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FDA officials address 'complete assessments' at DMF workshop

Posted 12 April 2021 | By Joanne S. Eglovitch 

FDA officials address 'complete assessments' at DMF workshop

The US Food and Drug Administration (FDA) held a question-and-answer webinar on 9 April to help the generic drug industry avoid problems with their Type II active pharmaceutical ingredient (API) drug master files (DMFs). Such mishaps can potentially derail the agency’s on-time review of generic drug applications.
The 3-hour webinar covered such topics as fee payments, completeness assessments, impurity assessments, facility identification and selecting starting materials and follows an earlier March 3 webinar on DMFs. At the earlier webinar, industry was invited to submit any lingering questions to the agency on DMFs.
DMFs are submissions to FDA that provide confidential information about facilities, processes or drug substances used in manufacturing drug products and are submitted with new drug applications, abbreviated new drug applications (ANDAs) and investigational new drug applications.
Under the Generic Drug User Fee Amendments of 2012 (GDUFA II), FDA cannot begin an ANDA review until it determines the relevant DMFs are “available for reference.” DMF holders must pay a user fee and have an approved completeness assessment (CA) in place before they can be referenced in applications.
FDA officials pointed out in the earlier March webinar that in fiscal year 2020, only 61% of DMFs were deemed complete and available for reference in the first review cycle.
Agency officials said the most common reasons for rejecting DMFs in the first review cycle were related to inadequate impurity controls, accounting for 80% of the deficiencies. Another major reason for rejecting DMFs was inadequate selection of starting materials.
When is a chemical a starting material?
FDA’s Anita Tiwari was also asked whether a commercially available chemical needs to be manufactured under current good manufacturing practices (cGMPs) to be deemed an acceptable regulatory starting material.
Tiwari responded that the “cGMP pathway starts from the first use of regulatory starting material in the drug substance manufacturing process. Therefore, commercially available chemicals as a starting material is not required to be performed under cGMP.”
Tiwari was also asked why raw materials such as fumaric acid, malic acid, and citric acid are not considered regulatory starting materials and therefore subject to a higher level of scrutiny.
She said that these materials are used as counter-ions and are covered by United States Pharmacopeia (​USP) and National Formulary (NF) monographs; therefore, they are not viewed as regulatory starting materials by the agency.
Maximum impurity limits
FDA’s Yongjun Gao was asked to specify the maximum limit for total impurities in a drug substance. She referred applicants to FDA’s Manual of Policies and Procedures (MAPP) 5017.2 for the answer to this question. She said that “the sum total of all impurity limits, including those for significant metabolites, should not exceed thresholds that may compromise product potency/assay through product expiry.”
Payment of fees
In other areas, FDA’s Hanah Pham was asked during the webinar whether a facility manufacturing API intermediates needs to pay a facility fee. Pham said that these facilities are not subject to GDUFA facility fees, but that a facility manufacturing intermediates for the finished dosage form must pay the facility fee.

Pham further noted that an API facility is not subject to an annual facility fee until the referencing ANDA is approved. If the ANDA is approved in the middle of a fiscal year, the new API facility is not required to pay the facility fee for that fiscal year. Instead, the facility will pay the API facility fee for the first time in the next fiscal year.
Pham was also asked if there was a way for DMF holders to learn their status in the review queue. She said that “we recommend that you stay in constant communication with all of your referencing applicants.”
Completeness assessments
FDA’s Jayani Perera was asked whether the FDA can expedite completeness assessment (CA) reviews if requested by the ANDA holder to reduce the likelihood of a refuse to receive (RTR) action. Perera said that the agency would consider requests to expedite the completeness assessment. He noted, however, that these requests are “rarely needed” because the industry does a good job in submitting DMF fee payments early on, at least three to months in advance of applications, rarely invoking an RTR.
Perera also noted that FDA will internally expedite a CA if an error was made by the agency.
Perera was also asked whether missing facility establishment identifier (FEI) on a DMF for a manufacturing, testing or an advanced intermediate manufacturing facility would impact the CA outcome of a Type II DMF.
He responded that the “Central File Number (CFN), the FEI and that the Data Universal Number  Systems (DUNS) numbers should be provided if available.”
In response to another question, Perera noted that the CA review starts when the DMF fee has been paid and an acknowledgement letter has been issued.
He added that “as stated in the GDUFA II commitment letter, the agency will strive to complete the initial completeness assessment reviews of 90% of the Type II API DMFS within 60 days of the later of the date of DMF submission or DMF fee payment.”
FDA webinar


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Tags: APIs, DMF, FDA, generics, US

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