YY/T 1302.2-2015 English PDF (YYT1302.2-2015)

This part of YY/T 1302 specifies process definition, validation, process effectiveness maintenance, etc. for the microbiological aspects of ethylene oxide sterilization. This part applies to the ethylene oxide sterilization process for medical devices and other related products or materials, provides solutions to various microbiological aspects in the development and validation of ethylene oxide (EO) sterilization processes.

YY/T 1302.2-2015
PHARMACEUTICAL INDUSTRY STANDARD
OF THE PEOPLE’S REPUBLIC OF CHINA
ICS 11.080.01
C 47
Physical requirements and microbiological
performance of ethylene oxide sterilization -
Part 2: Microbiological aspects
ISSUED ON: MARCH 02, 2015
IMPLEMENTED ON: JANUARY 01, 2016
Issued by: China Food and Drug Administration
Table of Contents
Foreword ... 3
1 Scope ... 4
2 Normative references ... 4
3 Terms and definitions ... 5
4 Process definition ... 5
4.1 Considerations of process definition ... 5
4.2 Process definition method ... 10
4.3 Troubleshooting of the sterilization process definition ... 17
4.4 Process challenge device (PCD) ... 19
5 Validation ... 23
5.1 Microbial performance qualification (MPQ) ... 23
5.2 Sterilization loading ... 25
5.3 Simulating expected process conditions ... 27
5.4 Confirming the release of load ... 27
5.5 Small batch release ... 28
6 Maintenance of process effectiveness ... 29
6.1 Failure investigation ... 29
6.2 Re-qualification ... 31
Physical requirements and microbiological
performance of ethylene oxide sterilization -
Part 2: Microbiological aspects
1 Scope
This part of YY/T 1302 specifies process definition, validation, process effectiveness maintenance, etc. for the microbiological aspects of ethylene oxide sterilization.
This part applies to the ethylene oxide sterilization process for medical devices and other related products or materials, provides solutions to various
microbiological aspects in the development and validation of ethylene oxide (EO) sterilization processes. This part also provides additional application guidelines for medical device manufacturers that use the ISO 11135-1:2007 and ISO/TS 11135-2:2008 standards, including those that use outsourced
sterilization plants or outsourced sterilization operations.
This part of YY/T 1302 does not include various factors that may affect the product's bioburden and sterilization process.
2 Normative references
The following documents are essential to the application of this document. For the dated documents, only the versions with the dates indicated are applicable to this document; for the undated documents, only the latest version (including all the amendments) are applicable to this standard.
GB/T 19974-2005 Sterilization of health care products - General requirement for characterization of a sterilization agent and the development, validation and routine control of a sterilization process for medical devices
ISO 11135-1:2007 Sterilization of health care products - Ethylene oxide - Part 1: Requirements for development, validation and routine control of a sterilization process of medical devices
ISO/TS 11135-2:2008 Sterilization of health care products - Ethylene oxide - Part 2: Guidance on the application of ISO 11135-1
ISO 11138-1:2006 Sterilization of health care products - Biological indicators development method is based on a number of factors, including the nature of the product's bioburden, packaging, production conditions, sterilization equipment, cost. Usually the biological indicator (BI) / bioburden (overkill) or other established methods are used to develop the parameters required to achieve the sterility assurance level (SAL) as required by the product. 4.1.2 Parameters on ethylene oxide exposure
Use the cycle development information and consider the SAL of the involved products to calculate the parameters of cyclic exposure of ethylene oxide. The recognized SAL includes:
a) For the product that contacts compromised tissue or a sterile part of the body, the SAL is 10-6;
b) For the product that does not contact the compromised tissue or a sterile part of the body, the SAL is 10-3.
Note: The SAL for products labeled “sterile” is usually 10-6. SAL requirements for products labeled as “sterile” may vary from country to country.
