Just What Is a Biologic, Anyway?

by Food and Drug Administration (FDA)

Good question. Back in the days when the most common biologics were vaccines and blood products, the answer was usually fairly simple.

But in the past few years many more products whose uses are similar to drugs have come on the market, blurring the line between drugs and biologics. In addition, some biologics, such as blood test kits, could be confused with products that are considered devices.

To set matters straight, it's helpful to start with a simple definition: Biological products are made from living organisms.

"[They] are derived from living material — human, plant, animal, or microorganism — and they're used for the treatment, prevention or cure of disease in humans," says Michael Beatrice, associate director for policy coordination and public affairs in FDA's Center for Biologics Evaluation and Research (CBER).

The technical definition, according to the U.S. Code of Federal Regulations, written in 1902, defines a biological product as "any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment or cure of diseases or injuries of man."

(At that time, the word "virus" could refer to what are now recognized as a variety of disease-causing microorganisms, including viruses, bacteria and protozoa.)

Since this original definition, what determines whether a product is a biologic has become even more complicated.

Just because a product comes from a natural source doesn't mean it's a biologic, Beatrice says. In general, biologics come from living organisms and, in the case of a product that is similar to a toxin or antitoxin, "work through a specific immune process, but not in all cases."

One product that is considered a biologic but does not work through an immune process is blood and its products when used for transfusion. CBER regulates and licenses all blood banks that deal in interstate commerce. In this case, blood used for transfusion is considered a therapeutic serum, which qualifies it as a biologic.

And test kits, such as those used to test for the hepatitis and AIDS viruses, are also considered biologics because they are used to verify that human blood is free of those viruses and safe for human use.

"They [the kits] are in vitro diagnostic biological products, but they fit the classic definition of a medical device," Beatrice says. "However, they are considered biologics because they are used to test and release a licensed biological product."

But similar kits used to test samples of blood for other purposes — for example, to diagnose a disease, such as rubella, or monitor its progress — fall under different regulation because their use to diagnose human disease makes them devices.

"Regardless of the source of a product," Beatrice says, "the intended use may dictate its regulation. You have to look at two things, the source and the intended use, to determine if a product is a drug, a biologic, or a device."

Production Challenges

Since biological products are derived from living organisms and are sometimes made in living organisms, their manufacture presents difficulties not encountered in drug manufacturing.

Traditional drug products usually consist of pure chemical substances that are easily analyzed after manufacture to determine safety, purity, potency, and effectiveness. Biologics, however, consist of delicate substances or cells that are sensitive to heat, to light, and to being shaken when in liquid form, and are easily susceptible to contamination.

"With a chemical, you don't need to worry about that [contamination]. Many chemicals can be produced by very hardy synthetic techniques that use a lot of heat and shaking," Beatrice says.

Because of this significant difference in how drugs and biologics are made, CBER monitors production of biologics from the early stages to make sure they turn out as expected.

"We look at everything," Beatrice says, "including, for example, the bacterial strain, the cells used to produce the product and how they were engineered to produce a protein, the quality of equipment, and the air in the facility while the growth of the organism takes place ... all the way to filling, packaging and labeling.

"You can analyze a pure chemical drug substance [after it is made] with known analytical technology — you can determine what you have and its purity. For the biological products, they tend to be complex mixtures of proteins and other biological substances that are not easily characterized and identified 100 percent."

Despite the differences in how drugs and biologics are made, there is a growing number of licensed biological products with therapeutic, or drug-like, uses now on the market. Examples include: Epogen (epoetin alfa), for treating anemia associated with chronic renal failure and Retrovir-related anemia in AIDS patients; Intron A (interferon alfa-2b), for treating hairy cell leukemia, genital warts, AIDS-related Kaposi's sarcoma, non-A, non-B hepatitis, and chronic hepatitis B; and Activase (alteplase, recombinant), for treating heart attacks.

Innovation

Biological technology is an ever-changing, evolving field and, as such, offers the potential for many innovative therapies.

Some of the most promising biotech products include those using recombinant DNA (rDNA) and various cell therapy technologies. According to Beatrice, although a small number of products using these technologies have been licensed, most are still under study.

Recombinant DNA technology involves genetic engineering, in which genes from one type of cell are spliced into genetic material of another cell, which, in turn, churns out the desired biological product.

An example of a biological product made using rDNA technology is the recently licensed antihemophilic factor (recombinant) for use in persons with hemophilia A to prevent and control excessive bleeding, including bleeding during surgery.

Antihemophilic factor (recombinant) is the first rDNA- derived clotting factor licensed by FDA. It is produced by Chinese hamster ovary cells that have been modified by recombinant DNA techniques to introduce and express the gene for human factor VIII. Factor VIII is the blood- clotting protein that is deficient or missing in persons with hemophilia A.

In another "first," FDA licensed the first in vivo (in the body) diagnostic imaging agent based on monoclonal antibody technology last December. OncoScint CR/OV (satumomab pendetide) detects a protein found at high levels on the surface of most ovarian and colorectal cancers.

About the Author

www.fda.gov
FDA is A United States government body that oversees medical devices, including contact lenses, intraocular lenses, excimer lasers and eyedrops. In the US, these products must be approved by the FDA before they can be marketed.