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CSL Behring quality and safety tour for the bleeding disorders community in Kankakee, IL, USA
From Left to Right, Bottom Row:
Wally Casey Sr. Vice President and General
Manager, Kankakee, CSL Behring
Carol Horton Administrative Assistant,
Public Affairs, CSL Behring
Claudia Black Executive Director, World
Federation of Hemophilia
Dennis Jackman Sr. Vice President, Public
Affairs, CSL Behring
Nathalie Messier Director of Operations,
CSL Behring Canada
Heinz Neuhaus General Manager, CSL
Behring, Canada
David Page Executive Director, Canadian
Hemophilia Society
Martin Summers Manager, Market
Research, Coagulation, CSL Behring
Janice Cannizzo Sr. Director, Coagulation
Marketing, CSL Behring
Kim Phelan Executive Director, Coalition
for Hemophilia B
Second Row:
Elizabeth Myles Communications Director,
World Federation of Hemophilia
Kevin Sorge Executive Director, New
England Hemophilia Association
Kerry Fatula Executive Director, Western
Pennsylvania Chapter of NHF
Garrett Bergman, M.D. Senior Director,
Medical Affairs, U.S. Commercial
Operations, CSL Behring
Ryan Faden Manager, State Government
Affairs, CSL Behring
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to save lives and improve the quality of life for people with rare and serious medical
conditions worldwide. Each step of the manufacturing process, from plasma donor to
disorders community.
At CSL Behring, we take the health of the people who use our lifesaving therapies very
seriously. We meet or exceed the most stringent international standards for plasma
product safety in accordance with regulatory agencies worldwide. Our dedication to
collecting safe plasma and producing the highest quality products is well known in the
plasma-protein therapies industry and throughout the patient communities we serve.
We believe our products have never been safer than they are today due to substantial
investments in product safety, manufacturing facility enhancements, and research and
development activities. In fact, during the past 25 years, the risk of virus transmission
through plasma-derived products has been nearly eliminated.
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Biotherapies Defined
CSL Behring biotherapies are plasma-protein related products and their recombinant
equivalents used in the treatment of rare and serious medical conditions. Biotherapies
are derived from either human plasma or genetically engineered cell lines. Biotherapies
have a wide variety of therapeutic uses. In different product forms, they are used to
treat coagulation disorders, immune deficiencies and Alpha1-antitrypsin deficiency
(Alpha-1), a type of hereditary emphysema, among other disorders. They are also used
in critical care settings to treat shock, burns, sepsis and to help heal wounds.
Plasma is the portion of blood that remains after red cells, leukocytes (white blood
cells) and platelets are removed. Plasma consists of water, salts, albumin, antibodies,
enzymes and other proteins. Plasma proteins perform a variety of functions, including
clotting blood, fighting diseases and other critical functions. By owning and operating
CSL Plasmaone of the largest and most sophisticated plasma collection networks
in the world, and by working closely with sourcing organizationsCSL Behring is
thoroughly committed to controlling the quality of the human plasma used to
make biotherapies.
Government and Industry Regulations
CSL Behring biotherapies are manufactured in state-of-the-art facilities under stringent,
controlled conditions. Each step of the manufacturing process contributes to the safety
of the products. CSL Behring also adheres to all government regulations set forth by
the countries in which we operate. In the U.S., this includes the Food and Drug
Administration, Clinical Laboratory Improvement Act (CLIA) and Occupational Safety
and Health Act (OSHA). In Europe, we adhere not only to requirements established
by the European Medicines Agency, but also to requirements specified by each of the
individual countries in which we operate.
Beyond governmental regulations, the Plasma Protein Therapeutics Association (PPTA),
the industry trade association, regulates each of its member organizations through
the International Quality Plasma Program (IQPP). IQPP establishes voluntary standards
that meet or exceed governmental regulations for collecting, processing and testing
of source plasma. Companies that meet or exceed these standards receive Quality
Standards of Excellence Assurance and Leadership (QSEAL) certification.
CSL Plasma, CSL Behrings plasma collection division, was among the first in the
industry to be QSEAL-certified through PPTAs IQPP program. To become and remain
certified, each of the companys plasma collection centers must meet all QSEAL
standards and pass all IQPP inspections.
In the United States, CSL Plasma also participates in the National Donor Deferral
Registry (NDDR). Developed by the PPTA, the NDDR registry is a nationwide database
of plasma donors who have been permanently deferred from donating plasma. By
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excluding previously deferred plasma or blood donors, this system further assures the
safety of plasma and plasma products. Implementation of a European NDDR is being
discussed by several European regulatory authorities.
