API DMFs for ANDAs: FDA Finalizes Guidance on Completeness Assessments

Regulatory NewsRegulatory News | 12 February 2016 |  By 

The US Food and Drug Administration (FDA)'s final guidance issued on Friday will help the generic drug industry prepare for completeness assessments for holders of Type II active pharmaceutical ingredient (API) drug master files (DMFs) that are or will be referenced in an abbreviated new drug application (ANDA).

The guidance, first released in draft form in 2012, lays out requirements for how companies will have to pay a DMF fee, which for FY 2016 is $42,170, when first referring to aDMF in a generic application and how Type II API DMFs will undergo FDA completeness assessments (CA).

“In order to ensure adequate time for the CA, FDA strongly encourages the DMF holder to submit a complete DMF and pay the DMF fee at least 6 months prior to the submission of an ANDA or PAS that will rely on the DMF,” the agency says.


The completeness assessments will address:

  • Is the DMF active?
  • Has the fee been paid?
  • Has the DMF been previously reviewed?
  • Does the DMF pertain to a single API?
  • Does the DMF contain certain administrative information?
  • Does the DMF contain all the information necessary to enable a scientific review?
  • Is the DMF written in English?

The entire form, listed as an appendix in the guidance, also includes an area where FDA can make an expedited assessment request.

If the DMF is found complete, FDA will post the DMF number on a publicly available list to indicate the DMF can be referenced by generic drug submission applicants.

If a DMF is found incomplete, the CA findings and comments will be compiled in a “GDUFA DMF Incomplete Letter” with an explanation. To correct the deficiencies, the DMF holder should submit an amendment, or if the DMF is in paper format and it has been five years or more since the DMF received a complete update, or if there have been more than five amendments to the DMF, FDA says the DMF holder should provide a “complete and comprehensive update.” If an update hasn’t been made, FDA says it will consider the DMF incomplete and the holder must submit an update for FDA to determine whether it passes the CA.

DMF holders are encouraged to submit files in eCTD format [RAPS is hosting a workshop on eCTD submissions 13-14 April].

No CA will be conducted if a generic drug submission contains all the necessary API information and does not reference a DMF. In such cases the generic drug submission applicant will also be required to pay the DMF fee, in addition to the FY 2016 facility fees:

  • Domestic FDF facility: $243,905
  • Foreign FDF facility: $258,905
  • Domestic API facility: $40,867
  • Foreign API facility: $55,867

ANDA applicants that reference a DMF with an unpaid fee will be provided notification of the DMF holder’s failure to pay. And after 20 calendar days FDA says the ANDA referencing the DMF will not be received.


Seven comments were submitted to the docket for the draft guidance. Generic drugmaker Sandoz called on FDA to provide definitions and examples of drug substances and manufacturing processes to help understand the acceptance criteria.

“For example, will different polymorphs of API be considered as one drug substance? Will various physical processes used to achieve various grades of API be considered as one manufacturing process?” Sandoz questioned.

In a footnote in the final guidance that was not included in the draft version, FDA offers an example of a complex API, which in addition to the recommendations in the CA Checklist, should include data for the agency to review a DMF on active ingredient sameness.

For enoxaparin sodium, FDA says: “listed sameness equivalence criteria in the draft guidance include mode of depolymerization, source material, physicochemical properties, disaccharide building blocks, fragment mapping, sequence of oligosaccharide species, and biological and biochemical assays. If the appropriate product-specific data is not in the DMF, the DMF will be deemed incomplete.”

As for an example of a manufacturing process (also not included in the draft guidance) for which certain process alternatives/changes may be permissible, FDA includes: “validated reprocess/rework procedures; micronization leading to different particle sizes (excluding nano particles); addition of a stabilizing agent for stability purposes; and minor process variation that leaves the chemical transformation the same, with little risk to the impurity profile.”

The Active Pharmaceutical Ingredients Committee, which is a group within the European Chemical Industry Council, also requested more information from FDA on a timeline for the CAs, though FDA just says that in order to ensure adequate time for the CA, the DMF fee should be paid “at least 6 months prior to the submission of an ANDA or PAS that will rely on the DMF.”

Janet Woodcock, FDA’s CDER director, told Congress recently that moving forward, it will take FDA about 15 months to respond to a generic firm’s ANDA, and in October 2016, companies can expect to get a response within 10 months.

The Bulk Pharmaceuticals Task Force, which is part of the Society of Chemical Manufacturers & Affiliates, also took issue in its comment with several items in the DMF checklist that it says do not enhance the Chemistry, Manufacturing, and Controls review and which “significantly increase the work required to compile a DMF submission,” and could be provided during an inspection, though the final guidance still includes them in the checklist.

Completeness Assessments for Type II API DMFs Under GDUFA Guidance for Industry

Generic Drug User Fee Amendments (GDUFA) - Frequently Asked Questions (FAQs)


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