YY/T 1302.1-2015 PDF English
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Physical requirements and microbiological performance of ethylene oxide sterilization - Part 1: Physical aspects
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YY/T 1302.1-2015: PDF in English (YYT 1302.1-2015) YY/T 1302.1-2015
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 1: Physical 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 ... 4
4 Equipment for ethylene oxide sterilization process ... 5
5 Determine the minimum temperature of product before preconditioning ... 12
6 Calculate humidity ... 14
7 Calculation of ethylene oxide concentration ... 17
8 Calculation by the use of flammability curves ... 19
9 Guide to statistical contrast methods for determining process equivalence 20
Appendix A (Informative) An example of a method for determining the
concentration of ethylene oxide gas based on the physical formula of an ideal
gas ... 26
Appendix B (Informative) Calculation example using a flammability curve ... 29
Physical requirements and microbiological
performance of ethylene oxide sterilization -
Part 1: Physical aspects
1 Scope
This part of YY/T 1302 specifies the physical requirements for the sterilization
of ethylene oxide.
This part is intended to provide guidance for sterilization equipment,
preconditioning, calculation of relative humidity, concentration of ethylene oxide,
flammability, statistical applications in process equivalents.
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 3836.1-2010 Explosive atmospheres - Part 1: Equipment - General
requirements
GB 3836.14-2014 Explosive atmospheres - Part 14: Classification of areas
- Explosive gas atmosphere
GB 50169-2006 Code for construction and acceptance of grounding
connection electric equipment installation engineering
GBZ 2.1-2007 Occupational exposure limits for hazardous agents in the
workplace Part 1: Chemical hazardous agents
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
3 Terms and definitions
The terms and definitions as defined in ISO 11135-1:2007 as well as the
following terms and definitions apply to this document.
GB 3836.14-2014;
b) The interior of the sterilizing cabinet shall also comply with the
requirements or equivalent requirements of the category T2 electrical
equipment in the zone IIB0 in GB 3836.1-2010 and GB 3836.14-2014;
c) Equipment and piping shall comply with the grounding requirements of GB
50169-2006 or other equivalent requirements;
d) The storage, disposal, use of ethylene oxide shall comply with relevant
national regulations;
e) When designing the sterilization cycle, the environment inside the
sterilizing cabinet shall be kept non-flammable.
4.1.2 Under abnormal conditions (such as equipment failure, power interruption,
test cycle, etc.), when the product is exposed to an ethylene oxide sealed
environment and lack proper ventilation (failure of air exhaust or ventilation
equipment, etc.), it shall pay attention to the hazard as caused by the
accumulation of the flammable and explosive ethylene oxide. The possibility of
this hazard is independent of the mixture used.
4.1.3 Fume hoods or ventilation areas (buildings, rooms) shall be equipped with
equipment that removes sterilized gases and restores them to a safe level (see
GBZ 2.1-2007).
4.1.4 For electromagnetic interference as caused by the equipment or
environment or both inside the workshop (such as a mobile phone) or outside
the workshop, it shall evaluate the impact on the sterilization process. When
designing the plant, it shall comprehensively consider the infrastructure
(appropriate grounding, shielded cables, circuit isolation, protective building
materials, etc.), to avoid interference with the sterilization process.
Note: For guidance on electromagnetic interference, see GB/T 17799.
4.2 Preconditioning area (outside sterilizing cabinet)
4.2.1 If the product is heated and humidified in the workshop, there shall be
equipment to adequately control and record the room temperature and humidity.
In ISO 11135-1:2007, humidity is only expressed in terms of relative humidity.
Humidity may also be recorded in other engineering units, such as dew point,
absolute humidity, water vapor pressure.
4.2.2 It shall use supporting air circulation to meet the requirements for the
temperature and humidity control and its distribution as specified in the
available rooms (areas).
4.2.3 During identification of equipment, it shall establish and record the air
4.3.4 It shall select the sensors which are suitable for the ethylene oxide
sterilization process (such as pressure, temperature, gas concentration, relative
humidity sensors, etc.).
4.3.5 If there is a deviation in the sterilization process, it shall use audible and/or
visual alarm to alarm the operator.
4.3.6 Sterilizing cabinets shall be mechanically (interlocked) designed to
prevent inadvertent contact loading prior to the completion of the sterilization
cycle. If the sterilization cycle fails, it shall be limited only to understanding the
fault condition and the employee contact loading which may has risk.
