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Bovine Viruses:Integrating a Quality by Design (QbD)
Approach into the Quality Control
of Bovine Raw Materials
David Onions PhD MRCVS FMedSci DVMS(hon) FRSE
Biologics Safety Testing
O-0800812
www.bioreliance.com
About BioRelianceBioReliance Corporation is a leading provider of cost-effective contract services to the pharmaceutical and biopharmaceutical industries, offering more than 1,000 tests or services related to biologics safety testing, specialized toxicology and animal health diagnostics. Founded in 1947, BioReliance is headquartered in Rockville, Maryland, with laboratory operations in Rockville and Scotland and offices in Tokyo, Japan, and Mumbai, India. The Company employs more than 650 people globally. For more information, visit www.bioreliance.com.
Key Services:• Custom Assay Development to fulfill your exact requirements• Biosafety Testing of biologicals for viruses, bacteria, mycoplasma, fungi• Cell Line Characterization including identity testing, genetic stability, EM, sequencing • Final Product Testing including biopotency testing, residual DNA, host cell proteins, cross-reactivity• Virus/TSE Validation Studies for all biological products• Contract GMP Production and Testing of viral vectors and cell banks • Veterinary Vaccine Services including characterization/identity, extraneous agent testing• Regulatory and Consulting Services
All work undertaken by BioReliance is in compliance with appropriate GLP or GMP standards.
Further information is available by visiting our website at www.bioreliance.com
Bovine Viruses: Integrating a Quality by Design (QbD) Approach into the Quality Control of Bovine Raw Materials 1
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1.1 Risk categoriesIn evaluating the viral risk of bovine products several factors have
to be evaluated. These include the risks associated with individual
viruses, the probability of the viruses being present in the mate-
rial and the procedures used to inactivate or clear contaminating
viruses.
An important aspect of the risk assessment is that viruses weak-
ly pathogenic in their host may be highly pathogenic in heter-
ologous hosts. Ovine Herpes virus 2 is non-pathogenic in sheep,
but causes high mortality when transmitted to cattle. Similarly
Herpes-B, a herpesvirus of monkeys, causes minimal disease in its
host species, but is a fatal infection in humans. Moreover, paren-
teral introduction of viruses in a therapeutic may overcome some
of the barriers normally limiting cross species transmission. Sev-
eral categories of viruses are of concern:
• Zoonotic viruses known to be transmissible from animals to
humans. Amongst those viruses considered as zoonotic in cat-
tle are: Rabies virus, Reovirus 3, Parainfluenza virus 3, rotaviruses,
noroviruses, Cache Valley virus, West Nile virus, and tick borne en-
cephalitis viruses.
• Animal viruses that replicate in human cells in vitro. Some
animal viruses replicate in human cells in vitro but evidence
of their zoonotic potential is weak or absent. For instance, the
human population is seronegative for infection by Bluetongue
virus, but the virus replicates efficiently in human cells and has
been proposed as an oncolytic vector.
• Viruses that infect human cells, fail to undergo productive
replication but may initiate disease. Experimental transmis-
sion of certain members of the herpesvirus, adenovirus and
polyomavirus families can result in tumour formation outside
their natural host. These events are associated with abortive
replication and often with integration of part of the viral ge-
nome into chromosomal DNA.
• Virus families that have shown a propensity to change
host range. For instance, a single mutation in Feline parvovirus
1 may have been responsible for its initial transmission to the
dog population, an event that is believed to have resulted in
the death of 25% of the young puppies in the first phase of the
outbreak. One of the most disturbing findings in recent years
has been the discovery of new parvoviruses in bovine serum,
whose properties and pathogenicity are only just beginning
to be evaluated. Retroviruses are also included in this group
because of the potential severity of the diseases associated
with this family and their recent history of cross species trans-
mission.
1.2 Probability of contaminationSome zoonotic viruses are geographically restricted by vectors or
other factors and pose a negligible risk to bovine materials har-
vested from the US, Europe, Australia and New Zealand. Never-
theless, each of these regions has their own viruses of concern,
such as Ross River virus, a zoonotic alphavirus found in Australia.
