Process Validation

EO Sterilization – When is requalification required?

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This article discusses the need to requalify EO sterilization validation and explains what is included in our EO sterilization procedure.

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EO Sterilization Cycle EO Sterilization When is requalification required?

Do you need an EO sterilization procedure?

ISO 11135-1 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. The overkill approach is the method recommended by Medical Device Academy’s EO sterilization procedure. If you use a contract sterilizer, the sterilizer will already have completed an Installation Qualification (IQ) and an Operational Qualification (OQ). You must 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)
  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)

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

EO Sterilization Cycle 1 150x150 EO Sterilization When is requalification required?
SYS-031 EO Sterilization Validation Procedure
This procedure was updated in 2024 to include recent versions of various standards and to incorporate changes to make the procedure consistent with other procedures in Medical Device Academy's turnkey quality system. The updated procedure defines the requirements for ethylene oxide (EO) sterilization validation and revalidation/requalification outsourced to a contract sterilizer.
Price: $299.00

What do MPQ and PPQ mean?

In the ISO 11135 standard, steps #4 and #5 listed above are referred to as the microbial performance qualification (MPQ), while #6 is the physical performance qualification (PPQ). For a successful MPQ, some 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.

What are BIs, CIs, and PCDs?

To avoid destructive testing, EO sterilization processes verify sterility by using process challenge devices (PCDs) located outside the device’s primary and secondary packaging. PCDs are more challenging to sterilize than the native bioburden on your device, and the PCDs can be quickly removed from a sterilized pallet without disturbing the wrapping of the pallet. PCDs are also referred to as external biological indicators (BIs). Biological indicators are used internally and externally to your primary sterile barrier packaging during the EO sterilization validation process, but only external BIs are used during routine EO sterilization. You can create your own customized PCD for devices that are especially difficult to EO sterilize (e.g., stopcocks), but you must verify that the PCDs are more challenging to kill than an internal BI in a fractional cycle. Commercially available PCDs often incorporate a chemical indicator (CI) into the label or the cap of the PCD, and some are incorporated into sophisticated tracking software with automatic incubators that read a barcode on the PCD label and detect the results of incubating the BIs in media. These systems are rapid, self-contained BIs that provide validated results in hours, minutes, or seconds.

BIs CIs and PCDs 1024x314 EO Sterilization When is requalification required?

Outsourcing EO sterilization and requalification

Ethylene oxide sterilization is usually outsourced to a contract sterilizer due to the environmental and safety requirements of working with EO. The contract sterilizer will provide a generic 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 to requalify/re-validate the sterilization process. Assuming there have been no problems or changes to the product or EO sterilization process, re-validation is not required at the end of the first year. However, companies are required to re-validate the process after two years–even if there have been no changes.

Longer frequencies for requalification 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 justify intervals of three or more years have multiple products that use the same EO sterilization process.

In this case, the manufacturer may alternate annually between three, four, or even five different product families that are using the same EO 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. This approach is valid if the products are made of similar materials and use the same EO sterilization process. 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 revalidation 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 products. 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 full, 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 exposed to a fractional or half-cycle can be re-sterilized 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 any product deterioration by a second exposure to EO would affect performance.

Other EO sterilization 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, the packaging and biological indicators often 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 of 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 full cycle to evaluate risks associated with the change.

Who should evaluate the need for EO sterilization requalification?

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

Bioburden Failure Analysis Webinar EO Sterilization When is requalification required?Additional Sterilization Training

Medical Device Academy has two webinar recordings related to sterilization validation:

If you need assistance with sterilization validation or bioburden failure analysis, please schedule a call with us by visiting our Contact Us page. 

EO Sterilization – When is requalification required? Read More »

Performance Qualification (PQ) for EO Sterilization Validation

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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 procedure was updated in 2024 to include recent versions of various standards and to incorporate changes to make the procedure consistent with other procedures in Medical Device Academy's turnkey quality system. The updated procedure defines the requirements for ethylene oxide (EO) sterilization validation and revalidation/requalification outsourced to a contract sterilizer.
Price: $299.00

 

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What is a Master Validation Plan and Do You Need One?

