Factors for Life.
2
Content
1. CSL Behring – your partner in coagulation disorders ...................... 5
2. Factors for life .................................................................................... 8
3. Plasma derived products .................................................................. 11
4. Recombinant products ..................................................................... 24
5. Summary ........................................................................................... 28
6. Abbreviations ................................................................................... 28
7. Literature .......................................................................................... 30
3
4
1. CSL Behring – your partner
in coagulation disorders
Coagulation factor concentrates
may be useful in a wide range of
clinical situations from inborn deficiencies to acute medical or surgical conditions.
Globally more than 1% of the
world‘s population is affected by
bleeding disorders such as haemophilia A, haemophilia B or von
Willebrand disease (VWD). In severe cases their treatment involves the prompt and proper use of
clotting factor concentrates.
Haemophilia A is caused by a deficiency of clotting factor VIII and
accounts for about 80 % of all
haemophilia cases. Haemophilia
B results from factor IX deficiency.
Nearly 1 % of the people worldwide have defects in the genetic
coding for von Willebrand factor
(VWF) leading to different types
of VWD.
Oral anti-coagulant therapy bears an increased bleeding risk
even at therapeutic doses and an
even more pronounced risk when
overdosed. Due to a variety of
interactions this is not unusual.
Acute major bleeds or emergency interventions require reversal
of oral anticoagulation with a
prothrombin complex concentrate (PCC), attempting to avoid a
haemostatic crisis.
Critically ill patients may develop
severe dyscoagulative conditions
e.g. disseminated intravascular
coagulation (DIC) or dilution coagulopathy. These patients may
benefit from treatment with specific factor concentrates replacing
the deficient proteins necessary
for a proper coagulation.
The goal of therapy is to decrease
the frequency and severity of
bleeds and to prevent the longterm complications. This is achieved by raising factor levels. Treatment can be administered either
as on demand therapy where
bleeds are treated upon occurrence or as prophylaxis. The individually tailored therapy enables
patients to have an improved
quality of life. For non-haemophilic patients in the intensive
care setting therapy is aiming at
avoiding imbalances in the coagulative system leading to fatal
bleeds or (micro)-thrombotic conditions.
tain their biological integrity. This
process provides opportunities to
obtain a variety of products from
this valuable raw material.
Products available are safe, effective and well investigated. CSL
Behring is committed to provide
one of the broadest ranges of
factor concentrates for coagulation disorders worldwide.
Products are made by two wellestablished technologies, plasmaderived products purified from
natural plasma or concentrates
manufactured by recombinant
technology that utilises the insertion of human genetic material
into a host cell of a foreign species.
From the donated plasma a range
of therapeutic proteins are extracted in a careful manner to re-
5
Virus safety is one essential
aspect of product quality and CSL
Behring does everything possible in order to reach the highest
standards. Strict donor selection
criteria have been implemented
and a large number of tests are
performed to minimise a potential virus and prion load in the
basic raw material. Methods for
clearing viruses from plasma can
be divided in two categories: Inactivation processes (e.g. pasteurisation) and removal steps (e.g.
precipitation, absorption, virus
filtration, monoclonal antibody
purification).
6
Pasteurisation is a unique procedure of pathogen inactivation and
was introduced by CSL Behring (at
that time called Behringwerke)
in 1979. It is a very effective method to inactivate enveloped and
non-enveloped viruses is in our
hands gentle enough to preserve
the high quality of the products.
Even though the HIV virus was
not known at that time, it was
later shown that pasteurisation
effectively inactivated this virus
in addition to other viruses.
Almost all steps of the manufacturing process contribute to the
safety of clotting factor concentrates, and over the last 25 years
the risk of virus transmission by
the application of plasma derived
products has become a theoretical risk.
CSL Behring’s long experience
in providing safe and effective
factor concentrates makes the
company an ideal partner in the
treatment of coagulation disorders and other situations requiring potentially life saving factor
preparations.
