Virus Clearance Strategy Using a Three-Tier Orthogonal Technology Platform - How to implement a risk-based approach to eliminate viruses using orthogonal technologies. - BioPharm International

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Virus Clearance Strategy Using a Three-Tier Orthogonal Technology Platform
How to implement a risk-based approach to eliminate viruses using orthogonal technologies.


BioPharm International Supplements


Viral Inactivation Using UVC Radiation

In this article, we propose implementing ultraviolet C (UVC) as a third orthogonal technology for virus clearance in the downstream purification process. UVC, newly developed as a virus-inactivation technology, targets small, nonenveloped viruses and offers another robust method for removing adventitious viruses. In UVC radiation, low-dose radiation at 254 nm destroys the viral nucleic acid while maintaining the structural and functional integrity of the protein of interest. IgG losses are <5%.33 The efficiency of viral inactivation and product recovery is sensitive to the viscosity and absorption coefficient of the protein solution and its residence time in the radiation chamber.34 However, further studies are on to demonstrate the effect of UVC, if any, on the protein-folding characteristics, disulphide bonds, glycosylation, and phosphorylation patterns of the protein of interest.

Disposability, a New Paradigm in Viral Clearance

When evaluating the reliability and robustness of nanofiltration, membrane chromatography, and UVC technologies as orthogonal steps in virus clearance, the inclusion of single-use disposables to the above platform is also gaining prominence. In addition to reduced capital costs, disposables provide the flexibility and ease of operation in process optimization and early stages of manufacturing. Further, disposables eliminate cleaning, sterilization, process validation, and the risk of carryover contamination in viral-clearance studies. Various scenarios presented so far have provided evidence that the disposable option for both nanofiltration and membrane chromatography has proven to be technically possible, and furthermore, cost effective.32,35 To underline such statement, cost-model scenarios have been developed and are used to help evaluate the economic justification of sourcing disposable technologies.36

Summary

Striking an optimum balance between ensuring high pathogen safety, achieving maximum product recovery, and meeting adequate regulatory expectations is a big challenge for the biopharmaceutical industry. Nanofiltration, membrane chromatography, and UVC, together used as a technology platform for virus clearance by removal, adsorption, and inactivation, provide robust and efficient clearance capability for all viruses with major focus on small, nonenveloped viruses such as PPV or MVM. Driven by regulatory guidance, technologies with the capability to remove or inactivate small, nonenveloped viruses should be implemented from an early stage into the downstream process of a biopharmaceutical to fulfill virus-clearance expectations. Furthermore, the disposable option, when integrated into this technology platform, offers higher flexibility in manufacturing, increased ease and speed of operation, and eliminates the risk of carry-over contamination. The present age recognizes several paradigm shifts in virus and contaminant clearance, which are scalable, economical, and orthogonal. Together with these, the trend toward disposables is a clear implication to combine steps and orthogonal strategies for every objective in bioseparation to realize the industry goals for yield and quality.

SUMA RAY, PhD, is a process development scientist, viral clearance and cell line development, Global Purification Technologies Group, and KLAUS TARRACH is a senior product manager of purification technologies, both at Sartorius Stedim Biotech, Goettigen, Germany, +49.551.308.3959,

References

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3. International Conference on Harmonization. Q5A. Viral safety evaluation of biotechnology products derived from cell lines of human or animal origin. Geneva, Switzerland; 1998.

4. European Commission (Enterprise Directorate General). EMEA Guideline on virus safety evaluation of biotechnological investigational medicinal products. London: 2006 Jun 28.

5. Committee for Proprietary Medicinal Products (CPMP). Note for guidance on virus validation studies: the design, contribution and interpretation of studies validating the inactivation and removal of viruses. CPMP/BWP/268/95;1996 Feb.

6. Anderson KP, Lie YS, Low MA, Williams SR, Fennie EH, Nguyen TP, Wurm FM. Presence and transcription of intracisternal A-particle related sequences in CHO cells. J Virol. 1990;64:2021–2032.

7. Anderson KP, Low MA, Lie YS, Keller GA, Dinowitz M. Endogenous origin of defective retrovirus-like particles from a recombinant Chinese hamster ovary cell line. Virol. 1991;181:305–311.

8. Dinowitz M, Lie YS, Low MA, Lazar R, Fautz C, Potts B, Sernatinger J, Anderson K. Recent studies on retrovirus-like particles in Chinese hamster ovary cells. Dev Biol Stand. 1992;76:201–207.

9. Shi L, Chen Q, Norling LA, Lau AS, Krejci S, Xu Y. Real-time quantitative PCR as a method to evaluate xenotropic murine leukemia virus removal during pharmaceutical protein purification. Biotechnol Bioeng. 2004;87(7):884–896.


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