The sterilization of medical devices is one of the most important safety factors for patient health. Unsterilized or poorly sterilized medical devices and products pose a severe threat to the patient’s health and life.
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Treatment of medical devices with Ethylene Oxide (EO) is a popular Sterilization technique used worldwide. ISO 1135:2007 was the standard used for process management and validation requirements of EO Sterilization until July 2014. It has now been replaced with ISO 11135:2014.
Differences between International and European Versions of ISO 11135:2014
The international and European versions of ISO 11135 show great resemblance to each other except in Annexes ZA and ZB. Also, the European version of the standard has adopted the corresponding elements of European Directive 90/385/EEC and European Directives 93/42/EEC, respectively:
- Essential requirement 7 from European Directive 90/385/EEC.
- Essential requirements 8.3 and 8.4 from European Directives 93/42/EEC.
Application of ISO 11135:2014 Requirements
General Aspects of ISO 11135:2014
Definition
ISO 11135:2014 defines Sterilization as a validated process that is used to make a product free from viable microorganisms under a sterility assurance level.
Implementation of Sterilization Process
Sterilization is carried out by a sterilizer installed in a dedicated facility. Outside the Sterilization room, Sterilization control equipment is installed. This equipment controls the Sterilization process according to defined parameters and requirements.
Composition of Agents Used in Sterilization Process
The agents used in Sterilization are either composed of pure Ethylene Oxide or are mixtures of carbon dioxide or nitrogen.
Precautionary Measures for Ethylene Oxide
It is advised to handle, store and use EO gas with great care because:
- It is highly toxic
- It is flammable
- It possesses the risk of explosion from 2.6% volume in air.
Steps Involved in Sterilization Process
The Sterilization process consists of two important steps:
- Preconditioning and
- Sterilization process.
Preconditioning
Preconditioning refers to achieving the required levels of humidity and temperature before the load introduction into the chamber. This process ensures the Sterilization process without considering the influence of any internal environmental factors.
Sterilization Cycle
The EO Sterilization process consists of the following steps:
Influence of Load Chamber
The load configuration in the chamber influences
- The pattern of product’s heat distribution
- Humidity levels
- EO gas penetration, and
- EO gas removal.
Design of Load Configuration
The design of load configuration should be planned in such a way that it assists during the Sterilization process by:
- Removing the air
- Helping in heat penetration
- Removing the humidity and
- Removing the EO during the process and at the end of the process.
Process Characterization & Safe Delivery of Sterilization Processes
Process characterization defines the range of process variables that are needed in ISO 11135. It puts forward four process variables. These variables should be documented in every phase of the Sterilization process.
1. Phase
Includes process variables associated with each phase.
2. Pre-conditioning
Pre-conditioning deals with time, temperature, humidity, and transfer time.
3. Sterilization cycle
The Sterilization cycle composes of exposure time, temperature, humidity, EO concentration, and pressure.
4. Aeration
Aeration or gassing is associated with time and temperature.
The manufacturer is responsible for checking whether his Sterilization facilities or contract Sterilization suppliers are establishing the Sterilization requirements of ISO 11135 or not.
Characterization of Equipment
This phase establishes equipment specifications to buy appropriate Sterilization equipment and in fulfilling the requirements of ISO 11135. In contrast to ISO 11135:2007, ISO 11135:2014 requires equipment specifications to fulfill requirements related to installation services.
These characterization requirements are mentioned in Annex D of ISO 11135. They guide the manufacturers (or their contract Sterilization suppliers) in this regard. According to Annex D:
- The Sterilization process equipment must be able to detect and alert deviations to the cycle parameter and
- Companies that are providing Sterilization services are responsible for fulfilling all requirements of Annex D of ISO 11135.
Definition & Description of Product
Definition of Process
Process definition influences process efficacy by establishing the product’s range of specifications for the Sterilization process. The former and latest versions of ISO 11135 do not share any remarkable difference among them in the process definition. Process definition relates to:
- A qualified Sterilization chamber and
- The records which support process parameters’ implementation on a Process Challenge Device or PCD.
Parts of Process Definition
The following can be the part of process definition:
- Biological Indicators or
- Sterility testing.
Validation & its Purposes
Validation of a defined Sterilization process helps deliver the product’s effective delivery and reproducibility within the Sterilization load.
