Cleaning Validation Acceptance Criterion

Are are fed up, tired of it all. Your boss has been harassing you to develop “a scientifically sound, logical, and rational basis for cleaning acceptance limits.” Should be simple enough, right? Yet, every time you ask someone about setting cleaning limits they look at you as if you have three, maybe four heads. Asking a consultant only makes things worse, leaving you more confused when they present you with more theoretical options than you ever imagined possible (but of course offering to help you solve the problem with a team of experts!) You’ve scoured the literature, yet haven’t found anything but theoretical discussions and vague references to the “Mullen and Fourman method.” Before kicking the cat or cursing your boss, let’s see what this is really all about.

Case Study

Let’s look at a case study. Let’s imagine that the situation deals with the removal of a biologically active protein from an equipment item cleaned with either CIP, COP, or manual techniques with a WFI final rinse. We are using rinse water as the means of detecting residue removal. Rinse water analysis is by nature an indirect measure of cleaning efficacy. The only direct measure of cleaning efficacy is surface analysis – typically performed by either visual or swab analysis. Rinse water analysis is however a common method used to verify cleaning efficacy, and when combined with surface analysis is often part of an effective cleaning validation program.

Maximum Acceptable Amount

So for this case, we want to determine the maximum acceptable amount of protein residue that can be carried over to the next batch of product produced in a specific piece of equipment. Let’s make a few assumptions and draw some conclusions from them.

  • Assume the equipment is a vessel with a 300 liter working volume.
  • Assume that the vessel’s nominal batch size ranges from 20 liters to 240 liters.
  • Assume the active protein has a therapeutic dose limit of 400 µg/ml.

Applying an industry standard safety factor of 1/1000 of a therapeutic dose, we can calculate the Maximum Allowable Carry-Over (MAC) to be:

MAC = (1/1000) x (400 µg/ml) = 0.4 µg/ml

8000 µg is the maximum amount of protein that can be carried over into the next batch (20l) of product and still meet the 1/1000th of a therapeutic dose criterion. This number can then be used to work backwards to calculate a rinse water acceptance limit.

To back-calculate the rinse water acceptance limit, we need to determine the amount of protein that if found in a rinse water sample, would result in 8000 µg of protein ending up in the next 20 liter batch of product. To determine this, we must again make several assumptions, but we will be conservative to provide for additional safety factors.

Let’s assume that we’ve performed our standard cleaning process on the vessel and are about to take a WFI rinse sample at the end of the rinse cycle. Let’s also assume that the cleaning process has left 8000 µg of protein on the surface of the vessel at the end of the cleaning cycle.

If we now rinse the vessel with 2.0 liters of WFI and all of the protein on the surface disassociates itself from the vessel and into the 2.0 liters of rinsate, then the concentration of protein in the rinse water would be:

(8000 µg)/2000ml = 4µg/ml

This value could be used as the rinse water acceptance limit as it relates back to the original goal of having less than or equal to 1/1000th of a therapeutic dose of the protein in the next batch of product.

Conclusion

Before concluding, let’s review a few of the assumptions that were made. To begin with, setting cleaning criteria for proteins can be difficult since the assumption that the protein remains active following the cleaning process is very conservative. Most proteins become denatured due to the high temperatures and the caustic nature of the detergents typically used.

Several other conservative assumptions also were applied in this case study. The first of these is the assumption that all of the protein that remains in the vessel after cleaning is going to disassociate during the production of the next production batch. While this is possible, it is most unlikely. We used the smallest batch size to calculate the limits to provide an additional safety factor. Similarly, the use of 2.0 liters for the rinsate volume is conservative. One could easily use a higher rinsate volume and derive a lower acceptance criterion; however, we have chosen this low rinsate volume to be intentionally conservative.

It should be noted that surface analysis via swabbing is typically used to corroborate and support the use of rinse water analysis. Similar techniques to those used to derive the rinse water analysis acceptance limits can be used for establishing swabbing acceptance limits.