Integrated Safety System
the selection of donors and testing of donations. The system includes purification of
the desired protein, virus inactivation and prion removal2, and multiple levels of quality
assurance, including both quality control and monitoring. The integrated safety system
is comprised of five processes:
1. Donor Selection and Plasma Testing
4. Batch Release
2. Protein Purification
Virus Inactivation/
Removal and
Prion Removal
Safety Processes
Donor Selection
Plasma safety starts with careful donor selection. Donation centers for source plasma
are monitored and located in areas with low viral (contaminant) marker rates in the
Batch Release
United States and in Europe (for products not licensed in the United States). For each
plasma collection center, the rate of positive testsindicating the presence of viruses
on all plasma donations collected is assessed for a six-month period. The viral marker
rates may not exceed a maximum number of confirmed positive donors for HIV, HCV
Pharmacovigilance
Product Safety
high-risk behavior. Those individuals who do not meet the rigorous requirements
required to donate plasma are deferred.
Only after donors have returned for a second donation within a six-month period, and
have again tested negative, will their first donation be released for further processing.
1
Learn more about the CSL Behring Integrated Safety System on the CSL Behring corporate Web
site: www.cslbehring.com/quality-safety
2
Prions are infectious agents comprised of proteins. Prions replicate through a mis-folding process
whereby an abnormally folded structure converts normal protein molecules into an abnormal form.
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Such donors are then classified as qualified donors and can typically donate regularly,
with continued monitoring of their health through physical examinations, vital signs
and health questionnaires. If a donor no longer meets safety and quality criteria, the
donor is permanently deferred.
Plasma Testing
Samples from each plasma unit are shipped to one of CSL Plasmas state-of-the-art
testing laboratories. CSL Plasma uses highly sensitive tests to check each sample for
evidence of specific blood-borne viruses. These tests include serology tests and nucleic
NAT/PCR Testing
Serology
Testing
NAT/PCR
HAV RNA
N/A*
12
HBV DNA
59
34
HCV RNA
82
23
HIV-1 RNA
22
11
B19V DNA
N/A*
Inventory hold is a voluntary industry initiative that allows for the retrieval of any
suspect donations before they are used. Units of plasma and donors can be traced
through lot numbers using the Donor Management System.
While a plasma sample is tested, the unit is held at a Plasma Logistics Center before it
is released for manufacturing. Inventory hold minimizes the chance of viruses entering
the plasma pool by discarding the plasma of a donor who tests positive for a viral
marker at a subsequent donation during the holding period. This assures us that the
first donation was not made during the window period4 for a virus infection: the time
between infection and the development of laboratory evidence of the infection
through serology or NAT. Only plasma from qualified, i.e. repeat, donors is suitable for
manufacturing. In this way, we make sure that only units that meet all our stringent
specifications are sent to manufacturing sites.
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As part of the manufacturing processes, viral inactivation and prion removal constitute
the primary means by which CSL Behring ensures the quality and safety of its products.
CSL Behring operates three state-of-the-art manufacturing sites in Marburg, Germany;
Bern, Switzerland; and Kankakee, Illinois, United States. CSL Ltd. also operates a stateof-the-art fractionation facility in Melbourne, Australia. All sites are operated in accordance with international quality and safety standards. At each site, units of plasma are
combined into a plasma pool. Each plasma pool is tested for the presence of viruses.
A pool is released for further processing to produce coagulation factors (and other
plasma proteins) based on non-reactivity to serological viral markers (HIV antibodies
and Hepatitis B antigens) and virus genome (HAV RNA5, HBV DNA6, HCV RNA, HIV-1
RNA and high titer B19V DNA). We integrate virus inactivation and removal procedures
as well as prion removal procedures in the manufacturing process of plasma-derived
products to produce highly effective products that are very safe.
Fractionation/Partitioning
RNA (ribonucleic acid) consists of a strain of nucleotides used in gene expression. RNA is the
genetic material present in most viruses.
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DNA (deoxyribonucleic acid) is a nucleic acid that contains the genetic instructions used in the
development and functioning of all known living organisms and some viruses.
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FVIII (Factor VIII or anti-hemophilic factor) is an essential blood clotting factor missing in
hemophilia A.
8
VWF (von Willebrand factor) is a blood glycoprotein involved in hemostasis. It is deficient or
defective in von Willebrand disease.
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FIX (Factor IX or Christmas factor) is a blood clotting factor missing in hemophilia B.
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Virus Reduction
During manufacturing the plasma undergoes processes that destroy viral structure.
