_g of material 10℃ (More information see details at AAMITIR 17-1997).
7.2.3.2 T_AA is kept at or below 60℃ unless the higher temperature is testified to be proper. Does not recommend the use of temperature above 60℃ because in many polymerization system, the nonlinear variation probability of occurrence such as percent crystallinity, the formation of free radicals, and peroxides degradation, are relatively high. (More information see details in AAMI TIR 17-1997)
Note 3: If the package contains liquid or other labile constituent, may need to select lower temperature for the consideration of safety.
7.2.3.3 Due to the material characterization shows that increasing the aging temperature is not feasible, can only choose the aging test of actual time.
7.3 Determination of accelerated aging factor
7.3.1 With Arrhenius formula, usually take Q₁₀ equal to 2 is a conservative method to calculate the aging factor.
Note 4: In the literature of research the package with full characterization can be used more positive reaction rate coefficient. For example, Q = 2.2~2.5. The level and nature of damage must be similar to that reported in the literature to assure the reaction temperature coefficient and accelerated aging temperature can be kept in corresponding limit. This is the responsibility of the manufacturer. More information sees AAMI TIR 17-1997.
7.3.2 Calculate accelerated aging factor (AAF) according to formula (1):
AAF ≡ Q₁₀^[(T_AA^-T_RT^)/10]            (1)
Where:
T_AA---accelerated aging temperature, unit is ℃;
T_RT---ambient temperature, unit is ℃.
7.3.3 The accelerated aging time (AAT) being equal to the actual aging time need to be established through dividing expectant (or asked) actual time by AAF. Calculate according to formula (2):
AAT ≡ RT_Y/AAF                (2)
Where:
AAT--- accelerated aging time;
RT_Y--- expectant aging time;
AAF--- accelerated aging factor.
The figure of temperature corresponding time is shown in Appendix A.
7.3.4 When lack of package information in research, the above guide provides relatively conservative aging factor. This may produce risk to manufacturer because this method may not properly forecast shorter shelf life. Emphasize on the most safety of the patient because it is not easy to obtain accurate and satisfied shelf life by acquiring necessary information.
7.4 Accelerated aging scheme procedure
7.4.1 Select value of Q₁₀
7.4.2 Determine expectant package shelf life according to the market requirement and product requirement.
7.4.3 Determine the time interval of aging test, include zero time.
7.4.4 Determine test conditions, ambient temperature (T_RT) and accelerated aging temperature (T_AA).
7.4.5 Calculate test duration time with Q₁₀, T_RT and T_AA.
7.4.6 Determine the characteristics of package materials, sealing strength and integrity test, sample specification and accepted code.
7.4.7 Implement accelerated aging to sample in T_AA. In addition, implement real time aging to sample under ambient temperature (T_RT).
7.4.8 Evaluate package performance relative to initial package demand after accelerated aging, such as package sealing strength and package integrity.
7.4.9 Evaluate package and package performance relative to initial package demand after real time aging. The estimated AFF method is a simple and conservative method for evaluating the long-term performance of package. However, like all accelerated aging technique, must be testified by real time aging data.
7.5 Appendix B gives examples for package shelf life test scheme.
8 Test guide after aging
8.1 Must evaluate the physical performance and integrity of package and materials after having experienced aging (include accelerated and real time).
8.2 The selected test is advised to challenge to the most critical performance or the most easily aging stress caused by failure of materials or package. F1585 can be used for test guide of porous barrier medical package.
8.3 The considerable selected physical strength performance include resistance to bending, puncture resistance, stretch-proof and elongation-proof, tear resistance, shock resistance, abrasion resistance, mapping device, microbial barrier (test method F1608), sealing strength (test method F88) and bursting strength (test method F1140).
8.4 The packaging is subjected to a confirmation of package integrity test, such as trace gas detection, dyeing liquid leakage (test method F1929), gas bubble leakage (test method GB/T 15171) or microbial method (the microbial challenge test on the whole package). These methods must be determined and form into documents.
8.5 Establish accepted code first before starting any package shelf life test. The zero time data can be used for the comparison with package performance data at the end of the shelf life test.
9. Formation of documents
9.1 Accelerated aging
9.1.1The test scheme must be planned in written form before test. Regulate accelerated aging conditions (test temperature, humidity, circle, and ambient temperature), time, sample specification, package description, time interval of package sample, and tests in various time intervals.
9.1.2 The used box body temperature and calibrated instruments used for measurement and supervising aging conditions should form into documents.
9.1.3 Test standards and methods used for evaluating package should form into documents.
9.1.4 List used equipment table for physical and microbial test (include calibration data).
9.1.5 The test results after aging (include statistics method used to determine if package meet the performance specifications standards) should form into documents.
 
