Manufacture of Immunoglobulin Products for Patients with Primary Antibody Deficiencies – The Effect of Processing Conditions on Product Safety and Efficacy

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.

Intravenous immune globulin and thromboembolic adverse events: A systematic review and meta‐analysis of RCTs

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Passive Serum Therapy to Immunomodulation by IVIG: A Fascinating Journey of Antibodies

“…This perception was challenged for the first time in 1983, when an experimental IVIG transmitted non-A, non-B hepatitis (later known as hepatitis C) (28). Subsequently, a few reports of HIV and non-A non-B hepatitis transmission by some IVIG products (29) led to reconsideration and regulation of viral safety norms in IVIG manufacturing (30). Currently, it is mandatory to use a minimum of two complementary methods of viral inactivation, of which at least one step must target the elimination of nonenveloped viruses.…”

Intravenous immunoglobulins in dermatology. Part 1: biological mechanisms and methods of administration

“…It is created from a combination of blood donors and plasma pools, and has been used in clinical practice for over 50 years . Using thousands of plasma pools generates a risk of pathogen transmission to the recipient . Fractionation, chromatography, virus inactivation and removal are the combined steps used today (in conjunction with donor screening) to decontaminate IVIg of infective diseases, including human immunodeficiency virus, hepatitis, prions and smaller encapsulated viruses .…”

“…2 Using thousands of plasma pools generates a risk of pathogen transmission to the recipient. 3 Fractionation, chromatography, virus inactivation and removal are the combined steps used today (in conjunction with donor screening) to decontaminate IVIg of infective diseases, including human immunodeficiency virus, hepatitis, prions and smaller encapsulated viruses. 2 Currently, the process of fractionation uses polyethylene glycol, which enables separation of IgG from plasma, which is then reprecipitated several times in conjunction with ethanol in order to create a clean product.…”