© ISO 2014 Sterilization of health care products — Chemical indicators — Part 1 General requirements Stérilisation des produits de santé — Indicateurs chimiques — Partie 1 Exigences générales INTERNAT[.]
General
Chemical indicators in ISO 11140 serve three key functions: first, they enable differentiation between unprocessed and processed items; second, they are used in specific tests and procedures such as the Bowie-Dick test to verify sterilization efficacy; and third, they are placed inside load items to assess whether the required process parameters have been achieved at the point of placement, ensuring effective sterilization.
ISO 11140 categorizes six indicator types based on their performance requirements, with three main categories aligned with their intended use Chemical indicators are further subdivided within these categories according to the specific sterilization process they are designed for Importantly, these categorizations are non-hierarchical, emphasizing that reaching a chemical indicator’s endpoint does not alone confirm sterilization success Instead, it should be considered as one of multiple factors in evaluating the overall effectiveness and acceptability of a sterilization process.
Table 1 — Categories according to intended use
Intended use Type Category Description (intended use)
Indicate exposure to a process to allow differ- entiation between unprocessed and processed items, and/or indicate gross failure of a steriliza- tion process.
Indicators for use in special applications, e.g
Bowie and Dick-type test 2 s2 “Special” indicator (e.g Bowie-
Dick) Requirements in accordance with ISO 11140-3, ISO 11140−4, and ISO 11140−5.
Indicators to be placed inside individual load items and to assess attain- ment of the critical process variables at the point of placement.
This indicator only reacts to one critical process variable.
Single variable indicator Requirements according to Type 3 This indicator reacts to more than one critical process vari- able.
Multivariable indicator Requirements according to Type 4 This indicator reacts to all critical process variables.
Integrating indicator Requirements according to Type 5 This indicator reacts to all critical process variables.
Emulating indicatorRequirements according to Type 6
Type 1: process indicators
Process indicators should be designed for individual items such as packs or containers to confirm direct exposure to sterilization They help distinguish between processed and unprocessed items, ensuring proper sterilization status confirmation.
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Type 2: indicators for use in specific tests
Type 2 indicators are designed for use in specific sterilization test procedures outlined in relevant standards These indicators and their systems are detailed in ISO 11140-3, ISO 11140-4, and ISO 11140-5, ensuring compliance with international sterilization testing requirements.
Type 3: single critical process variable indicators
A critical process variable indicator should be designed to respond to a specific critical process variable as outlined in section 5.2 Its primary purpose is to signal exposure to a sterilization process at a defined steady value (SV) of the selected critical process variable, ensuring compliance with sterilization standards outlined in sections 5.7 and 5.8.
Type 4: multicritical process variable indicators
A multicritical process variable indicator is designed to monitor two or more critical process variables, providing real-time feedback on sterilization exposure It is specifically intended to indicate when the process reaches the designated Survey Values (SVs) for selected critical variables, ensuring effective sterilization validation This device enhances process control by responding to key parameters outlined in sections 5.2, 5.7, and 5.8, supporting compliance with sterilization standards.
Type 5: integrating indicators
An integrating indicator must be designed to respond to all critical process variables, ensuring comprehensive monitoring of sterilization processes The process variables (SVs) are generated to meet or surpass the performance standards outlined in ISO 11138 series for biological indicators (BIs) The minimum SV should correspond to the lowest values necessary to achieve effective sterilization, as specified by international standards such as ISO 11135, ISO 11137, ISO 17665, or relevant local regulatory requirements.
NOTE The SVs demonstrate how the indicator integrates over the temperature range.
Type 6: emulating indicators
An emulating indicator must be designed to respond to all critical process variables involved in sterilization processes, ensuring accurate monitoring and validation These process variables (SVs) are derived from sterilization process parameters as outlined in international standards such as ISO 11135, ISO 11137 (all parts), and ISO 17665 (all parts), or established by regulatory agencies, ensuring compliance and reliability in sterilization validation.
