How FDA sorts generic drug application problems into major and minor

In fiscal 2025, companies seeking approval of generic drugs sent FDA 643 amendments the agency classified as major and 736 it classified as minor, according to the monthly activity report¹ from FDA's Office of Generic Drugs. Another 708 arrived unsolicited. The label on each one set the clock. FDA's goal for a minor amendment is three months. For a major one it is six to 10.

Those amendments are where most generic approvals are actually won. FDA approved 689 abbreviated new drug applications, or ANDAs, that year, and only 137 of them on the first review cycle, the same report shows. The rest needed at least one more round after FDA told the applicant what was wrong.

How the agency sorts problems into major and minor is laid out in a September 2024 guidance, a 2022 guidance on information requests and review letters, and the user fee agreement that covers fiscal 2023 through 2027. Together they decide how long a fixable flaw delays a cheaper version of a drug.

Three kinds of letters

During a review, FDA can tell an applicant about problems in three ways. An information request, or IR, asks "for further information or clarification that is needed or would be helpful to allow completion of the discipline assessment," in the words of FDA's fiscal 2025 performance report to Congress¹⁴. A discipline review letter, or DRL, conveys "preliminary thoughts on possible deficiencies" once one review discipline, such as bioequivalence, product quality or labeling, finishes its part.

Neither stops the review clock. FDA's guidance on information requests and discipline review letters¹⁰ (Revision 1, October 2022) says both differ from a complete response letter because they "do not represent a complete assessment of the entire application." A complete response letter, or CRL, ends the review cycle and lists every deficiency the applicant must fix. GxRadar covers those letters in its piece on complete response letters for generics.

Under the GDUFA III commitment letter¹³, every discipline except labeling, which has its own timetable, must send its IRs or DRLs by the midpoint of the first review cycle. A mid-cycle DRL "will assign a due date for response and identify major and minor deficiencies." The office's internal manual on the subject, MAPP 5220.5¹¹, sets out how staff issue them. In fiscal 2025 FDA sent 3,140 IRs on original applications and 1,949 DRLs, against 1,281 CRLs.

Any response to one of these letters becomes an amendment. Federal rules at 21 CFR 314.96¹² let an applicant amend an ANDA that is submitted but not yet approved. FDA then classifies the amendment.

What makes an amendment major

FDA's guidance, ANDA Submissions: Amendments to Abbreviated New Drug Applications Under GDUFA⁹ (Revision 1, September 2024), gives three anchor examples. A response is major if it involves "manufacturing a new batch of drug product for any reason," "performing a new BE study" (the bioequivalence test that compares a generic with its brand), or "developing new analytical procedures and providing full validation data." The new-batch category covers reformulation, a new source of active ingredient, a new manufacturing site, a new strength, unacceptable impurities and failed stability data.

An appendix lists more examples of potential major deficiencies, from poorly justified starting materials to impurities that need toxicology studies to qualify. Facility problems, the kind found in FDA inspections, are a hard line. A withdrawn 2001 guidance had treated minor manufacturing-practice problems as minor, the 2024 guidance notes, but "FDA's current thinking is that, in general, any good manufacturing practice or facility deficiency is, in fact, a major deficiency."

Minor is defined mostly by exclusion. Minor amendments "are those not classified as major or are a response to a deficiency that could be adequately resolved through an IR or certain DRLs." The guidance's examples are responses to minor drug substance deficiencies, incomplete dissolution data and "labeling deficiencies that have not been adequately addressed in response to an IR."

Two cautions apply. These categories are separate from the major and minor filing deficiencies FDA uses when it decides whether to receive an application at all. And FDA can change the class after reading the response. If a minor amendment turns out to need a preapproval inspection of any facility, the guidance says, FDA "will classify the submission as a major amendment and set an assessment goal of 10 months from the submission date."

Goal dates by class

GDUFA III's commitment letter sets the clocks, each to be met for 90 percent of submissions. Priority status, which depends on factors such as drug shortages and the number of approved competitors, is explained in GxRadar's article on how FDA prioritizes generic applications.

The guidance works through dated examples. An applicant answers a CRL on Nov. 13, 2024, with an amendment that adds a facility needing inspection. FDA classes it as a standard major amendment with a 10-month goal, so the new target date is Sept. 13, 2025. A CRL response limited to minor issues, filed July 8, 2024, gets a goal of Oct. 8, 2024. GxRadar's explainer on ANDA review goal dates covers how FDA has performed against these targets.

Eight years of amendments

FDA's monthly reports have counted major and minor ANDA amendments separately since fiscal 2018. GxRadar compiled the yearly totals.

Major amendments fell 46 percent from the fiscal 2019 peak of 1,189 to 643 in fiscal 2025, and complete response letters fell by roughly half from fiscal 2018. Minor amendments outnumbered major ones in fiscal 2024 and 2025, for the first time since fiscal 2018. The fiscal 2025 jump in information requests needs a caveat. FDA's report says that year's counts "have been updated due to a new tracking process," so they are not directly comparable with earlier years.

Fewer major amendments does not by itself mean fewer cycles. FDA's performance report puts the median number of review cycles to approval at two for applications received in fiscal 2023, the most recent cohort far enough along to judge. The report warns that figures for later cohorts will rise as slower applications are approved.

Arguing about the label

An applicant that thinks FDA misclassified a major amendment can ask for reconsideration by teleconference. The 2024 guidance says FDA will decide 90 percent of those requests within 30 calendar days, provided the applicant takes the first date offered. The performance report counts six requests in fiscal 2025 for a teleconference on reclassifying a major amendment or a standard review status, and FDA granted all six.

A separate route covers CRLs that are major only because of a facility problem. In fiscal 2025, applicants filed 82 requests to reclassify a facility-based major CRL amendment, and FDA granted 56 and denied nine, according to the monthly report.

FDA's proposal for the next user fee deal keeps both categories. GDUFA III expires in September 2027, and FDA held a public meeting on Sept. 17, 2026, on the proposed terms for fiscal 2028 through 2032, according to its GDUFA IV page¹⁵. The proposed GDUFA IV commitment letter¹⁶ keeps the same 3-, 6-, 8- and 10-month amendment goals and adds a new term, the "Significant Major deficiency," defined as one "the resolution of which is required before the continued assessment by multiple disciplines, e.g., a reformulation." Under the proposal, a discipline that finds one would communicate it in a CRL "as soon as is feasible." For readers following individual drugs, final outcomes appear on GxRadar's approvals tracker.