This article reviews some of the factors to consider when you are evaluating the need to repeat your ethylene oxide sterilization validation.
ISO 11135-1:2014 is the international standard for sterilization validation for Ethylene Oxide (EO or EtO) sterilizers. The standard “full” validation is required for initial qualification of your EO sterilization process. Full validation consists of the following:
- Process Challenge Device (PCD) validation
- Bioburden measurement
- EO residual measurement (as per ISO 10993-7:2008/R2012)
- Fractional Cycle (at least one)
- 3x Half Cycle
- 3x Full Cycle
In addition to the full validation, you might also validate partial loads and/or re-sterilization of product in the case of rework.
Ethylene oxide sterilization is typically outsourced to a contract sterilizer due to the environmental and safety requirements of working with EO. Typically the contract sterilizer will provide a standard validation protocol for full validation that is compliant with ISO 11135-1. However, the ISO 11135-1 standard requires that manufacturers perform annual process reviews to evaluate the need for re-validation of the sterilization process. Assuming there have been no problems, and no changes to the product or process, then re-validation is not required at the end of the first year. However, most companies are expected to re-validate the process after two years. So why do some companies perform re-validation after three years or more?
Longer Re-Validation Cycles
If there have been not changes to the sterilization process, the product or the biological indicators, then the manufacturer can use this as a justification for waiting until two years have elapsed before re-validating the ethylene oxide sterilization process. In addition, there should be no evidence of sterilization failures or other problems with the validated process. However, that alone is not necessarily enough to justify extending the duration between validations beyond two years. Companies that are able to justify intervals of three or more years have multiple products that are using the same sterilization process.
In this case, the manufacturer may alternate annually between three, four or even five different product families that are using the same sterilization process. In this case, one of the product families is being re-validated each year or every two years, but the interval between validations for any one product family is longer. If the products are made of similar materials and using the same sterilization process, then this approach is valid. If you only have one product, then you need to re-validate the sterilization process once every two years to verify the process remains effective.
Minimum Re-Validation Requirements
When you determine that it is time to re-validate your ethylene oxide sterilization process, you need to perform the following tests in order to meet the minimum requirements of ISO 11135-1:
- Bioburden measurement
- EO residual measurement
- One Fractional Cycle
- 3x Half Cycle
- One Full Cycle
The purpose of #1 is to verify that bioburden levels have not changed. In practice, most companies monitor bioburden on a quarterly basis and therefore this step should be routine. Step 2, EO residual measurement, should be performed in order to verify that there have not been minor changes to the product or process that would increase the concentration of EO, Ethylene Chlorohydrin (ECH) or Ethylene Glycol (EG) beyond the Tolerable Contact Limit (TCL). The purpose of this second test is to prevent localized irritation caused by residual chemicals from the ethylene oxide sterilization process.
Step 3 of the re-validation is intended to verify that a full injection of EO is more than required to kill the bioburden present for the number of injections required for a half-cycle. Therefore, if required minimum concentration of EO is 2 for two injections, two injections of a 3.6 EO concentration may be used for a half-cycle. Ideally, the Process Challenge Devices (PCDs) will be non-sterile after a fractional cycle, while the internal biological indicators will be sterile. After a half-cycle, all biological indicators, including the PCDs, should be sterile.
The final step is to perform a full cycle. Product from the full cycle is typically used for the EO residual testing. Any product from the full cycle that is not used for testing can be sold after sterility testing is complete.
Partial Loads & Rework
If you occasionally sterilize loads that are less than “full loads,” then you need to ensure that you have validated a minimum load or a specific partial load (e.g., half-pallet, instead of a full pallet). In the case of a partial or minimum load, you may identify different locations in your load that are considered “worst-case.” These are the locations that had PCDs that were not sterile in a fractional cycle.
Most companies do not have concerns about the cost of the actual sterilization runs during re-validation, and biological indicators are typically less expensive than boxes of product. The primary cost concern for re-validation is any product that must be scrapped. Therefore, many companies will accumulate dunnage (i.e., empty packaging or scrap product) over time in order to fill a sterilizer. This dunnage may be used to ensure that every load is a full load, or it may be only used for re-validation.
Another alternative to using dunnage for re-validation is to validate a rework process. Any product that is exposed to a fractional cycle or half-cycle can be resterilized in a full cycle. In order to justify the commercial use of that product, a company needs to validate that the product will not be damaged by exposure to two full cycles. One of the key acceptance criteria for rework is the EO residual levels in the product. However, the manufacturer also needs to determine if there has been any deterioration of the product by a second exposure to EO that would affect performance.
Many companies do a poor job of reviewing the potential impact of changes to product, packaging and biological indicators. Ideally, initial validation involves different lots of product, packaging and biological indicators to assess lot-to-lot variability. However, many times, the packaging and biological indicators consist of only one lot during validation. Minor changes to the tolerances may reduce the amount of ethylene oxide that is absorbed by the product or change the resistance o the biological indicator to the sterilization process. Therefore, these minor changes should trigger a re-validation.
Changes in suppliers with the same specification can also be difficult to evaluate. If a component is made of a material that absorbs EO, then it may be recommended to re-validate sterilization for any changes to suppliers of those components. Re-validation in these cases may consist of only a fractional cycle or only a full-cycle to evaluate risks associated with the change.
Who Should Be Making Evaluations
The evaluation of need for re-validation should include input of three types: 1) microbiological, 2) materials, and 3) performance. In order to make these assessments, typically a cross-functional team is needed. Someone with responsibility for design and development can assess performance impact of changes. A materials engineer is typically needed for assessment of interaction between components and EO. Finally, a microbiologist is needed to confirm that there is no impact related to biological indicators or bioburden.
Medical Device Academy also released a new webinar recording on the topic of Bioburden Failure Analysis last week – Read More…
If you need assistance with sterilization validation or bioburden failure analysis, please contact me by email at email@example.com or call me at +1.802.281.4381.