Biological Products Explained – FDA.gov
What is a biological product?
Biological products are regulated by the Food and Drug Administration (FDA) and are used to diagnose, prevent, treat, and cure diseases and medical conditions. Biological products are a diverse category of products and are generally large, complex molecules. These products may be produced through biotechnology in a living system, such as a microorganism, plant cell, or animal cell, and are often more difficult to characterize than small molecule drugs. There are many types of biological products approved for use in the United States, including therapeutic proteins (such as filgrastim), monoclonal antibodies (such as adalimumab), and vaccines (such as those for influenza and tetanus).
The nature of biological products, including the inherent variations that can result from the manufacturing process, can present challenges in characterizing and manufacturing these products that often do not exist in the development of small molecule drugs. Slight differences between manufactured lots of the same biological product (i.e., acceptable within-product variations) are normal and expected within the manufacturing process. As part of its review, FDA assesses the manufacturing process and the manufacturer’s strategy to control within-product variations. These control strategies are put in place to help ensure that manufacturers produce biological products with consistent clinical performance.
What is a reference product?
A reference product is the single biological product, already approved by FDA, against which a proposed biosimilar product is compared. A reference product is approved based on, among other things, a full complement of safety and effectiveness data. A proposed biosimilar product is compared to and evaluated against a reference product to ensure that the product is highly similar and has no clinically meaningful differences.
What is a biosimilar product?
A biosimilar is a biological product that is highly similar to and has no clinically meaningful differences from an existing FDA-approved reference product. These two standards are described further below.
What does it mean to be “highly similar”?
A manufacturer developing a proposed biosimilar demonstrates that its product is highly similar to the reference product by extensively analyzing (i.e., characterizing) the structure and function of both the reference product and the proposed biosimilar. State-of-the-art technology is used to compare characteristics of the products, such as purity, chemical identity, and bioactivity. The manufacturer uses results from these comparative tests, along with other information, to demonstrate that the biosimilar is highly similar to the reference product.
Minor differences between the reference product and the proposed biosimilar product in clinically inactive components are acceptable. For example, these could include minor differences in the stabilizer or buffer compared to what is used in the reference product.
Any differences between the proposed biosimilar product and the reference product are carefully evaluated by FDA to ensure the biosimilar meets FDA’s high approval standards.
As mentioned above, slight differences (i.e., acceptable within-product variations) are expected during the manufacturing process for biological products, regardless of whether the product is a biosimilar or a reference product. For both reference products and biosimilars, lot-to-lot differences (i.e., acceptable within-product differences) are carefully controlled and monitored.
What does it mean to have “no clinically meaningful differences”?
A manufacturer must also demonstrate that its proposed biosimilar product has no clinically meaningful differences from the reference product in terms of safety, purity, and potency (safety and effectiveness). This is generally demonstrated through human pharmacokinetic (exposure) and pharmacodynamic (response) studies, an assessment of clinical immunogenicity, and, if needed, additional clinical studies.
What is an interchangeable product?
An interchangeable product is a biosimilar product that meets additional requirements outlined by the Biologics Price Competition and Innovation Act. As part of fulfilling these additional requirements, information is needed to show that an interchangeable product is expected to produce the same clinical result as the reference product in any given patient. Also, for products administered to a patient more than once, the risk in terms of safety and reduced efficacy of switching back and forth between an interchangeable product and a reference product will have been evaluated.
An interchangeable product may be substituted for the reference product without the involvement of the prescriber. FDA’s high standards for approval should assure health care providers that they can be confident in the safety and effectiveness of an interchangeable product, just as they would be for an FDA-approved reference product.
What is the difference between a biosimilar and an interchangeable product?
As mentioned above, an interchangeable product, in addition to being biosimilar, meets additional requirements based on further evaluation and testing of the product. A manufacturer of a proposed interchangeable product will need to provide additional information to show that an interchangeable product is expected to produce the same clinical result as the reference product in any given patient. Also, for a product that is administered to a patient more than once, a manufacturer will need to provide data and information to evaluate the risk, in terms of safety and decreased efficacy, of alternating or switching between the products.
As a result, a product approved as an interchangeable product means that FDA has concluded it may be substituted for the reference product without consulting the prescriber. For example, say a patient self-administers a biological product by injection to treat their rheumatoid arthritis. To receive the biosimilar instead of the reference product, the patient may need a prescription from a health care prescriber written specifically for that biosimilar. However, once a product is approved by FDA as interchangeable, the patient may be able to take a prescription for the reference product to the pharmacy and, depending on the state, the pharmacist could substitute the interchangeable product for the reference product without consulting the prescriber. Note that pharmacy laws and practices vary from state to state.
FDA undertakes a rigorous and thorough evaluation to ensure that all products, including biosimilar and interchangeable products, meet the Agency’s high standards for approval.
Are biosimilars the same as generic drugs?
Biosimilars and generic drugs are versions of brand name drugs and may offer more affordable treatment options to patients. Biosimilars and generics are each approved through different abbreviated pathways that avoid duplicating costly clinical trials. But biosimilars are not generics, and there are important differences between biosimilars and generic drugs.
For example, the active ingredients of generic drugs are the same as those of brand name drugs. In addition, the manufacturer of a generic drug must demonstrate that the generic is bioequivalent to the brand name drug.
By contrast, biosimilar manufacturers must demonstrate that the biosimilar is highly similar to the reference product, except for minor differences in clinically inactive components. Biosimilar manufacturers must also demonstrate that there are no clinically meaningful differences between the biosimilar and the reference product in terms of safety and effectiveness.
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