Warning Letter due to Cross Contamination

In August, the US FDA issued a Warning Letter to a Turkish pharmaceutical manufacturer due to cross-contamination with penicillin in areas for non-beta-lactam production.

According to the FDA Warning Letter, penicillin was detected several times outside the penicillin manufacturing areas; 103 times in 2017, 44 times in 2018, and 9 times in 2019 until June 2019. For the FDA, it is important to underline that in total 7 times a manufacturing area for a non-beta-bactam US product was affected. In addition, common places such as a dining area used by employees from the penicillin and non-beta-lactam production were also affected. According to the FDA, it is not acceptable for common areas to be shared between penicillin and non-beta-lactam employees. The FDA also considers the company's control to prevent cross-contamination to be unacceptable. According to FDA, there is no safe level for penicillin contamination in non-beta-lactam products. At the same time, there is a high risk of penicillin contamination, which can even lead to the death of patients due to an anaphylactic shock.

In the response to the inspection deficiencies, the manufacturer stated that all retain samples of the US-American product were tested for penicillin contamination using a newly-validated analytical method, and no penicillin was found. Moreover, a penicillin monitoring study was carried out.

The FDA considers the answer to be insufficient, as the detection limit of the method is inadequate. The FDA refers to its own method with a detection limit of 0.2 ppb. The monitoring study is also judged by the FDA to be deficient because it was performed only one time, with only seven test points, none of which were within the manufacturing area of the US-American product.

FDA Expectations

The FDA now expects:

  • A plan for the full decontamination of the non-beta-lactam manufacturing area
  • A list of decontaminant solutions with validated evidence that the agents are capable of breaking the beta-lactam ring of the beta-lactam products manufactured.
  • A monitoring plan for the facility on how beta-lactam product residues will be monitored in the future.
  • A control plan showing the identified routes of beta-lactam contamination

The FDA positively evaluates the fact that the manufacturer has recalled all batches of the US-American product due to the defects identified. In addition, the FDA recommends engaging a GMP consultant to rectify the deficiencies.

For more detailed information please also see the FDA's Warning Letter to Deva Holding AS.

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