4.3.7 When the sterilizing cabinet is used to condition the product loading
(regardless of static or dynamic), it shall be able to adequately control and
record the sterilizing cabinet’s temperature, pressure, other parameters to
achieve the desired process conditions.
4.3.8 Since the process conditions within the sterilizing cabinet may reach the
dew point of the water, it shall evaluate the condensate on products and
equipment. In particular, the condensate at cold point will reduce the partial
pressure of water vapor in the sterilizing cabinet, resulting in additional steam
injection to maintain a constant pressure under static processing conditions.
Excessive condensate in the sterilizing cabinet or on the product/package will
impede the killing effect of ethylene oxide gas on the microorganism of the
product; meanwhile it will adsorb ethylene oxide gas and ethylene oxide
derivative. The adsorbed ethylene oxide gas will diffuse when the product
loading is ventilated or stored, endangering the health of the staff. In addition,
the condensate in the sterilizing cabinet or on the product load will re-evaporate
and make the humidity level in the headspace of the sterilizing cabinet exceed
the confirmed level.
4.3.9 For equipment designed to heat and humidify, the sterilizing cabinet shall
avoid direct humidification of the product loading (such as the use of manifolds
or partitions). Generally, it uses steam valves, traps and/or coalescing filters to
control the quality of the steam which enters the sterilizing cabinet. Steam water
shall not contain contaminants that affect the sterilization process or damage
the sterilizing cabinet or sterilized load.
4.3.10 It shall select the equipment that has sufficient control over the
parameters as provided and as selected by the monitoring, such as:
a) Pressure control;
b) Rate control (such as exhaust or gas injection);
c) Temperature control;
4.3.14 The distribution of temperature, humidity, sterilization gas shall comply
with the requirements of the sterilization process. It shall specify the available
sterilizing cabinet’s boundaries and product loading dimensions, to eliminate
the adverse effects due to too closeness of sterilized loading of the product and
the interior walls of the cabinet. These effects may include gas circulation
problems due to product’s obstruction, uneven heating of product loading due
to direct contact to cabinet wall as well as the interference of product to the
process monitoring instrument.
4.3.15 It shall use the infrastructure and/or engineering controls to ensure the
specified steam, appropriate gas, air and/or nitrogen are injected into the
cabinet.
4.3.16 It shall configure nitrogen and air injection filters to protect products and
equipment. If compressed air is in contact with the product, the air shall be
protected or treated, to ensure it is dry, oil-free and filtered.
4.3.17 When sterilizing products that do not contain protective packaging, it
shall follow the quality system of the manufacturer to configure sterilizing filter.
4.4 Ventilation system
4.4.1 After gas exposure, if using a room/zone/cabinet to ventilate the product,
it shall be equipped with equipment which continuously control and record the
air temperature. It shall be equipped with facilities which regularly check the air
flow and/or ventilation rate during the ventilation period, to verify compliance
with the originally validated performance specifications. If fresh air flows into
and out of the room/zone/cabinet changes, the temperature distribution of
room/zone/cabinet may exceed the confirmed tolerances. This will affect the
proper resolution of the ventilation product and/or the problem of employee
exposure to hazards.
4.4.2 The specified limits for the accuracy and reproducibility of measuring
instruments used in the ventilation process shall be in accordance with the
process requirements.
4.4.3 Ventilation rooms/zones/cabinets shall be easy to clean. The construction
materials are adapted to the cleaning process. In accordance with good
hygienic practices and manufacturer-defined procedures, carry out the cleaning
process.
4.4.4 It shall be equipped with facilities that identify the loading of different
products in the ventilated room/zone/cabinet.
4.4.5 In the event of a deviation, it shall use an audible and/or visual alarm to
prompt the operator.
n) Systems that supply steam and heat;
o) Vacuum equipment;
p) Weighing system;
q) Valve;
r) Pressure transmitter;
s) Timer;
t) Printer.
4.7 Safety
4.7.1 It shall use ethylene oxide gas with caution, because it is toxic, potentially
flammable, explosive. When selecting ethylene oxide sterilization and
ventilation equipment, it shall comply with national health and environmental
protection regulations.
4.7.2 It shall carry out risk assessment (sch as batteries and capacitors) on any
product which contains energy-storing components.