Within these regions, the probability of an endemic virus being in
a particular material, like foetal bovine serum (FBS), is dependent
on a number of factors; the frequency of infection, the ability of a
virus to cross the placenta and establish a viraemia in the foetus,
the length of the viraemic period and the size of the serum pool.
Other products like collagen, thyroid hormones and trypsin re-
quire their own unique, but similar assessments.
1.2.1 Sporadic virus infectionsSome virus infections, particularly those transmitted by arthro-
pods, are only sporadic. This is well illustrated by Cache Valley virus
contamination of US origin FBS. BioReliance have recorded four
major episodes of fermenter contamination by this virus (Onions
2004; Nims et al. 2008). While contaminations by this virus are
uncommon they are very serious. Cache Valley virus is a zoonotic
virus associated with fatal encephalitis. It grows to high titre in
CHO fermenters and, therefore, poses a major biohazard and a
formidable decontamination problem.
Contamination by this virus reveals the limitations of standard
serum testing conducted by some suppliers of serum. Typically
only 50ml to 100ml may be tested in an infectivity assay out of
a commercial lot of 1000 litres. A pool of that size may contain
samples from a thousand individual foetuses. Given that at peak
viraemia there may be only 103 to 104 iu/ml, and for most of the
short viraemic period the titre will be much lower, the final titre in
the pool may be below the detection limit in a 50ml sample. This
was confirmed by detailed analysis of one fermenter crash that
occurred several days after initiation. No change in cell viability
2 Bovine Viruses: Integrating a Quality by Design (QbD) Approach into the Quality Control of Bovine Raw Materials
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was noted until a few hours before the crash when all the cells
died. The replication rate of the virus was determined and by
back calculation it was shown that only 10 to 100 virions entered
the fermenter in 20 litres of serum (Onions et al 2004). Applying
this very low level of virus input into our model predicted a crash
within a few hours of the actual crash (Figure 1)
The recent contamination of Genzyme’s manufacturing pro-
cesses by Vesivirus 2117 is another example of a rare sporadic
contaminant that caused significant economic loss. Only two
examples of this calicivirus contaminating fermenters have been
recorded (Kurth et al 2006). Vesiviruses are of concern because of
their ability to replicate in the cells of a wide range of species and
their known ability to jump species. One notable example was
the development of a new disease in pigs, vesicular exanthema,
following the feeding of contaminated sealion meat to pigs. The
sealion virus spread from the US to Europe and also infected the
human population, before expensive and rigorous procedures
eradicated the disease.
The vesivirus that contaminated the commercial processes almost
certainly entered in bovine serum. Antibody to vesiviruses in
cattle is variable with some herds being seronegative and others
having high seropositivity; it is possible that cattle are sporadically
infected from some other reservoir (Kurth et al. 2006).
0
5E + 11
1E + 12
1.5E + 12
2E + 12
2.5E + 12
3E + 12
3.5E + 12
4E + 12
4.5E + 12
1 8 15 22 29 36 43 50 57 64 71 78 85 92 99 106 113 120 127 134 141 148 155 162 169 176 183 190 197
Total Cell Number in Fermenter
Tota
l Num
ber o
f Cel
ls
Time (hours)
Normal Cell GrowthCell number predicted by model of infection
Fermenter Crashed here: our model indicated only 10 to 100 viruses entered the fermenter in 20 litres of serum.
Figure 1 Modelled cell population dynamics in a fermenter following introduction of 1 to 100 infectious units of Cache Valley virus.
Bovine Viruses: Integrating a Quality by Design (QbD) Approach into the Quality Control of Bovine Raw Materials 3
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1.2.2 Common virus infectionsBovine viral diarrhoea virus (BVDV) and HoBi virus
In contrast to Cache Valley virus and Vesivirus 2117, a very high
proportion of FBS lots may contain Bovine viral diarrhoea virus
(BVDV). The reasons for the high prevalence are related to the
biology of the virus. Transplacental transmission of BVDV can lead
to foetuses and calves that are immunotolerant and persistently
viraemic. Estimates of foetal infection in unvaccinated herds
vary from 1 in 100 to 1 in 1000 so that every serum pool is likely
to contain one or more contaminated samples. The viruses
present in foetuses are non-cytopathic and can go unnoticed
as contaminants in cell cultures unless PCR or immuno-staining
are employed to detect the virus. FBS lots are screened by serum
producers using an infectivity assay that detects non-cytopathic
virus but the inherent statistical uncertainty in sampling a large
pool means that positives are missed. A solution is to institute
sub-pool testing and rejection of positive sub-pools but this adds
to material costs. For donor calf-serum, it has been possible to
develop closed herds that are free of BVDV but again this is an
expensive procedure. Given these uncertainties it is prudent for
manufacturers to re-test the serum before use.
