YY/T 1302.2-2015 PDF English
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Physical requirements and microbiological performance of ethylene oxide sterilization. Part 2: Microbiological aspects
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YY/T 1302.2-2015: PDF in English (YYT 1302.2-2015) 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 cycle indicates that the cycle can be
successfully repeated. The third successful cycle proves that the cycle can be
reproduced. The performance qualification shall be run in the production-type
sterilizing cabinet. The set parameters are same as the lower limit or lower than
the lower limit of the conventional parameters. Typically, setting one or more
process variables are same to the lower limit or less than the lower limit of the
conventional parameters. After finishing the IQ and OQ test, the performance
qualification is usually initiated. If the sterilization cycle fails, it requires
implementing a thorough investigation to determine the cause of the failure. If
a failure occurs due to mechanical or sterilizer-related failures, it shall take
corrective action and make corrections. If applicable, repeat this sterilization
cycle. If the failure is caused by insufficient sterilization process, it shall adjust
this process and make repeated qualification, until finishing three consecutive
successful cycles.
5.1.2 Confirming the cycle selection criteria
After reviewing the product design, materials, packaging, select the appropriate
process. The selected parameters will inactivate the microorganisms, without
adversely affecting the functionality of the product or packaging. If the specified
lower limit of process parameter does not demonstrate the kill rate of the
sterilization cycle, implement partial cycle at the lower limit of the process
variables to demonstrate the validity of the sterilization cycle of the lower limit
of the established specification. In some cycles, if it is not possible to adjust the
conditioning before and after sterilization, it may shorten the preconditioning
time, to obtain the minimum load temperature as specified in ISO 11135-1:2007.
beginning of sterile test, the EO-treated spore recovery rate decreases over
time. If it is proved that the analytical stage can provide a partial SLR, the final
specification to determine the sterilization process shall include the analytical
time and conditions.
Note: If possible, it shall design a validation cycle, so that the kill rate as generated
during the analytical phase of the sterilization process is not included in the time
required to achieve the required SAL. BI shall be removed from the load before
analysis. At the end of the cycle, it shall remove the BI and test samples as soon as
possible.
Samples shall be transferred into the laboratory as soon as possible after
conditioning (recommended within 48 hours). It shall establish the transport
services. The requirements for sample transportation shall be clearly outlined
in the validation scheme and post-conditioning instructions. If the sample test
is not stated in the standard operating procedures, it shall be clarified in the
scheme.
When the laboratory receives it, the product and biological indicators shall be
placed in the growth medium and cultured at the temperature and time as
recommended by the manufacturer, unless there are other established
alternatives.
If the product is positive during the test, it shall carry out a failure investigation.
Things to consider are explained in 6.1. If the cause cannot be determined, it
shall re-evaluate the parameters of the validation cycle. If possible, modify the
parameters appropriately. If the specific cause is identified, according to the
requirements of scheme or internal quality system, repeat the test for the
sample exposed during the validation cycle. If additional samples are not
available during a specific validation cycle, it may use a new test sample to
repeat this cycle.
Note: During the validation process, it shall carry out a bacteriostatic-antimicrobial test
to evaluate and record the impacts of the product’s EO adsorption on the sterility test
sample.
The product’s positive control shall be subjected to the same conditions as
loading in accordance with the actual situation, as well as all stages, including
the sterilization stage.
5.2 Sterilization loading
5.2.1 Overview
The sterilized load as used in the microbial performance qualification study shall
represent the product to be sterilized. A representative load may include the
effects of loading differences. Load configuration differences include, but are
not limited to, the number of cartons placed on the tray, the arrangement of the
cartons on the tray, the density of the product loaded on the tray, the wrapping
film of the cartons on the tray. In microbial performance qualification, it may use
the following several methods to handle the differences in such load
configurations:
a) According to the previously formed documents, study and select the worst
load configuration of the entire product family;
b) According to the technical judgment of the ethylene oxide sterilization
expert (the theoretical basis shall be documented), determine the worst
load configuration;
c) When the worst load cannot be identified in advance, in the study of
microbial performance qualification, the recommended load configuration
can represent all load configurations.
