Plasma for fractionation and plasma-derived products in the world Françoise Rossi,

1. Plasma for fractionation and plasma-derived products in the world Françoise Rossi, Head Regulatory Intelligence (LFB), Scientific and Regulatory Affairs Director (IPFA)

3. Regulatory Intelligence at LFB, a living activity • Watch upcoming regulatory trends, upstream public communication • Anticipate new requirements • Keep all professions atLFB informed of the current regulatory developments • Give to LFB all positions on regulatory impact that pharmaceutical regulatory developments can have on its activities and mobilize the skills of the professions on the texts under design, consultation and revision • Organize within LFB interactions with international health authorities via industrial federations such as IPFA, LEEM, EFPIA, … to ensure that regulatory requirements from health authorities are controlled in the interest of the industry and the respect of ethics • Argued these positions to the health regulatory agencies during joint meetings

4. Regulatory and Scientific Affairs at IPFA Mission IPFA, the international association of not-for-profit plasma fractionators, national blood services and other stakeholders, facilitates the activities of its member organisations in ensuring the safety and security of supply of high quality plasma and plasma products for the benefit of patients, based on the principle of voluntary, non remunerated donations

5. IPFA Core Purpose • Aligns its activities with the needs of all patients dependent on blood and plasma products and other donations of human origin rather than mere commercial opportunity • Aligned with wider Public Health considerations of healthcare resources • Nationally mandated/focused member organisations • Evolved from traditions of Self Sufficiency an important component of a global, regional and national strategy to safeguard the interests of all patients in a particular geographical community • IPFA Members are primarily reflecting a cultural, ethical and political preference for the VNRBD • Value recovered plasma • Support relationship with Blood donors

6. IPFA, Defend VNRBD • Strong contribution to the Dublin Consensus Statement on vital issues relating to the collection of blood and plasma and the manufacture of plasma products (Brian O Mahony, Alison Turner) • VoxSanguinis paper in response to Albert Farrugia from PPTA • All international activities aiming at fulfilling the aim of reaching Self-sufficiency by increasing the VNRBD supply

7. Regulatory and Scientific Activities at IPFA • Watch on upcoming regulatory texts • Comments on the texts during public consultations • Participation in Stakeholder Meetings with Authorities • Contribution to Authorities Workshops (FDA Rare therapeutic plasma Proteins, EU IVIg and EU FVIII Expert meetings, EDQM e.g. exclusion criteria…) • Request for ad hoc meetings with Authorities • Collaboration with Other Industry Associations (PPTA, EFPIA, …) • Interactions with Patients associations • Participation to the scientific program of the IPFA/PEI WorkshopON SURVEILLANCE AND SCREENING OF BLOOD BORNE PATHOGENS

8. Blood and Plasma

9. What is the collected blood for? • 37Millions blood bags, collected in 2010 in 45 EU countries, 17 Millions in the US allow many patients to receive blood components they need, i.e. red blood cells, platelets or plasma Red blood cells and platelets used to help during cancer and leukemia; to fight against accidental hemorrhage and blood lost during surgical procedures • Plasma can be used in its original form, particularly in the cases of acute hemorrhage with overall deficit of coagulation factors or as plasma for fractionation to be split into various proteins (immunoglobulin, clotting factors, albumin...) for the treatment of serious and often rare diseases in several major therapeutic fields, for therapeutic purposes in primary or secondary deficient patients

10. Plasma Donation • Source plasma Collection Recovered plasma Collection

11. Blood Donations in the world

12. Plasma for fractionation in the world 78 fractionation plants in the world => Asia 45 %, Europe 40 %, USA 15 % • A concentrated activity 48 M liters of fractionation capacity Commercial sector 40 M l. Non profit sector 8 M l. 45 % belong to 3 companies CSL / Baxter / Grifols-Talecris LFB one of the few players with a fractionation capacity > 1M.liters Source : Market Research Bureau 12

13. Plasma collection in USA + Europe ≈ 10 % financially compensated 1 M L ≈ 90 % non remunerated 8 M L +/- 30 M liters Plasma collected * USA + Europe 70% Source plasma (by apheresis) 30% Recovered plasma (from whole blood) < 5 % non remunerated < 1 M L > 95 % financially compensated 20 M L ---------------------------------------------------------------------------------------------------- +/- 10 M liters Plasma collected ** 13 *Source : Market Research Bureau ** Source : Council of Europe+ MRB

14. Therapeutic proteins in the World - albumin (> 10) - von Willebrand factor (6) - immunoglobulin (> 10) - fibrinogen (11) - factor VIII (> 10) - thrombin (5) - factor IX (> 10) - fibrin sealant (7) - factor VII (3) - prothrombin complex (> 10) - factor VIIa (1) - activated prothr. complex (2) - factor XI (2) - antithrombin (< 10) - factor XIII (2) - alpha-1-antitrypsin (4) - activated protein C (1) - C1-esterase inhibitor (3) - activated protein C (1)

