Reference Listed Drugs (RLD): What they are and why RLD sourcing matters in generic drug development

When developing a generic drug, one of the critical steps is identifying and sourcing the right Reference Listed Drug (RLD). But what exactly is an RLD, and why does RLD sourcing matter so much for generic drug development?

Let’s understand it through this blog.

What is a Reference Listed Drug (RLD)?

A Reference Listed Drug (RLD) is an FDA-approved drug product that serves as the benchmark for generic drug manufacturers filing an Abbreviated New Drug Application (ANDA).
You can think of it as the “gold standard” that your generic product needs to match.

When you’re preparing an ANDA, the RLD is the drug product you must demonstrate your generic is the same in several key ways, like:

• Active ingredients
• Dosage form
• Route of administration
• Strength
• Labeling (with certain permitted differences)
• Conditions of use

RLD vs. Reference Standard: What’s the Difference?

While these terms are often confused, they serve different purposes:

RLD: The approved drug product your generic is intended to duplicate. This is what you compare against for sameness requirements, labeling, and formulation.

Reference Standard: The specific drug product FDA selects that you must use for in vivo bioequivalence testing. Usually this is the RLD, but not always.

Finding Your RLD: The Orange Book

Use the electronic Orange Book. FDA now identifies RLDs explicitly in the electronic Orange Book’s ‘RLD’ column. Older printed notations (for example, legacy ‘+’ markings) caused confusion historically, so rely on the online Orange Book for the current RLD designations.

Important note: RLDs are typically drug products approved under section 505(c) of the FD&C Act—meaning they were approved based on safety and effectiveness findings.

The Challenge of RLD Sourcing

Here’s where RLD sourcing becomes critical: You need physical samples of the RLD or reference standard to conduct your bioequivalence studies. But what happens when:

• The RLD has been discontinued from marketing
• The RLD is in short supply
• You can’t obtain sufficient quantities for testing

When the RLD Is No Longer Available

If the RLD is listed in the Orange Book’s Discontinued Section, ANDA applicants should ask the FDA to determine whether the withdrawal was for safety or effectiveness reasons. This can be done through the mechanisms described in FDA guidance (for example, citizen petitions or controlled correspondence, where appropriate); consult the guidance to choose the appropriate pathway.

However, the FDA may also weigh additional practical considerations, such as:

• Whether the current reference standard is available only in limited quantities, making it difficult for ANDA applicants to source enough product for the required in vivo bioequivalence studies.
• Whether the potential new reference standard is approved across all RLD strengths, thereby streamlining development.
• Whether it is approved for the specific strength recommended in the FDA’s product-specific guidance for in vivo bioequivalence testing.

These considerations help prevent development bottlenecks. Especially during product shortages, to ensure that generic manufacturers have a viable, consistent reference point even when the original RLD is no longer accessible.

Key Steps for Successful RLD Sourcing

1. Identify the Correct RLD

Check the Orange Book to confirm which product the FDA has designated as the RLD for your intended generic drug.

2. Verify the Reference Standard

Confirm which product the FDA has selected as the reference standard for in vivo bioequivalence testing—this may be different from the RLD.

3. Assess Availability

Determine if the reference standard is currently marketed and available in sufficient quantities for your studies.

4. Contact FDA if Needed

If you have questions about which RLD to reference, or if you need FDA to select a new reference standard due to limited availability, submit controlled correspondence to FDA.

What to Include in Your ANDA?

When filing your ANDA, your basis of submission should include:

• Name of the RLD (including dosage form and strength)
• RLD application number
• For petitioned ANDAs: FDA-assigned docket number and approval letter for the suitability petition

Identify the RLD and any different reference standard clearly in the ANDA—following FDA’s ‘Basis of Submission’ recommendations and your eCTD Table of Contents. (See FDA guidance ‘Referencing Approved Drug Products in ANDA Submissions’ for details).

Common Mistakes to Avoid

• Confusing the reference standard with the RLD: Remember, your formulation and labeling comparisons are always to the RLD, even if you use a different product for bioequivalence testing.
• Attempting to change the RLD after submission: Pick the RLD carefully before submission. Changing the designated RLD after ANDA submission is problematic and generally requires close coordination with the FDA — in some cases, amendments or even withdrawal/resubmission may be necessary. If you anticipate uncertainty, use controlled correspondence before filing.
• Not checking for discontinued RLDs: If your RLD is in the Discontinued Section of the Orange Book, you must submit a citizen petition requesting that the FDA determine whether it was withdrawn for safety or effectiveness reasons.

Successful RLD sourcing requires careful planning and attention to FDA requirements. Understanding the distinction between RLDs and reference standards, knowing where to find this information in the Orange Book, and ensuring you can obtain adequate supplies for testing are all critical to a smooth ANDA submission process.

Partner with Spring Bio Solution for Seamless RLD Sourcing

At Spring Bio Solution, we understand that reliable RLD sourcing can make or break your bioequivalence studies. With a 99.9% success rate and expertise in managing 1,000+ global clinical trials, we’ve built a reputation as the trusted partner for strategic comparator sourcing and clinical trial supply chain management.

Our team combines deep market intelligence with over a decade of regulatory expertise to help you navigate the complexities of RLD sourcing—whether you’re dealing with discontinued products, limited availability, or urgent timelines.

Are you ready to streamline your RLD sourcing and ANDA submission process?

Connect with Spring Bio Solution today and discover how our experience, precision, and commitment to transparency can accelerate your path to market.

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