Cleaning Validation Mechanism’s – The Top Four!

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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. The four main types of cleaning mechanisms are:

  • Dissolution
  • Saponification
  • Wetting
  • Emulsifying

Many cleaning compound agents perform several functions at once. Butyl, for instance, can serve as a wetting or surface tension reducing agent as well as a solubilizing agent. It also can contribute to emulsifying capabilities when combined with anionic surfactants or soaps (alkali-metal salts of carboxylic acids).

Many cleaning compound agents perform several functions at once. Butyl, for instance, can serve as a wetting or surface tension reducing agent as well as a solubilizing agent. It also can contribute to emulsifying capabilities when combined with anionic surfactants or soaps (alkali-metal salts of carboxylic acids).

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 include:

  • 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 include:

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

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The Similarity Between Device Master Records & Chocolate Chip Cookies [Video]

The device design once complete, must be adequately transferred to manufacturing. This is typically accomplished through product specifications, standard operating procedures, work instructions and training.

Collection of Documents

Often a product specification is thought of as a document. The reality is the product specifications should be thought of as an association of written documents.

The product specifications typically include:

  • Assembly drawings
  • Component procurement specifications
  • Manufacturing instructions
  • Inspection
  • Test instructions
  • Digital data files
  • Manufacturing fixtures (jigs and molds)
  • Training materials
  • Artwork associated with labels
  • Acceptance criteria
  • Etc

Device Master Record (DMR)

The ultimate document to ensure adequate design transfer is the Device Master Record, or DMR.

The DMR is somewhat theoretical in that it is really a compilation of all the documents which are needed to realize the product.

For that reason, the DMR, is often established as an index which simply lists all of the documents needed to realize the product.

Contents of the DMR

The DMR typically includes the following documents:

  • Product specifications
  • Work instructions for device realization
  • Device history records/Forms to generate device history records
  • Component drawings/Specifications
  • Label artwork/Specifications
  • Test/Inspection methods
  • Software/Firmware
  • Validation Master Plan (VMP)

Since these documents may be revising and changing and may be at various distribution points, the DMR typically is an index of all the documents.

Chocolate Chip Cookie Analogy

One very common analogy is to envision the DMR as a chocolate-chip cookie recipe. If the DMR is complete, by providing the DMR to someone they can make the exact same chocolate-chip cookies.

While this is somewhat simplified, it’s an excellent analogy, but in order to make the perfect chocolate-chip cookie we would want specifications for the grade of flour, chocolate chips, sugar and other components.

We’d also like to know which equipment was validated, how they are tested/inspected, what are the instructions for each processing step, etc.

If we have all the relevant information we can reproduce the cookies exactly.

The DMR is the key to any successful design transfer whether it is an internal transfer to manufacturing or a transfer to a Contract Manufacturing Organization (CMO).

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The Four Phases of Conducting a Laboratory Investigation [Video]

The process which will be described here is based on the process discussed in the MHRA’s guidance on Out of Specifications Investigation.

When an out of specification, atypical or suspect result is obtained, it is particularly important that all solutions and reagents associated with the test are retained, as this will greatly assist the investigation.

The MHRA advocate laboratory investigations should proceed in four phases as follows:

Phase I(a)

Phase I (a) consists of a preliminary review, by the analyst, to determine whether there has been a clear and obvious error or event that caused the OOS, atypical or suspect result.

Phase I(b)

Phase I (b) occurs after phase 1(a) has failed to identify a clear and obvious cause. This is a more detailed investigation by the analyst and supervisor to identify a laboratory assignable cause.

Phase II

Phase II occurs after the phase I investigation has failed to identify a laboratory assignable cause for the OOS, atypical or suspect result and are driven by written and approved instructions in order to test particular hypothesis.

Phase III

In Phase III all the information obtained during Phases I and II of the laboratory investigation, and any manufacturing investigation, is reviewed and assessed, and a decision is made on the disposition of the batch

Learn More About Laboratory Investigations

If you would like to learn more about laboratory investigations click here for an overview of this course.

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