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Warning letters, 483s, Recalls, Import Alerts, Audit observations

Updated on February 11, 2025

The FDA inspected Colgate-Palmolive/Tom’s of Maine, Inc’s Sanford facility in the US in May 2024. Several lapses were observed during the audit, leading to the issuance of a Warning Letter by the USFDA in November 2024.

Lapses in Microbiological Control and Water Systems

  • Pseudomonas aeruginosa: Detected in multiple water samples, none of which were investigated for product impact and water system performance. The water was used to manufacture OTC products like Tom’s Simply White Clean Mint Paste and for the final rinse of equipment cleaning processes.
  • Ralstonia insidiosa: Multiple incidents of too numerous to count (TNTC) Ralstonia insidiosa  were recovered from water points of use. Product batches manufactured after these incidents were released based on microbial testing of the product, despite the compromised quality of water used as a component or to clean the equipment.
  • Paracoccus yeei: Recovered gram negative cocco-bacilli Paracoccus yeei in another OTC product, Wicked Cool! Anticavity Toothpaste. The firm did not have adequate specifications for the water used for the final rinse of equipment.
  • Inadequate Water System Qualification: After commissioning the water system with IQ/OQ in October 2019, data collection for PQ was completed in September 2022. However, this was reviewed and the performance qualification (PQ) report was presented only after the inspection in May 2024. The qualification was covered total aerobic count but lacked analysis of total organic carbon (TOC) and conductivity. It also did not cover the absence of gram-negative bacteria, which is required in the OTC product specification.

FDA Expectations for Purified Water System

The FDA’s expectations for Purified Water systems for pharmaceutical production are revealed through several FDA guides:

  • Guide To Inspections Of High Purity Water Systems (7/93)
  • Inspection Technical Guide, Water for Pharmaceutical Use
  • Inspection Guide, Microbiological Pharmaceutical Quality Control Labs (7/93)

A critical reading of these guides clearly delineates the FDA’s expectations for the qualification and control of Purified Water systems:

  1. System Design: The design of the water system should consider the type of product being manufactured. For parenteral products, Water for Injection (WFI) is required, while purified water may be used for topicals, cosmetics, and oral products.
  2. Installation Qualification (IQ): Verify that all components of the water system are installed according to design specifications. Ensure that all equipment, piping, and instruments are installed as per the approved design.
  3. Operational Qualification (OQ): Test the system under operational conditions to ensure it functions as intended. Include tests for flow rates, pressure, temperature, and initial microbial counts.

    4. Performance Qualification (PQ):

Conduct extensive testing to demonstrate consistent performance of the water system. Include testing for microbial counts, Total Organic Carbon (TOC), conductivity. Address seasonal variations by conducting PQ over at least one year. A three-phase approach to validate the water system is outlined:

  • Phase 1: Initial Phase: Establish operational parameters and develop cleaning/sanitization procedures and frequencies. Duration: 2 to 4 weeks.
    • Activities:
    • Daily sampling after each step in the purification process and at each point of use. Sampling procedure for point of use sampling should reflect how the water is to be drawn (e.g., if a hose is usually attached, the sample should be taken at the end of the hose).
    • At the end of this phase, Standard Operating Procedures (SOPs) for the operation of the water system should be developed and in place.
  • Phase 2: Consistency Phase: Demonstrate that the system consistently produces the desired water quality when operated according to SOPs. Duration: 2 to 4 weeks.
    • Activities:
    • Sampling will continue as in Phase 1.
    • At the end of this phase, compile the data to demonstrate that the system consistently produces the desired quality of water.
  • Phase 3: Long-Term Phase: Demonstrate that when the water system is operated in accordance with the SOPs over a long period of time like one year covering all seasonal variations, it will still consistently produce water of the desired quality. Duration: 1 year.
    • Activities:
    • Routine sampling according to established procedures and frequencies. Typically, daily sampling from at least one point of use, with all points of use tested weekly.
        • Monitor and capture any variations in feedwater quality that could affect the system’s operation and water quality.
        • The validation can be completed when the firm has one full year of data demonstrating that seasonal variations do not adversely affect the system.

5. Routine Monitoring and Control: Regular sampling and testing of water at various points in the system to monitor microbial levels. Implement controls for specific pathogens, such as gram-negative bacteria, especially if they are a parameter for finished products.

6. Maintenance and Sanitization: Regular maintenance and sanitization of the water system to prevent microbial growth and biofilm formation. Periodic cleaning and disinfection of the system components.

7. Documentation and Reporting: Maintain comprehensive documentation of all qualification, monitoring, and control activities. Detailed records of test results, maintenance activities, and corrective actions taken.

8. USP Purified Water Quality: Purified water should meet USP quality standards both chemically and microbiologically. It should not contain organisms capable of growing in the product.

9. Monitoring and Specifications: Appropriate specifications must be established for Purified Water and monitored. Specifications should consider the intended use of the water. Action or alert limits must be based on validation data and set low enough to signal significant changes from normal conditions. Water used for wet granulations or for any aqueous liquid preparations as well as for the laboratory should be of USP purified water quality both chemically and microbiologically.

Microbial Quality Specifications for Purified Water: Users should establish in-house specifications or fitness-for-use microbial levels.

  • Total Aerobic Microbial Count (TAMC): 100 CFU/mL (action limit)
  • Total Organic Carbon (TOC): 500 ppb
  • Conductivity: Not more than 1.3 µS/cm at 25°C (Stage 1)
  • Absence of Specified Microorganisms: Typically ensured for organisms such as:
    • Escherichia coli
    • Salmonella species
    • Pseudomonas aeruginosa
    • Staphylococcus aureus
    • Gram-negative microorganisms: As required by product specifications.

10. Identification of Isolates:When microbial testing of oral solid dosage forms shows high levels of total plate count, isolates should be identified. For topicals, inhalants, and nasal solutions, isolates from plate counts as well as enrichment testing should be identified. Identification should not be limited to USP indicator organisms.

When water is a major ingredient in drug products, including OTC products, it is critical to ensure that the water and water system are robustly designed and to have control, maintenance, and monitoring of the system to ensure it consistently produces water suitable for pharmaceutical use.

References:

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