Assessment of the potential of plasma fractionation processes to remove causative agents of transmissible spongiform encephalopathy

Abstract

Although there is no evidence that classical CJD (cCJD) can be transmitted by human blood or blood products in clinical practice, uncertainties surrounding new variant CJD (nvCJD) have led to the safety of plasma products derived from UK donors being questioned. To better define whether or not there is a risk of nvCJD being transmitted it is necessary to determine how the causative agent would partition across the separations processes used in the preparation of plasma products. The abnormal prion protein which is associated with transmissible spongiform encephalopathies (TSEs), such as CJD, has a low solubility, a high tendency to form aggregates and adheres to surfaces readily. If the physicochemical properties of the agent of nvCJD are similar to those of abnormal prion protein then nvCJD may be removed by precipitation and adsorption technologies used in plasma fractionation. Available data on the removal of TSE agents by such bioprocess technologies have been used to estimate the potential degree of reduction expected from each step in the plasma fractionation processes used by the SNBTS. The overall process reduction factors estimated are: 10(13) (albumin). 10(9) (immunoglobulins), 10(7) (factor IX, thrombin), 10(5) (fibrinogen), 10(4) (factor VIII) and 10(3) (factor II, IX and X); however, it will be necessary to establish the accuracy of these estimates by practical validation studies.

Studies on the Removal of Abnormal Prion Protein by Processes Used in the Manufacture of Human Plasma Products

“…By contrast, only a small proportion of PrP Sc could be accounted for in samples taken over chromatographic procedures, e.g., about 0.1% at steps 2, 11 and 13 (table 3). It is possible that PrP Sc may have partitioned into wash fractions which were not sampled; however, it seems more probable, given its adherent nature [16], that most PrP Sc remained adsorbed to chromatographic matrices following product elution.…”

“…Although brain homogenate has been widely used for this purpose its suitability in this respect is uncertain, other than in the study of tissue extractions. In addition, measurements by bioassay are time–consuming and very expensive, consequently TSE process validation studies have been restricted to the investigation of a relatively small number of process steps, with the result that only limited information is available concerning the effect of bio–process operations on the removal or partitioning of TSE agents [16]. …”

International Neonatal Immunotherapy Study

“…Owing to the physico-chemical characteristics of the abnormal prion protein, the process of partitioning and filtration during fractionation further reduces the risk of transmission in IVIG . 48 This theoretical risk must be considered in the context of the significantly increased risk of mort ality and morbidity in infant s eligible for the study .…”

Dealing with the uncertain risk of variant Creutzfeldt‐Jakob disease transmission by coagulation replacement products

“…These include the number of donations contributing to a plasma pool, the effects of the manufacturing process (Foster, 1999;Foster et al, 2000Foster et al, , 2004Reichl et al, 2002;Silveira et al, 2005;Truchot et al, 2006), the infectivity of the donation within the incubation period (SEAC, 2006b), the quantity of infused products and the recipient's age (Swerdlow et al, 2003; ) and immune function (Brown et al, 2009). The partitioning of prion infectivity during the manufacture of plasma products has been extensively investigated and is detailed elsewhere (Foster, 1999;Foster et al, 2000Foster et al, , 2004Reichl et al, 2002;Silveira et al, 2005;Truchot et al, 2006). While these studies largely demonstrate removal of prion agents in the manufacture of plasma products, this should be interpreted with caution in view of significant limitations in the methods used to model and estimate levels of infectivity.…”