WHO Norms and Standards: Blood Products & related Biologicals Dr Ana Padilla Blood Products & related Biologicals Quality and Safety: Medicines Essential Medicines and Pharmaceutical Policies Department Health Services and Systems Cluster World Health Organization

Biological Standardization (*) Constitutional responsibility World Health Organization Biological Standardization (*) Constitutional responsibility 28 March 2017 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 In vitro biological diagnostic devices Other biological products (*) Expert Committee for Biological Standardization

- implemented for more than 50 years - mandated by Member States International Biological Standardization by WHO - implemented for more than 50 years - mandated by Member States WHO is expected to be both a driving force and a key reference point on biological standardization issues

Implementation of strategic objective for quality of biologicals (WHO/HQ)

Blood Products & related Biologicals World Health Organization 28 March 2017 Blood Products & related Biologicals 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 Animal- derived sera Anti-rabies Anti-venoms (snake bites) Anti-tetanus toxins Anti-diphteria toxins Anti-botulism toxins Other related products Anticoagulant & fibrinolysis biological therapeutic products In vitro biological diagnostic devices Priority: IVDs applied to the control of blood and blood products safety

Quality Assurance and Safety: Blood Products and related biologicals World Health Organization 28 March 2017 Quality Assurance and Safety: Blood Products and related biologicals WHO standard setting functions*: to establish WHO Biological Reference Preparations to develop evidence based WHO Guidelines on Quality Assurance and Safety of specific products to support implementation of WHO Norms and Standards: (strengthen technical/regulatory capacity of MRAs & NCLs) to support operational strategies to improve access to quality products (*) Expert Committee on Biological Standardization

World Health Organization Blood Products & related Biologicals Strategic Plan (approved at 57th ECBS, 2006) 28 March 2017 WHO Essential Medicines List: Animal derived sera (IgS): Snake antivenom and anti-rabies immunoglobulins Human blood derived products: GMP production of plasma for fractionation WHO Biological Reference Standards for regulation and control of in vitro (biological) diagnostic tests Standardization of traditional and new technologies

WHO Essential Medicines List (I) World Health Organization WHO Essential Medicines List (I) 28 March 2017 Animal derived blood products Snake anti-venom immunoglobulins Anti-rabies imunoglobulins

1 patient treated = 1 life saved or 1 permanent disability prevented The Meeting urged WHO to: Improve availability of antisera by building 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

Antivenom sera are essential to prevent long-term disability & death World Health Organization 28 March 2017 Antivenom sera are essential to prevent long-term disability & death n Bites by Bothrops species – fer de lance and lancehead in central & South America Courtesy Prof D Warrell, Nuffield Department of Clinical Medicine, Oxford

Component 1: Global Quality Assurance Guidance World Health Organization Component 1: Global Quality Assurance Guidance 28 March 2017 Development of WHO Guidelines on the Production, Control and Regulation of animal plasma-derived immunoglobulins (encompassing e.g. control of starting materials and large-scale implementation and control of manufacturing steps) Elaborated in parallel to, and as a result of, WHO Regional and Bi-Regional Workshops

Countries represented Jakarta, May 2008 World Health Organization Countries represented Jakarta, May 2008 28 March 2017 SEARO WPRO Bangladesh India Indonesia Nepal Thailand Australia Cambodia Japan Malaysia Papua New Guinea China Philippines Vietnam

Countries represented Addis Ababa, July 2008 World Health Organization 28 March 2017 Countries represented Addis Ababa, July 2008 AFRO EMRO Benin, Cameroon, Côte d'Ivoire, Democratic Republic of Congo Ghana, Guinea, Kenya Mali, Niger, Nigeria South Africa, Senegal Tanzania, Uganda Zimbabwe Egypt Morocco Pakistan Saudi Arabia Tunisia

World Health Organization 28 March 2017 Fragility of production systems in developing world The document has been discussed in the field: Bi-Regional Workshops in Aisa and Africa: - Jakarta, May 2008 - Addis Ababa, June 2008 Global experts consultation Adoption requested to the 59th ECBS (2008)

Antivenom Is the Only Specific Antidote to Snake Venom Most important decision in the management of a victim is whether or not to give antivenom From Dr Ariaratne, Sri Lanka

Clinical Assessment: Need of Efficacy Test (reported by Dr Thapa, Nepal) 3 envenomed victims arrived in snakebite treatment center within half an hour but died during medication (Reported from Bharatpur Hospital during recent research) In Bhratpur Hospital, of the two cases, one with 98 ASV vials died but next with 94 vials survived (Pandey et al. 2007)