These virus inactivation processes include:
Pasteurization
Solvent/detergent treatment
Low pH treatment
In addition to removing viruses, our manufacturing processes also remove prions through:
Precipitation
Adsorption
Filtration
Batch-to-Batch Segregation
CSL Behring products are continuously monitored for safety and efficacy through our
extensive quality and safety systems, especially the pharmacovigilance (post-marketing
monitoring) and traceability. These systems provide an additional level of oversight by
tracking and monitoring any potential adverse events of manufactured products.
Pharmacovigilance is an important tool to monitor the safety of a product and detect
hitherto unknown adverse reactions. Traceability ensures that we can not only readily
trace our manufactured products to a patient, but also trace our products from patient
to a specific batch of products. Adverse events will be investigated, evaluated and
reported to appropriate regulatory bodies.
first-hand how our products are produced by touring one of our three manufacturing
facilities and one of our 73 plasma collection centers, I am sure you have many
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questions. The ensuing discussion will address how CSL Behring uses virology testing
and other safety measures to proactively reduce the possibility of blood-borne
pathogens in manufacturing our therapies. Your concerns are important to us and we
want to open this discussion to include your questions and comments about known
viruses and also about theoretical possibilities, most notably Creutzfeldt-Jakob disease
(CJD). This is meant to be a wide-open question and answer session. Please feel free to
ask any questions. Dr. Albrecht Grner, Head of Virology for CSL Behring, will start the
discussion by explaining the steps we employ to mitigate virus transmission.
D R . G R N E R (CSL BEHRING) : CSL Behring tests for viruses (pathogens) and employs
safety measures throughout the production process. This starts with our plasma donors
and continues to the patients who use our life-saving biotherapies. These safety processes
inactivate or remove currently recognized blood-borne pathogens and would potentially
inactivate or remove any yet unidentified blood-borne pathogens, including the agent
that causes Creutzfeldt-Jakob disease and West Nile virus. In essence, our existing
processes eliminate or reduce both actual and new, potentially emerging, pathogens.
The following diagram details the quality and safety steps employed to ensure safe and
effective products. Starting with the general population, we select only healthy donors,
thereby reducing the potential viral load. Then we test the plasma collected using
serology and NAT tests. Any plasma that tests positive is discarded. Inventory hold is
another step that makes it even more likely that only plasma without viruses is used in
manufacturing. The plasma is then pooled for manufacturing, tested again and then
subjected to processes to inactivate and remove any potential virus. Batch-to-batch
segregation further enhances safety, along with continual pharmacovigilance.
MARK BROOKER
Population
Donor selection
Donor screening (serology)
Nucleic acid testing (NAT)
Relative Risk
Inventory hold
Pathogen inactivation/removal
Cleaning/sanitization and
batch-to-batch segregation
Pharmacovigilance
Low
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know that donors from the United Kingdom have been excluded, but in addition
to this safety measure, have there been changes to the manufacturing process? For
todays products, what are the manufacturing steps that make them different from
the same product in the mid-1990s?
D E N N I S J A C K M A N (CSL BEHRING) : We take the risk of prions, including vCJD, very
seriously. We take a number of steps to address that risk including, of course, donor
exclusion. In addition, we use very sophisticated technology to clear prions. We are
RAY DATTOLI
confident that we have not only accurately modeled how our manufacturing processes
would clear prions, but also how the various safety steps employed throughout the
manufacturing process, such as, cleaning of equipment between batches, separation
of batches and the other steps, would prevent transmission.
R AY D AT T O L I (COMMITTEE OF TEN THOUSAND COTT) : My understanding from
the 1980s is that when plasma was pooled, we eventually realized that even one
donor infected with HIV would be enough to contaminate an entire batch. Could
you please address that issue?
D R . G R N E R (CSL BEHRING) : In the past, when there was neither solvent detergent
virus inactivation nor pasteurization, sufficient virus particles could definitely have been
present in the final product to transmit infection. Today, with virus inactivation and
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removal measures in place, even if a high load of virus, for example, HIV, were present
in a donation, especially a high load in the window phase of the infection, the virus
would be eliminated from the plasma pool prior to fractionation.
D R . B E R G M A N (CSL BEHRING) : To further respond to your concern, I would like to
reinforce the fact that virus inactivation and removal are the largest contributors to
product safety today. In the early 1980s, the procedures for virus inactivation and
removal did not exist. The belief is that viral inactivation and removal are most effective
if you start with the lowest amount of virus possible in the plasma. The goal of all the
steps that occur before virus inactivation and removal is to reduce the amount of virus
before getting to the inactivation and removal stages.
Donor Exclusionan Important Safety Step
R AY D AT T O L I (COTT) : I want to know whether at some point in the future you will
have so much confidence in virus inactivation and removal that you would start
accepting donors who are HIV positive or HCV positive.
