Establishing Active Ingredient Sameness for a Generic Enoxaparin Sodium, a Low Molecular Weight Heparin
[This is the FDA monograph referenced in Peter’s post. I would say the language is quite bullish for MNTA insofar as the FDA wants full characterization, not merely sameness with respect to FXa/FIIa. Emphasis below added by me.]
›Lovenox (enoxaparin sodium), a type of low molecular weight heparin (LMWH) produced by cleavage of heparin into smaller pieces, has been a part of anticoagulant treatment for over a decade. Therapeutic levels of this LMWH can be achieved rapidly and safely. Similar to heparin, LMWH is used to prevent blood clots in patients who have recently undergone surgery or who have medical conditions that may cause excessive blood clot formation. LMWH, however, has a longer half-life and a more predictable anticoagulant effect than heparin, and requires less frequent laboratory monitoring than heparin treatment. LMWH also results in fewer fatal adverse reactions than heparin. Because of these characteristics, LMWH can be used in a wider range of treatment settings (e.g., outpatient settings) than heparin.
Although four different types of brand name LMWH products have been approved by FDA, no generic versions of these drugs have been approved in the United States. On July 23, 2010, however, FDA approved the first generic for one of these products -- Lovenox (enoxaparin sodium injection) -- for use as an anticoagulant therapy.
A number of challenges had to be overcome before a generic enoxaparin sodium could be approved for marketing in the United States. In particular, unlike small molecule drugs that can be synthesized relatively easily and characterized readily with laboratory techniques, enoxaparin sodium is a complex semi-synthetic biologically-derived drug product made from pig tissue (porcine intestinal mucosa). Enoxaparin sodium is composed of a mixture of oligosaccharides (chains of sugars) that require a sophisticated set of analytical methods for adequate characterization.
Since enoxaparin sodium is made from heparin, the quality of heparin materials used to make enoxaparin can affect the quality of the final drug product (e.g., impurities). Therefore, the manufacturers of a generic enoxaparin sodium must ensure that the quality characteristics of their heparin source material are well controlled and suitable for use in the manufacture of a generic enoxaparin sodium.
As noted above, LMWH is made by breaking-up heparin into smaller chains of sugars, for example, via chemical reactions. Different chemical reactions can produce chains of various sizes, composition, and sequences. These factors can alter the absorption, distribution, metabolism, excretion, and efficacy of this drug in the body (2,3)— one reason why FDA classified each brand name LMWH product as a distinct chemical entity (e.g., enoxaparin sodium, dalteparin sodium, ardeparin sodium, tinzaparin sodium).
The chemical reaction used to make enoxaparin sodium results in oligosaccharide fragments of distinctive sizes and sequences. It also modifies the chemical structure of sugar residues at both ends of the fragments. Such chemical modifications may affect the activity of this drug (4). If a manufacturer wants to make a generic enoxaparin sodium, it has to design a manufacturing process that is capable of reproducing these distinct features of the drug. Otherwise, a generic enoxaparin sodium might not behave in the same way in the body as the brand name counterpart, Lovenox.
Thus, demonstration of “sameness” for enoxaparin sodium requires “state-of-the-art” analytical methods to show that the structural features of oligosaccharides in the generic enoxaparin sodium are equivalent to those in Lovenox.
In addition to these highly sophisticated tests, it is also important to show equivalence of functionality based upon anticoagulant activity, for example, by measuring activated partial thrombolastin time (aPTT) or the inhibition of factor Xa and factor IIa (two critical elements contributing to human blood clotting activity), as well as demonstrating similar behavior of the profiles of these anticoagulant activities in humans. Such tests provide additional assurance of equivalent efficacy of the drug.
Because of the complexity described above, FDA found that the criteria typically used to approve generic drugs (e.g., compendial requirements) were inadequate by themselves to characterize the “sameness” of enoxaparin sodium, and that additional criteria were needed. To address this issue, FDA developed a set of rigorous and overlapping criteria to be used in the approval of generic enoxaparin sodium (See Table 1).
Table 1. Criteria Used for Sameness Determination of Enoxaparin Sodium
1. Equivalence of heparin source material and mode of depolymerization
2. Equivalence of physiochemical properties
3. Equivalence in disaccharide building blocks, fragment mapping, and sequence of oligosaccharide species
4. Equivalence in biological and biochemical assays
5. Equivalence of in vivo pharmacodynamic profile
The first three criteria are used to ensure that the heparin source material, the chemical reaction used in the manufacturing process, and the structure (the distribution of molecular weight, chemical composition and sequence) of the active ingredient, enoxaparin sodium, in the generic drug product is equivalent to that in the brand name counterpart, Lovenox. The fourth and fifth criteria are used to ensure that the generic enoxaparin sodium has the same degree of anticoagulant activity as Lovenox. Together, these criteria ensure that a generic enoxaparin sodium will have the same active ingredient as Lovenox.
Using these criteria, FDA has approved a generic version of Lovenox (enoxaparin sodium injection). FDA determined that Sandoz demonstrated that all requirements for generic drug approval were met, including that its generic enoxaparin sodium has the same active ingredient as the brand name product, Lovenox.
REFERENCES
1. Collignon F, Frydman A, Caplain H, Ozoux ML, Le Roux Y, Bouthier J, Thébault JJ. Comparison of the pharmacokinetic profiles of three low molecular mass heparins--dalteparin, enoxaparin and nadroparin--administered subcutaneously in healthy volunteers (doses for prevention of thromboembolism). Thromb Haemost. 1995 Apr;73(4):630-40.
2. Samama MM, Gerotziafas GT. Comparative pharmacokinetics of LMWHs. Semin Thromb Hemost. 2000;26 Suppl 1:31-8.
3. Jeske WP, Neville B, Ma Q, et al. Effect of 1,6-anhdro bicyclic ring structure on the pharmacokientic behavior of low molecular weight heparin. Blood. 2004;104:abstract 1868.‹
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