1. The ‘Achilles’ project: a WHO initiative to support quality in the manufacturing of plasma for fractionation Dr Ana Padilla, Blood Products & related Biologicals Essential Medicines and Pharmaceutical Policies Department Health Services and Systems Cluster World Health Organization

2. WHO Norms and Standards: Blood Products & related Biologicals WHO Expert Committee on Biological Standardization WHO Blood Regulators Network

3. HSS/EMP/BPB: Teheran, Oct 08 3 |3 | OUTLINE  WHO Essential Medicines List  Plasma for Fractionation  The "Achilles" Project: Rationale and scope Project goals WHO action plan Expected outcomes OUTLINE

4. HSS/EMP/BPB: Teheran, Oct 08 4 |4 | Blood Plasma: a valuable human resource Medicinal products derived from human donations of blood and plasma play a critical role in health care

5. HSS/EMP/BPB: Teheran, Oct 08 5 |5 | Human Blood Plasma  Complex mixture of (glyco)proteins  Therapeutic product (plasma for transfusion = fresh frozen plasma)  Pooled plasma = starting material for fractionation to medicinal products:  Albumin  Blood Coagulation Factors (e.g. F VIII, FIX)  Immunoglobulins (IV, IM)  Serine proteases  Fibrin sealants Human Plasma

6. HSS/EMP/BPB: Teheran, Oct 08 6 |6 | WHO Essential Medicines List  Human derived blood plasma products – Plasma for Fractionation Blood Coagulation Factors: FVIII, PCC Human Normal Immunoglobulin (IV and IM) Anti-D immunoglobulin Anti-tetanus immunoglobulin Blood-derived medicinal products for the treatment of haemophilia and immune diseases are included in the WHO Model List of Essential Medicines

7. HSS/EMP/BPB: Teheran, Oct 08 7 |7 | What is the global situation ?  The global need for blood plasma products exceeds by far available supply  Plasma for fractionation available in industrialized countries to cover their needs  Alternatives to plasma products are not sufficiently available, or even not existent  hemophilia: recombinant products are expensive; gene therapy still experimental  normal immunoglobulin should cover the wide range of antigens (e.g. pathogens) prevailing in a population;  specific immunoglobulins can be sourced only in immunized populations Availability of blood plasma products

8. HSS/EMP/BPB: Teheran, Oct 08 8 |8 | Plasma Safety in highly regulated countries  Commitment of health politicians, strong regulation, reinforcement and continuous surveillance by authorities  Commitment of blood services and plasma fractionators  GMP implementation in manufacture of all blood plasma derived products èNo documented virus transmission by plasma products licensed within this regulatory framework > 10 years èBlood plasma products needs covered Plasma safety and availability: highly regulated countries

9. HSS/EMP/BPB: Teheran, Oct 08 9 |9 | Plasma « unused » for fractionation  Quality criteria for plasma for fractionation not met  GMP has not been a natural background for blood transfusion  Sensitivity of blood transfusion services to independent regulatory control  Need to strengthen experience & regulation of plasma and plasma products  Lack of government awareness: rationale for regulation  Lack of technical capacity of regulatory authorities Plasma «unused» for fractionation: countries with poor or limited regulations 5.8 million liters not recovered in developing countries (Burnouf, 2007)

10. HSS/EMP/BPB: Teheran, Oct 08 10 | Achilles Project: Rationale Blood plasma products in the WHO Essential Medicines List but no access to these products by developing countries because of: 1.Poor quality and safety of plasma (destroyed) 2.Need for introduction of blood products regulations 3.The Achilles project considers upgrading of plasma quality as the driving force for implementation of a safe blood program. 4.The project includes elements of quality, safety and economical benefits. 5.May attract more efficiently the attention of the authorities Achilles Project: Rationale

11. HSS/EMP/BPB: Teheran, Oct 08 11 | Conclusion:  Use of local plasma to improve supply of plasma products in developing countries, a legitimate option  Compliance with GMP, a key issue for successful PCF  Build-up technical expertise of local NRA and plasma supplier is a need  Common GMP standards, a basis for mutual recognition of quality standards and inspections results between NRA's  Independent regulatory systems for blood products regulation need to be established or strengthened in developing countries  Adoption of a Regional/International GMP standard facilitates regional collaboration between NRAs and implementation of PCF Achilles Project: Rationale

12. HSS/EMP/BPB: Teheran, Oct 08 12 | GMP implementation in Blood/Plasma Establishments: a key element to Quality and safety of plasma for fractionation Plasma contract fractionation programs Supporting access to blood plasma products Good Manufacturing Practices (GMP): an essential tool for improvement of safety