7
2. Factors for life
Figure 1: The coagulation cascade
Many options for treatment of bleeding situations*
Products
FI
FII, VII, IX, X
®
HaemoBeriplex P/N
complettan® P
FVIII
FIX
®
Beriate P
Berinin P
Helixate® NexGen Mononine®
Helixate® FS
Monoclate®-P
Haemate® P
Humate-P®
Table 1: Product portfolio of CSL Behring
8
®
FX
Factor X P
Behring
FXIII
Fibrogammin® P
VWF
®
Haemate P
Humate-P®
ATIII
Kybernin® P
The coagulation of blood is a complex mechanism. Early models of
the coagulation cascade were divided into two parts: the “intrinsic” and the “extrinsic” pathway.
But this was inconsistent with clinical observations in several key
respects and did not fully explain
the pathways leading to haemostasis in vivo. To address this a new
model was developed.
It consists of four consecutive
overlapping stages: initiation,
amplification, propagation and
stabilisation and explains some
aspects of haemostasis that a protein-centric model does not.
Initiation: This process takes place
on the surface of tissue factor (TF)bearing cells, such as fibroblasts
and platelets. Factor VII binds to
cellular TF and is activated. This
FVIIa/TF complex activates FX.
FXa generates a small amount of
thrombin which plays a role in
the amplification stage.
Amplification: Through the interaction of VWF, platelets adhere to the intravascular lesion
and become activated. The small
amount of thrombin generated
in the initiation phase activates
factors V, VIII and XI. Assembly of
the tenase- and prothrombinasecomplexes and large scale thrombin generation is initiated.
Propagation: The large scale
thrombin generation catalyses
the conversion of fibrinogen to
fibrin and a clot is formed. This
process leads to the activation of
FXIII, which is necessary for the final stage.
Stabilisation: The covalent cross
linking of the fibrin polymers that
make the clot insoluble.
Indication
Product
Haemophilia A
Beriate® P
Helixate® NexGen/FS
Monoclate®-P
Haemate® P; Humate-P®
von Willebrand Disease
Haemate® P; Humate-P®; Stimate®
Haemophilia B
Berinin® P
Mononine®
Life-threatening haemorrhages with Vit-K dependent factor deficiency
Beriplex® P/N (Prothrombin Complex
Concentrate)
Life-threatening haemorrhages with fibrinogen deficiency
Haemocomplettan® P
Deficiency of Factor X (Stuart-Prower factor)
Factor X P Behring
Factor XIII deficiency
Fibrogammin® P
Prophylaxis and therapy of thrombembolic episodes in AT III deficiency
Kybernin® P
Table 2: Products and indications
* Not all products are licensed globally and approved indications may divert between countries.
9
10
3. Plasma derived products
Donor selection and testing
Criteria for donor selection
First time donors
• Good health and a flawless medical history
• Check of vital signs, physical examination, lab analyses
• Infection screen of donation
• Quarantine until the next donation is screened negative
Regular donors
• Good health and medical history update
• Check of vital signs
• Infection screen of donation
• Minimum 60 days of inventory hold to cover
diagnostic window.
Exclusion of at-risk donors
Figure 2: Criteria for plasma donor selection
Product safety starts with the donor selection. Thus collection centres for sourced plasma are monitored and typically located in areas
of the U.S. or north/middle Europe
with low incidence of HIV and hepatitis. Each candidate donor un-
Pathogen
dergoes multiple testing procedures, including complete physical
examination, medical history and
laboratory analyses. The first donation from a sourced plasma
donor undergoes a quarantine
storage up to 6 months duration.
Serological testing
of every donation
HIV
Anti-HIV 1
Anti-HIV 2
HCV (Hepatitis C)
Anti-HCV
HBV (Hepatitis B)
HBsAg
Mandatory
NAT/PCR testing in
fractionation pool
Only when the donor returns for a
second donation within this time
period and again is tested negative, will the first donation be
released for further processing.
