Quality Assurance and Safety of Blood Products & Related Biologicals An update Dr Ana Padilla Blood Products & related Biologicals Quality Assurance and Safety: Medicines Essential Medicines and Pharmaceutical Policies Health Systems and Services World Health Organization

Blood Products & related Biologicals Mission (Strategic Plan) World Health Organization 1 January 2019 Blood Products & related Biologicals Mission (Strategic Plan) A WHO normative programme: 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. An Essential Medicines Programme: To support the achievement of the health related MDGs by assisting governments and organizations to ensure equitable access to effective medicines of assured quality and their rational use by prescribers and consumers

Quality Assurance and Safety: Blood Products and related biologicals World Health Organization 1 January 2019 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 Control of specific products or procedures to support implementation of WHO Norms and Standards: (strengthen technical/regulatory capacity of NRAs & NCLs) to support operational strategies to improve access to quality products (*) Expert Committee on Biological Standardization

Blood Products & related Biologicals World Health Organization 1 January 2019 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 immunoglobulins Anti-rabies Anti-venoms Anti-tetanus toxin Anti-diphteria toxin Anti-botulism toxin Other biological products Anticoagulant & fibrinolysis biological therapeutic products In vitro biological diagnostic devices (IVDs): Priority: Support of international regulations

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

WHO List of Essential Medicines World Health Organization WHO List of Essential Medicines 1 January 2019 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

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

World Health Organization Good Manufacturing Practices (GMP)*: an essential tool for improvement of safety 1 January 2019 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 *WHO Guidelines: Final document adopted by ECBS and ECSPP 2010

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

World Health Organization 1 January 2019 The ‘Achilles’ project*: A WHO initiative to assure safety and availability of blood products in developing countries * WHA Resolution 63.12 on "Availability, quality and safety of blood products" (adopted May 2010)

The “Achilles” project What do we have? Materials and mechanisms on which training and technical capacity can be provided to BE and regulatory authorities: WHO Guidelines: Production, control and regulation of plasma for fractionation; Viral Inactivation and Removal procedures; GMP for BE Biological reference materials: quality control of blood products and of blood safety related in vitro biological diagnostic devices (IVDs) Good Manufacturing Practices for Blood Establishments Assessment tool for blood regulatory systems (Blood Regulators Network) Coordination of international expertise: ECBS, BRN, WHOCC….. Expertise from other quality assurance programs in WHO

WHO “Achilles” project Action Plan (demonstration project) The “Achilles” project Work Plans(*) Work Plans imply development of specific and measurable indicators to monitor success and progress with the pilot countries. Examples are: Blood products regulations updated; BE GMP compliance; Decrease of GMP failures Quality assurance officers trained; Increase in plasma volume accepted for fractionation; Reduction of infectious disease markers in blood donors; Economic benefit: Availability of safe essential blood products (*) Demonstration project

WHO Blood Regulators Network (BRN) Membership: Leading regulatory authorities with responsibility for "regulation of all aspects of blood and blood products and with capacity to address emerging public health challenges" AFSSAPS, France; CBER/FDA, USA; Health Canada, Canada; Paul Ehrlich Institute, Germany; SwissMedic, Switzerland; Therapeutic Goods Administration; Australia Secretariat: WHO (Blood Products and related Biologicals, QSM/EMP) Scope of Activities: The Network addresses regulatory issues of global concern related to “blood, blood products and associated drugs and medical devices, including in vitro diagnostics (IVDs)” Terms of reference: http://www.who.int/bloodproducts/brn/BRN_TermsofReference.pdf

Objectives of the BRN Propose solutions to specific issues, especially emerging public health challenges (e.g. international communicable disease threats) Foster development of international consensus on regulatory approaches Promote science based convergence of policies Provide a model for developing regulatory bodies Routinely report conclusions and recommendations to the Expert Committee on Biological Standardization Terms of reference: http://www.who.int/bloodproducts/brn/BRN_TermsofReference.pdf

Expected Activities of the BRN Periodic and ad hoc meetings to discuss timely issues of common concern (face to face meetings and teleconferences): Emerging threats in relation to blood safety and blood supply New detection methods and pathogen inactivation technologies Regulatory standards (quality of products) Make public statements on issues based on consensus of the members ( BRN statement on older vs. younger stored Red Blood Cells Position Paper on Collection and Use of Convalescent Plasma as an Element in Pandemic Influenza Planning Collaborate on specific projects and tasks: Assessment criteria for blood regulatory systems

Assessment Criteria for National Blood Regulatory Systems WHO secretariat considers the development of assessment tools for blood regulatory systems will serve to evaluate gaps or areas for improvement both in national blood programs and regulatory groups of both developed and developing countries.

