The ‘Achilles’ project:

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. OUTLINE OUTLINE • WHO Essential Medicines List • Plasma for Fractionation • The "Achilles" Project: • Rationale and scope • Project goals • WHO action plan • Expected outcomes

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. Human Blood Plasma Human 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

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. Availability of blood plasma products 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

8. Plasma Safety in highly regulated countries Plasma safety and availability: 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 • No documented virus transmission by plasma products licensed within this regulatory framework > 10 years • Blood plasma products needs covered

9. Plasma « unused » for fractionation Plasma «unused» for fractionation:countries with poor or limited regulations • 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 • 5.8 million liters not recovered in developing countries (Burnouf, 2007)

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

11. Conclusion: Achilles Project: Rationale • 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

12. Good Manufacturing Practices (GMP): an essential tool for improvement of safety 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

13. TRACEABILITYFROM DONOR TO PATIENT Blood/Plasma donation Blood Components Patients Plasma-Derived Medicinal Product Plasma for Fractionation FRACTIONATION VIRAL INACTIVATION DONATION INFORMATION COMPONENTS PREPARATION TREATMENT GMP LOOK BACK SYSTEM

14. WHO and Plasma for Fractionation Plasma for Fractionation*a biological product inherent variability • 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 * WHO Technical Report Series 941, Annex 4: 56th WHO Expert Committee on Biological Standardization, 24-28 October 2005.

15. Assuring Blood/Plasma Safety:“Layers of Safety” 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

16. Plasma Contract Fractionation Programs(Need for GMP implementation) Nat.Reg. Authority Nat.Reg. Authority PLASMA SUPPLIER FRACTIONATOR GMP- common principles GMP Licensing Quality Assurance Program GMP Licensing across countries

17. Pathogen Threats 24 Aug 07 Migration Flows from Latin America Chagas disease • Over 2.0 billion airline passengers are traveling each year. • The battle against infections and the struggle for blood safety are closely interrelated ! • Infections are a global problem necessitating global collaboration!

18. Pathogen Threats Pathogen Threats • Impact of migrations: health safety/security • Standardization of in vitro biological diagnostic technologies • Convergence of regulatory policies • Track and monitor blood safety • Need 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

19. WHO “Achilles” project: Expected Outcomes WHO “Achilles” project: Project Goals • 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.

20. WHO “Achilles” projectAction Plan (demonstration project) WHO “Achilles” projectAction 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)

21. WHO “Achilles” project: Expected Outcomes WHO “Achilles” project: Expected Outcomes • 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

22. International Conference of Drug Regulatory Authorities (ICDRA): Recommendations, Bern 2008 Emerging Diseases: regulating blood products(ICDRA: Recommendations, Bern 08) • 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

23. Relevant Web site addresses Web site addresses www.who.int/bloodproducts www.who.int/biologicals www.who.int/medicines