KATHRYN C. ZOON, PH.D.
DIRECTOR, CENTER FOR BIOLOGICS
EVALUATION AND RESEARCH
FOOD AND DRUG ADMINISTRATION
DEPARTMENT OF HEALTH AND HUMAN SERVICES
SUBCOMMITTEE ON HUMAN RESOURCES AND
COMMITTEE ON GOVERNMENT REFORM AND OVERSIGHT
U.S. HOUSE OF REPRESENTATIVES
JULY 31, 1997
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
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
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
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.
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
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
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
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
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
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
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
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
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.
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.
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(Hypertext updated by jch 1999-JUL-16)
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