pathogen safety monograph - floseal pathogen_safety_mono_sop... · on two different occasions, with...

Pathogen Safety MonograPh Baxter BioSurgery Products [North America]

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In the production of plasma-derived therapeutics, patient safety is of paramount importance.

This monograph provides an overview of Baxter Healthcare’s measures utilized to help ensure high margins of safety with respect to viruses or other disease agents in its plasma-derived therapies for their BioSurgery portfolio of products.

These products include: TISSEEL [Fibrin Sealant], FLOSEAL Hemostatic Matrix, GELFOAM PLUS Hemostasis Kit and ARTISS [Fibrin Sealant (Human)].

As with all plasma derived products, the risks of viral transmissions cannot be totally eliminated.Please refer to Important Safety Information on page 17 of this brochure and included Instructions for Use/Prescribing Information.

I. Introduction II. Plasma-Derived Components

IIa. Plasma Sourcing

IIA1. Plasma Collection

IIA2. Plasma Donor Selection

IIA3. Plasma Screening

IIA3a. Inventory Hold with Polymerase Chain Reaction (PCR) Testing

IIA3b. Testing of Individual Plasma Donations, Plasma Mini-Pools and Production Pools

IIA3c. Prion Risk Reduction

IIB. Virus reductionIIB1. Virus Reduction Capacity

IIB2. State-of-the Art Manufacturing Facilities

IIB3. Dedicated Virus Inactivation Steps

IIB3a. Vapor Heat Treatment

IIB3b. Solvent/Detergent Treatment

IIB4. Contributing Virus Reduction Steps During Production

IIB4a. Chromatography

III. ANIMAL-DERIVED COMPONENTSIIIA. Product Components of Animal Origin

IIIB. Utilization as Part of the Manufacturing Process

IIIC. Sourcing

IIID. Safety/Manufacturing

IV. THE GLOBAL PATHOGEN SAFETY GROUPIVA. Cutting Edge Technology and Research

IVB. Research Success

IVC. Ongoing Research

V. REFERENCES

VI. FAIR BALANCE STATEMENTS

VII. SUMMARY

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I. INTRODUCTION

Baxter Healthcare Corporation – through Baxter BioScience – is one of the world’s leading plasma processing companies. We manufacture a broad spectrum of therapeutic proteins for the treatment of hemophilia, inherited and acquired immunological disorders, for critical care, and for hemostasis and tissue adherence in surgical settings.

The latter products, for hemostasis and tissue adherence, are contained in the BioSurgery portfolio of products.

Every stage of the manufacturing process for these products is subjected to rigorous quality control and quality assurance standards. At Baxter BioSurgery, we are constantly aiming to enhance pathogen safety – from selection of donors, through manufacturing, to our global pharmacovigilance process.

We recognize the importance of making our plasma products as safe as possible for our patients. Since the early 1990’s, our experts have been leading the way in plasma safety research, pioneer-ing many key innovations that have increased the quality and safety of plasma products industry wide. For example, Baxter was among the first companies to adopt the plasma inventory hold and Qualified Donor Program standards. Baxter strictly adheres to the standards of the Plasma Master File (PMF), a European regulatory document which describes the collection and control of Human Plasma for Fractionation that is processed into medicinal products.1

In November 2001, Baxter was one of the first companies to receive the Plasma Protein Therapeutics Association (PPTA) certification of compliance with the Quality Standards of Excel-lence, Assurance and Leadership (QSEAL) Program.2 This certification recognizes the company’s commitment to superior quality in plasma manufacturing and its processing into safe, plasma-de-rived products.

Baxter continues to utilize more stringent pathogen safety testing1 and to develop new virus re-moval and inactivation measures. In parallel, Baxter is also investing in recombinant technologies to help further improve the margins of safety of therapies.

This monograph gives a brief outline of some of the measures currently employed in the manufac-ture of Baxter’s plasma-derived therapeutics for the BioSurgery products.

II. PLASMA IIa. Plasma Sourcing

The plasma for the BioSurgery products for North America is sourced solely from plasmapheresis centers located within the United States.

The primary source of the plasma from which Baxter produces its plasma-derived BioSurgery products is the company’s own plasmapheresis centers, located within the U.S.

Baxter currently owns and operates approximately 60 plasmapheresis facilities in the U.S. under the name BioLife Plasma Services.3,4

Additional plasma is sourced under contract from other U.S. suppliers (e.g., Interstate Blood Bank, Inc.).4

Before a third-party supplier is accepted by Baxter, it must agree to a stringent set of conditions, including compliance with applicable regulations and guidelines.1

IIa1. Plasma Collection: complying with required and voluntary standards

All of the plasmapheresis centers, whether BioLife or other contracted U.S. plasma suppliers, are licensed and inspected by the FDA,3 registered with CLIA (Clinical Laboratory Improvement Amend-ments) and are inspected through their recognized associations. Where required, facilities are also licensed by individual state agencies. (Health Canada recognizes the FDA requirements and does not impose additional requirements for collection centers.)