5.1 The requirements given in this clause shall apply to all chemical indicators (CI) unless specifically excluded or amended in a subsequent clause or part of ISO 11140.
NOTE For ease of reading, only the term “indicator” is used hereinafter, although requirements do also apply to indicator systems. © ISO 2014 – All rights reserved 5
5.2 For the different sterilization processes, the following critical process variables are defined as being critical:
DRY HEAT Time and temperature
ETHYLENE OXIDE Time, temperature, relative humidity and ethylene oxide (EO) concentration
Time, temperature, moisture and formaldehyde concentration
Time, temperature, hydrogen peroxide concentration
5.3 The manufacturer shall establish, document and maintain a formal quality system to cover all operations required by this part of ISO 11140.
NOTE ISO 9001 and ISO 13485 describe requirements for quality systems for design, manufacture and testing.
Each indicator must be clearly labeled to indicate the specific process it is designed for, as outlined in sections 5.6 and 5.7 Additionally, indicators should be identified either by a numerical code from 1 to 6 or by a combination of a letter and number (e.g., e1, s2, i3, i4, i5, i6) to specify their category This labeling ensures proper identification and use of indicators across different processes, enhancing compliance and operational clarity.
For Type 3, 4, 5 and 6 indicators, each indicator shall be clearly marked with the SVs.
NOTE Some indicator manufacturers might use the category notation to provide additional guidance for the intended use of the chemical indicator.
When the indicator’s size or format prevents displaying the information in a six characters per centimetre font or larger, the required details must be included on the label and/or instructions for use.
5.5 The indicator shall comply with the requirements of this part of ISO 11140 for the duration of the shelf-life as specified by the manufacturer (see Annex A).
5.6 Abbreviated descriptions of the process shall be in accordance with the following symbols:
— all dry heat sterilization processes
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— all ethylene oxide sterilization processes
— all ionizing radiation sterilization processes
— all low temperature steam and formaldehyde sterilization processes
— all vaporized hydrogen peroxide sterilization processes
These descriptions are symbols and shall not be translated.
5.7 If the indicator is designed for use in a specific sterilization process, this information shall be stated or coded on the indicator, or within the technical information leaflet.
For example, if the indicator is designated for use in steam at 121 °C for 15 min, it would appear as follows:
Each packaging of indicators or accompanying technical leaflets must include essential information such as the indicator's type, process, and intended use; the critical process variables and their SVs it responds to; the expected change or colour range for color change indicators; detailed instructions for proper use; recommended storage conditions before and after use; details on the nature and time frame of changes during storage; potential interfering substances or conditions that may affect performance; and any necessary safety precautions to ensure safe and effective use.
When labeling products, it is essential to include the manufacturer’s or supplier’s name and address, as well as the EU’s authorized representative’s details if mandated by regional regulations Additionally, the label must specify the expiry date or the manufacturing date plus shelf life, presented in accordance with ISO 8601 standards (e.g., YYYY-MM) To ensure traceability, a unique code such as a lot number should also be included on the product label.
NOTE National or regional regulations could contain additional or different requirements.
The manufacturer must retain documented evidence confirming that, when used as intended, the indicator does not release any toxic substances in quantities that could pose health risks or compromise the sterilization process This ensures the indicator remains safe and effective before, during, and after sterilization, maintaining product integrity and safety standards.
Indicators designed for use with a specific test load must clearly display this information through a label, coding, or symbol, which should be included on the indicator itself, the packaging, and the technical leaflet If the indicator's size or format prevents affixing the symbol at a minimum of 5 mm, then the requisite information can be provided exclusively on the packaging and technical leaflet, ensuring proper communication of the indicator’s specific test load application in compliance with standards.
Figure 1 — Symbol for designation for use with a specific test load only
General
Resistometers, as outlined in ISO 18472, are essential for evaluating the performance of chemical indicators detailed in ISO 11140, excluding Type 2 indicators They enable precise control of test conditions and cycle sequences, ensuring repeatable studies on how process parameters affect indicators Unlike conventional sterilizers, resistometers provide controlled environments for accurate testing; attempting to replicate resistometer conditions with standard sterilizers may lead to misleading or inaccurate results.
