The core framework — pharmaceutical equivalence + bioequivalence + same clinical effect/safety profile, the A/B TE coding system, and RLD concepts — is unchanged. The changes below are the ones industry should track.
1. New Pathway for Requesting TE Evaluation of 505(b)(2) Products
The most significant substantive addition. The final guidance adds that a 505(b)(2) application holder may use the process in section 505(j)(7)(A)(v)(I) of the FD&C Act to request a TE evaluation where the sole difference from the relied-upon listed drug is a difference in inactive ingredients not permitted under 21 CFR 314.94(a)(9)(iii)–(iv). This is in addition to the existing citizen-petition route (21 CFR 10.25(a)/10.30).
Appears in: Section II.B.1 and FAQ 5.
2. Broader Grounds for FDA to Downgrade a TE Code
Section II.D (Revisions) now states FDA may change a TE code (e.g., AB → BX) not only due to facility/manufacturing issues, but also where FDA becomes aware of documented bioequivalence problems or significant potential for such problems, or where an approved application is under regulatory review. The 2022 draft only gave the facility-inspection example.
3. Expanded List of Scenarios Where a Product Won't Have a TE Code
- FAQ 2 (ANDAs): New bullet — if the ANDA itself is placed in the Discontinued Drug Product List (at approval or later), its TE code is removed.
- FAQ 3 (NDAs): Expanded to cover situations where the 505(b)(2) holder *withdrew* a TE request, or FDA *completed an evaluation and found the product not therapeutically equivalent* (the draft only addressed "has not made a request"). A new bullet also covers NDAs moved to the Discontinued Drug Product List.
4. New Footnote on Differences That Don't Defeat Therapeutic Equivalence
A new footnote clarifies that products can remain therapeutically equivalent despite differing in shape, scoring, release mechanism, packaging, excipients (colors/flavors/preservatives), expiration date, certain labeling aspects, and storage conditions — and notes a prescriber may still require a specific product as a "medical necessity" when such differences matter clinically. Not present in the 2022 draft.
5. Labeling-Equivalence Exception Narrowed with Specific Citation
The final guidance ties permissible labeling differences to 21 CFR 314.94(a)(8)(iv), rather than the more general statement in the draft that differing labeling "may not be considered therapeutically equivalent."
6. Inactive-Ingredients FAQ (FAQ 11) Strengthened
The final version states more directly that an ANDA product, "including any permissible differences in inactive ingredients," is considered therapeutically equivalent to its RLD — a firmer statement than the draft's "generally do not affect."
7. Updated/Superseded Guidance References
Several cited guidances have new statuses/dates:
- Bioequivalence Studies With Pharmacokinetic Endpoints — was draft (Aug 2021) in 2022; now final (May 2026).
- Determining Whether to Submit an ANDA or 505(b)(2) Application — was final (May 2019) in 2022; now listed as a new draft (August 2026).
- Applications Covered by Section 505(b)(2) draft date corrected from October 1999 to December 1999.
- A new citation to Referencing Approved Drug Products in ANDA Submissions (October 2020) is added to support the RLD/ANDA discussion.
- Orange Book Preface references updated from the 42nd edition (2022) to the 46th edition (2026).
8. Additional Regulatory Citation
Footnote support for FDA's facility/manufacturing adequacy determination now also cites 21 CFR 314.125(b), in addition to 314.127(a).
9. Administrative / Status Changes
- Document status changed from draft ("not for implementation") to final guidance — it now reflects FDA's current thinking and may be relied upon accordingly.
- Named CDER contact (Susan Levine) removed; only general Division of Drug Information contact info remains.
- Cover/branding changed from "Generics" to "Generic Drugs."
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