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KEDRION S.p.A.55051 Castelvecchio Pascoli (LUCCA)E-mail: [email protected]: +39 0583 1969697Fax: +39 0583 1969666operator +39 0583 19691

www.kedrion.com

Plasma Protein Therapeutics Association

5980

367

(03/

2013

)

Member of

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VISION

MISSION

VALUES

Everyone has the right to life, liberty and security of person* At times, natural, accidental and social causes stand in the way of the natural right to life, liberty and security of person. Because of the specific nature of its products, Kedrion helps individuals, communities and institutions to limit or remove the obstacles that prevent them from enjoying these rights.Kedrion contributes to transforming natural right (life, liberty, security) into the social right to live in the best possible conditions. To do this, it gathers, processes, activates and makes it possible to use the vital energy that is generated, regenerated, stored and carried in the blood, so that it can be transferred from human being to human being and so that anyone and everyone can enjoy fundamental rights.

*Universal Declaration of Human Rights, article 3

Kedrion produces and markets pharmaceuticals that are derived from human plasma and can improve people’s quality of life. It works to maintain standards of excellence in the sector and strives for continuous improvement to confirm its national leadership and increase its visibility and presence at the international level.It works to consolidate its role as the spokesperson acknowledged by the medical, scientific, health and institutional communities.In the international context, it aims to reinforce its role as strategic partner for health systems in countries aiming to achieve self-sufficiency in the field of plasmaderivatives.

Kedrion produces wealth for investors, workers and the local area and it achieves this in a way that is consistent with its vision and the values of responsibility, transparency, trust and respect for people.

Kedrion declares that:

• social responsibility is the guiding principle of the company’s activities• transparency and full information are central to its relationships with stakeholders• trust in the company and within it is constantly fostered by activities that are competent, honest and informedIts attention to and respect for people takes real form in the safety and quality of its products and processes.

Kedrion (www.kedrion.com) is a biopharmaceutical company specialized in the development, production, commercialization and distribution of plasma-derived products.

The company is the result of the merger, which took place in 2001, of different companies operating in the sector and it acquired a heritage of expertise that secures it a prominent role in Italy, in Europe and in the world.

Kedrion stands out for its great attention to the international horizon and for the promotion of the local community.

In Italy, Kedrion is a partner of the National Health Service for self-sufficiency in the field of plasma-derived pharmaceutical products. In addition, its expertise serves other strategic partnerships with health institutions in other countries.

The company’s competitive edge relies on the quality of its products, its relentless commitment to research and development.

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KEDRION’S 4 BUSINESS AREAS KEDRION QUALITY PROGRAMMEKedrion, in order to monitor products and processes and ensure their safety, has developed the Kedrion Quality Programme divided into 8 phases:

Production and commercialization of plasma-derived products obtained from the plasma fractionation process

Kedrion’s business model includes:

• collection of plasma in Italy and abroad.

• production of a broad range of biological products coming from plasma fractionation and purification.

• products marketing to final clients through a proprietary network in Italy, subsidiaries in EU, USA and Mexico, and more than 40 distributors in other countries. Kedrion, relying on its leading position on the Italian market, is working with the health institutions of other countries to export this service.

Commercialization of flu vaccines and synthetic pharmaceutical products

Kedrion’s main lines of business include:• commercialization of influenza vaccines under the trade name Kedrion, supplied by major European manufacturers; the vaccines are marketed only in Italy.

• sales of synthetic pharmaceuticals with the aim of extending its range with products complimentary to its plasma-derivatives.

Plasma collection and commercialization in foreign markets

Kedrion is engaged in the collection and marketing of plasma from international plasma collection centres. The plasma collected by such centres, as well as securing a supply of raw materials for Kedrion Group, is sold to other industry operators as well.

