1. 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

2. 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

3. - 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

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

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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 Addis Ababa, June 2008
Global experts consultation
Adoption requested to the 59th ECBS (2008)

15. 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

16. 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 )

17. 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

18. World Health Organization
Literature
World Health Organization
28 March 2017

19. World Health Organization
Literature
World Health Organization
28 March 2017

20. 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

21. 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

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

23. 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.

24. 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.

25. 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.

26. 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.

27. 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

28. 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.

29. 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

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

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

32. 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.

33. 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

34. 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)

35. 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

36. 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

37. 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

38. 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

39. 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

40. 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

41. WHO Biological Reference Preparations Global Measurement Standards

42. 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

43. 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!"

44. WHO Biological Reference Preparations Blood Products and related Biologicals
WHO Catalogue of Biological Reference Preparations:

45. World Health Organization
28 March 2017
Web site addresses

46. 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

47. 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

48. Migration Flows from Latin America Chagas disease

49. Technical capacity of National Regulatory Authorities
Blood Products Regulations

50. 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

51. 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

52. 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)

53. World Health Organization
28 March 2017
Web site addresses