Virus filtration is a physical separation process used to remove viruses from medical products such as vaccines, biotherapeutics, and plasma products. The goal of virus filtration is to prevent contamination of these products by removing any potential viral contaminants that may cause disease. As medical products are often cultured in systems using mammalian cells, there is always a risk of viral contamination from adventitious agents which are introduced during manufacturing. Virus filtration provides an effective safeguard against this risk.
How Virus Filtration Works
Virus filtration utilizes the difference in size between viruses and the therapeutic product of interest. Viruses are much smaller than cells or larger protein molecules. For example, viruses range between about 20-400 nanometers in diameter, while antibodies used in some biologic drugs are over 10,000 times larger at around 10 micrometers. In virus filtration, the product is flowed through a membrane with carefully controlled nanometer-scale pores. Viruses, due to their small size, are able to pass through these pores and are retained upstream of the membrane within the filter. Meanwhile, the desired product, being larger, is unable to pass through the pores and flows through to the downstream product tank. By ensuring the pore size of the membrane is smaller than all potential viral contaminants, virus filtration can effectively remove both known and unknown viruses from medical products.
Key Elements of a Virus Filtration System
There are several critical elements to a Virus Filtration system that enable it to reliably remove viruses while preserving the quality and yield of the therapeutic product:
- Virus retentive membrane: This is the filter element that separates out viruses based on size exclusion. It contains a tightly packed arrangement of nanometer-scale cylindrical pores. The pore size distribution and associated virus retention properties are precisely controlled during manufacturing.
- Feed and permeate tanks: The feed tank holds the product solution as it is flowed through the filtration system. The permeate tank collects the filtered product downstream of the membrane.
- Pressure pumps: Pumps are used to apply the necessary pressure to push the solution through the membrane pores from the feed to permeate side. Typical operating pressures are 1-4 bar.
- In-line sensors: Sensors monitor critical process parameters like pressure, flow rate, and temperature to ensure consistent virus removal performance.
- Skid frame: The filtration hardware is contained within a compact, self-contained skid frame for ease of installation and operation in manufacturing cleanrooms.
- Quality control methods: Post-filtration testing using spiking studies and PCR techniques help demonstrate effective virus clearance validation.
Understanding Virus Retention Mechanisms
There are two main biophysical interactions that govern how effectively virus filtration membranes can retain and separate viruses from larger product molecules:
Size Exclusion
As described above, the key size exclusion mechanism relies on the fact that viruses are small enough to pass through the cylindrical pores whereas the desired product is too large. For the filtration to perform consistently, the pore size distribution must be tightly controlled.
Adsorption
In addition to size, electrostatic and hydrophobic adsorption interactions can cause viruses to stick to the pore surfaces rather than pass all the way through. This adds another layer of retention capability beyond just size alone. Pore surface modifications or coatings can be designed to enhance these adsorptive interactions.
Together, careful tuning of both the size exclusion and adsorption virus retention mechanisms enables filtration membranes to achieve high log reduction values, often 4 logs or more, for a wide variety of viral contaminants. This helps ensure very high safety margins for viral clearance are achieved.
Validation and Quality Control
To demonstrate effective viral clearance, each new virus filtration process must undergo validation studies according to regulatory guidelines. This involves:
- Spiking challenge studies: Intentionally contaminating the product with a reasonable “worst case” envelope of virus types to test clearance.
- In-process hold studies: Verifying virus retention performance does not decline over multiple filter uses.
- Integrity testing: Ensuring the membrane pores remain intact using methods likediffusive flow or bubble point tests.
- Validation lots: Processing multiple full-scale validation batches for regulatory review.
Ongoing process and environmental monitoring also helps maintain consistent virus clearance throughout commercial production. With appropriately validated virus filtration systems, the risk of infective virus contamination in medical products can be virtually eliminated.
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