Quality Assurance and Safety of
Blood Products and related Biologicals
Dr Ana Padilla
Blood Products & related Biologicals
Quality Assurance and Safety: Medicines
Essential Medicines and Pharmaceutical Policies
Health Systems and Services
World Health Organization
OUTLINE

General background

Need for blood regulation: WHA Resolution 63.12

WHO Biological Reference Preparations

WHO snake antivenoms website
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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
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Blood Products & related Biologicals
Human blood derived products
Animal-derived immunoglobulins

Blood components (red cells, platelets, plasma)

Anti-rabies

Blood Coagulation Factors

Anti-venoms

Polyvalent Immunoglobulins (IV, IM)

Anti-tetanus toxin

Specific Immunoglobulins

Anti-diphteria toxin

Anti-botulism toxin




Anti-hepatitis B
Anti-rabies
Anti-tetanus
Anti-rhesus (anti-D)
Other biological products
Anticoagulant & fibrinolysis biological
therapeutic products

Albumin

In vitro biological diagnostic devices (IVDs):
Priority: Support of international regulations
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WHA63.12: "Blood Products" definition
"Any therapeutic substances derived
from human blood, including whole
blood, labile blood components and
plasma-derived
medicinal products"
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Blood Products & related Biologicals
WHO standard setting functions*:

Develop/establish/provide WHO Biological Reference Preparations

Develop/adopt/provide evidence based WHO Guidelines on Quality
Assurance and Control of specific products or procedures

Support enforcement and implementation of WHO Norms and
Standards:strengthen technical/regulatory capacity of NRAs & NCLs

Support operational strategies to improve access to quality products
(*) Consistent with the WHO mandate through the Expert Committee on Biological Standardization
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Blood Products and related Biologicals
Target Audiencies

National/Regional Regulatory Authorities

National/Regional Control and National/Regional Reference Laboratories

Blood Establishments and Plasma Fractionators

Manufacturers of animal derived blood products

Manufacturers of in vitro diagnostic tests

Public Health Departments/Public Healt Officers/Ministries of Health

Medical Professionals, Health Workers

Procurement agencies and NGO’s
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The Need for Blood Regulation:
the WHA Resolution 63.12
Dr Ana Padilla
Blood Products & related Biologicals
Quality Assurance and Safety: Medicines
Health Systems and Services
World Health Organization
The Need for Blood Regulation
 The inherent risks of blood and the complexity of providing
adequate, timely and equitable access to safe blood
products require an organized national or regional blood
system.
 Within that system, a competent blood products regulatory
authority assures that appropriate standards are met for
production of blood products and monitoring of blood
safety.
(*) Blood Products are defined as:
therapeutic substances derived from human blood, including whole blood,
labile blood components and plasma-derived medicinal products (WHA Resolution 63.12 on
availability, quality and safety of blood products).
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The Need for Blood Regulation:
WHAR63.12, May 2010
 WHA resolution 63.12 recognized that:
– “stringent regulatory control is vital in assuring the quality and
safety of blood products…” and
– urged Member States to “update their national regulations … in
order to ensure that regulatory control in the area of quality and
safety of blood products across the entire transfusion chain
meets internationally recognized standards.”
 Strengthening regulatory systems for blood products and building
technical capacity of national and regional blood regulatory
authorities is recognized as a fundamental need to assure global
availability of safe blood products
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TRACEABILITY
FROM DONOR TO PATIENT
Blood/Plasma
donation
Blood
Components
Plasma for
Fractionation
DONATION
INFORMATION
• donor population
• donor selection
• donor protection
• collection process
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COMPONENTS
PREPARATION, e.g.
• production process
• testing
• process control
• release
• storage & transport
Patients
Plasma-Derived
Medicinal Product
FRACTIONATION, e.g.
• production process
• viral inactivation
• QC & release
• storage & transport
The Need for Blood Regulation:
WHO ECBS/WHOBRN/WHOCC

