Background Regulatory Issues for Biopharmaceuticals

BACKGROUND

The aim of this chapter is to provide a comprehensive view on the regulatory issues for the approval of  a biosimilar product. In order to have a better understanding of the regulatory process involved, it is essential to appreciate the basic difference between small drug molecules and macromolecules and their approval process. Table 1 provides the definitions of different classes of medicinal drug products. Table 2 provides the steps involved in the drug approval process of small molecules. For the approval of a (small molecule) generic product, it must be pharma-ceutically equivalent and bioequivalent (Table 3). Biopharmaceuticals have a number of characteristics (Table 4) that set them aside from small molecule drugs (Crommelin et al., 2003). The efficacy and safety of biotech products depend on their complicated, rather labile shape built up of secondary, tertiary and sometimes quaternary structures.

The mission of a regulatory authority is to “Assure that safe, effective and high quality drugs are marketed in the country and are available to the people”. Safety of an innovator’s drug product, be it a small molecule or biopharmaceutical, is established through preclinical studies in animals and controlled clinical studies in humans. Efficacy is established through clinical studies in patients. A complete set of information on Chemistry, Manufacturing and Controls (CMC-section) is needed in the dossier submitted for approval to ensure that the drug substance and the drug product are, pure, potent and of high quality. The CMC section should include full analytical characterization, a description of the manufacturing process and test methods, and stability data. In addition to the establishment of safety and efficacy of the drug product, the approval process requires manufacturing of the drug product under controlled current good manufacturing practice (cGMP) conditions. The cGMP requirement ensures identity, potency, purity, quality and safety of the final product. These features include process robustness and reproducibility, validation, controls and testing. Batch release criteria are established to assure  complex manufacturing process of biopharmaceuti-cals involving living organisms. The production process should be controlled in every minor detail. Moreover, a long list of analytical techniques is presented to characterize biopharma-ceuticals, but in many instances full characterization is not possible with our current toolbox of analytical techniques.

A generic product (small molecule) contains the same active ingredient with inactive (most of the time) excipients as the reference product. As explained above, this is not always possible in biopharmaceu-tical protein products and therefore, these are not referred to as biogenerics. This biopharmaceutical product contains the active ingredient which is similar (but not necessarily equal) in characteristics to the reference product. For this reason, the generic biopharmaceutical products are referred to as fol-low-on proteins or follow-on biologics or biosimilar products. A biosimilar product has a pharmacological and therapeutic activity that is similar to the reference (comparator) product, but may differ in its pharma-ceutical equivalence (characteristics). Biosimilar products are not generic products since it could be expected that there may be subtle differences between the biosimilar and reference product from the innovator and are not interchangeable with brand name products.