D R . B E R G M A N (CSL BEHRING) : Dr. Grner has already expressed his opinion
that he would not accept such donors. Ray, I want to know how you feel about it.
Would you be willing to take a plasma-derived Factor VIII product under such
circumstances?
R AY D AT T O L I (COTT) : No, not at all. Its basically because of fear. In every vial,
I would wonder whether that plasma-derived product had gone through all the safety
steps. I presume that the more safety steps that are added the higher the cost; therefore, I fear the development of an economic situation where safety steps would be left
out to save money. We have not had an infection from a plasma-derived product since
1986, and now we have a much cleaner product; but if you show somebody who
holds the reins on Medicare-Medicaid numbers how much money could be saved by
removing safety steps, they might be tempted to eliminate some steps. Then anyone
who is unfortunate enough not to have good insurance coverage might be required to
use a cheaperand potentially less safe product.
D R . B E R G M A N (CSL BEHRING) : Yes, product choice is very important. If we were
to start taking donors who are HIV positive or HCV positive, for example, one of the
things we do not know is the maximum capacity of the process we have set up now.
Could we overwhelm the system? That is why I agree with Dr. Grner. We will never
knowingly accept donors who are HIV positive or HCV positive even though we know
GORDON NAYLOR
that our current system, with all these identified steps in place, would likely be more
than adequate to remove the virus load. We do not know what would happen if we
did not have all those steps, and we do not want to find out.
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how the safety measures all flow and work together. I would like you to put two
things together for me. Does recovered plasma follow the exact same safety steps
and manufacturing process as source plasma? And, what is the ratio of source
plasma to recovered plasma?
D R . B E R G M A N (CSL BEHRING) : Thank you for raising that question. Plasma used for
production is derived from either source plasma or recovered plasma. Source plasma is
collected through plasmapheresis from qualified donors. Recovered plasma is obtained
from whole blood donations from carefully selected donors. Selection criteria for
recovered plasma donors are comparable to those for source plasma. Furthermore,
both source and recovered plasma are subject to our rigorous quality control standards.
G O R D O N N AY L O R (CSL BEHRING) : Almost all the safety steps are the same for
recovered plasma. The only real difference in terms of safety steps is there is no
inventory hold with recovered plasma. The incremental effect of the inventory hold is
relatively modest for recovered plasma. Ethically, we could not, as a company, market
products which are from source plasma and recovered plasma and, therefore, have
two standards. We perform risk-residual calculations and through these we are quite
comfortable that the two are equivalent, a little different, but quite equivalent.
Globally, approximately 20% of CSL Behrings plasma is recovered. In the past, the
proportion of recovered plasma was much higher. This changed because our business
has grown as the global need for plasma has risen, and the additional plasma required
has come from source plasma centers, like the CSL Behring center you are visiting
today. The global need for therapies could not be met only with recovered plasma.
In Australia, CSL operates with a manufacturing source model derived primarily from
recovered plasma. This model is, in fact, used by other companies in many parts of the
world. We are, therefore, very familiar with the safety measures associated with both
types of plasma. In the United States, however, all bleeding disorder products sold by
CSL Behring use only source plasma.
R AY S TA N H O P E (NATIONAL HEMOPHILIA FOUNDATION NHF) : Going back to the
graph that shows how safety increases every step of the way, I disagree with the
line that hits zero at the pharmacovigilance stage. The risk of infection is not zero
and will never be zero. No one knows what the future holds. However, if a problem arises in the future, rather than deny its existence, like what happened in the
RAY STANHOPE
1980s, we want you to commit to investigating our concerns starting with your
own products. Will you commit to this?
D R . B E R G M A N (CSL BEHRING) : Point well taken. I can assure you we will be as
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discussion. Dr. Grner showed us a slide that indicated that the window period,
during which we can identify a donor who has an infection, has gotten shorter due
to nucleic acid testing. It is now not exceeding 30 and 40 days. We currently have
an inventory hold of 60 days on source plasma donations. How do you feel about
shortening inventory hold, to possibly 45 days, so the plasma can get into the
system quicker and we can increase our manufacturing? Would it matter whether
we are holding the donation for 45 days or 60 days?
M A R K B R O O K E R (WFH) : That is really more for regulators to decide and to review
the science. Your inventory hold is voluntary, and it is a good thing based on science.
Maybe, for reasons we do not know today, 60 days would make a difference. I do not
see the benefits of cutting back on the inventory hold. Also, I do not see how you
would really save by holding plasma in inventory less timeexcept perhaps on your
freezing storage costs.