This case study is intended to serve as an aid to those faced with the problems of establishing cleaning acceptance limits. Any number of approaches may be taken and for different cleaning scenarios, different approaches may be more or less appropriate. Regardless of the approach taken, document the rationale for the approach in the protocol or the master plan or both.

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  • Rajesh Singh Chauhan

    If Recovery not acheved the Target Value then what should be done.

  • Rajesh Singh Chauhan

    If Recovery not acheved the Target Value then what should be done.

  • IkbellmaN

    Hello

    my project of ending studies is about the validation of the glassware cleaning and i don’t have any method, can we use this method for the glassware ?

    please reply
    thanks in advance
    IkbellmaN

  • IkbellmaN

    Hello

    my project of ending studies is about the validation of the glassware cleaning and i don’t have any method, can we use this method for the glassware ?

    please reply
    thanks in advance
    IkbellmaN

  • PARUL

    we are working in finished product dept which are handling protin. i want to know the procedue for clening of accesory….

  • PARUL

    we are working in finished product dept which are handling protin. i want to know the procedue for clening of accesory….

  • Anuj Shah

    Hi,
    We are generally using swab technique for our cleaning validation , but there are some pieces of equipment were swabbing is not possible as the equipment is too large in size, so we are thinking to go for rinse sampling method, but we don’t know how to calculate the accpetance criteria as the rinsate for rinsing is an approximate volume, it could be more or less than that.

    Can you guide me on this.
    Thanks,
    Anuj

  • Anuj Shah

    Hi,
    We are generally using swab technique for our cleaning validation , but there are some pieces of equipment were swabbing is not possible as the equipment is too large in size, so we are thinking to go for rinse sampling method, but we don’t know how to calculate the accpetance criteria as the rinsate for rinsing is an approximate volume, it could be more or less than that.

    Can you guide me on this.
    Thanks,
    Anuj

  • hizbi_nzk@yahoo.com

    Hi,
    What happens if the limit is less than the analytical method’s LOD & LOQ as there are numerous compounds for which the acceptable carry over limit is very minute and don’t fall in the LOD and LOQ range.

  • hizbi_nzk@yahoo.com

    Hi,
    What happens if the limit is less than the analytical method’s LOD & LOQ as there are numerous compounds for which the acceptable carry over limit is very minute and don’t fall in the LOD and LOQ range.

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The Difference Between Qualification and Validation [Video]

There is a general saying within the life sciences:

“We qualify a system and/or equipment and validate a process”

A system and/or equipment must be qualified to operate in a validated process.

For example:

“You qualify an autoclave, whereas you validate a sterilization process”

Manufacturers should identify what validation and qualification work is done. All systems, equipment, processes, procedures should be reviewed and the manufacturer should decide what qualification and validation work needs to be performed.

Direct, Indirect or No Impact

All facility areas, utilities and process equipment must be assessed and classified as direct impact, indirect impact or no impact following an analysis of their impact on the identity, strength, quality, purity or safety of products manufactured at the facility and also the safety of the operators & environment.

Impact on Quality

Each system or item of equipment having direct or indirect impact on the product quality must be validated. The extent of validation or qualification should be determined by performing the risk assessment of that particular system or equipment.

Join the Discussion

Use our community to find our more about validation and qualification.
http://community.learnaboutgmp.com/t/qualification-vs-validation/874

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The Difference Between Prospective, Concurrent and Retrospective Validation

Unless you’re starting a new company you will need to plan on a variety of approaches.

Prospective validation occurs before the system is used in production, concurrent validation occurs simultaneously with production, and retrospective validation occurs after production use has occurred.

In this article we will discuss all three and also discuss the role the master validation plan (MVP) performs for each one.

1. Prospective Validation

Prospective validation is establishing documented evidence, prior to process implementation, that a system performs as is intended, based on pre-planned protocols.

