Blood Plasma Safety: Plasma Product Risks Are Low if Good Manufacturing
Practices Are Followed (Letter Report, 09/09/98, GAO/HEHS-98-205).
Pursuant to a congressional request, GAO provided information on blood
plasma safety, focusing on: (1) comparing the risk of incorporating an
infectious unit of plasma into further manufacturing from volunteer
versus paid plasma donors for human immunodeficiency virus (HIV),
hepatitis B (HBV), and hepatitis C (HCV); (2) examining the impacts on
frequent and infrequent plasma users when pooling large numbers of
plasma donations into manufactured plasma products; (3) assessing the
safety of end products from plasma after they have undergone further
manufacturing and inactivation steps to kill or remove viruses; and (4)
examining the recent regulatory compliance history of plasma
manufacturers.
GAO noted that: (1) viral clearance techniques have made the risks of
receiving an infected plasma product extremely low when manufacturers
follow all the procedures in place to ensure safety; (2) while paid
plasma donors are over one and a half times more likely to donate
potentially infectious units (1 in every 3,834 units), a number of
recent initiatives by the source plasma industry greatly reduce the
chances of these units being pooled for manufacturing (to 1 in every
10,959 units); (3) even with these initiatives in place, the risks are
still somewhat higher from plasma units donated by paid donors than from
volunteer donors; (4) limiting the number of donors whose plasma is
pooled for production into plasma products helps to reduce the risks of
viral transmission for those receiving these products; (5) presently, a
60,000-donor limit has been established for each individual plasma
product; (6) this effort has an impact on infrequent users by minimizing
their exposure to a certain number of donors for the few times they
would be infused with a plasma product; (7) for frequent users of plasma
products, this donor limit has a negligible impact because of the large
number of infusions that they receive and, thus, the large number of
pools that they would be exposed to in the course of their lifetime; (8)
a more significant step in reducing risk of infection occurs in
manufacturing--where all plasma products for intravenous use undergo
viral removal, inactivation procedures, or both--which virtually
eliminates enveloped viruses such as HIV, HBV, and HCV; (9) this is
supported by epidemiological data on the transmission of viruses through
plasma products since the introduction of adequate viral removal and
inactivation procedures in the late 1980s as well as laboratory data
that characterize the effectiveness of viral clearance through these
procedures; (10) certain advances are only effective if the processes
used to produce finished plasma products adhere to current good
manufacturing practices; (11) this, however, has not been the case with
all of the major manufacturing companies that produce plasma products;
and (12) without strict adherence to current good manufacturing
practices related to the efficacy of viral removal and inactivation
procedures, the safety of these plasma products could be compromised.
--------------------------- Indexing Terms -----------------------------
REPORTNUM: HEHS-98-205
TITLE: Blood Plasma Safety: Plasma Product Risks Are Low if Good
Manufacturing Practices Are Followed
DATE: 09/09/98
SUBJECT: Infectious diseases
Acquired immunodeficiency syndrome
Health hazards
Product safety
Quality control
Testing
Safety regulation
Medical supplies
Consent decrees
IDENTIFIER: AIDS
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Cover
================================================================ COVER
Report to the Chairman, Subcommittee on Human Resources, Committee on
Government Reform and Oversight, House of Representatives
September 1998
BLOOD PLASMA SAFETY - PLASMA
PRODUCT RISKS ARE LOW IF GOOD
MANUFACTURING PRACTICES ARE
FOLLOWED
GAO/HEHS-98-205
Blood Plasma Safety
(108348)
Abbreviations
=============================================================== ABBREV
ABRA - American Blood Resources Association
AIDS - test
ALT - alanine aminotransferase
DHS - Department of Health Services
DNA - test
FDA - Food and Drug Administration
HAV - hepatitis A virus
HBc - hepatitis B core
HBsAg - hepatitis B surface antigen
HBV - hepatitis B virus
HCV - hepatitis C virus
HIV - test
IGIM - immune globulin transmusular
IGIV - immune globulin intravenous
IMIG - intramuscular immune globulin
IVIG - intravenous immune globulin
LRF - log reduction factor
PCR - polymerase chain reaction
PPF - plasma protein fraction
RNA - test
Letter
=============================================================== LETTER
B-278739
September 9, 1998
The Honorable Christopher Shays
Chairman, Subcommittee on Human Resources
Committee on Government Reform and Oversight
House of Representatives
Dear Mr. Chairman:
Each year, an estimated 1 million people in the United States receive
products manufactured from human plasma. Many different components
of plasma are used for medical treatment, ranging from treating the
trauma of burns and surgery to replacing blood elements that are
lacking as a result of disease, such as hemophilia. In the 1980s,
before the mechanism of HIV transmission was understood, many
hemophilia patients used plasma products made from donations by
individuals infected with HIV, with 63 percent of all hemophilia
patients in the United States becoming infected as a result. Many
more contracted hepatitis B (HBV) and hepatitis C (HCV). While these
diseases have been transmitted in many fewer cases since the
introduction of antibody tests and viral inactivation and removal
processes, some safety concerns remain.
One of these concerns relates to plasma donors, who are unpaid or
paid. Through the volunteer sector, unpaid donors give whole blood,
from which the plasma may be separated and sent for further
manufacturing into plasma products. The commercial sector collects
plasma from paid donors, known as source plasma, for manufacture into
these same products. Some source plasma is also collected from
unpaid donors. There has been a long-standing concern that the
infectious disease rates among paid donors might be higher than those
of volunteer donors because paid donors may have a financial
incentive to conceal risk factors that would prevent them from
donating. Concerns have also been raised about the number of donors
to whom a recipient is exposed because the products are manufactured
by pooling many donations. Further, the efficacy of viral clearance
procedures used in manufacturing and the safety record of the
manufacturers clearly affect the ultimate safety of the products.
In light of these concerns, you asked us to undertake a study to (1)
compare the risk of incorporating an infectious unit of plasma into
further manufacturing from volunteer versus paid plasma donors for
HIV, HBV, and HCV; (2) examine the impacts on frequent and infrequent
plasma users when pooling large numbers of plasma donations into
manufactured plasma products; (3) assess the safety of end products
from plasma after they have undergone further manufacturing and
inactivation steps to kill or remove viruses; and (4) examine the
recent regulatory compliance history of plasma manufacturers.
In developing our information, we interviewed representatives of the
volunteer and commercial plasma sector and officials of the Food and
Drug Administration (FDA). We also attended technical conferences
and examined the scientific literature on the collection and
processing of plasma products and current good manufacturing
practices within the plasma industry. We obtained data from industry
representatives from which we calculated the chances of incorporating
an infectious unit of plasma into further manufacturing from
volunteer and paid donors. We did not independently verify data on
infectious disease rates, but they are the most current and complete
data available. We also obtained information on the effect of the
number of donations that are used in manufacturing on the safety of
the final products. We gathered information on the effect of viral
inactivation and removal techniques used to further reduce the risk
of viral transmission through plasma products. Finally, we obtained
inspection reports of plasma-derived-product manufacturing facilities
from the FDA that showed the agency's determination of whether these
facilities were in compliance with current good manufacturing
practices. We conducted our review from December 1997 to June 1998
in accordance with generally accepted government auditing standards.
(See app. I for a further discussion of our methodology.)
RESULTS IN BRIEF
------------------------------------------------------------ Letter :1
Viral clearance techniques have made the risks of receiving an
infected plasma product extremely low when manufacturers follow all
the procedures in place to ensure safety. While paid plasma donors
are over one and a half times more likely to donate potentially
infectious units (1 in every 3,834 units), a number of recent
initiatives by the source plasma industry greatly reduce the chances
of these units being pooled for manufacturing (to 1 in every 10,959
units). These initiatives include the use of only repeat donors (who
have been found to have lower rates of viral infection than
first-time donors) and a 60-day inventory hold on all units to allow
manufacturers to retrieve units from donors who subsequently test
positive or are otherwise disqualified. Even with these initiatives
in place, the risks are still somewhat higher from plasma units
donated by paid donors than from volunteer donors (where 1 in every
15,662 units are potentially infectious).
Limiting the number of donors whose plasma is pooled for production
into plasma products helps to reduce the risks of viral transmission
for those receiving these products. Presently, a 60,000-donor limit
has been established for each individual plasma product. This effort
has an impact on infrequent users by minimizing their exposure to a
certain number of donors for the few times they would be infused with
a plasma product. For frequent users of plasma products, such as
severe hemophilia patients, this donor limit has a negligible impact
because of the large number of infusions that they receive and, thus,
the large number of pools that they would be exposed to in the course
of their lifetime.
A more significant step in reducing risk of infection occurs in
manufacturing--where all plasma products for intravenous use undergo
viral removal, inactivation procedures, or both--which virtually
eliminates enveloped viruses such as HIV, HBV, and HCV. This is
supported by epidemiological data on the transmission of viruses
through plasma products since the introduction of adequate viral
removal and inactivation procedures in the late 1980s as well as
laboratory data that characterize the effectiveness of viral
clearance through these procedures. On the other hand, these
processes have limited effectiveness against non-lipid enveloped
viruses such as hepatitis A (HAV) and human parvovirus.
Certain advances--such as voluntary initiatives by the commercial
plasma industry, increasingly sophisticated screening tests that
close the "window period" between the time a donor becomes infected
and the time a particular laboratory test becomes positive, and viral
removal and inactivation procedures--are only effective if the
processes used to produce finished plasma products adhere to current
good manufacturing practices. This, however, has not been the case
with all of the major manufacturing companies that produce plasma
products. Recent FDA inspection reports highlight numerous instances
of noncompliance with current good manufacturing practices. These
problems have led to the imposition of consent decrees between FDA
and two manufacturing companies, the temporary suspensions of
production at one manufacturing facility, and shortages of some
plasma products. Although there have been no known cases of
transmission of HIV, HBV, or HCV from plasma products during the time
these problems were identified by FDA, it is clear that there were
numerous instances of noncompliance in the manufacture of plasma
products. Without strict adherence to current good manufacturing
practices related to the efficacy of viral removal and inactivation
procedures, the safety of these plasma products could be compromised.
Actions being taken by FDA and the plasma manufacturers since these
problems were identified should help to alleviate some of these
concerns.
BACKGROUND
------------------------------------------------------------ Letter :2
Plasma is the liquid portion of blood, containing nutrients,
electrolytes (dissolved salts), gases, albumin, clotting factors,
hormones, and wastes. Many components of plasma are used, and
include treatments for the trauma of burns and surgery and for
replacing blood elements that are lacking as a result of disease,
such as hemophilia. Table 1 lists the plasma components that are
currently available in the United States and their primary uses.