Baxter complies with all U.S. FDA recommendations and guidelines as pertains to Source Plasma collection.1

Additionally, all centers are certified and meet voluntary quality and safety standards as defined by the International Quality Plasma Program (IQPP) of the PPTA.4,5

the main IQPP standards for certification are as follows: 5

• Only plasma sourced from Qualified Donors can be used for manufacture into plasma-derived medical therapies.

• Only donors with permanent addresses within the community where the certified IQPP plasma collection center is located are to be accepted.

• IQPP-certified plasma collection centers located in the U.S. participate in the PPTA National Donor Deferral Registry (NDDR).

• IQPP-certified plasma collection centers initiate education and screening programs voluntarily to exclude high-risk donors.

• Employees of IQPP plasma collection centers are fully trained to perform their designated functions.

• IQPP-certified plasma centers are audited for adherence to current Good Manufacturing Practices (cGMP).

• IQPP-certified plasma collection centers must be in compliance with PPTA Source’s Viral Marker Alert limits for HIV-1/HIV-2 (Human Immunodeficiency Virus, types 1 and 2), HCV (Hepatitis C Virus) and HBV (Hepatitis B Virus).

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IIa2. Plasma Donor Selection: reaching the Qualified Donor Standard

Plasma is collected only from donors who have undergone full physical and medical history exami-nations,1,2,5 and who met the strict donor selection criteria as established per the FDA.6 Plasmapher-esis donors undergo an initial physical examination and survey of their medical history to ensure they are in good health and to assure that the donation procedure will not present a risk to the donor or to the recipient of the plasma-derived product.

To meet the Qualified Donor standard, per the voluntary IQPP and QSEAL standards of the PPTA, a plasmapheresis donor must complete two batteries of screening interviews and laboratory tests, on two different occasions, with negative test results, before his/her plasma may be used for manu-facture of plasma therapies.2,5

At every donation, the donor must answer a detailed questionnaire. The purpose of the questionnaire is to determine whether the donor is affected by anything from a long list of exclusion criteria1 in order to minimize the risk a donor could be carrying an infection transmissible by blood.

Examples of exclusion criteria include: past history of transmissible infection, high risk behavior, or previous residence in areas identified as high risk, among many others. For example, donations are not accepted from those who have resided in the UK for 3 months or more cumulatively between 1980 and 1996 because of the risk they may be carrying prions, the causative agent Bovine Spongi-form Encephalopathy/variant Creutzfeldt-Jakob disease (BSE/vCJD).1,5,7,8,9

Every plasma collection center must provide comprehensive viral marker rates on HIV1/HIV2, HCV and HBV infection levels in its donor population. 1,2,5

IIa3. Plasma Screening: conducting a thorough screening

Each individual plasma donation is tested for the presence of Hepatitis B Surface Antigen (HBsAg), and antibodies to HIV-1, HIV-2 and HCV. Mini-pools of plasma are tested by PCR as described below. Acceptable plasma undergos further plasma production pool testing when it arrives at the plasma processing facility.1 IIa3a. Inventory hold with Polymerase Chain reaction (PCr) testing and Lookback: addressing the problem of window donations

The effectiveness of routine antibody screening in preventing virus transmission is limited by the possibility of ‘window donations’ – donations where the donor is infected, but the viral rate is still below the detection limit of the corresponding assay.2,10

To avoid this, individual donations are kept in inventory hold for at least 60 days before being incor-porated into the production pool.1,2 If donors become positive for an infection marker (HIV, HCV, or HBV), they are immediately disqualified from giving further donations, and earlier donations still in inventory hold are removed and destroyed.1,2 If regular donors do not return within 6 months of the last donation to donate, they must repeat and pass the donor applicant procedure again.2

Polymerase Chain Reaction (PCR) testing is performed on sample donations to rapidly replicate selected segments of DNA (or RNA).11 This allows for detection of plasma that is reactive to HIV, HAV (Hepatitis A Virus), HBV, HCV and Human Parvovirus B19 (B19V) much earlier in the infectious cycle than conventional serological technologies can provide, therefore limiting the window pe-riod.1,2 Small samples of serologically negative donations are pooled using a 3-dimensional robotic pooling system. Each mini-pool contains samples of up to 512 donations.1 Only donations from

mini-pools with PCR-non-reactive results and below B19V cut-off are allowed to enter the produc-tion pool.1 Therefore, the risk that potentially infectious plasma may be entering the production pool is greatly reduced. A PCR positive mini-pool triggers an identification algorithm to identify the positive donation(s), confirm positivity, and if confirmed positive, said donations are destroyed, and the respective supplier is made aware of the infected donation(s). HIV, HBV or HCV-positive viral marker donors are permanently deferred from further donation and are added to the NDDR database to prevent inadvertent donation at another center. 1,5

IIa3b. testing of Individual Plasma Donations, Plasma Mini-Pools and Production Pools

Before a plasma donation is utilized for production, extensive individual plasma donation, mini-pool and production pool testing is performed by Baxter’s own, or contracted, serology and PCR laboratories.1 Production pools are also tested independently by a European Official Medicines Control Laboratory (OMCL) for HIV-1/2 antibodies, HBsAg and HCV PCR.

