Hospira Italy Facility Gets Warning Letter

On March 31, 2015, FDA issued a Warning Letter to Hospira S.p.A for GMP violations at the company’s Liscate, Italy facility that were cited during a May 2014 inspection.  

Violations observed during the 2014 inspection included violation of aseptic and sterile manufacturing GMPs, failure to investigation batch failures, inappropriate controls over computer and related systems in relation to master production and control records, and failure to properly record laboratory records. The Warning Letter states that FDA found Hospira’s response to the citations “lacks sufficient corrective actions.”

FDA states in the letter that the company had failed to create procedures to prevent microbiological contamination of sterile products and did not thoroughly evaluate all critical dynamic airflow studies operations to determine risks to product sterility. The agency also claims the company did not properly validate all aseptic and sterilization processes.

The letter states that the company’s response to the observation was inadequate,  “we acknowledge your response that you have performed smoke studies, and made limited modifications to the operation in an effort to reduce risks posed by the design deficiencies identified in our inspection. For example, we note that you made some minor changes to reduce rocking of the (b)(4) during the (b)(4) vial transfer operation described above in 1. a) 1. However, your response is inadequate because you have not committed to provide a thorough design assessment. You also failed to provide a video of the new smoke studies you indicated that you performed.”

Also detailed in the letter were violations regarding the rejection of  “possible integral units (i.e., units with intact container/closure systems) from media fills without a written justification or explanation.” FDA states, “these violations are similar to those found during the October 2012 inspection of your Irugattukottai, Sriperumburdur, India manufacturing site. Dynamic airflow study and media fill deficiencies were noted in Warning Letter (WL: 320-13-18), issued May 28, 2013. Your response to that warning letter stated that you implemented your Global Quality Strategy and Global Quality Plan in February 2013 for your manufacturing facilities. Provide evidence of the effectiveness of your implemented global corrective actions and preventive actions.”

In response to the company’s failure to investigate unexplained discrepancies or failure of a batch to meet specifications, FDA states the company “failed to conduct a thorough investigation for 103 complaints for (b)(4) injection related to discoloration of (b)(4) or (b)(4) solution between November 1, 2011 and October 31, 2013, and a more recent complaint on April 3, 2014. We acknowledge your commitment to continue the investigation of (b)(4) levels in (b)(4) vials per protocol KC3601-ENG. However, your response does not adequately address the impact of the effect of (b)(4) in that your medical assessment lacks an evaluation of whether the degradant poses a risk to patients.  In addition, your firm has not adequately addressed vulnerabilities in your manufacturing process that can be addressed to prevent the potential ingress of (b)(4).” 

FDA also states the “firm failed 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 (21 Code of Federal Regulations 211.68(b)) … 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. 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 letter also mentions a failure “to ensure that laboratory records included complete data derived from all tests necessary to assure compliance with established specifications and standards (21CFR 211.194(a)).” FDA states, “It is your responsibility to follow validated methods that include specific procedures to assess the suitability of your instruments.”

FDA asks in the letter that the company provide the agency with a comprehensive evaluation of the extent of the inaccuracy of the reported data with a detailed action plan to investigate the extent of the deficient documentation practices; a risk assessment regarding the potential effect on the quality of drug products that will also determine the effects of the company’s deficient documentation practices on the quality of the drug product released for distribution; and a management strategy that includes a detailed global corrective action and preventive action plan. 

Source: FDA.gov