BDI Pharma - Viral Safety Information

Viral Safety Information

In the plasma-derived pharmaceutical industry, manufacturers are acutely aware of viral safety issues because of a number of cases of transmission of HIV and Hepatitis C through the blood and plasma supply in the early 1980’s. The FDA has given approval to all coagulation factors and immune globulins on the market today, but each manufacturer has its own manufacturing process which generally includes several of many possible production methods, each of which work in different ways.

This Viral Safety Guide is an introduction to the pathogens of greatest concern and the methods manufacturers use to remove them. It is important to note that although all products available today have undergone several viral removal and inactivation processes during their manufacture, there is always risk associated with the use of a product containing a human plasma component.

For a product-specific list of viral safety methods, click here.

Pathogens

Before we look at the production methods intended to ensure that plasma products are safe for use, it is helpful to have a general understanding of the pathogens that can be transmitted in the blood.

Viruses are small, infectious particles made up of DNA or RNA that require a living host to reproduce. They can be divided into two groups: enveloped viruses that have a coating of protein that protects them, and non-enveloped viruses that lack this coating. The two types react differently to treatments that either remove the viral particles or inactivate them.

While there are a large number of viruses that can cause disease, there are several in particular whose ability to affect the blood and plasma supply is of greatest concern. These include:

· Human Immunodeficiency Virus (HIV)
· Hepatitis C Virus (HCV)
· Variant Creutzfeld Jakob Disease (vCJD)
· Hepatitis A
· Human Parvovirus B19

In addition to the viruses listed here that are known threats, plasma product manufacturers vigilantly monitor for new viral risks that may affect the safety of the blood supply. Recently emerging pathogens such as West Nile and SARS have resulted in new screening procedures to ensure that current safety measures are effective against these viruses. While the plasma industry closely monitors the safety of the plasma supply, viruses can evolve quickly, making it difficult to anticipate all safety risks.

Ensuring A Safe Product

How is plasma collected?

Product safety starts with the plasma collection process. Collection facilities carefully select their donors through a series of screening methods. Plasma is then collected through plasmapheresis, a process in which the donor’s blood runs through a machine that separates the plasma and red blood cells. The red blood cells are returned to the donor’s body as the plasma is collected. The plasma is then shipped to the manufacturer where it is purified and the necessary proteins are fractionated out.

Removal Processes vs. Inactivation Processes

Methods for clearing viruses from plasma are divided into two categories: viral inactivation processes, and viral removal processes. Other approaches to safety, such as recombinant and monoclonal technology, use fairly new scientific methods that employ minimal or no human plasma. Many products use a combination of the approaches listed below to offer a higher degree of safety.

Viral Removal

Viral removal processes use certain qualities of viruses that differ from the traits of the plasma to separate the two. Treatments separate viral particles from plasma on the basis of size, charge, or other unique chemical properties.

Filtration: Because viruses are so small, they can be filtered out of plasma on the basis of their size. The size of the filter is dictated by the size of the smallest known virus. Nano-filters and ultra-filters differ only in their pore size, but both are designed to catch even the smallest known viral particles. The disadvantage of this method is that just one particle slipping through infects the whole batch. For this reason, filtration is most effective in greatly reducing the viral load and is commonly used with other purification methods.

Chromatography: Chromatography is a process that can separate viral particles from plasma on the basis of electrical charge or affinity for a certain reagent. Once separated, the portion of the plasma that would contain any viral particles can be removed.

Precipitation and Absorption: There are reagents, such as caprylate or PEG (Polyethylene Glycol), that can cause viral particles to separate out from the mixture they are in, often by causing the particles to clump together. These clumps of viral particles may then be filtered from the plasma. Other reagents can absorb viral particles.

Viral Inactivation

Viral inactivation processes attack the viral particles themselves, causing them to be unable to produce disease. They are especially effective against any residual viral particles that may have slipped through one of the removal processes. All inactivation methods share a common disadvantage in that they are not specific only to viruses and may affect the plasma itself, making the important parts (such as a coagulation factor or immune protein) less effective. Safe stabilizing substances are commonly added to prevent the plasma components from being destroyed along with the viruses.

Solvent/Detergent Treatment: In Solvent/Detergent (S/D) treatment, plasma is treated with the combination of an organic solvent and a detergent, such as a mixture of Tri nbutyl phosphate (TnBP), and Polysorbate 80. This process chemically disrupts the lipid coat of enveloped viruses (see above for a description of enveloped and non-enveloped viruses). It is not effective against non-enveloped viruses.

Heat Treatment: In plasma that is heated through pasteurization, steam, or dry heat-treatment methods, the viral particles are physically changed and, as a result, inactivated. Heat treatment methods are commonly accompanied by the use of a stabilizing substance, preventing the heat from affecting the plasma itself.

pH Treatment: All biological molecules have an optimal pH at which they function. If a molecule is subjected to a pH too far from optimum, it may be denatured, or lose its chemical structure. Viral particles may be destroyed when subjected to an abnormally low pH. Digestive enzymes such as pepsin (an enzyme usually found in the stomach) may also be added to the low pH solution to assist in the removal of viral particles. Plasma proteins may be stabilized by reagents that prevent them from being denatured by the low pH.

Other approaches to safety

Most recently, new approaches to production specifically of coagulation factors have been developed that require little or no human plasma for production. Using advanced technology to produce factor proteins, rather than taking it from pooled human plasma, reduces the risk of contamination. Monoclonal production methods, first introduced in the 1980’s, were a solid step forward in viral safety of plasma products. Currently, recombinant technology, launched in the 1990’s, has provided the highest level of confidence in the safety of coagulation factors available in the market.

Monoclonal Products: In the production of monoclonal products, factor proteins are produced by cells cloned using the genetic material of a single human cell. The only human plasma contribution is the human DNA. Some monoclonal products are then combined with albumin, a human plasma product.

Recombinant Products: Recombinant products are manufactured using no human plasma components. In this technology, the portion of DNA which contains the code that instructs a cell to produce factor is cut out and “recombined” into a non-human cell. This cell is then able to produce the recombinant factor product. Further processing using some of the purification processes described above, such as chromatography and nanofiltration, are commonly applied to the recombinant product to further protect it.

For more information on blood safety, visit the National Hemophilia Foundation's website at www.hemophilia.org