4.7.3 The exposure to ethylene oxide in the workplace shall comply with the
occupational exposure levels of GBZ 2.1-2007.
5 Determine the minimum temperature of product
before preconditioning
5.1 Overview
5.1.1 In 9.5.4 a) 2) of ISO 11135-1:2007, it requires determining the minimum
temperature of the product before starting preconditioning. The loading
temperature before entering the preconditioning shall be determined in the
coldest zone. When the product which was too cold after placement enters
preconditioning, it shall dispose it with caution. Sudden changes in temperature
may cause product damage and/or large amounts of condensed water.
5.2 Simulation of expected process conditions
5.2.1 Process validation shall consider the most difficult sterilizing conditions to
be expected for loading. It shall evaluate the effects of loading temperature
limits on the sterilization process during transportation, handling, storage.
These expected loading temperature limits can be simulated at the time of
validation by including, but not limited to, the following methods:
is established during process validation. In monitoring and controlling
conventional production, each load shall be temperature probed prior to
preconditioning and compared to the value verified at the time of validation. Any
loading that does not meet the minimum requirements shall be maintained in
the storage area until the coldest load meets the specified requirements.
5.4.2 Hard-to-heat loading
It shall be specified that before entering the preconditioning zone or the
sterilizing cabinet, the product loading shall reach the minimum acceptable
temperature. This is especially important for loads that are difficult to heat or
that enter into the preconditioning zone below the dew point temperature or that
are preconditioned by a sterilizing cabinet. In all loads, the zone which shows
the lowest temperature will receive sufficient microbial challenges.
6 Calculate humidity
6.1 Static humidification
6.1.1 Process definition
Usually after being loaded in a sterilizing cabinet to subject to the vacuum
process, it designs a process to add or replenish the moisture and heat of the
load. When statically humidified, steam is injected into the sterilizing cabinet to
achieve a desired partial pressure and obtain a desired relative humidity level.
In most systems, because the load absorbs a large amount of the injected
moisture, in the steam holding stage of the sterilizing process, the control
system automatically controls the pressure of the sterilizing cabinet by
increasing steam injection. It may control the rate of steam injection to enhance
the effect of steam injection. Taking the injection rate control measures will allow
sufficient time for the steam to penetrate into the load, thereby resulting in better
heating and heat distribution effects.
6.1.2 Design a static humidification process
6.1.2.1 Low-vacuum process
It is used to sterilize loads that may contain pressure sensitive materials or
instruments. These processes often employ vacuum levels of about half
atmospheric pressure. In addition, use a lower vacuum rate to minimize the
effects of pressure changes on vacuum sensitive materials or instruments.
Using a low-vacuum level. During the initial vacuuming stage of the sterilization
cycle, most of the heat and moisture inside the product load remains in the load,
which requires little replenishment. The moisture level of the load remains
stable, because the process pressure is still greater than the steam pressure at
6.2.1 Process definition
Dynamic processing is a process of increasing the thermal energy (heat) of load.
It uses steam stream as the heating medium. The available heat depends on
the operating pressure during the dynamic processing stage. Pulsed steam
injection (PSI) and continuous steam injection (CSI) are two general methods.
6.2.2 Design dynamic processing stage
6.2.2.1 Operating pressure of dynamic processing
6.2.2.1.1 Determine the operating temperature of the sterilizing cabinet which
is used in the sterilization process.
6.2.2.1.2 Use the pressure-steam relationship table, to determine the absolute
pressure of the steam at the operating temperature of the sterilizing cabinet.
6.2.2.1.3 Use the pressure-steam relationship table, to select the desired
dynamic processing steam’s temperature. The corresponding absolute
pressure will be the maximum pressure for the dynamic process.
Note: The temperature of the dynamic steam process shall be lower than the
operating temperature of the sterilizing cabinet. Failure to maintain a pressure
below the saturated steam pressure at the operating temperature of the
sterilizing cabinet will result in excess condensate during the dynamic process.
6.2.2.1.4 For pulsed steam injection (PSI), in addition to determining the
maximum absolute pressure for dynamic processing, it shall also select the
minimum absolute pressure (temperature).