Other activities, among them in particular transfer of technological know-how

The other activities con be referred mainly to Technology Transfer.On the market of plasma-derived medicinal products, Kedrion has the skills and experience required to offer its technological know-how on:

• production of one or more products

• production of a whole product range

• development or upgrading of production lines or fractionation plants

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GENERAL PRODUCTION DIAGRAM

Immunoglobulins

Albumin Solutions

Coagulation Products

Plasma inhibitorsGeneral Production Diagram

SOURCE/RECOVEREDPLASMA

CRYO POOR PLASMA

S/D TREATEDPLASMA

CRYO PASTE

SUPERNATANTPLASMA

FRACTION II+III

FRACTION II

PROTHROMBINCOMPLEX

CONCENTRATE

FRACTION II+IIISUPERNATANTFRACTION IV

SUPERNATANT

FRACTION V

ALBUMIN SOLUTION

AT III

FACTOR VIII

FACTOR IX

i.v. IMMUNOGLOBULINSi.m. IMMUNOGLOBULINS

S/D TREATMENT

THAWING (-1ºC ÷ +3°C)

KEDRION PRODUCTS*EMOCLOT

EMOSINT

UMAN COMPLEX

AIMAFIXAntihaemophilic factor VIII concentrate

Antihaemophilic factor IX concentrate

DDAVP - desmopressin

Prothrombin complex concentrate

HAEMOPHILIA AND OTHER HAEMORRHAGIC DISEASES

CRITICAL CAREAT III KEDRION

UMAN ALBUMIN

Human antithrombin concentrate

Human albumin solution

Ig VENA

TETANUS GAMMA

IMMUNORHO/RHOGAM

i.v. standard immunoglobulin

i.m. hepatitis B immunoglobulin

i.m. tetanus immunoglobulin

i.m. anti-D immunoglobulinIMMUNE SYSTEM DISEASES

IMMUNOHBs/UMAN BIG

i.v. hepatitis B immunoglobulinVENBIG/KEYVEN

S/D TREATED PLASMAPLASMASAFE**

s/d treated plasma

____________________________________

* Kedrion manufactured and distributed products** Currently registered only in Italy

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HAEMOPHILIA AND OTHER HAEMORRHAGIC DISEASESPRODUCTION AND SAFETY

Two specific virus inactivation steps are applied to our plasma coagulation products

PRODUCTION DIAGRAM

THAWING (-1ºC ÷ +3°C)

SOURCE/RECOVEREDPLASMA

CRYO POOR PLASMA

PROTHROMBINCOMPLEX

CONCENTRATE

FACTOR IX

CRYO PASTE

FACTOR VIII

1st STEPS/D Treatment - a mixture of TNBP (tri-N-butyl-phosphate)

and a vegetable detergent (Tween 80):method effective against lipid enveloped viruses

2nd STEPDry Heat Treatment30 min at a temperature of 100º C

This method is effective against enveloped and non enveloped viruses; being applied at the end of the process it represents a further guarantee with respect to unpredictable cross-contamination

HAEMOPHILIA AND OTHER HAEMORRHAGIC DISEASES

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Product Characteristics:AIMAFIX is a highly purified double virus inactivated plasma-derived factor IX concentra-te. AIMAFIX has been employed for treatment of patients with haemophilia B since 1993 in more than 20 countries. Experience and a recent single blind randomized crossover study have shown that this pd-FIX is well tolerated, has a low thrombogenic activity and no evidence of inhibitor development.

Analytical values – average results on 51 consecutive batches of AIMAFIX** (1.000 I.U. /10 ml)

** Test performed according to European Pharmacopea (current edition)

Clinical use: Treatment and prophylaxis of bleeding in patients with haemophilia B (congenital factor IX deficiency).This product may be used in the management of acquired factor IX deficiency.Presentations: 500 I.U./10 ml, 1.000 I.U./10ml, 200 I.U./5 ml, powder and solvent for solution for infusion + set for reconstitution and administration. Storage: Store at temperature +2°C ÷ +8°C, protected from light.

Shelf Life: 2 years for 500 I.U./10 ml and 1.000 I.U./10 ml; 3 years for 200 I.U./5ml.

