Download Guidelines - World Health Organization

Assurance qualité des produits sanguins
et autres produits biologiques
Dr Ana Padilla
Assurance Qualité des Médicaments
Médicaments Essentiels et Produits de Santé
Organization Mondiale de la Santé
Web site addresses
http://www.who.int/bloodproducts
http://www.who.int/bloodproducts/snakeantivenoms
http://www.who.int/bloodproducts/catalogue
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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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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
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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WHO Working Groups
WHO Consultations
National/Regional
Reg. Authorities
WHO
Blood Establishments
Collaborating
Representation
Centres
Research
& Public Health
Institutions
WHO ECBS
Blood Products and
IVD Track
Other Standard
setting Organizations
(e.g.EDQM; ISO)
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Industry:
Manufacturers
Associations
Intnal Scientific
Societies
(e.g. ISBT, ISTH, IFCC)
Produits Sanguins d'origine Humain
Human Blood Derived Products
Blood Plasma: a valuable human resource
Medicinal products derived from
human donations of blood and plasma
play a critical role in health care
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Blood Products: Life-Saving Medicines
WHA Resolution 63.12
 Blood and blood components
– 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 , FVIII source
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 Plasma derivatives
Plasma for "fractionation“, further
purification of plasma proteins, e.g.
• Blood Coagulation Factors,
e.g. Factor VIII for treatment of
hemophilia A
• Specific Immunoglobulins,
e.g. anti-hepatitis B, anti-rabies,
anti-tetanus, anti-D
• IM and IV normal IgG
• Albumin,
involved in the regulation of body
fluids, used for resuscitation
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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TRACEABILITY
FROM DONOR TO PATIENT
Blood/Plasma
donation
DONATION
INFORMATION
Blood
Components
Patients
Plasma for
Fractionation
Plasma-Derived
Medicinal Product
COMPONENTS
PREPARATION
FRACTIONATION
VIRAL
INACTIVATION
Good Manufacturing Practices
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TREATMENT
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
*Proposed WHO Guidelines: Final document for submission at ECBS 2010
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Plasma Contract Fractionation Programs
(Need for GMP implementation)
GMP- common principles
Quality Assurance Program
PLASMA
SUPPLIER
GMP
Licensing
Nat.Reg.
Authority
Licensing
GMP
Nat.Reg.
Authority
FRACTIONATOR
across countries
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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)
Overall Goals (WHA Resolution 63.12)
The “Achilles” project
 To raise quality standards in blood establishments (BE)
 To reduce risk of transmission of infectious diseases
 Effective regulatory systems for blood products worldwide
 To make safe blood products available to patients
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
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
 Coordination of international expertise: ECBS, BRN, WHOCC…..
 Expertise from other quality assurance programs in WHO
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WHO Guidelines and Recommendations
http://www.who.int/bloodproducts/en/
WHO Guidelines on good manufacturing
practices for blood establishments
WHO Recommendations for the production, control
and regulation of human plasma for fractionation
WHO Guidelines on viral inactivation and removal
procedures intended to assure the viral safety
of human blood plasma products
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Préparations de Référence
Internationale (Étalons Internationals)
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
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WHO Biological Reference Standards*
Global measurement standards
 Tool for comparison of biological
measurement results worldwide
 Facilitate transfer of laboratory
science into worldwide clinical practice
 Underpin apropriate clinical dosage
 Facilitate convergence of international
regulations (e.g. blood products; blood
safety related IVDs)
*Established by the Expert Committee on Biological Standardization
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WHO Biological Reference Preparations
A tool for comparison of results worldwide
Regulatory
Authorities
WHO
IS/IRP
2ndary
Ref. Material
Manufacturers
and Blood
Establishments
Product Users
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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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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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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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ECBS: HIV (IVD Technologies)
http://www.who.int/bloodproducts/en/
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
ECBS: Hepatitis Viruses (IVD Technologies)
http://www.who.int/bloodproducts/en/
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 (IU)
HBsAg genotype reference panel
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)
Test developers,
manufacturers,
regulators,
blood
establishments,
fractionators,
reference
laboratories,
diagnostic
laboratories
Current IS both for HBsAg and HBV DNA are genotype A2: 1% of HBV infections worldwide
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How do we work?
– ECBS Blood Products and related Biologicals Track
– WHO Blood Regulators Network:
scientific/regulatory
– WHO Collaborating Centres:
Priority setting in the development of IBRPs
– WHO disease control programmes (infectious diseases):
Overview of global epidemiological data
– WHO Working groups for specific topics: research & public
health institutions; manufacturers associations;
– Coordination with other standard setting organizations and
professional organizations: ISBT, ISTH, IFCC, EDQM, EC
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Immunoglobulines d'origine animal
Produit thérapeutique d'origine animal
WHO Essential Medicines List

Animal derived blood products
–
Snake anti-venom immunoglobulins
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SNAKE ANTIVENOM IMMUNOGLOBULINS
VERY POOR REGULATORY CONTROL: Technology in the public domain
A - Collection of venoms
B – Horse Immunization
Protocols
C – Starting material of
animal derived sera
D – Fractionation &
Purification process
WHO Guidelines and Recommendations
ANIMAL DERIVED BLOOD PRODUCTS
 WHO Guidelines on production, control and regulation of
snake antivenom immunoglobulins
 WHO Database: clinically important venomous snakes
species and its worldwide geographical distribution together
with antivenoms for treatment of snakebite envenomings
 WHO website hosting both the Guidelines and database
(maps, pictures, products, manufacturers)
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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)
www.who.int/bloodproducts/snakeantivenoms
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WHO Database: Medically Important Snakes
Distribution maps, pictures & antivenoms
www.who.int/bloodproducts/snakeantivenoms
WHO Guidelines
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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.
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Web site addresses
http://www.who.int/bloodproducts
http://www.who.int/bloodproducts/snakeantivenoms
http://www.who.int/bloodproducts/catalogue
E-mail addresses: [email protected]; [email protected]
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