Mini Pool Plasma Fractionation: A Pragmatic Approach to Fill in Gaps of Supply and Access

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1 Mini Pool Plasma Fractionation: A Pragmatic Approach to Fill in Gaps of Supply and Access Magdy El Ekiaby, MD Egypt 7th Annual Bioplasma World Asia to 13 September 2018 Singapore

3 Global FVIII Consumption, WFH Annual Global Survey 2016 Figure B2. Mean global factor VIII use per patient (Data from 79 countries.) , ,324 Mean per patient IU PER PATIENT ,935 34,077 Median per patient High 10,578 7,945 7,543 7,085 Upper Middle Lower Middle Lower WORLD BANK ECONOMIC RANKING Economic category based on The World Bank Group 2016 rankings for Gross national income (GNI) per capita, Atlas method (current US$). (GNI in US dollars: D lower income, $0-$1,005; C lower middle income, $1,006 - $3,955; B upper middle income, $3,956 - $12,235 and A high income, $12,235 or more.) Numbers in Figure B2 are calculated based on reported factor VIII use and the number of identified hemophilia A patients. We do not have data on individual treatment. WFH humanitarian aid donations are included.

4 Supply of plasma-derived medicinal products (PDMP) WHO Blood safety and availability Fact sheet Reviewed June 2017 WHO urges establishment of sustainable blood and plasma programmes to achieve self-sufficiency of plasma-derived medicinal products Only 51 countries produce plasma-derived medicinal products (PDMP) million whole blood donations which can yield ~ 28 million Liters of plasma Only 14.4 million liters of plasma from 44 reporting countries was fractionated which reflects the big waste of plasma.

5 Current model for procurement or production of plasma products is not solving global insufficiency Can we think in a different way?

6 Lessons from IT industry

7 Mini Pool Plasma Fractionation Enabling National Blood Establishments to produce safe plasma coagulation factors and immunoglobulins

8 Developed solutions (Medical Devices) Mini-pool SD/F plasma and cryoprecipitate medical devices: CE Marked FSC Mini-pool SD/F PCC (under development) Mini-pool IV Ig (under licensing)

9 Intended use of medical devices External processing system of plasma and cryoprecipitate to: Concentrate target plasma proteins Virus inactivation of target plasma proteins Purification of the final product and removal of vasoactive materials through: Charcoal filtration 0.2µ Filtration Plasma and cryoprecipitate to be processed should comply with: Good Manufacturing Practice (GMP) Local and international regulations for preparation of high quality plasma and cryoprecipitate Blood establishments should have trained staff certified by Medical Device company to use the technology

10 Mini-Pool plasma fractionation (M-PPF) unit Small clean space with access control within a blood transfusion service Plasma pool donations instead of 100s 1000s Work with validated and licensed single use sterile medical devices Small number of trained and licensed technical staff Short processing time: SD-F Cryoprecipitate for production of FVIII is 6 hours Mini Pool Intravenous Immunoglobulins (MP-IVIG) production is 12 hours

11 Medical Devices SD/F Cryoprecipitate MP-IVIG

14 Blood Establishment Licensing by NRA + Production Facility for mini pool plasma fractionation

15 SD-F Cryoprecipitate Cryoglobulin suspended in 5% glucose saline Dose labeled for: FVIII VWF Fibrinogen FXIII Universal Blood Group Volume: ml for dose of 250 iu FVIII ml for dose 500 iu FVIII

16 Mini-Review Page 1 of 7 Role of the mini-pool cryoprecipitate technology for cost-saving and guarantee of local Factor VIII, Von Willebrand Factor and Fibrinogen product supply: Egypt experience Magdy El Ekiaby 1, Thierry Burnouf 2,3, Hadi Goubran 4, Mirjana Radosevich 5, Ahmed El Ekiaby 1 1 Shabrawishi Hospital Blood Transfusion and Hemophilia Treatment Center, Giza, Egypt; 2 Graduate Institute of Biomedical Materials and Tissue Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei; 3 International PhD Program in Biomedical Engineering, College of Biomedical Engineering, Taipei Medical University, Taipei; 4 Saskatoon Cancer Centre and College of Medicine, University of Saskatchewan, Saskatoon, Canada; 5 Human Protein Process Sciences, Lille, France Contributions: (I) Conception and design: All Authors; (II) Administrative support: None; (III) Provision of study materials or patients: M El Ekiaby, A El Ekiaby; (IV) Collection and assembly of data: M El Ekiaby, T Burnouf; (V) Data analysis and interpretation: M El Ekiaby, T Burnouf; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors. Correspondence to: Magdy El Ekiaby. Shabrawishi Hospital Blood Transfusion and Hemophilia Treatment Center, Giza, Egypt. magdyelekiaby@gmail.com. Annals of Blood. All rights reserved. aob.amegroups.com Ann Blood 2018

17 IBDs Registry in Egypt, AGS , 17% 543, 7% 1045, 14% 4504, 62% Hemophilia A Hemophilia B VWD RBDs

18 Production of S/D Cryoprecipitate Pooling 35 units dry cryo Processed by one S/D virus inactivation medical device production of 4000 units FVIII, VWF & >10 gm FI

