Wednesday, December 2, 2009

Should we care about…Vesiviruses?

By Ray Nims

Vesiviruses are single-stranded RNA viruses of family calicivirus, genus Vesivirus. They are non-enveloped and 30-40 nm in diameter, and the genus includes feline calicivirus, vesicular exanthema of swine virus, rabbit vesivirus, and San Miguel sea lion virus, as well as vesivirus isolate 2117.

source: Stewart McNulty, Queens University, Belfast, UK

Basis of Concern. Vesivirus 2117 has been isolated from biologics manufacturing processes employing Chinese hamster cell substrates on a number of occasions, the first being reported in 2003 (Oehmig et al., J. Gen. Virol. 84, 2837-2845, 2003), and additional occurrences being reported in 2008 and 2009.
The susceptibility of relevant manufacturing cell lines of different animal species to infection by this virus appears to be limited to the Chinese hamster. When infected, these cells undergo a relatively rapid lytic infection. The route of entry of the virus into biologics production processes has not been established with certainty, although the use of contaminated animal-derived materials, such as bovine sera, is considered to be the most likely source.

Regulatory Expectations. Vesivirus is not mentioned specifically in any regulatory guidance, as the detection of the 2117 isolate 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. At least three Contract Testing laboratories have announced rapid nucleic acid-based detection assays for vesivirus isolate 2117 within the past year. These assays are available for raw material screening and for in-process testing of biologics bulk harvest samples. Elimination of animal-derived materials (esp. bovine sera) from the manufacturing process may help to reduce the risk of experiencing this virus. Should this not be possible, treatment of the sera or sera-containing media should be considered. Studies on the inactivation of caliciviruses indicate that UV treatment may be effective (Duizer et al., Appl. Env. Microbiol. 70, 4538-4543, 2004; de Roda Husman et al., Appl. Env. Microbiol. 70, 50989-5093, 2004). Gamma-irradiation at the dosages normally used does not appear to be effective, as might be expected for a virus of this relatively small size. Studies using MMV indicate that high-temperature short-time (HTST)-treatment of medium containing bovine serum is effective in inactivating this virus (Schleh et al., Biotechnol. Prog. 25: 854-860, 2009), and would by implication be effective for vesiviruses in general.

Conclusions. Vesivirus isolate 2117 preferentially infects Chinese hamster cells and has been found to contaminate biologics manufacturing processes employing this cell substrate. It is now a virus of concern for the biopharmaceutical industry. Risk of infection of biological products with vesiviruses through use of bovine-derived materials such as bovine sera may be mitigated through implementation of UV or HTST treatment of media containing the sera and of viral purification processes capable of removing and inactivating an even smaller non-enveloped virus such as MMV.

1 comment:

  1. Excellent Blog Scott.