First, a primer on the definition of Blood plasma. Human Blood plasma is the yellow, protein-rich fluid that suspends the cellular components of whole Blood, that is, the red Blood cells, white Blood cells and platelets. Plasma is a very complex and not fully understood mixture of proteins that performs and enables many housekeeping and other specialized bodily functions. In Blood plasma, by far the most prevalent protein is albumin, approximately 32 to 35 grams per liter, which helps to maintain osmotic balance of the Blood. Science and medicine are unable to make Blood Plasma.
Blood plasma is accumulated by Blood banks and Blood collection facilities, principally, in two ways: plasma separated from donor collected whole Blood, and from donated plasma, a process by where whole Blood is drawn from a donor, the plasma is separated and then the remainder, less the plasma, is returned to the donor. The human body will completely replace the lost plasma in a matter of days.
Much the same as crude oil is broken down into its component parts, Blood plasma, once separated from the other components of whole Blood, can be further separated into a number of valuable Blood products. Some of these Blood products are very valuable. The process by which plasma is separated into some of its different component parts is known as fractionation. Blood plasma fractionation is not a new process. The fractionation industry grew out of the great need for Blood and Blood products during World War II. This urgent need to replace Blood, or at least the fluid volume of Blood, inspired Dr. Edwin Cohn, in 1940, to develop a method of isolating albumin. Modern technology has changed these processes considerably, improving the quality and variety of the derivative Blood component products available for use and further processing.
Plasma-derived products are manufactured from batches of Blood plasma collected from many thousands of Blood donors. The processing of one pooled lot of plasma can take up to six months and, because of concerns about infectious agents, by rule, the process begins with a 90-day quarantine period. Unlike cellular Blood components, Blood products derived from plasma can be treated with chemicals, heat, ultraviolet radiation or filtration to decrease cost and to increase ease of handling and distribution, and to increase the safety of the Blood supply. Each of these methods has some drawbacks: they may leave unsafe levels of some viruses, be very costly, and/or damage the Blood or Blood plasma.
Quantified and defined by volume, albumin continues to be the main product of the Blood plasma fractionation industry. Though there are many uses, its principal use is in restoring Blood volume in a wide variety of critical care settings.
Rather than using whole Blood transfusions, doctors are increasingly using individual Blood components such as red cells, white cells, platelets, and plasma. Plasma is fractionated into an increasing number of Blood products, including albumin, gamma globulins, blood-typing sera, clotting factors for people with hemophilia, and more. Umbilical Cord Blood and Free Cord Blood Registry products.
Immunoglobins constitute an important class of Blood plasma products. This is a group of antibodies made by the body as part of its immune response "team." These products generally confer immediate, though temporary, protection either from a specific agent, such as rabies virus or snake venom, or arising from a non-specific threat such as in cases where an individuals immune system is weakened due to serious illness or medical treatment which may have an adverse effect on the patient.
Two main groups of immunoglobins are produced:
The best known of the Blood plasma products are the Blood clotting factors, necessary for the wellbeing of those with hemophilia. These can be derived from donated Blood plasma and administered to individuals who are genetically unable to produce all of the components necessary for Blood clotting. The most commonly known need is for Factor VIII, a Blood clotting agent, by hemophiliacs.
NOW MORE ABOUT BLOOD PLASMA POOLING
This pooling of donated Blood plasma is made necessary by a new technique that substantially reduces costs and potentially facilitates an easier purifying of the plasma product. The "detergent cleansing" process is not cost effective in small batches.
The New York Blood Center developed this solvent-detergent technology, cleansers that dissolve the fatty coating of viruses such as some HIV, hepatitis B and hepatitis C, some of the so-called lipid-enveloped viruses. It then washes them out of the treated batch.
This process has been used in drugs made from Blood plasma, such as immune globulin or hemophiliacs' clotting factor, for years. But in 1994, the New York Blood Center created a company called Vitex, or V.I. Technologies Inc., to sell it for cleaning whole plasma. Vitex, in turn, licensed the Red Cross to distribute supplies.
The Red Cross markets SD plasma under the brand name PLAS+SD.