This is the preferred approach.

Production is not started until all validation activities are completed.

The MVP need not go into much detail about this approach since it’s the standard method, however, prospective validation follows a step wise process illustrated here.

The process commences with the development of a Validation Plan and then passes through the DQ, RA, IQ, OQ and PQ phases after which process, computer, analytical and cleaning validations are performed which are followed by a final report.

After which the instrument or equipment will be subject to preventative maintenance and requalification on a routine basis.

Periodic Basis

On a periodic basis all instrumentation and equipment should be reviewed. This review is intended to identify any gaps which may have developed between the time it was last qualified and current requirements.

If any gaps are identified a remediation plan will be developed and the process will start again.

The MVP

The MVP may need to describe what is done with product produced during prospective validation. Typically, it is either scrapped or marked not for use or sale.

The product may be suitable for additional engineering testing or demonstrations, but appropriate efforts need to be made to ensure this product does not enter the supply chain.

Ideally, all validation is done prospectively; i.e., the system is validated before use. However, there are cases and conditions which may prevent this.

2. Concurrent Validation

Concurrent validation is used to establish documented evidence that a facility and process will perform as they are intended, based on information generated during actual use of the process.

In exceptional circumstances (for example, in a case of immediate and urgent public health need) validation may need to be conducted in parallel with routine production. The MVP needs to define how product is managed throughout the process.

Typically, the product batches are quarantined until they can be demonstrated (QC analysis) to meet specifications.

The Right Decision?

The decision to perform concurrent validation should not be made in a vacuum. All stakeholders including management, Quality Assurance and the government regulatory agencies should all agree that concurrent validation is an acceptable approach for the system under consideration.

As always the principal requirement is patient safety is not compromised. The rationale to conduct concurrent validation should be documented along with the agreement to do so by all the stakeholders. This can be part of the Validation Plan or documented as a deviation.

The Process

The concurrent validation process is identical to that of prospective validation. The process starts with the development of a Validation Plan, followed by the DQ, RA, IQ, OQ and PQ phases after which process, computer, analytical and cleaning validations are performed, ending with a final report.

Again, routine preventative maintenance, requalification and periodic review are performed.

3. Retrospective Validation

Retrospective validation is validating a system that has been operating for some time. There are various schools of thought on how to approach retrospective validation. Some may feel that a full-blown validation is required to assure the system is functioning properly.

Others may feel that since the system has been in use, presumably without issues, validation is not necessary and a memo to file justifying why validation is not necessary may be issued.

Doing a full validation may not be required, since you already have proof that the system functions as required – at least in the situations in which production was conducted. Doing nothing, though, is a risk.

It’s likely that the controls haven’t been challenged so there may be some hidden flaws that haven’t been identified that could lead to non-conforming product, hazardous operating conditions, extended delays, etc.

Historical Data

Historical data can certainly be used to support validation. For example, if there is detailed and statistically-significant evidence that production runs are well controlled you could rationalize and justify not doing full validation.

During retrospective validation, it’s advisable that existing product be quarantined, and production put on hold until validation is complete.

As an exception, producing product as part of the validation exercise would follow concurrent validation. This may not be practical since product may have already been distributed, but caution is advised for the reasons outlined.

General Process

The general process for retrospective validation follows the same process as for prospective and concurrent validation except DQ is seldom performed, as the system has already been in use for some time.

Instead a survey and review of available information is performed. This normally occurs before the validation plan is created.

The MVP should also provide guidance on managing inventory during retrospective validation.

One Major Issue

One potential major problem that can occur with retrospective validation the determination of what action should be taken if an issue is found with the system during retrospective validation?

As with everything else, a risk-based decision is warranted. This could be anything from product recall, to customer notifications, to just documenting the justification of the decision why nothing was done.

Again, the MVP should provide guidance on dealing with situations concerning out of specification conditions revealed during retrospective validation, which should also definitely include involving regulatory support.

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