Major issues about antivenom preparations Enormous doses, uncertain benefit Reaction rates are very high Takes time to dissolve, froth Changing the tender for AVS supply by the authorities Very poor regulatory control No definite way reporting adverse reaction

World Health Organization Literature World Health Organization 28 March 2017

World Health Organization Literature World Health Organization 28 March 2017

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

3 major instruments to inform about potency and efficacy of Antivenoms Pre-requisite: Preclinical assessment of all antivenoms, using local venoms or venoms likely to have close similarities Clinical assessement: safety & efficacy Safety (reaction rates) Dose finding studies Observational prospective studies Randomised control trials (when possible) Post-marketting surveillance

a proposal to strenghten national capacities Capacity building for snake venoms production and antivenoms preclinical evaluation: a proposal to strenghten national capacities

Venoms production: Basic problems Lack of adequate venom production: Venoms used for production need to have appropriate quality and to be representative of the snake populations. Lack of endogenous capacity to assess the neutralizing potency of antivenoms at the preclinical level.

Consequences… The antivenoms produced using low quality, or non- representative venoms are deficient in terms of neutralizing potency and extent of coverage. The capacity to prepare high-quality venoms is a key component in any global strategy aimed at increasing the production and use of effective and safe antivenoms.

Consequences… The lack of endogenous capacity in many countries to assess the preclinical efficacy of antivenoms results in the introduction of antivenoms which are not effective to neutralize the venoms of a particular country or region.

Component 2: national/regional capacity building on venoms production To develop a programme to assist countries in the development of local snake venom production for antivenom manufacture, and in the development of local capacity for the preclinical assessment of antivenom efficacy using these venoms.

Components of the WHO proposal (Proposed WHO Consultation, 2009) Assistance to identify in-country organisations to host snake venom production and preclinical testing of antivenoms; Mobilize international experts through regional workshops and via specific contracts for direct assistance in countries; Regional support for countries through funding of contracted, independent quality assurance services by recognised non- commercial laboratories; Training exchanges (i.e.: venom QA laboratory facilities, laboratories for preclinical testing of antivenoms); Assistance in leveraging funding support for snake venom production and preclinical assessment of antivenoms projects

Expected outcomes A worldwide support in the availability of high-quality snake venom preparations for antivenom production and for preclinical assessment and quality control. Strenghtening of the endogenous national capacities to participate in antivenom production and control.

WHO Essential Medicines List (II) World Health Organization WHO Essential Medicines List (II) 28 March 2017 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

Blood Plasma: a valuable human resource Medicinal products derived from human donations of blood and plasma play a critical role in health care

World Health Organization 28 March 2017 The ‘Achilles’ project: a WHO initiative to assure safety and availability of blood products in developing countries

What is the global situation ? Background Blood-derived products are often unavailable in developing countries: patients suffering from hereditary bleeding disorders or congenital and acquired immune diseases do not have access to treatment The global need for blood plasma products exceeds by far available supply No realistic possibility of generating surplus products in developed countries to meet developing countries needs and, even when available, would be unaffordable.

What is the global situation ? Background Plasma for fractionation available in industrialized countries meet their needs "Developing countries will only be able to create an affordable and sustainable supply of blood derived products by using blood plasma collected in their own blood establishments and from their own populations" Plasma fractionation can be performed through plasma contract fractionation programs

What is the global situation ? What are the problems? Wastage of blood plasma in developing countries: (does not currently meet the standards required for product manufacture) Risk of transfusion-transmitted diseases and cross-border threats: (increasing internationally mobility of populations highlights need to strengthen quality assurance systems globally) Need to introduce a "plasma production culture" (GMP culture in blood establishments) Poor regulation of blood and blood products: (need for update of legal provisions and strengthen MRAs technical capacity)

WHO “Achilles” project: Expected Outcomes The “Achilles” project: Project Goals WHO “Achilles” project: Expected Outcomes Increase availability of safe blood derived products by: Supporting implementation of national validated quality and safety standards for blood establishments Raising the manufacturing activities of blood establishments to international standards Using reliable regulatory systems able to "prequalify" blood establishments: adherence to WHO standards for the manufacture of plasma for fractionation and to WHO GMP for blood establishments Using expertise and experience gained from developed countries

