Biotechnology of Human Plasma-Derived Medicines in Scope of Collaboration Perspectives within The Central European Initiative

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1 Biotechnology of Human Plasma-Derived Medicines in Scope of Collaboration Perspectives within The Central European Initiative Dr Vadim Sentchouk PHARMLAND LLC Deputy General Director PLASMAPHARM LLC General Manager

2 PHARMLAND COMPANY: brief description 1998 Belarus-Dutch joint venture Pharmland LLC was born. Investments from Netherlands ( ) - near 42 million US $ 308 employees Revenue 2017 (estimated) near 30 million US $ R&D Center GMP Certificates, ISO 9001 Manufacturing facilities sq.m. for: Tablets, Capsules, Sashes, Infusion solutions, Injections, Prefilled Syringes, Lyophilized Powders, Syrups, Suspensions, Medical Devices, Plasma-derived Products 2

3 HUMAN BLOOD PLASMA Human Blood Plasma is the liquid component of whole blood, and makes up approximately 55% of the total blood volume. It is composed primarily of water with small amounts of minerals, salts, ions, nutrients, and PROTEINS in solution. In whole blood, red blood cells, leukocytes, and platelets are suspended within the plasma. FRESH FROZEN PLASMA Plasma intended for the recovery of proteins that are labile in plasma is immediately frozen by cooling rapidly in conditions validated to ensure that a temperature of - 25 C or below is attained at the core of each plasma unit within 1 h of placing in the freezing apparatus. 3

4 FRACTIONATION OF HUMAN PLASMA The technology of plasma fractionation was first described in USA by Edwin J. Cohn in Modern technologies of plasma fractionation include technologies for the separation of biomolecules intended for the manufacture of plasma-derived products. Plasma Fractionation Plant chromatography, ultrafiltration, ultracentrifugation, nano-filtration, virus inactivation. 4

5 HUMAN PLASMA FOR FRACTIONATION (Monograph of European Pharmacopoeia and Belarus Pharmacopoeia) Liquid part of human blood; Intended for the manufacture of plasma-derived products. Collected from carefully selected, healthy donor free from detectable agents of transmissible infections. 5

6 PLASMA COLLECTION PLASMA CENTER In more than 600 specialized donation centers located in the U.S., Europe, and Canada, individuals may donate plasma through a process called plasmapheresis. Plasmapheresis is a sterile, self-contained, automated process where plasma is separated from red blood cells and other cellular components of blood which are then returned to the donor. Source plasma collection in the U.S. is regulated by the U.S. Food and Drug Administration (FDA) and, in Europe by the European Medicines Agency (EMA) and national regulatory authorities. 6

7 LABORATORY TESTS ARE CARRIED OUT FOR EACH DONATION TO DETECT THE FOLLOWING VIRAL MARKERS: antibodies against human immunodeficiency virus (anti-hiv-1 and anti-hiv-2) + HIV virus RNA hepatitis B surface antigen (HBsAg) + hepatitis B virus DNA antibodies against hepatitis C virus (anti-hcv) + hepatitis C virus RNA 7

8 THE PLASMA FRACTIONATION INDUSTRY is a sector of the Biopharmaceutical industry in which the plasma component of human blood is processed to produce therapeutic products. Europe and North America, with 77% of the plants, accounted for a combined 88% of global fractionation capacity. The Global Plasma Fractionation Market is estimated to grow to reach USD billion by 2021 from USD billion in The Europe Plasma Fractionation Market is estimated to grow to reach 7.04 USD billion by 2021 from 5.24 USD billion in Europe holds the second position of global market. Growth in this market is mainly attributed to growing aging population, rising incidences of bleeding and immune disorders, and growing use of immunoglobulin and alpha-1-antitrypsin. 8

9 In 2016 the top 5 players possessed 78% of total global fractionation capacity: Baxalta Inc. / Shire, USA / Ireland CSL Ltd., Australia Grifols S.A., Spain Octapharma AG, Switzerland Creat Group, China (RAAS Group, China / Bio Product Laboratory Ltd., UK / Biotest AG, Germany) Kedrion S.P.A, Italy LFB S.A., France Sanquin, Netherlands 9

10 PLASMA PROTEINS FOR CLINICAL USE Plasma Protein Albumin Immunoglobulins: Intravenous, Subcutaneous, Specific Coagulation factor VIII Von Willebrand Factor Coagulation factor IX Coagulation Factor X Coagulation factor XIII Prothrombin Complex Concentrate C1 inhibitor Antithrombin III Fibrinogen Alpha-I-Antitrypsin Indications for Clinical Use restoring of blood volume in trauma, burns and surgery patients, hypoalbuminemia passive prophylaxis, primary immunodeficiency disease, secondary immune deficiency diseases, Kawasaki's disease, chronic lymphocytic leukemia or HIV infection during childhood to prevent bacterial infections, bone marrow transplantation to prevent graft versus host disease and bacterial infections, immune thrombocytopenic purpura, Guillain Barré syndrome, polyneuropathies and other neurological disorders hemophilia A, genetic deficiency genetic deficiency hemophilia B, genetic deficiency genetic deficiency genetic deficiency hemophilia B, anticoagulant overdose hereditary angioedema congenital deficiency, disseminated intravascular coagulation congenital deficiency, massive haemorrhage hereditary deficiencies, emphysema and COPD cirrhosis 10