Blood Products & related Biologicals World Health Organization 1 January 2019 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 immunoglobulins Anti-rabies Anti-venoms Anti-tetanus toxin Anti-diphteria toxin Anti-botulism toxin Other biological products Anticoagulant & fibrinolysis biological therapeutic products In vitro biological diagnostic devices (IVDs): Priority: Support of international regulations

World Health Organization 1 January 2019 WHO Biological Reference Preparations* Global measurement standards (IS) Tool for comparison of biological measurement results worldwide Facilitate transfer of laboratory science into worldwide clinical practice Underpin apropriate clinical dosage Support harmonization of international regulations (e.g. blood products; blood safety related IVDs) *Established by the Expert Committee on Biological Standardization

WHO Biological Reference Preparations Blood Products and related Biologicals 60% of total IS or Ref Panels established between 1999-2009 WHO Catalogue of Biological Reference Preparations: www.who.int/bloodproducts

Standards required by CTS EU IVD Directive WHO standards available  Analytical Sensitivity Standards required by CTS EU IVD Directive WHO standards available Immunoassays   HIV1p24 Ag 2 IU/ml 1st WHO IS, 1992 (1000IU/ml) Anti-HBS 10 IU (detection limit) 2nd WHO IS, 2008 (100IU/ml) HBsAg 0.5 ng/ml (French or UK-standard) 0.130 IU (WHO HBsAg 2nd IS) (new CTS published, 2009) 2nd WHO International Standard for HBsAg: 33 IU/ampoule WHO dilutional reference panel Anti-HBc None WHO 1st IS, 2008 (50IU/ml) Anti-HIV subtype panel WHO Ref. Panel: 6 different subtypes NAT assays (qualitative and quantitative) HIV Analytical sensitivity (IU/ml) defined on WHO standards HIV-1 RNA 2nd IS (2005): 5.56 log10/ml HCV HCV RNA 3rd IS (2007): 5.19 log10/ml HBV HBV DNA 2nd IS (2006): 6.0 log10/ml HIV genotype panel 10 different genotypes WHO International Standards for Blood Grouping Reagents (minimum potency reagents)

WHO Biological Reference Preparations A tool for comparison of results worldwide Regulatory Authorities WHO IS/IRP 2ndary Ref. Material Manufacturers Product Users

World Health Organization In vitro diagnostic devices (IVDs)* Medical devices used in vitro for the examination of human specimens 1 January 2019 IVDs for infectious markers Viruses, bacteria, parasites, unconventional agents IVDs for Blood/plasma screening (blood safety) Confirmation of infection Diagnosis and monitoring Tests methods Serological assays (e. g. ELISA) Nucleic acid amplification techniques (NAT) *Priority: pathogens with impact on blood safety and international regulations

WHO IVD Standardization 2nd WHO CC* Meeting: 17-19 February 2009 World Health Organization WHO IVD Standardization 2nd WHO CC* Meeting: 17-19 February 2009 World Health Organization 1 January 2019 1 January 2019 Follow-up from the WHO CC Meeting in 2007 Coordinate needs/priorities with WHO programs Discuss priority projects: WHO Biological Reference Standards to optimally support global public health Coordinate proposals to the ECBS for endorsement and establishment and update strategic plan established in 2007 Strengthen collaboration (WHO CC-network model) *WHO CCs for Biological Standards & Standardization: CBER/FDA, USA; NIBSC, UK; PEI, Germany 24

World Health Organization WHO Biological Reference Standards Priority: blood safety-related IVDs 1 January 2019 Standardization of in vitro biological diagnostic technologies for the detection of microbial agents with an impact on the regulation and control of blood and blood products safety