SD BLOOD PLASMA (PLAS+SD)
Plasma pooling facilitates the treatment, for purposes of economies of scale, handling, distribution and Blood safety, of collected Blood Plasma. This collected and aggregated Blood plasma is placed in a common vat for this process. The process, producing what is known as Solvent Detergent Blood plasma (SD plasma, PLAS+SD), is a relatively new Blood plasma product. The process was approved by the Food and Drug Administration (FDA) in August of 1998. SD Blood plasma is a Blood product that has undergone treatment with the solvent tri-N-butyl phosphate (TNBP) and the detergent Triton X-100 to destroy any lipid bound viruses including: HIV1 and 2, HCV, HBV and HTLVI and II. The process does not destroy non-enveloped viruses such as parvovirus, hepatitis A virus, or any of the prion particles. The SD process includes the pooling of up to 500,000 units of thawed Fresh Frozen Blood Plasma (FFP), treating it with the solvent and detergent. The treated Blood plasma pool is then sterile filtered (and thus leukocyte-reduced) before being repackaged into 200mL aliquots or bags and re-frozen. This separation into smaller units is to facilitate handling, distribution and use by the the transfusion recipient or the Blood product reprocessor. SD Blood plasma can be stored for up to one year frozen at -18° C. When ordered for transfusion it is thawed in a water bath to a use temperature of 37° C, which takes approximately 25 to 30 minutes and can be kept refrigerated for up to 24 hours at 1° to 6° centigrade. Only ABO identical or compatible SD Blood plasma can be transfused.
SD plasma, now widely used, will replace some of the 2.5 million units of plasma, the liquid part of blood, used by tens of thousands of Americans to treat certain common diseases. It does not, however, clean the 13 million units of red Blood cells that are transfused into millions of Americans every year.
And it comes with a downside: The plasma can be washed only if donations from many thousands of donors is pooled. "Pooling," in this context, is defined as the mixing together, in a vat, of the Blood plasma that has been separated from the whole Blood donated by 2,000 to tens of thousands of Blood donors. This means that should a virus that does not respond to the plasma "washing technique," such as hepatitis A or some other dangerous or potentially dangerous new pathogen, slip in, many more people would be exposed. That is, every one of the thousands of Blood transfusion recipients who receive Blood products from this tainted Blood plasma "pool," would share that exposure to the virus or disease. Many physicians prefer to use packaged plasma that is from one donor and tracked from "arm to arm." This technique has been licensed in the United States; it is not yet licensed in Canada.
Some Disadvantages of Pooled SD Plasma
There are some disadvantages of Blood plasma pooling (SD Plasma) that are universally recognized. Most obviously, it is a pooled plasma product. A single donor infected with a pathogen not inactivated by this "SD treatment" will contaminate an entire pool and potentially infect many or all recipients receiving Blood plasma or Blood products exposed to Blood from the pool. For pooled SD Plasma this risk appears low from the lipid enveloped group of viruses, but outbreaks of Hepatitis A (HAV), a non-enveloped virus, have already been attributed to pooled SD treated Factor VIII concentrates. This is despite the theoretical neutralizing activity of the antibody to Hepatitis A virus from immune donors in these very large plasma pools. HAV may be an indicator for other recognized or unrecognized transmissible pathogens contaminating products derived from these huge plasma pools. These may include Parvovirus B19, new agents of hepatitis, the agent(s) of the spongiform encephalopathies like Creutzfeld-Jakob disease, and unexpected future pathogens. There is no testing of any Blood or Blood product for any prion disease.
One of the other problems is that some microorganisms are actually contained inside of the Blood cells; so many of these agents, while being effective to attack and kill microorganisms in the plasma or attached to cells, can not actually get to the microorganisms that are alive and well inside the cells.
By the way, what about those Blood cells? We, in the United States, transfuse a huge number of red cells and yet red Blood cells remain a major challenge in terms of our ability to sterilize them reliably. It has been clearly demonstrated that some microorganisms such as HIV will bind to the red Blood cell membrane. Photochemical methods have been tried, dimethylene blue and some oxidizers. Problems have remained with the fact that many of the agents which are effective to attack a lipid envelope; and the red Blood cell itself has a lipid envelope. Therefore, it is a trade-off between being able to get adequate viral kill while not destroying the red Blood cells.
Many groups are watching this plasma pooling process very carefully, among them, the House Committee on Government Reform, in their capacity of oversight of FDA. The FDA has been repeatedly warned about the dangers of Blood pooling.
According to Harvey Alter, MD, of the National Institutes for Health's Department of Transfusion Medicine "..... the risk of pooling is greater than the risk of the infections SD technology aims to prevent. Viral inactivation has great potential, but it should not be at the expense of converting single units to pooled products ....." It is very important that the FDA does not view the incremental safety of SD plasma as sufficient to justify removal of Fresh Frozen Plasma (FFP), or pool derived Blood products, from the open market."
