Validation of processes used to sterilize drug products and equipment are the most critical validation activities undertaken. The objective of Validation is to determine that the sterilization process will consistently achieve sterility and that it won’t have an undesirable effect on the device or its packaging.

Common elements in the validation of any sterilization process include

  • Sterilization Cycle Development
  • Biological and Physical Measurement Controls
  • Empty Chamber Studies
  • Loaded Chamber Studies
  • Routine Use/Ongoing Monitoring
  • Validation Maintenance/Change Control/Revalidation

According to the FDA Process, Validation is a requirement of the Current Good Manufacturing Practices Regulations for Finished Pharmaceuticals, 21 CFR Parts 210 and 211, and of the Good Manufacturing Practice Regulations for Medical Devices, 21 CFR Part 820, and therefore, is applicable to the manufacture of pharmaceuticals and medical devices.

Validation Protocols

FDA defines Validation Protocol as – A written plan stating how validation will be conducted, including test parameters, product characteristics, production equipment, and decision points on what constitutes acceptable test results.
It is important that the manufacturer prepare a written validation protocol which specifies the procedures and tests to be conducted and the data to be collected. The purpose of the collected data must be clear, it must reflect facts and be accurate. The protocol should specify a sufficient number of replicate process runs to demonstrate consistency in results and measure any process variations between runs. Validation documentation should include evidence of the suitability of materials and the performance and reliability of equipment and systems.

A Validation Protocol typically comprises of:

  • Purpose and objectives
  • Equipment
  • Tests to be performed and rationale
  • Detailed test methods
  • Acceptance criteria
  • Approvals
  • Effective date
  • Supporting documentation

Validation Documentation

FDA’s definition for Validation and relevant documentation – Establishing documented evidence which provides a high degree of assurance that a specific process will consistently produce a product meeting its pre-determined specifications and quality attributes.
It is essential that the validation process is documented and that the documentation is properly maintained. Approval and release of the process for use in routine manufacturing should be based upon a review of all the validation documentation, including data from the equipment qualification, process performance qualification, and product/package testing to ensure compatibility with the process.
For routine production, it is important to adequately record process details such as information on the equipment, ambient environment/temperature, etc. as well as any significant changes in conditions. Maintaining a log to input data periodically is useful in tracking performance and identifying causes for failure.

Validation Reports would comprise of Documentation regarding:

  • Assessments of equipment
  • Results of process testing
  • Deviations and rationale for determining impact on the validation study
  • Meeting of acceptance criteria
  • The establishment of processing parameters

Validation process for different Sterilization Methods:

1. Ethylene Oxide Validation

  • Equipment IQ, OQ, PQ
    • Do chamber studies with thermocouples, humidity sensors, EO concentration measurement devices. (Usually performed by contract by sterilizers.)
  • Fractional cycles with products and biological indicators (B.I.s are most commonly B. subtilis spore strips.)
    • Do chamber studies with thermocouples, humidity sensors, EO concentration measurement devices. (Usually performed by contract by sterilizers.)
  • Half & full cycles with biological indicators
  • Validation support testing
    • Product bioburden, B-F test, EO residuals

2. Radiation Validation

  • Dose mapping study
    • Dosimeters are placed in products at contract sterilizer.
  • Determination of product bioburden
    • First, do bioburden test method validation
  • Verification dose resistance experiment
    • Dose is determined based on product bioburden.
    • Irradiate products at “sublethal” verification dose level.
    • Test the verification dosed samples for sterility.
    • Before sterility test, do B-F testing to validate test method.

3. Steam Validation

  • IQ, OQ, PQ of steam sterilizer
  • Temperature profiles of product during sterilization cycles (using thermocouples)
  • Fractional and/or half cycles with product & B.I.s (G. stearothermophilus)
    • Then sterility testing of product & B.I.s