Dirty Hold Time Study of Equipment in a Sterile Manufacturing Facility
A Dirty Hold Time Study is conducted to determine the maximum allowable time that equipment can remain uncleaned after use without exceeding acceptable microbial contamination limits. This study ensures compliance with Good Manufacturing Practices (GMP) and helps establish cleaning validation parameters.
Objective
- To establish a validated maximum dirty hold time for equipment before cleaning.
- To prevent microbial contamination that could impact product sterility and quality.
- To ensure compliance with regulatory guidelines (FDA, EU GMP, WHO, PIC/S, MHRA, etc.).
Equipment Selection
Includes process equipment like:
- Mixing & Holding tanks
- Bioreactors
- Filling machines
- Machine change parts
- Transfer lines & tubing
- Filters & filtration systems
- Lyophilizers
- Isolators & Restricted Access Barrier Systems (RABS)
Focus on surfaces and areas prone to contamination, such as dead legs, crevices, and contact points.
Study Design
a. Time Intervals for Dirty Hold
- Select multiple time points (e.g., 1, 4, 8, 12, 24, 48 hours) after the last equipment use before cleaning.
- Worst-case scenarios may include longer hold times depending on facility requirements.
b. Environmental & Process Conditions
- Conduct study under normal operating conditions (temperature, humidity, air quality).
- Assess impact of different product residues on microbial growth.
c. Sampling & Microbial Testing
- Swab Sampling: Collect swabs from critical areas (e.g., difficult-to-clean surfaces).
- Rinse Sampling: For equipment where swabbing is not feasible.
- Bioburden Testing: Determine Total Aerobic Microbial Count (TAMC) and Total Yeast and Mold Count (TYMC).
- Microbial Identification: Identify any objectionable organisms (e.g., spore-forming bacteria, pathogens).
Acceptance Criteria
- Microbial contamination must remain within facility-specific and regulatory limits.
- No presence of objectionable microorganisms that could impact sterility.
If limits are exceeded, reduce the dirty hold time or adjust cleaning procedures.
Worst-Case Considerations
- High microbial load environments.
- Extended dirty hold times beyond normal conditions.
- Residue from different product formulations.
- Effect of temperature & humidity variations.
Data Analysis & Conclusion
- Establish the validated dirty hold time for each equipment type.
- Implement corrective actions if necessary (e.g., improved cleaning frequency).
- Document and integrate results into the Cleaning Validation Program (CVP).
Regulatory Compliance & Guidelines
- FDA (21 CFR Part 211): Requires equipment to be maintained in a sanitary condition.
- EU GMP Annex 15: Specifies cleaning validation requirements.
- WHO GMP & PIC/S Guidelines: Provide global standards for equipment cleaning and hold time studies.
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