Re-validation of EO Sterilization – When is re-validation required?

This article reviews some of the factors to consider when you are evaluating the need for EO sterilization re-validation.

ISO 11135-1:2014 is the international standard for sterilization validation for Ethylene Oxide (EO or EtO) sterilizers. The standard describes multiple methods of sterilization validation: 1) overkill approach, 2) single lot release, and 3) parametric release. The overkill approach is the most common method for validation of your EO sterilization process. If you are using a contract sterilizer, the sterilizer will already have completed an Installation Qualification (IQ) and an Operational Qualification (OQ). You will need to complete a Performance Qualification (PQ) for your product. A typical PQ for initial process validation consists of the following:

1. Process Challenge Device (PCD) validation
2. Bioburden measurement
3. EO residual measurement (as per ISO 10993-7:2008/R2012)
4. Fractional Cycle (at least one)
5. 3 Half Cycles
6. 3 Full Cycles (or 1 Full Cycle, if performed in parallel with the three half-cycles)

Most contract sterilizers already have one or more Process Challenge Devices (PCDs) that they have developed, and they may evaluate multiple PCDs in your fractional cycle to determine which PCDs are more challenging to kill than an internal biological indicator (BI). In addition to the above “typical” PQ, you might also choose to validate partial loads and/or re-sterilization of product in the case of rework.

In the ISO 11135 standard, #4 and #5 are referred to as the microbial performance qualification (MPQ), while #6 is referred to as the physical performance qualification (PPQ). For a successful MPQ, at least some of the PCDs must be non-sterile after a fractional cycle to demonstrate the ability to recover the BI challenge organism. After a half-cycle, however, all biological indicators should be sterile.

Ethylene oxide sterilization is typically outsourced to a contract sterilizer due to the environmental and safety requirements of working with EO. Usually, 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, companies are expected to re-validate the process after two years–even if there have been no changes. So why do some companies perform re-validation after three years or more?

Longer Re-Validation Cycles

If there have been no 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. Also, 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 can 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 active.

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 to meet the minimum requirements of ISO 11135-1:

1. Re-validation of PCD
2. Bioburden measurement
3. EO residual measurement
4. 1 Half Cycle
5. 1 Full cycle (to verify the EO residuals are acceptable)

The purpose of #1 is to verify that the resistance of internal BIs used in the half-cycle is more resistant than the product bioburden. The purpose of #2 is to verify that bioburden levels have not changed, and the type of organisms has not changed. In practice, most companies monitor bioburden quarterly, and therefore this step should be routine. Step 3, EO residual measurement, should be performed 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 third test is to prevent localized irritation caused by residual chemicals from the ethylene oxide sterilization process.

Step 4 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.

The final step is to perform a full cycle. The product from the full cycle is typically used for 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 is 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 to fill a sterilizer. This dunnage may be used to ensure that every load is a full load, or it may only be 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. 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.

Other Considerations

Many companies do a poor job of reviewing the potential impact of changes to a 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, half cycle, or a full-cycle to evaluate risks associated with the change.

Who Should Be Making Evaluations

The evaluation of the need for re-validation should include the input of three types: 1) microbiological, 2) materials, and 3) performance. To make these assessments, typically, a cross-functional team is needed. Someone with responsibility for design and development can assess the performance impact of changes. A materials engineer is generally needed for assessment of the interaction between components and EO. Finally, a microbiologist is needed to confirm that there is no impact related to biological indicators or bioburden.

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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 rob@13485cert.com or call me at +1.802.281.4381.