Clearance of Prions During Plasma Protein Manufacture
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)
- et al.
Transmission of BSE by blood transfusion in sheep
Lancet
(2000) - et al.
Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion
Lancet
(2004) - et al.
Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient
Lancet
(2004) - et al.
Reducing the risk of infection from plasma products: Specific preventative strategies
Blood Rev.
(2000) - et al.
Scrapie prions aggregate to form amyloid-like birefringent rods
Cell
(1983) - et al.
Solvent-dependent precipitation of prion protein
Biochim. Biophys. Acta
(2002) - et al.
Removal of abnormal prion protein by plasma fractionation
Transfus. Sci.
(2000) - et al.
Partitioning of TSE infectivity during ethanol fractionation of human plasma
Biologicals
(2004) - et al.
Purity of spiking agent affects partitioning of prions in plasma protein purification
Biologicals
(2002) - et al.
Monitoring plasma processing steps with a sensitive Western blot assay for the detection of the prion protein
J. Virol. Methods
(2000)
An improved Western blot assay to assess the clearance of prion protein from plasma-derived therapeutic proteins
J. Virol. Methods
Proteolytic inactivation of the bovine spongiform encephalopathy agent
Biochem. Biophys. Res. Commun.
The distribution of infectivity in blood components and plasma derivatives in experimental models of transmissible spongiform encephalopathy
Transfusion
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
Cited by (23)
Adverse effects of human immunoglobulin therapy
2013, Transfusion Medicine ReviewsCitation Excerpt :A theoretical risk remains based on a case of its transmission by blood transfusion [112]. Tests for prions are in development as are methods for their removal [113,114]. Ziegner et al [115] reported a series of immunodeficient patient with progressive neurodegeneration who had been exposed to immunoglobulin preparations.
Antibodies in infectious diseases: Polyclonals, monoclonals and niche biotechnology
2011, New BiotechnologyCitation Excerpt :Furthermore, although human IgG preparations used today have the highest safety record of all biologics and a clear pathway with the FDA, there are still some lingering fears regarding the chance of human poly Ig to transmit an infection, even if exceedingly low [18]. For example, UK citizens are still not allowed to donate their blood in the USA or the UK as a fall out of the prion incidents in the early 1990s, despite the fact that resins and complexing agents which remove prions, are well entrenched in poly IgG purification protocols from the plasma supply [19]. Although those concerns could be reduced through the use of mAbs produced via tissue culture or microbial expression systems, the cost per dose of mAbs is significantly higher and may not warrant development for many niche market products (Table 4).
Human immunoglobulin preparations
2009, Transfusion Medicine and Hemostasis: Clinical and Laboratory AspectsOxygen Therapeutics: Perfluorocarbons and Blood Substitute Safety
2009, Critical Care ClinicsCitation Excerpt :In the late 1990s, scientists discovered that a new variant of CJD could be transmitted from cattle to humans through the ingestion of cow brain and spinal cord material,29 which led the FDA to prohibit the transfusion of blood products from donors who spent extended periods of time in the United Kingdom. Although Biopure scientists have published studies showing that viruses and “transmissible spongiform encephalopathy agents” (the prion protein underlying CJD) can be cleared from their products,30 further experimental studies and long-term epidemiologic monitoring are warranted.31 Interference of PFCs and HBOCs on some routine laboratory tests could be a serious problem, especially if these products become available for mainstream use.
Human Immunoglobulin Preparations
2009, Transfusion Medicine and HemostasisPlasma fractionation in the world: Current status
2007, Transfusion Clinique et Biologique