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Cleaning Validation Life Cycle in Pharmaceutical Industry


Cleaning validation plays an important role in reducing the possibility of product contamination from pharmaceutical manufacturing equipment.

It demonstrates that the cleaning process adequately and consistently removes product residues, process residues and environmental contaminants from the manufacturing equipment / system, so that this equipment / system can be safely used for the manufacture of specific subsequent products (which may be the same or a different product).

The following consideration should be given when designing a cleaning process:

  • the solubility of the materials to be removed;
  • the design and construction of the equipment and surface materials to be cleaned;
  • the safety of the cleaning agent;
  • the ease of removal and detection;
  • the product attributes;
  • the minimum temperature and volume of cleaning agent and rinse solution; and
  • the manufacturer's recommendations

The cleaning validation protocol should describe the equipment to be cleaned, procedures, materials, sampling methods, acceptable cleaning levels, parameters to be monitored and controlled, and analytical methods.

Cleaning Validation Life Cycle – Stage 1

Equipment Related:

  • Materials of construction are identified for all pieces of equipment.
  • Equipment is designed/built with proper slopes to allow for free draining.
  • Spray coverage tests are performed for all systems/equipment with spray devices installed.
  • Identify areas that are difficult to reach or hard to clean

Product Related:

  • Cleaning solutions are selected based upon the chemical and physical properties of the in-process materials, buffers and actives to ensure adequate removal of the residuals.
  • Analytical methods used to test cleaning samples are validated.
  • Product specific small-scale studies are performed to ensure the cleaning process will adequately remove process related residues as well as demonstrate adequate swab recovery.

Cleaning Validation Life Cycle – Stage 2

Equipment Related:
  • Performed on actual commercial-scale equipment / system.
  • Acceptance criteria initially set by equipment capability.
  • Matrix / Family approach to optimize the number of trials.
Product Related:
  • Assess biochemical properties of the product and process intermediates.
  • Verify that the acceptance criteria demonstrate adequate removal.
Cleaning Parameters:
  • Verify that the TACT (Time, Action, Concentration, Temperature) parameters are consistent.

Typical approaches to establish Product Specific Cleaning Validation Acceptance Criteria
  • Product Specific approaches: 0.1% (1/1000th reduction)
  • Health Based Limits: LD50, NOAEL, ADE/PDE, TTC, Minimum therapeutic dose

Cleaning Validation Life Cycle – Stage 3

Equipment Related:
  • Maintain matrix / family approach.
  • Periodic re-validation against established acceptance criteria to verify the system is still within the validated state.
  • Assess process variability based upon historical data.
  • Develop Alert (Control) Limits as appropriate.
Product Related:
  • Evaluate new products against worst-case soilant: Small-scale coupon studies, Large-scale verification studies
  • Perform additional validation studies as required.
Cleaning Parameters:
  • Maintain parameters in validated state
  • Modifications handled through the change control system

Continuous Process Verification (CPV) and Statistics in General

Statistics are to be used to determine the amount of variability within a process. Process Capability (Cp, Cpk) and Process Performance (Pp, Ppk) are typically good tools used to perform this assessment.

Cleaning Validation Guidelines

Cleaning procedures has to be validated to comply the regulatory agency requirements. Here we mention the guidelines for cleaning validation in pharmaceutical industry-

  • FDA Guide to Inspections of Validation of Cleaning Processes
  • PIC/S Guideline Annex 15 discuss on Cleaning Validation
  • EU Guidelines Annex 15 address Cleaning Validation in a separate chapter. 
  • ICH Guideline Q7 “GMP for APIs”
  • PDA Technical Report No. 29,  Points to Consider for Cleaning Validation

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