Rigorous contamination control helps speed products to market.

There is a growing need for comprehensive, integrated strategies to ensure removal of potential virus contaminants in biopharmaceutical production. Filtration, purification, and separation technologies, as well as validation capabilities, help lower the cost of drug therapy development and accelerate time-to-market. The recommendations in this article will help companies achieve marketing approval and avoid compliance pitfalls after new drugs reach full-scale production by ensuring proper test sensitivity and reliability.

As the science of biotechnology progresses, companies need to consider a greater range of variables, from lab to production scale, to maximize opportunities for success. Compliance requirements for large-scale filtration in a production environment can be different from those encountered at the laboratory bench scale qualification level. Failure to apply proper integrity testing parameters for production virus filters can result in GMP non-compliance in the scale-up and manufacturing phases, which can lead to expensive cost overruns and lost productivity.

Viruses

Viruses are infectious disease-causing agents that reproduce only in living host cells and are transmissible in cell-free biological fluids, e.g. biopharmaceuticals. They are very small particles, 20-250 nm (0.02-0.25 µm), as small as 1/10 the size of the smallest bacteria. The general structure of a virus is a core with nucleic acid (RNA or DNA) within a protein “capsid” shell. Some viruses also feature an outer membrane layer or “envelope” that is host cell-derived and incorporates both host and viral-specific surface antigens. Sources of viral contamination may be donor-associated viruses from cell lines, plasma, or tissues. Other adventitious viruses can be introduced during production from culture media (serum), purified growth factors or other additives from biological sources, monoclonal antibodies used in downstream immunoaffinity purification processes, from environmental sources originating from the air or from operators, or from formulating agents of biological origin, e.g. albumin.

Regulatory Considerations

The regulatory position on viruses given in the FDA/International Congress for Harmonization (ICH) Harmonized Tripartite Guideline is that “Confidence that the infectious virus is absent from the final product will in many instances not be derived solely from direct testing for their presence, but also from demonstration that the purification regimen is capable of removing and/or inactivating the viruses.”1 Also, the European Committee on Proprietary Medicinal Products (CPMP) Notes for Guidance on Virus Validation Studies state, “...many instances of contamination in the past have occurred with agents whose presence was not known or even suspected at the time of manufacture.”2 In light of this regulatory guidance, considerations should include:

* Risk assessment based on potential for viral presence, load, and drug indication

* Incorporation of multiple viral clearance methods

* Validation of the viral log reduction factor of each process step

* Recognition that “orthogonal” methods (i.e. with different mechanisms) can be log additive

* Determination of the total process clearance factor

The overall strategy should include screening of source materials, employment of virus “barriers” such as air, vent, and liquid filtration or inactivation, incorporation of robust viral clearance in the purification process, and testing for viruses during production.