Table 1
Plasma Components and Their Primary Uses
Component Primary uses
---------------------------------- ----------------------------------
Albumin To restore plasma volume in
treatment of shock, trauma,
surgery, and burns
Alpha-1 proteinase inhibitor To treat emphysema caused by
genetic deficiency
Antihemophilic factor concentrate For prophylaxis and treatment of
(factor VIII) hemophilia A bleeding episodes
Anti-inhibitor coagulant complex To treat bleeding episodes in the
presence of factor VIII inhibitor
Antithrombin III To prevent clotting and
thromboembolism associated with
liver disease, antithrombin III
deficiency, and thromboembolism
Coagulation factor IX (human) For prophylaxis and treatment of
hemophilia B bleeding episodes and
other bleeding disorders
Cytomegalovirus immune globulin For passive immunization
subsequent to exposure to
cytomegalovirus
Factor IX complex For prophylaxis and treatment of
hemophilia B bleeding episodes and
other bleeding disorders and for
warfarin (anticoagulant) reversal
Hepatitis B immune globulin For passive immunization
subsequent to exposure to
hepatitis B
Immune globulin: intravenous and To treat agamma-and hypogamma-
intramuscular globulinemia; for passive
immunization for hepatitis A and
measles
Plasma protein fraction To restore plasma volume
subsequent to shock, trauma,
surgery, and burns
Rabies immune globulin For passive immunization
subsequent to exposure to rabies
Rho(D) immune globulin To treat and prevent hemolytic
disease of fetus and newborn
infant stemming from Rh
incompatibility and incompatible
blood transfusions
Tetanus immune globulin For passive immunization
subsequent to exposure to tetanus
Vaccinia immune globulin For passive immunization to
laboratory exposure to smallpox or
vaccinia
Varicella-zoster immune globulin For passive immunization
subsequent to exposure to chicken
pox
----------------------------------------------------------------------
Source: American Blood Resources Association, Basic Facts About the
Commercial Plasma Industry.
The various plasma-derived products are purified from the plasma pool
by a process known as fractionation. This process separates plasma
proteins based on the inherent differences of each protein.
Fractionation involves changing the conditions of the pool (for
example, 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 or through
filtration. One of the most 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 globulins.\1
It is estimated that each year, as many as a million patients rely on
products manufactured from human plasma: more than 400,000 are given
albumin, 15,000 to 18,000 are given factor VIII, 3,000 to 5,000
receive factor IX, greater than 20,000 receive immune globulin
intravenous (IGIV), and an estimated 100,000 to 500,000 receive
immune globulin intramuscular (IGIM). Additional patients receive a
variety of hyperimmune globulins and other specialized products.
--------------------
\1 It can take up to 7 months from the time plasma is collected until
there is a final product release. Approximate times for steps in
this process include collection and testing of the plasma (10 days),
inventory hold (60 days), staging and internal quality control (10
days), pooling of the plasma (1 to 2 days), fractionation process (7
to 10 days), collection of intermediates and runs for internal
quality control (20 days), preparation of final products (7 to 10
days), quality control testing prior to filling of final product (25
to 28 days), and manufacture and FDA testing and release of final
product (60 days). Recently, this last step has been reduced to 2
weeks or less for most products.
PLASMA DONATION
---------------------------------------------------------- Letter :2.1
Plasma used for plasma-derived products manufactured and distributed
in the United States can only be collected at facilities registered
with the FDA. Centers require donors to provide proof that they are
legally in the United States and have a local permanent residence.
About 85 percent of plasma is collected from paid donors in a
commercial setting and is known as source plasma. Through a process
known as plasmapheresis, the plasma is removed and the red cells are
reinfused into the donor. The remaining 15 percent of plasma is
collected from volunteer donors and is known as recovered plasma.
From the whole blood, plasma is "recovered"--that is, the red cells,
platelets, and cryoprecipitate are separated for transfusion and the
unused plasma is either transfused as plasma or sent for further
manufacturing into plasma products. On the basis of a European Union
policy position, many European countries are working toward
self-sufficiency in plasma products using an all-volunteer system,
although most countries continue to depend on U.S. products made
from paid donors and on source plasma obtained from U.S. donations.
Units of plasma collected as source plasma contain approximately 825
milliliters, while recovered plasma from whole blood donations
contain approximately 250 milliliters. Thus, more than three times
as many donated units of recovered plasma are required to make up a
pool of equal volume to one made up of only source plasma.
Approximately 370 paid plasma collection centers annually collect
about 11 million liters of plasma from 1.5 million donors, involving
a total of approximately 13 million separate donations each year.
The industry, through its trade organization, the American Blood
Resources Association, maintains a limited national donor deferral
registry that is checked for each first-time donor.\2 This is a list
of known donors who are unsuitable for further donations because of
positive test results. Repeat donors' records are checked at the
plasmapheresis center where the plasma is removed. Most of these
centers also ensure that donors are not migrating from one center to
another over the 48-hour minimum donation interval.\3 The vast
majority of source plasma is processed by four companies: Alpha
Therapeutic Corporation, Baxter Healthcare Corporation, Bayer
Corporation, and Centeon LLC.
An additional 1.8 million liters of plasma are collected annually
from approximately 8 million volunteer (not paid) donors who
contribute 12 to 13 million whole blood donations. Volunteer donors
give blood at American Red Cross blood centers and independent blood
centers represented by America's Blood Centers; 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 member facilities of
America's Blood Centers is currently sold only to the Swiss Red
Cross, which manufacturers the various plasma products and sells them
through U.S. distributors.
Paid donors typically receive between $15 and $20 for the 2 hours
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 can donate only once every 56 days since
their red cells are not reinfused as is done with the paid donor.
--------------------
\2 These 370 centers have been certified by the American Blood
Resources Association. Under the association's Quality Plasma
Program, collection centers are inspected by a third party for
compliance to specific standards, such as facility maintenance,
employee training, and donor screening. There are a total of 470
licensed plasma collection centers in the United States. The
additional 100 centers include some whole blood facilities licensed
to collect source plasma, centers that collect source plasma
exclusively for export, and others. These centers do not provide
source plasma to the four major fractionators for U.S. production.
\3 For example, centers may mark different fingers with florescent
dye or use other methods to identify donors.
DONOR SCREENING
---------------------------------------------------------- Letter :2.2
Donor screening is designed to prevent the donation of blood by
persons who have known risk factors or other conditions such as low
blood pressure. All prospective donors, both paid and volunteer, are
screened for medical history and risk behaviors. High-risk donors,
those whose blood or plasma may pose a health hazard, are encouraged
to exclude themselves. Everyone who seeks to donate plasma must
answer a series of behavioral and medical questions. If the answers
indicate high risk, the prospective donor is deferred from donating.
The screening requirements are completed before the donor is allowed
to give plasma. Additionally, paid donors must pass an annual
physical examination and a brief medical examination each time they
donate. Similarly, volunteer donors undergo a brief medical
examination each time they donate.
The American Blood Resources Association's National Donor Deferral
Registry is one method by which the plasma industry has attempted to
ensure that donors who are presenting to donate for the first time at
a plasma center are checked for past deferrals at other centers. The
American Red Cross has a similar system that is a national list of
those deferred through their blood collection system. Each member
facility of America's Blood Centers maintains its own donor deferral
list against which donors are checked.
TESTING OF DONORS
---------------------------------------------------------- Letter :2.3
All donors are tested for certain viruses known to be transmissible
through blood, including HBV, HCV, and HIV.\4 The specific screening
tests check for the presence of hepatitis B surface antigen (HBsAg),
antibodies to hepatitis C (anti-HCV), HIV-1 antigen (Ag) and
antibodies to HIV types 1 and 2 (anti-HIV).\5 Donors with repeatedly
reactive test results are rejected from further donations. (See app.
II for more information on testing procedures.) For units found to be
reactive on HIV tests, the positive units and all previously donated
plasma units not pooled for manufacture in the preceding 6 months are
retrieved, and those professional services who receive the plasma
products are notified according to federal regulations (21 C.F.R.
610.46).\6
All of the plasma fractionation companies have also received
permission from the FDA to begin clinical trials of the polymerase
chain reaction (PCR) technique, a more sensitive test that is now
available, to detect viral material for HIV, HBV, and HCV. PCR is
used to amplify the number of copies of a specific region of DNA or
RNA in order to produce enough DNA or RNA to be adequately tested.
This technique appears to be able to identify, with a very high
probability, disease-causing viruses such as HIV, HBV, and HCV.
Because PCR testing detects virus particles at the genetic level,
infected donors can be identified days or even months sooner than if
only traditional antibody or antigen testing is performed, thus
shortening the window period. PCR testing is being investigated
using minipools that can combine over 500 individual donations. All
plasma used in the manufacturing process that undergoes PCR testing
must be nonreactive for that specific test.\7
--------------------
\4 Additionally, paid donors are tested for syphilis every 4 months,
while every volunteer donation is tested for syphilis. Testing for
syphilis is performed, for the most part, as an indicator of
high-risk behaviors. The value of this testing has been debated.
\5 Antibody tests detect antibodies that the human body produces in
its immune response to a virus, whereas antigen tests detect a
component of the actual virus. Because it takes time to develop
antibodies, antigen tests detect infection earlier than antibody
tests.
\6 Additionally, tests are performed to examine the level of the
liver enzyme alanine aminotransferase (ALT). An abnormal ALT may be
an indicator of liver disease, a viral infection that causes liver
disease, or both. Units with unacceptable ALT levels are not used.
Whole blood donations are also tested for antibodies to human
lymphotropic virus types I and II, but source plasma is not screened
for this because it is cell associated and not found in plasma.
\7 Because of pooled sample testing, an individual unit still could
be positive but only at a very low titer. Such a low-titer unit may
not be detected using pooled PCR and thus would be added to the
manufacturing pool.
RISK OF INFECTIOUS UNITS
ENTERING PLASMA POOLS IS
SOMEWHAT HIGHER FOR PAID PLASMA
DONORS THAN FOR VOLUNTEER
DONORS
------------------------------------------------------------ Letter :3
We calculated the risk of incorporating an infectious unit of plasma
into a plasma pool for HIV, HBV, and HCV for both volunteer and paid
plasma donors. Overall viral marker rates for HIV, HBV, and HCV are
higher among individuals who present themselves to donate at paid
plasma centers than among those who come to volunteer blood centers.
This is due to higher HCV rates among paid donors. Units that test
positive are excluded. The incidence rate of collecting infectious
units from donors who are in the window period between the time they
become infected and the time they test positive is much higher among
paid plasma donors than among volunteer donors. However, a number of
safety initiatives have been instituted by paid plasma centers that
greatly reduce the likelihood of infectious units being pooled for
manufacturing. Nevertheless, the final--or residual--risk of an
infectious unit entering a plasma pool remains somewhat higher for
paid donors than for volunteer donors.
There are at least four potential ways in which viral agents go
undetected during donation and may thus be transmitted through blood
products.\8 First, there exists a very rare chronic carrier state in
which a clinically asymptomatic, yet infectious, donor will
persistently test negative on a donation screening test. Second, a
viral agent may have a large degree of genetic diversity so that
laboratory screening tests fail to identify some infectious donors
who harbor an atypical genetic variant. Third, laboratory error in
performing screening tests may occur, allowing positive units to be
made available for transfusion. Finally, the donor may have a
negative laboratory test during the window period before the virus is
detected by currently licensed screening tests. The majority of
cases in which an infectious donation will be included in a plasma
pool is a result of this last circumstance. As a result, modeling
techniques have been developed to determine the risk estimates of
incorporating these infectious window period units into the blood
supply.
To determine the marker rate for HIV in plasma donations, we obtained
data from California's Department of Health Services (DHS), which
collects information on these rates for volunteer blood donors and
paid donors at plasma collection facilities.\9 We obtained
information on HIV, HBV, and HCV viral marker rates from the American
Red Cross for donors who donate at their centers. The American Blood
Resources Association provided us with data on repeatedly reactive
test results for paid donors who donate at their centers. We
adjusted these data to obtain the viral marker rates.
