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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An Alternative View of the ICH Q10 Pharmaceutical Quality System (PQS)

The image below is that depicted by the International Conference of Harmonisation (ICH) Q10, Annex 2, and is supposed to depict a PQS or Pharmaceutical Quality System.

Typically, I really love the ICH. When we have to deal with outdated regulations from different global organizations it becomes a real nightmare trying to keep track of the nuances and the ICH has done a pretty good job of bringing several of the key organizations together and aligning them on how best to organize and meet the expected requirements.

That being said the diagram below and the depiction in Q10 of what a PQS should look like is greatly lacking.

Development Phases

In section 1.8 under the Quality Manual the ICH Q10 guidance states, “The description of the PQS should include: …(c) Identification of the pharmaceutical quality system processes, as well as their sequences, linkages and interdependencies.

Process maps and flow charts can be useful tools to facilitate depicting the pharmaceutical quality system processes in a visual manner”.

I completely agree.

The problem is using the graphical depiction they present in Annex 2 is completely worthless.

Basically they listed some of the PQS elements in a bar and then said they all apply to the entire product lifecycle, which simply isn’t true.

When we are in the development phase of our product lifecycle why would we do that under the change management system, or monitor process performance?

 

Controlling Change – No Value Add

There is no point in controlling changes for a product that is purposely being changed, nor does it offer any value to monitor the process performance for a process that has yet to be developed.

This isn’t a graphic depiction of the PQS, but rather a graphic of how they depict the lifecycle management (which also has some issues).

The PQS is the quality system and its subsystems and how they interrelate.

While it’s useful to look at how the PQS and product Lifecycle Management overlap and what elements of the PQS system are relevant at each lifecycle stage, it is not the point of the PQS, and even if that’s the end goal it’s not depicted here at all.

This image offers almost no value.

A Better Approach

So, what should this graphic look like?

While this is not a perfect view of a PQS, I would propose that the image below is a much better depiction of how the PQS should be visualized and a good place to start.

At the core of any quality system should be management. This goes back to Deming, who said, “Quality begins with the intent that is fixed by Management”.

Quality has to be rooted in the executive management team.

Define Core Quality Systems

Core quality systems then need to be defined. These are systems that impact all aspects of the business and include a Risk Management Policy, Resource Management, Document Control and CAPA systems.

All of the other subsystems, Deviations, Supplier Management, Equipment Qualifications, Validation, Material Management, etc, etc. all should be risk based or involve risk assessment, they all require resources and training, they call require documents (procedures, policies, records), and the CAPA system of course drives for process improvement regardless of the process.

Subsystems

All subsystems feed back into the main Management module. The subsystems listed, all are interconnected, with the exception of Post Market Systems.

The subsystems are important too, but they are farmed out to different groups and have different levels of importance depending on the stage of the product lifecycle.

Post Market Systems

The one exception is the Post Market Systems. This includes complaint management, product reviews, recall processes and other systems to support marketed products.

These generally do not interact with the other subsystems unless it is through the CAPA system or other management functions, but still utilizes all the systems under the management umbrella.

Alternate View

The PQS presented here, isn’t intended to be perfect, but I thought it was worth presenting an alternate view to the one presented by the ICH.

The ICH concept is a good one, and the ideas are fairly well laid out in the ICH, but the graphical representation of the PQS leaves a lot to be desired.

When establishing a PQS, it is better to start with something to what we’ve depicted here, and customize it as needed for the organization.

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How 21 CFR Part 11.3(7) Applies to Electronic Batch Records [Video]

When dealing with Part 11 it’s important to understand what an electronic signature actually means

The definition of electronic signatures or e-sigs can be found in 21 CFR Part 11.3(7).

Electronic Signature

An electronic signature or e-sig means a computer data compilation of any symbol or series of symbols executed, adopted, or authorized by an individual to be the legally binding equivalent of the individual’s handwritten signature.

Handwritten Signatures

We also need to understand what a handwritten signature means in the context of Part 11.
The definition of handwritten signatures can be found in 21 CFR Part 11.3(8).

Handwritten signature means the scripted name or legal mark of an individual handwritten by that individual and executed or adopted with the present intention to authenticate a writing in a permanent form.

The act of signing with a writing or marking instrument such as a pen or stylus is preserved. The scripted name or legal mark, while conventionally applied to paper, may also be applied to other devices that capture the name or mark.

Electronic Batch Records

Eric works in a Pharmaceutical company and he is responsible for the filling process of the batch been manufactured.

Each time Eric performs the filling process he has to populate a batch record with the appropriate details

After each step Eric must also fill in his signature and date to verify that he actually performed each task.

Eric is manually handwriting these details and they are legally binding to Eric.

21 CFR Part 11.3(8)

This is when 21 CFR Part 11.3(8) applies.

Fast forward 12 months and Eric’s company has implemented a brand new Manufacturing Execution System (MES) where all details around the batch manufacturing process are recorded electronically.

21 CFR Part 11.3(7)

Now when Eric performs the filling process he now populates everything electronically and signs with his username and password combination to verify that he has performed those tasks.

This is when 21 CFR Part 11.3 (7) applies.

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