dd December 2002
Reference No.: VSWG02145
In-Process Control Measures for Management of Non-Chronic Diseases
in Plasma Fractionation: Parvovirus B19
Since January 2002, the major producers of plasma-derived therapies in the United States have voluntarily instituted in-process control measures to help prevent the transmission of Parvovirus B19 through fractionated therapies. Although Parvovirus B19 infection causes a relatively benign disease with widespread prevalence, control measures directed at reducing the potential for Parvovirus B19 transmission have been instituted to further assure the safety of plasma-derived therapies. The in-process control measures currently in place consist of various testing protocols and inventory management techniques aimed at assuring low levels of Parvovirus B19 in the manufacturing pool; they are not intended as a donor screening mechanism.
control measures are an appropriate means of increasing the margin of safety
for plasma-derived therapies while retaining the desirable protective
acute Parvovirus B19 infection. However, such measures are not an
appropriate donor screening mechanism, nor is such an approach warranted for
non-chronic diseases such as Parvovirus B19.
As discussed later in this paper, there is no public health benefit to
be achieved through identification and notification of donors with high titer
Parvovirus B19 donations.
Unlike chronic, life-threatening diseases such as hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV), donor notification of Parvovirus B19 infection confers no health benefit to donors in the plasma donation setting and indeed, may cause undue concern and confusion. This is because most Parvovirus B19infections are asymptomatic and typically persist only for two weeks. Given this short period of viremia and the limited potential to impact the clinical course of the typically mild disease, in-process control measures are the most appropriate means for addressing Parvovirus B19.
Human populations are widely exposed to
, such as Parvovirus B 19. Parvovirus B19 is an acute, self-limiting
disease without chronic sequelae in normal individuals. It is a common cause of human
infections worldwide and is normally spread via the respiratory route. The most
common presentation of Parvovirus B19 infection is erythema infectiosum. Approximately 50% of children aged 15 are
seropositive, a prevalence that rises to more than 90% in the elderly (Edwards
et al., 1981, Brown et al. 1994). Infections in temperate climates are more
frequent in late winter to early summer, and the rate of infection may increase
in a cyclic manner every three to five years.
Importantly, most infections are asymptomatic.
prevalence and incidence of Parvovirus B19 infections in blood/plasma donors
are analogous to the normal population. Serological studies have shown that
approximately 50% or more of the donor population have neutrali
antibodies against Parvovirus B19 and approximately 1:20,000 to 1:40,000
donations during non-epidemic seasons will contain high titres of Parvovirus
B19 (Cohen et al., 1990. J. Virol. Methods; 30:233-238). In an epidemic season
up to 1:167 blood donations and in the non-epidemic season between 1:3,300 to >
1:6,000 donations contained NAT- detectable Parvovirus B19 DNA (Prowse et al.,
1997. Vox. Sang. 72: 1-10).
Antibodies to Parvovirus B19 are produced following infection, conferring protective immunity. The presence of Parvovirus B19 specific IgG signifies a past infection only, whereas the presence of IgM and/or virus DNA is indicative of a recent infection. In acute Parvovirus B 19 infections, viremia levels as high as 1012 to 1014 virus particles per milliliter of serum may be detected over a period of one to two days (Kurtzman et al., 1989).
Parvovirus B19 infections typically resolve with the appearance of neutralizing antibodies, starting about 5 days post infection for IgM and about 7 days post infection for IgG. The appearance of antibodies coincides with disappearance of virus from the circulation. As such, the period of high viremia lasts approximately 2 weeks. In some cases it has been observed that individuals with low level viremia continue to produce Parvovirus B19 for a longer period of time. However, chronic carriers have not been identified
Each of the major producers of plasma-derived
therapies has instituted validated viral inactivation measures
for the three viruses of major public health import: hepatitis B virus (HBV),
hepatitis C virus (HCV), and human immunodeficiency virus (HIV). Since the implementation of these
inactivation measures, there has been no reported case of HBV, HCV or HIV
transmission via plasma therapies
(Tabor E, Transfusion 1999, Nov – Dec; 39 (11 –12) 1160-68). The health risk associated with
posed by these
chronic, life-threatening diseases now appears to be adequately managed for
Additional safeguards for both chronic and
non-chronic diseases have been put in place through voluntary
standards programs such as
voluntary standards programs such h as the
Quality Standards of Excellence, Assurance and Leadership
(QSEAL). The following
five standards constitute the central tenets of the QSEAL program:
· Qualified Donor
· Inventory Hold
· Viral Marker Standard
acid Technology (NAT) testing for HIV,
HBV, and HCV
· Parvovirus B19 Control Limit
A brief summary of the relevant standards is provided below.
