Archive for Process Validation

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

This article explains what a master validation plan is and explains when it is appropriate to have a master validation plan and when a master validation plan is unneeded.

Process Validation Protocol What is a Master Validation Plan and Do You Need One?In the United States, there are two applicable regulations for medical device manufacturing process validation:

  1. 21 CFR 820.75
  2. ISO 13485, Clause 7.5.2

Neither the QSR regulation, nor the ISO Standard, include any mention of a master validation plan. There is a requirement for product realization planning, and a master validation plan could be an important 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 are 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 product technical 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 inclusion of process validation and software validation in a medical device license application for Class IV devices. None of those references mention 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, there is 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 the 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 the 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 the process validation as part of the design transfer activities when a new product is being developed. Quality plans are used to facility expansions and construction of new facilities. Some companies even include validation and revalidation plans in their process validation procedure and/or the 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 re-validation requirements, the plan should indicate when the last validation was performed and what the frequency of re-validation 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 a 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 nonconformities.

Procedures & Templates

If you are looking for a procedure (SOP) for process validation please click here.

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When and How to Repeat Your Ethylene Oxide Sterilization Validation

This article reviews some of the factors to consider when you are evaluating the need to repeat your ethylene oxide sterilization validation.

EO Sterilization Cycle When and How 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:

  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. 3x Half Cycle
  6. 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:

  1. Bioburden measurement
  2. EO residual measurement
  3. One Fractional Cycle
  4. 3x Half Cycle
  5. 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.

Other Considerations

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.

Bioburden Failure Analysis Webinar When and How to Repeat Your Ethylene Oxide Sterilization ValidationMedical 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 or call me at +1.802.281.4381.



Posted in: Process Validation

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