BVDV infects a wide range of cell lines including bovine, ovine,
canine, feline, equine, lapine, simian and insect cells (Potts et al.
1989; Bolin et al. 1994) and has contaminated veterinary vaccines
with devastating results (Barkema et al. 2001). Caution is required
in extrapolating species susceptibility from a few cell lines as
in some cases resistant variants can be selected (Dezengrini et
al 2006). Human cells have been regarded as resistant to BVDV
(Potts et al 1989) but recently there has been a report of human
cell infection (Uryvaev et al 2012). It is generally assumed that
BVDV does not infect widely used production lines like CHO and
NS0, however, recorded host ranges should never be taken as
absolute, as even minor mutagenic change can profoundly alter
host range and pathogenicity.
BVDV-1 & 2 are members of the genus Pestivirus within the
family Flaviviridae, which also contains classical Swine fever virus,
and Border disease virus. Recently a new virus HoBi, related to but
distinct from, BVDV-1 & 2 has been isolated from contaminated
cells. The source of the contamination was serum that had been
screened for BVDV. HoBi virus, which may be renamed BVDV-3
(Liu et al 2009), should be detected in serological assays for BVDV
using polyclonal antisera but several monoclonal antibodies used
in BVDV diagnosis do not cross react with HoBi. Similarly, standard
PCR tests for BVDV cells miss this virus and a specific PCR should
be employed if cells banks are being screened (Schirrmeier et al.
2004; Ståhl et al 2010).
In 2007 a new pestivirus, Bungowannah virus, was identified in
Australian pigs with myocarditis (Kirkland et al. 2007). This virus
appears to be an emerging infection and is currently restricted to
Australia. It is known that pestiviruses can cross species barriers,
for instance BVDV can infect pigs. As Australia is a major supplier
of FBS, it is important that a watching brief is maintained for the
presence of this virus in bovine serum.
BVDV enters the serum pool from immunotolerant, persistently
infected foetuses. However, if a foetus is infected late in the
third trimester it can mount an immune response and develop
antibody to BVDV. This antibody can neutralise BVDV present in
the pool and may mask infectious virus. Consequently in Europe,
tests for “inhibiting antibody levels” need to be conducted before
determining if infectious BVDV virions present. High levels of
inhibiting antibody can result in rejection of the pool. There are
some differences between the CVMP and CPMP requirements but
these are encompassed in the tests described below (see Table
1). These mandated tests are based on the incorrect assumption
that BVDV is monotypic for neutralisation whereas, in practice,
the use of different BVDV strains can profoundly alter the result
4 Bovine Viruses: Integrating a Quality by Design (QbD) Approach into the Quality Control of Bovine Raw Materials
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agent. Enormous amounts of data are developed in this process,
usually between 100 to 400 Mbp. Consequently, sophisticated
bioinformatic algorithms are required to analyse and verify virus
targets (the combination of MPS and interpretative algorithms
being termed MP-Seq™).
The basis of the method is to optimise the isolation of putative
viral sequences from serum or tissue while decreasing cellular
genomic nucleic acids, to vastly reduce the complexity of the
system. Typically this involves nuclease treatment to remove
cellular sequences followed by nuclease inactivation and
capsid dissociation in the presence of chaotropic agents and
finally, recovery of undamaged, encapsidated nucleic acid. The
remaining DNA and RNA targets are randomly primed and
sequenced.
