A novel approach to achieving modular retrovirus clearance for a parvovirus filter

Virus retentive filters are a key product safety measure for biopharmaceuticals. A simplistic perception is that they function solely based on a size-based particle removal mechanism of mechanical sieving and retention of particles based on their hydrodynamic size. Recent observations have revealed a more nuanced picture, indicating that changes in viral particle retention can result from process pressure and/or flow interruptions. In this study, a mechanistic investigation was performed to help identify a potential mechanism leading to the reported reduced particle retention in small virus filters. Permeate flow rate or permeate driving force were varied and analyzed for their impact on particle retention in three commercially available small virus retentive filters. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:959-970, 2016.

Section: Introductionmentioning

confidence: 99%

Mechanistic failure mode investigation and resolution of parvovirus retentive filters

LaCasse

Lute

Fiadeiro

et al. 2016

“…retroviruses are of a sufficiently large size that they would be effectively removed by either of the filter types tested. Filters with an even smaller pore size, i.e., 20 nm, have been shown to consistently remove retroviruses to undetectable levels from a range of different cell derived products . Where the removal of smaller viruses is important, filter selection/mode of action becomes more critical .…”

Section: Discussionmentioning

confidence: 99%

Virus elimination during the purification of monoclonal antibodies by column chromatography and additional steps

Roberts

2014

The theoretical potential for virus transmission by monoclonal antibody based therapeutic products has led to the inclusion of appropriate virus reduction steps. In this study, virus elimination by the chromatographic steps used during the purification process for two (IgG-1 & -3) monoclonal antibodies (MAbs) have been investigated. Both the Protein G (>7log) and ion-exchange (5 log) chromatography steps were very effective for eliminating both enveloped and non-enveloped viruses over the life-time of the chromatographic gel. However, the contribution made by the final gel filtration step was more limited, i.e., 3 log. Because these chromatographic columns were recycled between uses, the effectiveness of the column sanitization procedures (guanidinium chloride for protein G or NaOH for ion-exchange) were tested. By evaluating standard column runs immediately after each virus spiked run, it was possible to directly confirm that there was no cross contamination with virus between column runs (guanidinium chloride or NaOH). To further ensure the virus safety of the product, two specific virus elimination steps have also been included in the process. A solvent/detergent step based on 1% triton X-100 rapidly inactivating a range of enveloped viruses by >6 log inactivation within 1 min of a 60 min treatment time. Virus removal by virus filtration step was also confirmed to be effective for those viruses of about 50 nm or greater. In conclusion, the combination of these multiple steps ensures a high margin of virus safety for this purification process.

“…As filters remove viruses predominantly by a size‐exclusion mechanism, large viruses should be completely retained with the use of a small virus retentive filter . Stuckey et al have demonstrated that MuLV is completely retained by small virus filters even when significant parvovirus breakthrough is observed in co‐spiking experiments . An industry‐wide evaluation of small virus retentive filters also found that large enveloped viruses were reduced below the limit of detection in all 198 cases examined, providing additional rationale that viral testing only needs to be performed with smaller virus as a worst case scenario .…”

Section: Scientific and Technology Considerationsmentioning

confidence: 99%

Suitability of a generic virus safety evaluation for monoclonal antibody investigational new drug applications

Sipple

Nguyen

Patel

et al. 2019

Biologics produced from CHO cell lines with endogenous virus DNA can produce retrovirus‐like particles in cell culture at high titers, and other adventitious viruses can find their way through raw materials into the process to make a product. Therefore, it is the industry standard to have controls to avoid introduction of viruses into the production process, to test for the presence of viral particles in unclarified cell culture, and to develop purification procedures to ensure that manufacturing processes are robust for viral clearance. Data have been accumulated over the past four decades on unit operations that can inactivate and clear adventitious virus and provide a high degree of assurance for patient safety. During clinical development, biological products are traditionally tested at process set points for viral clearance. However, the widespread implementation of platform production processes to produce highly similar IgG antibodies for many indications makes it possible to leverage historical data and knowledge from representative molecules to allow for better understanding and control of virus safety. More recently, individualized viral clearance studies are becoming the rate‐limiting step in getting new antibody molecules to clinic, particularly in Phase 0 and eIND situations. Here, we explore considerations for application of a generic platform virus clearance strategy that can be applied for relevant investigational antibodies within defined operational parameters in order to increase speed to the clinic and reduce validation costs while providing a better understanding and assurance of process virus safety.