Warning Letter due to Deficiencies in the Purified Water System

In June, a US-American pharmaceutical manufacturer received a Warning Letter from the FDA due to deficiencies in the Purified Water System which concern - among other things - the design of the water system, monitoring, sampling and handling of CAPAs results. The water is used for the production of topical OTC products, i.e. medicinal products for application on the skin.

Exceedance of microbiological and TOC Limits

The FDA generally criticizes the quality of the purified water produced. For some time, the pharmaceutical company had been reporting quality problems with regard to test results. The limit for the total aerobic microbial count was exceeded several times. The excesses were sometimes so large that the samples could no longer be evaluated (TNTC = too numerous to count).

In more than 10 cases, the chemical limit values had also not been observed. The inspectors discovered excesses in the test point TOC (Total Organic Carbon). In addition, excessive microbiological levels were found which date back to 2016. No suitable corrective measures were taken.

The FDA sees a serious patient risk when using microbiologically contaminated topical products. The manufacturer's answer that the microbiological tests of the medicinal products have been ok cannot be accepted by the FDA. Contamination is not uniformly distributed and therefore samples are not necessarily representative. Thus, testing the finished product as the sole justification for batch release is not sufficient.

FDA criticises the Design of the Water Plant

The FDA also criticised the basic design of the system with which purified water is produced, its control, maintenance and monitoring. The FDA inspectors found evidence that the company had known of a biofilm formation in the system since 2016. Nevertheless, nothing was changed and  the water was still used. Interestingly, GMP defects in the water system had already been noticed in an FDA inspection in 2010 so that the design defects have now existed for almost 10 years.

Besides, sampling was also criticised by the FDA. Sampling was usually carried out after sanitising of the system and was then considered representative for the entire week. In addition, a hose with black and brown residues was criticised. This hose is used to dispense water for production, but the hose is removed for sampling. This means that the sample taken is no longer meaningful for the quality of the water used.

Now, the FDA expects among other things:

• An independent assessment of the water system design, its control and maintenance
• A comprehensive CAPA plan to improve the design of the system and its validation
• A timetable for the completion of the PQ and a validation report for the water system
• Evidence for the qualification of the employees who carry out the PQ
• A programme that describes the control, maintenance and monitoring of the system
• A revised sampling plan
• An overview of all microbiological test results of the water system over the last three years, including sample and sanitisation data
• An improved CAPA system with significant improvements in root cause investigation, quality oversight, handling of OOS/OOL results and documentation
• A detailed risk evaluation for all batches on the US-American market with regard to risks that may exist due to the water used

Please see the Warning Letter with the inspection defects in the pharmaceutical water system for further details.