Italian API Manufacturer Receives FDA Warning Letter for Data Integrity Issues

On July 7th the US FDA issued a Warning Letter to Trifarma S.p.A. for violating Good Manufacturing Standards at their facility in Rozzano, Italy. The company produces APIs and had been inspected early this year. As a result of the inspection and the response of the company to the GMP findings the FDA decided to issue a Warning Letter.

While so far mainly Indian Manufacturers have been blamed by FDA and EU Inspectors for data integrity issues, now also an European API manufacturer has been cited for that problem. According to the Warning Letter the firm deleted all electronic raw data supporting the companies high performance liquid chromatography (HPLC) testing. Moreover, Trifarma failed to retain basic chromatographic information such as injection sequence, instrument method or integration method for the tests.

In a response to the FDA the firm explained that it has been researching backup systems since July 2013 and will have a backup system online by the third quarter of 2014. But FDA is not satisfied with this answer. Some interim actions such as storing backup data on each computer, including the integration method as part of that data are not sufficient. The FDA expects to see backups of the injection sequence, the instrument method and audit trails. According to the FDA the firm does not address how it will ensure that electronic files are not deleted prematurely from local computers.

In addition further basic GMP provisions are not met in the lab. There are no proper controls in place to prevent the unauthorized manipulation of the raw electronic data. All persons in the lab were able to delete and/or adulterate data because all lab employees were granted full privileges to the computer systems. Some equipment in place in the lab such as the HPLC and the GC lacked active audit trail functions to record changes to data, including information on original results, the identity of the person making the change, and the date of the change.

The FDA also expected to see electronic raw data supporting cleaning, method and process validations but the company was not able to provide these data. Another critical deviation referred to the fact that the company did not document any training of production employees on the production operations they perform. The company did change an SOP on how to perform training at the manufacturing site in July 2013 in order to include on-the-job training but Trifarma is not following it's own procedures.

Interestingly the US FDA has used the information gathered in a previous inspection of another production site of the company to check the compliance in the Rozzano site. Trifarma received a 483 form on similar deficiencies for it's Ceriano Laghetto plant but did not take the necessary actions to check if similar problems exist also at other manufacturing sites. From this the FDA concluded that there is not robust quality system is in place. The FDA also references the ICH Q7 Guide GMP for APIs and expects form API manufacturers to meet the requirements stated in that Guide.

Source. FDA Warning Letter for Trifarma S.p.A.