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Could This NDA Delay Have Been Avoided?

Once a new drug application (NDA) has been accepted by the agency for filing, the PDUFA review clock starts. We all know the importance of the shortest time to market. Recently MannKind Corporation issued a press release stating that the FDA will not be able to complete the review of MannKind’s NDA for its ultra rapid-acting insulin therapy by the PDUFA date of January 16, 2010. The FDA’s was unable to complete the inspection of a third party supplier to MannKind. The third party was N.V. Organon, the supplier of the active ingredient recombinant human insulin.

It is not clear from the press release or publically available information, whether a last minute change was made to the file or if this was a scheduling issue for the inspectors. The N.V. Organon DMF for recombinant human insulin has been filed with the FDA since February 5, 2001. As you know, the length of time a DMF has been filed it not the important issue, what is important is whether the DMF has been referenced in any previous NDA submissions. This referencing of the DMF is the trigger for FDA review of the DMF.

Without the root cause of the delay, it remains unknown if there was anything that could be done to prevent this delay. There are steps that can be taken when identifying an API manufacturer that can have an impact on the time involved in the review of an NDA. The starting point as stated above is to find out if an active DMF is on file, and then, has any other company referenced that DMF in their NDA? What is the inspection history of the site? Review copies of recent Establishment Inspection Reports (EIRs). Have there been warning letters issued to the site? Review the responses if available. Foreign sites involve more time generally for execution of the inspections. Perform an on-site GMP and pre-approval inspection (PAI) audit well ahead of the expected agency PAI. Be as familiar and prepared with the site history as you can be prior to performing an inspection.

Once you have chosen a manufacturing or vendor site, you have to remain informed about changes occurring at the site which may impact your product and regulatory file.