Voluntary Standards
D E N N I S J A C K M A N (CSL BEHRING) : I want to mention the concept of voluntary
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reason for it to leave time for a second donation from the donors?
D R . B E R G M A N (CSL BEHRING) : This is true. The idea behind it is that in case we
miss something in the window period, we will pick it up in the second donation.
The question is: Now that the window period is shrinking, should our inventory
hold shrink too?
B O B R O B I N S O N (HEMOPHILIA FOUNDATION OF ILLINOIS HFI) : If CSL Behrings
inventory hold time were to change, I would encourage you to consider that it should
occur with quite a long lead time and a lot of education in the community. If the
industry were to decide that the inventory hold timeframe should change, then they
should announce this intended change two years ahead of time so the bleeding
disorders community can start discussing pros and cons.
Cytomegalovirus and Therapy Safety
L I N D A L E W W Y M A N - C O L L I N S (HFA) : I have a question about the
This means that the amount of CMV in plasma is very low. Furthermore, pathogen
inactivation methods eliminate CMV infectivity.
D R . B E R G M A N (CSL BEHRING) : In fact, CSL Behring markets a hyperimmune CMV
munity organizations can help with that. What industry can do is pharmacovigilance.
The most important thing is to be able to say after more than 20 years that there has
been no HIV, no Hepatitis C and no Hepatitis B contracted through plasma-derived
products. Thats what people can understand. I think we have been successful in
achieving that. Now we are in an era where people are considering the danger of
inhibitors and making choices based on that, not just virus safety. I think that is a
step forward.
D R . B E R G M A N (CSL BEHRING) : Thank you for your point about inhibitors. There
have been a lot of recent publications stating that inhibitor management is the biggest
challenge with hemophilia today.
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terms and make sure it passes muster with the regulatory bodies, the better for
everyone. We are enthusiastic about working with organizations and individuals who
are trying to spread this information.
B O B R O B I N S O N (HFI) : I also think there has been resistance to talk openly about
all of these safety measures because so many people did become infected and there
have been understandable emotions about that. I fear that the longer we delay talking
about the safety of plasma-derived products the more we get entrenched in the
discussions about recombinant products. There are manufacturers within the industry
who are doing everything in their power to move patients away from plasma-derived
products to recombinant products. The longer we stray from this issue and not show
that it is a viable option, it is going to be increasingly difficult to make it an option.
D R . B E R G M A N (CSL BEHRING) : Thats a good point. I also want to point out that
when we manufacture products from several million liters of plasma it is not only
coagulation therapies that we are concerned about manufacturing. The growth in the
intravenous immunoglobulin market is now the reason for expansion. Therefore, we
want to make sure the safety messages get out. The data of the last 23 years has
demonstrated safety across all our therapeutic categories.
M I C H E L L E R I C E (NHF) : I am a mother of two children and my oldest has Hepatitis C
contracted at a time when we were told the product was 98 percent virus free. As for
what industry can do, this type of discussion we are having is huge. For me personally,
the thought of ever having to go back to plasma-derived products was absolutely
terrifying. Attending this discussion I actually feel like it would not be the end of the
world to use a plasma-derived product. My children could do this safely. I do think
that because of fear some of us have felt reluctant to share this information. I think it
would be very beneficial to bring this kind of safety presentation out to local chapters
of community organizations. Fear has guided what I have done, but I can tell you that
watching the manufacturing processes makes me feel more comfortable. I encourage
you to continue to do tours like this with more people.
R AY S TA N H O P E (NHF) : I would say that it is important to give people a visual
format to understand the different safety steps and how they add to the complete
BOB ROBINSON
picture with the viral inactivation and removal being the strongest steps. You could
build on your relationships with local chapters and work with the hemophilia community
organizations to circulate this information. This would also show that whatever the
future holds your paramount concern is the safety of your customers.
Conclusion
By maintaining the highest standards of quality and safety in the manufacture of all
our products, we honor our commitment to saving lives and improving the quality of
life for people with rare and serious medical conditions worldwide.
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William Darbison
Volunteer, National Hemophilia
Foundation
William Darbison has volunteered for
the Hemophilia Foundation of Michigan,
the NHF, Human Rights Campaign and
Stitches Womens Initiatives. His daughter
is a symptomatic carrier of Factor VIII and
also has a PAI 1 disorder.
Raymond C. Dattoli
Board Member, Committee of Ten
Thousand (COTT)
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Gordon Naylor
Executive Vice President, Plasma,
Michelle Rice
industry can do is
pharmacovigilance.
David Page
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www.CSLBehring.com
CSL Behring is a subsidiary of CSL Limited