Plasma is the liquid portion of blood, containing nutrients, electrolytes (dissolved salts), gases, albumin, clotting factors, hormones, and wastes. Many different parts of plasma are used in treating the trauma of burns and surgery and for replacing blood elements that are lacking due to diseases such as hemophilia. According to estimates, each year about one million people in the United States receive products manufactured from human plasma. Plasma-derived products are purified from plasma pools by a process known as fractionation. This procedure involves a series of steps so that a single plasma pool yields several different protein products such as albumin and immune globulins. Plasma used for plasma-derived products manufactured and distributed in the United States may only be collected at facilities licensed and registered with the FDA. Centers require donors to provide proof that they are in the United States legally and have a local permanent residence. About 85 percent of plasma comes from paid donors in a commercial setting and is known as source plasma. The remaining 15 percent of plasma comes from volunteer donors and is known as recovered plasma. Units of plasma collected as source plasma contain approximately 825 milliliters; recovered plasma from whole blood donations contains approximately 250 milliliters. Thus, more than three times as many donated units of recovered plasma are required to make up a plasma pool equal in volume to one comprising only source plasma. Corporation, Baxter Healthcare Corporation, Bayer Corporation, and Centeon LLC. An additional 1.8 million liters of plasma are collected from approximately 8 million volunteer (not paid) donors, who contribute 12 to 13 million whole blood donations each year. These donors give blood at American Red Cross blood centers and independent blood centers represented by the trade group, America’s Blood Centers, and the plasma is recovered for further manufacturing. Plasma collected by the American Red Cross is fractionated under contract by Baxter Healthcare and the Swiss Red Cross and returned to the American Red Cross for distribution. Plasma collected at centers represented by America’s Blood Centers is sold only to the Swiss Red Cross, which manufactures the various plasma products and sells them through U.S. distributors. Paid donors typically receive between $15 and $20 for the 2 hours of time required to remove whole blood, separate the plasma from the cells and serum, and reinfuse the latter back into the donor. Source plasma donors may donate once every 48 hours but no more than twice a week. Whole blood donors may only donate once every 56 days because their red cells are not reinfused as they are with paid donors. All donors are tested for certain viruses known to be transmitted through blood, including HBV, HCV, and HIV. The specific screening tests check for the presence of hepatitis B surface antigen (HBsAg), antibodies to hepatitis C (anti-HCV), HIV-1 antigen, and antibodies to HIV types 1 and 2 (anti-HIV). Donors with positive test results are rejected from making further donations. The positive unit and all previously donated plasma units not pooled for manufacture in the preceding 6 months are retrieved, and those professional services that receive the plasma products are notified according to federal regulations (21 CFR 610.46). The risk of incorporating a potentially infectious plasma unit into a plasma pool for HIV, HBV, or HCV is somewhat higher for donations from paid donors than for donations from volunteer donors. Information we obtained on viral marker rates for volunteer donors from the American Red Cross and for paid donors from the American Blood Resources Association (which represents paid plasma collection centers) showed viral marker rates among individuals who offer donations to paid plasma centers to be one and a half times higher than rates among those who come to volunteer blood centers. This is due to higher HCV rates among paid donors. In addition, incidence rates of HIV, HBV, or HCV are higher among paid donors than they are for volunteer donors, according to our review. These rates include donors who pass the initial screening tests and donate but who subsequently seroconvert and whom a screening test later detects during another donation as being positive. Thus, potentially infectious units from these donors could be incorporated into a plasma pool for manufacturing. HIV incidence rates are 19 times higher for paid donors than for volunteer donors; HBV and HCV rates are 31 times and 4 times higher, respectively. included in that pool if it were made exclusively from donations from paid donors. Concerns have been raised about the size of plasma pools because larger pools expose recipients of plasma products to more donors, raising the risk of infection. Manufacturers have recently taken steps to reduce the size of the plasma pools they use for producing plasma derivatives. Modeling techniques indicate that this effort can affect infrequent users of these products by minimizing their exposure to a certain number of donors. Frequent users of plasma products, such as hemophiliacs, however, tend not to benefit from these techniques because of the large number of different pools to which they are exposed during their lives. As recently as a year ago, FDA believed that initial fractionation pools