Appendix A
(Normative appendix)
Accelerated aging of polymer
 
A. 1 Accelerated aging that thermal aging of package at selected temperature is equal to room temperature aging in a year.
Time-temperature
When polymer thermal aging at selected temperature, the time relative to a year room temperature time (weeks)
Q₁₀ = △10℃ reaction rate constant
Assure room temperature = 22℃
Q₁₀= 1.8
Conservative rate recommended by FDA 1991.
Q10=2.0
Conservative accepted rate of first-order chemical reaction.
Q10= 2.0
Temperature   time/weeks
Weeks (equal to a year’s room temperature aging)
Aging temperature/℃
The temperature upper limit recommended by most of medical polymers
Figure A.1 Accelerated aging of polymers
 
 
Appendix B
(Descriptive appendix)
Examples for package shelf life test scheme
B.1 Select conservative AAF evaluating value, eg. Q₁₀=2. (See figure B.1)
  
Note: real time aging package test is equal to accelerated aging package test.
Figure B.1 Package shelf life test scheme
B.2 Determine aging time point corresponding to expectant shelf life, for example, 2-year and 3-year time point.
Note: Usually use trend analysis to characterize the impact of aging on materials and package features. The time point of accelerated aging should be set at least one point, but must have the time point corresponding to expectant shelf life (expectant shelf life is divided by aging factor). However, only use on accelerated time point, such risk will happen, namely, can not attain early warning from front accelerated time point and lead to test failure. The trend analysis is advised to consider at least three time point.
B.3 Prepare test samples according to determined production process.
Note: Package used for zero time, sterilization and accelerated aging may not package product or package simulating product.
B.4 Sterilize package with determined sterilization process. Sterilization process may influence the stability of materials or package. Before aging research, materials and package are advised to suffer maximum sterilization conditions or expectant used circling frequency.
B.5 If necessary adjusts samples’ situations according to GB/T 4857. 2. In proper cases, simulating transport according to ASTM D 4169. The packages used in the test should contain actual products.
Note: Generally the package performance test to determine long-term impact of transport and storage on package is included in the aging scheme. Whether to carry on performance test before or after aging depends on whether this research will simulate storage on hospital shelf or manufacturer shelf and subsequent transport. There may also be unnecessary circumstances, if it is known that package is unqualified or the performance limit is known (such as sealing strength, penetration, shock resistance, etc. ) and this is appropriate to the concrete packaged products which has been documented testified and can meet expectant products, then the physical test data are enough.
B.6 Start to implement real time aging and accelerated aging. In corresponding time period, adopts regulated accelerated aging temperature. The length of time of samples laid in the elevating temperature box can be calculated by formula (1) in 7.3.2 and formula (2) in 7.3.3. In the formula AAF refers to accelerated aging factor and AAT is accelerated aging time.
For example, Q₁₀= 2, ambient temperature=23℃, test temperature=55℃,
AAF=2.0^(5.5-23)/10;
AAF= 2.0^3.2=9.19;
AAT=365d/9.19;
AAT≡39.7d≡12 months (equivalent real time)
Note: Impact of humidity needs be considered accompany with temperature. This will combine high humidity period and low humidity period into test cycles. The aging cycle can be design to consideration of impact of humidity.
B.7 After accelerated aging, evaluate if the package performance can conform with desire.
B.7.1 If the accelerated aging results meet the accepted code, it only represents the shelf life of product is determined conditionally, and it should also depends on real time aging research results.
B.7.2 If the accelerated aging results can not meet the accepted code, the process of production needs to be inspected, or redesign the failed medical instruments or package, or tries to determine shorter shelf life, or waits to real time aging results. If real time aging results can be accepted, then shelf life can be determined. This is caused by accelerated aging procedure more strict than real procedure.
B.8 After real time aging, evaluate whether package performance meets desire.
B.8.1 If real time aging results meet accepted code, then shelf life of product can be determined.
B.8.2 If real time aging results can not meet accepted code, shelf life must reduce to the longest shelf life for the success of real time test. If product has been invested into market according to accelerated aging data, must carry on careful review, and form into documents, and adopt corresponding measures.
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