Use of MMV as a Single Worst-Case Model Virus in Viral Filter Validation Studies

Abstract

Demonstrating the virus clearance capability of a purification process is an important aspect of biopharmaceutical process development. A key component of the viral safety of the process is the inclusion of a parvovirus-grade filter as an effective and robust virus removal step. Traditional methodologies for viral clearance studies have been based on a conservative, data-intensive approach, but recent trends in the field of virus clearance and process development show evolution towards streamlined and more efficient study designs that are based on understanding the mechanism of viral clearance by downstream unit operations. The publication of scientific datasets and awareness of the underlying mechanisms involved with these unit operations have fueled this trend. Here, the concept of virus validation on a parvovirus-grade filter using a parvovirus as single, worst-case model virus is presented. Multiple lines of evidence are provided to support this proposal, including a review of published literature and Amgen historical data. The adoption of this approach provides benefits in terms of cost savings for executing viral clearance studies, but it also simplifies the necessary dataset and focuses on only supplying value-added information to demonstrate the viral safety of the process.

Mille-feuille paper: a novel type of filter architecture for advanced virus separation applications

“…2B. It has been argued that MVM serves as a suitable ''worst-case'' model system in viral filter validation studies, 41 as it is extremely resistant to physical and chemical inactivation. 3 presents the flow properties of the mille-feuille filters of varying thickness.…”

Virome of US bovine calf serum

“…Parvoviruses are particularly difficult to remove by filtration, likely due to small capsid sizes of 20–30nm (Caballero et al, 2014; Gefroh et al, 2014; Kwon et al, 2014). Based on viral particle size, the 100nm pore filtration step used in the manufacture of fetal bovine serum is not expected to completely remove parvoviruses.…”

“…Based on viral particle size, the 100nm pore filtration step used in the manufacture of fetal bovine serum is not expected to completely remove parvoviruses. The small ssDNA genomes of ~5Kb may also make parvoviruses resistant to different viral nucleic acid inactivation methods (Caballero et al, 2014; Gefroh et al, 2014; Kwon et al, 2014). The FDA mandated testing for the detection of extraneous viruses (9 CFR 111.47) includes serological tests for parvovirus antigens of bovine parvovirus ( Bocaparvovirus genus), canine parvovirus ( Protoparvovirus genus), feline panleukopenia virus ( Protoparvovirus genus), and porcine parvovirus ( Protoparvovirus genus), following tissue culture infections.…”

Surface chemistry and morphology in single particle optical imaging

“…The size of viruses varies from 20 nm to 300 nm [13]. In particular, the smallest viruses so far are found to be around 18-22 nm in diameter [14], only slightly smaller than the human antibodies with an average size of 12 nm [15,16]. While the commonly used detection methods for virus detection are conventional immunoassays and polymerase chain reaction (PCR), the former assay is limited with quantification problems and the latter requires well-established tools with high instrumentation costs and experienced labor.…”