Wednesday, December 30, 2009

Can Cache Valley Virus Trash Your Manufacturing?

By Dr. Ray Nims

Cache Valley virus is a single-stranded RNA virus of family bunyavirus, genus Bunyavirus. It is enveloped and nominally 80-120 nm in diameter. Cache Valley virus was first isolated in Utah in 1956 and is carried by mosquitoes. It has since been found to be a widespread virus, having been isolated in Texas, Michigan, North Carolina, Indiana, Virginia and Maryland, for example.

source: Nims et al., BioPharm. Int. 21: 89-94, 2008

Basis of Concern. Cache Valley virus is known to infect livestock, causing birth defects. There have been two reports of encephalitic disease in humans attributed to Cache Valley virus. This virus has been isolated from biologics manufacturing processes employing Chinese hamster cell substrates on a number of occasions from 2000 to 2004 (Nims et al., BioPharm. Int. 21: 89-94, 2008). The route of entry of the virus into biologics production processes has not been established with certainty, although the use of contaminated bovine serum is considered to be the most likely source. Thus far the virus has only been known to infect manufacturing processes employing bovine serum.

Regulatory Expectations. Cache Valley virus is not mentioned specifically in any regulatory guidance, as the detection of this virus in biologics production has been reported only within the past decade. It is the intent of the guidance, however, that occurrences of viral contamination in biologics manufacturing be dealt with through implementation of specific testing methods as required to assure detection of future recurrences (e.g., ICH Q5A R1). In addition, it is expected that the route of entry of the virus be established and that the process be remediated so that future recurrences are prevented where possible (e.g., 1997 Points to Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human Use).

Mitigating Risk. Although many Contract Testing laboratories offer rapid nucleic acid-based detection assays for Cache Valley virus, raw material screening for this virus using such assays does not appear to be a viable means of eliminating risk. The industry experience thus far indicates that Cache Valley virus may be a low level, non-homogeneous contaminant of bovine serum. Viral screening performed on one bottle out of a large lot of serum therefore is no guarantee that this virus will not be encountered. Elimination of animal-derived materials (esp. bovine serum) from the manufacturing process may help to reduce the risk of experiencing this virus. Should this not be possible, treatment of the serum or serum-containing media should be considered. Gamma-irradiation has been demonstrated to be effective in inactivating this virus in bovine serum (Gauvin, 2009). UVC treatment of media containing bovine serum also appears to be quite effective at inactivating Cache Valley virus (Weaver, 2009).

Conclusions. Cache Valley virus infects livestock and has been found to contaminate biologics manufacturing processes employing bovine serum. It is a virus of concern for biologics manufacturers employing bovine serum which has not been gamma-irradiated. Risk of infection of biological products with Cache Valley virus through use of bovine serum may be mitigated through implementation of gamma-irradiation of the serum, or UVC- or high-temperature short-time (HTST) treatment of media containing the serum and of viral purification processes capable of removing and inactivating enveloped viruses.

No comments:

Post a Comment