Clearance of Prions During Plasma Protein Manufacture

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Protein products isolated from human plasma are an important class of therapeutics that are used to treat patients afflicted with hereditary deficiencies, trauma, and severe infections. Because of the human origin of the starting material for the production of these biological products, there is a risk of transmitting infectious agents, including viruses and the infectious agents that cause transmissible spongiform encephalopathies (TSEs). The agent that is thought to cause TSEs is a disease-associated, misfolded form of the prion protein or PrPSc. Unlike viruses, there are no donor screening tests for TSEs available, and PrPSc is resistant to traditional viral inactivation methods. Therefore, manufacturers of plasma products are faced with special challenges to ensure product safety with respect to TSEs. Fortunately, a growing body of evidence supports the capacity of manufacturing processes to remove infectious prions from the product stream during the purification of plasma products. This can be attributed in part to the unusual physicochemical nature of PrPSc, which is distinct from that of soluble therapeutic proteins. Although there is no reported TSE transmission through the use of plasma products to date, many unknowns remain to be addressed through long-term epidemiologic monitoring and further experimental studies.

Section snippets

Clearance Capacity of Manufacturing Steps

Modern methods of purifying plasma proteins for pharmaceutical use are based on the Cohn Fractionation process that was originally developed in the laboratory of Edwin J. Cohn at the Harvard Medical School and published in 1946. The original Cohn Fractionation methodology used a series of shifts in temperature, pH, ionic strength, and ethanol addition to progressively precipitate the protein components of plasma. Current manufacturing practices are often referred to as “Cohn Fractionation” but

Model Systems for Analyzing Prion Clearance

The methods used to evaluate prion removal capacity of a manufacturing process are based on those developed to evaluate the removal of viral pathogens. Because it is impractical as well as imprudent to introduce pathogens into actual production facilities, pathogen removal by a manufacturing step is assessed using scaled-down models of the production process that are spiked with a known amount of high-titer infectious agent. After the fractionation, the amount of the agent in the resulting

Conclusions

The prevalence of vCJD outside the United Kingdom population is extremely low, and vCJD cases have not been reported in most countries. As a safety measure, United Kingdom–sourced plasma has not been used as source material for purifying plasma proteins since 1998. With the implementation of stringent geographic donor deferral measures and the demonstration of prion removal capacity by manufacturing processes, plasma products are considered to be at minimum risk with respect to TSE/CJD

References (28)

  • R.C. Hartwell et al.

    An improved Western blot assay to assess the clearance of prion protein from plasma-derived therapeutic proteins

    J. Virol. Methods

    (2005)
  • A.H. McLeod et al.

    Proteolytic inactivation of the bovine spongiform encephalopathy agent

    Biochem. Biophys. Res. Commun.

    (2004)
  • P. Brown et al.

    The distribution of infectivity in blood components and plasma derivatives in experimental models of transmissible spongiform encephalopathy

    Transfusion

    (1998)
  • P. Brown et al.

    Further studies of blood infectivity in an experimental model of transmissible spongiform encephalopathy, with an explanation of why blood components do not transmit Creutzfeldt-Jakob disease in humans

    Transfusion

    (1999)
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