Voluntary Industry
standard NAT/PCR
testing in plasma
pool (PPTA)
NAT/PCR test
performed in
plasma pool by
CSL Behring*
–
–
HAV (Hepatitis A)
–
–
Parvovirus B19
–
–
–
Rejection of positive donations
Table 3: Testing procedure at CSL Behring – voluntary industry standard is always met
* For the majority of products
11
The laboratory analyses of each
donation includes serological tests
for HIV-1/2 antibodies, hepatitis B virus (HBV) surface antigen
(HBsAg) and hepatitis C Virus
(HCV) antibodies. As the time
from infection to the development of antibodies (the diagnostic
window) varies between the different viruses, there is a need for
an additional test to minimise
the risk of processing a donation
contaminated with virus antigens
or pathogenic viral genetic material. CSL Behring implemented a
sensitive nucleic acid amplification technique (NAT) known as
polymerase chain reaction (PCR)
to further reduce the potential
virus load of plasma pools. To minimise the exclusion of relevant
raw material (plasma), a pooling
strategy of minipools has been
implemented allowing to discard
NAT/PCR reactive minipools and/
or donations only. CSL Behring‘s
NAT/PCR test** will detect genomic sequences of HBV, HCV, HAV,
HIV-1 and high titres of Parvovirus B19. In addition to this donor/
minipool-testing, CSL Behring performs an in process control on the
manufacturing pools to increase
safety.
Since introduction, the NAT/PCR
testing strategy has been proven
to be very effective in reducing
the virus load in the plasma pool,
resulting in a significant increase
of the safety margin.
Prions
Measures to minimize the risk of prion transmission
• No donors with a family history of CJD
• No donors who received human pituitary hormones/dura mater or cornea transplantation
• No plasma from the U.K.
• Integration of prion reduction steps into manufacturing process
Until now prions could never be
demonstrated in human plasma.
However, four cases* of variant
Creutzfeldt-Jakob-disease (vCJD,
associated with mad cow disease
or bovine spongiform encephelopathy, also known as BSE) have
been confirmed in the U.K. in
recipients of non-leukodepleted
red cells donated by donors, that
a few years later were diagnosed
with vCJD. Therefore the criteria
for donor selection have been reviewed and CSL Behring has implemented these criteria:
* May 2007
** For the majority of products.
12
Donors with a family history of
CJD or who were treated with
human pituitary hormones or
received a dura mater or cornea
transplantation are excluded. Additionally, there is no processing
of plasma from the U.K. All guidelines and regulations regarding
collection of plasma and donor
deferral are met wherever plasma
is collected for CSL Behring or the
final products are distributed.
Furthermore CSL Behring has integrated effective prion reduc-
tion steps into the manufacturing
processes for a further decrease
of the potential risk. For Haemate® P and Humate-P® CSL Behring
uses cryoprecipitation, Al (OH)3 adsorption, glycine precipitation and
NaCl precipitation as well as glycine precipitation, dialysis, ultracentrifugation and sterile filtration to
achieve a high prion removal capacity. Recently authorities investigated the risk of transmission of vCJD
from plasma-derived products and
found it to be extremely minimal.
Quarantine and inventory hold of source plasma
Quarantine and inventory hold for safety
New donor
1. Donation
Quarantine up to 6 months
(lab test neg.)
Inventory hold (min. 60 days)
+
2. donation
(lab test neg.)
Inventory
hold
After second donation new donor becomes regular donor
Regular donor with donation > 6 months since last donation
Regular donor
(donation e.g. every 2 weeks)
7. Donation
(lab test neg.)
Plasma for
processing
Inventory hold (min. 60 days)
8. Donation
(lab test neg.)
Inventory hold (min. 60 days)
9. Donation
(lab test neg.)
-
Inventory hold (min. 60 days)
10. Donation
(lab test neg.)
-
Inventory hold (min. 60 days)
11. Donation
(lab test neg.)
-
Inventory hold (min. 60 days)
12. Donation
(lab test pos.)