STATEMENT BY KATHRYN
C. ZOON, PH.D.DIRECTOR,
SUBCOMMITTEE ON HUMAN RESOURCES
U.S. HOUSE OF
PLASMA POOLING AND FRACTIONATION PROCESS
Human plasma proteins for therapeutic use
have been manufactured from large pools of plasma for over 50 years. In order to
manufacture plasma derived products, most domestic manufacturing facilities have been
designed to work at large scales, using large plasma pools to permit manufacturing of
sufficient quantities of products. These plasma pools are derived by combining units from
individual donations. The number of units combined into a common mixture for processing is
known as "pool size." Typically, plasma pool sizes will range from
thousands to hundreds of thousands of individual units. For certain products, the
use of large pools of plasma (or the pooling of multiple manufacturing batches into larger
lots) may contribute to product consistency and efficacy. For example, the production of
Immune Globulin (Human), used to treat Hepatitis A, is mandated by FDA regulation at or
above a minimum scale of 1,000 donors to ensure the inclusion of a broad spectrum of
antibodies (see 21 C.F.R. 640.102(d)).
Pooled Blood plasma approach
Plas+SD gets its name from solvent-detergent washing, a process that inactivates all viruses in the plasma and washes away "lipid-enveloped viruses," which include HIV and hepatitis B and C. It is controversial because the washing requires the pooling of plasma from up to 2,500 donors. Increasing a patients exposure to so many donors flies in the face of traditional thinking, experts say. "For pooled plasma to receive widespread acceptance, a major shift will have to take place in the way people think about Blood products," said Bernard Horowitz, PhD, executive vice president and chief scientific officer of V.I. Technologies in Melville, N.Y., the manufacturer of the solvent-detergent plasma. "What virus inactivation does is provide you with a way of achieving zero risk, despite pooling," Horowitz said.
"Solvent-detergent treatment has been used since 1985 on a variety of blood products in Europe without a single reported incidence of transmission of lipid-enveloped viruses", according to Horowitz, one of the inventors of the process. "Worldwide, 35 million doses of solvent-detergent treated products have been administered, again without a single report of virus transmission", he added.
Findings from Congressional Report on Blood Safety.
The size of plasma pools for fractionated products can increase the risk of infectious disease transmission.
In the United States, there are over 400 FDA-licensed plasma collection facilities and 5 principal pharmaceutical firms engaged in plasma fractionation. U.S. plasma collection facilities conduct approximately 13 million plasmapheresis collection procedures annually and provide 60 percent of the world's need for plasma. Plasmapheresis, a method of collecting plasma from the donor instead of whole blood, increases the plasma yield from each donor and can reduce the number of donors in each pool of plasma from which products are manufactured.
Source plasma is the non-cellular fluid portion of blood that is used as a raw material in the production of plasma-based therapies. These products are used in the treatment and diagnosis of conditions such as cardiac surgery, immune disorders, hemophilia, burns, trauma, and to provide protection against Hepatitis B, Rh disease and tetanus.
These products are made with the pooled plasma of up to 60,000 people for some products. Some potential donors have HIV, Hepatitis and other infectious diseases. Therefore, manufacturers attempt to reduce the viral load of the initial plasma prior to manufacturing, creating a greater safety margin.
But some viruses get through the donor screening process, and viral inactivation procedures such as heat treatments, pasteurization and solvent detergents are used in an effort to kill the remaining viruses in the pool.
Therefore, donor pool size is equivalent to risk. Reduction in pool size reduces the number of donors to which a recipient of fractionated products is exposed. The fewer the donors to which a recipient is exposed, the less the risk.
First-time donors present the greatest risk to the plasma and blood supply. Ninety-five percent of plasma donations which test positive for HIV or Hepatitis B or C come from first time donors who do not return to make a second donation within 3 months.
Some companies are using this information to develop new approaches to manufacturing Blood products that enhance the safety of pooled Blood plasma products. In 1994, Immuno-U.S., a major producer of plasma products, established a rigorous, multi-phase first-time donor applicant rejection system. Under this policy, the company destroys all plasma from first-time donors who do not return to make a second donation within 3 months and undergo a second round of viral testing. This eliminates the chance that a donor in the window period of hepatitis or HIV infection is donating only for the screening test results.
Immuno-U.S. has also instituted an inventory hold for 3 months in which units of plasma from first-time donors which have been screened and found suitable for production are placed on hold for 90 days. If the donor is found to be reactive to screening tests on a subsequent donation or if the donor does not return to donate again with the 90-day period, the previous plasma is destroyed. This is to eliminate the possibility of a window case of Hepatitis or HIV, where the donor may have donated only to get tested for an infectious agent. Ninety-seven percent of plasma units collected by Immuno are followed by at least one additional donation by the same donor and thus have the benefit of this inventory hold follow-up.