After exposure to a sterilization process where all critical process variables reached or exceeded the specified levels, the indicator's condition should remain unchanged for at least six months when stored under the manufacturer's recommended conditions This ensures the indicator provides a reliable, visible response or endpoint over time, confirming effective sterilization is maintained.
If indicators that have undergone incomplete changes deteriorate during storage—either reverting to their original state or gradually completing the change reaction—this information must be clearly included in the technical documentation provided by the manufacturer, as specified in section 5.8 f).
6.1.4 Indicators for steam processes shall be tested according to the method in 7.4 and the specified values in 11.7 The visible change or end point shall not be reached.
NOTE The dry heat test is designed to ensure that indicators for steam require the presence of steam in order to respond.
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Type 1 indicators
6.2.1 After exposure of the indicator, the visible change shall be clearly observable (see Clause 8).
The migration of the indicator agent through the substrate to the surface opposite the application site must not occur before, during, or after the designated sterilization process, as verified by the testing method outlined in section 7.2 and referenced in section 5.9.
Type 2 indicators
Specific requirements for Type 2 indicators and indicator systems are given in ISO 11140-3, ISO 11140-4, and ISO 11140-5.
Types 3, 4, 5 and 6 indicators
6.4.1 After exposure of the indicator to the SVs of critical process variables, the end point shall be clearly observable.
The indicator agent must not offset, bleed, or penetrate the substrate or contacting materials during use unless specified as a design feature This requirement applies before, during, and after the sterilization process, as tested according to method 7.2 (refer to section 5.9 for additional details).
General
Compliance testing for specific indicator types, as outlined in Clauses 6 to 13, should be conducted by exposing the indicators to the prescribed conditions using ISO 18472-compliant equipment Following exposure, the indicators must be examined to verify they meet the specified requirements, ensuring accurate and reliable performance.
Specific test methods for radiation indicators are not given here Performance requirements for radiation indicators are given in 8.5.
NOTE Test equipment and methods for Type 2 indicators are contained in ISO 11140-3, ISO 11140-4 and ISO 11140-5.
Off-set (transference)
Apply a second layer of similar substrate in direct contact with the chemical indicator to enhance performance Ensure the indicator undergoes sterilization according to the manufacturer’s guidelines Conduct a visual inspection of the indicator, substrate, and second substrate layer before and after sterilization to verify compliance with standards 6.2.2 or 6.4.2.
Procedure — Steam indicators
7.3.1 Load the indicator on to a suitable sample holder The sample holder shall not affect the performance of the indicator or impede exposure to critical process variables.
The sample holder must enable the indicator or indicator system to be directly exposed to testing conditions, ensuring accurate performance assessment Since different indicators may require specific sample holder designs, it is recommended that third parties consult the indicator manufacturer for appropriate guidance Proper sample holder compatibility is essential for reliable test results and device compatibility.
7.3.2 Before initiating a test cycle, the inner surface of the resistometer shall be heated to the required temperature. © ISO 2014 – All rights reserved 9
When conducting tests with a loaded sample holder in the resistometer, first evacuate the chamber to 4.5 kPa ± 0.5 kPa within 60 seconds Next, admit steam rapidly to reach the desired test temperature in 10 seconds or less Maintain these conditions for the specified exposure duration to ensure accurate testing After the exposure period, evacuate the resistometer again to 10 kPa or less within 60 seconds, then introduce air to restore ambient pressure, completing the testing cycle.
7.3.4 Immediately remove the indicator from the resistometer to avoid prolonged exposure to critical process variables during testing Visually examine for compliance and record the result.
Procedure — Dry heat indicators
7.4.1 Load the indicator on to a suitable sample holder The sample holder shall not affect the performance of the indicator or impede exposure to critical process variables.