Consistent with WHA Resolution 63.12, WHO adopts:
 WHO
assessment criteria for national blood regulatory
systems (2011)
 WHO Guidelines on GMP for blood establishments
(2010)
 WHO Guidelines on Production, control & regulation of
plasma for fractionation (2007)
 Establishment of Biological reference materials for the
control of blood products and blood safety IVDs (ongoing)
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The Need for Blood Regulation:
Assessment criteria for national blood regulatory
systems (ECBS 2011)*
1. To identify essential control functions that should be
undertaken by an effective/functional NRA to assure the
quality, safety and efficacy of blood and blood products
as well as IVDs and associated drugs
2. To establish standard indicators for these functions in
order to allow NRAs to assess their performance in the
regulation of blood and blood products
*Developed by the WHO BRN and global consultation process
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13
An example
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46th ECSPP Meeting, Oct. 2011
62nd meeting ECBS, Oct. 2011
The Need for Blood Regulation
ICDRA 2010: Blood and Blood Products Workshop
 WHO should focus on capacity building for
implementation of Quality Assurance Systems for blood
and blood products through development of independent
regulatory authorities
– Primary attention should be placed on strengthening
regional regulatory networks
– Education and training are needed to make best use
of the GMP Guidelines and Assessment Criteria for
national blood regulatory systems
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TRACEABILITY
FROM DONOR TO PATIENT
Blood/Plasma
donation
Blood
Components
Plasma for
Fractionation
DONATION
INFORMATION
• donor population
• donor selection
• donor protection
• collection process
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COMPONENTS
PREPARATION, e.g.
• production process
• testing
• process control
• release
• storage & transport
Patients
Plasma-Derived
Medicinal Product
FRACTIONATION, e.g.
• production process
• viral inactivation
• QC & release
• storage & transport
Plasma Contract Fractionation Programs
(Need for GMP implementation)
GMP- common principles
Quality Assurance Program
PLASMA
SUPPLIER
FRACTIONATOR
across countries
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GMP
Licensing
Nat.Reg.
Authority
Licensing
GMP
Nat.Reg.
Authority
WHA 63.12: Availability, quality and safety
of blood products
2. REQUESTS the Director-General:
2. (4) to ensure sustainable development and provision of
WHO International Biological Reference Preparations
for use in the quality control and regulation of blood
products and related in vitro diagnostic devices;
(5) to improve access by developing countries to WHO
International Biological Reference Preparations and to
the scientific information obtained in their validation in
order to assure appropriate use of these preparations
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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 regulatory convergence of
international regulations (e.g. blood
products; IVDs – infectious agents)
*Established by the Expert Committee on Biological Standardization
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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
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HIV (IVD Technologies)
WHO International Standard or Reference Panel
Test
Current
Serology
HIV-1 p24 antigen, 1st IS (IU)
NAT
Test developers,
Anti-HIV, Ref Panel (no unitage)
manufacturers,
(HIV-1 subtypes: A, B, C, CRF_01, O; HIV-2)
regulators, blood
establishments,
HIV-1 RNA 2nd IS (IU)
fractionators,
HIV-1 RNA Genotype 1st Ref Panel (no unitage) reference laboratories,
diagnostic
(A,B,C,D, AE, F, G, AG-GH, groups N & O)
laboratories
HIV-2 RNA 1st IS (IU)
1st
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Users
Hepatitis Viruses (IVD Technologies)
Test
Serology
NAT
WHO International Standard or Reference Panel
Current
Users
Hepatitis B surface antigen, 2nd IS (IU) - adw2
Anti-Hepatitis B virus core antibodies, 1st IS (IU)
Anti-Hepatitis B immunoglobulin, human, 2nd IS (IU)
