Intravenous immunoglobulin formulations

Robak T, Salama A, Kovaleva L, Vyhovska Y, Davies SV, Mazzucconi MG, Zenker O, Kiessling P. Efficacy and safety of Privigen, a novel liquid intravenous immunoglobulin formulation, in adolescent and adult patients with chronic immune thrombocytopenic purpura. Hematology 2009 14(4) 227-36. 

The development of freeze-drying for the production of blood derivatives was pioneered during World War II (96,97). It is used for the stabilization of coagulation factor (98,99) and intravenous immunoglobulin (IgG iv) products, and also for the removal of ethanol from intramuscular immunoglobulin (IgG im) solutions prior to their final formulation (Fig. 2). 

The resuspended and formulated Fraction II precipitate normally contains some aggregated IgG and trace substances that can cause hypotensive reactions in patients, such as the enzyme prekail ikrein activator (186). These features restrict this type of product to intramuscular adininistration. Further processing is required if products suitable for intravenous adininistration are required. Processes used for this purpose include treatment at pH 4 with the enzyme pepsin [9001-75-6] being added if necessary (131,184), or further purification by ion-exchange chromatography (44). These and other methods have been fiiUy reviewed (45,185,187,188). Intravenous immunoglobulin products are usually suppHed in the freeze-dried state but a product stable in the solution state is also available (189). 

This adverse reaction was probably due to the presence of allohemagglutinins A and B and high molecular weight IgG complexes in the formulation. Specifications in phar-macopeial monographs and product hcenses require that intravenous immunoglobulin be free of significant titers of anti-A anti-B antibodies (SEDA-24, 385). 

A novel DNA virus, TT virus, has been implicated as a cause of post-transfusion hepatitis. A high prevalence of TT virus infection has been found in patients who received blood or blood components, such as factor VIII and IX concentrates. However, the PCR for TT virus DNA was negative in aU 17 patients with immunodeficiency, who were treated prophylactically with intravenous immunoglobulin, as well as in 15 tested immunoglobuhn formulations (137). 

Acute renal insufficiency after intravenous immunoglobulin therapy has been reported in association with the injection of iodinated radiocontrast agents (144). Contrast media and intravenous immunoglobuhn formulations containing maltose or sucrose both have toxic effects on renal cells. 

The pathophysiology of acute renal insufficiency due to immunoglobulins is probably related to hyperosmolar renal damage, due to sucrose present in 50 ml intravenous formulations (13,43,85-87). Acute renal insufficiency has also been attributed to sucrose in a kidney allograft... 

Maltose is used in oral and parenteral pharmaceutical formulations and is generally regarded as an essentially nontoxic and nonirritant material. However, there has been a single report of a liver transplantation patient with renal failure who developed hyponatremia following intravenous infusion of normal immunoglobulin in 10% maltose. The effect, which recurred on each of four successive infusions, resembled that of hyperglycemia and was thought to be due to accumulation of maltose and other osmotically active metabolites in the extracellular fluid. ... 

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