____________________________________‘Pharmacokinetics, thrombogenicity and safety of a double viral inactivated factor IX concentrate compared with a prothrombin complex concentrate.’ A. Ruiz-Sáez, A. Hong, A. Arguello, M. Echenagucia, A. Bodas, F. Fabbrizzi, F. Minchilli and N.B. De Bosch, Haemophilia (2005), 11: 583-588

Product Characteristics: EMOCLOT is a highly purified plasma-derived factor VIII concentrate. The concentrate is albumin-free, double virus-inactivated and contains large amounts of von Willebrand factor (vWF:RCo/FVIII:C ratio approx 0.39). EMOCLOT has been employed for treatment of patients with haemophilia A since 1992 and it has been associated to a very low risk of inhibitor development. In a retrospective survey carried out in 99 haemophilia A patients, (31 previously untreated patients PUPs and 68 minimally treated patients MTPs), only 7 (7,1 %), all with severe haemophilia A, had developed inhibitors.

Clinical use: Treatment and prophylaxis of bleeding in patients with haemophilia A (congenital Factor VIII deficiency)Treatment of acquired Factor VIII deficiency. Treatment of hemophiliacs with antibodies against Factor VIII. Efficacy of EMOCLOT in von Willebrand’s disease has not been proved by a specific clinical trial, therefore the product is not indicated in von Wille-brand’s disease. Presentations: 500 I.U./10 ml, 1.000 I.U./10 ml, powder and solvent for solution for infu-sion + set for reconstitution and administration. Storage: Store at temperature + 2°C / +8°C, protected from light. Shelf Life: 3 years.___________________________________‘Occurrence of inhibitors in previously untreated or minimally treated patients with haemophilia A after exposu-re to a plasma-derived solvent-detergent factor VIII concentrate.’ A. Gringeri, M. Monzini, G. Tagariello, A. Scaraggi, P.M. Mannucci and the Emoclot15 study members, Haemophilia (2006), 12: 128-132

EMOCLOT AIMAFIX

Analytical values – average results on 63 consecutive batches of EMOCLOT** (1.000 I.U. /10 ml)

** Test performed according to European Pharmacopea (current edition)

Analysis YEARS 2010/2011Activity FVIII

(I.U./vial) 1017

Specific activity(I.U./mg) 113

vWF:Ag(I.U./vial) 56

vWF:RCo(I.U./vial) 428

vWF:RCo/Ag(ratio) 0,70

vWF:RCo/FVIII(ratio) 0,41

Total proteins(mg/ml) 0,9

Albumin Absent

Analysis YEARS 2009/2011Specific activity

(I.U./mg) 116

Total proteins(mg/ml) 99

Heparin(I.U./vial) 44

ATIII(I.U./vial) 0,98

Activated Factors AbsentFII Activity(I.U./vial) Not detectable

FVII Activity(I.U./vial) Not detectable

FX Activity(I.U./vial) Not detectable

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UMAN COMPLEXProduct Characteristics: UMAN COMPLEX is a highly purified, double virus-inactivated, prothrombin complex concentrate containing: human plasma coagulation factor IX (Christmas factor), human plasma coagulation factor II (Prothrombin), human plasma coagulation factor X (Stuart-Prower factor).

The lack of factor VII (± 1,3 I.U./vial) and the content of ATIII (± 1,2 I.U./vial) and heparin (± 60 I.U./vial) could suggest a less thrombogenicity of the product, leaving the efficacy and the anti-inhibitor activity unchanged. Clinical use: -Treatment of bleeding and perioperative prophylaxis of bleeding in acquired deficiency of the prothrombin complex coagulation factors, such as deficiency caused by treatment with vitamin K antagonists, or in case of overdose of vitamin K antagonists, when rapid correction of the deficiency is required- Treatment of bleeding and perioperative prophylaxis in congenital deficiency of any of the vitamin K dependent coagulation factors when purified specific coagulation factor product is not available.Presentation: 500 I.U./20 ml, powder and solvent for solution for infusion + infusion set. Storage: Store at temperature + 2°C ÷ +8°C, protected from light. Shelf Life: 3 years.

