What did the FDA criticise in the Design of a Water System?

In a recent Warning Letter, the FDA addresses deficiencies in a water system. Two references from the US GMP rules are cited. On the one hand, 21 CFR 211.63 with reference to equipment and, on the other hand, 21 CFR 211.100 with reference to process controls ('validation'). What bothered the FDA?

The water system is used for the manufacture of oral and topical medicinal products. The first deficiency criticised by the FDA is design deficiencies. The authority explicitly criticised 'dead legs' at every point-of-use in production. The FDA pointed out in its Warning Letter the risks that these design flaws could pose. It considers stagnant water with the possible formation of a biofilm to be a hazard. It also fears the risk of inadequate sanitisation of the system, especially the pipes.

The FDA also criticises inadequate monitoring. In particular, it refers to tests for undesirable microorganisms ('objectionable microorganisms'). Burkholderia cepacia complex (BCC) is explicitly mentioned here. In its Warning Letter, the FDA even refers to a link to an FDA notice regarding BCC  

The company's commitment to update the work instructions for the water system is not enough for the FDA, as this does not solve the design flaws, among other things. The FDA also criticised the unvalidated use of alternative microbiological testing methods. It wants to see the suitability of the culture medium and incubation conditions to ensure the recovery of the microbiome. The validation should show that the method is at least comparable to the pharmacopoeia method. The company responded to this criticism with trend analysis data. Here, too, the FDA criticises the fact that this trend data is based on unvalidated methods. 

In this respect, the FDA not only requires method validation of the alternative microbiological methods, but also specifically targets further measures for the water system.

It would like to see

• A comprehensive and independent assessment of the water system and its maintenance. A consultant with knowledge of water systems should definitely be involved in this assessment.
• A remediation plan for the installation and operation of a suitable water system with an appropriate maintenance and monitoring programme with corresponding microbiological limits.
• A detailed risk assessment addressing the potential impact of the observed water system issues on the quality of all medicinal product batches currently distributed in the United States. Actions to be taken in response to the risk assessment. Examples include customer notifications and product recalls.
• A validation protocol and validation report for the water system.

Conclusion: Water systems are increasingly coming under scrutiny by the FDA. Design aspects should be part of the planning and qualification process when purchasing and installing such systems.

Please see the FDA website for the full Warning Letter.