GDUFA II Key changes and implications for API manufacturer and drug master file (DMF) holders

The Teva api regulatory team has taken a good long look at the new GDUFA II commitment letter issued by the US FDA and has come up with the following highlights to help understand the implications and benefits of the updated regulation for DMF holders.

The original GDUFA (Generic Drug User Fee Amendments) was designed to increase the FDA review efficiency and reduce the gap in generic application approvals. GDUFA II is intended to further streamline and quicken the application processes. It was reauthorized in August 2017 and came into effect on October 1st 2017 and will remain in effect until the end of September 2022.

This article will give you an overview of the changes from API manufacturer and DMF holder perspective.

What’s new?

  1. New Performance Goals

DMF Completeness Assessment (CA) initial review: 90% of Type II API DMFs complete within 60 days of the later of the date of the DMF submission or DMF fee payment.

  1. Communication of DMF Review Comments

DMF review comments to be issued in parallel with the review comments relating to the DMF for the ANDA.

  1. Teleconferences to Clarify DMF First Cycle Review Deficiencies

DMF holders have 20 business days from issuance of the first cycle deficiency letter to submit a teleconference request.

DMF holders may request an email exchange with the FDA in lieu of the teleconference. The request must list the specific issues to be addressed. The DMF holder can submit one follow up email to obtain additional clarification from the FDA, if needed.

  1. DMF First Adequate Letter

Once a DMF has undergone a full scientific review and has no open issues related to the review of the referencing ANDA, the FDA will issue a First Adequate Letter.

  1. DMF No Further Comments Letter

Once a DMF has undergone a complete review and the ANDA referencing the DMF has been approved or tentatively approved, FDA will issue a no further comments letter.

  1. Guidance on Post-Approval Changes to Drug Substances

By October 1, 2018 the FDA will issue a guidance regarding post-approval changes to a Type II API DMF and submission mechanisms for ANDA applicants who reference the Type II API DMF.


GDUFA II puts the DMF filings and review processes into scope: faster review upon submission, timely scientific review, more options for communication in cases of unclear questions, and more clarity on the status of DMF reviews.

The FDA’s commitment to improving their review procedures is dependent on the API manufacturers cooperation. In order for the procedures to work we must:

  • Improve the quality and content of our files.
  • Respond faster to scientific review comments to stay in line with the ANDA review round.
  • Make full and efficient use of the communication channels on offer.

Additionally API manufacturers should take careful note of all updated guidelines given to ANDA holders as many have a direct impact on drug substance submissions that include:

“ANDA Submissions – Refuse to Receive” (RtR) guidance, lists specific requirements for drug substances regarding the definition of the regulatory starting materials and limits of impurities.”

“ANDA Submissions – Amendments to Abbreviated New Drug Applications Under GDUFA” draft guidance that lists items from a DMF review that can become a major amendment to the ANDA.”

“Good ANDA Submission Practices” draft guidance that addresses requirements from Drug Substance manufacturers.”

Manufacturer data presented in Type II API DMF must include all manufacturing facilities involved in the manufacturing and testing of the drug substance in order to correctly identify them in the corresponding ANDA.


The FDA’s goal of approving ANDAs in the first review cycle depends upon improving the DMF review process. It is therefore vital to reduce the total number of review cycles and the time for response from the DMF holders, to increase the chances of first cycle ANDA approval. Teva api’s global team is closely monitoring the newly published regulations and working on constant improvements of the submissions in order to provide best support for our customers.

Disclaimer: Information in this article represents Author’s interpretation of the GDUFA II commitment letter and is provided to outline Teva api‘s commitment to support our customers. Author or Teva api are not responsible for readers’ use of the information for any other purpose.


About the author

Olga Progrebinsky has a Ph.D. degree in Organic Chemistry from Tel-Aviv University and has worked in Teva api’s regulatory affairs group for 13 years and is currently the Sr Dir Regulatory Affairs at Teva api. The Teva api global RA team is spread across 10 countries and provides regulatory support to all Teva api sites and all Teva api customers worldwide.