Pharma Focus Asia

Analytical and statistical comparability of generic enoxaparins from the US market with the originator product

Pierre A.J. Mourier, Christophe Agut, Hajer Souaifi-Amara, Fréderic Herman, Christian Viskova

Abstract

Low-molecular-weight heparins (LMWHs) are complex anticoagulant drugs, made from heparin porcine mucosa starting material. Enoxaparin sodium manufactured by Sanofi is one of the most widely prescribed LMWHs and has been used since 1993 in the USA. In 2010, US Food and Drug Administration approval for supplying generic enoxaparin was granted to Sandoz and subsequently to Amphastar. Little is known, however, of the differences in composition of these preparations. In this study, samples from several batches of generic enoxaparins were purchased on the US market and analyzed with state of the art methodologies, including disaccharide building blocks quantification, nuclear magnetic resonance (NMR), and a combination of orthogonal separation techniques. Direct high-performance liquid chromatography analysis of the different enoxaparin batches revealed distinct process fingerprints associated with each manufacturer. Disaccharide building block analysis showed differences in the degree of sulfation, the presence of glycoserine derivatives, as well as in proportions of disaccharides. Results were compared by statistical approaches using multivariate analysis with a partial least squares discriminant analysis methodology. The variations were statistically significant and allowed a clear distinction to be made between the enoxaparin batches according to their manufacturer. These results were further confirmed by orthogonal analytical techniques, including NMR, which revealed compositional differences of oligosaccharides both in low- and high-affinity antithrombin fractions of enoxaparin.

Citation: Pierre A.J. Mourier, Christophe Agut, Hajer Souaifi-Amara Analytical and statistical comparability of generic enoxaparins from the US market with the originator product doi:10.1016/j.jpba.2015.07.038

Received: 5 June 2015 Revised: 22 July 2015 Accepted: 26 July 2015 Available online: 29 July 2015

Copyright:© 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ).

Conflict of interest

P. Mourier, C. Agut, F. Herman, and C. Viskov are employees of Sanofi. H. Souaifi-Amara is a Sanofi external consultant from Experis™ IT, Life Sciences, Nanterre, France.

Role of the funding source

The study was carried out by Sanofi R&D employees as part of their research duties. The external consultant was contracted by Sanofi for the work performed on this project. All authors contributed to the drafting of the manuscript with editorial assistance provided by a medical writer, paid for by Sanofi. The decision to submit the article for publication was shared by all authors.

Acknowledgments

This study was funded by Sanofi. Editorial support in the preparation of this article was provided by M. Calle, Excerpta Medica, funded by Sanofi.

Abbreviations

AT, antithrombin; ATIII, antithrombin III; BSA, bovine serum albumin; CNBr, cyanogen bromide; CTA, cetyltrimethylammonium; CZE, capillary zone electrophoresis; EMA, European Medicines Agency; FDA, US Food and Drug Administration; Gal, galactose; GlcA, glucuronic acid; GPC, gel permeation chromatography; HILIC, hydrophilic interaction liquid chromatography; HPLC, high-performance liquid chromatography; HSQC, heteronuclear single quantum correlation spectroscopy; LMWH, low-molecular-weight heparin; mAU, milliabsorbance units; MS, mass spectrometry; NIPALS, non-linear iterative partial least squares; NMR, nuclear magnetic resonance; PLS-DA, partial least squares discriminant analysis; RSD, relative standard deviation; SAX, strong anion exchange; SD, standard deviation; Ser, serine; TPPI, time proportional phase incrementation; VIP, variable importance in the projection; Xyl, xylose

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