-
Donor gets informed
Donations in inventory are
discarded
Permanent exclusion of donor
Time
Figure 3: Quarantine and inventory hold of plasma
All source plasma donations
which have passed the laboratory
tests are frozen and stored for a
minimum of 60 days. The purpose
of this procedure is to be able to
react to post donation information. If a donor is tested positive
after the next donation, the pre-
vious donations can be identified
and discarded. Such a procedure
is very effective when applied
to a group of regular donors as
is the case with CSL Behring. No
plasma pool had to be rejected
for the last 6-7 years.
Inventory hold procedures are
not regulatory requirements but
for CSL Behring it is another part
of our commitment to provide
the safest possible products (adhering to voluntary industry standard „IQPP“ of the PPTA).
13
Plasma purification
Purification
CSL Behring integrates virus inactivation and elimination procedures in the
production process to obtain highly effective and safe products.
With the process of donor selection and testing it is possible to
reduce the potential virus load in
the plasma pools to a minimum.
To ensure a very high level of
safety, virus elimination and inactivation steps are included in
the production process. The aim
of CSL Behring is to produce products with the highest possible
degree of safety and quality. Each
coagulation factor has its own
characteristics in regards to physio-chemical sensitivity and thus
not all products can be treated
exactly alike.
CSL Behring integrates purification steps and virus inactivation
and elimination procedures to
achieve highly effective and safe
products.
In the following you will find a
short description of CSL Behring’s
main manufacturing processes involved in the production of plasma derived coagulation factors.
Please note that not all virus inactivation/removal procedures are
employed for every product.
Virus elimination steps
a) Plasma fractionation
The recovery of the plasma proteins from human plasma is called
fractionation. This process is based
on the inherent differences of
each protein. Fractionation involves changing the conditions
of the product intermediates
(e.g. the temperature, the ionic
strength or the acidity) so that
proteins become insoluble and
14
precipitate. The CSL Behring coagulation factor concentrates are
produced using a modified Cohnfractionation. First the frozen
plasma is thawed and pooled.
The proteins, which are insoluble
under cold conditions (VWF/FVIII
and FI (fibrinogen)) are separated
by centrifugation and contained
in the so called cryoprecipita-
te. In a next step the vitamin K
depending coagulation factors
(F II, VII, IX and X) are adsorbed
from the supernatant and after that factor XIII precipitation
takes place through addition of
alcohol. Immunoglobulins and albumin are precipitated by increasing the alcohol concentration.
Plasma fractionation
Process
Intermediates
Plasmaprotein Concentrates
Cryoprecipitate
FVIII, VWF, Fibrinogen
Frozen plasma
Thawing
Centrifugation
Cryodepleted plasma
DEAE-Ionexchange-Chromatography
QAE-Ionexchange-Chromatography
PCC, Thrombin, FIX, FX
C1 Inhibitor
Adsorbed cryodepleted plasma
Ethanol-precipitation (8 %)
Centrifugation
8 % precipitate (fraction I)
FXIII
8 % supernatant
Affinitychromatography
Antithrombin III
Adsorbed 8 % supernatant
Ethanol-precipitation (25 %)
Centrifugation
25 % precipitate
(fraction II + III)
Immunoglobulin
25 % supernatant
Ethanol-precipitation (40 %)
Centrifugation
40 % precipitate (fraction IV+V) Human Albumin, API
40 % supernatant
Figure 4: CSL Behring plasma fractionation-procedure
15
b) Monoclonal purification and affinity chromatography
Monoclonal purification
1. Addition of factor containing solution
antibodies
2. Column of monoclonal antibodies with
affinity to a specific coagulation factor
3. Forming of coagulation factor/antibody
complexes on the column and washout
of potential contamination
contaminant
Ca++
Ca++
Ca++
4. After washout the specific coagulation
factor is eluted
Ca++
Ca++
Ca++
Ca++
Ca++
Ca++
5. Purified factor concentrate
Figure 5: Scheme of monoclonal purification
Monoclate-P®/Mononine®
Antibodies against
VWF and FIX
Virus elimination
e.g. Mononine®
5,8 - ≥ 8,1 log10*
buffer
* log10 = common (base 10) logarithm
The monoclonal purification of
Mononine® and Monoclate-P®
is an innovation of CSL Behring
that utilises the affinity of mo-
16
noclonal antibodies to VWF or
FIX respectively. Complexes with
the factor proteins are formed
and bound to the column and by
rinsing with a buffered solution,
viruses and plasmaprotein impurities are eliminated.
