Scientific considerations in the review and approval of generic enoxaparin in the United States

Abstract

In 2010, the US Food and Drug Administration (FDA) approved a generic low-molecular-weight heparin without clinical safety or efficacy data under the Abbreviated New Drug Application (ANDA) pathway. To enable a determination of active ingredient sameness of generic and innovator enoxaparin products, the FDA developed a scientifically rigorous approach based on five criteria: first, equivalence of physicochemical properties; second, equivalence of heparin source material and mode of depolymerization; third, equivalence in disaccharide building blocks, fragment mapping and sequence of oligosaccharide species; fourth, equivalence in biological and biochemical assays; and finally, equivalence of in vivo pharmacodynamic profile. In addition to fulfillment of these criteria, FDA also used in vitro, ex vivo and model animal data to ensure there was no increased immunogenicity risk of the generic enoxaparin product relative to the brand name product. The approval of the highly complex enoxaparin product using this framework under the ANDA pathway represents a major development. It also suggests that analytical and scientific advancements may in certain cases allow the elimination of unnecessary in vivo testing in animals and humans.

Synthetic oligosaccharides can replace animal-sourced low–molecular weight heparins

“…Only a fraction of oligosaccharides in LMWH exhibit anticoagulant activity. The structural heterogeneity in LMWHs results in batch-to-batch differences in saccharide composition and sequence and anticoagulant activity (6). …”

Homogeneous low-molecular-weight heparins with reversible anticoagulant activity

“…Chemoenzymatic synthesis offers a promising approach toward this goal. A homogeneous product reduces the complexity for the quality control during the manufacturing process and is compatible with standard approval processes by regulatory agencies 24 . Although the structures produced through chemoenzymatic synthesis are limited by the substrate specificities of the enzymes, their synthetic capability can be expanded through better understanding of enzyme properties.…”

Consistency of quality attributes for the glycosylated monoclonal antibody Humira® (adalimumab)

“…18 Specific glycosylation patterns (i.e., the composition of attached sugar moieties) of antibodies can also be used as an indicator of a consistent manufacturing process or to identify the effect that changes to the manufacturing process have on the molecule. 19,20 Characterized by the degree of galactose sugar molecules, one of the major glycoforms of mAbs, including adalimumab, is the agalactosyl fucosylated biantennary oligosaccharide (G0F) species that contains fucose but no terminal galactosylation. 21 Evidence that glycosylation patterns affect protein function is accumulating, and differential glycosylation has been shown to influence serum clearance in human studies of therapeutic antibodies with oligomannose sugars, [21][22][23] antibodydependent cell-mediated cytotoxicity or complement-dependent cytotoxicity, 18,21,24 and serum half-life due to differences in binding to the Fc receptors.…”