HBsAg genotype reference panel (15 members)
Hepatitis A virus RNA 1st IS (IU)
Hepatitis B virus DNA 2nd IS (IU) – genotype A2
Hepatitis B virus DNA Genotype 1st Reference Panel
Genotypes A, B, C, D, E, F, G (no unitage) Hepatitis C virus RNA 2nd IS (IU)
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Test developers,
manufacturers,
regulators,
blood
establishments,
fractionators,
reference
laboratories,
diagnostic
laboratories
Therapeutic Products: Blood coagulation factors,
Inhibitors, Anticoagulants and Fibrinolytic agents
–
–
–
–
–
–
–
–
–
–
–
Antithrombin concentrate
Blood Coagulation factors concentrates (FVIII, FIX, FII&X)
Fibrinogen concentrate
Albumin
Plasmin and plasminogen activator inhibitor 1
Protein C, plasma and concentrate
Protein S
Streptokinase
Tissue Plasminogen Activator
Unfractionated and LMW Heparin
Urokinase (HMW)
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Human Immunoglobulins
–
–
–
–
–
–
–
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Anti-D (Rh0)
Hepatitis A
Hepatitis B
Rabies
Rubella
Tetanus
Varicella Zoster
WHO Biological Reference Preparations
A tool for comparison of results worldwide
Regulatory
Authorities
WHO
IS/IRP
2ndary
Ref. Material
Manufacturers
Product Users
(e.g. blood establishments,
clinical labs etc.)
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WHO Biological Reference Standards*
Development & Establishment
1. Selection of candidate materials
7. Characterization of final product
2. Characterization of candidate
materials
8. Stability studies (incl. statistical
analysis)
3. Dilution of materials
(dilution matrix)
9. WHO international collaborative
study (incl. statistical analyses)
4. Inactivation (if needed)
5. Freeze-drying
6. Feasibility studies
10. WHOCC & Working Groups
11. Report to ECBS and decision
12. Storage and distribution
*Recommendations for the preparation, characterization and establishment
of international and other biological reference standards (revised 2004); Annex 2, WHO TRS, No 932, 2005.
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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,….)
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WHO Biological Reference Preparations
Blood Products and related Biologicals
Number of preparations
120
100
60% of total IS or Ref Panels
established between 1999-2009
80
60
40
20
0
In vitro Diagnostic Tests
Therapeutic products
Blood Safety and
General Hematology
Coagul.Factors/
Thrombolytic Agents
Immunological
Reagents
Total
55
13
10
78
0
25
11
36
WHO Catalogue of Biological Reference Preparations: www.who.int/bloodproducts
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Documents
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WHA 63.12: Availability, quality and safety of
blood products. What is next?
WHO is requested to report back in May 2014 to
the WHA (through the Executive Board) on
actions taken by Member States and WHO to
implement this resolution
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Web site addresses
http://www.who.int/bloodproducts
http://www.who.int/bloodproducts/snakeantivenoms
http://www.who.int/bloodproducts/catalogue
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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
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Analytical
Sensitivity
Standards required by CTS
EU IVD Directive
WHO standards available
2 IU/ml
1st WHO IS, 1992 (1000IU/ml)
10 IU (detection limit)
2nd WHO IS, 2008 (100IU/ml)
0.130 IU (WHO HBsAg 2nd IS)
(new CTS published, 2009)
2nd WHO International Standard for HBsAg:
33 IU/ampoule
WHO dilutional reference panel
Immunoassays
HIV1p24 Ag
Anti-HBS
HBsAg
WHO 1st IS, 2008 (50IU/ml)
Anti-HBc
Anti-HIV subtype panel
WHO Ref. Panel: 6 different subtypes
NAT assays (qualitative and quantitative)
HIV
HIV-1 RNA 2nd IS (2005): 5.56 log10/ml
HCV
HBV
Analytical sensitivity (IU/ml)
defined on WHO standards
HIV genotype panel
HCV RNA 3rd IS (2007): 5.19 log10/ml
HBV DNA 2nd IS (2006): 6.0 log10/ml
10 different genotypes
WHO International Standards for Blood Grouping Reagents (minimum potency reagents)
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