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STATEMENT BY

KATHRYN C. ZOON, PH.D.

DIRECTOR, CENTER FOR BIOLOGICS

EVALUATION AND RESEARCH

FOOD AND DRUG ADMINISTRATION

DEPARTMENT OF HEALTH AND HUMAN SERVICES

BEFORE THE

SUBCOMMITTEE ON HUMAN RESOURCES AND

INTERGOVERNMENTAL RELATIONS

COMMITTEE ON GOVERNMENT REFORM AND OVERSIGHT

U.S. HOUSE OF REPRESENTATIVES

JULY 31, 1997

I. INTRODUCTION

Mr. Chairman and Members of the Committee, I am Dr. Kathryn Zoon, Director, Center for Biologics Evaluation and Research (CBER) of the Food and Drug Administration (FDA). I appreciate this opportunity to discuss the safety implications of plasma pool sizes in the manufacture of fractionated blood products. My testimony also will address FDA measures which ensure the safety of all pooled plasma derived products.

Let me state up front that FDA believes there should be upper limits set on plasma pool size for public health reasons which I will discuss later in this testimony. It is important to remember, however, that pool size is only one factor to be considered in minimizing the risks associated with plasma derived products. This is one of many different approaches to reducing the risks of blood and plasma derived products.

II. PRODUCT SAFETY

On June 5, 1997, FDA testified before this Committee on its efforts designed to ensure the safety of the blood supply, particularly plasma derived products. Let me briefly reiterate some of the most recent steps that FDA has taken directed towards improving and ensuring the safety of the blood supply and plasma derived products.

CBER's internal emergency response procedures have been improved to facilitate a more effective response to potential and actual emergency situations. The lead responsibility for conducting inspections of plasma fractionators has been transferred to the field organization (Office of Regulatory Affairs). Recent inspections have been more comprehensive and greater attention has been given to good manufacturing practices (GMPs) in the manufacture of blood and plasma derived products. Moreover, FDA has provided enhanced public access to recalls and withdrawals of fractionated plasma products by providing easily accessible information through the Internet, faxes, and e-mail.

FDA continues to utilize a five layer system of overlapping safeguards, each contributing to blood and blood product safety. With donor screening, potential donors are provided educational materials and asked specific questions by trained personnel about their health and medical history. Potential donors whose blood may pose a health hazard are asked to exclude themselves. Donors also are excluded based on risk of malaria, Creutzfeldt-Jakob Disease (CJD), and acute illness. In addition, donated blood is tested for blood-borne agents such as Human Immunodeficiency Virus-1 (HIV-1), HIV-2, Hepatitis B (HBV), Hepatitis C (HCV), and syphilis. Blood establishments must keep current a list of individuals who have been deferred as blood or plasma donors and check all potential donors against that list to prevent use of units from deferred donors. Blood products are quarantined until products have been tested and donation records have been verified. Blood establishments must investigate any breaches of these safeguards and correct system deficiencies that are found by the establishments or through FDA inspections.

Recent advancements in blood safety include the following. In March 1996, FDA approved the HIV-1 p24 antigen test and issued recommendations for its implementation. These tests improve blood safety by further closing the "window period" before antibodies to HIV develop. FDA issued guidance to blood establishments on the deferral of donors who immigrated from countries with HIV-1 Group O (a new strain of HIV for which testing methods were unavailable). FDA also advised manufacturers of test kits to modify their kits to enhance sensitivity to detect HIV-1 Group O specimens. In September 1996, FDA issued a final regulation on "Current Good Manufacturing Practices for Blood and Blood Components: Notification of Consignees Receiving Blood and Blood Components at Increased Risk for Transmitting HIV Infection." The final rule requires blood establishments and consignees to quarantine previously collected whole blood, blood components, Source Plasma, and source leukocytes from donors with reactive screening tests for HIV. Blood establishments also must perform confirmatory testing for donations that test reactive for HIV and notify consignees of prior collections so that they may take further action. FDA now requires plasma derivative manufacturers to file monthly reports on adverse experience reactions of potential infectious disease transmissions associated with their products. FDA has been working with manufacturers to ensure that all plasma derived products have adequate viral clearance in manufacturing and, in the interim, has instituted lot release testing for HCV nucleic acid for any non-viral inactivated immune globulins.