___________________________________‘Pharmacokinetics, thrombogenicity and safety of a double viral inactivated factor IX concentrate compared with a prothrombin complex concentrate.’ A. Ruiz-Sáez, A. Hong, A. Arguello, M. Echenagucia, A. Bodas, F. Fabbrizzi, F. Minchilli and N.B. De Bosch, Haemophilia (2005), 11: 583-588

Quantitative composition UMAN COMPLEX(500 I.U. / 20ml)

* Factor IX titrated in accordance to international standard

EMOSINTProduct Characteristics: EMOSINT (DDVAP - desmopressin) is a synthetic analogue of vasopressin. Originally DDAVP was designed for treating diabetes insipidus. EMOSINT increases FVIII and vWFactor plasma concentrations when administered to patients with vWD or mild and moderate haemophilia A. Following an initial clinical trial performed in 1977 DDAVP has become widely used for the treatment of these diseases. DDAVP is the treatment of choice for type I Von Willebrand disease and mild and mode-rate haemophilia A.Clinical use: - Mild and moderate haemophilia A - type I von Willebrand disease; - Preparation for surgery of haemophiliacs and patients with von Willebrand disease;Presentations: 10 ampoules, 4 mcg/0,5 ml; 10 ampoules, 20 mcg/1 ml. Storage: Store at temperature + 2°C ÷ +8°C, protected from light. Shelf life: 2 years when stored in intact package.

________________________________‘Desmopressin (DDAVP): The first thirty years.’ P.M. Mannuci, A.B. Federici, G. Castaman, F. Rodeghiero, A. Coppola, G. Di Minno, M. Cattaneo, Haemophilia (2008), 14 (1);‘Guidelines for the diagnosis and management of von Willebrand disease in Italy.’ A.B. Federici, G. Castaman and P.M. Mannucci for the Italian Association of Haemophilia Centres (AICE), Haemophilia (2002), 8: 607-621WFH publications: - Protocols for the Treatment of Hemophilia and von Willebrand Disease - The Basic Science, Diagnosis and Clinical Management of Von Willebrand Disease

Human Plasma factor IX * 500 I.U./vialHuman Plasma factor II 500 I.U./vialHuman Plasma factor X 400 I.U./vial

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IMMUNE SYSTEM DISEASES PRODUCTION AND SAFETY

The precipitation and removal of fraction I and III as well as the precipitation and filtration of fraction II+III in the production process, have been validated for all our immunoglobulins. A specific inactiva-tion step (S/D treatment) has been added for both i.m. and i.v. immunoglobulins. Ig VENA and VENBIG also have a fifth specific inactivation step: low pH treatment and pepsin treat-ment at low pH, respectively.

Production Diagram

SOURCE/RECOVEREDPLASMA

CRYO POOR PLASMA

SUPERNATANTPLASMA

FRACTION II+III

FRACTION II

i.v. IMMUNOGLOBULINSi.m. IMMUNOGLOBULINS

S/D TreatementA mixture of TNBP (tri-N-butyl-phosphate)and Sodium Cholate

Pepsin treatment at low pH Low pH treatment

Three Validated Virus Removal steps1. Precipitation and removal of Fraction I2. Precipitation and filtration of Fraction II+III3. Precipitation and removal of Fraction III

1st, 2nd, 3rd STEP4th STEP

5th STEP (VENBIG) 5th STEP (Ig VENA)

IMMUNE SYSTEM DISEASES

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Ig VENA

Clinical use: Replacement therapy in adults, and children and adolescents (0-18 years) in:Primary immunodeficiency syndromes with impaired antibody production • Hypogammaglobulinaemia and recurrent bacterial infections in patients with chronic lymphocytic leukaemia, in whom prophylactic antibiotics have failed.• Hypogammaglobulinaemia and recurrent bacterial infections in plateau phase multiple myeloma patients who have failed to respond to pneumococcal immunisation.• Hypogammaglobulinaemia in patients after allogeneic haematopoietic stem cell tran-splantation (HSCT).• Congenital AIDS with recurrent bacterial infections. Immunomodulation in adults, and children and adolescents (0-18 years) in:• Primary immune thrombocytopenia (ITP), in patients at high risk of bleeding or prior to surgery to correct the platelet count.• Guillain Barré syndrome.• Kawasaki disease

ANALYTICAL VALUES - average results on 150 batches EFFICACY CONSISTENCY

Product Characteristics: Ig VENA is Kedrion’s human normal immunoglobulin 5% for i.v. use. It is a fully functional native immunoglobulin with five different validated steps of viral inactivation/removal and a high level of efficacy and tolerability.