13. HSS/EMP/BPB: Teheran, Oct 08 13 | TRACEABILITY FROM DONOR TO PATIENT COMPONENTS PREPARATION DONATION INFORMATION FRACTIONATION VIRAL INACTIVATION TREATMENT GMP LOOK BACK SYSTEM Blood/Plasma donation Plasma for Fractionation Blood Components Plasma-Derived Medicinal Product Patients

14. HSS/EMP/BPB: Teheran, Oct 08 14 | WHO and Plasma for Fractionation  Quality of blood/ plasma is dependent on collection, preparation, testing, storage and transport  Quality of plasma for fractionation influences the range, quantity, quality, and safety of plasma derivatives WHO Recommendations for the Production, Control and Regulation of Human Plasma for Fractionation (adopted in November 2005) www.who.int/medicines www.who.int/bloodproducts Plasma for Fractionation* a biological product inherent variability * WHO Technical Report Series 941, Annex 4: 56th WHO Expert Committee on Biological Standardization, 24-28 October 2005.

15. HSS/EMP/BPB: Teheran, Oct 08 15 | Assuring Blood/Plasma Safety : “Layers of Safety” 1. Donor selection criteria (epidemiological data) 2.Deferral procedures: national registries to avoid use of collections from previously unsuitable donors 3.Laboratory testing for infectious disease markers: selection of kits and validation 4.Implementation of GMPs in blood/plasma collection establishments Assuring Blood/Plasma Safety : “Layers of Safety”

16. HSS/EMP/BPB: Teheran, Oct 08 16 | Plasma Contract Fractionation Programs (Need for GMP implementation) GMP Licensing GMP Licensing Quality Assurance Program across countries PLASMA SUPPLIER FRACTIONATOR Nat.Reg. Authority Nat.Reg. Authority GMP- common principles

17. HSS/EMP/BPB: Teheran, Oct 08 17 | Pathogen Threats 24 Aug 07 Over 2.0 billion airline passengers are traveling each year. S The battle against infections and the struggle for blood safety are closely interrelated ! S Infections are a global problem necessitating global collaboration! Migration Flows from Latin America Chagas disease

18. HSS/EMP/BPB: Teheran, Oct 08 18 | Pathogen Threats  Impact of migrations: health safety/security  Standardization of in vitro biological diagnostic technologies  Convergence of regulatory policies  Track and monitor blood safety èN eed to strengthen blood products regulations worldwide to ensure availability of safe blood and blood products in the face of known and emerging threats, including emerging infectious diseases Pathogen Threats

19. HSS/EMP/BPB: Teheran, Oct 08 19 |  Increase availability of safe blood derived products by: Supporting implementation of national validated quality and safety standards for blood establishments Using expertise and experience from developed countries  WHO Guidelines for good manufacturing practices (GMP) in blood establishments are being developed to support implementation. WHO “Achilles” project: Expected Outcomes WHO “Achilles” project: Project Goals

20. HSS/EMP/BPB: Teheran, Oct 08 20 | WHO “Achilles” project Action Plan (demonstration project)  Development of comprehensive GMP guidelines to support training and inspection activities: GMP Guidelines for Blood Establishments (high priority project, ECBS 2009)  Upgrading quality assurance systems and regulatory expertise initially in 2 pilot countries.  Development of specific and measurable health care outcomes to monitor success and progress (e.g. plasma available, reduction of infectious disease markers in blood donors, decrease of GMP failures, economic benefit) WHO “Achilles” project Action Plan (demonstration project)

21. HSS/EMP/BPB: Teheran, Oct 08 21 |  Sustainable and affordable blood plasma derived essential medicines  Optimal use and benefit from donated blood plasma  Increased quality and safety of all blood products in blood establishments  Substantial contribution to public health programs  International agreed standards for blood establishments  Potential application of QA and GMP principles to other medical disciplines  Involvement of developing countries in international BT activities WHO “Achilles” project: Expected Outcomes

22. HSS/EMP/BPB: Teheran, Oct 08 22 | International Conference of Drug Regulatory Authorities International Conference of Drug Regulatory Authorities (ICDRA): Recommendations, Bern 2008  Recognizing the need worldwide for blood products regulation to ensure availability of safe blood and blood products in the face of known and emerging threats, including emerging infectious diseases, WHO should: » Take steps to further develop and strengthen national/regional blood regulatory authorities and to promote cooperation » Provide harmonized "assessment criteria for blood regulatory systems" (BRN): convene a consultation of NRAs to review Draft assessment tool » Prioritize development of Guidelines on GMP for Blood Establishments » Promote introduction of WHO recommended plasma standards by NRAs Emerging Diseases: regulating blood products (ICDRA: Recommendations, Bern 08)

23. HSS/EMP/BPB: Teheran, Oct 08 23 | www.who.int/bloodproducts www.who.int/biologicals www.who.int/medicines Web site addresses Relevant Web site addresses