III. CREUTZFELDT-JAKOB DISEASE (CJD)

The issues raised in the January 29, 1997 hearing before this Committee on CJD still hold true today. (FDA's January 29, 1997 testimony is appended for reference.) FDA has acted to reduce the theoretical risk of CJD transmission through blood and blood products. Although the risk for transmission of CJD through the blood supply is only theoretical, FDA has acted proactively to defer high risk donors and has recommended voluntary withdrawal of affected products. FDA first issued guidance on CJD in 1987 concerning the deferral of donors who had received human growth hormone derived from human pituitary sources. FDA issued an interim policy in a memorandum dated August 8, 1995, regarding blood products and plasma derivatives. This memorandum further broadened its guidance on donor exclusions for CJD risk and called for withdrawal of implicated blood products. A provision was made for release of affected products in case of a documented shortage provided that the products carried a special label. In December 1996, FDA issued its latest guidance on precautionary measures to reduce the possible risk of transmission of CJD by blood and blood products. There is presently no test available to screen blood donors for the presence of CJD. In fact, there is still controversy over the nature of the causative agent.

FDA continues to work with it sister agencies, National Institutes for Health (NIH) and the Centers for Disease Control and Prevention (CDC), to review studies and surveillance data on CJD. With CDC and NIH, FDA continues to evaluate the risk of CJD transmission through the blood supply.

IV. BACKGROUND: PLASMA DERIVED PRODUCTS

Each year, approximately 14 million units of whole blood are collected from about 8 million volunteer donors to make components that are transfused directly into more than 3.5 million Americans. Some of the plasma from these collections (recovered plasma from Whole Blood) is used for fractionation into plasma derived products. Approximately an additional 12 million units of Source Plasma are collected through plasmapheresis for processing into derivatives. These products include albumin used to restore plasma volume, clotting factors used to treat hemophiliacs, and immunoglobulins used to treat or prevent a variety of diseases.

It is estimated that per annum the number of patients who rely on products manufactured from human plasma is as follows: more than 400,000 are given albumin; 15,000-18,000 are given Factor VIII; 3000-5000 receive Factor IX; greater than 20,000 receive intravenous immune globulins (IVIG); and approximately 100,000 to 500,000 receive intramuscular immune globulins (IMIG). Additional patients receive a variety of hyperimmune globulins and other specialized products.

V. 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)).

Units of plasma collected as Source Plasma contain approximately 500-800 milliliters while recovered plasma from Whole Blood donations contain approximately 200-250 milliliters. A pool comprised only of recovered plasma includes units from more individuals donations than a pool of equal volume comprised only of Source Plasma because of the difference in volumes.

The various plasma derived products are purified from the plasma pool by the fractionation process. The basic methods for plasma fractionation were first developed and refined in the 1940s. These methods form the basis for the plasma derivative industry practices today.

Fractionation is a process which separates plasma proteins based on the inherent differences of each protein. Fractionation involves changing the conditions of the pool (e.g., the temperature or the acidity) so that proteins that are normally dissolved in the plasma fluid become insoluble, forming large clumps, called precipitate. The insoluble protein can be collected by spinning the solution at high speeds. One of the very effective ways for carrying out this process is the addition of alcohol to the plasma pool while simultaneously cooling the pool. For this reason the process is sometimes called cold alcohol fractionation or ethanol fractionation. This procedure is carried out in a series of steps so that a single pool of plasma yields several different protein products, such as albumin and immune globulin.

As knowledge of plasma proteins increased, additional methods were developed to prepare still more unique proteins from plasma. These methods could be added on to the basic cold alcohol fractionation. For example, in the 1960s it was learned that simply thawing frozen plasma at low temperature resulted in a white precipitate called cryoprecipitate that could be separated from the plasma by centrifugation. This substance proved to be very rich in Factor VIII, the clotting factor used to treat Hemophilia A. Factor VIII is then purified from the cryoprecipitate. The plasma fluid left over after the cryoprecipitate is harvested can then be processed to yield albumin and immune globulin.

VI. VIRAL INACTIVATION/REMOVAL PROCESSES

Just as the desired plasma derived products can be separated from each other by chemical or physical means based on the individual properties of the product, contaminating viruses may concentrate selectively in certain fractions because of their properties. The risk to a patient from any particular agent may vary with the particular plasma derivative. Thus, FDA believes that all plasma derived products should undergo viral inactivation or removal procedures to ensure safety.

Most plasma derivative products are processed to inactivate or remove viruses. At present, the technology exists to inactivate lipid enveloped viruses such as HIV, HBV, and HCV. The technology to inactivate heat stable, non-lipid enveloped viruses, such as the Hepatitis A virus, or agents such as CJD while preserving the functions of plasma proteins is not currently available.

There are highly effective mechanisms for removing or inactivating certain viruses. Two different methods of inactivation are heating and chemical inactivation. These inactivation procedures must be rigorous enough to inactivate the contaminating virus without destroying the plasma derivative. Some manufacturers have incorporated more than one viral inactivation or removal procedure during the manufacturing steps. This combination of inactivation or removal procedures provides additional assurances of safety.

