Guidance Breakdown: FDA Revises Its 2018 Guidance on Submitting Amendments to ANDAs
A newly revised guidance updates a previous version and includes some major changes. We break it down.
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The FDA announced revised final guidance, “ANDA Submissions – Amendments to Abbreviated New Drug Applications under GDUFA.”
This guidance describes how the assessment goals under the most recent reauthorization of GDUFA III apply to amendments to either ANDAs or prior approval supplements (PASs) submitted to the FDA. This guidance also details amendment classifications and explains how amendment submissions may affect an application’s assessment goal dates.
The FDA considers each submission to an application under assessment to be an amendment. These submissions will be classified based on the content submitted and issued a goal date consistent with that classification, in addition to other considerations in the GDUFA III Commitment Letter. The types of amendments and assessment goals described in this guidance only apply to submissions that have been received for substantive assessment.
Who should pay attention to this guidance: Generic drug manufacturers, contract service providers, regulatory affairs departments, and facilities involved in manufacturing and testing are the primary entities impacted by this guidance.
Key changes from the 2018 guidance
Framework and Legal updates: The 2024 revision reflects updates from GDUFA III, which became effective in October 2022, while the 2018 version was based on GDUFA II. The reauthorization of GDUFA in 2022 led to modifications in performance goals and procedures, designed to streamline ANDA assessments and reduce the number of assessment cycles.
Expanded Scope on Amendments: The 2024 version elaborates more extensively on different categories of amendments (major, minor, unsolicited) and their associated timelines under the new performance goals in GDUFA III. While the 2018 guidance already categorized amendments, the 2024 revision integrates newer goals and procedures.
Timelines for Reviews and Assessments: Both documents outline timelines for acting on amendments, but the 2024 revision introduces more specific conditions tied to standard vs. priority assessments. For example, the time frame for priority assessments is refined with clearer rules about pre-approval inspections and how those affect the review timelines.
Emphasis on Pre-Submission Facility Correspondence (PFC): The 2024 version places greater importance on the role of Pre-Submission Facility Correspondence (PFC). It introduces additional rules about how the PFC submission timing can impact the amendment's review process, especially if facilities are added or changed during the review.
Greater Detail on Performance Goals: The 2024 guidance introduces a more detailed breakdown of performance goals for reviewing major and minor amendments, unsolicited amendments, and amendments related to tentatively approved ANDAs.
Updated Categories for Major and Minor Amendments: The 2024 version expands on the types of deficiencies and situations that would result in a major or minor amendment. For instance, major amendments now include more specific criteria for issues such as new facility requirements, bioequivalence studies, and new manufacturing processes.
Clarified Processes for Amendments to Tentatively Approved ANDAs: The 2024 guidance introduces a clearer pathway for handling amendments to ANDAs that have received tentative approval. It details how changes in manufacturing or facility compliance status can influence review timelines.
Introduction and background
The newly revised guidance document provides instructions on how applicants should submit amendments to their ANDAs or PASs under the provisions of GDUFA III, which was reauthorized in 2022.
This guidance supersedes the previous 2018 version, updating the amendment classifications, review timelines, and performance goals while reflecting changes brought by GDUFA III. It also provides guidance on how amendments are classified and the timelines that applicants can expect for their review.
Key Updates in GDUFA III:
Performance Goals: The guidance aligns with the GDUFA III commitment letter, which outlines the timelines and goals for reviewing amendments to ANDAs and PASs.
Classification System: Amendments continue to be classified as either major or minor, with the FDA providing specific timelines based on whether a preapproval inspection is necessary. The addition of Pre-Submission Facility Correspondence (PFC) as a key factor in determining timelines is also emphasized.
The GDUFA program, initially passed in 2012, was designed to help the FDA meet goals for reviewing generic drug applications by imposing user fees on applicants. It must be reauthorized every five years, and GDUFA III came into effect on October 1, 2022.
