Model Viruses

The selection of model viruses for the purpose of validation is critical and must take into account the nature and origin of the producer cell line; the model virus should be close to identical to a virus suspected in the cell line, or closely related to viruses that might infect the cell, e.g. retroviruses for recombinant or hybridoma cells.

In order to achieve a maximum reduction factor for virus, the model virus should be grown to high titers and should be detectable in a simple but sensitive assay. Care has to be taken when concentrating a virus solution in order to increase the volumetric titer: the aggregation of viral particles might lead to an increased but not relevant mechanical removal by means of filtration, or a decrease in inactivation due to protection of viral particles in the core of the aggregate.

Typically, the removal or inactivation of virus is described as "log 10 reduction", i.e. the decadic logarithm of the titer reduction.

With regard to a potential infection by an unknown virus, the model viruses for the validation of virus clearance have to cover a broad range of virus features.

Selection criteria for the choice of model viruses

Virus	Family	Genus	Natural host	Genome	Envelope	Size	Shape	Resis- tance
Vesicular stomatitis virus	Rhabdo	Vesiculo-virus	Equine Bovine	RNA	yes	70x175 nm	Bullet	Low
Parainfluenza virus	Paramyxo	Paramyxo-virus	Various	RNA	yes	100-200+ nm	Pleomorph Spherical	Low
MuLV	Retro	Type C oncovirus	Mouse	RNA	yes	80 - 110 nm	Spherical	Low
Sindbis virus	Toga	Alphavirus	Human	RNA	yes	60 - 70 nm	Spherical	Low
BVDV	Flavi	Pestivirus	Bovine	RNA	yes	50 - 70 nm	Pleomorph Spherical	Low
Pseudorabies	Herpes		Swine	DNA	yes	120 - 200 nm	Spherical	Medium
Poliovirus Sabin Type 1	Picorna	Enterovirus	Human	RNA	no	25 - 30 nm	Icosahedral	Medium
Encephalomyo- carditis virus (EMC)	Picorna	Cardiovirus	Mouse	RNA	no	25 - 30 nm	Icosahedral	Medium
Reovirus 3	Reo	Orthoreo- virus	Various	RNA	no	60 - 80 nm	Spherical	Medium
SV 40	Papova	Polyoma- virus	Monkey	DNA	no	40 -50 nm	Icosahedral	Very high
Paroviruses (canine, porcine)	Parvo	Parvo- virus	Canine Porcine	DNA	no	18-24 nm	Icosahedral	Very high

As a rule process validation has to be performed at the manufacturing scale, using equipment of identical type and size. The contamination of manufacturing equipment with virus is evidently not desireful and depending on the manufacturing scale even not technically feasible. Therefore two strategies are accepted for the validation work with virus:

More About Validation Validation Procedures Validation of Viral Clearance Calculation of the Clearance Factor

• the use of a replica for a small scale production or
• a linear downscaled model of the manufacturing equipment, on condition that all relevant process parameters are fully representative for the production scale.

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