Developed as part of a joint venture between Boehringer and Eli Lilly, empagliflozin is a sodium glucose co-transporter-2 (SGLT-2) inhibitor intended to reduce blood glucose levels in patients with type 2 diabetes and was submitted to the US Food and Drug Administration (FDA) in March 2013.
However, the companies received a complete response letter this week for the New Drug Application (NDA) referencing previously observed manufacturing deficiencies at Boehringer’s facility near Mainz, Germany, where empagliflozin will be made.
The quality control issues resulted in a Warning Letter last May and included failure to thoroughly investigate critical deviations in the manufacturing of ingredients, and failure to conduct thorough complaint investigations after the presence of foreign particles were found in APIs.
The letter also “referenced findings related to commercial drug production that were observed during an inspection in November 2012,” Boehringer spokesman Dr. Ralph Warsinsky told in-Pharmatechnologist.com, and “these deficiencies need to be resolved before the approval of the empagliflozin application.”
Culture Improvement & Investment
Following receipt of the Warning Letter last year, Boehringer has undergone a review of its manufacturing systems and processes, Warsinsky told us, in order to optimize manufacturing and quality control, and to prepare for the FDA re-inspection that is currently underway.
“The goal is to implement appropriate and sustainable measures to optimize manufacturing and quality control and to prepare for the FDA re-inspection that is currently underway.”
Amongst the actions already carried out, he continued, was strengthening the quality management structure in the Operations Division and formalising a “Culture improvement program” for all employees to encourage a more quality-focused mindset and behaviour.
Moreover, the firm has invested over €100m ($137m) since receiving the warning “to address immediate issues and improve standards” and, according to Warsinsky, there is more investment to come at the site.
“In the last five years the company has invested more than €520m in modernizing different parts of the Ingelheim manufacturing site,” Warsinsky said, with a further €330m planned for 2014/2015 to upgrade the facilities.
The European Medicines Agency (EMA) also received the firms’ marketing authorization application (MAA) for empagliflozin in March 2013 but when contacted this morning the agency told us it did not comment on medicines that are still under evaluation.
However, Warsinsky told us: “The ongoing evaluations of the empagliflozin marketing applications outside of the US are not impacted at this time.”