The Parvovirus B19 standard was implemented to minimize the potential for the
transmission of Parvovirus B19 through plasma derived therapies. Under th
standard, companies have validated their individual NAT based in-process
control t est systems
to assure that high levels of Parvovirus B19 are not present in plasma
manufacturing pools. In this way, es
a a greater
assurance of the safety of plasma therapies vis-à-vis
Parvovirus B19 is achieved.
The current control limit in the manufacturing
pool for Parvovirus B19 is 105IU per
mL. While the QSEAL control limit control limit assures that no manufacturing
pool will contain more than 105IU per mL, the Parvovirus B19 levels
in actual manufacturing pools
can be substantially
lower than this limit. Recent Parvovirus
B19 quantitative NAT test data on manufacturing pools created using the
IU per mL standard showed Parvovirus B19 levels in the pool lower than 10 5IU per
mL. These lower actual Parvovirus B19
titers are due to the robust design of the
test system and the resulting detection and removal of moderately titered
Parvovirus B19 plasma.
Moreover, viral inactivation methods validated for enveloped viruses such as HBV, HCV and HIV have been shown to reduce levels of non-enveloped viruses such as Parvovirus B19. Consequently, the industry standard control limit of 105 IU of Parvovirus B19 per mL for manufacturing pools actuality results in much lower levels once viral inactivation methods are applied. A further reduction in the standard control limit may have the unintended consequence of excluding donations that have high levels of beneficial Parvovirus B19 antibody.
inactivation methods validated for enveloped viruses such as HBV, HCV and HIV
have been shown to reduce levels of non-enveloped viruses such as Parvovirus
B19. Consequently, the industry
standard control limit of 10 5 IU
of Parvovirus B19 per mL for manufacturing pools actuality results in much
lower levels once viral inactivation methods are applied. A further reduction
in the standard control limit may have the unintended consequence of excluding
donations that have high levels of beneficial Parvovirus B19 antibody.
Under the Qualified Donor standard, plasma
intended for fractionation can be collected only from individuals who have
demonstrated a commitment to the process through completion of two full health
and screening procedure, including serology and NAT testing for the three major
chronic viruses (HBV, HCV, HIV). The
Inventory Hold standard requires that each donation be held for a minimum
period of 60 days prior to pooling or manufacture. This
standard permits the retrieval of
donations from individuals who subsequently test positive for a chronic virus
or about whom some adverse post donation information is learned.
Under the NAT
standard manufacturers must implement NAT testing for every donation as a donor
screening mechanism for HBV, HCV and HIV.
Using the NAT methodology, it is possible to detect infectious
individuals sooner and prevent the possibility of a potentially infectious but
undetected donation from entering a manufacturing pool. In addition, NAT testing helps realize the
public health benefit to be achieved through early detection, notification and
treatment for individuals infected with these chronic diseases.
In-process control measures can be defined as a
set of testing protocols and inventory management techniques
at reduc ing the
potential for non-chronic disease transmission through preventing
high titer donations entering the plasma
pool. Although specific testing
protocols and inventory management techniques for Parvovirus B19 vary company to
company, they share
the same goal: tion
of plasma derived therapies. To a greater extent than for chronic
diseases where the focus is on individual donors and donations, t To
a greater extent than for chronic diseases where the focus is on individual
donors and donations, the focus of in-process control measures aimed
at non-chronic diseases is the management of the manufacturing
pool. Accordingly, donor identification
and notification are not part of the in-process control methods used to manage
Parvovirus B19 titers in manufacturing pools.