table 1: Serology and PCr tests Used for Identification of Infection Markers in Individual Plasma Donations, Plasma Mini-Pools and Production Pools 1,12

INFECTION MARkER TESTED TEST

hIV1 / hIV 2 antibodies Serology†‡

hCV antibodies Serology†‡

hBsag Serology†‡

hIV 1 PCr**‡

haV PCr**‡

hBV PCr**‡

hCV PCr**‡

Parvovirus B19V genomes

(Production pool cut-off 104 IU - B19V DNA/ml) This is Baxter specific and exceeds voluntary QSEAL requirements.1,2

PCr**‡

† Individual plasma donation testing ** Plasma mini-pool testing‡ Production pool testing

• If any of the serology tests is reactive, the units will not be used for manufacturing of plasma-derived products, and must be withdrawn and not be released to Baxter.1

• All individual plasma donation, mini-pool and production pool testing must be non-reactive and not exceeding the cut-off for B19V before release into the manufacturing process.1

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The prevalence of B19V infection in the normal population13 would make it impossible to eliminate the presence of B19V in plasma donations without compromising the supply of plasma products.

As a result, the PPTA standards (QSEAL) agree on a maximum load in plasma production pools of 105 IU B19V DNA/ml.2

As of February 2007, Baxter voluntarily adopted a more stringent cut off of 104 IU B19V DNA/ml for all BioSurgery products.1 The virus reduction steps included in the production processes of plasma-derived products further reduce this low level load.

Baxter’s pre-production screening exceeds the QSEAL voluntary industry production standards.1,2

Baxter exceeds these standards by not only PCR testing the plasma for HIV, HBV, and HCV, but also by testing the plasma for HAV, which is not a requirement for QSEAL certification.1,2

Baxter also exceeds these standards by establishing a lower cut-off of 104 IU B19V DNA/ml vs. a cut-off 105 IU B19V DNA/ml, per the QSEAL standards.1,2

The QSEAL program incorporates standards to reduce the possibility that at-risk donations could enter the manufacturing pool. The main QSEAL standards include:2

• Regulation of donor selection

• Implementation of a 60-day inventory hold

• Use of PCR screening for HIV, HBV, HCV

• Testing for Human Parvovirus B19

• Assurance that plasma is collected from low risk populations.

IIa3c. Prion risk reduction

The BSE epidemic in the UK cattle population that began in the 1980’s (with highest annual inci-dence rates >37,000 cases in 1992)14 has also been identified in other countries, although on a much smaller scale.15

Through 2007, three cases, one of them imported, have been reported for the U.S., and 10+ cases have been reported in Canada.7,15

Due to the implementation of stringent measures, the BSE incidence has since been in exponential decline, with 67 UK cases reported for 2007.14

As bovine-derived materials are also used in a number of pharmaceutical applications, rigorous regulations have been established on a worldwide basis to minimize patient risk. These com-plementary risk-reduction parameters cover, among other factors, the country of origin, source animals, the bovine tissue used, methods employed to prevent cross-contamination with higher risk materials, production processes and a quality assurance program that will guarantee traceability and product consistency.8,16

Manufacturing processes should also take into consideration viral inactivation/removal steps, which may reduce the risk for transmission of Transmissible Spongiform Encephalopathy (TSE) agents.8

Ingestion of BSE-contaminated meat is the presumed cause of a new neurodegenerative dis-ease, variant Creutzfeldt-Jakob disease (vCJD). There have been approximately 195 cases of vCJD reported world-wide as of mid-August 2006--83% in the UK, 10% in France and only isolated cases in other countries.17

The decline in BSE cases and the measures undertaken to exclude BSE-contaminated meat from human consumption have also resulted in a continuous decline in vCJD cases in the UK since its peak in the year 1999.17

There have been four presumptive documented cases of vCJD, all of them in the UK, which have been associated with transfusions of red cells.18

Although these were not associated with plasma or plasma derived products, and although the risk for U.S. plasma is already very low, a number of precautionary donor exclusion criteria have been added to ensure this risk is reduced to theoretical levels.

People who have the following do not qualify as plasma donors.1

• History of Creutzfeldt-Jakob disease (CJD) or with family history of this disease

• Indications of vCJD

• Receipt of a dura mater graft or corneal transplant, or xenotransplant recipients

• Receipt of human pituitary growth hormone or other extracts of the pituitary gland

• Residency in the UK 3 months or more cumulatively from 1980 through 19969

• Receipt of a transfusion of blood or blood components in the UK between 1980 to the present.

This is only a partial list of disqualifying conditions.

The experimental studies using model prions spiked into plasma or plasma product intermediates performed up to now have demonstrated that the steps used during the manufacturing processes of plasma derivatives (as listed in Table 2) can demonstrate higher safety margins for the theoretical risk of prion infectivity from the final products of the plasma pool.16,19,20

table 2: Prion removal Capacity of the thrombin Manufacturing Processes Vh S/D Viral Inactivation Process19,20,21

MANUFACTURING STEP MEAN REDUCTION FACTOR (log10)

Cryoprecipitation, followed by removal of thrombin precursor from Cryosupernatant *†

2.6

Ion exchange Chromatography † 1.9

* Thrombin VH (Vapor Heated)FLOSEAL Hemostatic Matrix, GELFOAM PLUS Hemostasis Kit

†Thrombin VH S/D (Vapor Heated, Solvent/Detergent treated)TISSEEL [Fibrin Sealant], ARTISS [Fibrin Sealant (Human)]

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IIB. Virus reduction

While the rigorous donor selection and highly sensitive PCR testing of donated plasma aid in re-ducing the risk of viral transmission, any screening procedure has a detection limit and can only test for known viruses.1

Therefore, the manufacturing process must include effective virus inactivation/removal steps to further reduce the risk of potential viral contamination.

Virus inactivation/removal steps are treatments capable of destroying virus infectivity either chemi-cally (e.g., solvent/detergent treatment) or physically (e.g., denaturation by heat, chromatogra-phy).

IIB1. Virus reduction Capacity: validated to the International Standards

The reduction capacity of each of Baxter’s dedicated virus inactivation/removal steps has been validated by studies in accordance with the international standards.16

1.Down-scaling: Validation studies are scaled-down to a laboratory scale version of the produc-tion process. They should be performed in a separate laboratory to avoid deliberate introduction of any virus into the production facility.

2.equivalence: The validity of the scaling down should be demonstrated by comparing suitable validation parameters of the scaled-down model with the full scale procedures, e.g. reaction time, temperature, equipment, pH, etc. As far as is practical, the scaled-down processes should simulate the full-scale manufacturing processes. It should represent worse case scenario conditions of the manufacturing process to inactivate or remove viruses or TSE agents.

3.Virus spiked runs: Virus reduction capacity is quantified by adding a known amount of test virus before the virus reduction step is performed and calculating the reduction factor from the amount of virus (infectivity) still present afterwards. Diverse viruses (e.g. different sizes, enveloped or non-enveloped, and different levels of resistance to physicochemical treatment) are used.

IIB2. State-of-the-art Manufacturing facilities: providing high quality therapies

Baxter’s state-of-the-art manufacturing facilities have been designed to ensure the production of high quality plasma and gelatin-derived therapies.

IIB3. Dedicated Virus Inactivation Steps: striving for safer therapies

Dedicated viral reduction steps are designed specifically to inactivate viruses during the manufac-turing process.

Dedicated virus inactivation steps for Baxter BioSurgery plasma-derived products may include:

• Vapor-heat (VH) treatment• Solvent/detergent (S/D) treatment

A product-specific combination of virus inactivation steps has been developed to provide an optimal combination of viral reduction capacity with preservation of stability and biological activity of the individual plasma protein.

As testimony to our rigorous donor selection process, plasma screening, effectiveness of PCR and viral inactivation procedures, at date of publication, there have been no confirmed transmissions of HIV, HAV, HBV, HCV, B19V or prion disease attributable to the BioSurgery products.*22

IIB3a. Vapor heat treatment: destroying virus infectivity of both enveloped and non-enveloped viruses (haV)

Vapor heat treatments are effective against lipid-enveloped e.g, HIV, HBV, HCV viruses and some non-lipid enveloped viruses (e.g., HAV).13

The critical parameters for viral inactivation are temperature, incubation time and residual mois-ture content.23

At Baxter, our proprietary vapor heating process involves vapor heating of lyophilized process inter-mediates with residual moisture content of 7-8%.23 Time and temperature parameters are specific to individual products. These parameters allow for effective heat transmission to viruses while at the same time maintaining the biochemical integrity of the protein.

As an example of the viral inactivation capacity of the vapor heating process, and with thrombin being a component of each of the plasma-derived BioSurgery products, the inactivation kinetics of Thrombin VH and Thrombin VH, S/D treatments are shown in Figures 1 and 2 below.

figure 1: Virus Inactivation Kinetics for thrombin Vapor heating 24,25*‡†

*FLOSEAL Hemostatic Matrix, GELFOAM PLUS Hemostasis Kit‡Data represents means of duplicate runs at 7% and 8% Residual Moisture Content (RMC), respectively.†No significant inactivation was achieved for MMV (Mice Minute Virus); in a separate study, B19V was inactivated by 3.5 logs.L.O.D.= Level of DetectionHIV-1= Human Immunodeficiency Virus 1; BVDV= Bovine Viral Diarrhea Virus; PRV= Porcine Pseudorabies Virus

As with all plasma derived products the risks of viral transmissions cannot be totally eliminated.Please see Important Safety Information on page 17 and enclosed Instructions for Use/Prescribing Information

8 HIV-1

HAV

BVDVPRV

viru

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[lo

g]

Minutes at 60ºC Minutes at 80ºC

7

6

5

4

3

2

1

00

After ly

ophilizatio

n

Spiked materia

l180 360 505 0 30 55

Arrows indicate reduction to L.O.D.

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figure 2: Virus Inactivation Kinetics for thrombin Vh S/D Vapor heating 26,27*‡†

This is a graphical representation of the reduction in virus titer seen in the Thrombin VH S/D process. Actual mean values for both HAV and HIV-1 was 1.6, and for BVDV and PRV was 1.1.

