Saturday 17 August 2013

Cleaning validation

Cleaning validation is the (validation process) documented evidence that the Cleaning process which are employed or carried out perfectly or not. Cleaning validation is carried out in every pharma industry. Cleaning validation is a wide process so let us see in brief.


To avoid contamination of the pharmaceutical (product) , principle or adequate and required cleaning procedures are essential. The Cleaning procedures must  be, strictly follow carefully established and validated methods of execution. Now this applies equally to the manufacture of pharmaceutical products and bulk active ingredients.


Several questions should be addressed, _when evaluating- the cleaning process. For example :
  1. At what point does a piece of equipment or system become clean? 
  2. What is accomplished, by hand ,scrubbing, rather than just a solvent wash? 
  3. How variable are the manual, cleaning processes from batch to batch and product to product? 
  4. Are   the different cleaning processes are required for different products in contact with a piece of equipment? 
  5. Frequency of cleaning 

Cleaning procedure

  • Cleaning procedures for products and processes which are very similar,- do not need to be individually -validated. 
  • At least three consecutive applications of the cleaning procedure should be performed. 
  • Raw materials sourced from different suppliers may have different physical properties and impurity profiles. Such are differences should be considered when designing  cleaning  procedures, -as the materials may behave differently. 
  • It is usually not considered acceptable to “test until clean”. 
  1. Cleaning procedures for product changeover should be fully validated. 
  2. Normally only the cleaning procedures for product contact surfaces need to be validated.
  3.  Consideration should be given to non-contact parts into which product may migrate.- For example, seals, flanges, mixing shaft- fans of ovens & heating elements etc. 
  4. Equipment should be confirmed to be visually clean following batch-to-batch cleaning procedures. Cleaning procedures for product changeover should be fully validated. 
  5. Normally only cleaning procedures for product contact surfaces need to be validated. 
  6. Consideration to be given to non-contact parts into which product may migrate._ For example, seals, flanges, mixing shaft and fans of ovens & heating elements etc. 
  7. Equipment should be confirmed to be visually clean following batch-to-batch cleaning procedures. 


A Validation protocol should include the following
  • The objective of the validation process. 
  • Responsibilities for performing and approving the validation study . 
  • Description of the equipment to be used. 
  • The interval between the end of production and the beginning of the cleaning procedures. 
  • Cleaning procedure, to be used for each product, each manufacturing system or each piece of equipment.
  1. Any routine monitoring requirement.
  2. Sampling procedures, including the rationale for why a certain sampling method is used. 
  3. Data on recovery studies to be done where appropriate.
  4. Analytical methods contains the limit of detection and the limit of quantitation of those methods.
  5. The acceptance criteria , including the rationale for setting the specific limits, When revalidation will be required. 
  6. The Validation Protocol should be formally approved by the company management. Quality Assurance should be involved in the approval of protocols and reports. 
  7. A final validation report should be prepared . The report should be approved by the management. 
  8. The cleaning process should be documented in an SOP. 


Records kept of cleaning validation performed in such a manner that the following information is readily available :
  • The area or piece of equipment cleaned.
  • The person who carried out the - cleaning.
  • When the cleaning was carried out.
  • The SOP defining the cleaning process.
  • The product which was previously processed,- on the equipment to being cleaned. 
The cleaning record should be signed by the operator who performed the cleaning and by the person responsible for the production and should be reviewed by Quality Assurance.


  1. Operators Personnel who perform The cleaning routinely should be trained in the application of validated cleaning procedures.
  2. Training records should be available for all training carried out. 
  3. Operators carrying out manual cleaning procedures should be supervised at regular intervals. 


  • The design of the equipment should be carefully examined. 
  • Dedicated equipment should be used for products which are difficult to remove. 

Microbial aspects

  1. The existence of conditions favorable to reproduction of micro organisms (e.g. moisture) and the time of storage should be considered. 
  2. The aim should be to prevent excessive microbial contamination. 
  3. The period of storage of equipment before cleaning and after cleaning must be established. 
  4. In general , equipment should be stored dry. 


  1. Samples should be drawn according to a written sampling plan. 
  2. There are two methods of sampling that are considered to be acceptable, direct surface sampling (swab method) and the use of rinse solutions. 
  3. A combination of the two methods is generally the most desirable and  particularly in circumstances where accessibility of equipment parts can mitigate against direct surface sampling. 


  • The efficiency of cleaning procedures -for the removal of detergent residue should be evaluated.
  • The composition of detergents should be known to the manufacturer. 

Analytical methods

The analytical methods should be validated before the cleaning validation study is carried out. 
  • Specific and sensitive. 
  • should be challenged in combination with the sampling methods used. 


Should be logically based on a consideration of the materials involved and their dosage regimes. The limits should be practical and achievable and verifiable. 

The approach for setting limits can be :
  • Product specific cleaning validation for all products. 
  • Grouping into product families and choosing a “worst case” product, 
  • Grouping into groups of risk (e.g. very soluble products, or similar potency or highly toxic products,difficult to detect). 

Carry Over

Carry-over of product residues should meet defined criteria, :
  • No more than 0.1% of the normal therapeutic dose of the following product. 
  • No more than 10 ppm of any product will appear in another product. 
  • No quality of residue will be visible on the equipment after cleaning procedures are performed. 
  • For certain allergenic,ingredients like- penicillins, cephalosporins or potent steroids and cytotoxics, the limit should be below the limit of detection by best available analytical methods.
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