Warning Letter for US Contract Manufacturer: Cleaning, Contamination Control and Stability Studies criticised

In March, the American authority FDA issued a Warning Letter to a US pharmaceutical manufacturer due to numerous violations of GMP. Among other things, inadequate cleaning of the equipment, errors in the stability studies as well as in contamination control were found.

The inspection took place in July 2018. In August 2018, the manufacturer submitted a response with proposals for remedying the defects. According to the FDA, the measures proposed were not sufficient and a Warning Letter followed.

Numerous deficiencies were identified regarding the cleaning of the production equipment. This is particularly critical for a contract manufacturer, as he deals with many different products from different customers. Specifically, the FDA lacked a determination of the hold times for dirty equipment and its validation.  The exhaust system on a capsule machine had never been cleaned since its installation in 2007. According to the Warning Letter, those deficiencies were already noticed during the inspections performed in 2012 and 2016. The FDA now expects a comprehensive cleaning strategy, which should at least consider the following points: the toxicity of the products, the solubility of the products in the cleaning agents, the determination of the products that are most difficult to clean and the locations in the equipment that are most difficult to clean.

Significant deficiencies were also found in the stability programme. For example, the stability plans lacked testing methods, storage conditions and the duration of stability studies. The reports on stability studies also lacked data on some batches at several test points. Those findings had also been criticised during the inspections in 2012 and 2016.

For the FDA, another serious issue - especially for a contract manufacturer with a large number of different products and materials - is the lack of contamination control and the prevention of mix-ups. The FDA found batches of different substances not labelled as "rejected" in the incoming goods area.  In an "ante room" between two manufacturing areas, which is not monitored for temperature and humidity, the FDA discovered two open boxes of "in-process" tablets. In his response, the manufacturer indicated that this "ante room" is also connected to the HVAC system of the production rooms and that the tablets are tested at the end of production.  This is insufficient for the FDA who classifies storage as uncontrolled (lack of evidence of temperature/humidity compliance) and clarifies, that quality cannot be tested into the product.

The documentation of the production was also a cause for complaint. The FDA found that manufacturing data was recorded on uncontrolled notebooks or loose sheets. One notebook in the production area contained release labels for raw material and other loose labels with product information.  Even if the manufacturer wrote in his response to the FDA that employees who do not document properly in the future will be dismissed immediately, this is not a satisfactory response for the FDA. The FDA requires a comprehensive examination of all documentation systems in both the manufacturing and laboratory areas, as well as an assessment of which processes are insufficient from a GMP point of view. The FDA requires a CAPA plan that corrects the documentation processes and ensures correct and complete GMP documentation.

You can find the complete Warning Letter for a US contract manufacturer on FDA's website.