The sample holder must enable the indicator or indicator system to be directly exposed to test conditions, ensuring accurate evaluation As different indicators may require specific sample holder designs, it is essential to consult the indicator manufacturer for proper guidance This approach helps ensure compatibility and reliable testing outcomes.
7.4.2 Preheat the resistometer to the required test temperature.
Place the loaded sample holder in the resistometer, close the access port, and start the process cycle Ensure that the surface temperature of the indicator reaches the required temperature within the resistometer in no more than 1 minute for accurate testing.
7.4.4 Maintain the conditions for the required exposure time.
7.4.5 At the end of the exposure period, immediately remove the indicators from the resistometer and cool to 100 °C or less in a period not exceeding 1 min.
7.4.6 Visually examine for compliance and record the result.
Procedure — EO indicators
7.5.1 Load the indicator on to a suitable sample holder The sample holder shall not affect the performance of the indicator or impede exposure to critical process variables.
The sample holder must enable the indicator or indicator system to be directly exposed to test conditions, ensuring accurate performance assessment Since different indicators may require specialized sample holder designs, it is essential to consult the indicator manufacturer for specific guidance Properly designed sample holders are crucial for reliable testing and optimal results.
7.5.2 Before initiating a test cycle, the sample, sample holder and the inner surface of the resistometer shall be equilibrated to the required temperature.
When using the resistometer with a loaded sample holder, evacuate the device to 10 kPa ± 0.5 kPa, then introduce sufficient water vapor to achieve the desired relative humidity Next, admit ethylene oxide to reach the required concentration within one minute or less; for zero gas exposure cycles, no ethylene oxide should be introduced, and if applicable, the diluent gas must also be supplied accordingly.
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Ensure that the testing vessel is free from traces of ethylene oxide when conducting a zero gas exposure cycle, as tests should not be performed if residual EO is present Maintain the specified conditions for the entire required exposure duration to ensure accurate results Within 1.5 minutes after the exposure period ends, reduce the ethylene oxide concentration around the indicator to a level that will no longer influence its readings, ensuring reliable and safe testing procedures.
7.5.4 Immediately remove the indicator from the resistometer to avoid prolonged exposure to process critical variables during testing Visually examine for compliance and record the result.
Procedure — Low temperature steam and formaldehyde indicators
7.6.1 Prepare an aqueous solution of formaldehyde at a concentration of 1 mol/l ± 0,01 mol/l The formaldehyde concentration of this solution shall be established by the use of a validated analytical method.
7.6.2 Preheat the formaldehyde solution to 60 °C ± 0,5 °C.
7.6.3 Load the indicator on to a suitable sample holder The sample holder shall not affect the performance of the indicator or impede exposure to critical process variables.
The sample holder must enable the indicator or indicator system to be directly exposed to test conditions, ensuring accurate results As different indicators may require specific sample holder designs, it is recommended that third parties consult the indicator manufacturer for proper guidance and compatibility.
7.6.4 Immerse the indicator, loaded on to the sample holder, in the formaldehyde solution.
Ensure that the indicators are completely immersed in the formaldehyde solution and do not float to the surface.
7.6.5 Maintain these conditions for the required exposure time.
7.6.6 At the end of the exposure period, reduce the formaldehyde concentration surrounding the indicator to a level that will no longer affect the indicator, within 1,5 min.
7.6.7 Immediately remove the indicator from the resistometer and visually examine for compliance Record the result.
Procedure — Vaporized hydrogen peroxide indicators
7.7.1 Load the indicator on to a suitable sample holder The sample holder shall not affect the performance of the indicator or impede exposure to critical process variables.
The sample holder must enable the indicator or indicator system to be directly exposed to test conditions, ensuring accurate performance assessment Since various indicators may require different sample holder designs, it is essential to consult the indicator manufacturer for specific guidance on compatibility and setup Proper design of the sample holder is crucial for reliable testing and optimal results.
7.7.2 Before initiating a test cycle, the sample, sample holder and the inner surface of the resistometer shall be equilibrated to the required temperature.
