FDA’s Generic Drug User Fee Act (GDUFA) – Drug Master Files (DMFs)

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)
DMF $26,720
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

FDA Learns from ‘Listening Sessions’ on the Re-proposed FSMA Rules

 

Senior Food and Drug Administration officials, including Mike Taylor, FDA Deputy Commissioner for Foods and Veterinary Medicine, traveled to Georgia, North Carolina, Florida, California and Vermont in recent weeks for “listening sessions” with stakeholders to discuss the agency’s re-proposed Food Safety Modernization Act rules. The agency also hosted a public meeting November 13 in College Park, Md. on the supplemental rules.

In a recent FDA Voice blog, Taylor says the emphasis in these sessions has shifted from concerns about the cost of certain measures to “mostly clarifying questions about the content of the rules,” and what has to be done once the rules take effect. “We’re getting down to the nitty gritty of implementation,” he says. However, there appears to be ongoing confusion about the water quality and testing requirement for produce growers. The agency is “committed to providing clear guidance so that expectations are understood,” Taylor says.

In the listening sessions and in their discussions with state representatives, the FDA officials were asked how the agency plans to pay for its FSMA-related activities.

“It is urgent that FDA receive adequate funding for the training, technical assistance, state partnerships and import oversight that is essential for sound implementation of the FSMA rules beginning in late 2016 and 2017,” Taylor says.

The agency will be relying heavily on its state counterparts to provide training, technical assistance and compliance oversight, he said.

He reported separately on the New England listening session in another blog post, noting that many stakeholders are “finding the complexity of the proposed rules daunting, such as the technical underpinnings of the E.coli benchmark for water quality and the various boundary lines and exemptions that determine who is covered.” The agency has opted not to take a “one size fits all” approach, which has contributed to making the rules more complicated.

“This only underscores our responsibility to explain the rules clearly and to provide education, technical assistance and guidance,” Taylor says.

Indeed, these activities are likely to be among the agency’s biggest challenges in achieving a successful implementation of FSMA both for domestic and imported foods.

FDA has declined requests for extensions of the December 15 deadline for public comment on its re-proposed rules, citing its urgent need to move forward because of its court-imposed deadlines for implementing the final rules.