*TISSEEL [Fibrin Sealant], ARTISS [Fibrin Sealant (Human)]‡ Data represents means of duplicate runs at 7% and 8% Residual Moisture Content (RMC), respectively. † In a separate study, B19V was inactivated by >4 logs.

L.O.D.= Level of Detection

HIV-1 = Human Immunodeficiency Virus 1; BVDV = Bovine Viral Diarrhea Virus; PRV = Porcine Pseudorabies Virus

IIB3b. Solvent/Detergent (S/D) treatment: inactivating lipid-enveloped viruses

The S/D method works by disrupting the lipid envelope, thereby irreversibly inactivating the ability of lipid-enveloped viruses such as HBV, HCV, and HIV to infect cells.13

For those products which are solvent/detergent treated (e.g., TISSEEL [Fibrin Sealant], ARTISS [Fibrin Sealant (Human)])21,28 Baxter employs a 3-component solvent/detergent (S/D) process, incubating the process intermediates with the organic solvent tri(n-butyl)phosphate (TNBP)and the detergents Triton X-100 and Tween 80.29

This robust process produces rapid results, inactivating all lipid-enveloped viruses tested within 2 minutes or less,29,30,31 providing a high margin of safety,29,30 while leaving the structure and func-tion of the therapeutic proteins unchanged.32

As discussed earlier, as thrombin is a component in each of the BioSurgery products, refer to Table 3 as an example for results of validation studies investigating the S/D treatment for Thrombin VH S/D.

8 HIV-1

HAV

BVDVPRV

viru

s ti

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[lo

g]

Minutes at 80ºC

7

6

5

4

3

2

1

0

All Viruses reduced to L.O.D.

Spiked Thrombin intermediate

After lyophilization

0 20 40 60 80 100 120 140

table 3: S/D Virus Inactivation Validation Studies for thrombin Vh S/D29,30*

VIrUSS/D

ConCentratIon(% of norMaL) ‡

ProteIn ConCentratIon**

reDUCtIon faCtor (Log10)

†

hIV-1 100 Low ≥ 5.4

100 High ≥ 5.2

10 Regular ≥ 5.2

BVDV 100 Low > 5.3

100 High ≥ 5.2

10 Regular > 6.0

PrV 100 Low ≥ 6.0

100 High ≥ 6.4

100 Regular > 6.9

* TISSEEL [Fibrin Sealant], ARTISS [Fibrin Sealant (Human)]‡ Normal = as per manufacturing scale** Protein concentration was tested at both the lower and upper limits of the specified protein concentration range, as well as at “regular” manufacturing process protein concentration† The symbols > and ≥ indicate that the final virus infectivity was below the limit of detection.HIV-1 = Human Immunodeficiency Virus type 1;BVDV = Bovine Viral Diarrhea Virus;PRV = Porcine Pseudorabies Virus.

IIB4. Contributing Virus reduction Steps During Production

The dedicated virus inactivation steps outlined in the previous section have been included in the manufacturing process specifically for pathogen inactivation.

There are also steps included in the production process for completely different reasons that also have the secondary benefit of removing pathogens, and are contributing viral reduction steps.

Purification methods, such as chromatography, contribute to pathogen safety by removing both enveloped and non-enveloped viruses.

IIB4a. Chromatography: saving protein, losing viruses

Ion exchange chromatography, used most frequently for protein purification, takes advantage of electrical charge differences between the plasma-derived product and impurities, including viruses. This process allows the plasma product to bind to the chromatography column, while impurities are washed out.33

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III. ANIMAL-DERIVED COMPONENTS IIIa. Product components of animal origin

Some products used for pharmaceutical or medicinal purposes contain components that are animal-derived. These components are purposely added to the final product and may either be ac-tive ingredients (e.g., cross-linked bovine-derived gelatin granules in FLOSEAL Hemostatic Matrix, or the porcine-derived gelatin sponge in GELFOAM PLUS), or an excipient, an inert substance of the final product.16

IIIB. Utilization as part of the manufacturing process

During the manufacturing of products, animal-derived components may be used as an excipient; however, they are not intended to be part of the final product. An example of this is heparin.16

Heparin is utilized early in the manufacturing steps of sealer protein (a component of TISSEEL [Fi-brin Sealant] and ARTISS [Fibrin Sealant (Human)]) to prevent activation of clotting factors, how-ever is not intended to be a component of the final product.

