- A biologic is manufactured in a living system such as a microorganism, or plant or animal cells. Most biologics are very large, complex molecules or mixtures of molecules. Many biologics are produced using recombinant DNA technology.
- A drug is typically manufactured through chemical synthesis, which means that it is made by combining specific chemical ingredients in an ordered process.
- Drugs generally have well-defined chemical structures, and a finished drug can usually be analyzed to determine all its various components. By contrast it is difficult, and sometimes impossible, to characterize a complex biologic by testing methods available in the laboratory, and some of the components of a finished biologic may be unknown.
- Therefore, for biologics, “the product is the process.” Because the finished product cannot be fully characterized in the laboratory, manufacturers must ensure product consistency, quality, and purity by ensuring that the manufacturing process remains substantially the same over time. By contrast, a drug manufacturer can change the manufacturing process extensively and analyze the finished product to establish that it is the same as before the manufacturing change.
- The living systems used to produce biologics can be sensitive to very minor changes in the manufacturing process. Small process differences can significantly affect the nature of the finished biologic and, most importantly, the way it functions in the body. To ensure that a manufacturing process remains the same over time, biologics manufacturers must tightly control the source and nature of starting materials, and consistently employ hundreds of process controls that assure predictable manufacturing outcomes.
- Process controls for biologics are established separately for each unique manufacturing process/product, and are not applicable to a manufacturing process/product created by another manufacturer. These process controls may also be confidential to the original manufacturer. Therefore, it would be difficult or impossible for a second manufacturer to make the “same” biologic without intimate knowledge of and experience with the innovator’s process.
Generics Drugs versus Follow-On Biologics
- To be approved as a generic, a drug must have the same active ingredient, strength, dosage form, and route of administration as the reference drug, and it must also be “bioequivalent.” This means that generic drugs are the same chemically as their innovator counterparts and that they act the same way in the body. The bioequivalence of the generic drug is demonstrated through relatively simple analyses such as blood level testing, without the need for human clinical trials. In approving a generic drug under 505(j) of the FDCA, FDA determines that the generic is “therapeutically equivalent” to the innovator drug, and is interchangeable with it.
- FDA has stated that it has not determined how interchangeability can be established for complex proteins (http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/default.htm, November 2010). Historically, FDA has permitted interchangeability only when two products are “therapeutic equivalents.” However, when the follow-on manufacturer establishes a new manufacturing process, beginning with new starting materials, it will produce a product that is different from and not therapeutically equivalent with that of the innovator. Because of the complexity of biologics, the only way to establish whether there are differences that affect the safety and effectiveness of the follow-on product is to conduct clinical trials.