ethylene oxide sterilization validation Archives

Performance Qualification (PQ) for EO Sterilization Validation

The article explains requirements for a performance qualification (PQ) of EO sterilization validation and how it is different from other PQ process validations.

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Mind your ps and qs 1024x291 Performance Qualification (PQ) for EO Sterilization Validation

Performance Qualification (PQ) – What is the difference between an IQ, OQ, and PQ?

When you are performing a process validation, the acronyms IQ, OQ, and PQ sometimes confuse. IQ is the installation qualification of the equipment used in your validated process. The purpose of the installation qualification is to make sure that your equipment was installed correctly–this includes calibration and connection to utilities. OQ is the operational qualification. The purpose of the operational qualification is to make sure that the equipment you are using is capable of operating over the range of parameters that you specify to make your product. The PQ is a performance qualification. The purpose of the performance qualification is to ensure that you can consistently make a product within specifications (i.e., repeatable).

Different Definitions for Operational Qualification (OQ)

The GHTF guidance document for process validation provides the following definition for an OQ: “Establishing by objective evidence process control limits and action levels which result in a product that meets all predetermined requirements.” ISO 11135-1:2014, the international standard for ethylene oxide (EO) sterilization validation, provides a slightly different definition for an OQ: “process of obtaining and documenting evidence that installed equipment operates within predetermined limits when used in accordance with its operational procedures.” The difference in these two definitions is essential because the OQ is typically performed by contract sterilizers and does not need to be repeated unless there is a significant change or maintenance to the sterilizer that requires repeating the OQ. In contrast, when you perform an OQ for packaging, the OQ is specific to the packaging materials you are going to be sealing. Therefore a new OQ is required whenever new packaging materials are developed. For EO sterilization, the analogous step of the validation process is called a microbial performance qualification (MPQ).

Performance Qualification (PQ) = MPQ + PPQ

A performance qualification (PQ) for ethylene oxide sterilization validation consists of two parts: 1) microbial performance qualification (MPQ), and 2) physical performance qualification (PPQ). The microbial performance qualification is intended to determine the minimum process parameters for the EO sterilizer sufficient to ensure product bioburden is killed. These parameters are referred to as the half-cycle because the full production cycle will be twice as long in duration. For example, a half-cycle consisting of 3 injections will correspond to an entire cycle of 6 injections.

What are fractional cycles?

Fractional cycles are typically shorter in duration than the duration of a half-cycle. The purpose of a fractional cycle is to demonstrate that external biological indicators (BIs) located outside of your product, but inside the sterilization load, are more challenging to kill than internal BIs. Fractional cycles are also be used to demonstrate that the product bioburden is less resistant than the internal BIs. To achieve both of these objectives, it is typical to perform two fractional cycles at different conditions to make 100% kill of internal BIs and partial external BI kill in one fractional cycle, and 100% kill of product bioburden but only partial kill of internal BIs in the other fractional cycle. When your goal is partial kill, you should also target more than one positive BI, because this reduces the likelihood that poor technique resulted in a BI positive from growth.

Microbial Performance Qualification (MPQ)

The microbial performance qualification (MPQ) typically consists of three half-cycles and one or more fractional cycles. 100% kill of external BIs is not required for the MPQ during a half-cycle–only the internal BIs must be 100% killed, but the external BIs are only useful if 100% kill of the external BIs is achieved in the full cycles. If you are re-validating the sterilization process, you are only required to complete one-half cycle and one fractional cycle. For re-validation, the fractional cycle is intended to achieve a 100% kill of product bioburden. Still, only partial kill of internal BIs to verify that the product bioburden remains less resistant to sterilization than the internal BIs. You are also required to perform bioburden measurements of non-sterile products for the initial MPQ and re-validation to demonstrate that bioburden can be adequately recovered from the product and measured.

Physical Performance Qualification (PPQ)

The physical performance qualification (PPQ) typically consists of three full cycles and measurement of EO residuals in accordance with ISO 10993-7:2008. If PPQ is performed during the MPQ, then it is only necessary to complete one full cycle–assuming the MPQ consists of at least three half-cycles. If you are performing a re-validation of the sterilization process, then you are required to complete three full cycles and measurement of EO residuals.

Repeatability, Reproducibility, Product Variability and Environmental Factors

Typically a performance qualification (PQ) is intended to verify that the same person can repeat the process multiple times, other people can reproduce the first person’s results and any variation product from lot to lot will not prevent the process from producing an acceptable product. Besides, any variation in environmental factors should be assessed during a PQ. In sterilization processes, however, the equipment is typically automated. Therefore, variation between operators is usually a non-issue. Also, sterilization lots typically consist of a large volume of products where multiple samples are tested for sterility. Therefore, performing three runs sufficiently challenges the repeatability and reproducibility of the sterilization process–including any product variability. The issue of environmental variations in heat and humidity is addressed by designing preconditioning cycles into the sterilization process. Sensors are included in each validation load to verify that the process specifications were achieved and maintained for temperature and humidity. Still, the sensors also help to identify the worst-case locations in a load to use for sampling and placement of BIs.

If you are interested in learning more about sterilization validation, please read our blog from last year on an evaluation of the need to re-validate your sterilization process, or you can watch our webinar on sterilization and shelf-life testing. You can also purchase our procedure for EO sterilization validation by clicking on the link below.

Purchase the EO Sterilization Validation Procedure (SYS-031) – $299

EO Sterilization Cycle 1 150x150 Performance Qualification (PQ) for EO Sterilization Validation

SYS-031 EO Sterilization Validation Procedure

This new procedure defines the requirements for ethylene oxide (EO) sterilization validation and revalidation which has been outsourced to a contract sterilizer.

Price: $299.00

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

18 Comments / Process Validation / By Robert Packard / ethylene oxide, ethylene oxide sterilization validation

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

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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:

Process Challenge Device (PCD) validation
Bioburden measurement
EO residual measurement (as per ISO 10993-7:2008/R2012)
Fractional Cycle (at least one)
3 Half Cycles
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:

Re-validation of PCD
Bioburden measurement
EO residual measurement
1 Half Cycle
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.

Purchase the EO Sterilization Validation Procedure (SYS-031) – $299

EO Sterilization Cycle 1 150x150 Re validation of EO Sterilization When is re validation required?

SYS-031 EO Sterilization Validation Procedure

This new procedure defines the requirements for ethylene oxide (EO) sterilization validation and revalidation which has been outsourced to a contract sterilizer.

Price: $299.00

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.

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