Summary
During the past 25 years, heparin extraction and purification processes have changed.
The results of these changes are reflected by the continuous increase in potency of
the International Standard for heparin. This increase is due not only to a higher
purity, but also to a number of changes in the physicochemical characteristics of
heparin. For long time, all these changes have been disregarded as non-critical by
regulatory authorities. Heparin marketing authorisation was reviewed only two years
ago and Pharmacopoeia monographs were reviewed just for the addition of new tests,
mainly aimed at tackling the oversulfated chondroitin sulfate (OSCS) crisis. Currently,
heparin monographs are again under revision. Such changes, different for each manufacturer,
have caused a further increase in the heterogeneity of individual batches of heparin.
This review aims at showing that chemical, physical and biological characteristics
of heparin (such as disaccharide composition, amount of low sulfated and high sulfated
sequences, molecular weight profiles [MW], activities, structural artifacts, fingerprints
and glycosaminoglycans impurities) are all process-dependent and may significantly
vary when different processes are used to minimise the content of dermatan sulfate.
The wide heterogeneity of the physico-chemical characteristics of currently marketed
heparin and the lack of suitable and shareable reference standards for the identification/quantification
of process-related impurities caused, and are still causing, heated debates among
scientific institutions, companies and authorities.
Keywords
Heparin - dermatan sulfate - process-related impurities