Cleaning Validation is a documented evidance to assure that a cleaning process removes residues of the active pharmaceutical ingredients of the product manufactured in a equipment, which is suitable for processing  medicinal products.


Type of Contaminants

  • Chemical: Residues of the previous product
  • Biological: Microorganisms
  • Physical: Particulate Matters

Solubility of API shall be mentioned as per below table - 



LD50 of API shall be mentioned as per below table - 


Cleanability of API shall be mentioned as per following table - 


All euipments parts shall be identified as per rational criteria and categories as per below - 

  • Hard to clean
  • Direct contact with product
  • No direct contact with product

Sampling Techniques

Visual Inspection
Surface Swab Sampling (For chemical and microbial analysis)
Rinse Sampling (Rinsing with solvent)

Method of Analysis

Method of analysis used for determination of possible contaminants residues must be specific and sensitive. The selection of analytical method should be validated for at least below parameters - 
  • Precision
  • Specificity 
  • Linearity and Range
  • Limit of Detection
  • Limit of Quantification
  • Stability of solution
  • Recovery from equipment of surface

For Worst Case Cleaning Validation Approach


Calculation of Maximum Allowable Carry Over (MACO) of Active Residue for Rinse Analysis


Accetability Limits

  • Visual Inspection Criteria: No quantity of residue should be visible to naked eyes on the equipment after cleaning procedures are performed.
  • 10 ppm Criteria: Not more than 10 ppm of API of previous product is permitted in next product.
  • Dose based Criteria: Not more than 1/1000 of minimum daily therapeutic dose of the previous product in the maximum daily dose of next product.

The acceptability limits for microbiological sample shall be determined based on -

  • Total Aerobic Microbial Count (TAMC): NMT 1000 cfu/swab (for dirty equipment), NMT 100 cfu/swab (for cleaned equipment).
  • Total Combined Yeasts and Moulds  (TYMC): Less than 10 cfu/swab (for both dirty and cleaned equipment)


Hold time for cleaning of equipments

  • Dirty equipment hold time period: 24 hrs.
  • Cleaned equipment hold time period: 48 hrs.

Revalidation shall be performed in case of any of the following events - 

  • Introduction of new facility, equipment, process or product
  • Change in cleaning procedure
  • Change in cleaning agent
  • Change in regulatory requirements etc.


As per 21 CFR 211.67(a) requires that any equipment, including dedicated and multipurpose equipment, is “cleaned, maintained, and, as appropriate for the nature of the drug, sanitized and/or sterilized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality, or purity of the drug product beyond the official or other established requirements.” You must therefore ensure that residues (e.g., active ingredients, cleaning agents) are adequately removed from product contact surfaces of all equipment during product changeovers and/or between production campaigns, depending on the types of materials and surfaces in use.

Cleaning procedures should be well-documented and consistent for their intended use. Cleaning validation programs should provide assurance that residues are effectively removed from product contact surfaces, and manufacturers should select test methods that demonstrate their effectiveness. FDA does not provide extensive guidance on conducting cleaning validation but does recommend consulting guidelines published by various trade and professional associations for additional information (e.g., International Society for Pharmaceutical Engineering, Parenteral Drug Association).


As per ICH guideline the cleaning validation protocol should include:

  • the objectives of the validation process;
  • the people responsible for performing and approving the validation study;
  • the description of the equipment to be used, including a list of the equipment, make, model, serial number or other unique code;
  • the interval between the end of production and the commencement of the cleaning procedure (the interval may be part of thevalidation challenge study itself) – the maximum period that equipment may be left dirty before being cleaned, as well asthe establishment of the time that should elapse after cleaning and before use;
  • the levels of microorganisms(bioburden);
  • the cleaning procedures (documented in an existing SOP, including definition of any automated process) to be used for each product, each manufacturing system or each piece of equipment;
  • all the equipment used for routine monitoring, for example, conductivity meters, pH meters and total organic carbonanalysers;
  • the number of cleaning cycles to be performed consecutively;
  • the sampling procedures to be used (direct sampling, rinse sampling, in-process monitoring and sampling locations) and the rationale for their use;
  • the data on recovery studies(efficiency of the recovery of the sampling technique should be established);
  • the analytical methods (specificity and sensitivity). including the limit of detection and the limit of quantification;
  • the acceptance criteria (with rationale for setting the specific limits) including a margin for error and for sampling efficiency;
  • Documentation of the choice of cleaning agent and approval by the quality unit, which should be scientifically justified.
  • revalidation requirements.


References:

  • Health Canada
  • ICH Annex 3
  • 21 CFR 211.67: Equipment cleaning and maintenance


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