To perform testing with the loaded sample holder in the resistometer, begin by admitting sufficient water vapor, if necessary, to elevate the relative humidity (RH) to the specified level Next, introduce vaporized hydrogen peroxide to achieve the target test concentration rapidly, typically within a short time frame Ensuring proper control of humidity and peroxide concentration is crucial for accurate and reliable resistometer testing results.
Ensure that hydrogen peroxide is not present (0 min exposure time) during initial testing Maintain the specified conditions consistently throughout the required exposure period to ensure accurate results After the exposure time, reduce the hydrogen peroxide concentration around the indicator to a level that no longer influences its reading, ensuring precise analysis.
7.7.4 Immediately remove the indicator from the resistometer to avoid prolonged exposure to process critical variables during testing Visually examine for compliance and record the result.
8 Additional requirements for process (Type 1) indicators
Process indicators printed or applied on to packaging material
Process indicators may be printed on packaging material or presented as self-adhesive labels, pouches, packaging tapes, tags, insert labels, etc.
Process indicators for steam sterilization processes
Following exposure to the specified test conditions, the process indicator shall perform as shown in
Table 2 If the indicator is intended to be used only at 121 °C or 134 °C, then testing may only be conducted at that temperature (see 5.7).
Table 2 — Test and performance requirements for Type 1 process indicators for
Test environment Test time Test temperature
No change or a change that is markedly different from the visible change as specified by the manufacturer
Visible change as specified by the manufacturer
Saturated steam 2,0 min ± 5 s 121 °C (+3/0 °C) Acceptable result Unacceptable result
Saturated steam 10,0 min ± 5 s 121 °C (+3/0 °C) Unacceptable result Acceptable result
Saturated steam 0,3 min ± 5 s 134 °C (+3/0 °C) Acceptable result Unacceptable result
Saturated steam 2 min ± 5 s 134 °C (+3/0 °C) Unacceptable result Acceptable result
Dry heat 30 min ± 1 min 140 °C (+2/0 °C) Acceptable result Unacceptable result
NOTE The dry heat test is designed to ensure that process indicators for steam require the presence of steam in order to respond (see 6.1.4).
Process indicators for dry heat sterilization processes
Following exposure to the specified test conditions, the process indicator shall perform as shown in
Table 3 — Test and performance requirements for Type 1 process indicators for
Test environment Test time Test temperature
No change or a change that is markedly different from the visible change as specified by the manufacturer
Visible change as specified by the manufacturer
Dry heat 20 min ± 1 min 160 °C +5/0 °C Acceptable result Unacceptable result
Dry heat 40 min ± 1 min 160 °C +5/0 °C Unacceptable result Acceptable result
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Process indicators for ethylene oxide sterilization processes
The process indicator must demonstrate performance in accordance with the specifications outlined in Table 4 after exposure to designated test conditions Testing should be conducted exclusively at the specified temperature, either 37 °C or 54 °C, depending on the indicator’s intended use, as specified in section 5.7.
An EO gas test should only be conducted when there is no detectable ethylene oxide present If a color change occurs during the test without any obvious presence of EO gas, it is essential to verify the complete absence of ethylene oxide to ensure accurate results and safety.
Table 4 — Test and performance requirements for Type 1 process indicators for
Test environment Test time Test tempera- ture
Relative humidity (RH) Gas concentration
No change or a change that is markedly different from the visible change as specified by the manufacturer
Visible change as specified by manufacturer the
EO gas 90 min ± 1 min 60 °C ± 2 °C ≥85 % none Acceptable result Unacceptable result
60 % ± 10 % RH 600 mg/l ± 30 mg/l Acceptable result Unacceptable result
60 % ± 10 % RH 600 mg/l ± 30 mg/l Unacceptable result Acceptable result
Ethylene oxide indicators typically react within approximately 20 minutes ± 15 seconds at a temperature of 54 °C ± 1 °C However, their effectiveness can be compromised by the presence of carbon dioxide or other gases in the system To ensure accurate results, the indicator should be tested in an environment containing at least 80% carbon dioxide or other gases mixed with ethylene oxide, especially if interference is suspected.