Heat inactivation is the heating of the product at a specific temperature for a specific time under defined conditions. FDA regulations require that albumin (Human) and Plasma Protein Fraction (PPF) be heated for 10-11 hours at 60 degrees Centigrade in the final container to ensure viral inactivation (see 21 C.F.R.  640.91(e), 640.81). Certain viruses, such as HIV, are fairly fragile and are readily inactivated by these heating procedures.

Chemical inactivation involves the addition of certain chemicals to the plasma preparation. For example, some manufacturers add certain solvent/detergent mixtures in their manufacturing processes. The chemicals are removed later in the manufacturing scheme. These processes disrupt viruses that contain lipid-envelopes, such as HIV, HCV, or HBV, without destroying the plasma derived products. HIV and other viruses have a lipid membrane surrounding the viral core. The lipid membrane contains critical viral proteins needed for infection of host cells. Disrupting the viral lipid envelope renders the virus non-infectious. Other viruses which do not have a lipid envelope are not inactivated by these procedures.

Steps that purify the plasma protein may simultaneously remove viral particles whether or not the particles contain a lipid envelope. One example of a viral removal procedure is the use of a monoclonal antibody column to purify a plasma derivative such as Factor VIII. In this instance, antibodies to the Factor VIII are generated in large amounts in tissue culture. The antibodies are attached to a support within a column. The plasma pool or intermediate product is passed through the column. The Factor VIII binds to the specific antibody while the fluid containing other plasma derived products, and possibly contaminating viruses or other agents, flows through the column. The Factor VIII can later be removed from the antibody column. These processes do not inactivate any contaminating agent but may remove them from the desired Factor.

In the 10 years since the adoption of adequate viral inactivation procedures, there has not been any confirmed case of HIV transmission through a plasma derivative. Recent experience involving Hepatitis A transmission through clotting factors and HCV by intravenous immune globulins produced without adequate viral inactivation procedures, however, reminds us of the need to remain vigilant and to continue our efforts to improve product safety.

Each of these inactivation or removal processes has its particular advantages. Except for the heating of albumin and PPF which is mandated by regulation, the inactivation or removal process may vary with each manufacturer. During the approval process, FDA requires a manufacturer to demonstrate by laboratory studies the effectiveness of its process and to provide validation to ensure that the process works as expected, time after time. FDA evaluates the clearance methods and the validation studies when reviewing license applications. These operating procedures practices also are reviewed during inspections.

VII. CURRENT PLASMA POOL SIZE ESTIMATES

FDA has not established an upper limit to the size of plasma pools for the manufacture of plasma derived products. FDA regulations are silent on pool size requirements except to specify the minimum pool size for the manufacture of Immune Globulin (Human), a product used to treat Hepatitis A (see 21 C.F.R. 640.102(d)). Therefore, FDA has limited information concerning the pool size used by manufacturers of plasma derived products.

According to information obtained from a plasma fractionators' trade organization, for the manufacture of albumin, Factor VIII, Factor IX, and the immune globulins, an initial fractionation pool was estimated to contain 1,000 to 10,000 Source Plasma units, or as many as 60,000 recovered plasma donations. For some products, smaller pools may be used; for instance, specific immune globulins, such as anti-Rho-D¹, are thought to be manufactured from plasma pools collected from between 150 and 2500 donors. Recent information indicates that the pool size, after adjustment for combination of intermediates, may result in the pooling of material from several hundred thousand donors for single lots of some products.

In some cases, the plasma pool size equals the sum of all plasma donor units used in the starting pool for manufacture of one lot of final product. More often during manufacturing, intermediate material derived from more than one starting pool may be combined into one lot prior to processing into final product. In these cases, the plasma pool size is the sum of all the plasma pools from which the intermediate products were derived. Plasma derived products from other pools may be combined during the fractionation process or added to the final product. For example, albumin is added during intermediate processing steps or to a final product, such as Factor VIII, for use as an excipient or stabilizer. This albumin often has been derived from another plasma pool.

VIII. CURRENT FDA ASSESSMENT OF POOL SIZE

FDA's goal is to continue to minimize the risks associated with blood and plasma derived products. One possible means of minimizing risk is to reduce plasma pool size in the manufacturing of plasma derived products. FDA believes that there should be upper limits set on plasma pool size for public health reasons.

The benefits of limiting pool size are that the infectious risk for infrequent users would be reduced in instances where the prevalence of the infectious agent is low. Reduction in pool size might also lessen the impact of recalls and withdrawals on supply of the products.