6.2.2.2 Description and setting of pulsed steam injection
6.2.2.2.1 With the operation of the vacuum system, steam is injected into the
sterilizing cabinet until the maximum value of the pressure setting in the
“processing stage” is met. The steam supply is stopped. The vacuum system
then reduces the pressure in the sterilizing cabinet, until the minimum value of
the pressure setting in the “processing stage” is met. At this point, the steam
injection is resumed, until the maximum value of the pressure setting in the
“processing stage” is met. The steam injection/vacuuming process continues to
meet the requirements for setting value in the “process hold stage”. The change
of final pulsed steam injection pressure is similar to the sawtooth pattern
between the maximum pressure and the minimum pressure at the “processing
stage”.
6.2.2.2.2 Program the setting values of the maximum, minimum, expected
“processing hold time” of determined steam injection pressure into the control
system.
K represents a constant for a given mixture of ethylene oxide;
Mavg represents the average molar mass of the gas mixture;
Mdg represents the molar mass of the diluent gas;
Meo represents the molar mass of ethylene oxide;
n represents the number of moles of gas;
p represents the gas pressure;
pEO represents the partial pressure of ethylene oxide gas as injected into the
sterilizing cabinet;
R represents a gas constant;
T represents the absolute temperature of the ethylene oxide/diluted mixture in
the sterilizing cabinet after the sterilization gas is injected;
V represents the volume.
7.3 Ideal gas equation
Under the conditions of finishing gas injection and the temperature is equalized,
calculate the average density of ethylene oxide gas in the sterilization system,
based on the ideal gas equation (4):
This equation is based on the following assumptions:
a) The sterilizing cabinet is empty;
b) An ethylene oxide mixture, water steam and air (and diluent gas, if used)
are used as an ideal gas;
c) The information indicated on the label on the gas cylinder is accurate.
During gas injection, the mass fraction of the mixed gas remains the same;
d) The pressure reading for the determination of partial pressure may be
absolute pressure or gauge pressure.
7.4 Calculation
The ideal gas equation is transformed and multiplied by a constant K. Either
pure ethylene oxide or a mixed gas can be used to calculate the ethylene
oxide’s concentration by the use of equation (5).
determining process equivalence
9.1 Overview
One way to determine equivalence is to perform a statistical comparison of the
performance of each device over the required control range. If all devices can
operate within the expected control range and meet certain confidence levels,
these devices can be said to be equivalent. Note that this statistical contrast
does not use the T test, the F test, or other test methods to prove that the
process is the same. The content of the evaluation is used to demonstrate that
different devices can operate in a given range of predetermined processes with
a certain degree of statistical confidence.
One way is to choose a set of parameters that indicate whether the device is
capable of running the required process. Parameters include (but are not limited
to):
a) The temperature of the sterilizing cabinet at a setting time point within the
cycle (for example, the end of the conditioning or the beginning of the gas
exposure);
b) The relative humidity of the sterilizing cabinet (for example, the end of the
conditioning or the prophase at the beginning of the gas action after the
condition is stabilized);
c) The concentration of ethylene oxide in the sterilizing cabinet (if directly
measured, after an allowable stabilization cycle);
d) The increase in ethylene oxide pressure or the weight of ethylene oxide
injected;
e) The loading temperature at a setting time point during the cycle (if using a
loading probe).
Determine which parameters will be used for unilateral analysis or bilateral
analysis:
a) When the parameter is necessarily greater than a minimum value, use the
unilateral analysis;
b) When the parameters are necessarily within a predetermined range, use
the bilateral analysis.
Once the parameters at different time points have been defined, collect the data
required in the cycle with the appropriate number of statistics.
Use a predetermined sampling plan to select the appropriate number of
b) If there is a clear performance change due to equipment upgrades, it is
necessary to evaluate the equivalence of the data before and after the
upgrade separately.
c) If the change is due to an upgrade of the equipment, all sterilized
equipment may not be upgraded at the same time. In order to select a
suitable representative sample, the user will need to determine when each
sterilizing cabinet is upgraded.
d) If the sterilization parameter table changes at this stage, the parameter
list’s change is due to the parameter change, it is necessary to evaluate
the equivalence of the data before and after the change separately.
There is a finite probability that the data will not pass the normal test, even
though the data is completely normal. If the evaluation of equipment problems,
parameter table’s changes, data assembly indicates that the data is free of any
problems, it may accept that the normal test is valid and continue with the
equivalence validation. The principle of this decision shall be recorded.
