FDA Issues Warning Letter to Italian API Manufacturer

FDA has issued a warning letter to Trifarma S.p.A. due to  “significant” deviations from current good manufacturing practice (CGMP) for the manufacture of APIs observed during a Jan. 27–29, 2014 inspection of the company’s manufacturing facility in Rozzano, Italy. Violations centered on the collection, retention, and security of analytical data, as well as insufficient employee training procedures. FDA said the firm’s response to violations found during the inspection lacked sufficient corrective actions. 

The CGMP deviations listed in the letter included deficiencies similar to those cited in a FDA-483 Form from the November 2013 inspection of Trifarma’s Ceriano Laghetto, Italy plant. “It is essential that your firm implement a robust global quality system. FDA strongly recommends that your firm’s executive management immediately undertake a comprehensive and global assessment of your manufacturing operations to ensure that your systems and processes, and ultimately, the APIs you manufacture, conform to FDA requirements,” FDA noted in the letter.

Specific violations at the Rozzano facility include failure to maintain complete data derived from all testing, and to ensure compliance with established specifications and standards pertaining to data retention and management. FDA noted that the company did not retain complete raw data from testing performed to ensure the quality of APIs. The firm had deleted all electronic raw data supporting high performance liquid chromatography (HPLC) testing of API products released to the US market. In addition, FDA noted that the firm failed to retain basic chromatographic information such as injection sequence, instrument method, or integration method for the tests.

In addition, the company failed to prevent unauthorized access or changes to data and to provide adequate controls to prevent omission of data. Specifically, FDA says, the laboratory systems did not have access controls to prevent deletion or alteration of raw data; all laboratory employees were granted full privileges to the computer systems. FDA noted that the company has instituted some audit trails for chromatography data, but the company’s response did not describe the audit trails for the processing of the data on all systems. Plans to retain electronic raw data lacked proper safeguards to ensure they cannot be deleted prematurely. The company also lacked electronic raw data supporting cleaning, method, and process validations.  

In a third major violation area, FDA noted that Trifarma failed to ensure that employees receive appropriate and documented training on the particular operations that the employee performs. Management was unaware that they should follow the SOP for the issuance of CoAs, which provides for a review of relevant analytical data. The inspection also revealed that the firm was not following a training SOP that was updated in July 2013.
In the letter, FDA noted that the review indicates that Trifarma’s quality unit is not able to fully exercise its responsibilities. “It is essential that you provide the quality unit with the appropriate authority and staff to carry out its responsibilities. We also recommend that you hire a qualified consultant to provide your firm’s staff with guidance and training on CGMP and laboratory data integrity,” FDA notes in the letter.

Source: FDA