Products with multiple sterility assurance levels - Some products contain components or assemblies that are different for the intended use. In the kit, components for un-compromised skin or mucosa or that are not expected to come into contact with the patient have different SAL requirements than components that are expected to come into contact with internal tissues, nervous systems or blood. Based on the intended use of the device, the
sterilization process shall achieve the required kill rate for each component. 4.1.3 Product packaging
The product package shall be breathable and resistant to changes of
vacuum/pressure rise as well as vacuum/pressure rise rates.
4.1.4 Process development method
If the product is produced in a controlled environment and the amount of bioburden continues to be low, the process development method used to
identify sterilization parameters may be the bioburden/biological indicator method. But it needs understanding different microbial species on the product. 4.1.5 Considerations in sampling for process development study
Before the start of the study, the process development study shall consider the following two factors:
a) Determine the method of use: Partial negative method or direct counting method. If partial negative method is used to obtain data, it is
compare the suitability of BI/IPCD with the EPCD to be used for routine monitoring. Since the multi-layer penetration of the loading of conventional product pallet will affect the final kill rate, it takes longer to achieve the same kill rate as obtained in the test cabinet. Therefore, all parameters developed in the test sterilizing cabinet shall be determined in the production-type equipment as a part of the validation process.
In addition, the ratio of the test-type load volume to the available volume of the test-type cabinet shall represent the ratio of the load volume used in the production-type cabinet to the volume of production-type cabinet. The
comparison between test-type load and the production-type load shall be based on the equivalence of the load, which shall be equivalent not only in terms of weight/volume ratio, but also in terms of the challenge of the product and the loading configuration for the sterilization process.
4.1.6.3 Parameters
It may compare the following factors to determine the relationship between the studies as performed in both the test-type and production-type sterilizing cabinets:
a) Setting value and range of temperature inside the preconditioning room (if used);
b) Setting value and range of relative humidity inside the preconditioning room (if used);
c) Preconditioning time;
d) Setting value and range of temperature in the sterilizing cabinet;
e) Setting value and range of relative humidity in the sterilizing cabinet; f) Setting value and range of gas concentration in the sterilizing cabinet (if there is a gas analysis instrument in the test sterilizing cabinet);
g) The sterilant (gas mixture) used (i.e., the volume fraction of all gases); h) Gas residence time;
i) Vacuum pressure / transfer depth and rate;
j) Microbial kill rate;
k) Setting value and range of temperature in the analysis room (if used); l) Range of temperature and relative humidity in the load.
It is generally considered that the position of lowest temperature or the position Note: At the end of the cycle, it shall retrieve the BI and product sample as soon as possible. Once the sample is retrieved, follow the confirmed method to carry out the biological test.
4.2.2.2 Direct counting method
Survival curve method or direct counting methods include applying the infected PCD to increasing EO exposure time, taking BI out of the PCD, calculating (counting) the number of viable microorganisms on each BI. As described in Appendix A of ISO 11135-1:2007, this method may obtain the number of viable microorganisms used to establish a survival curve.
Generally, the microbial kill rate follows the first-order kinetic principles. When the sterilization conditions (i.e., process temperature, RH, EO concentration) remain within specification range during the residence time period, the kill rate approaches a straight-line in a semi-logarithmic plot. Use the regression analysis of the logarithm of viable bacteria and the corresponding gas exposure time, the relevant technologies may be used to establish a survival curve (Figure 1 and Figure 2). Then, use the slope of the regression line to establish the SLR of the microbial biomass of the PCD (i.e., the time required for the microbial count to decrease by 90% or 1 logarithm).
Note: Under a given set of conditions, the SLR of a PCD is a specific value. Multiple variables, such as product size and complexity, sterilizer size, loading configuration, may affect the heat, moisture, EO permeability during routine sterilization process. 4.2.2.3 Partial negative method
Partial negative analysis method means that during the sterilization cycle, some, but not all, biological indicators are inactivated. It includes HSK, limited HSK, SMC methods.
In general, the above three calculation methods may estimate the D value associated with a given sterilization process, to determine the appropriate EO exposure time during a conventional sterilization process.