GDUFA III introduces enhancements to the program, including performance goals that are meant to improve the efficiency of the review process. The goal is to reduce the number of review cycles needed for ANDAs, allowing for quicker approvals while maintaining high standards of safety and quality. This guidance document focuses on amendments submitted to the FDA after the initial submission of an ANDA or PAS.
Types of amendments
Amendments submitted to the FDA are classified into three categories:
Major Amendments
Minor Amendments
Unsolicited Amendments
1. Major Amendments
Major amendments typically require extensive review by the FDA due to the complexity or significance of the proposed changes. A major amendment can substantially affect the assessment timeline, especially if a preapproval inspection is required.
Examples of major amendments include:
Manufacturing a new batch of the drug product for any reason, including changes in composition, source of the API, manufacturing site, bioequivalence (BE) study, or major manufacturing processes.
Performing a new BE study.
Developing new analytical procedures and providing full validation data.
Revisions to critical quality attributes (CQAs) or methods for controlling them.
Performance goals for major amendments
Standard Assessment (No Preapproval Inspection Required): 90% of major amendments will be reviewed within 8 months.
Standard Assessment (Preapproval Inspection Required): 90% of major amendments will be reviewed within 10 months.
Priority Assessment (No Preapproval Inspection Required): 90% of priority major amendments will be reviewed within 6 months.
Priority Assessment (Preapproval Inspection Required and Complete PFC Submitted): 90% of priority major amendments will be reviewed within 8 months.
Priority Assessment (Preapproval Inspection Required and PFC Issues or Late Submission): 90% of priority major amendments will be reviewed within 10 months.
2. Minor Amendments
Minor amendments involve changes that are easier to assess and typically require less extensive review than major amendments. These are often related to minor issues that can be resolved through an Information Request (IR) or a Discipline Review Letter (DRL).
Examples of minor amendments include:
Minor deficiencies in the drug substance or drug product.
Incomplete dissolution data.
Labeling deficiencies that are relatively straightforward to address.
Incomplete documentation that does not involve major changes to the product.
Performance goals for minor amendments
The FDA will review and act on 90% of minor amendments within 3 months, whether the amendment is part of a standard or priority assessment.
3. Unsolicited Amendments
Unsolicited amendments are those that are submitted without the FDA requesting additional information. These can either be major or minor, depending on the content of the submission. For instance, if an unsolicited amendment addresses significant deficiencies, it may be classified as a major amendment.
Performance goals for unsolicited amendments
The FDA generally aims to act on unsolicited amendments by either the original goal date or by the timeline applicable to standard or priority amendments, whichever is later.
Assessment goals
The FDA uses goal dates to ensure that submissions are assessed within a reasonable period. These goals depend on several factors, including whether the amendment is classified as major or minor, whether the ANDA or PAS is subject to a standard or priority assessment, and whether a preapproval inspection is necessary.
Amendments to original ANDAs
Major Amendments (Standard): If no preapproval inspection is required, the FDA will act within 8 months. If a preapproval inspection is needed, the timeline extends to 10 months.
Priority Major Amendments: For priority amendments with no preapproval inspection, the FDA will act within 6 months. If a preapproval inspection is required and a PFC is timely submitted, the timeline is 8 months. Otherwise, it can extend to 10 months.
Minor Amendments (Standard or Priority): The FDA will act on 90% of standard or priority minor amendments within 3 months.
Amendments to PASs
The FDA applies similar timelines for amendments to PASs as it does for ANDAs. However, PASs may also include performance goals based on whether they are standard or priority and whether a preapproval inspection is required.
Changes to classifications or assessment goals
The FDA reserves the right to change the classification of an amendment or modify its assessment goals based on the content of the submission. For instance, if new information is introduced that requires a preapproval inspection, a minor amendment could be reclassified as a major amendment.
In some cases, the FDA may defer assessment of an unsolicited amendment if the discipline assessments are close to completion or if the amendment introduces significant new information. The goal date will be adjusted accordingly based on the nature of the amendment.