In addition, we obtained information on incidence rates among
American Red Cross and American Blood Resources Association donors to
adjust for the effect of such variables as first-time donor versus
repeat donors, the length of the interdonation interval (the time
period between donations), and the number of seroconverters found
among plasma donors.\10 We also compared the residual risk of a
potentially infectious plasma donation by a volunteer versus paid
plasma donor actually entering a plasma pool by examining the effect
of the length of the window period as well as the use of only
"qualified donors" and the 60-day inventory hold program instituted
by the paid plasma industry. (See app. I for the calculations we
used to derive our risk estimates).
--------------------
\8 Stephan Kleinman and others, "The Incidence/Window Period Model
and Its Use to Assess the Risk of Transfusion-Transmitted Human
Immunodeficiency Virus and Hepatitis C Virus Infection," Transfusion
Medicine Reviews, Vol. 11 (1997), pp. 155-72.
\9 The term "viral marker rates" refers to the rate at which a
particular group has confirmed-positive tests for particular viruses,
in this case for HIV, HBV, and HCV.
\10 Seroconverting donors are those donors who are recently infected
and test negative on a currently licensed test. Donors who have
seroconverted will test positive.
OVERALL MARKER RATES OF
INFECTION ARE HIGHER AMONG
PAID DONORS
---------------------------------------------------------- Letter :3.1
Although it has been difficult to obtain data on viral marker rates
among paid plasma donors, data collected by California highlight
differences between paid plasma and volunteer whole blood donors.\11
As shown in table 2, among the 833,178 units tested, 89 units (.0107
percent) tested positive for HIV-1.\12 Donations at plasma centers
showed a higher rate of testing positive for HIV-1 than did donations
at blood banks. Plasma centers had an HIV-1 rate of .0266 percent
(26.6 per 100,000 units tested), while units collected at blood banks
had a rate of .0032 percent (3.2 per 100,000 units tested). Thus,
California plasma centers had over an eight-fold higher rate of HIV-1
positive donations than blood banks had among their volunteer donors.
Table 2
HIV-1 Antibody Test Results From
California Blood Banks and Plasma
Centers, July to December 1996
Number of
confirmed Number of
HIV-1 positive
positive donations
Facility type Units tested units per 100,000
---------------- ------------ ------------ ------------
Blood banks 566,677 18 3.17
Plasma centers 266,501 71 26.64
Total 833,178 89 10.68
----------------------------------------------------------
For both blood banks and plasma centers in California, the
seroprevalence rates for HIV have decreased significantly over time.
More than 7 million units were tested at California blood banks
between 1990 and 1996. Over this period, HIV-1 seroprevalence among
donors declined from .015 percent to .003 percent. Over 4.5 million
units were tested at California plasma centers during this same time
frame. The HIV-1 seroprevalence among plasma donors declined during
this period from .056 percent in 1990 to .027 percent in the second
half of 1996. However, while the rates of HIV are dropping in both
groups, there is a consistent pattern of higher marker rates among
paid donors than among volunteer donors. (See fig. 1.)
Figure 1: Reported Confirmed
HIV Rates Among Donations in
California, 1990 to 1996
(See figure in printed
edition.)
Note: Rates are per 100,000 commercial plasma donations and
volunteer whole blood donations.
Source: DHS, Office of AIDS, Dec. 1997.
Although the California data were based on similar reporting
requirements and time frames for paid and volunteer donors, they only
examined HIV marker rates. There was also some question as to
whether multiple counting of donors may have skewed the results of
the reporting. Because of these concerns, we also obtained
information on marker rates from the American Red Cross and American
Blood Resources Association for donors who presented themselves to
donate at their respective collection centers.
We obtained data from the American Red Cross on 2,954,773 volunteer
whole blood donations from donors less than 60 years old (those used
for plasma products) between January 1, 1996, and June 30, 1997.\13
This includes donations that have occurred since the introduction of
the HIV-1 antigen screening test, implemented on March 15, 1996. As
shown in table 3, these data showed that 6.9 out of every 100,000
donations were found to test positive for HIV, while the rates were
33.4 per hundred thousand for HBsAg, and 112.4 per hundred thousand
for HCV (results from confirmatory testing).\14 Assuming that no
donation is positive for more than one virus, then 1 of every 6,549
volunteer donations is potentially infectious for HIV, HBV, or HCV.
Table 3
Marker Rates Among Volunteer Donations,
January 1, 1996, to June 30, 1997
Number of Number of positive
confirmed positive donations per
Marker units 100,000
---------------- ------------------ --------------------
Anti-HIV 205 6.94
HBsAg 987 33.40
Anti-HCV 3,320 112.36
Total 4,512 152.70
----------------------------------------------------------
We obtained data from the American Blood Resources Association on 4.6
million paid plasma donations in the second half of 1994.\15 The
donations contained in these data only included repeatedly reactive
test results--confirmatory testing was not performed. We have
therefore adjusted these data by the rate at which repeatedly
reactive donations confirm positive based on the rates seen in
American Red Cross whole blood donations. As shown in table 4, these
data showed that approximately 3.7 out of every 100,000 donations
were positive for HIV, while the rates were 30.9 per hundred thousand
for HBsAg and 226.2 per hundred thousand for HCV. Assuming that no
donation is positive for more than one virus, then 1 of every 3,834
paid donations is potentially infectious for HIV, HBV, or HCV.
Table 4
Marker Rates Among Paid Plasma
Donations, July to December 1994
Number of Number of positive
confirmed positive donations per
Marker units\a 100,000
---------------- ------------------ --------------------
Anti-HIV 169 3.67
HBsAg 1,423 30.93
Anti-HCV 5,655 226.20
Total 7,247 260.80
----------------------------------------------------------
\a Adjusted by the rates at which whole blood donations that are
repeatedly reactive are confirmed positive.
These three data sets show differing viral marker rates for volunteer
and paid plasma donors. The California data show much higher HIV-1
marker rates for paid plasma donors than volunteer donors. However,
the data from the American Blood Resources Association show lower
rates for HIV, similar rates for HBV, and higher rates for HCV than
data obtained from the American Red Cross. Overall, the rates for
paid donors are 1.7 times higher than the rates for volunteer donors,
which is due to the higher rates among paid donors for HCV.
--------------------
\11 DHS received results for HIV-1 and HIV-2 antibody testing from
blood banks and plasma centers. For the last 6 months of 1996 they
received results from 49 blood banks and 15 plasma centers. This
information represents about 74.4 percent of the overall California
facilities required to report HIV-1 and HIV-2 antibody test results.
A recent updating of the facilities that are required to respond
indicates that the response rate was actually higher than 74.4
percent.
\12 Two units also tested positive for HIV-2 with supplemental
unlicensed testing. To date, FDA has not licensed a confirmatory
test for HIV-2 infection. However, cross-reactivity between HIV-1
and HIV-2 is a strong possibility in instances where HIV-2 is
confirmed by existing unlicensed testing.
\13 These data represent 33 percent of the total collections by the
American Red Cross during the time period noted above. Data were
collected from 19 regions from an ongoing data collection and
analysis effort by the American Red Cross. The regions represented
in this data set make up the Infectious Diseases Data Center.
\14 The data presented for HBV include only HBsAg screening and not
anti-HBc (hepatitis B core) screening. Because there are few
contemporary studies determining the infectivity of reactive anti-HBc
donations that are HBsAg nonreactive (and therefore are believed to
be derived almost entirely from either immune individuals or
individuals with false reactivity to the anti-HBc screening test),
and because plasma donations from the commercial sector are not
screened for anti-HBc, the contribution of anti-HBc is not addressed.
\15 Information on HCV is based on a smaller data set of 2.5 million
donations. All data were collected from approximately 340 source
plasma collection centers that were certified under the Quality
Plasma Program at the time.
VOLUNTARY STANDARDS
INTRODUCED BY THE SOURCE
PLASMA INDUSTRY TO REDUCE
TRANSMISSION OF VIRUSES
---------------------------------------------------------- Letter :3.2
The source plasma industry has recently introduced voluntary
standards aimed at reducing the viral risks posed by two categories
of paid plasma donations: donations from one-time donors and
donations from donors who may be in the window period. One-time
donors are a concern because some data show that the rates of viral
infection are much higher among such donors. The individuals may
either not be aware that they are infected or may be test-seeking.
Donors in the window period are a concern because they may not be
aware of their infection and the screening tests will not detect the
infection.
The first voluntary initiative, implemented in July 1997, eliminates
the use of plasma from one-time donors. This standard requires that
no units of plasma can be accepted for further processing unless the
donor has successfully passed at least two health history interviews
and two panels of all required screening tests within a 6-month
period. Qualified donors are those who have passed through these
criteria. Applicant donors, on the other hand, are individuals
presenting themselves who have not been previously qualified as a
donor in the past 6 months.
This standard on first-time donors does not apply to volunteer
donors. Neither the American Red Cross nor America's Blood Centers
imposes such a requirement for the use of plasma recovered from whole
blood donations. Because the patterns of donation are very different
for volunteer whole blood donors (who can donate no more frequently
than once every 8 weeks) compared with paid plasma donors (who can
donate as often as twice a week), the volunteer sector does not view
a restriction that would require holding plasma until a donor returns
to be a practical requirement. In fact, the average interval between
donations for an American Red Cross donor is about 5 months.
A second industry initiative is an inventory hold program that holds
source plasma donations for 60 days. During this time, if a donor
seroconverts and subsequently tests positive--or is otherwise
disqualified--the earlier donation can be retrieved from inventory
and destroyed. This standard, however, does not establish a true
quarantine program that would exclude units from donors in the window
period of infection, when viral infection cannot be determined. A
donor who was within the window period could return 2 days after the
initial donation, pass both health history interviews and screening
tests, and contribute infected units that would be used after 60
days, if the donor were not tested again at a time outside the window
period. The data provided to us for estimating risks for source
plasma donations take this possibility into account.
Furthermore, the 60-day inventory hold period does not appear to be
adequate for all viruses under consideration, based on published
data. The window period for HIV, HBV, and HCV, using detection of
seroconversion as an end point, are approximately 22 days, 59 days,
and 82 days, respectively.\16 Thus, the 60-day hold period does not
encompass the window period for HCV and is barely within the limit
for HBV. However, the majority of window period units would be
interdicted as most of these would fall within the 60-day hold
period. PCR testing would close the window period for these viruses
to approximately 11 days for HIV, 34 days for HBV, and 23 days for
HCV.\17 As a result, if such testing becomes available for mass
screening, the 60-day inventory hold would cover the window period
for these three viruses.
--------------------
\16 George Schreiber and others, "The Risk of Transfusion-Transmitted
Viral Infections," New England Journal of Medicine, Vol. 334 (June
27, 1996), pp. 1685-90.
\17 George Schreiber and others, "The Risk of Transfusion-Transmitted
Viral Infections."
INCIDENCE RATE FOR PAID
DONORS IS HIGHER THAN FOR
VOLUNTEER DONORS
---------------------------------------------------------- Letter :3.3
We found the incidence rates of HIV, HBV, and HCV infection to be
much higher for paid donors than for volunteer donors. These rates
include donors who pass the initial screening and donate but
subsequently seroconvert and are detected at a later donation. As a
result, potentially infectious units from these donors may have been
incorporated into a plasma pool for manufacturing.
