Serious FDA Warning Letter issued to European Manufacturer of sterile Drugs, Part 1

In case of serious violations of GMP requirements, the American FDA issues a Warning Letter to the company in question. The company must react to this within 15 working days and submit a corrective action plan to the FDA. The FDA inspected the Hungarian company Teva Pharmaceutical Works Private Limited from 21 to 29 January, 2016 and the inspector witnessed serious violations of GMP requirements. The company's reply on 22.02.2016 was not sufficient and led to a Warning Letter issued on 13.10.2016. The violations were considered to be so serious by the FDA that the company was added to the list of import bans already on 27.05.2016.

The violations observed are referred to the respective GMP requirements of 21 CFR Part 211 by the authority. In this case, the deficits were divided into 7 different chapters.

In this first part, we cover the violations of 21 CFR 211.192: "Your firm failed to thoroughly investigate any unexplained discrepancy or failure of a batch or any of its components to meet any of its specifications, whether or not the batch has already been distributed". Here, the insufficient investigation of failures in media fill or sterility testing was criticized.

31 contaminated units were identified in one media fill. In addition, media fills for other filling lines yielded one or more contaminants. The company attributed the contamination in these media fills to aseptic technique breaches by their employees. Various breaches were identified relating to the set-up, filling and changing of the filling tank. The investigations were insufficient. The microorganisms found in the contaminated units were not identified. However, this identification is crucial for the FDA in order to determine the sources as well as potential risks. The FDA's target is obvious: Each contamination must be identified!

The investigations of positive sterility tests were also considered insufficient. They did not adequately assess the hazards for the aseptic filling operation. Furthermore, the company did not determine whether other batches made on the same production line were affected. It was also criticized that several positive sterility tests results were invalidated during batch release testing although the company used sterility testing kits that should minimize potential contamination.

The company's response to these observations was inadequate. In the response to their Warning Letter, the FDA expects the following:

• a comprehensive review of all positive sterility tests and media fill failures since January 2014 and reassessment of the root causes, corrections and conclusions with regards to the sterility of marketed commercial batches
• revised media fill SOPs with regards to the identification of microorganisms from each contaminated media fill
• revised sterility failure investigation SOP
• a retrospective evaluation of all videos of the aseptic manufacture of batches distributed to the United States
• an assessment of the adequacy of the facility, equipment and processes as well as a comprehensive CAPA plan that fully identifies microbial contamination risks throughout the filling operation. In addition, description of improvements to assure high confidence in the sterility of the products.

Source: FDA Warning Letter to Teva Pharmaceutical Works Private Limited Company