Immuno reports that as a result of the 3-month inventory hold, the company removed and destroyed 8 times more potentially risky plasma than would have been removed without the benefit of this program. The inventory hold program results in removal and destruction of almost 1% of the plasma collected by Immuno which otherwise would be acceptable for use by FDA standards. However, this has resulted in greater costs of production.
The fewer donations from individual donors that go into a plasma pool, the safer that pool will be. In addition, viral load has been reduced by companies which locate centers in pleasant and supportive environments, with child care. These provisions in turn encourage frequent, regular donation by desirable, low-risk donors in communities with low incidence of infectious disease.
COST of BLOOD
PLAS+SD sells for approximately $124, as opposed to about $45 for non-SD, single-donor fresh-frozen plasma (FFP.)
Prices rise. The cost of a red blood cell unit will increase from $144 to $215 per unit.
These prices vary greatly depending on which one of the 37 Red Cross regional Blood centers originating the sale.
Areas Specific to Plasma Derivatives
At the minimum, it is recommended that pooling be conducted in an environmentally controlled but not necessarily classified area (one with some level of particulate control). Manual pooling may take place either in jacketed tanks or in tanks in a temperature controlled area. Some firms have automatic equipment for "harvesting" plasma from bags or plastic bottles. These units are often equipped with HEPA-filtered areas where plasma is exposed. Although the filters may be designed to meet Class 100 conditions, this environment is not required during the pooling process. All filters should be recertified at an established frequency.
Alternative methods of processing are common and are employed mainly to recover clinically useful and economically valuable material that comes from a moderately limited starting material. CBER allows combinations of fresh source materials, tailings (residual liquid remaining after filling), older powders, frozen pastes, and reworked product to be used to manufacture Albumin or PPF, as long as the final product meets specifications. The potency and molecular integrity of material to be reworked must be evaluated to ensure that it is not compromised. Any reworking/reprocessing procedures must be validated to show that they are equivalent to licensed manufacturing procedures, and must be CBER-approved in a supplement or original license.
It is unacceptable for material from final containers in which bacterial growth occurs to be used for further manufacturing [21 CFR 640.81(g) and 640.91(g)]. Similarly, it is unacceptable to blend lots to reduce the level of adulterants, e.g., endotoxins below action limits, unless a manufacturing step designed to reduce the adulterants is used, and the process is validated and approved by CBER.
SOPs must be in place that describe the conditions and specifications for reprocessing/reworking, along with SOPs that describe conditions requiring disposal of product. A product that requires reprocessing must be sterile.
Report on any reprocessing/reworking, i.e., repooling, blending, etc., that is performed. Identify the products that undergo such procedures; the conditions under which such procedures are performed; and who approves the reprocessing plan. If failed lots are to be reworked, is an investigation conducted and documented to determine the cause of the failure before reprocessing? See also section B.3.j.4.
Environmental Control Systems
Procedures must be in place for limiting access to controlled and classified areas.
Generally, less frequent monitoring is expected in areas in which upstream steps are performed, e.g., pooling and fractionation. These steps may be performed in unclassified, but "controlled" environments (ones with some level of particulate controls). As the process moves further downstream, e.g., purification, more frequent monitoring is expected. Purification areas should be classified to a minimum of Class 100,000. With the exception of plasma pooling and fractionation, which are known to generate non-viable and viable particulates, monitoring should be performed during production. Environmental monitoring of particle counts in areas in which there are alcohol vapors may have to be performed with explosion-proof equipment.
1) Ensure that key equipment and procedures (those that could affect product quality, e.g., autoclaves, heat treatment baths, filling equipment and product contact surfaces, filling and closing of containers, lyophilizers, depyrogenation equipment) used by the firm are suitable for their intended uses.
2) Is key equipment appropriately cleaned or tagged as to status, identified, calibrated, inspected or checked, qualified and/or validated, and revalidated when necessary, according to a written program? (Refer to "Guideline on General Principles of Process Validation"; see Part VI, REFERENCES, #11).
3) Are maintenance programs/procedures in place and followed?
4) Review SOPs for equipment cleaning procedures and determine if they are validated and followed. Equipment, e.g., tanks for plasma pooling and fractionation, must be cleaned, but not necessarily sterilized. See Part VI, REFERENCES, #19.
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last updated 09/19/2005 bloodbook.com