The Evolution of the Safety of Plasma Products from Pathogen Transmission—A Continuing Narrative

Abstract

Chronic recipients of plasma products are at risk of infection from blood-borne pathogens as a result of their inevitable exposure to agents which will contaminate a plasma manufacturing pool made up of thousands of individual donations. The generation of such a pool is an essential part of the large-scale manufacture of these products and is required for good manufacturing practice (GMP). Early observations of the transmission of hepatitis by pooled plasma and serum led to the incorporation of heat treatment of the albumin solution produced by industrial Cohn fractionation of plasma. This led to an absence of pathogen transmission by albumin over decades, during which hepatitis continued to be transmitted by other early plasma fractions, as well as through mainstream blood transfusions. This risk was decreased greatly over the 1960s as an understanding of the epidemiology and viral aetiology of transfusion-transmitted hepatitis led to the exclusion of high-risk groups from the donor population and the development of a blood screening test for hepatitis B. Despite these measures, the first plasma concentrates to treat haemophilia transmitted hepatitis B and other, poorly understood, forms of parenterally transmitted hepatitis. These risks were considered to be acceptable given the life-saving nature of the haemophilia treatment products. The emergence of the human immunodeficiency virus (HIV) as a transfusion-transmitted infection in the early 1980s shifted the focus of attention to this virus, which proved to be vulnerable to a number of inactivation methods introduced during manufacture. Further developments in the field obviated the risk of hepatitis C virus (HCV) which had also infected chronic recipients of plasma products, including haemophilia patients and immunodeficient patients receiving immunoglobulin. The convergence of appropriate donor selection driven by knowledge of viral epidemiology, the development of blood screening now based on molecular diagnostics, and the incorporation of viral inactivation techniques in the manufacturing process are now recognised as constituting a “safety tripod” of measures contributing to safety from pathogen transmission. Of these three components, viral inactivation during manufacture is the major contributor and has proven to be the bulwark securing the safety of plasma derivatives over the past thirty years. Concurrently, the safety of banked blood and components continues to depend on donor selection and screening, in the absence of universally adopted pathogen reduction technology. This has resulted in an inversion in the relative safety of the products of blood banking compared to plasma products. Overall, the experience gained in the past decades has resulted in an absence of pathogen transmission from the current generation of plasma derivatives, but maintaining vigilance, and the surveillance of the emergence of infectious agents, is vital to ensure the continued efficacy of the measures in place and the development of further interventions aimed at obviating safety threats.

Expression of the gene encoding blood coagulation factor VIII without domain B in E. coli bacterial expression system

“…However, these concentrates were associated with serious side effects for patients. Due to the pooled plasma from multiple donors, they served as a source of hepatitis B virus and later hepatitis C virus since 1989 (Fletcher et al, 1989; Tobler et al, 1997; Rougemont, 2023 ). Moreover, in the early 1980s, 60–80% of hemophilia patients became infected with human immuno-deficiency virus (HIV) through these lyophilized concentrates (Curran et al, 1983 ; Evatt et al, 2006 ; Rougemont, 2023 ).…”

“…Due to the pooled plasma from multiple donors, they served as a source of hepatitis B virus and later hepatitis C virus since 1989 (Fletcher et al, 1989; Tobler et al, 1997; Rougemont, 2023 ). Moreover, in the early 1980s, 60–80% of hemophilia patients became infected with human immuno-deficiency virus (HIV) through these lyophilized concentrates (Curran et al, 1983 ; Evatt et al, 2006 ; Rougemont, 2023 ). A significant breakthrough in hemophilia treatment came with the discovery of the human factor IX and factor VIII genes in 1982 and 1984, respectively (Lusher et al, 1993 ).…”

Complexing Protein-Free Botulinum Neurotoxin A Formulations: Implications of Excipients for Immunogenicity

“…Although HSA can be produced in recombinant form from non-human sources (reviewed in [ 67 ]), the vast majority of HSA included in pharmaceuticals is still of human origin, normally purified from human blood donations. Although concerns have been raised repeatedly that human blood products carry a very remote potential risk of being contaminated with human pathogens, such as small viruses (experience with human immunodeficiency virus in blood products) or prions (experience with BSE), HSA produced under well-controlled good manufacturing practice (GMP) conditions is considered to be safe (reviewed in [ 68 ]). Very few serious side effects have been reported despite the fact that HSA solutions are the most frequently used biopharmaceuticals, with literally hundreds of millions of doses applied since the mid-1940s (reviewed in [ 65 , 66 ]).…”

Expanding applications of allogeneic platelets, platelet lysates, and platelet extracellular vesicles in cell therapy, regenerative medicine, and targeted drug delivery

“…Recent articles [ 99 , 100 ], inspired by vast knowledge on complementary measures needed to guarantee the viral safety of fractionated pooled plasma-derived medicinal products [ 34 , 140 , 141 ], stressed the fact that HPLs, when made from pooled PCs, inherently have statistically higher risks of contamination by blood-borne viruses. It was demonstrated that lysates made from PCs pathogen-reduced by psoralen/ultraviolet (UV) A [ 142 – 145 ], riboflavin/UV treatment [ 146 ] or short-wave UV light treatment [ 147 ] can maintain their functionality to support the propagation of therapeutic MSC in vitro.…”