Process indicators for radiation sterilization processes
Following exposure to the specified test conditions, the process indicator shall perform as shown in Table 5.
Table 5 — Test and performance requirements for Type 1 process indicators for environment Intensity Test Peak wave- length Absorbed dose Test time
No change or a change that is markedly different from the visible change as speci- fied by the manufacturer
Visible change as specified by the manufacturer
Ultraviolet radiation ≥ 3,3 W/m 2 254 nm N/A 120 min ± 5 min Acceptable result Unacceptable result
Ionizing radiation N/A N/A 1 kGy ± 0,1 kGy N/A Acceptable result Unacceptable result
Ionizing radiation testing evaluates whether indicators respond appropriately to sterilization doses, with thresholds set at 10 kGy ± 1 kGy A result is considered unacceptable if the indicator responds outside the designated range, while an acceptable result confirms proper performance Notably, ultraviolet radiation testing ensures that indicators do not react to non-ionizing sources like sunlight, with a mercury vapor lamp providing the appropriate peak wavelength for accurate assessment This testing adheres to ISO 2014 standards, ensuring reliable validation of sterilization indicators.
Process indicators for low temperature steam and formaldehyde
8.6.1 Following exposure to the specified test conditions, the process indicator shall perform as shown in Table 6.
If no formaldehyde test has been conducted, it indicates the absence of formaldehyde; however, if a color change occurs without any apparent presence of formaldehyde, further verification may be necessary to confirm its complete absence.
Table 6 — Test conditions and performance requirements for Type 1 process indicators for
Test condition Test time Test temperature Gas concentration
No change or a change that is markedly different from the visible change as specified by the manufacturer
Visible change as specified by the manufacturer
Absence of formalde- hyde 90 min ± 1 min 80 °C ± 2 °C none Acceptable result Unacceptable result
For- maldehyde 20 s ± 5 s 60 °C ± 0,5 °C 1,0 mol/l ± 0,01 mol/l Acceptable result Unacceptable result
For- maldehyde 15 min ± 15 s 70 °C ± 2 °C 1,0 mol/l ± 0,01 mol/l Unacceptable result Acceptable result
For indicators designed for low-temperature steam and formaldehyde sterilization cycles operating below 55°C or above 65°C, testing must be conducted at the maximum temperature and formaldehyde concentration specified by the manufacturer This ensures accurate validation of the indicator's performance under the intended sterilization conditions.
Note: The manufacturer may need to conduct additional functional tests on the indicator using low-temperature steam and formaldehyde processes to ensure its suitability for these specific applications.
Process indicators for vaporized hydrogen peroxide sterilization processes
Following exposure to the specified test conditions, the process indicators shall perform as shown in
The hydrogen peroxide test should only be conducted when hydrogen peroxide is present If a color change occurs without the apparent presence of hydrogen peroxide, it may indicate that hydrogen peroxide is absent, and further verification of its complete absence is necessary.
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Table 7 — Test conditions and performance requirements for Type 1 process indicators for
Test condition Test time Test temperature Gas concentration
No change or a change that is markedly different from the visible change as specified by the manufacturer
Visible change as specified by the manufacturer
Absence of hydro- gen peroxide 45 min ± 5 min 50 °C ± 0,5 °C None Acceptable result Unacceptable result
Hydrogen perox- ide 7 s ± 1 s 50 °C ± 0,5 °C 2,3 mg/l ± 0,4 mg/l Acceptable result Unacceptable result
Hydrogen perox- ide 6 min ± 1 s 50 °C ± 0,5 °C 2,3 mg/l ± 0,4 mg/l Unacceptable result Acceptable result
9 Additional requirements for single critical process variable (Type 3) indica- tors
9.1 Single critical process variable indicators shall be designed for one of the critical process variables to be monitored, as listed in 5.2.