Observe the data trend of the parameters that have not passed the normal test,
to determine whether there is a real shift in the parameters. A smaller shift is a
smaller shift in the new calibration correction or a shift in the sensor’s lag time.
This lagging shift occurs in terms of relative humidity and ethylene oxide
sensors. Usually, this shift may cause the data to fail to pass the normal test,
but the data for this shift may be converted to the master table. For this type of
data, it may be appropriate to use the “maximum limit” or “minimum limit” data
conversion method to standardize (normalize) the data.
If the data is steeper than the normal curve (for example, the proportion of the
tail which is less than a normal distribution), then it may be assumed that the
normal data will provide a more conservative assessment than the standard
data to be used. In this case, it is not necessary to convert the data and obtain
a normal distribution. A normal test which uses a less tail proportion will allow
these data to pass the normal requirement.
Note: Even if the root cause for the failure of the normal test is not found, the data is
still non-normal. Finding the root cause is simply that the reason for non-normality is
known, meanwhile it helps to define the actions as required to complete the data
analysis.
If the data is truly non-normal, it may be necessary to convert these data to a
normal state. Statistical analysis of pp and ppk can be performed on these
converted data, instead of raw data. In general, converting data will result in a
more conservative assessment of pp and ppk values and there is a greater
likelihood that the required values will not be reached.
9.2.5 Interpretation of data
Appendix A
(Informative)
An example of a method for determining the concentration of ethylene
oxide gas based on the physical formula of an ideal gas
A.1 100% ethylene oxide sterilizer
A.1.1 Calculation formula
When the sterilant as injected into the sterilizing cabinet is 100% ethylene oxide
gas, the concentration of ethylene oxide gas in the sterilizing cabinet may be
calculated by the relationship as shown by the formula (A.1).
Where:
MEO - 44.054 g/mol (molar mass of ethylene oxide);
cEO - The average concentration of ethylene oxide gas, in milligrams per liter
(mg/L);
pEO - The partial pressure of ethylene oxide gas as injected into the sterilizing
cabinet, in kilopascals (kPa).
A.1.2 Example 1 - Partial pressure method
Based on the calculation of partial pressure. After the conditioning stage is
completed, 100% ethylene oxide gas is injected into the sterilizing cabinet. At
this time, the temperature is 51.7 °C, the partial pressure is 0.3643 atm
(36.9127 kPa). The concentration of ethylene oxide gas (cEO) in the sterilizing
cabinet can be determined by the use of formula (A.1).
The concentration of ethylene oxide gas can be expressed by 0.6022 g/L
multiplied by 1000 mg/g.
A.1.3 Example 2 - Ethylene oxide weight method
Appendix B
(Informative)
Calculation example using a flammability curve
B.1 Example
B.1.1 The expected exposure conditions are:
a) Use a low vacuum sterilization cycle;
b) The concentration of ethylene oxide is 500 mg/L (31.016 kPa);
c) The relative humidity is 50% (8.804 kPa);
d) The temperature is 57 °C;
e) The initial pressure is 101.3 kPa.
B.1.2 According to the requirements of 8.3 ~ 8.8, calculate the partial pressure
and volume fraction of air, nitrogen and steam (considered as inert gas),
ethylene oxide gas at each stage of the sterilization cycle. The examples for
calculating the partial pressure and volume fraction are as follows:
a) Pre-vacuum to 45.378 kPa: After the first pre-vacuum, the sterilizing
cabinet still contains 100% volume of air, but its partial pressure is reduced;
b) Nitrogen purge: Add nitrogen from 45.378 kPa to 101.253 kPa. The partial
pressure of air is still 45.378 kPa, whilst the partial pressure of nitrogen is
55.875 kPa. Therefore, it may divide each partial pressure by the total
pressure to calculate the volume fraction of each gas. For example, the
partial pressure of nitrogen and steam is 55.875 kPa, the total pressure is
101.253 kPa, the volume fraction of nitrogen and steam is
(55.875/101.253) x 100 = 55.2%;
c) At each stage prior to the injection of ethylene oxide, it may follow the
requirements of b) to continue calculating each partial pressure and
corresponding volume fraction.
See Table B.1 for details.
......
Source: Above contents are excerpted from the PDF -- translated/reviewed by: www.chinesestandard.net / Wayne Zheng et al.
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