World Health Organization Good Manufacturing Practices (GMP): an essential tool for improvement of safety 28 March 2017 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

TRACEABILITY FROM DONOR TO PATIENT Blood/Plasma donation Plasma for Fractionation Blood Components Plasma-Derived Medicinal Product Patients FRACTIONATION VIRAL INACTIVATION DONATION INFORMATION COMPONENTS PREPARATION TREATMENT Good Manufacturing Practices

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

WHO “Achilles” project Action Plan (demonstration project) Development of comprehensive GMP guidelines to support training and inspection activities: GMP Guidelines for Blood Establishments (ECBS 2009) Development of Work Plans: upgrading quality assurance systems, regulatory expertise and national regulations initially in 2 pilot countries (ECBS 2009) Work Plans imply development of specific and measurable indicators to monitor success and progress with the pilot countries (e.g. regulations updated; BE GMP compliance; quality assurance officers trained; increase in plasma volume for fractionation…) (*) Demonstration project: First steps action plan 2009

WHO “Achilles” project: Expected Outcomes Optimal use and benefit from donated blood plasma Use of local plasma to improve supply of blood derived medicinal products Increase quality and safety of all blood products in blood establishments Apply internationallly agreed standards for blood establishments Sustainable and affordable blood plasma derived essential medicines Potential application of QA and GMP principles to other medical disciplines Substantial contribution to public health programs

WHO Biological Reference Preparations Global Measurement Standards

WHO Biological Reference Preparations Global measurement standards World Health Organization 28 March 2017 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 of blood products and high risk IVDs To accelerate transfer technology

WHO Biological Reference Preparations Strategic Plan World Health Organization WHO Biological Reference Preparations Strategic Plan 28 March 2017 Impact of migrations: health safety/security Standardization of in vitro biological diagnostic technologies Convergence of regulatory policies Track and monitor blood safety "The battle against infections and the struggle for blood safety are closely interrelated!"

WHO Biological Reference Preparations Blood Products and related Biologicals WHO Catalogue of Biological Reference Preparations: www.who.int/bloodproducts

World Health Organization 28 March 2017 Web site addresses

Priority Projects for Biological Reference Preparations WHO Collaborating Centres' Meeting (29-30 January 2007) WHO Recommendations: Annex 2, WHO TRS, No 932, 2005 ECBS 2009 2008 2007 HCV RNA (3rd)* Anti-Syphilitic (2nd)* Anti-HBs (2nd)* Anti-HBc* HIV-1 gt1 (2nd)** HIV-2 RNA* HBV gt2** Anti-HCV** Anti-T. cruzi** Consultation Feasibility studies Collaborative study *IS **Panel 1the anti-HIV antibody panel will also be extended; 2two panels for HBsAg- and NAT-tests

WHO IVD Standardization Priorities 2009 World Health Organization WHO IVD Standardization Priorities 2009 World Health Organization 28 March 2017 28 March 2017 WHO Collaborating Centres Meeting in 2009 Identify and coordinate needs/priorities within WHO Disease oriented Departments IHR-core laboratory capacity Anti-Trypanosma cruzi (Chagas) reference panel HBV genotype panel (DNA and HBsAg) H. Scheiblauer 47

Migration Flows from Latin America Chagas disease

Technical capacity of National Regulatory Authorities Blood Products Regulations

World Health Organization International Conference of Drug Regulatory Authorities (ICDRA): Recommendations, Bern 2008 28 March 2017 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

Essential Element of a public health system Quality Assurance & Safety: Blood Products and related Biologicals. Programme Overview WHO standard setting functions for Biological Products (WHO Constitution ……….) Global Norms and Standards: Quality Assurance regulatory and biological standardization functions Expert Committee on Biological Standardization WHO Essential Medicines List WHO Biological Standards for blood safety-related diagnostic tests Essential Element of a public health system

World Health Organization 28 March 2017 WHO Working Groups National/Regional Reg. Authorities WHO Consultations Experts Partners & Collaborations WHO CC for Biological Standards & Quality Assurance WHO ECBS Expert Advisory Panels Industry: Manufacturers Associations Research & Public Health Institutions Other Standard setting Organizations (e.g.BIPM, EDQM, ISO) Intnal Scientific Societies (e.g. ISTH, ISBT, IFCC)

World Health Organization 28 March 2017 Web site addresses www.who.int/bloodproducts www.who.int/biologicals www.who.int/medicines