9.2 Single critical process variable indicators tested at the SV (test point 1) shall reach the end point (see Table 8).
9.3 Single critical process variable indicators tested at the SV minus the tolerance (test point 2) shall not reach the end point (see Table 8).
10 Additional requirements for multicritical process variable (Type 4) indicators
10.1 Multicritical process variable indicators shall be designed for two or more of the critical process variables to be monitored, as listed in 5.2.
10.2 Multicritical process variable indicators tested at the SV (test point 1) shall reach the end point (pass condition) (see Table 8).
10.3 Multicritical process variable indicators tested at the SV minus the combined tolerances (test point
2) shall not reach the end point (fail condition) (see Table 8).
The 10.4 multicritical process variable indicators for low-temperature steam and formaldehyde, tested under specific time and temperature sterilization values (SVs) in dry heat conditions—where moisture is absent but all other parameters match the SVs—must not reach the endpoint, as detailed in Table 8.
The dry heat test verifies that multicritical process variable indicators for low-temperature steam and formaldehyde only respond when steam is present This ensures the reliability and accuracy of the indicators in detecting the presence of steam under specified conditions, confirming their suitability for sterile processing environments (ISO 2014).
Table 8 — Test and performance requirements for Type 3 and Type 4 indicators
Sterilization process Test point a Test time Test temperature
Low temperature steam and formalde- hyde
When testing multicritical process variable (Type 4) indicators, the indicator must reach its end point at the specified set value (SV) during initial testing, demonstrating proper performance Additionally, when tested at all other SVs minus the combined tolerances, the indicator should not reach its end point, ensuring accuracy across different process conditions For detailed examples of these testing procedures, please refer to Annex B.
11 Additional requirements for steam integrating (Type 5) indicators
Integrating indicators for steam sterilization must be designed to monitor all critical process variables, ensuring accurate detection of exposure to sterilization conditions These indicators should reach a definitive endpoint that confirms the process has met the specified sterilization parameters The indicators' performance must align with the critical process variable tolerances outlined in Table 9 to ensure consistent and effective sterilization validation.
11.2 Integrating indicators for steam shall have SVs at 121 °C and 135 °C and at one or more equally spaced temperature points in the range of 121 °C to 135 °C.
11.3 Integrating indicators for steam tested at all of the SVs (Test point 1) shall reach the end point (pass condition) (See 11.2).
11.4 Integrating indicators for steam tested at all of the SVs minus the time and temperature tolerances (test point 2) shall not reach the end point (fail condition) (see Table 9).
11.5 The SVs for time at 121 °C and 135 °C shall be specified and shall not be less than 16,5 min at 121 °C and 1,2 min at 135 °C.
The integrating indicator temperature coefficient is determined from the slope of the curve plotting log SV and/or SV versus temperature, ensuring an accurate representation of temperature effects This coefficient should fall within the range of 10 °C to 27 °C to maintain consistency and reliability Additionally, the correlation coefficient of the linear regression curve must be at least 0.9, indicating a strong linear relationship between the variables for precise data analysis.
NOTE See Figure C.1 The manufacturer’s SVs can be used to determine the integrating indicator temperature coefficient.
11.7 Integrating indicators for steam exposed to dry heat at 140 °C ± 2 °C for 30 min ± 1 min shall not reach the end point.
NOTE The dry heat test is designed to ensure that integrating indicators for steam require the presence of steam in order to respond.
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11.8 The manufacturer shall state clearly any factors of which he is aware that can adversely affect the efficacy of the sterilization process but which are not detectable by the indicator, or not detectable in a manner that will give assurance of satisfactory attainment of that critical process variable [see 5.8 g)].
12 Additional requirements for ethylene oxide integrating (Type 5) indicators
12.1 Integrating indicators for ethylene oxide shall be designed for all critical process variables and reach an end point indicating exposure to sterilization conditions at defined critical process variables within the relevant tolerances given in Table 9.
