Quality Assurance and Safety of Blood Products & related Biologicals

1. Quality Assurance and Safety of Blood Products & related Biologicals Dr Ana Padilla Blood Products & related Biologicals Quality and Safety: Medicines Essential Medicines and Pharmaceutical Policies Department Health Systems and Services Cluster World Health Organization

2. 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 • In vitro diagnostic devices • Biological therapeutics (*) Expert Committee for Biological Standardization (annual meetings)

3. Definition of Biologicals (WHO) • Biological sources • Crude, semi purified extracts or purified fractions • of microbial, animal or human tissues Produced by biological processes Traditional/ Recombinant DNA/ Other biological technologies Biological assay - Complex molecular structure- Cannot be characterized by physicochemical criteria alone

4. Blood Products & related Biologicals Animal-derived immunoglobulins Anti-rabies Anti-venoms Anti-tetanus toxin Anti-diphteria toxin Anti-botulism toxin 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 Other biological productsAnticoagulant & fibrinolysis biological therapeutic products • In vitro biological diagnostic devices (IVDs): Priority: Support of international regulations

5. ECBS: Quality Assurance and Safety of Blood Products and related biologicals 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) (*)ExpertCommitteeonBiologicalStandardization (*) WHO Collaborating Centres for Biological Standardization

6. WHO Essential Medicines List (I) • Animal derived blood products • Snake anti-venom immunoglobulins • Anti-rabies imunoglobulins

7. PRODUCTION 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

8. The Meeting urged WHO to: Improve availability of antisera bybuilding 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

9. WHO Consultative Meeting (January 2007) • Deaths or disability resulting from snakebite envenomings could be avoided if • a) sufficient supply of antivenom immunoglobulins of controlled and assessed quality ensured, • b) logistics and distribution policies improved • c) education on clinical use and management of the disease provided • Shortage of antivenoms: Global strategy/action coordinated by WHO

10. 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 231 medically important snake species. Need to disseminate information on distribution of these 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. 10 WHO Snake Antivenoms Website |January 5, 2020

11. Medically Important Snakes EURO: 6 Species (Cat 1: 1) SEARO/WPRO: 80 Species (Cat 1: 39) AMRO: 74 Species (Cat 1: 33) MULTI: 12 Species (Cat 1: 8) AFRO/EMRO: 59 Species (Cat 1: 31) 11 WHO Snake Antivenoms Website |January 5, 2020

12. 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 website to distribute accurate data that can be used to plan improvements to existing supply and distribution.

13. Distribution Maps 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)

14. Antivenoms: Data sources An antivenoms database was created using data verified by individual manufacturers, providing: Manufacturer data (address and contacts) Product data (venoms used for immunization, label claims of species coverage) Production registration/licensing data sought from 62 NRA’s in AFRO, EMRO, SEARO & WPRO Available literature on preclinical/clinical efficacy and clinical safety reviewed Decisions based on NRA compliance & literature 14

15. Product recommendations There are few products for which we have evidence of registration with relevant NRA’s and good quality, published evidence of acceptable safety and efficacy. Several manufacturers would not provide data on the species used to provide immunizing venoms (i.e.: location of origin or supplier data) Products without evidence of registration by an appropriate NRA were excluded. Products for which no positive preclinicalor clinical data available were also excluded.

16. Antivenoms: Subsaharan Africa

17. Antivenoms: EMRO 17

18. Literature

19. Literature

20. 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.

21. Guiding selection of reference venoms Annex of the Guidelines provides listings, based on available clinical evidence of the highest priority species. Combined with distribution data assembled for the website project this provides information needed for experts to further prioritize essential venoms for use in antivenom production. Regional reference venoms are essential as: Sources of standardized immunogens for raising antivenoms; Reference materials for standardized preclinical assessment by both manufacturers and NRA’s. Creates a framework for uniform comparison.

