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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 1980s. 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,
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.
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:
Immunodeficiency Virus (HIV)
Hepatitis C Virus (HCV)
Variant Creutzfeld Jakob Disease (vCJD)
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 donors blood runs through a
machine that separates the plasma and red blood cells. The red blood
cells are returned to the donors 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 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.
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
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 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
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.
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 1980s, were a solid step forward in viral
safety of plasma products. Currently, recombinant technology,
launched in the 1990s, 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