12.2 Integrating indicators for ethylene oxide shall have SVs for time at 37 °C and 54 °C that shall be specified and that shall not be less than 75 min at 37 °C and 30 min at 54 °C.
Upon exposure to solubilized vapor (SV) under specified conditions of time, temperature, and 60% relative humidity (RH) ± 10 % RH, the integrating indicator must not reach the endpoint if ethylene oxide is absent Failure occurs if the indicator reaches the endpoint under these conditions, indicating inadequate protection or impairments in sterilization effectiveness Ensuring the integrating indicator does not turn color or change when exposed to these parameters confirms proper sterilization validation This criterion is essential for maintaining sterilization process integrity and ensuring product safety.
The manufacturer must clearly identify any known factors that could negatively impact the effectiveness of the sterilization process These factors may not be detectable by measurement indicators or may not provide reliable assurance of achieving the critical process variables required for effective sterilization Ensuring transparency about such factors is essential to maintaining sterilization reliability and patient safety.
NOTE Some regulatory authorities require that demonstration of the performance of an integrating indicator be conducted in parallel with an appropriate BI.
Table 9 — Test and performance requirements for Type 5 indicators
Sterilization process Test point a Test time Test temperature b Gas concentration mg EO/l
For integrating (Type 5) indicators, testing involves specific criteria at multiple test points to ensure accurate performance The indicator must reach its end point at all sterilization validation points (SVs) to pass, while at all other points minus the effects of time and temperature, it should not reach the end point, indicating a fail For steam sterilization Type 5 indicators, at least three temperature SVs are required—specifically at 121°C, 135°C, and one or more intermediate temperatures evenly spaced between these two In contrast, ethylene oxide Type 5 indicators require two temperature SVs at 37°C and 54°C to validate their effectiveness across different sterilization conditions.
13 Additional requirements for emulating (Type 6) indicators
Emulating indicators must be designed for all critical process variables involved in the sterilization process outlined in section 5.2 These indicators should effectively demonstrate exposure to the sterilization process by reaching an endpoint that indicates the process's completion at specified critical variables Additionally, they must operate within the defined tolerances specified in Table 10 to ensure process validation and compliance with standards.
13.2 Emulating indicators tested at the SV (test point 1) shall reach the end point (pass condition).
13.3 Emulating indicators tested at the SV minus the combined tolerances (test point 2) shall not reach the end point (fail condition).
13.4 Emulating indicators for steam exposed to dry heat at 140 °C ± 2 °C for 30 min ± 1 min shall not reach the end point (see 6.1.4). © ISO 2014 – All rights reserved 17
NOTE The dry heat test is designed to ensure that emulating indicators for steam require the presence of steam in order to respond.
The manufacturer must clearly disclose any factors known to potentially compromise the efficacy of the sterilization process These factors may not be detectable by standard indicators or may not provide sufficient assurance of achieving the critical process variables Ensuring transparency about such limitations is essential for maintaining sterilization effectiveness and patient safety.
Table 10 — Test and performance requirements for Type 6 indicators
Test time min temperature Test
For testing emulating (Type 6) indicators, ensure that at Test Point 1, the indicator reaches its end point (pass condition) when tested at the Service Validator (SV) Additionally, at Test Point 2, the indicator must not reach its end point when tested at all SVs minus combined tolerances, confirming a fail condition Refer to Annex B for an example of testing emulating indicators.
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Method for demonstrating shelf-life of the product
Product shelf-life testing must be conducted following a well-defined, pre-established protocol that specifies sample size, sampling methods, and data evaluation criteria This protocol ensures a standardized approach to testing and must be developed before starting the study to guarantee accurate and reliable results.
NOTE National or regional regulation can contain additional or different requirements Compliance with quality management International Standards (in particular ISO 9001 and ISO 13485) could require additional or different provisions.
A.2 Product samples shall be stored in their normal packaging at, or above, the maximum temperature and RH recommended for storage These conditions shall be controlled and monitored.
A.3 All performance attributes shall maintain the original specifications throughout the shelf-life.