If these studies are carried out in a test-type/study-type cabinet, since the test- type/study-type cabinet is different from the production-type cabinet in terms of loading volume, tray configuration, density, performance characteristics of sterilizing cabinet, the actual production exposure time as required to achieve the same killing level may be different. It shall use a partial cycle of “killing all” to determine that the BI survival curve of the sterilization process does not cause serious tailing.
4.2.3 Biological indicators / bioburden
The biological indicator/bioburden method refers to the use of the amount of BI method or the full bioburden method as developed during the use period, but shall ensure that the sterilization cycle can reach the target SAL.
It shall evaluate the effects of changes in product components, packaging, production methods, or environment on the product’s bioburden and its
resistance.
The overkill cycle includes the use of BI with a bacterial count of 106 placed inside the product. This procedure shall allow the BI sample to be sterile. This process can be performed twice to achieve 12SLR, or the data obtained using the process can be calculated to achieve the desired exposure time of the SAL. When using a dilution gas to control the pressure of the sterilizing cabinet during EO exposure, it is necessary to consider the effect of the average concentration of continuously reduced EO gas in the surrounding headspace of the load. 4.2.4.2 Cycle calculation method
One of the methods as described in A.3 of ISO 11135-1:2007 is used to
establish conventional processing parameters for a log reduction value of biological indicator spore of at least 12SLR. When conducting these studies, it shall consider the followings:
a) It shall implement all test cycles when the process temperature, humidity, average concentration of EO gas are less than or equal to the proposed
lower limit conditions, to establish minimum production parameters to
ensure acceptable kill rates.
b) It requires increasing the exposure time to compensate for the injection and removal time of sterilant. For example, use half of the time for injection and removal of sterilant as the estimated equivalent exposure time. If used, it shall include the time of injection of nitrogen blanket.
c) If using the counting method, the amount of viable bacteria as obtained in one cycle shall be less than 1 × 101, to ensure that no tailing occurs. It shall establish and comply with a linear correlation statistical range of log reduction.
d) It shall determine and validate that the calculated 12SLR exposure time is reproducible in a production-type sterilizing cabinet which has production load. This can be achieved by running a sterilization cycle to obtain the calculated 9SLR exposure time, during which the biological indicators
contained in the appropriate number of identified PCD are sterile.
4.2.5 Other methods - Full bioburden method for cycle development
4.2.5.1 Overview
The implementation of full bioburden method may also use the product sample which contains the bioburden as the biological indicator. In this method, use the product sample of known bioburden, instead of biological indicator, to
implement the direct counting method or partial negative method as described in A.3 of ISO 11135-1:2007. If using this method, it shall pay attention to the following:
a) Determine that the sample bioburden used shall be a representative
sample of the product batch that passes the test.
b) Samples of the products used shall be taken from regular production
batches, to ensure they are truly representative.
c) When calculating the exposure time of the production cycle, it shall consider the kill rate as generated during the injection and removal
process of the sterilant.
d) The test cycle parameters for temperature, humidity, gas concentration shall be equal to or lower than the recommended minimum value for the
product cycle.
e) Propagation of bioburden microorganisms may result in reduced EO
resistance, thereby resulting in a reduction in SAL in the final process as relative to the original resistance of the isolate under natural conditions. 4.3 Troubleshooting of the sterilization process definition
4.3.1 Overview
In the event that all positive results, all negative results, and/or linear slopes are not available, it may take the following measures.
4.3.2 Obtaining full positive result
4.3.2.1 Method of using a new process to obtain full positive result
If in the study where the EO residence time is zero, a partial or total kill rate is produced, the sterilization process may be too harsh and it is recommended to re-evaluate the sterilization parameters during the cycle development. It may reduce the gas concentration or conditioning temperature to modify this sterilization process. Use new parameters to finish the process development. In the conventional conditioning process, it may implement a more severe cycle or a cycle used in the study, in which the requirements for product function, packaging function and EO residue level are met, meanwhile the quality
management documents applicable to the product parameter release (if used) is completed.