Allander et al (2001) first applied this approach to bovine
serum resulting in the surprising discovery of two new bovine
parvoviruses BPV-2 and BPV-3. Studies by BioReliance scientists
using MP-SeqTM confirmed these findings and resulted in
the finding of a new parvovirus BAAV-2, a member of the
dependovirus genus (Onions and Kolman 2010). As discussed
below, these are very frequent contaminants of serum and
parvoviruses are amongst the most resistant viruses known,
posing a challenge for inactivating procedures. Little is known of
the tropism of BPV-2 & 3, even within their host species, but this
family of viruses have shown major changes in host range. The
onset of the canine parvovirus pandemic around 1979 is believed
to have followed cross transmission of a feline virus following
a single mutation in the capsid gene. In contrast, BAAV-2 and
possibly the other bovine dependovirus BAAV-1, has a wide host
range with BAAV-2 able to infect human cells.
New parvoviruses were not the only surprising discoveries. In a
survey of four different FBS serum lots from major manufacturers,
2 out of 4 batches had complete sequences of bovine noroviruses
and 2 also had sequences of kobuviruses (Onions 2011). In both
cases it was possible to reconstruct the complete genomes of
these viruses and, as the samples had been nuclease treated,
these genomes were contained within capsids and therefore
potentially infectious (see Figure 2).
(BioReliance unpublished; Patel et al. 2005; Kalaycioglu et al. 2012).
This area needs discussion and revision by the European regulatory
groups particularly in the light of the discovery of HoBi virus.
Bovine polyomavirus (BPyV)Bovine polyomavirus is another virus that is extremely common in
virus pools when assessed by PCR (Schuurman et al 1991) and, in
this case, there are significant concerns for human therapeutics.
The virus had originally been discovered as a productive infection
in primate cells and was initially thought to be a monkey virus
until it was determined that it was a contaminant from serum
used in cell culture. BPyV is of particular concern because, like
other members of the polyomavirus family, it is can oncogenically
transform cells in culture (Schuurman et al 1992). There is good
serological evidence that it is a zoonotic virus; Parry and Gardener
(1986) demonstrated that seroconversion was common in people
with occupational exposure to cattle (71% in veterinarians) but
essentially absent in the general population. No detailed follow
up molecular study has been conducted to determine whether
BPyV sequences are found in cancers of at risk populations.
The high prevalence of the virus by PCR poses a particular
problem as a PCR positive result does not necessarily indicate the
presence of an infectious virus. This has led to the development
of an infectivity assay that should be conducted on unirradiated
serum where a PCR positive result is recorded (Nairn et al. 2003).
As discussed below, where the PCR signal is above a threshold it
is also advisable to conduct infectivity assays on irradiated serum
to ensure no infectious virus has survived. It should be noted
that standard infectivity assays for bovine viruses do not detect
BPyV and a specific assay involving multiple passages with PCR
endpoints is required to detect low level contamination (Nairn
et al 2003).
1.3 Recent developments in testing raw materials Many of the assumptions about the frequency of particular
viruses in serum have had to be radically revised following the
introduction of massively parallel sequencing, sometimes referred
to as deep sequencing. Massively parallel sequencing (MPS) is a
powerful new method for the identification of viruses and other
adventitious agents, without prior knowledge of the nature of the
Bovine Viruses: Integrating a Quality by Design (QbD) Approach into the Quality Control of Bovine Raw Materials 5
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Noroviruses are known causes of diarrhoea in humans and there
is evidence to suggest cross species transfer of bovine viruses to
the human population (Widowson et al 2005). Kobuviruses are
particularly interesting and important contaminants. This member
of the Picornaviridae was unknown to veterinary science until it
was detected as a contaminant of HeLa and Vero cells (Yamishita
et al 2003). Since then it has been recorded as an important cause
of diarrhoea in young calves. The MP-SeqTM data regarding its
presence in FBS suggests this is not a rare contaminant and it has
the potential to be as serious a contamination agent as Vesivirus
2117 or Cache Valley virus. The virus can be cytolytic in cell cultures
but until more is known about the virus, there is a case for adding
specific PCR endpoints to in vitro cultures. This is supported by
the data on the detection of vesivirus in fermenters, where the
virus only became detectable towards the end of 14 days culture
period (BioReliance personal communication).
