Abstract
Early preparations of immunoglobulin (Ig) manufactured from human plasma by ethanol (Cohn) fractionation were limited in their usefulness for substitution therapy in patients with primary antibody deficiencies (PAD), as Ig aggregates formed during manufacture resulted in severe systemic reactions in patients when given intravenously. Developments in manufacturing technology obviated this problem through the capacity to produce concentrated solutions of intact monomeric Ig, revolutionizing PAD treatment and improving patient life expectancy and quality of life. As the need for Ig has grown, manufacturers have refined further manufacturing technologies to improve yield from plasma and produce therapies, which are easier and less expensive to deliver. This has led to the substitution, partly or wholly, of ethanol precipitation by other techniques such as chromatography, and has also stimulated the production of highly concentrated solutions capable of rapid infusion. Ig products have been associated, since their inception, with certain adverse events, including infectious disease transmission, hemolysis, and thromboembolism. The introduction of standardized manufacturing processes and dedicated pathogen elimination steps has removed the risk of infectious disease, and the focus of attention has shifted to other problems, which appear to have increased over the past 5 years. These include hemolysis and thromboembolism, both the cause for substantial concern and the subject of recent regulatory scrutiny and actions. We review the development of manufacturing technology and the emerging evidence that changes for the optimization of yield and convenience has contributed to the recent incidents in certain adverse events. Industry measures under development will be discussed in terms of their potential to improve safety and optimize care for patients with PAD.
Highlights
DEVELOPMENT OF MANUFACTURING METHODS FOR THERAPEUTIC IMMUNOGLOBULIN PREPARATIONS Immunoglobulins (Igs) may claim to be, historically, the first therapeutic plasma product, with Emil von Behring’s work on diphtheria antitoxin and von Behring and Kitasato’s demonstration [1] that serum of rabbits immunized with tetanus toxin contained activity against experimentally induced tetanus poison, which provided protection to non-immunized rabbits exposed to tetanus
While large prospective multicenter studies are needed to confirm and augment this work, we suggest that agencies seeking to ensure, for financial reasons, more “rational” Ig therapy would do well to consider the funding of such studies if patient care is to be optimized
SUMMARY AND CONCLUSION Ig therapies are life-saving medicines, which have revolutionized the treatment of a large number of rare and severe chronic immune deficiency and autoimmune disorders
Summary
DEVELOPMENT OF MANUFACTURING METHODS FOR THERAPEUTIC IMMUNOGLOBULIN PREPARATIONS Immunoglobulins (Igs) may claim to be, historically, the first therapeutic plasma product, with Emil von Behring’s work on diphtheria antitoxin and von Behring and Kitasato’s demonstration [1] that serum of rabbits immunized with tetanus toxin contained activity against experimentally induced tetanus poison, which provided protection to non-immunized rabbits exposed to tetanus. Ehrlich [2] demonstrated that protection was correlated with the amount of antitoxin administered. Antibody preparations such as these, where protective antitoxin is generated through the immunization of animals, still have a role in the treatment of some conditions [3]. Initial clinical experience with the immune serum globulin (ISG) fraction from Cohn’s scheme quickly led to limiting administration to the intramuscular and subcutaneous routes, as severe systemic reactions occurred in patients given this product intravenously
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