IgG Subclasses

A Post Marketing Surveillance prospectic study on side effects of Ig VENA on 192 pa-tients assessed the extremely low incidence of Adverse Drug Reaction related to Ig VENA infusions (*).

European Pharmacopeia Internal Controls Average on 151

BatchesMono + dime: ≥ 90% Mono + dime: ≥ 90% 99,5%

Fragments: ≤ 5% Fragments : ≤ 5% 0,45%AntiHBsAg-Ab (UI/ml)

≥ 0,05 AntiHBsAg-Ab (UI/ml) ≥ 0,05 2,1

Polymers: ≤ 3.0% Polymers: ≤ 3.0% 0,05%IgA content: not required IgA: (μg/ml) ≤ 50 4,3 IgM content: not required IgM: (μg/ml) ≤ 10 0,6Aluminium: not required Aluminium ppb ≤ 200 22Ig anti D: not required Ig anti D: no reaction negative

PKA (UI/ml): ≤ 35 PKA (UI/ml): ≤ 35 <2ACA %: ≤ 50 ACA %: ≤ 50 26

Batch Ig1 (g/l) (24,3-37,2) Ig2 (g/l) (12,4-22,1) Ig3 (g/l) (0,90-1,50) Ig4 (g/l) (0,10-0,50)

087601 29,8 20,6 1,20 0,36

087610 32,7 21,5 1,15 0,36

087625 31,3 21,5 1,10 0,38

087636 35,8 18,0 1,48 0,48

087647 35,8 19,7 1,37 0,43

087651 34,3 20,6 1,31 0,48

Average 33,26 20,32 1,27 0,42

European Pharmacopeia Internal Controls AverageFc Integrity: ≥ 60% Fc Integrity: ≥ 60% 95,83%

Number of Patients (%) Number of ADRs (%) Type of ADR Symptomatology

ADR During Infusion 4 (2.1%) 4 (34%) Mild 2 Fever 2 Headache

ADR After Infusion 5 (2.6%) 8 (66%) Mild 7 Fever 1 Headache

Total 9/192 pc. (4,7%) 12/1670 treat. (0,7%)

Number and type of ADRs in 1670 treatments with Ig VENA on 192 patients

INTEGRITY

Presentations: Ig VENA 50 g/L 20 ml solution for infusion; 50 g/L 50 ml; 100 ml; 200 ml solution for infu-sion + infusion set.Storage: Store at temperature between + 2°C ÷ +8°C, protected from light. Shelf life: 2 years when stored in intact package. ___________________________________‘Terapia con immunoglobuline per via endovenosa: studio prospettico di sorveglianza degli effetti collaterali.’ A. Soresina, A.G. Ugazio, Rivista di Immunologia e Allergologia Pediatrica (2007), 5: 37-45;‘Intravenous Immunoglobulin Therapy in the treatment of the acute phase of chronic idiopathic thrombocytopenic purpura in adults.’ A. Grossi, F. Balestri, D. Tognoni, F. Minchilli, B. Fiorentino, C. Guarnieri, M. Scarpellini, S. Guazzini, Haema (2006), 9 (4): 567-571

VENBIG / KEYVENBProduct Characteristics: VENBIG is a human hepatitis B immunoglobulin for i.v. administration, with a very high safety profile guaranteed by five validated inactivation/removal steps. Clinical use: • Prevention of hepatitis B virus recurrence after liver transplantation for hepatitis B virus liver failure in combination with antiviral therapy.• Immunoprophylaxis of hepatitis B:- In case of accidental exposure in non-immunised subjects (including persons whose vac cination is incomplete or status unknown)- In haemodialysed patients, until vaccination has become effective- In the newborn of a hepatitis B virus carrier-mother- In subjects who did not show an immune response (no measurable hepatitis B antibodies) after vaccination and for whom a continuous prevention is necessary due to the continuous risk of being infected with hepatitis B.Presentations: VENBIG 500 I.U./10ml; 2.500 I.U./50ml; powder and solvent for solution for infusion + infusion set.Storage: Do not store above 25°C.Shelf life: 3 years.

