1. WHO Norms and Standards: Blood Products & related Biologicals Dr Ana Padilla, Blood Products & related Biologicals Medicines Policy and Standards Department Health Technology and Pharmaceuticals Cluster World Health Organization

2. HTP/PSM/QSD: 58thECBS, 08 Oct 07 2 |2 | Implementation of strategic objective for quality of medical products (WHO/HQ)

3. HTP/PSM/QSD: 58thECBS, 08 Oct 07 3 |3 | Biological Standardization (*) Constitutional responsibility  WHO is mandated by it's Member States to "…develop, establish and promote international standards for biological products."  In practice, biological products cover »Vaccines »Blood and blood products »Biological therapeutics »In vitro diagnostic devices (*) Expert Committee for Biological Standardization

4. HTP/PSM/QSD: 58thECBS, 08 Oct 07 4 |4 | - implemented for more than 50 years - mandated by Member States International biological standardization by WHO WHO is expected to be both a driving force and a key reference point on biological standardization issues

5. HTP/PSM/QSD: 58thECBS, 08 Oct 07 5 |5 | ECBS: Quality Assurance and Safety of Blood Products and related biologicals (QSD) WHO standard setting functions* :  to develop WHO Biological Reference Preparations  to produce WHO Guidelines on Quality Assurance and Control of specific products  to support implementation of WHO Norms and Standards: (strengthen technical/regulatory capacity of Medicines Regulatory Authorities & Control Laboratories) (*) Expert Committee on Biological Standardization (*) WHO Collaborating Centres for Biological Standardization

6. HTP/PSM/QSD: 58thECBS, 08 Oct 07 6 |6 | Blood Products & related Biological Animal- derived sera  Anti-rabies  Anti-venoms (snake bites)  Anti-tetanus toxins  Anti-diphteria toxins  Anti-botulism toxins Human blood derived products  Blood components (red cells, platelets, plasma)  Blood Coagulation Factors  Polyvalent Immunoglobulins (IV, IM)  Specific Immunoglobulins  Anti-hepatitis B  Anti-rabies  Anti-tetanus  Anti-rhesus (anti-D)  Albumin  In vitro biological diagnostic devices Priority: IVDs applied to the control of blood and blood products safety Other related products Anticoagulant & fibrinolysis biological therapeutic products Quality Assurance and Safety of Blood Products and related Biologicals

7. HTP/PSM/QSD: 58thECBS, 08 Oct 07 7 |7 | QSD Strategic Plan Support access to life-saving medicines: – Prequalification concept applied to antisera Blood products standards setting: –WHO Reference materials and Guidelines –GMP for blood and plasma establishments –Regional Regulatory Networks QSD Strategic Plan (approved at 57 th ECBS, 2006)

8. Support Access to life-saving medicines

9. The Meeting urged WHO to: Increase the production of antisera by building the technical capacity and expertise of regulatory authorities and manufacturers creating a prequalification system. Improve management of diseases through adequate distribution and improved clinical guidance. coordinate collaboration and partnerships (resource mobilization) 1 patient treated = 1 life saved or 1 permanent disability prevented

10. HTP/PSM/QSD: 58thECBS, 08 Oct 07 10 | n Courtesy Prof D Warrell, Nuffield Department of Clinical Medicine, Oxford Antivenom sera are essential to prevent long-term disability & death

11. HTP/PSM/QSD: 58thECBS, 08 Oct 07 11 | The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. © WHO 2004. All rights reserved WHO 6 regions (Total population: 6, 290, 149, 374) Manufacture of animal derived sera for therapeutic use India Pakistan Thailand Myammar Russia Indonesia Philippines Australia Egypt S-A Croatia Brazil Wales France Mexico Costa Rica Vietnam Serbia Ouzbekistan India South-Africa Iran Israêl China Algeria Small local manufacturers in some Latin American countries and North Africa

12. HTP/PSM/QSD: 58thECBS, 08 Oct 07 12 | Fragility of production systems in developing world Further to the Committee discussion, the document will be tested in the field. Workshops in: Indonesia, March 2008 Kenia, May 2008 Adoption to be requested to the 59 th ECBS (2008)

13. A - Collection of venoms B – Horse Immunization Protocols C – Starting material of animal derived sera D – Fractionation & Purification process PRODUCTION OF ANTIVENOM IMMUNOGLOBULINS: Technology in the public domain (not protected by intelectual property)

