Submission & ApprovalLast reviewed April 2026

Reference Listed Drug(RLD)

An FDA-approved drug product identified in the Orange Book that a generic drug sponsor relies on for an Abbreviated New Drug Application.

Usage Examples

The ANDA identified the RLD as Product X 10mg tablet, matching the listed dosage form and strength.
After the RLD was withdrawn, FDA designated a Reference Standard for ongoing testing.
A Suitability Petition requested FDA permit a different dosage form than the RLD.

What is RLD?

A Reference Listed Drug (RLD) is the FDA-approved innovator drug product designated by FDA as the basis for bioequivalence and therapeutic equivalence determinations for generic applications (ANDAs) under section 505(j) of the FDCA. The RLD establishes the comparator for all ANDA content — the generic must match the RLD on active ingredient, dosage form, strength, route of administration, labeling, and bioequivalence.

FDA designates an RLD in the Orange Book for each drug product category. If the RLD is withdrawn from the market, FDA may designate a Reference Standard — a different listed drug the ANDA sponsor uses for testing purposes — while the RLD remains the legal basis for the application.

Identifying the correct RLD is one of the highest-leverage decisions in an ANDA program. RLD selection drives the bioequivalence study design, the labeling requirements, and the patent and exclusivity landscape the ANDA will face. Sponsors can request an RLD determination from FDA for products where the Orange Book status is ambiguous.

Regulatory Context

This term appears most often in submission & approval workflows where submission quality, regulatory evidence, and audit readiness depend on consistent language. It is commonly referenced alongside FDCA SECTION 505J, 21 CFR 314.

FDAICHEMA

When This Matters

The ANDA identified the RLD as Product X 10mg tablet, matching the listed dosage form and strength.
After the RLD was withdrawn, FDA designated a Reference Standard for ongoing testing.
A Suitability Petition requested FDA permit a different dosage form than the RLD.

Common Mistakes

Treating submission readiness as a formatting-only check without lifecycle validation.
Using outdated guidance references across modules and summaries.
Missing cross-functional review between RA, CMC, and quality before submission.

Related Regulations

FDCA SECTION 505J21 CFR 314

Frequently Asked Questions

FDA may designate a Reference Standard for bioequivalence testing purposes when the RLD is no longer marketed. The RLD remains the legal basis for the ANDA filing even when withdrawn, unless the withdrawal was for safety or effectiveness reasons (in which case the ANDA may not be approved).

Generally no — an ANDA must match the RLD exactly on dosage form, strength, route of administration, and active ingredient. Sponsors seeking to vary these can file a Suitability Petition requesting FDA permit the variation, or use the 505(b)(2) pathway.

FDA designates the RLD in the Orange Book, typically the originator NDA product. Where multiple versions of the drug exist (different manufacturers, labelings, or dosage forms), FDA selects one listed drug as the RLD for each category. The Orange Book preface explains the designation process.