15. Critical factors for Therapeutic Plasma Proteins • Safety • Clinical efficacy • Supply • Affordability

16. Quality Management of Donations Adequate recruitment and retention activities Careful handling of donors Prudent selection processes Friendly and clear communication with donors How - Integrated in quality management system - Regular follow-up based on Quality Indicators - Corrective and preventive actions, timely and adequately Objectives Continuous improvement of the quality of processes and products - Donor recruitment and retention practices - Donor eligibility - Donor handling in a quality environment - Medical selection - Blood donation process - Donation testing and screening - Donor vigilance Requirements - Personnel, all educated and trained - Processes described in SOPs - Quality indicators - Longitudinal review and follow up

17. And Biotechnology ?

18. And analogues through Biotechnology? • The Promise of Biotechnology Production of human plasma proteins in “Unlimited supply of cheap, virus-free plasma proteins” • Bacteria Insulin • Yeast Albumin • Mammalian cell cultureFactor VIII, Factor IX, Factor VII, VWF, Fribrinogen,… • AnimalsC1-inhibitor, Antithrombin III, Factor VIIa, mAbs, … • Fish (tilapia)Factor VII , … • Plants (tobacco, alfalfa) Factor VIII, Albumin, Macrophage Act. Factor, Erythroprotein, Protein C , …

19. Pro’s and cons of plasma-derived products  Life-saving in countless cases (over decades) Fully physiological (but not always homogeneous)  Ultra-high purity is not a prerequisite in all cases Several products from one source (cost efficient) • Virus transmissions (past) • Emerging/unknown threats • Limited supply (past?)

20. Some issues with Biotechnology, … … Example of Recombinant FIX compared to Plasma-derived FIX • Supply: not guaranteed, only one manufacturer • Safetyviruses: equivalentprions: risk absent (?) • Inhibitor formation: equivalent (so rare) • Natural structure: different • Clinical efficacy: lower recovery in blood*: higher dosage required • Price: higher (20 - 40%) * Poon 2002, Ewenstein 2002

21. Debate on inhibitors: comparing two articlesBlood Transfusion 2010;8(4) Mannucci PM, Blood Transfus 2010;8(4):288-91 Franchini M, Blood Transfus 2010;8(4):292-6

22. Lessons from 25 years of biotechnology • Biotechnological production of plasma proteins often requires expensive expression systems • Pharmacokinetics of recombinant proteins often is unfavourable in comparison to their plasma-derived counterparts • Purification process costs are not lower than for their plasma-derived equivalents • Plasma products meet similar standards of purity and safety • Plasma will continue to be needed as a source material for the production of therapeutic proteins

23. So back to Plasma, Plasma Products and Supply Future for Plasma Collection/ Plasma Products

25. PLASMA COLLECTED IN 2008 (000’s liters)(source : EU Commission + MRB – Marketing Research Bureau)

26. Self-Sufficiency for Plasma-derived products = Self sufficiency for Immunoglobulin • So, is there a problem? • Increasing demand for pd-products from both developed and developing countries – in both existing and new indications • Ideally, manufacturers require at least 3 major products (IVIg, Albumin, Coag. Fact.) to maintain economic stability • Recovered plasma availability primarily determined by demand for blood components • Wastage of plasma • ?Strategies to safeguard EU supplies? • ?Diminishing health care budgets?

27. Does Plentiful national plasma supply always deliver equitable patient access? • Probably yes in countries with high healthcare resources • Probably no in resource constrained countries unless integrated into national healthcare policies • national healthcare budgets remain the dominant constraint and collections from less wealthy countries serve not the country of origin but wealthier countries Is this troublesome?

28. A safe, secure and sustainable supply of plasma products for European patients ? • Should be driven by • Patient need and • Demand from healthcare providers and underpinned by evidence-based clinical guidelines • Should recognise EU is a cultural, politically and economically diverse region • Should promote altruism and recognise potential relationship and interaction between all forms of donations (blood, plasma, bone marrow, cord blood, organs, tissues, etc.) • Should avoid competition of donors

29. Finally, What are the essential components of a [European] Strategy? Maximize recovered plasma collection from all countries and where necessary expand source plasma collection – sensitive to local cultural, economical and political preferences Establish EU database on all plasma collection/ product supply Supplement ‘competitive market’ with EU strategy for secure supply Support eg WHO programmes to widen regulatory competence and implantation of GMP compliant systems in blood establishments in emerging/developing countries Ensure strategies safeguard the interest of all patients dependent on the ‘act of donation’ of all substances of human origin. All such acts may be considered as ‘Services of General Economic interest” and free from normal markets and competition considerations

30. Thank you for your attention ! rossi@lfb.fr

31. Back up

32. Members • BelgiumBelgische Rode Kruis CAF-DFC • Brazil Hemobras • Canada HémaQuébec • England Bio Products Laboratory • France LFBBiomédicaments • France Établissement Français du Sang • Greece Hellenic National Blood Centre • JapanJapanese Red Cross Plasma Fractionation Centre • Netherlands Sanquin Blood Supply Foundation • New Zealand New Zealand Blood Service • South AfricaNational Bioproducts Institute • USA Bloodsource • Observer European Blood Alliance (EBA)