Cleaning Validation Methods

Cleaning can be defined as the removal of residues from previous batch, other residues, and traces of cleaning agents. There are several mechanisms associated with cleaning of equipment. The mechanisms involved can be mechanical action, chemical action between the residues and the cleaning agent.

The selection of cleaning agent and mechanism involved in cleaning is largely dependant on the process residue to be cleaned.

Cleaning Mechanisms

The cleaning mechanism totally depends on the selection of cleaning agent and type of residue to be cleaned. Following can be the one of the methods involved in cleaning of residues,

  • Dissolution
  • Saphonification
  • Wetting
  • Emulsifying

Dissolution

Dissolution is the process by which a solid or liquid forms a homogeneous mixture with a solvent or solution. This can be explained as a breakdown of the crystals into individual ions, atoms or molecules and their transport into the solvent

The mechanism involved in this type of cleaning is solubility of the residue in the cleaning agent or solvent. The monobasic buffers i.e. sodium chloride are soluble in cool and hot WFI.

Ethylene glycol butyl ether is soluble in water as well as oil is also used in solubilizing agent. Chelating agents and builders are added to the formula to keep water hardness from interfering with the cleaning process.
Rate of dissolution is depend on,

  • Nature of solvent or residue to be dissolved
  • Temperature of solvent
  • Presence of mixing
  • Area of contact
  • Presence of inhibitors

Saphonification

Saponification can be defined as “hydration reaction where free hydroxide breaks the ester bonds between the fatty acids and glycerol of a tri-glyceride, resulting in free fatty acids and glycerol”, which are each soluble in aqueous solutions.

This process specifically involves the chemical degradation of lipids, which are not freely soluble in aqueous solutions. Heat treated lipid residues are difficult to remove than non-heat residues due to polymerization.

Saphonification plays a critical role in cleaning lipids which are present in the areas of process involving cell growth and cell processing i.e. Bacterial fermentation, Cell disruption process

Wetting

Wetting can be defined as a process “involves the lowering of the surface tension of the cleaning solution, thus allowing it to better penetrate residues that are adhered to equipment and piping surfaces”. Wetting agents, or surfactants, are often used in relatively small amounts and they can substantially reduce the quantities of cleaning agent (in this case, alkali) required for residue removal.

Advantages of Wetting

  • Lowers the surface tension of the cleaning solution
  • Allow better penetrate residues which are adhered to equipment
  • Used in small amount
  • Sticky residues which are hydrophobic in nature get easily removed

Water acts as a solvent that breaks up soil particles after the surfactants reduce the surface tension and allow the water to penetrate soil (water is commonly referred to as “the universal solvent”).

Emulsifying

Emulsifying and suspending agents are often used to keep residues from precipitating by providing “hydrophobic groups” onto which hydrophobic areas of residues can associate, thus preventing them from associating with other residues and forming larger particles which are likely to leave solution.

These agents also typically have “hydrophilic groups” which keep them very soluble in aqueous solutions of moderate to high ionic concentrations. Emulsifiers increase the capacity of a cleaner to emulsify non-soluble compounds in the cleaner. i.e. anionic soap surfactants, cationic surfactants, neutral surfactants

Advantages of Emulsifying agents,

  • Prevent association of residues
  • Allow the residue to precipitate and not allow thdse residue to redeposit on surface

Learn more about Cleaning Validation

If you would like to learn more about Cleaning Validation click here to enter our cleaning validation forum.

What do you think about this article? Have your say by leaving your comments below.

0
shares

  • g srinivasarao

    plz update the knowldge.

  • g srinivasarao

    plz update the knowldge.

  • hi

    i had query related area calculation for the cleaning validation, how we have calculate and how we have determine the area and acceptance limit.

  • hi

    i had query related area calculation for the cleaning validation, how we have calculate and how we have determine the area and acceptance limit.

  • kamlesh gupta

    how we will decided the cleaning validation if the least soluble product coming continues four times.

  • kamlesh gupta

    how we will decided the cleaning validation if the least soluble product coming continues four times.

  • kamlesh gupta

    how we will decides sampling quantity of granules and sterile samples during the process validation

  • kamlesh gupta

    how we will decides sampling quantity of granules and sterile samples during the process validation

  • Good Knowledge.

  • Good Knowledge.

  • ananda tarate

    can we use sodium lauryl sulphate as a cleaning agent ?if yes,how the process takes place ?

  • ananda tarate

    can we use sodium lauryl sulphate as a cleaning agent ?if yes,how the process takes place ?

Similar articles:

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.

7
shares

Similar articles:

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.

0
shares

TOP

Similar articles: