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Key Issues Dialogue: Quality & Safety

Featuring thought leaders in the bleeding disorders community

Biotherapies for Life

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

Lew Collins Board Member, Hemophilia


Federation of America
Kisa Carter Director of Public Policy,
Hemophilia Federation of America
Bill Darbison Volunteer, National
Hemophilia Foundation
Christine Kuhinka Manager, Corporate
Communications, CSL Behring
Third Row:
Kimberly Haugstad Executive Director,
Hemophilia Federation of America
Mark Brooker Sr. Public Policy Officer,
World Federation of Hemophilia
Richard Walters Director, Coagulation
Marketing, CSL Behring
Patrick Collins Director, Public Affairs,
CSL Behring
David Clark, Ph.D. Chairman, Coalition
for Hemophilia B
Maureen Powell Director of Human
Resources, CSL Behring
Joesph Kleiber Vice President for Chapter
Services, National Hemophilia Foundation
Michelle Rice Regional Director for Chapter
Services, National Hemophilia Foundation
Fourth Row:
Ray Dattoli Board Member, Committee of
Ten Thousand and Hemophilia Federation
of America
Jeffrey Alcorn Sr. Director of Quality,
Kankakee, CSL Behring

Raymond Stanhope Immediate Past


Board Chairman, National Hemophilia
Foundation
Top Row:
Glenn Mones Former Vice President of
Government Affairs, National Hemophilia
Foundation
Daniel LiVolsi Volunteer, Hemophilia
Foundation of Illinois
Gordon Naylor Executive Vice President,
Plasma, Supply Chain and Information
Systems, CSL Behring
Albrecht Grner Head, Pathogen Safety,
CSL Behring
Tom Woods Director of Engineering
Services, CSL Behring
Daniel Ferris Director, Manufacturing,
CSL Behring
Kim Isenberg Manager, State Government
Affairs, CSL Behring
Scott Ramseyer Director, Supplier
Management, CSL Behring
Dale Rosene Director, HSE and Risk
Management, CSL Behring
Andy Newsom Director of IT, CSL Behring
Michelle Azzarelli Sr. Director of Finance,
CSL Behring
Laurie Schweigert Sr. Director, Research
and Development, Kankakee, CSL Behring
Chad Feay Executive Director, Hemophilia
of Indiana

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Key Issues Dialogue: Quality & Safety


Featuring thought leaders in the bleeding disorders community
This discussion is sponsored by
CSL Behring for patients,

Commitment to Quality and Safety


CSL Behring is committed to producing high-quality, safe and effective biotherapies

caregivers and healthcare

to save lives and improve the quality of life for people with rare and serious medical

providers in the bleeding

conditions worldwide. Each step of the manufacturing process, from plasma donor to

disorders community.

patient, reflects the companys long-standing commitment to quality and safety. To


showcase this process, CSL Behring invited representatives from the bleeding disorders
community to tour one of their three manufacturing plants and one of their 73 plasma
collection facilities. Representatives visited the Kankakee, IL plant and the Melrose, IL
plasma collection center.
CSL Behring virologists, hematologists and plasma collection and manufacturing
experts were on site to explain the companys quality and safety paradigm and answer
questions from the patient representatives. These experts included Albrecht Grner,
Ph.D., Head of Pathogen Safety; Garrett Bergman, M.D., Senior Director, Medical
Affairs, U.S. Commercial Operations; Gordon Naylor, Executive Vice President, Plasma,
Planning and Logistics; Wally Casey, Senior Vice President and General Manager
Kankakee; and Daniel Ferris, Director of Manufacturing, Kankakee, among others.
This Dialogue is presented in two parts. The first part is an introduction to the
CSL Behring Integrated Safety System, as presented by Dr. Albrecht Grner and
Daniel Ferris. The second part features a discussion among members of the patient
organizations and CSL Behring representatives.

I. CSL Behring Integrated Safety System


Introduction

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

Integrated Safety System1


An integrated safety system for the production of plasma-derived products starts with

Donor Selection and


Plasma Testing

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

5. Pharmacovigilance (market monitoring)

3. Virus Inactivation/Removal and Prion Removal


Protein Purification

The inactivation and removal 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 protein purification, virus inactivation and removal and is
completed by multiple levels of quality control, verified by quality assurance. Each step
of the manufacturing process contributes to the safety of our products. For the past
25 years, the risk of virus transmission through the use of plasma-derived products has
been and continues to be extremely remote.