19 Production of S/D Cryoprecipitate 285,250 units dry cryo 8,158 S/D medical devices 53,631 bags 250 IU FVIII and 43,895 bags 500 IU FVIII Cost of Medical device/ IU FVIII= US 7 cents Cost of imported FVIII Concentrates= US 21 cents

20 Egyptian low dose prophylaxis using S/D cryoprecipitate Twelve severe hemophilia A kids without FVIII inhibitor and negative for HBV, HCV and HIV serological markers Regular prophylaxis with the mini-pool S/D cryoprecipitate with a mean annual FVIII dose of 1, years follow up: Mean annual bleeding rate 2 bleeds (0 4) No reported moderate or severe adverse events No seroconversion for HBV, HCV or HIV No development of FVIII inhibitors Mean annual cost/kg/year= USD 72 compared to USD 216 when using imported CFCs

21 FVIII Inhibitors No inhibitors were developed in our small cohort of PUPs managed with S/D cryoprecipitate FVIII low dose prophylaxis In an age matched cohort of severe hemophilia A PUPs that were included in SIPPET study, inhibitor development ranged 20% for PD CFCs and 35% for recombinant CFCs Possible reasons for decreased rate of inhibitors in our low dose prophylaxis cohort: Early start of S/D cryoprecipitate FVIII infusion before development of arthropathy and inflammatory process Low dose FVIII may has a tolerating effect Rich content of VWF reduces direct exposure of infused FVIII to immune system Mild processing of cryoprecipitate decreases alteration of FVIII molecule antigen make up; hence reduced immunogenicity

22 FVIII Inhibitors By passing agents to manage bleeding in patients with FVIII inhibitors are too expensive for developing countries ITI needs highly specialized centers with expertise Minimum dose of FVIII for ITI is 50 IU/Kg 3 times weekly for a period 6 33 months Based on this for ITI the total annual dose is close to 8000 IU/kg/year with annual cost of USD 1600/kg/year

23 There is a need to call on action to reduce risk of inhibitor development; Can blood establishments play a role? Safe treatment products S/D cryoprecipitate for first 50 exposure days may reduce viral and inhibitor risk Cryoprecipitate has low inhibitor risk but high viral risk CFCs reduce viral risk, but increase inhibitor risk

24 Egypt Experience; economic efficiency Production of: Total FVIII production= 32 million IU FVIII Cost of production of S/D cryoprecipitate is USD 2.24 millions Importing similar amount of FVIII CFCs would have costed USD 6.72 millions The saving is close to USD 4.4 millions If we also add the saving due to the lower incidence of inhibitor development; the cost saving becomes more significant

25 Intravenous Immunoglobulins (IVIG)

26 FDA approved indications 1. Treatment of primary immune deficiencies 2. Prevention of bacterial infections in B Cell CLL with hypogammaglobulinemia 3. Prevention of coronary artery aneurysm in Kawasaki disease 4. Prevention of infections, pneumonitis and acute GVHD after BMT 5. Reduction of serious bacterial infection in pediatric HIV cases 6. To increase platelet count in patients with ITP

28 MP-IVIG Medical Device

29 Virally Inactivated 5% IVIG Solution

ORIGINAL RESEARCH A randomized multicenter study: safety and efficacy of mini-pool intravenous immunoglobulin versus standard immunoglobulin in children aged 1-18 years with immune

30 ORIGINAL RESEARCH A randomized multicenter study: safety and efficacy of mini-pool intravenous immunoglobulin versus standard immunoglobulin in children aged 1-18 years with immune thrombocytopenia Mohsen Elalfy, 1 Marwa Reda, 1 Islam Elghamry, 1 Omar Elalfy, 2 Mohamed Meabed, 3 Nada El-Ekiaby, 4 Mahmoud A. El-Hawy, 5 Hadi Goubran, 6 and Magdy El-Ekiaby 7 Volume 00, August 2017 TRANSFUSION 1

31 Summary Mini-Pool plasma fractionation is successfully developed It offers developing countries an access to use domestic plasma for preparation of plasma products with safety and efficacy similar to industrial products It can be an intermediate step in the preparation for large scale plasma fractionation projects MP-IVIG medical device can be a practical tool to prepare hyper immunoglobulin from convalescent plasma in epidemic areas It can be also used to prepare strategic products such as antihepatitis B and anti-d hyper immunoglobulin

32 Acknowledgement Collaborators France: T Burnouf, M Radisovic (HPPS) Egypt: H Goubran (Cairo University) M El Sayed, G Sobhy, N Nabil, K Fathy, A Abdalla, Suzan, A. El Ekiaby, M El Ekiaby (Shabrawishi Hosp. BTC)) Switzerland: Research Foundation for Medical Devices (not for profit) Viral Inactivation Plasma Systems (V.I.P.S., SA)

33 شكرا Thank you

Magdy El Ekiaby, MD Shabrawishi Hospital BTC & HTC Cairo, Egypt

Magdy El Ekiaby, MD Shabrawishi Hospital BTC & HTC Cairo, Egypt Are plasma and cryoprecipitate still used? They are still largely used for treatment of hereditary bleeding disorders in many resource limited