Since prevalence rates of viral markers merely indicate the
proportion of infected persons in the population at a given time,
independent of when infection occurred, they do not accurately
portray the chances of incorporating an infectious window period unit
into a plasma pool. Thus, to calculate the risk of collecting
potentially infectious units--the incidence rate--the number of
individuals who are seroconverting and the time between donations for
such individuals (the interdonation interval) need to be taken into
account.
INCIDENCE RATE FOR
VOLUNTEER DONORS
-------------------------------------------------------- Letter :3.3.1
The data used to calculate incidence rates among volunteer donors are
based on approximately 1 million donations from repeat donors under
the age of 60 for the American Red Cross between July 1, 1996, and
June 30, 1997. The interdonation interval for these donors averaged
154 days. However, repeat donors account for only 80 percent of
volunteer blood donations. Thus, incidence calculations from
first-time donors also need to be taken into account to obtain an
overall risk estimate of collecting an infectious window period unit.
A modified screening test was used to determine incidence rates among
first-time donors, which showed that first-time whole blood donors
have a 2.4 times higher HIV rate of prevalent infections than repeat
donors.\18 This information is combined to estimate the total
incidence among volunteer blood donors. (See table 5.)
Table 5
Estimated Incidence Rates for Volunteer
Donations, July 1, 1996, to June 30,
1997
Repeat Total
donors First-time (per 100,000
Marker (80%) donors (20%) person-years)\a
-------------- ---------- ------------ ----------------
Anti-HIV and 2.59 6.22 3.31
Ag
HBsAg 6.25 15.02 8.01
Anti-HCV 11.65 28.96 14.91
----------------------------------------------------------
\a Person years is the number of donations multiplied by the mean
time between donations divided by 365 days.
--------------------
\18 M. P. Busch and others, "Estimation of HIV Incidence in U.S.
Blood Donors Using a Novel Detuned Anti-HIV EIA Test Strategy," Fifth
Conference on Retroviruses and Opportunistic Infections (Chicago,
Ill.: Feb. 1-5, 1998). We used a similar calculation to estimate
incidence rates for HBV and HCV among volunteer donors.
INCIDENCE RATE FOR PAID
DONORS
-------------------------------------------------------- Letter :3.3.2
We also obtained data from the American Blood Resources Association
that were based on all of the approximately 4 million donations at
the American Blood Resources Association-member centers over a
4-month period in the second half of 1997. The average interdonation
interval among these donors was 5.3 days. The American Blood
Resources Association's qualified donor program does not collect
plasma from first-time donors; therefore, no adjustment is needed for
first-time donors. Table 6 shows the incidence rates among qualified
source plasma donors for this period.\19
Table 6
Estimated Incidence Rates for Paid
Donations, July 1, 1997, to October 31,
1997
Total
(per 100,000
Marker person-years)\a
------------------ --------------------------------------
Anti-HIV 61.80
HBsAg 245.50
Anti-HCV 63.52
----------------------------------------------------------
\a Person years is the number of donations multiplied by the mean
time between donations divided by 365 days.
When comparing the incidence rates between paid and volunteer plasma
donors, we found that the incidence rates for HIV, HBV, and HCV were
much higher for paid donors. HIV incidence rates were 19 times
higher among paid donors (61.8 versus 3.3 for volunteer donors),
while HBV and HCV rates were 31 times (245.5 versus 8.0) and 4 times
higher (63.5 versus 14.9), respectively.
--------------------
\19 The incidence rates for paid donors for HIV are based on antibody
test results, whereas the rates for volunteer donors are based on
antibody and antigen tests.
RESIDUAL RISKS FOR
INCORPORATING AN INFECTIOUS
UNIT INTO A PLASMA POOL ARE
HIGHER FOR PAID DONORS THAN
FOR VOLUNTEER DONORS
---------------------------------------------------------- Letter :3.4
Calculating the chances that an infectious unit will be made
available for pooling includes factoring in the length of the window
period expressed as a fraction of a year. Calculating this residual
risk is a more statistically appropriate way to determine the true
impact of window period donations.
RESIDUAL RISK FOR
VOLUNTEER DONORS
-------------------------------------------------------- Letter :3.4.1
We calculated the residual risk of a potentially infectious unit
being made available for pooling for units collected from volunteer
donors. These estimates are shown in table 7.
Table 7
Estimated Residual Risk for Volunteer
Plasma Donations
Estimated
residual risk
per million
Marker donations Point estimate
------------------ ---------------------- --------------
Anti-HIV and Ag 1.45 1:689,655
HBsAg 12.95 1:77,220
HBsAg (with 28.89 1:34,614
adjustment)\a
Anti-HCV 33.50 1:29,850
Total 47.91 1:20,872
Total (with 63.85 1:15,662
adjustment)\a
----------------------------------------------------------
\a Adjusted for the transient response on the HBsAg test.
The estimated adjusted risk per million donations--that is, the
residual risk--represents the incidence rate multiplied by the window
period for each virus. The resulting point estimate for the risk of
pooling an HIV seronegative unit from a window period donation is 1
in 689,655.\20 For HBV and HCV, the corresponding estimates are 1 in
77,220 and 1 in 29,850, respectively. When combined, we calculated
the risk of incorporating an infectious HIV, HBV, or HCV window
period unit into a plasma pool from volunteer donors at 1 in every
20,872 units.\21
Some researchers believe that an additional factor should be taken
into account when determining the risks associated with HBV.\22 This
is because individuals who become infected with HBV show different
patterns of response over time on the HBsAg test. (See app. I for a
more complete discussion.) If such an adjustment is taken into
account, the estimated total incidence per 100,000 person years for
HBsAg would be 17.9, with an estimated adjusted risk per million
donations of 28.9 and a point estimate of 1 in 34,614. This would
yield an overall risk of incorporating an infectious window period
HIV, HBV, or HCV unit into a plasma pool of 1 in every 15,622 units
(instead of 1 in 20,872 without the adjustment).\23
--------------------
\20 Estimates that are commonly quoted are point estimates. However,
confidence intervals give a better sense of possible risk. Point
estimates are necessary for calculating purposes but should not be
construed as definitive. Scientists know that statistical
measurement is not precise. Thus, they calculate a range, or
confidence interval, of estimates that is wide enough that they are
confident in believing that the real number is somewhere between the
two endpoints of the range.
\21 This calculation assumes that the risks of incorporating a
potentially infectious HIV, HBV, or HCV window period unit are
independent. In fact, some units might be infectious with more than
one virus. However, data on the over 4 million source plasma
donations used in these analyses show that among the 215 confirmed
positive donors, only 1 was positive for more than one virus.
\22 George Schreiber and others, "The Risk of Transfusion-Transmitted
Viral Infections."
\23 The data from which the adjustment factor is calculated are based
on tests in use in the late 1970s and early 1980s. Current HBsAg
tests are more sensitive, extending the time period of HBsAg
detection. However, there have been no contemporary studies using
current tests defining the duration of HBsAg reactivity in
individuals with acute infection. Data from one recently presented
paper suggest that an adjustment based on current tests might result
in a rate of 1 in 46,156 for HBV, with an adjusted total risk of 1 in
17,670.
RESIDUAL RISK FOR PAID
DONORS
-------------------------------------------------------- Letter :3.4.2
We also calculated the estimated residual risk for paid plasma
donors, with and without a 60-day inventory hold. (See table 8.)
Table 8
Estimated Residual Risk for Paid Plasma
Donations
Without 60- With 60-day
day hold hold
-------------- --------------
Risk Risk
per per
millio millio
n Point n Point
donati estima donati estima
Marker ons te ons te
-------------------------------------- ------ ------ ------ ------
Anti-HIV 37.25 1:26,8 1.47 1:680,
46 272
HBsAg 396.84 1:2,52 53.84 1:18,5
0 74
Anti-HCV 142.70 1:7,00 35.94 1:27,8
8 24
Total 576.79 1:1,76 91.25 1:10,9
5 59
----------------------------------------------------------------------
The point estimate for the risk of collecting an HIV window period
unit at a paid plasma donation center is 1 in 26,846. For HBV and
HCV, the corresponding estimates are 1 in 2,520 and 1 in 7,008,
respectively. Overall, the risk of incorporating an infectious HIV,
HBV, or HCV window period unit into a plasma pool without taking into
account the 60-day inventory hold program was 1 in 1,765 for paid
plasma donors--12 times the risk for volunteer donors.
To obtain an overall residual risk of incorporating a potentially
infectious window period unit into a plasma pool from paid donors,
the American Blood Resources Association data also took into account
the effect of the 60-day inventory hold program for source plasma.
This resulted in an overall risk estimate that would allow for the
interdiction of numerous infectious window period units captured by
the 60-day hold program. The resulting point estimate for the risk
of pooling an HIV seronegative unit that is from a window period
donation is 1 in 680,272. For HBV and HCV, the corresponding
estimates are 1 in 18,574 and 1 in 27,824, respectively.
Thus, the overall residual risk for paid plasma for HIV, HBV, and HCV
is 1 in 10,959, compared with 1 in 20,872 for volunteer donors.\24
This would mean that approximately 5.5 infectious units would be
included in every 60,000 paid donations, whereas about 2.9 infectious
units would be included in every 60,000 volunteer donations. Using
the estimates based on the adjustment for HBV among volunteer donors
(1 in 15,662) would mean that 3.8 infectious units would be included
in every 60,000 volunteer donations.
--------------------
\24 The window period calculation for anti-HIV for volunteer donors
is based on the antigen test. However, data for paid plasma
donations are based on the HIV antibody test. Thus, we used a 22-day
window period to calculate the incidence rate in paid donors because
this is the length of the window period using the HIV antibody test.
If the antigen test were used to calculate a risk estimate for paid
plasma donors, the risk would be reduced to 1 in 1,000,000 (instead
of 1 in 680,272). However, this does not change the overall risk of
incorporating an infectious window period unit into a plasma pool to
any degree for the three viruses studied in this report. If the
antigen window period calculation were used to calculate the overall
risk from paid donors of incorporating an infectious HIV, HBV, or HCV
unit into a plasma pool, the risk would change only slightly to 1 in
11,016.
OVERALL COMPARISON OF
RISKS OF POOLING
INFECTIOUS UNITS
-------------------------------------------------------- Letter :3.4.3
When comparing the overall residual risk of incorporating an
infectious window period unit into a plasma pool for each of the
three viruses examined in this study, the rates for HIV for volunteer
and paid plasma donors are virtually identical (1 in 689,655 and 1 in
680,272, respectively); the rates for HCV are also similar (1 in
29,850 to 1 in 27,824). The major difference can be found for donors
infected with HBV, where the residual risk for volunteer plasma
donors is 1 in 77,220 compared with 1 in 18,574 for paid plasma
donors. But taking into account the adjustment factor for HBV in
volunteer plasma donors, the adjusted HBV estimate for volunteer
donors becomes 1 in 34,614. Thus, while the risk for HBV
transmission is greater for paid donors, the overall residual risks
for the three viruses are closer once the 60-day hold is taken into
account (1 in 15,662 for volunteer plasma donors versus 1 in 10,959
for paid plasma donors). This difference in the overall residual
risk is statistically significant. Thus, the data suggest that the
current risks of incorporating an infectious unit into a plasma pool
remain somewhat higher for paid donors.\25 (See table 9.)