WHO Biological Reference Standards* Development & Establishment World Health Organization WHO Biological Reference Standards* Development & Establishment 1 January 2019 Characterization of final product Stability studies (incl. statistical analysis) WHO international collaborative study (incl. statistical analyses) WHOCC & Working Groups Report to ECBS and decision Storage and distribution Selection of candidate materials Characterization of candidate materials Dilution of materials (dilution matrix) Inactivation (if needed) Freeze-drying Feasibility studies *Recommendations for the preparation, characterization and establishment of international and other biological reference standards (revised 2004); Annex 2, WHO TRS, No 932, 2005.

World Health Organization Documents World Health Organization 1 January 2019

Collaborating Centres: Paul-Ehrlich-Institute in Germany The PEI was redesignated as a WHO Collaborating Centre for Quality Assurance of Blood Products and in vitro Diagnostic Devices in July 2009 The PEI is also an active partner of WHO in other areas, e.g. Vaccines Advanced Therapy Medicinal Products

PEI New Areas of Responsibility since 2007 Advanced Therapy Medicinal Products haematopoietic stem cells tissue- engineered products tissue preparations (classical) gene therapy somatic cell therapy cells and vectors - therapy: cardio-vascular disease infectious disease cancer monogeneic inherited disease preventive vaccine pancreatic islet cells, chondrocytes xenotransplantation tissue repair, substitution: autologous chondrocyte transplantation (ACT), manipulated stem cells musculo-skeletal tissues, amnion, heart valves, skin, cornea, blood vessels

Blood Products & related Biologicals World Health Organization 1 January 2019 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 immunoglobulins Anti-rabies Anti-venoms Anti-tetanus toxin Anti-diphteria toxin Anti-botulism toxin Other biological products Anticoagulant & fibrinolysis biological therapeutic products In vitro biological diagnostic devices (IVDs): Priority: Support of international regulations

WHO Essential Medicines List World Health Organization WHO Essential Medicines List 1 January 2019 Animal derived blood products Snake anti-venom immunoglobulins Anti-rabies immunoglobulins

World Health Organization Poor quality and poor regulatory control World Health Organization 1 January 2019

A - Collection of venoms WHO GUIDELINES ON PRODUCTION, CONTROL AND REGULATION OF ANTIVENOM IMMUNOGLOBULINS: Technology in the public domain A - Collection of venoms B – Horse Immunization Protocols C – Starting material of animal derived sera D – Fractionation & Purification process

A functional starting point Guidelines for the Production, Control and Regulation of Snake Antivenom Immunoglobulins approved by ECBS in 2008 Major component was an Annex containing a listing of medically important snake species. Need to disseminate information on distribution of venomous species and to provide basic data about the antivenoms that are currently appropriate. These are fundamental steps towards creating a platform for improving access to these products. 34 WHO Snake Antivenoms Website | January 1, 2019

http://www.who.int/bloodproducts/ snake_antivenoms/snakeantiveno mguide/en/index.html

Red or orange question marks (?) WHO Database: Medically Important Snakes Distribution maps, pictures & antivenoms Red or orange question marks (?) (Indicates expected presence not yet confirmed due to lack of exploration Allocation to CATEGORY 1 shown in red (Indicates common, widespread species that causes numerous snake bites with high morbidity, disability or mortality) Allocation to CATEGORY 2 shown in orange (Indicates highly venomous and capable of causing morbidity, disability or mortality, but exact country data lacking, or less frequently implicated in these countries)

WHO Database www.who.int/bloodproducts/snakeantivenoms

WHO web site: Target Audiences Central information source for data on the current availability of antivenoms for specific species. Aimed at a wide audience, that includes: National Regulatory Agencies Ministries of Health Antivenom Manufacturers Medical Professionals, Health Workers Procurement Personnel in Industry and NGO’s Objective is to use the web site to distribute accurate data that can be used to plan improvements to existing supply and distribution.

World Health Organization Web site addresses 1 January 2019 http://www.who.int/bloodproducts http://www.who.int/bloodproducts/snakeantivenoms http://www.who.int/bloodproducts/catalogue