In setting upper limits on pool size, potential adverse consequences also must be considered. Decreasing pool size may decrease the number of vials available from a batch. With small size batches, quality monitoring and release testing could consume a large portion of the batch. Decreasing batch size in existing plants may result in sub-optimal processing. Decreasing batch size in existing plants might decrease overall product availability.

It should be noted, also, that reducing pool size necessarily would require the production of a larger number of lots of any given product to be produced in order to maintain the supply of that product at a constant level. Therefore, for the full benefit of the smaller pools to be realized by the recipients of these products, measures also must be taken to insure that the recipients are not exposed to more lots of product and, thereby, to more pools.

It may be that there are other approaches to reduce risk, including additional and more sensitive testing methods, improved donor screening processes, improved viral clearance procedures, and improved plasma management practices. FDA is committed to examining all of these possibilities.

IX. HISTORY OF FDA ACTIONS RELATING TO POOL SIZE

Many of the steps mentioned above, such as donor screening, donor testing, donor deferral, product quarantine, reporting requirements, viral clearance, and FDA inspections, greatly reduce the disease risks associated with plasma derived products. Continuous efforts, however, need to be made to reduce the risks to ever lower levels. Although reducing the pool size of plasma derived products has been under consideration for some time, increased attention to this issue has risen because of consumer interest, CJD, and recent recalls.

At the March 1995 Blood Products Advisory Committee (BPAC) meeting, FDA asked whether reducing the size of plasma pools from which plasma derived products are manufactured would be an effective precaution against transfusion-transmitted diseases and under what circumstances FDA should consider mandating limits to the scale at which certain plasma derived products are manufactured. BPAC made no recommendation to adjust pool size for plasma derived products.

In response to further discussions with consumer groups and recommendations of this Committee in its August 1996 report, FDA reconsidered the issue of pool size and brought the issue to the December 1996 BPAC for reconsideration. The following limits were discussed for implementation in the short term: 15,000 donors per pool for products manufactured from source plasma and 60,000 donors per pool for products manufactured from recovered plasma. Over the longer term, FDA proposed, for discussion, further reductions of pool sizes. Additionally, FDA also proposed that whenever possible a plasma derivative such as albumin that is added as a stabilizer or excipient to another product should be derived from the same plasma pool as the product to which it is added.

Industry representatives voiced concerns that significant reductions in plasma pool size were not feasible primarily due to cost and manufacturing capability considerations. No recommendation on pool size was made by BPAC as it was determined that there was insufficient data on which to base a policy decision.

On February 7, 1997, the International Plasma Products Industry Association (IPPIA) wrote FDA after reviewing the proposals made at the December 1996 BPAC meeting and urged that there be no further discussion on limiting pool size. The letter stated that no safety benefits would result from pool size reduction. Further, IPPIA stated that pool size reduction would result in significant product supply reductions, as well as very significant time and costs increases involved for remodeling manufacturing facilities to accommodate smaller production scale equipment.

In response to that letter, FDA stated a continued interest in setting practical upper limits on plasma pool size. FDA pointed out that pool size limits could limit risk of disease transmission for patients who are infused infrequently and lessen the impact of product withdrawals or recalls. This remains FDA's position.

On June 26, 1997, FDA sent a letter to certain plasma fractionators requesting detailed information on plasma pool size. The purpose was to collect additional information upon which to base a final decision on pool size. The letter also asked for information on plasma recovery practices which may further increase the pool size. FDA has not fully assessed the interim estimates of pool size obtained in response to this letter. After more detailed information is collected, analyzed, and verified, FDA will be able to make a more informed proposal on limiting pool size.

Since FDA's request, IPPIA has expressed interest in continuing to discuss with FDA the issues related to increased plasma product safety. IPPIA met with FDA on July 14 to further those discussions.

X. CONCLUSION

FDA faces significant challenges in helping to ensure the safety of plasma derived products. We must strive for improvements in the regulation and management of plasma derived products and the plasma fractionation industry. As a part of this effort, we believe that there should be practical upper limits on pool size for the above-mentioned public health reasons. It is important to remember that pool size is only one factor to be considered in ensuring the safety of plasma derived products. Good manufacturing practices and our enforcement of those practices is also an important part of the system of overlapping safeguards that contribute to the safety of plasma derived products, and we remain vigilant in our efforts to enforce the good manufacturing practice regulations through the use of regulatory inspections.

¹This is used to prevent complications during pregnancy when there are different Rh types between the mother and fetus.

(Hypertext updated by jch 1999-JUL-16)
http://www.fda.gov/ola/1997/plasma.htm

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