1.4 Integrating Testing and Risk Mitigation with Quality by DesignAs the biotechnology industry matures there is increasing em-
phasis on Quality by Design (QbD) principles as formulated in
ICH guidance document Q8 (R2) Pharmaceutical Development
(2009). Encompassed within QbD is a control strategy designed
to ensure that a product of required quality will be produced con-
sistently. Elements of the control strategy focus on input materials
and the “design space” that affects control of those materials. The
difference between the traditional approach and a QbD approach
to raw materials is worth examining; FBS is used in the example
below but the principles apply to all bovine materials.
1.4.1 Required, traditional screening methods for FBS and
bovine materials
The CPMP note for guidance on the use of bovine serum, and the
European Pharmacopoeia recommend that serum producers test
serum before inactivation. A combination of specific and general
tests are used to detect: Bovine viral diarrhoea virus (BVDV), Bovine
adenovirus (BAV), Bovine parvovirus (BPV), Bovine respiratory
syncitial virus (BSRV), Reovirus type 3 (Reo 3), parainfluenza virus
type 3, (PI3V), infectious bovine rhinotracheitis virus (BHV-1), Rabies
virus (RV) and Bluetongue virus (BTV). Virus infection is determined
by a combination of cytopathic effect, haemadsorbtion and
specific immunofluorescence assays.
The US Code of Federal Regulations 9 CFR section 113.53
requires a similar approach using Vero cells and bovine
cells. Bovine turbinate cells are employed because of their
high susceptibility to BVDV. Although PI3V and BHV-1 are
not specifically mentioned they are detectable in standard
9 CFR tests for bovine viruses. The tests are prescriptive in their
requirements but it is possible to design protocols that meet
both European and US regulatory requirements. (Table 1)
Figure 2 Detection of Bovine Kobuvirus by MP-SeqTM.
6 Bovine Viruses: Integrating a Quality by Design (QbD) Approach into the Quality Control of Bovine Raw Materials
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These in vitro assays achieve the aim of screening for the viruses
that were considered of main concern over two decades ago.
However as MP-SeqTM technology has shown, these are not
necessarily the commonest virus infections and they specifically
miss detecting critical viruses like bovine polyomaviruses.
Vesivirus 2117 is also likely to missed in these assays as it replicates
more efficiently in CHO cells than in standard bovine indicator
cells (BioReliance unpublished). At a minimum it is now usual to
add screening for bovine polyomavirus initially by PCR, followed
by infectivity assays for positive material. Some manufacturers
have also put in place specific screening for Cache Valley virus and
Vesivirus 2117. One advantage of PCR in the latter cases is that the
presence of non-infectious virus increases the sensitivity over an
infectivity assay, in the case of Cache valley virus the PCR assay
was about 400 times more sensitive (Onions 2004).
1.4.2 A new approach to raw material quality control
An inherent part of traditional testing strategies was the belief that
it was possible, with a high degree of certainty, to select sera free of
adventitious agents and that if a material passed a 9 CFR or CPMP
test it was safe to use. The greater understanding of viruses pres-
ent in serum that has come from new technologies like MP-SeqTM,
emphasises the need for a quantitative risk based approach.
A new approach to raw material quality control involves 3 or 4
steps:
1. Understanding the universe of potential contaminants in the
raw material.
2. Developing specific, quantitative assays for those viruses,
taking account of the statistical limitations of sampling from
the raw material pool.
TitleDuration (weeks)
Assay description CVMP assay CPMP assayCombined CVMP/CPMP assay
US assay
Determination of inhibition levels of bovine serum on multiplication of BVDV
64 passages, then 2 week titration
032940 032920 032931
Determination of inhibition levels of bovine serum on detection of BVDV
2 2 week titration 032941 032921 032932
Detection of viral contaminants in bovine serum
64 passages, 8-spot slides
032942 032922 032933
Detection of BVDV in bovine serum 64 passasges, 2-chamber slides for BVDV
032943 032923 032934
Combined CPMP/9 CFR 64 passages, 2-chamber slides, plates
n/a 032930 n/a 032930
Bovine 9 CFR 42 passages, 2-chamber slides, plates
032910 n/a n/a032900 (7 viruses)032901 (9 viruses)
Table 1 BioReliance assays available to meet Regulatory requirements
Note for “Guidance on the use of bovine serum in the Manufacture of Human Biological Medicinal Products”. Committee for Proprietary Medicinal Products 2003. CPMP/BWP/1793/02.