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

and HBV, as currently defined by PPTAs viral marker standard.


All potential donors undergo an initial physical examination before donating plasma and
complete in-depth questionnaires about their medical history and lifestyle, including

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

acid amplification technology/polymerase chain reaction (NAT/PCR) tests. A failed unit


Window Period for Detection of Viral Infection
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*

*N/A (not applicable) since serology testing is


not reliable for these viruses. NAT/PCR is used
instead.

will be destroyed, and the donor will be permanently deferred.


Nucleic acid Amplification Technology (NAT) detects the genetic material of a
transfusion-transmitted virus like HIV before the body has time to form antibodies.
This sensitive screening technique detects viruses earlier than serological testing3.
Polymerase chain reaction (PCR) is a type of NAT used to amplify specific regions
of a DNA or RNA strand via enzymatic replication. CSL Behring was the first
biopharmaceutical company to conduct NAT/PCR testing of source plasma for the
human immunodeficiency virus (HIV), Hepatitis A (HAV), Hepatitis B (HBV), Hepatitis C
(HCV) and Parvovirus B19 (B19V).
Inventory Hold, Look-back and Traceability

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.

Seroconversion is the development of detectable specific antibodies to microorganisms in the


blood serum as a result of infection or immunization. Serology (the testing for antibodies) is
used to determine antibody positivity. Prior to seroconversion, the blood test is seronegative
for the antibody; after seroconversion, the blood test is seropositive for the antibody.
4
A window period for detection of viral infection is the time interval between initial viral infection
and subsequent detection of that infection. For serology testing, the window period is
dependent upon the time necessary for antibodies to appear. In NAT/PCR testing, the window
period is dependent upon the time necessary for viral nucleic acids (RNA) to manifest.

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If new information becomes available regarding a donors health status, previous


donations from that individual, stored in inventory hold, can be retrieved and destroyed
prior to pooling for fractionation, via this look-back process. This process helps ensure
that the highest quality plasma is used in producing plasma-derived therapies.
Virus Inactivation/Removal and Prion Removal

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

Fractionation (partitioning) is the process by which defined plasma proteins are


recovered from human plasma by isolation, purification and concentration to
manufacture pure and safe products. The partitioning steps include:
Precipitation and/or adsorption
Separation of the liquid phase from solid phase by depth filtration, centrifugation
or chromatography.
Coagulation factor concentrates FVIII7 and VWF8/FVIII and fibrinogen are recovered
from cryoprecipitate after careful thawing, since these proteins are insoluble, while FIX9
is obtained from cryodepleted plasma. Other proteins, including FX, PCC (FII, FVII, FIX
and FX), FXIII, C1-INH, ATIII, immunoglobulins, API and albumin, are also recovered
from plasma by protein specific precipitation/adsorption steps, including modified
Cohn fractionation processes and immunoaffinity chromatography.

RNA (ribonucleic acid) consists of a strain of nucleotides used in gene expression. RNA is the
genetic material present in most viruses.
6
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.
7
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.
9
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

Sodium thiocyanate treatment

Furthermore, specific methods, such as virus filtration, are integrated in the


manufacturing process of some plasma-derived products to remove viruses. CSL
Behring was the first biopharmaceutical company to develop and utilize virus filtration.
During this process, protein solutions are filtered through membranes with very small
pore sizes (typically 15-40 nm).
Prion Removal

In addition to removing viruses, our manufacturing processes also remove prions through:
Precipitation

Adsorption

Filtration

Batch-to-Batch Segregation

All reusable equipment and material is sanitized to avoid contamination of a subsequently


manufactured product batch. The efficacy of these processes has been validated.
Quality Control and Quality Assurance

Quality control measures are operational throughout each stage of manufacturing.


These stages include in-process control of product intermediates, filling and packaging,
and final product release testing, including stability testing. All processes are further
monitored by Quality Assurance auditing.
Pharmacovigilance and Traceability

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.

DR. ALBRECHT GRNER

II. Expert Panel Discussion


PAT R I C K C O L L I N S (CSL BEHRING) : Now that you have had an opportunity to see

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

Safety of Plasma Pooling


High

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

Every safety step reduces the risk.

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D A V I D PA G E (CANADIAN HEMOPHILIA SOCIETY CHS) : Dr. Grner, could you

elaborate on variant Creutzfeldt-Jakob disease (vCJD)? We know that in the past


large plasma pools were considered a bad thing, but are they different for vCJD?
D R . G R N E R (CSL BEHRING) : As you know, vCJD is a degenerative neurological

disorder. It is often referred to as transmissible spongiform encephalopathy and is


caused by prions. Prions are infectious proteins that are misfolded versions of normal
brain proteins. When a prion protein comes in contact with a normal twin, it may
induce the normal protein to assume the abnormal shape, resulting in a pathogenic
protein. The resulting chain reaction may continue until prions accumulate to dangerous
levels, causing cellular malfunction and eventual degeneration of the brain.
As there is evidence that prions may be present in blood, especially in non-leucodepleted
erythrocyte concentrates10, it cannot be excluded that prions may also be present in
plasma. Based on available data the amount of prions in donated plasma is very low,
thus pooling will most likely result in a dilution of prion material in the plasma pool for
fractionation. This low level of prions will be removed by the manufacturing process
of plasma derived products to a very high degree, resulting in an appropriate margin
of safety.
M A R K B R O O K E R (WORLD FEDERATION OF HEMOPHILIA WFH) : Regarding vCJD, I

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

10

Red blood cell concentrates with white blood cells included.

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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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Source Plasma, Recovered Plasma and Safety


K I M B E R LY H A U G S TA D (HEMOPHILIA FEDERATION OF AMERICA HFA) : I appreciate

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
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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

transparent as possible in sharing what we know about potential transmissions. We

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have systems in place where if something new appeared to be transmitted through a


blood sample, everyone would know within a very short period of time. Both formal
and informal mechanisms would be activated. We are not resting on our laurels and
saying transmission could never happen again. Therefore, whenever advances in safety
measures occur, we will diligently explore whether implementing these new measures
makes sense.
The Window Period
D R . B E R G M A N (CSL BEHRING) : I have another topic I would like to offer for

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
DENNIS JACKMAN

standards. When a company adheres to voluntary standards, the market recognizes


that the company is committed to quality. We would not walk away from these
voluntary standards. Furthermore, a new company entering the same market without
these standards would be noticed.
It is important for people to know which companies carry the QSEAL certification from
the Plasma Protein Therapeutics Association (PPTA). This certification proves that a
company adheres to voluntary standards that we believe are important to product
safety. In addition, it is important to know which companies have plasmapheresis centers
that are certified with the International Quality Plasma Program, another PPTA program.
The concept of a 60- and 45-day inventory hold was established before nucleic acid
testing was in place. Science has changed quite a bit since then, but regulations have
not changed to reflect these changes. We should be open to considering regulatory
changes based on scientific advances.

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B I L L D A R B I S O N (NHF) : Regarding a system of inventory hold, isnt part of the

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

cytomegalovirus (CMV). You do not defer CMV-positive donors. I work in a


neo-natal intensive care unit and babies are not given CMV-positive products.
Does your pathogen inactivation get rid of CMV?
D R . G R N E R (CSL BEHRING) : Herpes viruses, such as CMV, are cell-associated.

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

immunoglobulin because there is a need for it to treat transplant recipients.


Community Organizations and Industry Working Together to Get Out
the Message on Product Safety
LEW COLLINS

D R . B E R G M A N (CSL BEHRING) : What can community organizations do to help

get these messages across?


D A V I D PA G E (CHS) : I think it is important to get the message out and I think com-

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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D E N N I S J A C K M A N (CSL BEHRING) : The more we can explain this in straightforward

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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About the Participants


Dr. Garrett E. Bergman
Senior Director, Medical Affairs, U.S.
Commercial Operations, CSL Behring
Dr. Garrett Bergman provides scientific
and medical support to the commercial
operations division of the company. A
pediatrician by training, Dr. Bergman
enjoyed a productive clinical and academic career for 15 years at the Medical
College of Pennsylvania, leaving to enter
the biopharmaceutical industry. He has
worked in both large pharmaceutical and
small start-up biotherapies companies for
more than 20 years, primarily in Clinical
Research and Development.
Mark Brooker

Senior Policy Officer, World Federation


of Hemophilia (WHF)

DR. GARRETT BERGMAN

Mark Brooker has worked for the World


Federation of Hemophilia (WHF) for more
than ten years. He is responsible for
safety and supply of treatment products
and data and demographics of the global
bleeding disorders community. Mark also
organizes the WFH Global Forums and
regulator's workshops. He also conducts
the WFH Annual Global Survey.
Wally Casey
Senior Vice President and General
Manager, Kankakee Plant, CSL Behring
Wally Casey is responsible for manufacturing operations at the Kankakee, IL
facility. In this role, he oversees all
functional management areas to ensure

the company business objectives are


attained. He is also responsible for formulating strategic plans and directing
their implementation.
Lew Collins
Member, Board of Directors, Hemophilia
Federation of America (HFA)
Linda Lew Wyman-Collins, BSN, RNCNIC, been involved with HFA for many
years. She has overseen the infusion suite
at HFA symposia and sits on the HFA
Medical Advisory Board. She has made
presentations at various symposia and
has published articles on women's bleeding disorders. Lew has also been involved
in lobbying activities in Washington, D.C.
and on the state level for 12 years. Lew
has two sons with severe Hemophilia A,
two symptomatic daughters with carrier
status, a granddaughter with carrier
status, and a husband with severe
Hemophilia A.
Patrick Collins
Director, Public Affairs, CSL Behring
Patrick is responsible for U.S. public
policy at CSL Behring. Prior to joining
the company in 2001, Patrick served as
Director of Government Affairs at the
National Hemophilia Foundation. He has
also served as a liaison to the New York
City Council for a city agency in the
administration of Mayor Rudolph Giuliani
and was on the staff of a New York
State Senator.

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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)

MICHELLE RICE

Raymond Dattoli currently serves as a


board member of the Committee of
Ten Thousand (COTT) and a committee
member of the Hemophilia Federation of
America, having previously served seven
years as a board member of HFA. Ray
was the first hemophilia patient to enroll
in clinical trials for Cryo and factor VIII.
He has been self-infusing factor since
1968 and tested positive for HIV in 1986.
In 1996, Ray co-founded an HIV support
group. He also established a deep sea
fishing trip for HIV-positive hemophiliacs.
Ray had two cousins and one uncle with
hemophilia.
Dan Ferris

Director of Manufacturing, Kankakee, IL,


CSL Behring
Dan Ferris is responsible for manufacturing
and logistics at the Kankakee, IL facility.
He has worked for CSL Behring and its
predecessor companies since 1989. He
received a bachelors degree in General

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Engineering and an M.B.A. from Olivet


Nazarene University.
Dr. Albrecht Grner
Head of Pathogen Safety, CSL Behring,
Marburg, Germany
Dr. Albrecht Grner is responsible for all
aspects of pathogen safety of biologicals
manufactured at CSL Behring. He oversees
studies designed to evaluate the virusand prion-reduction capacity of CSL
Behring's manufacturing processes for
both currently manufactured products
and products in development. In this
capacity, he assesses the risk of pathogen
transmission by biologicals, including the
potential risk of new emerging pathogens.
He has worked as a virologist for more
than 35 years. He is a member of the
Pathogen Safety Steering Committee
of the Plasma Protein Therapeutics
Association (PPTA) and is also a member
of the blood-borne pathogen assessment
subcommittee of the German Blood
Advisory Committee (Arbeitskreis Blut).
Kimberly Haugstad

Executive Director, Hemophilia Federation


of America (HFA)
Kimberly Haugstad is executive director
of the HFA. She is passionate about
grassroots advocacy and is committed
to achievement through collaboration.
Kimberly has served the bleeding disorders
community by volunteering for the
Wisconsin-based Great Lakes Hemophilia
Foundation on the advocacy committee

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About the Participants


and as a member of the board. Kimberly
also volunteers for the National
Hemophilia Foundations public policy
working group as well as the Committee
of Ten Thousands Government Relations
Working Group.
Dennis Jackman
Senior Vice President, Public Affairs,
CSL Behring
Dennis Jackman is responsible for
company efforts to ensure patient access
to therapies as impacted by public policy.
Dennis oversees policy development,
government and industry affairs, internal
and external communications and
ally/coalition development globally. His
areas of expertise include reimbursement,
regulatory policy and international trade.
I think it is important to get
the message out and I think
community organizations
can help with that. What

DAVID PAGE

Executive Director of the Canadian


Hemophilia Society (CHS)
David Page currently serves as the
executive director of CHS. Previously, he
served as a volunteer with the organization for more than 20 years, acting as
President from 1992 to 1994. In 2001,
he left education to work at CHS. David
was a member of the World Federation
of Hemophilia Executive Committee from
2000 to 2008 and remains Chair of its
Blood Product Safety, Supply and
Availability Committee. He is a member
of the Safety Committee of HmaQubec, the supplier of blood and blood
products in the province of Quebec. David
has severe factor IX deficiency hemophilia.
He lives just outside Quebec City.

