Another FDA Warning Letter due to Deficiencies in the Water System

Once again, the US-American FDA has issued a Warning Letter to a US-American pharmaceutical manufacturer, whose main criticised topics concern deficiencies in the handling of CAPA & OOS as well as in cleaning and a defective water system.

Inappropriate examination of deviations

The FDA describes the system for investigating deviations and OOS results as inadequate. Not only the root cause investigation but also the definition of measures as well as the adherence to time specifications regarding deviations investigation and the evaluation of deviations in the monitoring of the water system have been criticized. The FDA has reported that between June 2017 and September 2018, a total of 14 deviation investigations out of 39 partially serious issues were not completed. During this period, production was nevertheless continued.

In its reply, the US-American pharmaceutical manufacturer stated that the quality unit would close the open deviations within 30 days. For the FDA, this answer is not sufficient as it does not address the possible effects that could arise from the insufficiently investigated deviations. The FDA now expects a retrospective review of all these deviations/OOS cases and the implications that may exist for product batches on the US market. In addition, the FDA expects a tabular overview of all OOS cases since 2017 for raw materials, IPCs, released finished products and stability testing.

Deficiencies in the pharmaceutical water system

The water system is also subject to criticism. The FDA sees no evidence that the manufacturer has the design, control, maintenance and monitoring of the water system under control so that pharmaceutical water can be consistently produced in the quality required. The FDA also describes sampling as inadequate. During the review of the 2018 data, the FDA noticed that the limit values for TOC and once for conductivity had not been complied with several times. A validation of the sanitization of the system is also missing. The FDA considers the response of the pharmaceutical manufacturer to be insufficient as no details have been given as to how the validity of the system is to be established in detail. The FDA also lacks a retrospective assessment of possible repercussions on product quality that could be caused by the water used.

Inadequate cleaning

Deficiencies in the cleaning of the manufacturing equipment are also part of the Warning Letter. For example, the FDA considers the cleaning of equipment that is used to manufacture several products (so-called shared equipment) to be insufficient. Transfer hoses that are used for multiple products were also not tested. The FDA now expects cleaning to be validated for every part of the plant that is used for multiple products. In particular, the toxicity, water solubility and accessibility during cleaning should be discussed using a worst case approach.

Shortcomings in the stability programme

The stability programme of the manufacturer was also criticised. According to the FDA, the company's current stability programme cannot demonstrate the drugs' shelf life through their expiry date. For example, the method validation for testing the finished drugs for degradants was not completed. The management was only able to present a cart full of raw data without evaluation by the quality unit.

Interestingly, the deficiencies mentioned are not new for the FDA. Similar infringements were found and warned during inspections in 2010, 2012, 2014 and 2017. The manufacturer had been notified of these via so-called Forms 483. Now, the current Warning Letter was first issued in 2019.

Please see the the FDA's Warning Letter to TG United for more detailed information.