5.2.5 Repeated use of loading
In the study of microbial performance qualification, when the sterilized load can
be repeatedly used (products, fillers, or simulated products), adequate analysis
of loading is important.
After multiple uses of the product loading, the humidity and gas infiltration affect
the response ability of the package to the physical conditions of the sterilization
process. After multiple use of the load, it shall consider re-pack it, to ensure that
the validation study will not be adversely impacted.
5.3 Simulating expected process conditions
It shall consider the effect of the coldest or driest environment of the year on
EO sterilization, as shown in YY/T 1302.1.
5.4 Confirming the release of load
If the following requirements are met, the product load used for validation study
may be released to the customer:
a) If applicable, the bioburden level of such products is within normal limits;
b) The validation process parameters have been successfully obtained;
c) After the partial gas exposure cycle is successfully completed, the load
has been re-sterilized in the full cycle;
It shall meet the remaining validation requirements. Meanwhile, it shall record
the principles for developing the validation cycle’s criteria, to ensure obtaining
and using historical information. Where applicable, it may be used to
demonstrate product equivalence, cycle equivalence, or both.
6 Maintenance of process effectiveness
6.1 Failure investigation
6.1.1 Overview
If due to a biological failure, it is confirmed that the study fails to meet the
established requirements, it shall carry out a failure investigation and maintain
the records. Failure investigations shall focus on potential differences (changes)
between the failure cycle and the previous success cycle. Issues to consider
include but are not limited to the following:
6.1.2 Sterilization process or equipment problems
6.1.2.1 Potential process differences
Potential process differences include but are not limited to:
a) Whether the physical environment in which the loading is located before
conditioning has changed (e.g., the loading temperature before
preconditioning);
b) Whether the recorded process parameters have changed significantly
during preconditioning, conditioning or exposure process;
c) Whether the environment of the EO storage area has changed significantly;
d) Whether there is a significant change in the source or purity of the vapor
source;
e) Whether all key personnel involved in the process are properly trained.
6.1.2.2 Potential device differences
Potential device differences include but are not limited to:
a) Whether the sterilizing cabinet has been modified;
b) Whether the monitoring equipment or process equipment has changed;
c) Whether preventive maintenance and calibration have been implemented
c) Whether the procedures for preparing and testing the PCD comply with
the requirements;
d) Whether there are new employees involved and whether they are trained;
e) Whether the entire laboratory has recently been subjected to preventive
maintenance and calibration of the equipment;
f) Whether the environment of the test area has undergone physical or
microbiological changes; whether microbiological deviations have
occurred; whether the established limits have been exceeded;
g) In the process of receiving, quality control inspection, storage, use of BI,
whether the handling and storage methods are different.
6.1.4.2 Biological indicators (BI)
6.1.4.2.1 Biological indicator issues
Biological indicator issues include but are not limited to:
a) Whether BI or packaging materials come from different batches or
suppliers;
b) Whether BI is in use during its validity period (i.e., it does not exceed the
validity period as specified by the manufacturer);
c) Whether BI and PCD preparation are done in the same way;
d) Before, during and after the transportation, EO-conditioning, post-
sterilization conditioning, whether the sample is stored under specified
conditions;
e) Whether the BI positive and negative controls are qualified.
6.1.4.2.2 Solution
If the cause can be clearly indicated, such as human error or equipment failure,
and the cause is found to be an independent event, it is acceptable to repeat
this cycle. If the reason cannot be clearly indicated, it is recommended to
implement a partial cycle to verify the cycle parameters. If necessary, it may
adjust the cycle parameters. Meanwhile it is recommended to repeat the
validation, until the three consecutive cycles are successfully completed.
6.2 Re-qualification
6.2.1 Main items of re-qualification
......
Source: Above contents are excerpted from the PDF -- translated/reviewed by: www.chinesestandard.net / Wayne Zheng et al.
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