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GDUFA: Its impact on the Type II Drug Substance Drug Master File (DMF)

Updated: Jul 10, 2023

The U.S Food and Drug Administration (FDA) has worked with industry to streamline the Abbreviated New Drug Application (ANDA) approval process since the early 2010s. The administrative powers to do so began with the enactment of the Generic Drug User Fee Act (GDUFA) in 2012 (GDUFA I) and reauthorization of the act in 2017 (GDUFA II). The FDA has begun several initiatives to streamline the review process to be able the meet the review goals for an ANDA enacted under GDUFA. In light of GDUFA, the review of the Type II Drug Substance Drug Master Files (DMF) has received renewed attention as they are an integral part of ANDAs. This post highlights some FDA initiatives undertaken to enhance the DMF review process and provide guidance to the pharmaceutical industry.

Timeline Expectations: FDA has provided a clear timeline recommendation for the ANDAs. The overlapping review timelines for ANDA including a Type II DMF review are visualized in Figure 1. FDA recommends that a referenced DMF be submitted with all fees paid, a minimum of 6 months prior to ANDA submission. Adhering to these recommendations facilitates FDA meeting the GDUFA performance goals of reviewing and providing a filing decision for 90% of standard ANDAs within 10 months and 90% of priority ANDAs within 8-10 months of the submission date.

Abbreviations: CA=Completeness Assessment; CR= Complete Response; DTD=DMF Target Date; IR=Information Request OGD=Office of Generic Drugs: OPQ=Office of Pharmaceutical Quality; QDD=Quality Due Date; TCIR =Timely Consult and Early Information Request.

(Reproduced from FDA CDER SBIA-DMF Drug Substance Workshop, March 2021, DMF Poster 1: Timeline for DMF Risk-based Assessment and Improvement of the First Cycle Approval Rate)

Completeness Assessment (CA): During drafting of GDUFA, FDA noted various ANDA deficiencies due to insufficient information in the referenced Type II DMFs.

In an effort to curtail these deficiencies from impacting ANDA review timelines, FDA issued the Guidance for Industry: Completeness Assessment for Type II API DMFs Under GDUFA, October 2017. The goal of the CA is to review the DMF based on the checklist provided in the guidance document, assess if the DMF is adequate to be referenced in an ANDA, and ensure that the DMF contains all necessary information to support a scientific review of the DMF along with the ANDA.

KASA Initiative: A knowledge-aided assessment and structured application (KASA) is being discussed at the FDA which will enhance the review process for the DMFs. KASA is an advanced IT system for regulatory review and management using structured submission data based on three pillars: 1) Assessment of risk to quality by establishing rules and algorithms; 2) Risk mitigation by assessing product design, understanding and quality standards; and 3) Risk mitigation by manufacturing and facility, when needed, performing pre-approval inspection.

The intent of the initiative is to modernize the regulatory assessment so as to provide a lifecycle view of quality assessments, contain built-in algorithms and decision trees, deliver a computer aided analysis, offer structured assessment, and integrate with other internal FDA databases. Full implementation of KASA will help address the challenge to manage the influx of information with better review functions, easier and automated data retrieval and faster review turnaround times. Currently, FDA resources are being invested to build this database from the DMF applications to support the structured approach in KASA. In conjunction with this effort, FDA has initiated discussions with International Council of Harmonisation (ICH) to revise the M4Q Guideline The common Technical Document for the Registration of Pharmaceuticals for Human Use: Quality, wherein industry would provide a structured submission that would directly feed into the FDA systems and help expedite the review process.

Facility Inspections and Form 3938: A new electronic form (Form 3938) is being developed for DMFs which is expected to contain similar content to Form 356h submitted with ANDAs. Form 3938 will standardize the review of facility information, creating a way for this information to be easily extracted into FDA’s inspection database, facilitating risk-based inspections of sites worldwide. This will improve transparency to the facilities that require inspection prior to ANDA approval.

A 2-day workshop was recently held by FDA -CDER-Small Business & Industry Assistance (SBIA) to engage the industry and provide guidance on the DMF submission process. This workshop was preceded with virtual poster presentations, where attendees had an opportunity to ask questions which were addressed at the workshop. This workshop was pursued by a follow-up webinar to respond to any further questions from industry coming out of the workshop. Such a multi-tier engagement demonstrates FDAs commitment to work with the industry and communicate the current thinking by the Agency.

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