Stages of Validation
What must be recorded During Validation
ISO 11135:2014 requires the following to be recorded during validation:
- Validation activities;
- PCD;
- Load configurations and
- Product/process definitions.
Contents of the Validation Report
The validation report must contain the following:
- EO process specifications and
- Supplemental considerations for
- Inert gas flushing and
- Post-inert gas flushing and
- Conditioning stage.
Phase of Installation Qualification
This phase requires the manufacturer to:
- Check the compliance of installed equipment with defined specifications during
- Process characterization
- Equipment characterization and
- Applicable safety standards.
- Define the operating procedures and instructions required for the appropriate and safe operations (such as EO storage, instrument calibration, operation, etc.).
IQ services associated with equipment management (such as outsourced maintenance and technical support) are part of ISO 11135. As part of design control, the standard also requires the assessment and documentation of any installed equipment changes.
Phase of Operational Qualification
During operational qualification, the capability of equipment and ancillary system which deliver operating ranges is demonstrated by calibrating and testing of all the instruments that are used for:
- Monitoring;
- Controlling;
- Indicating or
- Recording purposes.
For example, an operational qualification document can mention the following:
- The achievable pressure for air admission and
- Correctly positioned temperature sensor in the chamber to measure correct temperature difference etc.
Moreover, to demonstrate the working ability of all software systems including ancillary equipment during worst-case conditions, it is necessary to test them during fault conditions.
Phase of Performance Qualification
Microbiological Classification (MPQ)-Stage 1
MPQ consists of the following
- Achieving specified SAL when the least microorganisms on the PCD are killed by the application of most critical parameters of defined process and
- Reduction of exposure time is of the key factors of lethality.
The MPQ establishes the effectiveness of the Sterilization process in a specific Sterilization process.
Overkill Approach-(Method 1)
It is a conservative method and consists of either of:
- 3 Sterilization runs having a half-cycle exposure time which must be able to kill all the BI that at least has a population of 106 and a short-duration cycle which is required to validate BI recovery technique, or
- Various cycles depend on the BI recovery method. This determines the process parameter routines. This process parameter delivers 12 Spore Long Reduction (SLR) of the BI by extrapolating a surviving microorganism probability.
Bioburden Approach-(Method2)
This approach establishes a product bioburden level and selects BI, which is more resistant than the product bioburden level. This approach aims to establish the Sterilization cycle rate by placing BI at critical locations and running the Sterilization cycle at graded or single exposure time. This depends upon methods used for BI recovery.
Physical Performance Qualification (PPQ)-Stage 2
This stage consists of
- Checking whether critical processes specifications are met everywhere in the Sterilization load throughout the cycle’s duration or not and
- Whether the Sterilization process is reproducible.
This can be exemplified in form of a question such as:
“Is the humidity level within the acceptable range, which is established by the process definition throughout the preconditioning phase’s duration or not?” The documentation of PPQ is done by running three runs of the Sterilization process consecutively. This must meet all the acceptance criteria. ISO 11135 allows PPQ and MPQ to be performed during the same runs of Sterilization. However, an additional run of Sterilization must be run in case of PPQ with the full routine process.
Annual Review of Sterilization Process
The purpose of conducting this annual review for a validated Sterilization process is to confirm the product SAL by reviewing IQ/OQ/PQ. The manufacturer shall document the review and microbiological studies.
Through this review, ISO 11135 requires the following:
- Confirmed calibration status of control and monitoring equipment;
- Periodic review of specified equipment must be performed for their
- Performances
- Temperature and
- Humidity profiles and
- The applied changes.
- Confirmation that the sterilized equipment has not met any changes in terms of their design, manufacturing, and packaging material, PCD, and suppliers, etc.
Assessment for Change
The expected results of this evaluation must match the PCD acceptance and bioburden confirmation at least.
Assessment for Equivalence
According to AAMI TIR28:
“It does not require that the equipment be physically identical, and even if the parameters delivered by the equipment are not statistically identical, the processes delivered can still be equivalent if they are all capable of running the process within the defined, validated process limits.”
In cases where many different equipment types are being used for the same validated process, this process equivalence can reduce the number of tests. During equivalence assessment, an equivalence rationale can be documented to evaluate:
- Any additional Sterilization equipment that has been introduced in the ongoing validation process and
- Any additional products that have been introduced in the ongoing validation process.