Beriate® P/Berinin® P
Beriplex® P/N
Fibrogammin® P
Ionexchange
chromatography
Virus elimination
buffer
In the case of ionexchange chromatography for the products
Beriate® P, Berinin® P, Fibrogammin® P or Beriplex® P/N different
ionexchange chromatography gels
are used to bind the coagula-
tion factors due to their different
ionic characteristics. Subsequent
rinsing with buffer eliminates
plasmaprotein impurities and virus particles.
This purification process effectively reduces the viral load. For increased safety CSL Behring implemented additional inactivation/
elimination steps (e.g. pasteurisation, virus filtration).
17
c) Virus filtration (Beriplex®P/N, Mononine®)
Principle of virus filtration
Basic material with virus particles
75 nm - Filter
35 nm - Filter
Product after virus filtration
Elimination of viruses
e.g. Beriplex®P/N: HIV ≥ 7,3 log10, BVDV 4,4 log10
Figure 6: Virus filtration – example of two filters with different pore sizes
The principle of virus filtration involves the use of filters with a defined small pore
size removing viruses with a
diameter larger than the pore
18
size. The main advantage of this
method is that a complete elimination of larger viruses can be
achieved without any changes
in the quality of the derived pro-
duct. Virus filtration may only be
used if the desired protein has a
smaller size than the pores in the
filters.
Virus inactivation
Pasteurisation
Pasteurisation – an effective technology
Factor VIII
nonenveloped virus
Pasteurisation
(10 h or more depending
on the product; 60° C
in aqueous solution)
enveloped virus
Pasteurisation
Factor VIII
inactivated virus
inactivated virus
Figure 7: The efficacy of pasteurisation
The pasteurisation of coagulation
factor concentrates is mastered
to perfection by CSL Behring. It
is used for almost all CSL Behring
plasma-derived coagulation factors. The relatively simple principle is based on heating the products
for 10 hours or more depending
on the product at a temperature
of 60° C in aqueous solution. The
addition of stabilising agents such
as sucrose and glycine or neutral
salt protects the plasma proteins
against denaturation.
The S/D treatment only inactivates non-enveloped viruses. CSL
Behring however utilises pasteurisation. Its main advantage is the
inactivation of a wide range of
enveloped as well as non-enveloped viruses.
More than 8 billion VWF:RCo IUs
of Haemate P/Humate-P, the first
pasteurised VWF/FVIII concentrate, have been infused over the past
25 years and not a single case of
proven virus transmission has been
documented. In addition, Haemate P/Humate-P pasteurisation has
also led to the effective inactivation of the following emerging
viruses: influenzavirus, coronavirus, bunyavirus and flavivirus.
Pasteurising proteins
Solution of proteins
Addition of stabilising agents
Pasteurisation (10 h or more depending on the product; 60° C in aqueous solution)
Elimination of non-toxic stabilising agents
Continued production process
Figure 8: Pasteurisation – flow scheme
19
No documented case of virus transmission in the 25 year history of
Haemate® P/Humate® P, the first effectively virus inactivated VWF/FVIII.
Validation of virus reduction steps
Laboratory experiments are performed to evaluate the efficacy
of virus reduction. The different
manufacturing steps are run in
a laboratory scale. Through the
addition of a defined amount of
virus it is possible to quantify the
reduction of virus after individu-
al procedures. The major test-viruses as requested by the authorities are: HIV, BVDV (bovine viral
diarrhoea virus) as a model for
hepatitis C and G virus, herpes
virus, HAV, and CPV (canine parvovirus) as a model for parvovirus B19. In all laboratory tests it
is necessary to maintain the conditions of relevant parameters in
the manufacturing processes to
obtain correct results. All tests
are performed for each virus separately and repeated to provide
valid data.
