By Charles “Chris” Celeste, Director of Regulatory Information and Submissions
Two years have passed since passage of the Generic Drug User Fee Act (GDUFA).
GDUFA is a significant law that introduced new requirements for active pharmaceutical ingredient (API) manufacturers, including fees associated with their Type II drug master files (DMFs), as well as for establishment registrations and for conversion of type II DMFs into Electronic Common Technical Document (eCTD) format.
The FDA does not require that a DMF be filed. The information may be submitted directly in a new drug application (NDA) or in an abbreviated new drug application (ANDA). So why submit a DMF? One reason is to maintain confidentiality of the proprietary information of the active pharmaceutical ingredient. Another is that a single DMF may support multiple applications.
Currently, FDA does not require that the DMF be submitted in eCTD format, but the agency has said the electronic format can aid in the review of the application.
Upon receipt of an initial submission, FDA’s DMF staff will check that the file is complete. If the file is found acceptable, the agency will send a letter to the DMF holder (for foreign DMF holders, the U.S. Agent will receive a copy of the letter) acknowledging receipt of the DMF. If the file is found to be incomplete, a letter will be sent detailing the missing information. Once that information has been provided, FDA will issue the acknowledgement letter. DMF holders are obligated to submit all changes as amendments, to notify authorized parties of changes, to properly maintain the DMF (with annual reports), and to issue Letters of Authorization to each customer to the DMF.
Reporting a change to a DMF can be done at any time through the submission of an amendment. But the DMF holder needs to notify customers of any changes.
It is important for DMF holders to remember that DMFs are not approved or disapproved by the agency. A DMF is reviewed to determine whether it is adequate to support a specific application. If the file is acceptable, FDA will consider it available for reference and will issue a letter to the DMF holder indicating that it has “No Further Comments.”
The Drug Master Files require a one-time only fee. If a holder has paid a DMF fee for a Type II active pharmaceutical ingredient, the holder is not required to pay a subsequent drug master file fee when that Type II active pharmaceutical ingredient drug master file is subsequently referenced in drug application submissions. According to the Act, the DMF fee will be due no later than the date on which the first generic drug submission is submitted that references the associated Type II API DMF. FDA is recommending that the DMF fee be paid at least 6 months prior to the submission of an ANDA. This will ensure that the Completeness Assessments can be performed and the DMF will be available to reference. This will require the ANDA applicant and DMF holder to communicate regarding the timing of the submission of the application. FDA has issued a draft “Guidance for Industry: Initial Completeness Assessments for Type II API DMFs Under GDUFA” listing the information the agency will check for in the DMF.
In addition, FDA will be accepting written requests from the DMF holder within 10 working days from the issuance of a deficiency letter to discuss any questions regarding the letter. The holder will need to provide an outline of the questions to be addressed and will be limited to the content of the deficiency letter. FDA will allow for a 30 minute conference call per DMF holder per month.
FDA will be performing risk-adjusted biennial cGMP surveillance inspections of the API and finished dosage form (FDF) manufacturers. The agency will be prioritizing inspections related to ANDAs that are approvable or eligible for tentative approval and establishments that have not previously been inspected. FDA will post the inspection classification results and the date of the last inspection on its website. Also, the agency will be making use of foreign inspection classifications.
In addition to the user fees on the type II DMFs, FDA will impose an annual fee for each facility registration of an API manufacturer. Here is the fee schedule for FY 2015, which began October 1, 2014.
GDUFA FEE SCHEDULE FOR FY 2015
|Fee Category||Fee rates for FY 2015|
|Original ANDA||$58,730 (per application)|
|PAS* ANDA||$29,370 (per PAS)|
|Domestic Facility FDF||$247,717 (per facility)|
|Foreign Facility FDF||$262,717(per facility)|
|Domestic Facility API||$41,926 (per facility)|
|Foreign Facility API||$56,926 (per facility)|
- Prior Approval Supplement