To use the equipment, qualified OQ and IQ Sterilization equipment must deliver the same process parameters. Also, the use of equipment depends upon the performance qualification test which is performed
- With original equipment in the same chamber, or
- Using reduced MPQ and PPQ to ensure delivery of process parameters to the products within defined tolerances. The reduced MPQ should be achieved with the required level of microbiology lethality.
The addition of a product to validated process depends upon:
- Its documentation which is equivalent to an existing qualified product, or
- Internal PCD.
Equivalence assessment also includes a technical review which considers:
- Product safety
- Quality
- Performance and
- The final decision for inclusion.
Routine Monitoring, Control, & Release of Product
It is the responsibility of the manufacturer to ensure:
- Routine release of the product and
- Delivery of validated and specified Sterilization process to every run of the products.
Routine Sterilization Activities
Monitoring during routine Sterilization products consists of:
- Checking Sterilization process parameters and
- Use of biological indicators for products’ attestation that have been exposed to the EO gas.
Requirements of Latest Version of ISO 11135
Supplemental tests such as endotoxin or EO residuals may be required for releasing the Sterilization load. These supplemental tests depend upon:
- Type of product
- Product’s exposure to human beings
- Finished medical device’s risk classification
If the load is not meeting the acceptance criteria, the manufacturer will look for those deficiencies to prevent the recurrence of such deficiencies. They can also implement a new qualification after repairing the equipment before its use again in any Sterilization process.
After considering the product that he has used during validation, the manufacturer can release the load after him
- accepting the functionality of product/packaging and residual EO following after repeated exposures
- ensuring that the products from MPQ have been fully exposed to the specified Sterilization method.
Product Release based on Documented Review
Product release based on the documented review of records is also known as parametric release. It must ensure the delivery of essential physical Sterilization process parameters to the specifications established during validation. This product release is consequently unrelated to biological indicator or PCD testing.
It is necessary to consider supplemental requirements during Sterilization validation. This helps in establishing the specifications. These specifications will then be verified in the routine during the alternative release process.
Use of Specific Sterilization Equipment
As per the ISO 11135’s requirements, it is necessary to use specific equipment while Sterilization. For example:
- Use of analytical instruments for direct analysis of humidity while conditioning, and
- Use of analytical tools for determining EO concentration during EO exposure time.
Parametric Checking for Parametric Release
Single Lot Release for Research & Development Purpose
Annex E of ISO 11135:2014 defines the requirements that are applied to single lot releases for the research and development of medical devices. These medical devices are intended to be used at clinical trials. By releasing a single lot batch, companies will not have to go through a complete Sterilization validation. The Sterilization process will be considered validated if the packaged product is assigned to a product family. Without a single lot release, the process of Sterilization approval will consist of three main stages.
Completion of the First Stage
After completing the first stage, the samples are taken at locations where it is challenging to achieve Sterilization. According to ISO 11737-2, these samples, along with internal PCD (and external PCD if it is used), will be subjected to sterility testing.
Completion of the Second Stage
At the end of the second stage of Sterilization, the new internal PCD (which has replaced the first one in Sterilization load) along with new external PCDs (if they are used) will be tested. This will be done under ISO 11737-2.
Final Stage
Conclusion
ISO 11135:2014-compliant manufacturers will enable themselves to establish a Quality Plan. This Quality Plan can affect the following:
- Sterilization equipment e.g.,
- detecting equipment for deviation to cycle parameters
- sterilizer with a vaporizer.
- The Sterilization process which is under control to a detailed list of variables, and
- Sterilization validation by checking the capability of new equipment or the considerations of new Sterilization process variables.
The quality action plan shall:
- Be defined
- Implemented
- Show whether a re-validation is necessary or not
- If it cannot demonstrate the necessity of re-validation, it should at least state that there is no impact.
To determine that Sterilization and product SAL equipment are appropriate, the manufacturer must review and document their Sterilization processes annually. This review will also help show that changes that are applied to products and processes are not affecting the sterility and Sterilization processes.
Annex E has also been introduced in ISO 11135. This annex is related to single-lot releases. These single-lot releases are applied for research or clinical investigation. The introduction of this annex will help in reducing uncertainties associated with previous manufacturers.
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