Therapeutic Solutions of Human Albumin – The Possible Effect of Process-Induced Molecular Alterations on Clinical Efficacy and Safety

Human albumin solutions were developed as therapeutic during the Second World War to address blood loss due to battlefield injury. This indication was based on the recognition that albumin provided most of the oncotic capacity of human plasma. For the succeeding sixty years, this formed the basis for the use of albumin in traumatology and emergency medicine. In more recent times, the pharmacological properties arising from albumin's complex structure have become a focus of attention by clinical researchers. In particular, albumin, through anti-inflammatory and anti-oxidant properties, has been proposed as an agent for the treatment of sepsis, cirrhosis and other inflammatory states. Some evidence for these indications has accrued from a number of small clinical trials and observational studies. These studies have not been confirmed in other large trials. Together with other investigators, we have shown that the process of plasma fractionation results in alterations in the structure of albumin, including those parts of the molecule involved in anti-oxidant and anti-inflammatory effects. Albumin products from diverse manufacturers show heterogeneity in their ability to address these effects. In this article, we review the historical development of albumin solutions, pointing out the variations in fractionation chemistries which different manufacturers have adopted. We suggest ways by which the manufacturing processes have contributed to variations in the physico-chemical properties of molecule. We review the outcomes of clinical studies assessing the role of albumin in ameliorating conditions such as sepsis and cirrhosis, and we speculate as to the extent which heterogeneity in the products may have contributed to variable clinical outcomes. Finally, we argue for a change in the perception of the plasma product industry and its regulatory overseers. Historically, albumin has been viewed as a generic commodity, with different preparations being interchangeable in their clinical application. We suggest that this implied biosimilarity is not necessarily applicable for different albumin solutions. The use of albumin, in indications other than its historical role as a plasma expander, can only be validated by clinical investigation of each separate albumin product.