Validation process
For all plasma derived products CSL Behring validates the manufacturing processes for the capacity of
elimination and inactivation of viruses. For every product effective virus reduction (= inactivation and
removal) is being performed and all products of CSL Behring have high total reduction factors.
20
Mean value of total reduction factors (log10)
Enveloped viruses
Non-enveloped viruses
HIV
BVDV
Herpes virus
HAV
Parvoviruses
Beriate® P
≥ 10.0
≥ 12.4
8.7
6.6
≥ 8.7
Berinin® P
≥ 15.6
≥ 11.9
≥ 12.6
7.6
4.4
Haemate® P
≥ 12.1
≥ 12.7
11.6
9.2
≥ 10.2
Monoclate® P
≥ 13.7
≥ 7.3
≥ 9.2
Mononine®
≥ 11.7
≥ 12.2
≥ 15.5
≥ 5.1
≥ 12.0
Beriplex® P/N
≥ 22.8
≥ 15.2
≥ 23.1
6.1
6.3
Fibrogammin® P
≥ 17.2
≥ 13.3
≥ 14.6
9.0
≥ 7.3
Haemocomplettan® P
≥ 12.4
≥ 12.7
≥ 9.1
≥ 7.7
≥ 8.4
Kybernin® P
≥ 15.1
≥ 15.7
≥ 14.8
≥ 5.4
10.4
Table 4: Total reduction factors for different CSL Behring products. Virus reduction for Parvoviruses includes Parvovirus B19 inactivation, when
pasteurisation experiments were performed.
According to the German PaulEhrlich Institute the benchmark
for total reduction factor for enveloped viruses is > 10 log10 levels
and for non-enveloped viruses
> 6 log10 levels. In almost all cases
CSL Behring exceeds these benchmarks. Table 4 shows the CSL Beh-
ring levels of overall reduction
factors for enveloped as well as
non-enveloped viruses.
Quality control
CSL Behring conducts quality control measures after every single
process step and additionally at
the end of the manufacturing process. This repeated control ensures
the consistent high quality of the
products.
CSL Behring‘s safety processes were
among the first to be certified by
the PPTA‘s internationally recognised safety program, QSEAL. Regular
inspections by health authorities
ensure compliance with global industry standards.
21
22
Supernatant
Cryoprecipitate
Haemocom- Beriplex® P/N
plettan® P
FII / FVII /
FIX / FX
Table 5: CSL Behring products and their respective purification steps
Virus
filtration
Chromatography
Monoclonal
purification
Pasteurisation
Precipitation
and/or
adsorption
steps
Cryoprecipitation
Process
Product
FI
Beriate® P
FVIII
FVIII
Haemate® P, Monoclate® P
Humate-P®
VWF/FVIII
Berinin® P
FIX
Overview of purification steps
Mononine®
FIX
Factor X P
Behring
FX
Fibrogammin® P
FXIII
Kybernin® P
ATIII
23
4. Recombinant products
Next to purification from human
plasma, coagulation factors can
be provided through recombi-
nant technology. CSL Behring has
contributed to several processes
involved in recombinant manu-
facturing of FVIII such as Helixate® NexGen/FS.
The rFVIII manufacturing phases
Manufacturing process
Phase I: Fermentation
• Cell bank
• Propagating
• Cultivation
Phase II: Purification
• Purification by monoclonal AB adsorption*
• Virus inactivation by S/D treatment
Phase III: Formulation
• Formulation**
• Final processing
Figure 9: Manufacturing process of recombinant factors
* The immuno chromatography
was orignally developed by
Scripps Clinic, La Jolla, California
for what is now CSL Behring.
24
** The albumin free sucrose formulation was developed by
Behringwerke AG.
Fermentation
Baby Hamster Kidney (BHK) cells
are used for the expression of
human factor VIII. This cell line
is well investigated and has been
cultured for many years. After
transfecting the factor-VIII gene
into the cells, they have the ability to synthesise human factor VIII.