Gordon Naylor
Executive Vice President, Plasma,

Michelle Rice

Supply Chain and Information Systems,


CSL Behring

National Hemophilia Foundation (NHF)

industry can do is
pharmacovigilance.

David Page

Gordon Naylor is responsible for plasma


supply, global planning and supply chain
management for CSL Behring as well as
information systems for the CSL group.
He is responsible for meeting the
organizations plasma needs as well as
balancing plasma supply and the global
manufacturing network with the needs
of plasma products markets served by
CSL Behring. His areas of expertise
include general management, strategic
planning, engineering, and information
systems. Mr. Naylor is chairman of the
PPTAs Source Board of Directors.

Regional Director for Chapter Services,

Michelle Rice is a regional director


for chapter services for the NHF. She
previously served as Executive Director
of Hemophilia of Indiana for nine years.
Her accomplishments include creating
a coalition to advocate for change in
Indiana Medicaid inpatient coverage
resulting in an amendment authorizing
the implementation of reimbursement for
inpatient clotting factor. In addition, she
helped craft legislation insuring access to
the Indiana Hemophilia Treatment Center
(IHTC) and she collaborated with the
IHTC and Delta Dental to develop a

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dental insurance plan for people with


bleeding disorders in Indiana. Michelles
commitment to increasing access to
hemophilia patient care, research, and
awareness through education and
coalition building has led to several
honors, including the NHFs Humanitarian
of the Year Award, Advocate of the
Year, and Outstanding Cooperation
and Teamwork Award, as well as board
positions and affiliations with prominent
hemophilia and health care organizations.
Michelle is a parent of two boys with
severe hemophilia.
Bob Robinson

Executive Director, Hemophilia


Foundation of Illinois

KIMBERLY HAUGSTAD

Bob Robinson has spent the last 20 years


providing marketing and fundraising
support to the not-for-profit community
in Illinois. Bob develops and supports
organizations that empower individuals
to be self-sufficient and self-directed by
helping them build strong support systems. Prior to joining the Foundation as a
staff member, he served the organization
as a volunteer, where he was active on
committees and served as President and
on the Board of Directors.
Raymond W. Stanhope

Chair, Board of Directors, National


Hemophilia Foundation (NHF)
Ray Stanhope has also served as
President of the Lone Star Chapter of
NHF, President of National Hemophilia

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Foundation (NHF), Vice Chair of the NHF


Board of Directors and Chair of the
Board of Directors from 2007 to 2009.
Ray served on both the Advocacy and
Blood Safety Committees at the NHF. He
has also worked closely with the Food &
Drug Administration on Blood Safety
issues and with the Centers for Disease
Control on quality of care for the hemophilia community. Mr. Stanhope has
severe Factor IX deficiency hemophilia
About CSL Behring
CSL Behring is a leader in the plasma
protein therapeutics industry. Committed
to saving lives and improving the quality
of life for people with rare and serious
diseases, the company manufactures and
markets a range of plasma-derived and
recombinant therapies worldwide.
CSL Behring therapies are indicated for
the treatment of coagulation disorders
including hemophilia and von Willebrand
disease, primary immune deficiencies
and inherited respiratory disease. The
companys products are also used in
cardiac surgery, organ transplantation,
burn treatment and to prevent hemolytic
diseases in newborns.
CSL Behring operates one of the worlds
largest plasma collection networks, CSL
Plasma. CSL Behring is a subsidiary of
CSL Limited, a biopharmaceutical
company headquartered in Melbourne,
Australia. For more information, visit
www.cslbehring.com.

www.CSLBehring.com
CSL Behring is a subsidiary of CSL Limited

2009 CSL Behring LLC


IO# 09-MSC-016