Table 9
Residual Risks for Volunteer and Paid
Plasma Donations
Residual risk
(1,000,000
donations) Point estimate
-------------- --------------
Volunt Volunt
Marker eer Paid eer Paid
-------------------------------------- ------ ------ ------ ------
Anti-HIV 1.45 1.47 1:689, 1:680,
655 272
HBsAg 28.89 53.84 1:34,6 1:18,5
14 74
Anti-HCV 33.50 35.94 1:29,8 1:27,8
50 24
Total 63.85 91.25 1:15,6 1:10,9
62 59
----------------------------------------------------------------------
--------------------
\25 The calculations of residual risk for the two groups are based on
slightly different models, but both take into account the possibility
of window period donations from donors whose last donation is
nonreactive on the currently licensed screening tests.
MANUFACTURER REDUCTIONS IN
PLASMA POOL SIZES TEND TO NOT
BENEFIT FREQUENT USERS
------------------------------------------------------------ Letter :4
Concerns have been raised about the size of plasma pools because
larger pools mean that a recipient of a product is exposed to more
donors, raising the risks of infection because larger pools have more
potentially infectious units included. In response to these
concerns, 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 have an impact on
infrequent users by minimizing their exposure to a certain number of
donors. However, for frequent users of plasma products, such as
hemophilia patients, this limit has a negligible impact due to the
large number of different pools to which they are exposed throughout
their lifetime.
The different proteins that make up the various components of plasma
are present in only minute quantities in a single donation of plasma.
Therefore, most plasma product manufacturing facilities have been
designed to work at large scales, using large plasma pools made up of
donations from numerous donors, in order to permit manufacturing of
sufficient quantities of products. The number of units combined into
a common mixture for processing is known as the pool size.\26
There has been discussion by the plasma industry, FDA, consumer
groups, and some Members of Congress regarding the potential benefits
of reducing the sizes of pools used by manufacturers to produce
finished plasma products. While no units of plasma known to be
positive for viruses are combined in plasma pools for production,
infectious units may escape detection. A single unit has the
potential to contaminate an entire pool. The larger the number of
donors who contribute plasma to a pool, the greater the possibility
that there will be at least one infectious unit included. Based on
the estimates we calculated above, a pool of as few as 11,000
donations will still include one infectious unit.
--------------------
\26 Here we use the term "pool size" to include the total number of
donors whose units are used in the production of a particular product
and any material taken from other donations that were not in the
initial manufacturing pool. Thus, the pool sizes to which we refer
include the total number of donors to whom a recipient of a product
is exposed.
MANUFACTURERS HAVE REDUCED
PLASMA POOL SIZES
---------------------------------------------------------- Letter :4.1
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. However, in response to congressional
inquiry, the 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 occurred. 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.\27 This
albumin often has been derived from another plasma pool that contains
donations from others that are not part of the original pool.
As a result of the concerns raised about pool size, the four major
plasma fractionators have 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 IGIV. This measurement takes into account
the composition of starting pools, the combining of intermediates
from multiple pools, and the use of plasma derivatives as additives
or stabilizers in the manufacturing process. However, prior
production streams are still being processed and distributed; as a
result, products distributed through the end of 1998 may have been
produced from pools that exceeded the 60,000-donor limit.
The American Red Cross has also chosen to voluntarily reduce the size
of the plasma pools from which its products are manufactured. As a
policy, the American Red Cross has a 60,000-donor limit for plasma
products that are further manufactured by Baxter Healthcare.
Seventy-five percent of all American Red Cross plasma manufactured by
the Swiss Red Cross is presently at the 60,000 limit, with plans to
have all production at that level in the near future.
--------------------
\27 Excipients are additives, other than the active ingredient of a
drug, that confer a desired property on the final dosage form. This
may include a preservative to prevent microbial growth or a
stabilizer that maintains potency. A stabilizer maintains the
integrity of the active ingredient against chemical degradation or
physical denaturation.
MODELING TECHNIQUES SHOW
POTENTIAL BENEFITS OF
REDUCTIONS IN POOL SIZE FOR
INFREQUENT USERS
---------------------------------------------------------- Letter :4.2
Modeling techniques have been used to determine the degree of
infectivity present in plasma pools of varying sizes. One major
study using such a technique found that limiting the number of donors
in a pool may only be beneficial for infrequent recipients.\28 For
example, the researchers calculated that for an infectious agent with
a prevalence of 1 in 500,000 (such as a rare or emerging virus), a
pool made up of 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 (100 infusions), this same pool size of 10,000
would yield an 86 in 100 chance of exposure to that agent, based on
an assumption that the products would come from different pools.
This effect is not significantly decreased by reducing the number of
donors in a pool. Table 10 shows the effect of manufacturing scale
on risk of exposure.
Table 10
Effect of Manufacturing Scale on Risk of
Exposure
Chance of exposure
(percent)
----------------------
Infreq Modera Freque
uent te nt
users users users
(1 (10 (100
infusi infusi infusi
Scale of manufacturing on) ons) ons)
---------------------------------------------- ------ ------ ------
Prevalence of agent = 1 in 500,000
----------------------------------------------------------------------
60,000 11 70 100
25,000 5 39 99
10,000 2 18 86
6,000 1 11 70
2,500 0.5 5 39
Prevalence of agent = 1 in 50,000
----------------------------------------------------------------------
60,000 70 100 100
25,000 39 99 100
10,000 18 86 100
6,000 11 70 100
2,500 5 39 99
Prevalence of agent = 1 in 5,000
----------------------------------------------------------------------
60,000 100 100 100
25,000 99 100 100
10,000 86 100 100
6,000 70 100 100
2,500 39 99 100
----------------------------------------------------------------------
Source: Thomas Lynch and others, "Considerations of Pool Size in the
Manufacture of Plasma Derivatives."
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 not have a major effect on those
who are frequent recipients of such products.
It is also important to note that 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
of recipients of this product increased with the number of positive
HCV lots infused and the quantity of HCV viral material infused.
However, not all recipients were infected; the highest percentage of
seroconversions seen with the highest levels of HCV virus infused did
not exceed 30 percent.\29
The reasons for not observing seroconversions in 100 percent of the
recipients may be due to two factors: (1) the recipient's dose and
(2) the reduction of infectiousness related to steps in the
manufacture of the product in addition to viral removal and
inactivation, such as duration of storage.
--------------------
\28 Thomas Lynch and others, "Considerations of Pool Size in the
Manufacture of Plasma Derivatives," Transfusion, Vol. 36 (1996), pp.
770-75.
\29 Joseph Bresee and others, "Hepatitis C Virus Infection Associated
With Administration of Intravenous Immune Globulin: A Cohort Study,"
Journal of the American Medical Association, Vol. 276 (Nov. 20,
1996), pp. 1563-7.
RISK OF INFECTION REDUCED
THROUGH VIRAL INACTIVATION AND
REMOVAL TECHNIQUES
------------------------------------------------------------ Letter :5
Since it is possible that certain infectious units could make it
through the donor screening, deferral, and testing process,
manufacturers have introduced additional steps in the fractionation
process to inactivate or remove viruses and bacteria that may have
made their way into plasma pools. These techniques virtually
eliminate enveloped viruses, such as HIV, HBV, and HCV. However,
they are only partially effective against nonenveloped viruses, such
as HAV and human parvovirus.\30
All plasma components listed in table 1 undergo viral inactivation or
removal steps during the manufacturing process.\31 To be effective,
inactivation techniques must disrupt the virus, rendering it
noninfectious. The two main inactivation techniques are heat
treatment and solvent-detergent treatment. 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.\32 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.
However, solvent-detergent inactivation is only partially effective
in eliminating non-lipid-coated viruses, such as HAV or human
parvovirus.
To disable the virus without inactivating plasma derivatives, a
delicate balance in these procedures must be maintained. Heat and
chemicals are particularly damaging to plasma proteins. A number of
potentially safer methods are in use or under investigation. These
include the use of filters to remove virus particles on the basis of
the size of the virus; antibodies to capture the desired protein,
while the viruses and unwanted components are washed away;\33 and
irradiation to inactivate viruses. Virucidal agents that can be
removed during further manufacturing and exposure to ultraviolet
light may also be safer methods for disabling viruses. Genetic
engineering techniques are also being used to produce recombinant
factors VIII and IX--that is, the genes to produce the proteins have
been cloned and harvested in the laboratory. These products have, so
far, been found free of human viruses. However, manufacturing of
these recombinant products may include the use of human-derived
products during production or as excipients in the final container.
FDA has approved recombinant factor VIII and IX.
Determining the effectiveness of these different procedures is
accomplished by assessing the amount of viral clearance obtained
through a particular inactivation or removal process. It is based on
the amount of virus that is killed or removed and, therefore, the
extent to which these processes eliminate viruses through
manufacturing. Individual manufacturing steps can be specifically
designed for viral clearance or they may be intended primarily as a
purification process that will also assist in killing or removing
viral agents. To meet FDA approval of their particular inactivation
or removal technique, manufacturers must separately validate each
clearance step.
The viral inactivation and removal steps currently in use have all
been demonstrated to reduce the levels of virus and, in many cases,
likely eliminate them. (See app. III for a more complete discussion
of viral clearance.) Even when the virus is not completely
eliminated, a significant reduction in viral load is of value. While
theoretically even a single virus is capable of causing infection,
research has shown that infection is much more likely to occur with
higher concentrations of virus.\34 As a result of these techniques,
there have been no documented cases of HIV, HCV, or HBV transmission
since 1988 for plasma products that were properly inactivated.
--------------------
\30 Parvovirus is the cause of Fifth disease, a common childhood
illness, which is usually mild and of brief duration. Approximately
50 percent of the population has been infected by parvovirus at some
time.
\31 FDA has encouraged manufacturers to incorporate viral
inactivation or removal procedures for enveloped viruses. Currently,
only two IGIM products are manufactured without the use of viral
inactivation procedures.
\32 Extensive research has carefully calculated specified
temperatures and times for different heat treatment processes. For
example, FDA regulations require that albumin (human) and plasma
protein fraction be heated for 10 to 11 hours at 60 degrees
centigrade in the final container and in the presence of defined
stabilizers to ensure viral inactivation (21 C.F.R. 640.91(e),
640.81).
\33 One example of this process is the use of a monoclonal antibody
column to purify a plasma derivative such as factor VIII. In this
case, antibodies to the factor VIII are generated in large amounts in
tissue culture. The antibodies are attached to a support within the
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 possible
contaminating viruses and other agents, flows through the column.
The factor VIII can later be separated from the antibody column.
\34 Joseph Bresee and others, "Hepatitis C Infection Associated With
Administration of Intravenous Immune Globulin."
RECENT NONCOMPLIANCE WITH
CURRENT GOOD MANUFACTURING
PRACTICES COULD JEOPARDIZE THE
SAFETY OF PLASMA PRODUCTS
------------------------------------------------------------ Letter :6
Although viral inactivation and removal techniques have been shown to
be highly effective, they are only useful if the steps in the
manufacturing process are carried out properly. Recent FDA
inspections of plasma fractionation facilities have found numerous
violations of current good manufacturing practices. Without strict
adherence to these practices, the safety of plasma products could be
compromised.
The objective of good manufacturing practices is to ensure that
plasma products are safe, effective, adequately labeled, and possess
the quality purported. To achieve this goal, plasma manufacturers
should operate in compliance with applicable regulations and
principles of quality assurance.
