Serious FDA Warning Letter issued to European Manufacturer of sterile Drugs, Part 2

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 regulations. The company's reply on 22. February 2016 was not sufficient and led to a Warning Letter issued on 13. October 2016. The violations were considered to be so serious by the FDA that the company was put on import alert already on 27. May 2016.

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

In this second part, we cover the violations of 21 CFR 211.113 (b) "Your firm failed to establish and follow appropriate procedures that are designed to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes" and of 21 CFR 211.42 (c)(10) "Your firm failed to establish an adequate system for monitoring environmental conditions in aseptic processing areas".

Two aspects were criticized with regard to 21 CFR 211.113: "inadequate aseptic techniques" and "mechanical faults during media fill". The inspector supported the "inadequate aseptic techniques" with a video recording of a line set-up followed by the filling. It showed the following incorrect behaviour:

  • an employee handed a pen to another employee directly above the stopper bowl
  • an employee was sitting on the floor during line set-up and did not change his gown afterwards
  • an employee was leaning against the cleanroom wall
  • an employee left the door of an RABS open for a considerable time during the filling without working in the immediate area

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

  • a risk assessment of this inadequate aseptic behaviour of the employees
  • assessment of other possible deviations of correct aseptic behaviour during the filling (e.g. by a comprehensive evaluation of other video recordings)
  • up-to-date information demonstrating that all aseptic filling lines are "under control"
  • statements of the company 
  • also, they expect company statements on how the "aseptic processing operation design" and staff competencies can be improved and how the controls (QA oversight) during daily operations can be ensured

The following was observed during a media fill. The company rejected numerous filled vials during a media fill due to mechanical problems (issues with the conveyor belt motor). About 3,700 filled vials were not incubated and the media fill was invalidated without adequate justification. The company indicated that it would have released the filled vials of this production batch as a sub-lot. However, a procedure for such a case was not available.

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

  • a list of all production batches that were discarded due to mechanical problems or other reasons and the associated CAPA measures taken
  • a comprehensive list of all media fills performed after January 2011 (including filling date, number of units run and incubated, number of positive units and annotation of whether the fill was aborted)
  • a description of circumstances under which any portion of a media fill batch was incubated as a separate segment and whether any positive were detected
  • a modified procedure which ensures that the media fill simulates the actual production practices and clearly specifies the circumstances that lead to the abortion of a media fill

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

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