contained 1,000 to 10,000 source plasma units or as many as 60,000 recovered plasma units. In response to inquiries from your Subcommittee, however, FDA obtained information from plasma manufacturers showing that after adjusting for the combination of intermediates, pooling of material from several hundred thousand donors for single lots of some products sometimes took place. For example, albumin can be added during intermediate processing steps or to a final product, such as factor VIII, for use as an excipient or stabilizer. This albumin often comes from another plasma pool containing donations that are not in the original pool. Because of concerns about pool size, the four major plasma fractionators voluntarily committed to reducing the size of plasma pools, measured by total number of donors, to 60,000 for all currently licensed U.S. plasma products, including factor VIII, factor IX, albumin, and immune globulin intravenous. This measurement takes into account the composition of starting pools, combining of intermediates from multiple pools, and use of plasma derivatives as additives or stabilizers in the manufacturing process. Prior production streams are still being processed and distributed, however, so that products distributed through the end of 1998 may still be produced from pools that exceeded the 60,000-donor limit. further manufactured by Baxter Healthcare. Seventy-five percent of all American Red Cross plasma manufactured by the Swiss Red Cross is now at the 60,000-donor limit, with plans for all production to adhere to the limit in the near future. In a study employing the modeling technique noted above, researchers found that limiting the number of donors in a pool may only be marginally beneficial for infrequent recipients, who might be exposed to an emergent unknown infectious agent with a low prevalence in the donor population, which current manufacturing processes did not inactivate or remove. As an example, the researchers calculated that for an agent with a prevalence of 1 in 500,000 (for example, a rare or emerging virus), a pool comprising 10,000 donations would yield a 2 in 100 chance of exposure to that agent for a one-time recipient. For frequent users of plasma products (that is, 100 infusions during a lifetime), however, this same pool size of 10,000 would yield an 86 in 100 chance of exposure to that agent, assuming that the products would come from different pools. Reducing the number of donors in a pool does not significantly decrease this effect. Thus, these modeling data suggest that smaller plasma pool sizes will reduce the likelihood of transmission of viral agents to infrequent users of plasma products but will have only a minor impact on frequent recipients of such products. In addition, risk of exposure does not always equate with risk of infection. In fact, risk of exposure is always greater than or equal to risk of infection. For example, the recent transmission of HCV by a plasma derivative that had not undergone viral inactivation procedures showed that the risk of seroconversion for recipients of this product increased with the number of positive HCV lots infused and the quantity of HCV viral material infused. Not all recipients were infected, however, because the highest percentage of seroconversions seen with the highest levels of HCV virus infused did not exceed 30 percent. Not all recipients experience seroconversions because of two factors: (1) each recipient’s dose and (2) the reduction of infectiousness due to steps in the manufacturing process in addition to viral removal and inactivation. As mentioned, certain infectious units could make it through the donor screening, deferral, and testing process. Manufacturers have, therefore, introduced additional steps in the fractionation process to inactivate or remove viruses and bacteria that may have gotten into plasma pools. These techniques virtually eliminate enveloped viruses such as HIV, HBV, and HCV. They are only partly effective, however, against nonenveloped viruses such as HAV and human parvovirus. All types of plasma derivatives undergo viral inactivation or removal. The two main methods of inactivation are heat treatment and solvent-detergent treatment. To be effective, inactivation techniques must disrupt the virus, rendering it noninfectious. Heat treatment is accomplished either by exposing the freeze-dried product to dry heat or suspending it in a solution. Another technique heats the completely soluble liquid product with the addition of various stabilizers such as sucrose and glycine. The second technique, solvent-detergent washing, exposes the product to an organic solvent to dissolve the lipid coat of viruses, rendering them inactive without destroying the plasma-derived products. The lipid membrane contains critical viral proteins needed for infection of host cells. Disrupting the viral lipid envelope renders the virus noninfectious. Solvent-detergent inactivation is only partly effective, however, in eliminating nonlipid-coated viruses such as HAV or human parvovirus. Assessing the amount of viral clearance obtained through a particular inactivation or removal process determines the effectiveness of these different procedures. This assessment is based on the amount of virus that is killed or removed and therefore the extent to which these processes eliminate viruses through manufacturing.