TRIFARMA S.p.A. (ITALY) RECEIVES WARNING LETTER (070714)

LETTER IS SIMILAR TO ONE RECEIVED BY CERIANO LAGHETTO PLANT (11/13)

The FDA inspected the Trifarma S.p.A. pharmaceutical manufacturing facility, located at Via Pavese 2, Rozzano, Italy from January 27 – 29, 2014.  They identified significant deviations from current good manufacturing practice (CGMP) for the manufacture of active pharmaceutical ingredients (APIs).

Three Observations were noted (see below) that have historically been observed within other Warning Letters previously issued by the FDA.  It is surprising that this firm was not aware of several of those Warning Letters to include a Form FDA 483 received by another of their Italian plants.

“1.    Failure to maintain complete data derived from all testing and to ensure compliance with established specifications and standards pertaining to data retention and management.

Your firm did not retain complete raw data from testing performed to ensure the quality of your APIs. Specifically, your firm deleted all electronic raw data supporting your high performance liquid chromatography (HPLC) testing of all API products released to the U.S. market. In addition, your firm failed to retain basic chromatographic information such as injection sequence, instrument method or integration method for the tests. Your firm’s lack of data control causes us to question the reliability of your data.

In addition, your laboratory management was unaware of, and therefore did not follow, the written procedure detailing the review of analytical data. Furthermore, your management confirmed that the review of analytical data did not include evaluating the system suitability parameters to ensure proper column performance.

Your response states that your firm has been researching backup systems since July 2013 and will have a backup system online by the third quarter of 2014. Your response also states you have begun provisionally storing backup data on each computer, including the integration method as part of that data. However, you do not address the backup of the injection sequence, the instrument method or audit trails.  In addition, your response does not address how your firm will ensure that electronic files are not deleted prematurely from local computers.

In response to this letter, provide a comprehensive corrective action plan addressing the foregoing concerns. Include information regarding system-wide changes, revised procedures, and appropriate retraining of employees that will be implemented immediately to ensure retention of complete electronic raw data for all laboratory instrumentation and equipment.”

COMMENT:

Deleting of electronic raw data, especially with HPLC, is not new.  Several firms to include Wockhardt’s Walui and Chikalthana Facilities, Maharasthtra Receive Warning Letter (11/25/13) (posted on 12/3/13) and Dr. Reddy’s Laboratories Indian Mexican API Facilities Cited by FDA in Warning Letter (posted 7/06/11) within recent years have been cited for the failure to retain basic chromatographic information. In addition, as noted within the Warning Letter ICH Q7 discusses the need to provide system suitability to assure proper column performance.  Also, responses to Observations need to be complete and comprehensive. 

“2.    Failure to prevent unauthorized access or changes to data and to provide adequate controls to prevent omission of data.

Your firm did not have proper controls in place to prevent the unauthorized manipulation of your laboratory’s raw electronic data.  Specifically, your laboratory systems did not have access controls to prevent deletion or alteration of raw data. The inspection noted that all laboratory employees were granted full privileges to the computer systems.

In addition, prior to January 7, 2014, HPLC and gas chromatograph (GC) computer software 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.

Your response states your Agilent GC system and HPLC systems now have audit trails, with (b)(4) more GC systems to be upgraded by the second quarter of 2014. However, your response did not describe the audit trails for the processing of the data on your Agilent systems. Your response also states your firm has begun to retain electronic raw data on the local hard drive, but without proper safeguards to ensure they cannot be deleted prematurely. Such safeguards will not be implemented until the third quarter of 2014.

In response to this letter, provide your corrective action plan to prevent deletion and alteration of electronic data. In addition, describe with more detail your firm’s new archival process and provide assurance that it will consistently function to prevent the types of failures described above from recurring in the future.

We also note that your firm lacked electronic raw data supporting cleaning, method and process validations.  In response to this letter, provide a corrective action plan to review all related test methods associated with products distributed to the U.S. in light of the lack of supporting raw data. 

COMMENT:

Laboratory electronic data systems require a hierarchy of access controls by users that include every level from no changes permitted to full access to change.  Again, the FDA has cited other firms for this same issue.  Please visit my Blog entitled “Failure to Protect Computerized Data – A Reminder of Sandoz and Cephazone Pharma’s FDA Warning Letter Issues (9/03/13)  Audit trails were also again noted in this Citation, and were more specific as to the FDA’s various concerns.

“3.    Failure to ensure that employees receive appropriate and documented training on the particular operations that the employee performs.

Your firm did not document any training of production employees on the production operations they perform. Specifically, operators in Synthesis Plant (b)(4) did not have any documented on-the-job training associated with the production operations they perform. In addition, your management was unaware that they should follow the SOP for the issuance of CoAs, which provides for a review of relevant analytical data. Without documented training, there is a lack of assurance that your employees can reliably execute their API manufacturing responsibilities requirements.

Your response states your firm had updated your training SOP in July 2013 to include on-the-job training along with CGMP training However, the current inspection revealed that your firm is not following this procedure.”

COMMENT:

Observation #3 is self-explanatory.  In addition, the FDA found that the Client is not following the training SOP.  Unless SOPs that exist on one’s site are followed, the FDA will very likely cite that Client.

GENERAL:

The FDA also reminded this firm that their Ceriano Laghetto, Italy plant received similar deficiencies to those cited in this Form FDA 483 and subsequent Warning Letter. “It is essential that your firm implement a robust global quality system.”