22. WHO global concerted action: Implementation needs To develop regional reference venoms of clinical relevance and strengthen the technical capacity in regulatory agencies to assess the preclinical efficacy of antivenoms and development of appropriate reporting systems To establish local burden of snakebite envenomings so that market needs can be identified in a consistent way To develop distribution policies in support to epidemiology data collection procedures and clinical management training 2nd Stakeholders meeting: February 2010

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

24. Blood as Source of Life-Saving Medicines Blood for transfusion Whole blood collected into containers, anticoagulant to prevent clotting, cold chain Blood components, obtained from whole blood by separation (centrifuge or apheresis): Red blood cells: Oxygen transport Platelets: Hemostasis (preventing bleeding) Plasma: clotting factors, immunoglobulins etc. Cryoprecipitate Plasma derivatives Plasma "fractionation“, further purification of plasma proteins, e.g. Clotting factors, e.g. Factor VIII for treatment of hemophilia A Immunoglobulins, e.g. proteins administered by IM and IV routes to bind e.g. pathogens or toxins Albumin, involved in the regulation of body fluids, used for resuscitation Blood-derived medicinal products for the treatment of haemophilia and immune diseases are included in the WHO Model List of Essential Medicines

25. WHO List of Essential Medicines • 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

26. The ‘Achilles’ project: A WHO initiative to assure safety and availability of blood products in developing countries

27. The "Achilles" ProjectRational (I) • Plasma derivatives often unavailable in developing countries • The global need 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

28. The "Achilles" Project Rational (II) • Considering that plasma for fractionation available in industrialized countries meets 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 with fractionators even if abroad

29. Specific issues in developing countries • Availability and affordability of products • Wastage of plasma • Risk of transfusion-transmitted diseases • Poor regulation of blood and blood products • Lack of reporting systems

30. Wastage of blood plasma A significant volumen of plasma collected in developing countries is discarded because of: • Lack of appropriate technology • Lack of regulation: unmet quality criteria for fractionation • Lack of GMP implementation in blood establishments • Need to strengthen experience on production, control & regulation of plasma for fractionation

31. The “Achilles” project Main Goals To increase the availability of essential plasma derived products for developing countries by supporting their implementation of national validated quality and safety standards for plasma for fractionation: • Raising quality standards for production activities in blood establishments • Providing a framework to make use of, otherwise destroyed plasma, for the fractionation of plasma derivatives • Using expertise and experience from developed countries The project includes elements of quality, safety and economical benefits

32. 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

33. 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 Good Manufacturing Practices

34. 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

35. 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

36. 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 • Biological reference materials: quality control of blood products and of blood safety related IVDs • Practical workshops supporting implementation • Regional networks: regulatory authorities and BE • Coordination of international expertise: ECBS, BRN, WHOCC….. • Expertise from other quality assurance programs in WHO • Support from WHO Regional Offices and Country Offices

37. The “Achilles” projectAction Plan • Development of comprehensive GMP guidelines to support training and inspection activities: WHO GMP Guidelines for Blood Establishments are being developed (high priority) • Development of country Work Plans aiming to upgrade quality assurance systems and regulatory expertise (demonstration project)

38. The “Achilles” project: Expected Outcomes • Use of local plasma to improve supply of blood derived medicinal products • Sustainable and affordable blood plasma derived essential medicines • Increased quality and safety of all blood products in blood establishments • Optimal use and benefit from donated blood and plasma • Independent regulatory systems for blood products established • Potential application of QA and GMP principles to other medical disciplines • Substantial contribution to public health programs

39. WHO Biological Reference Preparations Global Measurement Standards

40. WHO Biological Reference PreparationsGlobal measurement standards • 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)

41. In vitro diagnostic devices (IVDs)*Medical devices used in vitro for the examination of human specimens • 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

42. ECBS: HIV (IVD Technologies)

43. Distribution of HIV Subtypes and CRFs by 2005

44. ECBS: Hepatitis Viruses (IVD Technologies) Current IS both for HBsAg and HBV DNA are genotype A2: 1% of HBV infections worldwide

45. HBV genotypes

46. WHO Biological Reference Preparations Hemostasis and Thrombosis (Diagnosis & Therapy)

47. ECBS: Hemostasis and Thrombosis 6th International Standard Factor VIII/vWF, plasma (IU) Defines the IU for five analytes in plasma Established 2009 8th International Standard Factor VIII:C concentrate (IU) Suitable both for clotting and chromogenic methods Established 2009

48. ECBS: Hemostasis and Thrombosis 4th International Standard Thromboplastin, human, recombinant, plain • International Sensitivity Index value assigned Established 2009 6th International Standard Unfractionated Heparin (IU) • Established 2009

49. Coordination of standards setting activities • WHO CC plans of work in the development of IVD IRPs • Updates on emerging/re-emerging pathogens • New test strategies & emerging technologies • WHO Collaborative studies • WHO disease control programmes (infectious diseases): Overview of global epidemiological data • Collaboration of Regional Offices: participating laboratories and identification of candidate materials • Coordination with other standard setting organizations and international organizations (ISBT, ISTH, EDQM, EC,….)

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