The above steps may not solve the problem. This may be due to the nature of the infected product in the product loading, but it shall be demonstrated that the infected product is completely inactivated to ensure the SAL of the product. Similarly, it shall also consider an audit of the product or its packaging, to ensure that both are not the cause of the problem.
4.3.4 Obtaining a full negative result
When positive results cannot be eliminated, it shall evaluate the following as potential causes:
a) Incomplete humidification or low humidity of load/sample;
b) Distribution of inoculated bacteria (bacterial products only);
c) The conditions reached by some parts of the sterilizing cabinets are inconsistent;
d) The distribution of entire loading temperature is not balanced;
e) Excessive humidification (> 90%);
f) Product design;
g) Packaging design;
h) Inappropriate process parameters.
If full negatives are still not available, it shall review this process and consider increasing temperature and EO concentration or reconfiguring the load, to aid in the penetration of the sterilant. It shall operate with caution, to avoid affecting the integrity of the sterilized product or package.
Note: Even with a harsh and well-perfected cycle, within the reasonable exposure time of this cycle, the device design may result in a sub-negative result in the worst-case position of the product. In this case, the product may need to be redesigned, to improve the penetration of the sterilant or may require sterilization methods other than EO sterilization.
4.4 Process challenge device (PCD)
4.4.1 Overview
The process challenge device (PCD) is a microbial challenge system, for assessing the kill rate of selected process parameters. Typically, the PCD contains a biological indicator of a known number of spores of Bacillus astrophaeus or another microorganism that has been shown to have an EO
products which are most difficult to sterilize in the load.
It shall regularly review the relationship between the EPCD and the sample of the contaminated product, to determine that the sterilized product has not changed, and the EPCD still represents the products which are most difficult to sterilize in the load.
4.4.3 Suitability of PCD
After selecting the PCD, use partial cycle study to demonstrate the suitability of the selection. The results of this study shall show that the resistance of the PCD is greater than or equal to the resistance of the bioburden at the position most difficult to sterilize of the product (see 8.6 of ISO 11135-1: 2007). When the product is made from natural fibers and materials or a production process which contains a high humidity, these studies are especially important.
If these studies show that the bioburden’s resistance of the product is greater than the expected PCD resistance, it selects one of the following methods: a) Develop a new PCD that has the same or greater resistance to the
bioburden of the product;
b) Before sterilizing, pre-condition the product to reduce the amount of bioburden;
c) Evaluate the product, process, or both, to determine how to reduce the amount or resistance of the bioburden (e.g., by changing the raw materials or manufacturing processes used, by improving the manufacturing
environment or modifying product design, etc.);
d) Use full bioburden method to make confirmation. If the external PCD’s resistance is stronger than the internal PCD, in the half-cycle validation study, it may not be necessary to prove that the external PCD is
completely killed. If the study indicates that the internal PCD is placed in the position “most difficult to sterilize” and no viable bacteria are detected on the internal PCD, this method is effective. If, in the validation process, it requires that the external PCD which has higher resistance is all
inactivated, the resulting cycle exposure time will provide an additional safety factor that exceeds the minimum requirements.
Note: When conducting a comparative study, it is recommended that the batches and preparations of the biological indicators used for the samples be the same, to reduce the effects of resistance changes between different batches of BI.
4.4.4 Example of PCD
4.4.4.1 Example of internal PCD
showing higher difficulty in sterilization.
Note 1: When the sterilizer load contains more than one product family, it shall use the PCD that represents the most challenging product family to monitor the sterilization process.
Note 2: If the user changes the packaging of the biological indicator, it shall re-evaluate the impact on the resistance of the biological indicator.
5 Validation
5.1 Microbial performance qualification (MPQ)
5.1.1 Overview
Typically, performance qualification requires three consecutive successful validation cycles, to demonstrate the reproducibility of the first cycle. The first successful cycle indicates that the fatality rate of the proposed cycle can be reached. The second successful cyc...