IIIC. Sourcing

The cross-linked bovine gelatin granules in the FLOSEAL product are derived from bovine hide collagen (“corium”) from U.S. born and raised animals. The cattle are less than six months old, are subject to a USDA veterinary inspection pre-mortem, and are slaughtered at USDA-inspected facili-ties. 34

Certification from the supplier is also required to verify that the feed the animal was provided ex-cluded meat-and-bone meal (MBM), the primary source for potential exposure to BSE.34

The raw material used as the source for the bovine gelatin (bovine hides) is classified as “tissue with no detected infectivity” as it has never been shown to contain TSE agents, even in infected animals.34 Cow’s milk also falls within the category of tissues with no detectable infectivity.35

IIID. Safety/Manufacturing

The selected bovine collagen undergoes several manufacturing processing steps (e.g., treatment in sodium hydroxide and heat36,37) that are designed to reduce the risk of viral transmission.37

table 4: Reduction Factors for Virus Removal and/or Inactivation During the Manufacture of Gelatin Matrix37

Manufacturing stepVirus Reduction Factor of Virus Tested

BVDV PPV

Base Treatment (NaOH) >5.42 3.99

Chemical Cross-linking >4.96 1.06

Heat Treatment >6.46 1.87

No viruses could be detected in the initial hide collagen. A study showed that the hide collagen used in FLOSEAL Hemostatic Matrix production did not induce any cytopathic change attributable to viral growth for a test period of 21 days.38

Additionally, the hide collagen cultures showed negative immunofluorescent response when tested for viruses such as Bovine Viral Diarrhea Virus (BVDV), Bovine Parvovirus (BPV), Rabies and several other viruses.38

Hides used in FLOSEAL gelatin manufacturing are procured in a manner to prevent potential cross-contamination.34

The aforementioned sodium hydroxide treatment has a secondary safety benefit that has been shown to have a prion reduction capacity of at least 4.6 logs, which provides an added safety measure.39

IV. THE BAXTER GLOBAL PATHOGEN SAFETY GROUPThe Baxter Global Pathogen Safety Group has been, by virtue of a significant presence at interna-tional and regulatory meetings as well as numerous scientific publications, a leader in the field of plasma safety in plasma-derived and recombinant therapeutics.

IVa. Cutting edge technology and research

the group’s research is particularly focused on advancing Baxter’s response to potential new threats to pathogen safety:

• Prions of BSE and other spongiform encephalopathies

- Performing prion clearance studies to demonstrate significant safety margins of Baxter products

- Researching and developing all necessary changes in manufacturing processes to ensure prion safety

• Assessment of new ’threats’

- At the request of patients, treaters, or regulatory bodies

• Researching new virus inactivation and reduction technologies

- For recognized, new, or newly emerging pathogens

The Group also works closely with the industry association, the PPTA, to improve standards for the manufacturing of plasma protein therapeutics and to raise levels of plasma product safety.

Baxter, through the Pathogen Safety Group, has held the Chair of the PPTA Pathogen Safety Steering Committee since 2004, and is an active member of the TSE, the West Nile Virus and the Pandemic Preparedness task forces.

The Pathogen Safety Group is also in regular dialogue with regulatory authorities in the European Union, the United States and Japan, and makes numerous contributions to scientific meetings, publications and functions organized by patient organizations.

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IVB. research Success

The Baxter Global Pathogen Safety Group has been able to establish and validate the effectiveness of current pathogen reduction steps for TSE-agents and emerging threats, including studies with the highly pathogenic West Nile Virus.

The Baxter Global Pathogen Safety Group has made the results of its research available to nu-merous communities who specialize in plasma-processing/plasma-derived therapy in a number of recently published papers.

• Berting A et al., “Inactivation of Parvovirus B19 During STIM-4 Vapor Heat Treatment of Three Coagulation Factor Concentrates”, Transfusion, 2008; Accepted, on the web, not yet in print as of 6/2/08.

• Modrof J et al., “Neutralization of Human Parvovirus B19 by Plasma and Intravenous Immuno globulins”, Transfusion, January 2008;48:178-186.

• Planitzer C et al., “West Nile Virus Neutralization by US plasmaderived Immunoglobulin Products”, The Journal of Infectious Diseases, 2007, Aug 1;196(3): 435-40.

• Seitz R et al.,”Impact of vCJD on blood supply”, Biologicals. 2007 Apr; 35(2):79-97.

• Kreil TR et al.,”H5N1 influenza virus and the safety of plasma products”, Transfusion. 2007 Mar; 47(3):452-9.

• Kreil TR et al.,“Removal of small nonenveloped viruses by antibody-enhanced nanofiltration during the manufacture of plasma derivatives”, Transfusion. 2006 Jul; 46(7):1143-51.

• Berting A et al., “Effective poxvirus removal by sterile filtration during manufacture of plasma derivatives”, J Med Virol. 2005 Apr; 75(4):603-7.

• Kreil TR, “West Nile virus: recent experience with the model virus approach”, Dev Biol (Basel). 2004; 118:101-5.

• Kreil TR et al.,”West Nile virus and the safety of plasma derivatives: verification of high safety margins, and the validity of predictions based on model virus data”, Transfusion. 2003 Aug; 43(8):1023-8.

• Kreil TR et al., “TT virus does not contaminate first generation recombinant factor VIII concen-trate”, Blood. 2002 Sep 15; 100(6):2271-2; author reply 2272.

IVC. ongoing research

Information intended for future publication is also available to interested parties from Baxter Bioscience, Medical Information Division.

email: [email protected] : (866) 424-6724

V. FAIR BALANCE STATEMENTS

artISS [fibrin Sealant (human)] Indications

ARTISS is indicated to adhere autologous skin grafts to surgically prepared wound beds resulting from burns in adult and pediatric populations.

ARTISS is not indicated for hemostasis.