________________________________‘Protocol liver biopsies in long-term management of patients transplanted for hepatitis B-related liver disease.’S. Targhetta, F. Villamil, P. Inturri, P. Pontisso, S. Fagiuoli, U. Cillo, A. Cecchetto, S. Gianni, R. Naccarato, P. Buerra, World Journal of Gastroenterology (2006), 12: 1706-1712Pr

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Product Characteristics: IMMUNOHBS is an hepatitis B immunoglobulin for i.m. administration. Its safety is guaranteed by four validated virus inactivation/removal steps.Clinical use: Prevention of hepatitis B virus re-infection after liver transplantation for hepatitis B indu-ced liver failure.Immunoprophylaxis of hepatitis B - In case of accidental exposure in non-immuni sed subjects (including persons whose vaccination is incomplete or status unknown)- In haemodialysed patients, until vaccination has become effective- In the newborn of a hepatitis B virus carrier-mother- In subjects who did not show an immune re-sponse (no measurable hepatitis B anti-bodies) after vaccination and for whom a continuous prevention is necessary due to the continuous risk of being in-fected with hepatitis B.Presentations: IMMUNOHBs 180 I.U./1ml; 540 I.U./ 3 ml solution for injection, for intramuscular use; 1000 I.U./3 ml with pre-filled ready-to-use syringe. Storage: Store at temperature + 2°C ÷ +8°C. Shelf life: 3 years.

__________________________________‘Protocol liver biopsies in long-term management of patients transplanted for hepatitis B-related liver disease.’S. Targhetta, F. Villamil, P. Inturri, P. Pontisso, S. Fagiuoli, U. Cillo, A. Cecchetto, S. Gianni, R. Naccarato, P. Buerra, World Journal of Gastroenterology (2006), 12: 1706-1712

IMMUNOHBs / UMAN BIG IMMUNORHO / RHOGAMProduct Characteristics: IMMUNORHO is Kedrion’s human anti-D immunoglobulin in powder, for i.m. use, its sa-fety profile is guaranteed by four validated inactivation/removal steps. Clinical use: Prevention of Rh(D) immunisation in Rh(D) negative women.• Antenatal prophylaxis - Planned antenatal prophylaxis - Antenatal prophylaxis following complications of pregnancy including: Abortion/threate-ned abortion, ectopic pregnancy or hydatidiform mole, intrauterine fetal death, transpla-cental haemorrhage resulting from ante-partum haemorrhage, amniocentesis, chorionic biopsy, obstetric manipulative procedures e.g. external version, invasive interventions, cordocentesis, blunt abdominal trauma or fetal therapeutic intervention.• Postnatal prophylaxis - Delivery of a Rh(D) positive (D, Dweak, Dpartial) babyTreatment of Rh(D) negative persons after incompatible transfusions of Rh(D) positive blood or other products containing red blood cells e.g. platelet concentrate.Presentation: IMMUNORHO 200 mcg (1.000 I.U.) and 300 mcg (1.500 I.U.), powder and solvent for solution for injection for i.m. use; 300 mcg (1.500 I.U.), solution for injection for i.m. use.Storage: Store below 25°C.

Shelf life: 3 years.

Product Characteristics: TETANUS GAMMA is Kedrion’s human tetanus immunoglo-bulin ready to use, in pre-filled syringe for i.m. use, its safety profile is guaranteed by four validated inactivation/removal steps. Clinical use: 1. Post-exposure prophylaxis.Immediate prophylaxis after tetanus prone injuries in pa-tients not adequately vaccinated, in patients whose immunisation status is not known with cer-tainty, and in patients with severe deficiencyin anti-body production.2. Therapy of clinically manifest tetanus. Active tetanus vaccination should always be ad-ministered in conjunction with tetanus immunoglobulin unless there are contraindications or confirmationof adequate vaccination.Presentations: TETANUS GAMMA 250 I.U./1 ml; 250 I.U./2 ml; 500 I.U./2 ml solution for injection for intramuscular use.Storage: Should be stored in a refrigerator +2°C ÷ +8°C, protected from light. Shelf life: 3 years.

TETANUS GAMMA

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CRITICAL CAREProduct Characteristics: Highly purified double virus-inactivated antithrombin concentrate.

