FDA Posts Warning Letter for Hospira Facility in Italy
The US Food and Drug Administration has posted a Warning Letter to Hospira, dated March 31, 2015, for cGMP violations for finished pharmaceuticals at the company’s pharmaceutical manufacturing facility in Liscate, Italy, based on an FDA inspection at the facility from May 5 to 9, 2014 and May 12 to 13, 2014. The FDA said it reviewed the firm’s response dated June 4, 2014 and that it lacked sufficient corrective action and acknowledged subsequent receipt of the company’s correspondence on August 4, 2014, October 2, 2014, December 4, 2014, and February 9, 2015.
The company was cited for failing to establish and follow appropriate written procedures to prevent microbiological contamination of drug products purporting to be sterile, and that include validation of all aseptic and sterilization processes. Specifically, the agency said that the firm did not evaluate all critical operations during dynamic airflow studies to determine risk to product sterility. It said that the firm did not evaluate significant aseptic interventions during dynamic airflow studies (smoke studies) to determine how the movement of air and personnel during aseptic operations could pose risks to product sterility. The agency also said that the firm rejected possible integral units (i.e., units with intact container/closure systems) from media fills without a written justification or explanation. The agency acknowledged that the company had completed a media-fill performance qualification, but that is protocol (Shut Down Media Fill Qualification Protocol KC4103-PQ) was inadequate because it did not provide criteria that adequately defined when vials are to be rejected. The agency is asking the company to provide its categorization criteria and justification for rejection of vials from a media fill.
The agency said that those violations are similar to those found during the October 2012 inspection of the company’s Irugattukottai, Sriperumburdur, India manufacturing site. Dynamic airflow study and media fill deficiencies were noted in a Warning Letter issued May 28, 2013.The response to that Warning Letter stated that the company implemented a Global Quality Strategy and Global Quality Plan in February 2013 for its manufacturing facilities. The agency is requesting that the company provide evidence of the effectiveness of its implemented global corrective actions and preventive actions.
The FDA also said that the company failed to thoroughly investigate unexplained discrepancies or failures of a batch or any of its components to meet any of its specifications. The agency said that the firm failed to conduct a thorough investigation for 103 complaints for discoloration of a product between November 1, 2011 and October 31, 2013, and a more recent complaint on April 3, 2014. The agency said that the company investigated the cause of the discoloration but did not adequately consider all possible causes of the discoloration, including a failure to perform a step in the manufacturing process.
The agency also cited the firm for failure to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records or other records. Specifically, it noted that the company’s high-performance liquid chromatography (HPLC) and gas chromatography (GC) data acquisition software did not have sufficient controls to prevent the deletion or alteration of raw data files. During the inspection, the investigator observed that the server that maintained electronic raw data for HPLC and GC analyses (the J drive) contained a folder named “Test,” and that chromatographic methods, sequences, and injection data saved into this folder could be deleted by analysts. The investigator also found that data files initially created and stored in the “Test” folder had been deleted, and that back-up files were overwritten. In addition, because no audit trail function was enabled for the “Test” folder, the agency said that the firm was unable to verify what types of injections were made, who made them, or the date or time of deletion.
“Your response indicates that you have added computer controls to prevent the deletion of folders and files in the J drive for electronic raw data,” said the agency in its Warning Letter. “However, you provide no evidence demonstrating how your firm will prevent deletion of newly created folders and files in each of your computer systems. We acknowledge your commitment to hire a third-party consultant to address the inadequacies of your data systems. However, your response is inadequate as it fails to address how you will enable and review audit trail functions for all of your analytical computer systems.” The agency is asking the company to provide specific details about the comprehensive controls in place to ensure the integrity of electronic raw data generated by all computer systems used to support the manufacture and testing of drug products. The agency said itidentified a similar inspectional finding during the December 2013 inspection of the company’s Irugattukottai, Sriperumburdur, India, manufacturing facility and noted this finding in an Untitled Letter, issued April 16, 2014.
The agency also cited the company for record-keeping procedures for certain analytical testing procedures that raised issues relating to the accuracy and integrity of the data used to support the safety, effectiveness, and quality of the drug products manufactured.