Mass balance analysis of contaminated heparin product.
A quantitative analysis of a recalled contaminated lot of heparin sodium injection U.S. Pharmacopeia (USP) was undertaken in response to the controversy regarding the exact nature of the contaminant involved in the heparin (HP) crisis. A mass balance analysis of the formulated drug product was performed. After freeze-drying, a 1-ml vial for injection afforded 54.8±0.3 mg of dry solids. The excipients, sodium chloride and residual benzyl alcohol, accounted for 11.4±0.5 and 0.9±0.5 mg, respectively. Active pharmaceutical ingredient (API) represented 41.5±1.0 mg, corresponding to 75.7 wt% of dry mass. Exhaustive treatment of API with specific enzymes, heparin lyases, and/or chondroitin lyases was used to close mass balance. HP represented 30.5±0.5 mg, corresponding to 73.5 wt% of the API. Dermatan sulfate (DS) impurity represented 1.7±0.3 mg, corresponding to 4.1 wt% of API. Contaminant, representing 9.3±0.1 mg corresponding to 22.4 wt% of API, was found in the contaminated formulated drug product. The recovery of contaminant was close to quantitative (95.6-100 wt%). A single contaminant was unambiguously identified as oversulfated chondroitin sulfate (OSCS).
Liu
Zhenling
Z
Lanzhou University, People's Republic of China.
Xiao
Zhongping
Z
Masuko
Sayaka
S
Zhao
Wenjing
W
Sterner
Eric
E
Bansal
Vinod
V
Fareed
Jawed
J
Dordick
Jonathan
J
Zhang
Fuming
F
Linhardt
Robert J
RJ
D019905:Benzyl Alcohol / Q000032:analysis; D002808:Chondroitin Lyases / Q000378:metabolism; D002809:Chondroitin Sulfates / Q000032:analysis; D002851:Chromatography, High Pressure Liquid / Q000379:methods*; D003871:Dermatan Sulfate / Q000032:analysis; D004340:Drug Contamination; D019075:Electrophoresis, Capillary / Q000379:methods*; D006493:Heparin / Q000032:analysis*; D019763:Heparin Lyase / Q000378:metabolism; D012965:Sodium Chloride / Q000032:analysis
D003871:Dermatan Sulfate; D012965:Sodium Chloride; D006493:Heparin; D002809:Chondroitin Sulfates; D002808:Chondroitin Lyases; D019763:Heparin Lyase; D019905:Benzyl Alcohol