Clinical use: In patients with congenital antithrombin deficiency:- Prophylaxis of deep vein thrombosis and thromboembolism in high risk patients (especial-ly during surgery or during the peri-partum period), in association with heparin if indicated;- Prevention of progression of deep vein thrombosis and thromboembolism in association with heparin, when indicated. In patients with acquired antithrombin deficiency:disseminated intravascular coagulation (DIC) associated with: severe sepsis, politrauma, burns, pregnancy; other acute consumption coagulopathies.Presentations: AT III KEDRION 500 I.U./10ml;1.000 I.U./20ml; powder and solvent for solution for infusion. Storage: Store in refrigerator at +2°C ÷ +8°C, protected from light. Shelf life: 3 years. The reconstituted product may be stored for 8 hours at a temperature below 30°C, or in a refrigerator at 2°C ÷ 8°C.___________________________________‘The microangiopathy of pregnancy.’A. D’Angelo, L. Valsecchi on behalf of the ATIII-EPAS Study group. Haematologica Reports (2005), 1 (10)

AT III KEDRION

Production Diagram

SOURCE/RECOVEREDPLASMA

CRYO POOR PLASMA

1st STEPAT III crude preparation is pasteurized at 60° C for 10h

2nd STEPNanofiltration with two different filters at 35nm and 15 nm

Two different steps of viral inactivation (pasteurization) and virus removal (nanofiltration) are applied to ATIII Ke-drion before sterile filtration and subsequent filling and lyophilization.

AT III PRODUCTION AND SAFETY

Activity 50±5 I.U./mlpH 6,0-7,5

Osmolality ≥ 240 mosmol/KgSolubility ≤ 10 min

Specific Activity ± 5,0 I.U./mg proteinsProteic Composition ≥ 90% AT

Heparin Content 0,1 I.U. of Heparin/I.U. ATEterolog Proteins Absent

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AT III

KEEP LIFE FLOWING

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UMAN ALBUMIN Product Characteristics: UMAN ALBUMIN is a human albumin solution with a very low content of aluminum, poly-mers and aggregates:

Clinical use: Restoration and maintenance of circulating blood volume where volume deficiency has been demonstrated, and use of a colloid is appropriate. The choice of albumin rather than artificial colloid will depend on the clinical situation of the individual patient, based on official recommendations.Presentations: UMAN ALBUMIN 200gr/l (in 50 and 100 ml vial); 250gr/l (in 50 ml vial); 5gr/100 ml (in 250 ml vial); solution for infusion. Storage: Do not store the product above 30°C, protected from light.Shelf life: 3 years when stored in intact package. _________________________________‘Switch therapy with ciproflaxin vs. intravenous ceftazidime in the treatment of spontaneous bacterial peritonitis in patients with cirrhosis: similar efficacy at lower cost.’P. Angeli, S. Guarda, S. Fasolato, E. Miola, R. Craighero, F.D. Piccolo, C. Antona, L. Brollo, M. Franchin, U. Cillo, C. Merke, A. Gatta, Alimentary Pharmacology & Therapeutics (2006)

Production Diagram

SOURCE/RECOVERED PLASMA

CRYO POOR PLASMA

SUPERNATANT PLASMA

FRACTION II+IIISUPERNATANT

FRACTION IVSUPERNATANT

ALBUMIN SOLUTION

FRACTION V

1st STEPPrecipitation and Removal ofFraction I

2nd STEPPrecipitation and filtration of Fraction II+III

3rd STEP Precipitation and filtration of Fraction IV4th STEPPrecipitation of crude Fraction V5th STEP Heat treatment at 60°C for 10h (pasteurization)

Five different steps have been validated for their ability to remove/inactivate viruses. Four steps are part of the Cohn fractionation method while a specific step of pasteurization has been added.

UMAN ALBUMIN PRODUCTION AND SAFETY

Analysis Results on 120 consecutive batches Eu. ph requrementsAluminium 18 mcg/l < 200 mcg/lPolymers and aggregates 1,4% < 5%pKA 3,5 I.U./ml < 35 I.U./mlSodium (20% - 25%) 129 mmoli/l < 136,5 mmoli/l

Total proteins 196 g/l 190-210 g/l (±10% quantitystated on the label)

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