To ensure that manufacturing processes, including inactivation
procedures, follow current good manufacturing procedures, FDA is
authorized to inspect plasma fractionation establishments. If the
manufacturer does not conform to the standards in its license or the
regulations such that the safety and purity of the product is not
ensured and this constitutes a danger to health, necessitating
immediate corrective action, and the deficiencies are well
documented, FDA may pursue an action to suspend the facility's
license.
When deficiencies are noted during an inspection, FDA may also issue
a warning letter to the facility. A warning letter does not suspend
operations but rather gives the facility an opportunity to correct
deviations. A warning letter acts as notification to a firm that FDA
considers its activities to be in violation of statutory or
regulatory requirements and that failure to take appropriate and
prompt corrective action may result in further action by FDA.
Recent inspections conducted at the four major fractionation
companies found numerous deficiencies in each company's adherence to
current good manufacturing practices and resulted in consent decrees
with two of the companies. (See table 11.)
Table 11
Outcomes of Recent FDA Inspections
Number of
Inspecti observatio
Company on year ns found Outcome
------------ -------- ---------- ----------------------
Alpha 1997 139 Consent decree with
Therapeutic FDA\a
Baxter 1997 96 No regulatory action
Healthcare
Bayer 1997 107\b No regulatory action
Corporation
Centeon 1996 87 Consent decree with
FDA
----------------------------------------------------------
\a A consent decree of permanent injunction is a court-ordered action
against a firm or individual, which either mandates corrective
actions that must be taken or which prohibits the operation of the
firm unless and until such actions are taken.
\b Thirty observations were found at Bayer's Berkeley, California,
facility; 77 were found at its Clayton, North Carolina, facility.
Many of the facilities slowed production as the firms reallocated
resources to work on their corrective actions. The consent decree
with Centeon required the company to cease distribution of all but
two of its products while it brought its manufacturing standards into
compliance with FDA statutes and regulations. In May 1997, FDA
authorized the distribution of Centeon's products from the facility.
In a subsequent inspection, completed in July 1998, FDA found that
Centeon had failed to fully comply with the consent decree and was
notified to immediately cease manufacturing, processing, packing,
holding, and distributing all biological and drug products
manufactured at its facility. However, exceptions could be made for
products deemed medically necessary.
Examples of observations found by FDA inspectors during inspections
of various plasma fractionation facilities included the following:
-- In-house developed software that had not been validated was
being used for performance of finished product testing.
-- Calibration and preventive maintenance records were incomplete
and sometimes inaccurate.
-- Reports of problems with plasma products after distribution were
not being reviewed and investigated in a timely manner.
-- Viral inactivation processes used on several lots of factor VIII
had deviations that were undetected or not corrected.
-- Albumin product lots that failed final container testing for
sterility were reprocessed by repooling, and there was no
validation for these reprocessing steps.
-- The cleaning process and removal of cleaning agent residues from
fractionation kettles, bulk tanks, buffer tanks, or centrifuge
bowls were not validated.
-- Albumin manufacturing processes were not validated, and final
products did not consistently conform to release specifications.
(In 1997, 54 percent of albumin lots for one company failed
final container inspection due to visible evidence of
proteinaceous material.)
To overcome these problems, the major fractionation companies have
taken certain steps, such as increasing quality assurance and quality
control and production staff and training, implementing capital
investments at the fractionation facilities, and equipment process
validation.
FDA has also taken several actions within the last year to better
ensure manufacturer compliance with current good manufacturing
practices. In a previous study examining the safety of the blood
supply, we had found inconsistencies in FDA inspection practices.\35
As a result of this and another study examining FDA's regulatory role
in the field of biologics, a new inspection program was adopted.\36
Under this program, FDA has designated two groups of investigators:
one to focus on blood banks and plasmapheresis centers and another to
focus on plasma fractionation and manufacturers of allergenic
products, therapeutics, licensed in-vitro diagnostics, and vaccines.
This approach is intended to ensure that all FDA current good
manufacturing practice inspections are conducted by a single agency
unit using a similar approach. If properly implemented, these
actions by plasma manufacturers and FDA should help alleviate the
problems related to adherence to current good manufacturing practices
and quality assurance.
--------------------
\35 Blood Supply: FDA Oversight and Remaining Issues of Safety
(GAO/PEMD-97-1, Feb. 25, 1997).
\36 Office of Inspector General, Review of the Food and Drug
Administration's Inspection Process of Plasma Fractionators,
A-03-97-00350 (Washington, D.C.: Department of Health and Human
Services, June 1997).
AGENCY COMMENTS
------------------------------------------------------------ Letter :7
We provided copies of a draft of this report to FDA and the Centers
for Disease Control and Prevention for their review. Both generally
agreed with our findings. They provided technical comments, which we
incorporated as appropriate. We also provided copies of the draft
report to the American Red Cross, the American Blood Resources
Association, and the International Plasma Products Industry
Association. Each provided technical comments, which we incorporated
as appropriate. The American Blood Resources Association provided
additional data on viral marker rates, which we have included.
---------------------------------------------------------- Letter :7.1
We will send copies of this report to the Secretary of Health and
Human Services, the Lead Deputy Commissioner of FDA, and others who
are interested. If you have any questions or would like additional
information, please call me at (202) 512-7119 or Marcia Crosse,
Assistant Director, at (202) 512-3407. Other contributors to this
report were Kurt Kroemer, Project Manager, and Richard Weston, Senior
Social Science Analyst.
Sincerely yours,
Bernice Steinhardt
Director, Health Services Quality
and Public Health Issues
CALCULATIONS FOR RISK ESTIMATES
=========================================================== Appendix I
Our analysis of viral risks from volunteer and paid plasma donors
included calculations for the three major viruses known to be
transmissible through plasma products--HIV, HBV, and HCV--and is
based on a model that calculated similar estimates for whole blood
donations.\37 We did not estimate risks associated with nonenveloped
viruses, where current removal or inactivation techniques are only
effective to a limited extent, because no screening tests are
currently used for these viruses. The nonenveloped viruses currently
known to be transmitted through plasma, primarily HAV and human
parvovirus, are generally not life threatening.\38
The window period outlined in our calculations is based on the
"conventional" window period--defined as the interval between the
time the donor acquired the infection and the development of a
positive laboratory test. The conventional window period differs
from the "infectious" window period
if there is a lag between the acquisition time of infection and
the donor's ability to transmit the infection to others by blood
transfusion. Theoretically, such a lag would exist if, on
initial exposure to the virus, the donor were able to sequester
the virus in the organs of the immune system before becoming
infectious.\39
Experimental animal evidence suggests that the difference between the
conventional and infectious windows for retroviruses, such as HIV,
may range from 2 to 14 days.\40
Two ways of measuring risk of infection from blood transfusions are
to examine prevalence and incidence of disease. Prevalence indicates
the overall proportion of infected persons in the population at a
given time, independent of when the infection occurred. Incidence is
the proportion of persons newly infected in the population during the
period of time under study, or the rate of new infections. As such,
incidence is calculated as the number of seroconverters divided by
the person-time of observation, where the person-time of observation
equals the number of donations multiplied by the mean time between
donations (interdonation interval). To calculate the overall
residual risk from window period donations, the incidence rate is
multiplied by the length of the window period from seroconverting
(repeat) donors. Adjustment factors can also be used to incorporate
the effect of first-time donors and probability estimates for donors
who do not return but may be in the infectious window period when
they donate.
--------------------
\37 George Schreiber and others, "The Risk of Transfusion-Transmitted
Viral Infections."
\38 Bernard Horowitz and others, "Viral Safety of Solvent-Detergent
Treated Blood Products," in Virological Safety Aspects of Plasma
Derivatives, F. Brown, ed., Vol. 81 (1993), pp. 147-61.
\39 Stephan Kleinman and others, "The Incidence/Window Period Model
and Its Use to Assess the Risk of Transfusion-Transmitted Human
Immunodeficiency Virus and Hepatitis C Virus Infection."
\40 M. T. Niu and others, "Primary Human Immunodeficiency Virus
Type 1 Infection: Review of Pathogenesis and Early Treatment
Intervention in Humans and Animal Retrovirus Infections," Journal of
Infectious Diseases, Vol. 168 (1993), pp. 1490-1501.
VIRAL MARKER RATES
--------------------------------------------------------- Appendix I:1
Information on viral marker rates among volunteer and paid plasma
donors in California was obtained from California's Department of
Health Services, Office of AIDS, HIV/AIDS Epidemiology Branch. Data
illustrated in figure 1 are for HIV-1 confirmed positive test
results. Starting in the second quarter of 1991, the totals do not
include autologous donations. Information pertaining to data for the
second half of 1996 were obtained from 49 blood banks and 15 plasma
centers, representing approximately 75 percent of the overall
California facilities required to report HIV antibody test results to
DHS.\41
Table I.1 outlines the calculations for the viral marker rates for
volunteer plasma donors. This information was obtained from 19
American Red Cross regions and was based on 2,954,773 donations from
donors under age 60. This is approximately 33 percent of the total
number of donations made to the American Red Cross during the
reporting period of this data collection effort (January 1, 1996, to
June 30, 1997).
Table I.1
Marker Rates Among Volunteer Donations
Number Percent Calculation
---------------- -------- -------- --------------------
Anti-HIV marker
----------------------------------------------------------
Repeat reactive 2,551 .09 2,551 � 2,954,773
Confirmed 1,185 46.45 1,185 � 2,551
negative
Confirmed 1,161 45.51 1,161 � 2,551
indeterminate
Confirmed 205 8.04 205 � 2,551
positive
Positive 6.94 NA 100,000 x (205 �
donations per 2,954,773)
100,000
HBsAg marker
----------------------------------------------------------
Repeat reactive 1,404 .05 1,404 � 2,954,773
Confirmed 417 29.70 417 � 1,404
negative
Confirmed NA NA NA
indeterminate
Confirmed 987 70.30 987 � 1,404
positive
Positive 33.40 NA 100,000 x (987 �
donations per 2,954,773)
100,000
Anti-HCV marker
----------------------------------------------------------
Repeat reactive 5,728 .19 5,728 � 2,954,773
Confirmed 1,289 22.50 1,289 � 5,728
negative
Confirmed 1,119 19.54 1,119 � 5,728
indeterminate
Confirmed 3,320 57.96 3,320 � 5,728
positive
Positive 112.36 NA 100,000 x (3,320 �
donations per 2,954,773)
100,000
----------------------------------------------------------
Note: NA = not applicable.
There were 205 confirmed positive HIV donations found among the 19
regions reporting for the Infectious Disease Data Center. The number
of positive donations per 100,000 is derived by dividing these 205
cases by the number of total donations and then multiplying the
resulting figure by 100,000. For HIV, this calculation yielded an
estimated 7 positive donations per 100,000 given at American Red
Cross centers. Similar calculations can be used to obtain estimates
for HBV and HCV. To obtain our estimate of 1 in every 6,549
volunteer donations as potentially infectious for HIV, HBV, or HCV,
we added the positive donations per 100,000 for each virus (6.93 +
33.40 + 112.36) and divided 1 million by this amount.
Table I.2 outlines the calculations for the viral marker rates for
paid plasma donations. The calculations are based on 4,600,000
donations for HIV and HBV and 2,500,000 donations for HCV made in the
second half of 1994 to 340 American Blood Resources Association
collection centers. The number of confirmed positive donations is
obtained by multiplying the number of units found to be repeatedly
reactive by the rate at which units are confirmed positive in
volunteer whole blood donations for the specific virus in question.
