1. 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

2. 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

3. 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

4. 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

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

6. 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

7. 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

8. 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

9. 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

10. 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 on "Availability, quality and safety of blood products" (adopted May 2010)

11. 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

12. 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

14. 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:

15. 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:

16. 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

17. 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.

18. 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

19. 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

20. WHO Biological Reference Preparations Blood Products and related Biologicals
60% of total IS or Ref Panels established between
WHO Catalogue of Biological Reference Preparations:

21. 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): 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)

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

23. 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

24. WHO IVD Standardization 2nd WHO CC* Meeting: 17-19 February 2009
World Health Organization
WHO IVD Standardization 2nd WHO CC* Meeting: 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

25. 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

26. 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.

27. World Health Organization
Documents
World Health Organization
1 January 2019

28. 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

29. 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

30. 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

31. 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

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

33. 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

34. 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

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

36. 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)

37. WHO Database

38. 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.

39. World Health Organization
Web site addresses
1 January 2019