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This article explains what a master validation plan is, when is it appropriate to have a master validation plan, and when you need one.

Process Validation Protocol What is a Master Validation Plan and Do You Need One?

Master Validation Plan

In the United States, there are two applicable regulations for medical device manufacturing process validation: 1) 21 CFR 820.75, and 2) ISO 13485, Clause 7.5.2. Neither the QSR regulation nor the ISO 13485, include any mention of a master validation plan. There is a requirement for product realization planning, and a master validation plan could be an essential part of that planning. However, master validation plans are not mentioned anywhere.

MDD – Master Validation Plan?

For companies that manufacture CE Marked products, the term validation appears in the MDD (93/42/EEC as modified by 2007/47/EC) a total of two times. Only one of those references is specific to process validation, but there is no mention of a master validation plan. The single mention of validation appears in Annex VII, and the reference is specific to the requirement for including a copy of the sterilization validation report in a technical product file.

CMDR – Master Validation Plan?

For companies that hold one or more Canadian Medical Device Licenses, “validation” appears in the Canadian Medical Devices Regulations (CMDR) a total of eight times (four times as part of the French translation). The first four references are part of the definition of validation, where the CMDR is referring to design validation. The remaining four references specifically mention the requirement for the inclusion of process validation and software validation in a medical device license application for Class IV devices. None of those references say of a master validation plan.

IQ/OQ/PQ Requirements?

Not only is there no mention of a requirement for master validation plans in any of the medical device regulations, but there is also no mention of installation qualification (IQ), operational qualification (OQ), or performance qualification (PQ). The only mention of validation protocol or report appears in 21 CFR 820.70 as it refers to using validation protocols for validation of software controlling automated equipment.

21 CFR 210 or 21 CFR 211 requirements?

The requirements for medical devices historically are derived from pharmaceutical regulations–which included the requirement for process validation. However, neither 21 CFR 210 nor 21 CFR 211 mention master validation plans (need to verify). They also don’t mention IQ/OQ/PQ requirements.

Where did the idea for Master Validation Plans Come From?

GHTF/SG3/N99-10:2004 is the guidance document that was created by the Global Harmonization Task Force’s Study Group 3 for guidance on process validation. The guidance even includes templates for a master validation plan, IQ, OQ, and PQ. The guidance indicates that the purpose of a master validation plan is to plan validation and revalidation activities. There are other planning documents that could be used instead. For example, design plans include process validation as part of the design transfer activities when a new product is being developed. Quality plans are used for facility expansions and construction of new facilities. Some companies even include validation and revalidation plans in their process validation procedure and/or sterilization validation procedure.

For companies that have equipment that requires validation, I like to use an equipment register that identifies calibration, preventive maintenance, validation, and revalidation requirements as part of the equipment register. This allows me to use one single document to manage all the planning of calibration, preventive maintenance, and validation. If there are no validation requirements, then the appropriate column of the equipment register will indicate “n/a.”

What is a Master Validation Plan?

A master validation plan (MVP) is simply a plan for your equipment and process validation activities. All the equipment, processes, and software requiring validation should be included in the MVP. The plan should reference the applicable protocol and report for each item in the plan. If there are revalidation requirements, the plan should indicate when the last validation was performed and what the frequency of revalidation should be. Ideally, similar equipment will use the same validation protocols that are controlled documents and pre-approved. Over time the number of reports referenced will increase, but the plan should only reference the most recent approved protocol(s).

Some companies include the rationale or triggers for revalidation in the plan–just as you would for a record retention table. However, other companies will include this detail in the validation protocol and/or in the process validation procedure. The rationale for revalidation only needs to be in one of three places, and duplication of the information just encourages errors and audit non-conformities.

Procedures & Templates

We also have a process validation procedure.

What is a Master Validation Plan and Do You Need One? Read More »

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