(See table I.1 for these confirmed positive rates for each virus.)
The number of positive donations per 100,000 is derived by dividing
the number of confirmed positive donations by the total number of
donations and multiplying by 100,000. Similar calculations can be
used to obtain estimates for HBV and HCV. To obtain our estimate of
1 in every 3,834 paid donations as potentially infectious for HIV,
HBV, or HCV, we added the positive donations per 100,000 for each
virus (3.67 + 30.93 + 226.20) and divided 1 million by this amount.
Table I.2
Marker Rates Among Paid Plasma Donations
Number of
repeatedly
reactive Number of confirmed Number of positive donations per
Marker donations positive donations\a 100,000
----------- -------------- -------------------------- --------------------------------
Anti-HIV 2,116 169.28 x (2,116 x .080) 3.67 x [(169 � 4,600,000) x
100,000]
HBsAg 2,024 1,422.87 x (2,024 x .703) 30.93 x [(1,423 � 4,600,000) x
100,000]
Anti-HCV 9,750 5,655.00 x (9,750 x .580) 226.20 x [(5,655 � 2,500,000) x
100,000]
-----------------------------------------------------------------------------------------
\a Based on rates found among volunteer whole blood donors.
--------------------
\41 California Health and Safety Code, Chap. 7, Sect. 120980(j).
INCIDENCE RATES AND RESIDUAL
RISK
--------------------------------------------------------- Appendix I:2
Table I.3 outlines the incidence rates among repeat volunteer plasma
donors, while table I.4 outlines the corresponding overall incidence
rates for volunteer donors, taking into account first-time donations.
These calculations are drawn from 1 year of donations for which the
American Red Cross had the most recently available data (1,098,942
donations from July 1, 1996, to June 30, 1997).
Table I.3
Incidence Rates Among Repeat Volunteer
Plasma Donations
Rate Calculation
-------------------------------- --------------------- --------------------------------
Anti-HIV marker: 12 seroconverters
-----------------------------------------------------------------------------------------
Seroconverters per 100,000 1.09 100,000 x (12 � 1,098,942)
donations
Incidence per 100,000 person- 2.59 (12 x 100,000) � [1,098,942 x
years (154 � 365)]
Risk per million donations 1.14 10 x (2.59 x 16\a � 365)
HBsAg marker: 29 seroconverters
-----------------------------------------------------------------------------------------
Seroconverters per 100,000 2.63 100,000 x (29 � 1,098,942)
donations
Incidence per 100,000 person- 6.26 (29 x 100,000) � [1,098,942 x
years 18.59\b (154 � 365)]
6.26 x 2.97
Risk per million donations 10.12 10 x (6.26 x 59\a � 365)
30.05\b 10 x (18.59 x 59\a � 365)
Anti-HCV marker: 54 seroconverters
-----------------------------------------------------------------------------------------
Seroconverters per 100,000 4.91 100,000 x (54 � 1,098,942)
donations
Incidence per 100,000 person- 11.65 (54 x 100,000) � [1,098,942 x
years (154 � 365)]
Risk per million donations 26.17 10 x (11.65 x 82\a � 365)
-----------------------------------------------------------------------------------------
Note: Interdonation interval = 154 days.
\a Window period (in days).
\b The second number contains a calculation based on the transient
antigenemia for HBV. The duration of this transient period has been
estimated at 63 days. An interdonation interval of 154 days suggests
that 41 percent of donors with transient antigenemia would be
identified by the HBsAg test (63 � 154 = .41). It is believed that
70 percent of HBV-infected donors show this transient effect, 25
percent have a primary antibody response but no detectable
antigenemia, and 5 percent become long-term carriers. See J. H.
Hoofnagle and others, "Serologic Responses in Hepatitis B," in Viral
Hepatitis: A Contemporary Assessment of Etiology, Epidemiology,
Pathogenesis, and Prevention, G. N. Vyas and others, eds.
(Philadelphia, Pa.: Franklin Institute Press, 1978), pp. 219-42;
and L. T. Mimms and others, "Effect of Concurrent Acute Infection
With Hepatitis C Virus on Acute Hepatitis B Virus Infection," British
Journal of Medicine, Vol. 307 (1993), pp. 1095-7. The following
represents the adjustment factor incorporated into the calculation:
-- (.70 x 41) + (.25 x 0) + (.05 x 100) = 33.7 percent;
-- 1 � .337 = 2.97 (correction factor); because only 33.7 percent
of donors seroconverting for HBV are likely identified with the
HBsAg test, the observed incidence rate of HBsAg is multiplied
by 1 � 0.337 or 2.97; and
-- 6.26 x 2.97 = 18.59, where 6.26 is the incidence rate per
100,000 person-years for HBsAg without the adjustment factor.
To obtain an incidence rate for repeat donors, we multiplied the
number of seroconverters (12) by 100,000 and divided the resulting
number by the total number of donations times the interdonation
interval as a fraction of a year. We calculated an incidence rate
per 100,000 person years for HIV at 2.59. Taking this rate and
multiplying it by the window period (as a fraction of a year)
resulted in a risk per million of 1.1. Similar calculations can be
used to obtain estimates for HBV and HCV.
Table I.4
Total Incidence Rates and Residual Risk
Estimates Among Volunteer Plasma
Donations
Rate Ratio Calculation
---------------------------------- -------------- ------------- ----------------------
Anti-HIV marker
-----------------------------------------------------------------------------------------
Repeat donors (80%) 2.59 (See table I.3.)
First-time donors (20%) 6.22 2.59 x 2.4
Estimated total incidence (per 3.31 (2.59 x .8) + (6.22 x
100,000 person-years) .2)
Estimated adjusted risk (per 1.45 10 x [3.31 x (16\a �
million donations) 365)]
Point estimate 1:689,655 1,000,000 � 1.45
HBsAg marker
-----------------------------------------------------------------------------------------
Repeat donors (80%) 6.26 (See table I.3.)
18.59\b
First-time donors (20%) 15.02 6.26 x 2.4
Estimated total incidence (per 8.01 (6.26 x .8) + (15.02 x
100,000 person-years) 17.87\b .2)
(18.59 x .8) + (15.02
x .2)
Estimated adjusted risk (per 12.95 10 x [8.01 x (59\a �
million donations) 28.89\b 365)]
10 x [17.87 x (59\a �
365)]
Point estimate 1:77,220 1,000,000 � 12.95
1:34,614\b 1,000,000 � 28.89
Anti-HCV marker
-----------------------------------------------------------------------------------------
Repeat donors (80%) 11.65 (See table I.3.)
First-time donors (20%) 27.96 11.65 x 2.4
Estimated total incidence (per 14.91 (11.65 x .8) + (27.96
100,000 person-years) x .2)
Estimated adjusted risk (per 33.50 10 x [14.91 x (82\a �
million donations) 365)]
Point estimate 1:29,850 1,000,000 � 33.5
=========================================================================================
Total 47.91\c 1:20,872 1,000,000 � 47.91
63.85\b,c 1:15,662\b 1,000,000 � 63.85
-----------------------------------------------------------------------------------------
Note: First-time donors are 2.4 times more likely to donate a
positive unit than repeat donors.
\a Window period (in days).
\b Calculation based on the transient antigenemia for HBV.
\c Total risk per million donations.
Since approximately 80 percent of whole blood donations are collected
from repeat donors, a correction factor is made taking into account
the weighted average of first-time donation to ascertain the
estimated total residual risk (for HIV, this is 3.32 incident cases
per 100,000 person-years). To determine the risk that a donor was
already infected and in the infectious, seronegative window period,
the adjusted incidence rate for HIV of 3.32 was multiplied by .044
(the 16-day window period for antigen expressed as a fraction of a
year), yielding a residual risk of 1.5 per million donations. Our
point estimate was calculated by taking this residual risk and
dividing by 1 million. Similar calculations can be used to obtain
estimates for HBV and HCV.
Table I.5 highlights the corresponding incidence rates and residual
risk for paid plasma donors without taking into account the 60-day
hold program. This information was obtained from the American Blood
Resources Association and was based on 4,011,449 donations from 370
collection centers from July 1997 through October 1997. The
confirmed positive donations were analyzed to ensure that they were,
in fact, from qualified donors. Additionally, donation histories
were examined for approximately 16,000 nonreactive donors
(representing 300,288 donations) to obtain probability estimates for
the effect of donors who did not return but may have donated a
seronegative, but infectious, window period unit at their last
donation. Calculations made above for volunteer donors were done in
a similar fashion for paid plasma donors to obtain incidence rates,
risks per million donations, and a point estimate.
Table I.5
Incidence Rates and Residual Risk
Estimates for Paid Plasma Donations,
Without the 60-Day Inventory Hold
Program
Rate Ratio Calculation
------------------------ -------------- ------------- --------------------------------
Anti-HIV marker: 36 seroconverters
-----------------------------------------------------------------------------------------
Seroconverters per .89 100,000 x (36 � 4,011,449)
100,000 donations
Incidence per 100,000 61.80 (36 x 100,000) � [4,011,449 x
person-years (5.3 � 365)]
Risk per million 37.25 10 x [61.80 x (22\a � 365)]
donations 27.09\b 10 x [61.80 x (16\a � 365)]
Point estimate 1:26,800 1,000,000 � 37.25
1:36,900\b 1,000,000 � 27.09
HBsAg marker: 143 seroconverters
-----------------------------------------------------------------------------------------
Seroconverters per 3.56 100,000 x (143 � 4,011,449)
100,000 donations
Incidence per 100,000 245.50 (143 x 100,000) � [4,011,449 x
person-years (5.3 � 365)]
Risk per million 396.84 10 x [245.5 x (59\a � 365)]
donations
Point estimate 1:2,520 1,000,000 � 396.84
Anti-HCV marker: 37 seroconverters
-----------------------------------------------------------------------------------------
Seroconverters per .92 100,000 x (37 � 4,011,449)
100,000 donations
Incidence per 100,000 63.52 (37 x 100,000) � [4,011,499 x
person-years (5.3 � 365)]
Risk per million 142.70 10 x [63.52 x (82\a � 365)]
donations
Point estimate 1:7,008 1,000,000 � 142.7
Total 576.79\c 1:1,734 1,000,000 � 576.79
566.63\b,c 1:1,765\b 1,000,000 � 566.63
-----------------------------------------------------------------------------------------
Note: Interdonation interval = 5.3 days.
\a Window period (in days).
\b Calculation based on the incorporation of the antigen window
period to determine its effect on the overall calculations for paid
plasma donors. This was done in order to compare similar window
periods for volunteer and paid plasma donors.
\c Total risk per million donations.
Table I.6 outlines the overall residual risk of incorporating an
infectious window period unit from a paid plasma donor into a plasma
pool. This table takes into account the effect of the 60-day
inventory hold program to interdict window period units.
