Dead Leg in Pharmaceutical Water System leads to Warning Letter

Due to deficiencies found in an FDA inspection, a US pharmaceutical manufacturer has now received a Warning Letter. Among other things, a dead leg in the pharmaceutical water system is listed as a deficiency. However, numerous other GMP deficiencies were also described.

The manufacturer, which produces OTC products, failed to validate its manufacturing process (process performance qualification). The validation plan submitted subsequently is not sufficient for the FDA, as the manufacturer did not provide any information on the missing validations of other OTC products. In addition, according to the FDA, the manufacturer has not demonstrated that the manufacturing processes are designed and controlled to reproducibly produce batches of steady consistency and quality.

Another deficiency is the water system used to produce purified water (PW). According to the FDA, it was not designed and maintained for its intended use. For example, the PW system contains a dead leg and did not circulate continuously, which can encourage the development of biofilm. If the water is not used, it will stagnate in the system unless the valves are opened. Stagnant water can also be the source of a biofilm in the water system. The validation report submitted after the fact is not sufficient for the FDA. It does not address seasonal fluctuations (note: the validation of a water system usually runs over a year), does not describe how the system should be maintained or the actual conditions of use of the system.

The stability programme is also criticised. For example, the manufacturer has given an OTC product a shelf life of five years. At the time of the inspection, however, no sufficient stability data was available, neither under normal nor under accelerated conditions. The manufacturer assumed this shelf life on the basis of the shelf life of another product, which, however, did not contain the active ingredient of the product concerned here. The FDA understandably disagreed with this explanation.

You can find the original Warning Letter to Profounda on the FDA website.

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