Reference Listed Drugs – The Backbone of Formulations

Reference-listed Drugs (RLDS) are the foundation of generic drug development. These are the first drugs the U.S. Food and Drug Administration (FDA) approved for a given formulation, dosage, and therapeutic use. The FDA, a regulatory body responsible for ensuring the safety and efficacy of pharmaceutical products, plays a pivotal role in the approval and regulation of RLDS. 

Once approved, the RLDS are the official reference for evaluating future generic versions.

When a company develops a generic drug, it submits an Abbreviated New Drug Application (ANDA) to the U.S. Food and Drug Administration (FDA). Instead of repeating animal or human trials, the application demonstrates that this new drug is equivalent to the Reference-Listed Drug (RLD) in terms of quality, strength, and performance. 

By relying on existing data, developers avoid unnecessary testing, reduce costs, and accelerate access to treatment, providing practical benefits for the industry and patients.

 

Where did the Reference-listed Drugs system begin?

The Hatch-Waxman Act, passed in 1984, established the legal basis for using RLDS. Officially known as the Drug Price Competition and Patent Term Restoration Act, this law created a framework to support the approval of generic drugs in the United States.

It was designed to make medicines more affordable while protecting the efforts of companies that had invested in original research. The law allowed generic manufacturers to reference approved drugs while giving originators time-based incentives to continue developing new treatments. That balance still shapes global pharmaceutical regulation today.

 

Requirements for approval

To receive approval, a generic product must be demonstrated to be equivalent to the Reference Listed Drug (RLD) in several key areas: the active ingredient, dosage form, strength, route of administration, labelling, and usage conditions. Equivalence means that the generic version provides the same therapeutic outcome as the Reference-Listed Drug (RLD) based on already reviewed and accepted data.

 

Why Reference-listed Drugs Matter

The presence of a Reference-Listed Drug reduces duplication and brings predictability to the development process, reassuring all stakeholders about the systematic nature of drug development. Instead of starting from scratch, companies build on approved data to create safe and effective alternatives that benefit manufacturers, regulators, and patients alike.

Generics are expected to deliver the same clinical effect as their reference product. That outcome depends on the integrity of the RLD, which sets the standard for performance and compliance.

 

Development advantages

Using an RLD lowers the cost of entry for generic alternatives. It helps shorten development timelines and supports more efficient regulatory reviews. Developers can focus on demonstrating equivalence rather than conducting full-scale trials, accelerating the availability of essential medications.

 

Temperature control and heavyweight shipments

Reference-listed drugs come with approved handling conditions. The data defines their temperature ranges, and teams always protect them, whether shipping one box or a whole pallet.

The stakes are higher when these products are shipped in heavyweight or bulk formats. There is more volume to protect, more time in transit, and more pressure on every link in the chain. The risk is not just about temperature. 

It’s about consistency, timing, and control throughout the entire process.

This kind of shipment requires planning that reflects the product’s profile. Teams validate routes, match packaging to volume and duration, and actively track each shipment with readiness to respond when conditions change.

CRYOPDP operates in this space. We manage heavyweight pharmaceutical shipments that require precise temperature control and regulatory compliance. Every decision is built around the product’s needs and the standards it must meet. Medicines that serve as the reference point have no room for error. Our job is to make sure they arrive exactly as intended.