Important Safety Information

for topical Use only. Do not inject artISS directly into blood vessels. Intravascular application of

artISS may result in life-threatening thromboembolic events.

Do not use ARTISS in individuals with a known hypersensitivity to aprotinin.

ARTISS is made from human plasma. It may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

Apply only as a thin layer.

Use caution when applying with pressurized gas.

Exposure to solutions containing alcohol, iodine or heavy metals may cause ARTISS to be

denatured.

Adverse reactions occurring in greater than 1% of patients treated with ARTISS were skin graft failure and pruritus.

Please see accompanying full Prescribing Information.

fLoSeaL [hemostatic Matrix] Indications

FLOSEAL is indicated in surgical procedures (other than ophthalmic) as an adjunct to hemostasis when control of bleeding by ligature or conventional procedures is ineffective or impractical.


FLOSEAL must not be injected into blood vessels, or allowed to enter blood vessels. Do not apply in the absence of active bleeding. Extensive intravascular clotting and even death may result.

Do not use FLOSEAL in the closure of skin incisions because it may interfere with the healing of the skin edges.

Do not use FLOSEAL in patients with known allergies to materials of bovine origin.

FLOSEAL is made from human plasma. It may carry a risk of transmitting infectious agents, e.g., viruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

FLOSEAL is not intended as a substitute for meticulous surgical technique and the proper applica-tion of ligatures or other conventional procedures for hemostasis.

The maximum swell volume of approximately 20% is achieved within about 10 minutes. Excess FLOSEAL (material not incorporated in the hemostatic clot) should be removed from the site of application using gentle irrigation.

FLOSEAL should not be used in conjunction with methylmethacrylate or other acrylic adhesives.

RX only: For safe and proper use of this device, please refer to full device Instructions For Use.

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tISSeeL [fibrin Sealant] Indications

TISSEEL is indicated for use as an adjunct to hemostasis in surgeries involving cardiopulmonary

bypass and treatment of splenic injuries due to blunt or penetrating trauma to the abdomen, when control of bleeding by conventional surgical techniques, including suture, ligature and cautery, is ineffective or impractical.

TISSEEL has been shown to be an effective sealant as an adjunct in the closure of colostomies.

TISSEEL is a satisfactory hemostatic agent in fully heparinized patients undergoing cardiopulmonary bypass.


for topical Use only. Do not inject tISSeeL directly into blood vessels. Intravascular application of

tISSeeL may result in life-threatening, thromboembolic events.

Do not use TISSEEL in individuals with a known hypersensitivity to aprotinin.

TISSEEL is contraindicated in the treatment of severe or brisk arterial bleeding.

As with any other protein products, hypersensitivity or allergic/anaphylactoid reactions may occur in very rare cases.

TISSEEL is made from human plasma. It may carry a risk of transmitting infectious agents, e.g., vi-ruses, and theoretically, the Creutzfeldt-Jakob disease (CJD) agent.

Apply only as a thin layer.

Use caution when applying with pressurized gas.

Exposure to solutions containing alcohol, iodine or heavy metals may cause TISSEEL to be dena-tured.

Especially in coronary bypass surgery, TISSEEL should be applied with caution to minimize any risk of inadvertent intravascular application. The safety and effectiveness of TISSEEL used alone or in combination with biocompatible carriers in neurosurgical procedures or other surgeries involving confined spaces have not been evaluated.

Please see accompanying full Prescribing Information.

geLfoaM PLUS hemostasis Kit Indications

GELFOAM PLUS is intended as a hemostatic device for surgical procedures when control of capillary, venous, and arteriolar bleeding by pressure, ligature, and other conventional procedures is either ineffective or impractical.

Thrombin (Human) used without the Gelfoam Sterile Sponge is not indicated for hemostasis.


GELFOAM PLUS should not be used in closure of skin incisions, because it may interfere with the healing of the skin edges. GELFOAM PLUS should not be placed intravascularly, because of the risk of embolization.

GELFOAM PLUS is not recommended for use other than an adjunct for hemostasis.

GELFOAM PLUS contains thrombin, which is made from human plasma. It may carry the risk of trans-mitting infectious agents, e.g., viruses, and theoretically the Creutzfeldt-Jakob disease (CJD) agent.

While packing a cavity for hemostasis is sometimes surgically indicated, GELFOAM PLUS should not

be used in this manner unless excess product not needed to maintain hemostasis is removed. When-

ever possible, GELFOAM PLUS should be removed after use in laminectomy procedures and from fo-ramina in bone, once hemostasis is achieved. This is because GELFOAM Plus may swell to its original size on absorbing fluids, and produce nerve damage by pressure within confined bony spaces.

GELFOAM PLUS is not recommended in the presence of infection. There have been reports of fever associated with the use of Gelfoam Sterile Sponge, without demonstrable infection.

RX Only: For safe and proper use of this device, please refer to full device Instructions For Use.

VI. REFERENCES

1. Baxter Healthcare, Data on file.

2. PPTA QSEAL program: http://www.pptaglobal.org/en/qseal.cfm, accessed on April 25, 2008.

3. http://www.plasmazentrum.at/en/about-biolife/history.html, accessed on May 17, 2008.