Code of Federal Regulations Title 9 (9 CFR). Animal and Animal Products (2008). Part 113.53. Requirements for Ingredients of Animal Origin used for Production of Biologics.
Code of Federal Regulations Title 9 (9 CFR). Animal and Animal Products (2008). Part 113.46. Detection of Cytopathogenic and/or Haemadsorbing Agents.
Code of Federal Regulations Title 9 (9 CFR). Animal and Animal Products (2008). Part 113.47. Detection of Extraneous Viruses by the Fluorescent Antibody Technique.
European Pharmacopoeia, 6th Edition, supplement 6.0, 01/2008:2262 Bovine Serum
Bovine Viruses: Integrating a Quality by Design (QbD) Approach into the Quality Control of Bovine Raw Materials 7
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3. Relating the potential viral load in a given batch of raw
materials to inactivating procedures like gamma-irradiation.
4. Where no inactivating steps are in place for the raw material,
adding monitoring assays later in the process to ensure the
viruses are eliminated.
Understanding the range of contaminants that may be present is
best determined through the use of new technology like MP-SeqTM
that makes no assumptions about the nature of the virus (or other
biological contaminant), or its ability to replicate in a set of pre-
determined indicator cells. MP-SeqTM is not likely to become a
routine batch by batch quality control tool until sequencing costs
fall further. However, several manufactures are now embracing the
concept of reviewing the data from MP-SeqTM on several batches
of raw materials from a given supplier. This approach should be
linked to agreements that tightly specify the geographical source
of the materials so that the MP-SeqTM data are reflective of the
universe of contaminants from that supply source.
As discussed above this technology provided indications that new
viruses like BPV-2, BPV-3, BAAV-2, Bovine norovirus and Bovine
kobuvirus were frequent, and often high level, contaminants
of serum. The next stage is to develop specific assays for these
viruses. In the case of BPV-2 and 3 permissive cell systems have
not been identified and therefore specific PCR assays have been
used to determine the frequency and level of viral genomes
in serum. As shown in the figure below, these specific PCR
tests confirmed the high frequency and the very high levels of
circulating genomes present.
Finally the viral load should be linked to inactivating procedures.
In Europe it is now a requirement to use gamma-irradiated serum
in vaccine manufacture, but in a QbD approach it is important
to understand the limitations of inactivation by irradiation.
Standard irradiation involves treatment with 35Gy, but where
batch irradiation is used, outer parts of the batch may receive
higher doses impairing the quality of the serum. The kinetic
inactivation curves for gamma irradiation are essentially first
order. The dose required to produce a 1 log10 inactivation of the
virus, or D value, varies between viruses but lies in the range
of 3.9 to 5.3kGy for several major groups (Sullivan et al. 1971).
Protection in a serum environment is likely to increase protection
for viruses and, as Plavsic & Bolin (2001) demonstrated, ssDNA
viruses like circoviruses and parvoviruses are remarkably resistant
to irradiation. This has important consequences for analysing FBS
which may contain BPV-2 and BPV-3 genomes at levels above the
capacity of irradiation to inactivate. An appropriate approach is to
screen batches by quantitative PCR using only those batches with
a low level of genomes. For instance, the control might specify an
inactivation capacity 3 log10 greater than the virus load.
Where no serum inactivating steps are in place then, as part of the
QbD approach, appropriate in process tests should be conducted.
An evaluation of the capacity of a downstream purification
process to inactivate or remove the contaminants identified
in serum should also be undertaken. Implementation of this
approach would have avoided the catastrophic contamination
of rotavirus vaccines by porcine circoviruses introduced in
contaminated trypsin.
8 Bovine Viruses: Integrating a Quality by Design (QbD) Approach into the Quality Control of Bovine Raw Materials
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Bovine Viruses: Integrating a Quality by Design (QbD) Approach into the Quality Control of Bovine Raw Materials 9
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