14. WHO Norms and Standards WHO Biological Reference Preparations Global Measurement Standards

15. HTP/PSM/QSD: 58thECBS, 08 Oct 07 15 | WHO Biological Reference Preparations Global measurement standards  Tool for comparison of biological measurement results worldwide  To facilitate transfer of laboratory science into worldwide clinical practice  To support harmonization of international regulations  To accelerate transfer technology

16. HTP/PSM/QSD: 58thECBS, 08 Oct 07 16 | Establishment of WHO Biological Reference Standards * 7.Characterization of final product 8.Stability studies (incl. statistical analysis) 9.International collaborative study (incl. statistical analyses) 10. Experts Working Groups 11. Report to ECBS and decision 12. Storage and distribution 1.Selection of candidate materials 2.Characterization of candidate materials 3.Feasibility studies 4.Inactivation (if needed) 5.Dilution of materials (dilution matrix) 6.Freeze-drying *Recommendations for the preparation, characterization and establishment of international and other biological reference standards (revised 2004); Annex 2, WHO TRS, No 932, 2005.

17. HTP/PSM/QSD: 58thECBS, 08 Oct 07 17 | WHO Biological Reference Preparations Blood Products and related Biologicals WHO Catalogue of Biological Reference Preparations: www.who.int/bloodproducts

18. HTP/PSM/QSD: 58thECBS, 08 Oct 07 18 | Analytical Sensitivity Standards required by CTS EU IVD Directive, Annex II, ListA WHO standards available Screening and rapid assays anti-HIV-1/2none1 st WHO IRP anti-HIV1/2subtypes anti-HTLV-I/IInoneNone (required) anti-HCVnoneIn process (2009) HBsAg 0.5 ng/ml (French or UK-standard) 2.6 IU (WHO HBsAg 2nd IS) 2 nd WHO International Standard for HBsAg: 33 IU/ampoule WHO dilutional reference panel anti-HBcnoneIn process (2008) NAT assays (qualitative and quantitative) HIV Analytical sensitivity (IU/ml) defined on WHO standards HIV-1 RNA 2nd IS (2006) 5.56x10 5 IU/ml HCVHCV RNA 2st IS (2003) 10 5 IU/ml HBVHBV DNA 2st IS (2006) 10 6 IU/ml HTLV I/IINone

19. HTP/PSM/QSD: 58thECBS, 08 Oct 07 19 | Meeting of the WHO CCs (29-30 January 2007): WHO Biological Reference Preparations for the detection of microbiological agents with an impact on the regulation and control of the safety of blood and blood products www.who.int/bloodproducts/ivd/infectious_markers

20. HTP/PSM/QSD: 58thECBS, 08 Oct 07 20 | WHO Biological Reference Standards Priority: blood safety-related IVDs Standardization of in vitro biological diagnostic technologies for the detection of microbial agents which could be transmitted to humans, with an impact on the regulation and control of blood and blood products safety

21. HTP/PSM/QSD: 58thECBS, 08 Oct 07 21 | Priority Projects for Biological Reference Preparations WHO Collaborating Centres' Meeting (29-30 January 2007) ECBS200920082007 HCV RNA (3 rd )* 2007 Anti-Syphilitic (2 nd ) * 2008 Anti-HBs (2 nd )* 2008 Anti-HBc* 2009 HIV-1 gt 1 (2 nd ) ** 2009 HIV-2 RNA * 2009 HBV gt 2** 2009 Anti-HCV** 2009 Anti-T. cruzi** Consultation Feasibility studies Collaborative study 1 the anti-HIV antibody panel will also be extended; 2 two panels for HBsAg- and NAT-tests *IS **Panel WHO Recommendations: Annex 2, WHO TRS, No 932, 2005

22. Revisiting Chagas disease Geneva – 04-06 July 2007 "The establishment of the WHO Global Network to combat Chagas disease occurs in the broader context of the WHO’s renewed fight against neglected tropical diseases". "While Chagas disease is controlled in many countries in the Americas, commitment must be strengthened as elimination of the disease is now attainable". "Cases identified in non-endemic countries have demonstrated the need to globalize our efforts" said Dr Margaret Chan, WHO Director-general. Chagas disease meeting – Geneva 4-6 July 2007 Press release

23. HTP/PSM/QSD: 58thECBS, 08 Oct 07 23 | Migration Flows from Latin America Chagas disease

24. HTP/PSM/QSD: 58thECBS, 08 Oct 07 24 | Proposal for development of a WHO reference panel for control of anti-T cruzi antibody tests Chagas disease is now a global health problem due to the migration of people from endemic to non-endemic areas Appropriate control of in vitro diagnostic tests for the detection of anti-Trypanosoma cruzi antibodies (for blood screening and clinical diagnosis) is needed There is a global need for the regulation and control of diagnostic test kits

25. HTP/PSM/QSD: 58thECBS, 08 Oct 07 25 | Testing for T. cruzi Infection: Serological Tests for Detecting Antibodies  Screening tests –Indirect hemagglutination assay (IHA) –Enzyme-linked immunosorbent assay (ELISA)  Confirmatory tests –Indirect immunoflourescence assay (IFA) –Radio-immuno-precipitation assay (RIPA) –Immunoblot/Western blot  Rapid tests Antigens used for tests –Whole parasite lysates or semipurified antigenic fractions (epimastigote stage) –Trypomastigote excretory-secretory antigens (TESAs; major component trans-sialidase) –Cocktail of recombinant proteins –Synthetic peptides

26. HTP/PSM/QSD: 58thECBS, 08 Oct 07 26 | Plasma units anti-T. cruzi positive for ELISA, HAI, IFI and RIPA/Western Blot from North country (e.g. Mexico). Plasma units anti-T. cruzi positive for ELISA, HAI, IFI and RIPA/Western Blot from South country (e.g. Brasil). Plasma units clear negative from endemic area Development of the WHO International Reference T.cruzi Panel: CANDIDATE MATERIALS:                                      T. cruzi I T. cruzi IIa T. cruzi IIb T. cruzi IIc T. cruzi IId T. cruzi IIe Linajes filogenéticos de Trypanosoma cruzi Adapted from Souto et al. 1996; Fernandes et al. 1998; Brisse et al. 2000, 2004. TCII TCI

27. HTP/PSM/QSD: 58thECBS, 08 Oct 07 27 | Challenges (I)  Biological standardization is a specialized scientific exercise with rapid development  Need to address existing, new and emerging technologies with impact in public health  Need to keep pace with new approaches in standardization  Coordination with other standard setting organizations (e.g. ISO)

28. HTP/PSM/QSD: 58thECBS, 08 Oct 07 28 | Challenges (II)  Proliferation of tests in the biological field: international-global issue  Need for standardization essential to the regulation and quality control of tests  Need to assure access to appropriate reference materials by developing countries  Need to promote appropriate use of biological reference materials

29. WHO Norms and Standards: Guidelines and Recommendations

30. HTP/PSM/QSD: 58thECBS, 08 Oct 07 30 | WHO Guidelines & Recommendations Scope and Added Value Promote global harmonization to secure quality and safety of blood products and related biologicals – Help the understanding and interpretation of international regulations – Support implementation of international regulations – Support compliance of international regulations

31. HTP/PSM/QSD: 58thECBS, 08 Oct 07 31 | WHO Guidelines & Recommendations Strengthening technical skills of both regulatory systems and manufacturing capacity – Build bridges between regulatory systems – Bring expertise to regulators and manufacturers in need Used as the basis of national regulations/worldwide regulations

32. HTP/PSM/QSD: 58thECBS, 08 Oct 07 32 | WHO Guidelines on Viral Inactivation and Removal Procedures intended to assure the Viral Safety of Human Blood Plasma Products (adopted in November 2001) www.who.int/biologicals www.who.int/bloodproducts

33. HTP/PSM/QSD: 58thECBS, 08 Oct 07 33 | WHO Recommendations for the Production, Control and Regulation of Human Plasma for Fractionation (adopted in November 2005) www.who.int/bloodproducts www.who.int/medicines

34. Support implementation of WHO Norms and Standards

35. HTP/PSM/QSD: 58thECBS, 08 Oct 07 35 | Essential Medicines List Blood Derived Products Blood Products: – Blood Coagulation Factors: FVIII, PCC – Human Normal Immunoglobulin (IV and IM) Sera and Immunoglobulins: –Anti-rabies, anti-venoms (animal derived) –Anti-D & anti-tetanus immunoglobulin (human)

36. HTP/PSM/QSD: 58thECBS, 08 Oct 07 36 | Options for the Provision of Blood/Plasma Derivatives Use of products derived from local plasma –Local fractionation –Plasma Contract Fractionation program Importation of finished products Use a combination of approaches

37. HTP/PSM/QSD: 58thECBS, 08 Oct 07 37 | Blood/Plasma donation Plasma for Fractionation Blood Components Plasma-Derived Medicinal Products TRACEABILITY FROM DONOR TO PATIENT COMPONENTS PREPARATION DONATION INFORMATION FRACTIONATION VIRAL INACTIVATION TREATMENT GMP LOOK BACK SYSTEM Patients

38. HTP/PSM/QSD: 58thECBS, 08 Oct 07 38 | Plasma Contract Fractionation Programs (Need for GMP implementation) GMP Licensing GMP Licensing Quality Assurance Program across countries PLASMA SUPPLIER FRACTIONATOR NRA GMP- common standard Audits

39. HTP/PSM/QSD: 58thECBS, 08 Oct 07 39 | Use of local plasma for contract fractionation to improve supply of plasma products in developing countries  Is an opportunity to have access to plasma derivatives  Will have a high positive impact on public health  Compliance with GMP in the production of plasma for fractionation is a key issue for successful Plasma Contract Fractionation  Enforcement & implementation of GMP in blood/plasma establishments is a must for mutual recognition of plasma quality standards  Expertise of local MRA and of local plasma suppliers is needed

40. HTP/PSM/QSD: 58thECBS, 08 Oct 07 40 | Application of GMP is a highly productive area for improvement of safety GMPs for blood collection establishments –Structuring the national blood programme –Quality and safety of plasma for fractionation –Plasma Contract Fractionation activities

41. HTP/PSM/QSD: 58thECBS, 08 Oct 07 41 | Regional Office for the Americas (AMRO): 35 countries WHO GMP Workshops North America Regional GMP Workshop

42. HTP/PSM/QSD: 58thECBS, 08 Oct 07 42 | The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. © WHO 2004. All rights reserved Quality Assurance Systems for Blood Products in Asian Countries Harmonization of Regulations: Workshop, Bangkok 31 Oct-2 Nov 2004 WHO West Pacific and South Asia Region Workshop: India, Indonesia, Japan, Korea, Malaysia, Thailand, China WPROSEARO

43. HTP/PSM/QSD: 58thECBS, 08 Oct 07 43 | The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. © WHO 2004. All rights reserved East Mediterranean Regional Office: 21 countries Workshop Cairo, January 2005 (13 countries equivalent to 62 % of total EMRO Region) EMR Regulatory Network

44. HTP/PSM/QSD: 58thECBS, 08 Oct 07 44 | International Conference of Drug Regulatory Authorities International Conference of Drug Regulatory Authorities (ICDRA) Recommendations, Seoul 2006  Regulation of Blood and Blood-Derived Products: Global Challenges »Update legal provisions to strengthen blood products regulation »Facilitate GMP enforcement in blood and plasma establishments »Support cooperative network for leading regulatory agencies »Promote creation of regional networks of national authorities involved in the regulation of blood and blood products »Strengthen development of WHO international reference materials for validation control of blood screening tests »Encourage development of risk-based regulatory strategies

45. HTP/PSM/QSD: 58thECBS, 08 Oct 07 45 | www.who.int/bloodproducts www.who.int/biologicals www.who.int/medicines Web site addresses

46. HTP/PSM/QSD: 58thECBS, 08 Oct 07 46 | National/Regional Reg. Authorities Other Standard setting Organizations (e.g.BIPM; ISO) Experts Global representation Industry: Manufacturers Associations Intnal Scientific Societies (e.g. ISTH, ISBT, IFCC) Research & Public Health Institutions WHO ECBS Expert Advisory Panels WHO Working Groups WHO CC for Biological Standards WHO Consultations

47. HTP/PSM/QSD: 58thECBS, 08 Oct 07 47 | TSE Major Categories of Infectivity (authoritative information on the assignment of TSE infectivity in human and animal tissues) http://www.who.int/bloodproducts/TSE Intended to assist regulatory authorities and manufacturers in conducting risk assessment studies and selecting measures to reduce the risk of transmitting TSE through medicinal products Proposed update based on new scientific information emerged (CWD has been included for the first time) has been compiled by an Expert Advisory Group cordinated by Dr P. Brown (Baden, Austria)

48. HTP/PSM/QSD: 58thECBS, 08 Oct 07 48 | Addressing infectious risks The battle against infections and the struggle for blood safety are closely interrelated !