Table I.6
Incidence Rates and Residual Risk
Estimates for Paid Plasma Donations,
With the 60-Day Inventory Hold Program
Incidence
per
100,000 Residual
person- risk per Point
Marker years million estimate Calculation
------ --------- -------- ---------- ------------------
Anti- 61.80 1.47 1:680,272 1,000,000 � 1.47
HIV ~1.00\a 1:1,000,00 1,000,000 � 1.00
0\a
HBsAg 245.50 53.84 1:18,574 1,000,000 � 53.84
Anti- 63.52 35.94 1:27,824 1,000,000 � 35.94
HCV
Total 91.25 1:10,959 1,000,000 � 91.25
90.78\a 1:11,016\a 1,000,000 � 90.78
-----------------------------------------------------------
\a Calculation based on the incorporation of the antigen window
period to determine its effect on the overall calculations for paid
plasma donors. This was done in order to compare similar window
periods for volunteer and paid plasma donors.
The residual risk per million in table I.6 was obtained from the
American Blood Resources Association and included several probability
estimates for window period donations when the last donation was
positive and for window period donations when the last donation was
nonreactive. These latter probability estimates were performed for
the approximately 300,000 nonreactive donations that made up the
American Blood Resources Association's data set. The residual risk
per million of approximately 1.0 for HIV is based on an antigen
window period unit of 16 days. This was calculated from information
obtained from the American Blood Resources Association, which
indicated that PCR testing would reduce the residual risk to .49 per
million donations (11-day window period). Thus, the 1.0 used in our
calculations to estimate the 16-day antigen window period is simply
the midpoint between 1.47 for anti-HIV (22-day window period) and .49
using PCR testing.
When final comparisons are made, the overall risk of incorporating an
infectious HIV, HBV, or HCV window period unit into a plasma pool was
1 in 20,872 for volunteer plasma donors (or 1 in 15,662 taking into
account the transient nature of HBV) and 1 in 10,957 for paid plasma
donors.
ADDITIONAL INFORMATION ON TESTING
PROCEDURES
========================================================== Appendix II
FDA's protocols for viral testing stipulate that if the initial test
for viruses is reactive, then a retest should be performed to verify
the initial result. If the retest is also reactive, the blood
facility should perform a second, more specific test to confirm the
presence of the viral marker.\42 Deciding whether a donation is or is
not positive is also affected by the sensitivity and specificity of
the viral tests.\43 Initial tests are fast and usually automated and
screen large numbers of samples. They are extremely sensitive in
order to minimize the number of false-negative outcomes.
Confirmatory tests are more time consuming and usually less sensitive
than initial tests but are very specific. Table II.1 outlines the
different types of viral test results and the consequent actions.
Table II.1
Results From and Actions After Viral
Testing
Result Definition Action
------------------------- ------------------------- --------------------------
Initial test results
--------------------------------------------------------------------------------
Initially reactive Initial test is reactive. A retest in duplicate is
performed.
Repeatedly reactive One or both duplicate A confirmatory test is
tests are reactive. performed (this test is
not always required); the
prospective donor is
deferred, and the
collected unit is
discarded.
Negative Initial test is negative; None; the donor is not
or if reactive, both deferred.
duplicate tests are
negative.
Confirmatory test results
--------------------------------------------------------------------------------
Indeterminate Duplicate tests are The donor is deferred and
repeatedly reactive and the collected unit is
confirmatory test is discarded.
neither positive nor
negative.
Positive Duplicate tests are The donor is deferred and
repeatedly reactive and the collected unit is
confirmatory test is discarded.
positive.
--------------------------------------------------------------------------------
Any unit that is repeatedly reactive is considered positive even if
confirmatory tests determine that the testing procedure produced a
false-positive result. Such results require that the donor be
deferred. FDA recommends but does not require that donors who are
repeatedly reactive but indeterminate or negative by a confirmatory
test should be notified and placed on donor deferral registries.
As an added precaution against the inclusion of any plasma that may
contain undetectable HIV virus, one company performs additional tests
for the HIV antibody. Each donation is tested according to the
standards noted above by supplementary testing using a different
antibody test than that used in the initial screening procedure. The
testing uses "minipools" derived from samples of 64 donations.\44
Units corresponding to test samples that are confirmed reactive for
anti-HIV at individual sampling are then rejected and the donor is
deferred. Only nonreactive donations are considered to be acceptable
for further manufacture.
PCR testing--which is more sensitive than licensed antigen or
antibody detection methods currently used to screen collected
plasma--will be done on pools of plasma rather than single donations.
This approach is being pursued because of the constant state of rapid
evolution of nucleic acid diagnostics and increased
cost-effectiveness of pool testing. FDA has noted that it considers
pool testing an interim step, but the agency does believe that
testing of plasma pools has public health benefits and should be
implemented. Consistent with this position, tests for plasma pools
are now under "investigational new drug" status and are planned to be
used by all fractionators to test all units of donated plasma in
minipools.
Some companies have also determined that every product lot that is to
be released should be tested one more time to ensure that there were
not errors during the testing of the plasma, testing of the pools,
and the manufacturing of the product. Final testing of lots for some
companies includes tests for HBsAg, while other companies test for
HIV using antibody testing and for HIV, HBV, HCV, and HAV using PCR
tests.
--------------------
\42 A false-negative test result fails to detect the viral marker in
a sample that contains the viral marker. A false-positive test
result incorrectly indicates that the viral marker is present in a
sample that lacks the viral marker. Confirmatory tests can also
yield "indeterminate" results, meaning that it is not possible to be
certain whether the individual is infected with the virus. Some
studies have suggested that--depending on the population--most
indeterminate confirmatory tests are probably negative. The status
of donors who have indeterminate test results is resolved over time
by additional testing. Units that test repeatedly reactive for HIV,
HBV, and HCV may not be used for transfusion or for further
manufacturing regardless of the more specific or confirmatory test
results, except in special circumstances.
\43 "Sensitivity" is the probability of a unit's testing positive if
a viral marker is truly present. As sensitivity increases, the
number of persons whose blood contains the virus but who are missed
(false negatives) by being incorrectly classified decreases. In
other words, sensitivity = true positives � (true positives + false
negatives). "Specificity" is the probability of a unit's testing
negative if a virus is truly absent. A highly specific test is
rarely positive when a virus is not present and therefore results in
fewer persons without the virus being incorrectly classified (false
positives). In other words, specificity = true negatives � (true
negatives + false positives).
\44 Minipool testing is done by taking samples of individual
donations and combining them. If the minipool is found to be
reactive for anti-HIV, then the reactive sample is identified by
individual sample testing.
VIRAL CLEARANCE THROUGH
INACTIVATION AND REMOVAL
========================================================= Appendix III
Heating and chemical inactivation are the two main methods in use
today to inactivate viruses. Heating in solution, terminal dry heat,
vapor heating, and dry heat under solvent are commonly used. For
chemical inactivation, manufacturers typically use solvent-detergent
techniques, ethanol (during fractionation), and low pH. Viral
removal steps include partitioning and nanofiltration. Partitioning
during purification includes ethanol fractionation and
chromatography, whereas nanofiltration can be accomplished through
adsorption or through filters that discriminate to 15 to 100
nanometers.
To be effective, viral inactivation techniques must destroy at least
one of the essential elements of viral replication.\45 These
techniques work in different ways to accomplish this task.
Photosensitizing techniques use light-activated dyes that are
irradiated, causing the dyes to convert to molecules that can destroy
DNA or membrane lipoproteins. Heat treatment denatures viral
proteins and nucleic acids, rendering them incapable of viral
replication. Irradiation processes inhibit viral DNA by inducing
breaks and linkages. Solvent-detergent techniques destroy the viral
envelope in lipid-enveloped viruses. Viral removal methods,
including chromatography and filtration, physically separate virus
particles and other impurities from the desired plasma proteins.
Validation of viral clearance steps is accomplished through a
scaled-down production method to a laboratory model. Material is
spiked with a marker virus (such as bovine viral diarrhea virus for
HCV or duck hepatitis B virus for HBV); titers are then compared in
the starting and ending material after performing the operations
dictated by the laboratory model. This scaled-down model must
maintain the physical parameters that will replicate the production
method, including time, temperature, pressure, concentration, flow
rates, and pH. It must also maintain the physical dimensions of
volume, load, and surface area and column dimensions. These
validation models cannot demonstrate complete elimination of a virus,
but they can highlight the difference in titers in the beginning and
end of the production model. This modeling will highlight the actual
viral kill that has been accomplished through inactivation, removal,
or both. The effect of multiple clearance steps may be combined if
each step is independently validated and each is based on a mechanism
that is different from other clearance steps.
Units that have been tested for HIV that were in the window period
show a range of genome copies per milliliter of 10\3 to 10\7 (with
occasional spikes to 10\8 range), while seropositive units are in the
range of 10\3 to 10\6 . For albumin, the viral log reduction factor
(LRF) using pasteurization has been shown to be greater than 7, while
partitioning during fractionation shows LRFs to be greater than 6.\46
Additionally, there have been no cases of HIV, HCV, or HBV
transmission through albumin since initiation of heating (at 60
degrees Celsius for 10 hours) of the final containers. For IGIM, the
cumulative LRF for HIV in one model was greater than 10.9 (6.2 using
ethanol fractionation and 4.7 using solvent-detergent techniques).
For IGIV, the cumulative LRF for one process was greater than 17.5
(5.9 using ethanol fractionation, 5.2 using solvent-detergent
techniques, and 6.4 using pH 4). Processes for IGIV from another
model show LRFs of 13.2 and 11.4 using ethanol fractionation and heat
treating or ethanol fractionation and a pH of 4 using Pepsin,
respectively). For antihemophilic factor, the cumulative LRF for one
process was greater than 15.7 (5.2 using purification and 10.5 using
heat treating at 60 degrees Celsius for 10 hours), while another
company's procedure showed LRFs of greater than 12 (2 using affinity
chromatography and greater than 10 using solvent-detergent
techniques). Similar reductions are found for coagulation factor IX.
Thus, these LRFs for HIV are well above the levels of genome copies
per milliliter found in units that are from window period and
seropositive donations.
For HCV, genome copies per milliliter found in window period units
ranges from 10\3 to 10\8 , while seropositive units range from 10\3
to 10\6 . For albumin products, LRFs for HCV model viruses have been
shown to be greater than 11 using pasteurization and processing
techniques. For IGIM, the corresponding LRF for one process was
greater than 10.1 (3.3 using ethanol fractionation, greater than 5
using solvent-detergent techniques, and 1.8 using filtration). For
IGIV, one company's clearance profile was greater than 11.5 (3.2
using ethanol fractionation, greater than 4.2 using solvent-detergent
techniques, and greater than 4.1 at pH 4), while another procedure
showed an LRF greater than 10.1 (3.5 using ethanol fractionation and
greater than 6.6 using heat treating at 60 degrees Celsius for 10
hours). For antihemophilic factor, one process had a cumulative LRF
of greater than 17.0 (7.6 using affinity chromatography, greater than
4.5 using solvent-detergent techniques, and greater than 4.9 using
dry heating). LRFs greater than 10.3 are found for coagulation
factor IX. Again, these LRFs are well above the levels of genome
copies per milliliter found in units that are from window period and
seropositive donations.
--------------------
\45 Viral replication requires cell attachment by the virus to a cell
receptor, penetration of the cell, replication and translation of
viral nucleic acids, and exit from the cell with integrated viral
particles.
\46 LRF = log x [(V1 x T1) � (V2 x T2)], where V1 = volume of
starting material, T1 = concentration of virus in starting material,
V2 = volume of material after process step, and T2 = concentration of
virus after the step. LRFs less than 1 are not considered
significant, whereas LRFs greater than 4 are clearly effective.
*** End of document. ***