To develop a high-quality generic drug, it is important to choose the right Reference Listed Drugs (RLD). For every pharmaceutical company applying for an ANDA or working on comparative studies, identifying and right RLD sourcing is one of the most important steps in the product development journey.

But what exactly is an RLD/comparator drug, and why does effective Reference Listed Drug sourcing matter so much?
Let’s explore this in simple terms.

What Is a Reference Listed Drugs (RLD)?

A reference listed drug is an FDA-approved brand-name medicinal product that serves as the benchmark to manufacture a new generic medicine. It is the comparison standard for demonstrating pharmaceutical equivalence and therapeutic equivalence.

While developing a new generic, manufacturers must match their medicinal product to the RLD in several key elements:

• Active ingredient
• Dosage form
• Route of administration
• Strength
• Conditions of use
• Labeling (with allowed differences)
  

Consider the RLD as the gold standard. The generic formulation must align with the Reference Listed Drug.

RLD vs. Reference Standard (RS): Major Difference

Both terms are often confused, but RLD and RS perform different functions:

• Reference Listed Drug (RLD): The FDA-approved medicinal product your generic must match in formulation, labeling, and therapeutic claims.
• Reference Standard (RS): A product selected by the FDA for your in vivo bioequivalence study. The RS is generally the RLD, but not always.

This difference is important to avoid regulatory delays, particularly when applying for ANDA submissions.

To Find the Right RLD: Check FDA Orange Book

Check the Orange Book, where the FDA identifies RLDs in the “RLD” column. Older printed versions with “+” symbols are outdated and can cause mistakes. Most RLDs originate from products approved under section 505(c) of the FD&C Act, meaning the FDA assesses them for safety and efficacy.

Why RLD Sourcing Can Be Challenging:

RLD sourcing becomes complicated when:

• The medicinal product is discontinued
• The RLD is in short supply
• Quantities available are too low for bioequivalence (BE) studies
• The Reference Standard (RS) differs from the RLD
  

When an RLD`s approval is discontinued, applicants must ask the FDA whether withdrawal was for efficacy or safety reasons. It can be requested through controlled correspondence or a citizen petition, depending on the circumstances.

Additionally, the FDA may consider:

• Whether the Reference Standard (RS) is accessible in usable quantities
• Whether the RS supports the specific strength required in product-specific guidance
• Whether all dosage strengths are accessible across the RLD family
  

This avoids product development bottlenecks and supports continuous development of generic medicines.

Four Important Points for Right RLD Sourcing:

• Identify the Right RLD: Verify the correct RLD through which new generic medicinal product will be compared.
• Evaluate the Market Availability: Specify whether you can access appropriate quantities through European RLD suppliers or international procurement channels.
• Confirm the Reference Standard: Checkout if the FDA needs a different medicinal product for bioequivalence (BE) study.
• Communicate with FDA When Needed: If the RLD`s approval is no longer exist or insufficient, get clarification via controlled correspondence.

What Should Be Included in Your ANDA?

Your ANDA must have:

• Name, dosage form, and strength of RLD
• Application number of RLD
• Suitability petition approval (if applicable)
• Identification of the RS in case different from the RLD

For detailed formatting rules, please refer to FDA Guidance

Common Mistakes to Avoid:

• Confusing the RLD with the RS
• Trying to switch RLDs following ANDA submission
• Not checking the Discontinued Part of the Orange Book
• Failing to verify the availability of multi-strength
  

Selection of the right RLD saves time, cost, and helps prevent unnecessary regulatory complications.

Partner with Ikris Pharma Bulgaria for Simplified RLD Sourcing:

Ikris Pharma Bulgaria specializes in bulk RLD supply, European RLD procurement, and end-to-end RLD supply chain management for pharmaceutical companies across the US, EU, Australia, Africa, Japan, and other emerging markets.

As a leading reference listed drug supplier in Bulgaria, we are known for providing:

• Global access to difficult-to-obtain RLDs/comparator drugs
• Comparator drug sourcing for clinical/BE studies
• Market intelligence on availability of specific product 
• 100% traceable and compliant supply routes
• Temperature-controlled/cold-chain logistics
  

We have a lot of experience in simplifying complex challenges during sourcing. We ensure the availability of RLDs and RS materials remain uninterrupted for your drug development projects.