For the industrial production of
FVIII these cells are cultivated
in a bioreactor containing fresh
medium. All cells are genetically
identical and therefore produce
identical FVIII molecules which
are released into the medium.
Continuously the factor VIII con-
taining harvest solution is removed
and purified to the final rFVIIIproduct.
Recombinant FVIII-Helixate® NexGen/FS
r
ote
m
Co
III
FV
8o
KD
ding
90
K
r
to
ina
Term
D
pAML 3R8c1
B
or
DHPR
Pro
ce
sequen
f
Virus plasmid with total
human F VIII gene integrated
Plasmid integrated into DNA
of baby hamster kidney cells
Cell culture produces human
FVIII and transports it to medium
Harvesting of human FVIII
150 copies/cell
Figure 10: Production steps of recombinant FVIII
Monoclonal purification
Procedure is described on page 16.
25
Solvent/detergent (S/D) virus inactivation
Inactivation by using S/D
Factor VIII
enveloped virus
nonenveloped virus
inactivated
virus
nonenveloped virus
Treatment with the combination
of a solvent and a detergent
Factor VIII
Figure 11: S/D virus inactivation
Due to the presence of retroviruslike particles in rodent cell lines
and in order to reduce adventitious viruses potentially present
in the fermenter harvest, virus
reduction methods are included
also in the manufacturing process
of recombinant proteins. The S/D
virus inactivation is implemented into the manufacturing process, as a well known method to
effectively inactivate enveloped
viruses due to a destruction of
the lipid envelope. Without the
envelope, viruses cannot infect
target-cells and further virus rep-
lication is inhibited. The integrity
of the therapeutic proteins is not
affected.
Validation studies show that S/D
combined with the manufacturing‘s virus reduction capacity
is sufficient.
Formulation of recombinant FVIII
Albuminfree formulation
• Formulated with sucrose
• Reduction of foreign proteins
Reduced risk of anaphylaxis
Figure 12: Formulation process
This formulation process was developed by CSL Behring. Helixate®
NexGen/FS is stabilised with sucrose. It is one more step to mi-
26
nimise the use of foreign proteins. Until now 2,5 billion IUs of
Helixate® NexGen/FS have been
infused and there has never been
a case of transmission of an infectious agent reported.
27
5. Summary
The elimination and inactivation
of viruses in the manufacturing
process of products is achieved by
a series of measures. It starts with
the selection of donors and testing of donations, proceeds with
purification, virus inactivation
and elimination and is completed
by multiple measures of quality
control and quality assurance.
The pasteurisation used by CSL
Behring for most of the products
is a very effective elimination
procedure for enveloped and
non-enveloped viruses and has
been in use for > 25 years. Products may have a further virus inactivation/elimination step if the
quality of the individual product
is not jeopardised. For products
incompatible with pasteurisation
combinations of other virus inactivation/elimination steps are implemented.
6. Abbreviations
BVDV
Bovine Viral Diarrhoea Virus
CJD
Creutzfeldt-Jakob-Disease
DNA
Deoxyribonucleic acid
F
Factor
HAV
Hepatitis A Virus
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HIV
Human Immundeficiency Virus
HSV
Herpes Simplex Virus
28
NAT-PCR Nucleic Acid Amplification TechnologyPolymerase Chain Reaction
PPTA
Plasma Protein Therapeutics Association
PRV
Pseudorabies Virus
RNA
Ribonucleic acid
S/D
Solvent-detergent treatment
(virus inactivation method)
TF
Tissue Factor
VWD
von Willebrand Disease
VWF
von Willebrand Factor
29
7. Literature
1. Abshire TC et al.: Sucrose formulated
recombinant human antihemophilic
factor VIII is safe and efficacious for
treatment of hemophilia A in home
therapy. Thromb Haemostas 2000;
83(6): 811-816
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Please find below packaging inserts for all products.
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Commercial Development Coagulation
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D-35041 Marburg
Germany
110060 E 0706/PC
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