11 Country Population Potential Plasma for Fractionation Collection National state owned fractionator Private owned fractionator Plasma Fractionation Capacilty Open markets to products fulfilling relevant regulatory requirements Self-sufficiency In Human Plasma and Products Austria L No Octapharma, Austria L Yes Albania L No No 0 Yes No Belarus L «RNPC Transfusiology and medbiotechnology» Pharmland JV LLC L L Yes Bulgaria L No No 0 Yes No Bosnia and Herzegovina L No No 0 Yes No Hungary L No Kedrion, Italy L Italy L No Kedrion, Italy L Macedonia L No No 0 Yes No Моldova L No No 0 Yes No Poland L No No 0 Yes No Romania L No No 0 Yes No Serbia L No No 0 Yes No Slovakia L No No 0 Yes No Slovenia L No No 0 Yes No Ukraine L Blood Centers Biofarma L Yes Croatia L No No 0 Yes No Montenegro L No No 0 Yes No Czech Republic L No No 0 Yes No Total (CEI) L Total (USA) L (2016) L (2007) 11

12 Country Population Potential Plasma for Fractionation Collection Austria L Albania L Belarus L Bulgaria L Bosnia and Herzegovina L Hungary L Italy L Macedonia L Моldova L Poland L Romania L Serbia L Slovakia L Slovenia L Ukraine L Croatia L Montenegro L Czech Republic L Total (CEI) L Total (USA) L (2016) L (2007) 12

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14 PHARMLAND HUMAN PLASMA PLANT: brief history The new Plasma plant was constructed according to the Investment Agreement between Pharmland JV LLC and Government / Ministry of Health of the Republic of Belarus from 3 August, 2013, and in force till Investments 23 million US$. The construction of Plasma Plant was finished in During analytical equipment, technological skids and systems were installed, Plasma Plant validations finished. The first fractionation trials with plasma batches, albumin and immunoglobulin purification started from October Marketing Authorization, GMP certification, regular fractionation of plasma, plasma-derived products manufacturing and sales from December 2017 March

15 PHARMLAND PHARMACEUTICAL PLASMA-DERIVED PRODUCTS: ALBUPHARM - Albumin solutions (Eur./Belarus Pharm.): 5% solution 20% solution 25% solution IMMUNOPHARM - Intravenous Immunoglobulin (IVIG) solutions (Eur./Belarus Pharm.): 5% solution 10% solution 16,5% solution PHARMACLOT - Coagulation Factor VIII (Eur./BelarusPharm.): Lyophilized powder 500 I.U., 1000 I.U. per vial. PHARMAFIX - Coagulation Factor IX (Eur./Belarus Pharm.): Lyophilized powder 500 I.U., 1000 I.U. per vial. 15

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17 PHARMLAND PLASMA PLANT CAPACITY: L of plasma per year for fractionation and manufacturing of finished products for Belarus and other markets L of plasma for Belarus market 2017 (100%): Albumin near 1250 kg (from L of plasma), IVIG near 120 kg (from L of plasma), CF VIII near 35 mln IU (from L of plasma), CF IX near 5 mln IU (from L of plasma), Up to L of plasma per year for fractionation and manufacturing of intermediates (cryopaste, prothrombin complex, fraction II+III (or II), fraction V) and finished products for other markets 17

18 PLASMA SOURCES FOR PHARMLAND PLASMA PLANT : L now available, collected by the government plasma centers; Ministry of Health of the Republic of Belarus shall be obliged to supply plasma for fractionation according to the Investment Agreement with Pharmland; L will be available in , collected by the government plasma centers according to the Investment Agreement with Pharmland; L will be available within , collected by Pharmland owned plasma centers; Pharmland started its own investment project at the end of 2016; up to L Pharmland is now in negotiations to buy additional plasma from Georgia, Latvia, Poland, and.. 18

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40 Matteo Renzi Prime Minister, Italy Maria Linna Marcucci Co-owner of Kedrion Biopharma s.p.a, Italy Vadim Sentchouk Pharmland LLC 40 Deputy General Director

41 Perspectives of Collaboration in Biotechnology of Human Plasma- Derived Medicines on the strategic objectives of the Central European Initiative Pharmland Plasma Fractionation Plant with L Plasma Fractionation capacity: Albumin products for 84 million people Immunoglobulin products for 45 million people Coagulation Factors products for 45 million people Support CEI Member States on their path towards regional and European integration and cooperation in: Plasma Collection, Plasma Fractionation, Manufacturing of Plasma-Derived Medicinal Products, Investigation of NEW Plasma-Derived Medicinal Products, Support CEI Member States on their path to reach self-sufficiency in Human Plasma and Plasma-derived Products 41

42 We be of one blood, ye and I from "The Jungle Book" by Rudyard Kipling (1894) 42