In-process control measures for Parvovirus B19
include the use of
include the of NAT testing
algorithms. Like NAT testing for
chronic diseases, NAT testing for Parvovirus B19 involves the utilization of
sample minipool matrices. A reactive
result from a minipool permits the identification of subsets (e.g., rows and
columns) of plasma units in which the reactive donation
exists. In this scenario, some
companies may trace back to the single infectious plasma donation
while others may identify a group of donations
in which the infectious donation
exists. In either case, manufacturers take
steps to eliminate high titer plasma donations
from the manufacturing pool.
In-process control measures do not constitute a
medical diagnostic test or donor screening methodbecause
for the simple reason that not all reactive
donations are identified and not all reactive donations are discarded
as part of the in-process control methodology.
As noted above, the industry standard control limit for Parvovirus B19 is 105 IU per mL.
This limit is appropriate to minimize the likelihood of Parvovirus
Additionally, in some circumstances non-reactive
may be discarded as a result of the in-process control approach to managing
non-chronic diseases. Although specific
practices vary from company to company, each company has optimized its internal
process control steps to maximize the opportunities for eliminating high titer
plasma from production pools. At the
same time, companies strive to maximize the utilization of suitable plasma
without unnecessarily discarding otherwise acceptable donations. Consequently, the industry has instituted
in-process control methods that allow for flexibility in the specific
strategies employed to achieve the objective of managing the titers of
Parvovirus B19 in manufacturing pools.
Non-chronic diseases present public health considerations that are different from those of chronic, life threatening diseases such as HBV, HCV and HIV. For chronic diseases, identification and notification of infected individuals is a public health imperative. However, this public health imperative stands in contradistinction to non-chronic conditions that have little public health impact.
Non-chronic viruses are acute and self-limiting
in normal individuals. Moreover,
individuals who contract Parvovirus B19 typically are asymptomatic and develop
a life-long immunity within two weeks of infection. More significant sequelae are rare and usually occur only in
particularly susceptible populations with preexisting conditions. Many of the conditions that could result in
more significant disease also would be a basis for rejecting a potential donor during routine health screening. Thus, the
the public healt h rationale
for donor notification is obviated by the fact that such individuals would
likely be deferred from donating plasma.
Furthermore, no meaningful opportunity would exist to provide donor notification. Even assuming some public health benefit could be gained by donor notification, in-process control protocols require between 25 to 60 days for the identification of a high titer Parvovirus B19 donation. As a consequence, an infected donor would have already cleared the virus and developed sufficient antibodies to confer a life-long immunity by the time notification occurred. Any medical information provided to the donor at this time would not be actionable. Given these circumstances, the psychological impact of donor notification must be weighed against the immateriality of the information presented.
Indeed, it may be considered unethical to notify a donor of non-actionable medical information that will increase anxiety, fear, or concern, and result in no potential medical benefit. Donor notification of a positive Parvovirus B19 test result would have to occur in the same setting where other donors are notified of a reactive test result for life threatening diseases such as HBV, HCV and HIV. For persons with no medical or scientific background it can be difficult to clearly distinguish between non-chronic viruses such as Parvovirus B19 and more significant, life altering conditions such as HIV/AIDS. Donor notification in these circumstances would likely do more harm than good.
establishment of voluntary industry standards, the plasma fractionation
industry has instituted in-process control measures that effectively minimize
the potential for the transmission of Parvovirus B19. The methodologies utilized to address non-chronic viruses such as
Parvovirus B19 are different than those established to address chronic
and potentially life-threatening diseases such has HBV, HCV and HIV. For non-chronic viruses, donor identification
and notification are not warranted due to the low public health impact of such
diseases and the lack of opportunity to meaningfully impact the course of
clinical illness in individuals infected with the disease. Furthermore, the
objective of in-process control measures is to strike a balance between the
elimination of plasma that may transmit virus and the retention of sufficient antibodies
so that immune globulin preparations remain efficacious. Manufacturers of plasma therapies also must
be given enough flexibility in the design of their in-process control steps to
allow for the optimal use of available plasma for the production of
therapies. By accommodat ingflexib l e
approaches and establish i ng
appropriate control limit s to
minimize the potential for transmission of Parvovirus B19 , the
plasma fractionation industry has demonstrated its commitment to provide
a safe and stable supply of plasma derived therapies.