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.
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.
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:
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.
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.
The agents used in Sterilization are either composed of pure Ethylene Oxide or are mixtures of carbon dioxide or nitrogen.
It is advised to handle, store and use EO gas with great care because:
The Sterilization process consists of two important steps:
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.
The EO Sterilization process consists of the following steps:
The load configuration in the chamber influences
The design of load configuration should be planned in such a way that it assists during the Sterilization process by:
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.
Includes process variables associated with each phase.
Pre-conditioning deals with time, temperature, humidity, and transfer time.
The Sterilization cycle composes of exposure time, temperature, humidity, EO concentration, and pressure.
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.
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:
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:
The following can be the part of process definition:
Validation of a defined Sterilization process helps deliver the product’s effective delivery and reproducibility within the Sterilization load.
ISO 11135:2014 requires the following to be recorded during validation:
The validation report must contain the following:
This phase requires the manufacturer to:
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.
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:
For example, an operational qualification document can mention the following:
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.
MPQ consists of the following
The MPQ establishes the effectiveness of the Sterilization process in a specific Sterilization process.
It is a conservative method and consists of either of:
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.
This stage consists of
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.
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:
The expected results of this evaluation must match the PCD acceptance and bioburden confirmation at least.
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:
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
The addition of a product to validated process depends upon:
Equivalence assessment also includes a technical review which considers:
It is the responsibility of the manufacturer to ensure:
Monitoring during routine Sterilization products consists of:
Supplemental tests such as endotoxin or EO residuals may be required for releasing the Sterilization load. These supplemental tests depend upon:
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
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.
As per the ISO 11135’s requirements, it is necessary to use specific equipment while Sterilization. For example:
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.
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.
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.
ISO 11135:2014-compliant manufacturers will enable themselves to establish a Quality Plan. This Quality Plan can affect the following:
The quality action plan shall:
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.
If you are a manufacturer who is looking for ISO 11135:2014 compliant systems in Europe, contact TSQ&E. Our team of experts will help you understand every aspect of ISO 11135 so that you can establish yourself as a pioneer institution in the management and validation requirements of EO Sterilization.