Differentiation of Generic Enoxaparins Marketed in the United States by Employing NMR and Multivariate Analysis

Abstract

The U.S. Food and Drug Administration defines criteria for the equivalence of Enoxaparin with Lovenox, comprising the equivalence of physiochemical properties, heparin source material and mode of depolymerization, disaccharide building blocks, fragment mapping and sequence of oligosaccharide species, biological and biochemical assays, and in vivo pharmacodynamic profile. Chemometric analysis of the NMR spectra, utilizing both (1)H and (1)H-(13)C HSQC NMR experiments, of Lovenox and Enoxaparin, the latter being the generic version of the former, revealed that Lovenox and the four Enoxaparin compounds produced by Sandoz (Enoxaparin and Fibrinox), Winthrop, and Amphastar exhibit dissimilarities in terms of their composition. All of the collected samples had expiry dates between 2012 and 2015. These studies, in addition to chromatographic analysis, highlighted signatures that differentiated the branded material from the generic products.

Analysis of solid-state heparin samples by ATR-FTIR spectroscopy

“…14 It is worth emphasising that it was never the aim of either of these approaches to detect contamination with OSCS in particular, rather to define an approach for the detection, in principle, of any alien species, among samples of variable composition. While this approach has been developed further in a series of papers by the same authors to include two dimensional ( 1 H-13 C) NMR, 15,16 these approaches, nevertheless, still require access to a high-field NMR spectrometer and skilled technical assistance to meet the standards required to ensure reproducibility.…”

“…Sample preparation and data collection are simple and, furthermore, are suitable for adaptation to a portable format, which will be convenient for producers and regulators alike. 16 CS-C samples and 21 DS (green for monosulphated chondroitin samples and teal for disulphated chondroitin samples), 11 HA (purple) and 6 OSCS (including the OSCS selected for contamination study later (aquamarine)) samples, as well as an OSAS and DeS sample, also used in the contamination study ( Fig. 2.3) are compared.…”

Comparative Pharmacological Profiles of Various Bovine, Ovine, and Porcine Heparins

“…This observation has been reported in an earlier publication. 19 Heparin, and its analogues, are used during surgery and dialysis, and are often used to coat indwelling catheters and other devices where the vascular system is exposed. As such, the ability to reverse the biological effects of heparins is of considerable importance.…”

Biosimilars of low molecular weight heparins: Relevant background information for your drug formulary

“…Overall the similarity of generic enoxaparin (Teva) has good lot‐to‐lot consistency. The US‐marketed generic enoxaparins from Sandoz/Momenta, Winthrop and Amphastar, compared to the originator from Sanofi, exhibit dissimilarities in terms of their composition, but the clinical relevance of this differences in unclear and possible irrelevant . Furthermore, many of the publications or authors are sponsored by the originator, so one cannot exclude conflict of interest …”

“…13,14 Most of the experimental work on quality control and structural characterization has been done with enoxaparin. 15 Enoxaparin is derived from heparin extracted from porcine intestinal mucosa, by depolymerization that leads to lower molecular weight 17,18 Furthermore, many of the publications or authors are sponsored by the originator, so one cannot exclude conflict of interest. 19,20 Small differences in chemical structure may result from the production process or the porcine heparin source.…”