These frequently asked questions have been developed for the CDER Small Business and Industry Assistance Web site to help small pharmaceutical businesses understand the regulatory process for therapeutic biological products.
- What is a biological product?
Biological products, like other drugs, are used for the treatment, prevention or cure of disease in humans. In contrast to chemically synthesized small molecular weight drugs, which have a well-defined structure and can be thoroughly characterized, biological products are generally derived from living material--human, animal, or microorganism-- are complex in structure, and thus are usually not fully characterized.
Section 351 of the Public Health Service (PHS) Act defines a biological product as a “virus, therapeutic serum, toxin, antitoxin, vaccine, blood, blood component or derivative, allergenic product, or analogous product, … applicable to the prevention, treatment, or cure of a disease or condition of human beings.” FDA regulations and policies have established that biological products include blood-derived products, vaccines, in vivo diagnostic allergenic products, immunoglobulin products, products containing cells or microorganisms, and most protein products. Biological products subject to the PHS Act also meet the definition of drugs under the Federal Food, Drug and Cosmetic Act (FDC Act). Note that hormones such as insulin, glucagon, and human growth hormone are regulated as drugs under the FDC Act, not biological products under the PHS Act.
- What Center has the regulatory responsibility for therapeutic biological products?
Both the FDA’s Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER) have regulatory responsibility for therapeutic biological products, including premarket review and oversight. The categories of therapeutic biological products regulated by CDER (under the FDC Act and/or the PHS Act, as appropriate) are the following
- Monoclonal antibodies for in vivo use.
- Most proteins intended for therapeutic use, including cytokines (e.g., interferons), enzymes (e.g. thrombolytics), and other novel proteins, except for those that are specifically assigned to the Center for Biologics Evaluation and Research (CBER) (e.g., vaccines and blood products). This category includes therapeutic proteins derived from plants, animals, humans, or microorganisms, and recombinant versions of these products. Exceptions to this rule are coagulation factors (both recombinant and human-plasma derived).
- Immunomodulators (non-vaccine and non-allergenic products intended to treat disease by inhibiting or down-regulating a pre-existing, pathological immune response).
- Growth factors, cytokines, and monoclonal antibodies intended to mobilize, stimulate, decrease or otherwise alter the production of hematopoietic cells in vivo.
Please refer to the Transfer of Therapeutic Biological Products to the Center for Drug Evaluation and Research for updates that further define the categories of biological products that are regulated by CDER and CBER.
- Are the biologic development requirements different than the requirements for a new drug product?
Biological products are a subset of drugs; therefore both are regulated under provisions of the FDC Act. However, only biological products are licensed under section 351 of the PHS Act. (As previously noted, some therapeutic protein products are approved under section 505 of the FDC Act, not under the PHS Act.)
Following initial laboratory and animal testing that show that investigational use in humans is reasonably safe, biological products (like other drugs), can be studied in clinical trials in humans under an investigational new drug application (IND) in accordance with the regulations at 21 CFR 312. If the data generated by the studies demonstrate that the product is safe and effective for its intended use, the data are submitted as part of a marketing application. Whereas a new drug application (NDA) is used for drugs subject to the drug approval provisions of the FDC Act, a biologics license application (BLA) is required for biological products subject to licensure under the PHS Act. FDA form 356h is used for both NDA and BLA submissions. FDA approval to market a biologic is granted by issuance of a biologics license.
- What are the requirements for licensing a biologic?
Issuance of a biologics license is a determination that the product, the manufacturing process, and the manufacturing facilities meet applicable requirements to ensure the continued safety, purity and potency of the product.
Among other things, safety and purity assessments must consider the storage and testing of cell substrates that are often used to manufacture biologics. A potency assay is required due to the complexity and heterogeneity of biologics.
- What does safety mean?
The word safety means the relative freedom from harmful effects, direct or indirect, when a product is prudently administered, taking into consideration the character of the product in relation to the condition of the recipient at the time.
- What is purity?
Purity means relative freedom from extraneous matter in the finished product, whether or not harmful to the recipient or deleterious to the product. Purity includes but is not limited to relative freedom from residual moisture or other volatile substances and pyrogenic substances.
- What is potency?
The word potency is interpreted to mean the specific ability or capacity of the product, as indicated by appropriate laboratory tests, to yield a given result.
- Does FDA issue license certificates upon approval of a BLA?
Approval to market a biologic is granted by issuance of a biologics license (including US license number) as part of the approval letter. FDA does not issue a license certificate. The US License number must appear on the product labeling.
- Why are biologics regulated under the PHS Act?
As mentioned above, biologics are subject to provisions of both the FD&C Act and the PHS Act. Because of the complexity of manufacturing and characterizing a biologic, the PHS Act emphasizes the importance of appropriate manufacturing control for products. The PHS Act provides for a system of controls over all aspects of the manufacturing process. In some cases, manufacturing changes could result in changes to the biological molecule that might not be detected by standard chemical and molecular biology characterization techniques yet could profoundly alter the safety or efficacy profile. Therefore, changes in the manufacturing process, equipment or facilities may require additional clinical studies to demonstrate the product's continued safety, identity, purity and potency.
The PHS Act also provides authority to immediately suspend licenses in situations where there exists a danger to public health.
- 10. How is the manufacturing process for a biological product usually different from the process for drugs?
Because, in many cases, there is limited ability to identify the identity of the clinically active component(s) of a complex biological product, such products are often defined by their manufacturing processes. Changes in the manufacturing process, equipment or facilities could result in changes in the biological product itself and sometimes require additional clinical studies to demonstrate the product's safety, identity, purity and potency. Traditional drug products usually consist of pure chemical substances that are easily analyzed after manufacture. Since there is a significant difference in how biological products are made, the production is monitored by the agency from the early stages to make sure the final product turns out as expected.
- What is comparability testing of biologics?
A sponsor may be able to demonstrate product comparability between a biological product made after a manufacturing change and a product made before implementation of the change through different types of analytical and functional testing without additional clinical studies. The agency may determine that the two products are comparable if the results of the comparability testing demonstrate that the manufacturing change does not affect safety, identity, purity, or potency. For more information see FDA Guidance Concerning Demonstration of Comparability of Human Biological Products including Therapeutic Biotechnology-derived Products.
- Where can I find additional information about therapeutic biologics?
There are several guidances that may be helpful.
- "Changes to an Approved Application for Specified Biotechnology and Specified Synthetic Biological Products" (PDF - 33KB)
- "Content and Format of INDs for Phase I Studies of Drugs Including Well-Characterized, Therapeutic, Biotechnology-derived products" (PDF - 42KB)
- "Providing Clinical Effectiveness of Human Drugs and Biological Products"
- "Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use" (PDF - 140KB)
- Who should I contact if I still have questions about therapeutic biologics?
You should contact the Regulatory Project Manager (RPM) in the Office of New Drugs review division that is assigned responsibility for your application. As with all drugs regulated by CDER, applications are reviewed by a multidisciplinary review team. For biologics, the Chemistry, Manufacturing, and Controls (CMC) information is reviewed by staff in the Office of Biotechnology Products and manufacturing facility-related information is reviewed by the Therapeutics Facilities Review Branch in the Office of Compliance.