JULY 31, 1997
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.
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