5. IQPP Program Description, V1.8, February 2008.

6. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?CFRPart=640&showFR=1&subpartNode=21:7.0.1.1.7.7, as accessed June 12, 2008.

7. http://www.cdc.gov/ncidod/dvrd/bse/ as accessed on April 30, 2008.

8. Official Journal of the European Union;28.1.2004; C 24/6-24/19.

9. http://www.fda.gov/cber/gdlns/cjdvcjd.htm#iv, accessed on Oct. 1, 2008.

10. Schreiber GB et al. The risk of transfusion-transmitted viral infections, New Engl J. Med 1996; 334:1685-1690.

11. http://www.medterms.com/script/main/art.asp?articlekey=4807 as accessed May 01, 2008.


13. World Health Organization, WHO Technical Report, Guidelines on viral inactivation and removal procedures intended to assure viral safety of human blood plasma products, Series No. 924, 2004, pgs.150-224.

14. http://www.oie.int/eng/info/en_esbru.htm as accessed on April 30, 2008.

15. http://www.oie.int/eng/info/en_esbmonde.htm as accessed on April 30, 2008.

16. International Standard, Medical Devices Utilizing Animal Tissues and Their Derivatives, ISO22442-3, First Edition, 2007-12-15.

17. http://wwwn.cdc.gov/travel/yellowBookCh4-VariantPrions.aspx as accessed May 01, 2008.

18. http://www.hpa.org.uk/hpr/archives/2007/news2007/news0307.htm as accessed May 13, 2008.

19. Baxter Healthcare, Data on file, FEIBA/Factor IX /Factor VII / Prion removal / FINAL REPORT Study No.: PR080608; Filed: reg674e; Jan. 22, 2007.

20. Baxter Healthcare, Data on file, Thrombin NG / Prion Clearance during IEX / Final Report, Study No.: PR010702; Filed: reg677e; Jan. 24, 2008.

21. ARTISS [Fibrin Sealant (Human)] Product information Sheet, Dated 3/2008.







28. TISSEEL [Fibrin Sealant], Dated 12/2007.




32. Kiss Joseph E., Taking the Next Step in Blood Transfusion Safety: Viral Inactivation of Plasma and Plasma Products, Transfusion Medicine Update, July 1994.

33. http://en.wikibooks.org/wiki/Proteomics/Protein_Separations_-_Chromatography/Ion_exchange, as accessed June 10, 2008.


35. WHO Guidelines on tissue infectivity distribution in transmissible spongiform encephalopathies, 2006.


37. FLOSEAL Instructions for Use, Dated 3/05.



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VII. SUMMARY

In the production of plasma-derived therapeutics, Baxter offers a high level of assurances of safety.

Plasma is collected from Baxter’s own plasmapheresis centers or from contracted suppli-ers that meet all of the quality and safety standards defined by the IQPP of the PPta. all are IQPP-certified.

all adhere to the U.S. fDa requirements for Source Plasma collection.

Serology screening tests are performed on individual plasma donations for hBsag and antibodies to hIV 1/hIV 2 and hCV. these must be non-reactive before release to Baxter. If reactive, they will not be used for manufacturing and must be withdrawn.

PCr testing for hIV, haV, hBV, hCV and B19V is performed for mini-pools of the individual donations. only non-reactive donations and B19V donations below the cut-off will be released for further production. reactive donations, or B19V donations above cut-off will be withdrawn.

all donations are kept in inventory hold for at least 60 days before being incorporated into the production pool.

Production pools are tested again for hBsag and antibodies to hIV 1/hIV 2 and hCV as well as by PCr for hIV 1, hIV 2, haV, hBV, hCV, and B19V. Production pools must be non-reactive and below cut-off of 104 IU B19V Dna/ml.

effective prion risk reduction is achieved by obtaining plasma from low risk donors. In experimental studies, some manufacturing steps have been shown to be effective in prion reduction.

a dedicated viral reduction step of vapor heat treatment is utilized in the production of all plasma-derived therapies for the BioSurgery products. Some of the products also incorporate a dedicated solvent/detergent treatment (tISSeeL [fibrin Sealant], artISS [fibring Sealant (human)]) process.

Contributing virus reduction steps during production include ion exchange chromatography for thrombin Vh S/D.

In compliance with international guidelines, measures have been taken to ensure the safety of the bovine components used for the manufacturing of our bovine-derived gelatin granules. the manufacturing procedure incorporates processing steps to reduce the risk of viral transmis-sion, and as a secondary benefit, has shown to reduce prion titer, providing an added margin of safety.

Continuing research, development and introduction of improved safety measures are of key importance to the Baxter global Pathogen Safety group.

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Baxter, ARTISS, FEIBA, FLOSEAL, and TISSEEL are registered trademarks of Baxter International Inc.GELFOAM is a registered trademark of Pharmacia & Upjohn Company LLC, used under license.All other products or trademarks appearing herein are the property of their respective owners.

BS1952 03/2009

pathogen safety monograph - floseal pathogen_safety_mono_sop... · on two different occasions, with...

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