Analytical and statistical comparability of generic enoxaparins from the US market with the originator product.
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.
Sanofi, 13, Quai Jules Guesde, 94403 Vitry-sur-Seine, France. Electronic address: pierre.mourier@sanofi.com.
Pierre A J
PA
Mourier
Sanofi R&D, 371, rue du Professeur Joseph, 34184 Montpellier, France. Electronic address: christophe.agut@sanofi.com.
Christophe
C
Agut
External consultant from Experis™ IT, Life Sciences, 92723 Nanterre, France for CMC Biostatistics & Programming, Sanofi, Centre de recherche Vitry-sur-Seine, 13, quai Jules Guesde, 94403 Vitry-sur-Seine, France. Electronic address: Hajer.souaifi-amara-ext@sanofi.com.
Hajer
H
Souaifi-Amara
Sanofi, 13, Quai Jules Guesde, 94403 Vitry-sur-Seine, France. Electronic address: frederic.herman@sanofi.com.
Fréderic
F
Herman
Sanofi, 13, Quai Jules Guesde, 94403 Vitry-sur-Seine, France. Electronic address: christian.viskov@sanofi.com.
Christian
C
Viskov
D000925:Anticoagulants / Q000032:analysis*; D002626:Chemistry, Pharmaceutical; D002851:Chromatography, High Pressure Liquid; D004187:Disaccharides / Q000032:analysis; D016002:Discriminant Analysis; D016568:Drugs, Generic / Q000032:analysis*; D017984:Enoxaparin / Q000032:analysis*; D016018:Least-Squares Analysis; D009682:Magnetic Resonance Spectroscopy; D015233:Models, Statistical; D015999:Multivariate Analysis; D011786:Quality Control; D013431:Sulfates / Q000032:analysis; D013678:Technology, Pharmaceutical / Q000379:methods; D014481:United States
D000925:Anticoagulants; D004187:Disaccharides; D016568:Drugs, Generic; D017984:Enoxaparin; D013431:Sulfates
Analytical comparability; Chemometrics; Disaccharide quantification; Enoxaparin; Generic; Nuclear magnetic resonance