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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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‘To the Cloud or not to the Cloud, that is the question.’

While it’s certainly a familiar question, with apologies to Hamlet, there is a question that tends to come first: “What is the Cloud in the first place?” Have you seen this on-line graphic lately of a young child who is just looking at you with the caption – ‘There is no cloud…’

Information Workers

The reality for most ‘information workers’ is that as long as your keyboard, mouse and monitor have something to plug into and data displays, all you really need to see is where that ‘something’ plugs into the wall so you can be sure you have a physical connection.

What’s on the other side of the wall – or even if there is strictly speaking no ‘other side’ – is not the users concern. You don’t need to have physical computing resources right next to you as long as the ‘virtual machine’ you are working on is properly provisioned and the latency (or ‘lag/response time’) isn’t large enough to be an issue.

Enterprise

The physical computing resources matter if you are doing a lab analysis with physical samples on instruments or using an automated line to produce product. In the land of data analysis, reporting and document production, the data needs to be available, not present.

From the enterprise perspective however, what is ‘present’ behind the wall is a true concern. Since compliance to regulations means ‘control,’ how the cloud supplies and protects those resources and the information they provide needs to be documented under a defined quality management system. While cloud vendors are glad to quote services and prices, they have not always been forthcoming about how things are done in their building.

Outsourcing

The move to the cloud is a physical move – of your data, applications and possibly compute and platforms – to somewhere else. The somewhere is physical while your usage and controls become logical and virtual. If that makes you feel uneasy – or if you prefer ‘risk averse’ – you are not alone.

Outsourcing is a concept that brings joy to financial / accounting types, but for those involved with compliance, quality and validation, it brings a new set of challenges and concerns. It should recall the words of Mr. Murphy – “Nothing is as easy as it looks, everything takes longer than you expect AND if anything can go wrong, it will – usually at the worst possible time.”

Current warning letters addressing data integrity have focused on site forensics – data in trash cans, bags of shredded records. When it comes to the cloud, there is no ‘there’ for you to access – unless there are the careful negotiations, detailed SLAs and rigorous audit/ follow-up required to give your enterprise the confidence it needs to move forward.

Do your current internal resources have the expertise and the flexibility to deal with a vendor you have to trust significantly? This is more complex than a contract manufacturer where you can review the SOPs for compliance, watch the process and then have the product independently tested.

GxP Compliance

The draw of the cloud is that everything is ‘out there’ – available ‘just by an e-mail’ – and not running up costs on your premises. What will happen if suddenly it isn’t ‘there?’ Whose fault will it be – oh, must be the vendor. Good idea – blame the vendor – but there’s many a wire between your ‘here ‘ and their ‘there.’

Will it be your communication vendor, some nameless third party supplier or cloud hardware, software or internal network failure? There are many ABCs in the cloud – SaaS, IaaS, PaaS, Haas, AaaS, ITaaS – and the list goes on. It is critical to have the proper support to be able to straighten all those letters out to spell ‘GxP compliance.’

Cloud Provider

Everyone wants their cloud provider to look like the image below. But that will take attention to detail, technical understanding and the ability to ask ‘the next questions’ needed to assure quality and compliance.

Those will include security at multiple levels and how are they going to maintain those perfect cables when the one in the middle breaks?

There are many items to be considered – here are some more:

  • What application(s) and data are going to be ‘sent to the cloud?’
  • What in-house processes / systems need to access that data?
  • Where will the data physically be held and what are the laws in that location if outside of the USA?
  • What are the backup provisions for the cloud providers’ servers and storage?
  • What is the security plan – including physical, logical and access controls?
  • How will your audit resources be granted access and under what ground rules?
  • Does the vendor provide a Quality Manual or Quality Management System document for review?
  • Does their contract include a ‘non-cookie cutter’ Service Level Agreement (SLA) that details your focus points?

John English is an independent contractor with The Azzur Group.

If you would like any help with CSV related projects please visit www.azzur.com.

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Changes to equipment and documentation is an integral part of the whole GMP process in any regulated facility. In this article we will discuss how equipment is designed in a GMP facility and how good documentation practices are an essential part of quality assurance and GMP.

The content of this article has been taken from module 7 of our eLearning module on Good Manufacturing Practices (cGMP) within the life sciences.

You can view this module in full by viewing the video below.

cGMP eLearning Module – Compelling, Engaging and Interactive

 

Equipment

All equipment is designed, constructed and located to suit their intended use and to facilitate easy maintenance and cleaning.

Equipment is installed in such a way as to prevent any risk of error or of contamination, and cleaned according to detailed and written procedures and stored only in a clean and dry condition.

Production equipment should be designed in such a way as not to present any hazard to the products.

The parts of the production equipment that come into contact with the product must not be reactive, additive or absorptive to such an extent that it will affect the quality of the product and thus present any hazard.

Any defective equipment should, if possible, be removed from production and quality control areas, or at least be clearly labelled as defective. When not in use, equipment should be covered to ensure it remains clean.

Balances

Balances and measuring equipment of an appropriate range and precision should be available for production and quality control operations.

All measuring devices are required to be calibrated and checked at defined intervals by appropriate methods, and adequate records of such tests should be maintained.

Utilities

Fixed piping should be clearly labelled to indicate the contents and where applicable, the direction of flow.

Water pipes used in production (e.g. Purified Water, Water for Injection) are sanitised according to written procedures that detail the action limits for microbiological contamination and the measures to be taken.

Electrical circuits should be identified, and a record maintained of the load on each circuit to prevent inadvertent overload.

Documentation

Good Documentation Practices are an essential part of quality assurance and GMP.

It is important for a manufacturer to get the documentation right in order to get the product right.

GMP Documentation e.g. Site Master File, Specifications, Batch Manufacturing Formulae, Batch Manufacturing Records, Processing, Labelling, Packaging, Testing Instructions, Standard Operating Procedures, Protocols, Technical Agreements, Records, Certificates of Analysis, Reports etc. should contain the following attributes of a good document:

They should be:

  • Attributable
  • Legible
  • Contemporaneous
  • Original
  • Accurate
  • Complete
  • Durable
  • Corroborated
  • Version Based
  • Accessible
  • And Authorized

Change Control

Change to GMP documentation, equipment, processes, systems, instrumentation, test methods, etc. are required to be controlled under a formal change control program.

This program must consist of Quality oversight to review the proposed changes, evaluate the potential impact of the change, determine any potential risk to product quality, and to establish the required level of supplemental validation/documentation required for the change.

In many instances, changes will also require submission to the Health Authority for approval of the change.

For example, changes impacting the submission documentation are subject to post approval change guidances according to the Health Authority regulations.

Change Control is a critical aspect of the GMP systems.

If you want to learn more about cGMP or if you want to evaluate our eLearning module for your company you can find more information here.

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