It is not uncommon for FDA Warning Letters to cite concerns regarding pharmaceutical water systems, although such citations seem to have become more frequent recently. One example, published earlier this week, includes an entire section focused primarily on water. The initial observations highlight concerns about the quality of water at the use points for manufacturing and rinsing:

“Your firm produced (b)(4) water and used it as a component in your OTC drug products and as a final rinse after equipment cleaning.

A. You recovered Pseudomonas aeruginosa in multiple (b)(4) water samples, from June 2021 to October 2022. This water was used to manufacture Tom’s Simply White Clean Mint Paste, batch (b)(4), and for the final rinse of numerous equipment cleaning processes. None of these incidents were investigated to assess product impact and water system performance.

B. You also reported multiple incidents where too numerous to count (TNTC) Ralstonia insidiosa was recovered from water points of use. Your investigations included testing of new samples collected at least 4 days after the initial sampling. Batches manufactured after these incidents were released based on the microbial testing of the finished OTC product despite the quality of the water used as a component or to clean the equipment.”

If P. aeruginosa is being recovered from water samples for months on end, it indicates a major, systemic issue. Similarly, the recovery of Ralstonia insidiosa, another gram-negative species, at TNTC (too numerous to count) levels suggests a complete lack of microbial control within the system. Without a review of the system or its data, the most likely causes are a combination of poor system design, lack of a contamination control strategy, inadequate maintenance, and ineffective sanitization procedures. When data such as this are reported, the issues are typically multivariate.

Also addressed was the requirement to use a validated process to produce water not only for formulation but also for cleaning operations.

“You failed to adequately qualify your (b)(4) water system that produced water used for equipment cleaning and in formulating your product.”

Initial cleaning and rinse water may be of lower purity than the water used for manufacturing but must meet at least potable (EPA drinking water) quality standards. However, final rinse water must match the quality of the water used in formulation.

Additionally, the absence of chemical testing during the Performance Qualification (PQ) for the water system was also addressed.

“This [water system] qualification was performed using a validation criterion of (b)(4) for total aerobic count but lacked the analysis for total organic carbon (TOC) and conductivity. Also, the absence of gram-negative microorganisms, which is required in your OTC product specifications, was not addressed.”

Given the nature of the products manufactured at this site, it is assumed that the required water quality would be USP Purified Water or a comparable classification. A properly prepared Performance Qualification (PQ) should include specifications, testing, and analysis for both microorganisms and chemical impurities in the water. For USP waters, this testing must include, at a minimum, conductivity and Total Organic Carbon (TOC).

The FDA’s noted requests regarding the water system reflect typical expectations for water systems used in pharmaceutical and consumer product manufacturing. In addition to a remediation plan, a new Contamination Control Strategy (CCS) should be developed. This strategy should include a risk assessment to identify and address potential microbial risks within the system.

“In response to this letter, provide:

• A comprehensive remediation plan for the design, control, and maintenance of the water system.
• (b)(4) water system validation report. Also include the summary of any improvements made to system design and to the program for ongoing control and maintenance.
• Your total microbial count limits to monitor whether this system is producing water suitable for the intended uses for each of your OTC products.
• A detailed risk assessment addressing the potential effects of the observed water system failures on the quality of all drug product lots currently in U.S. distribution or within expiry. Specify actions that you will take in response to the risk assessment, such as customer notifications and product recalls.”

For this incident, a thorough review of the design and procedures is recommended, starting with the implementation of a monitoring program for the feed water, which is the most likely source of gram-negative bacteria entering the system. After using risk assessment tools to identify gaps in the design and operation, necessary upgrades should be made. Once a Contamination Control Strategy (CCS) is developed, a system requalification should be performed, which includes inter-component monitoring across the entire generation, storage, and distribution network. Cleaning and sanitization plans, as well as their intervals, should be verified by actively monitoring system performance over an extended period.

The original Warning Letter can be seen here in its entirety.

https://www.fda.gov/inspections-compliance-enforcement-and-criminal-investigations/warning-letters/colgate-palmolivetoms-maine-inc-687043-11052024