Transcript WHO Norms and Standards: Blood Products & related Biologicals Dr Ana Padilla Blood Products & related Biologicals Quality and Safety: Medicines Essential Medicines and Pharmaceutical.

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
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 biological diagnostic devices
Other biological products
(*) Expert Committee for Biological Standardization
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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
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Implementation of strategic objective
for quality of biologicals (WHO/HQ)
Two units but a functionally integrated approach to biological standardisation
Biological standardisation
Covers vaccines, blood products, other biologicals
and in vitro diagnostics
QSS/IVB/FCH
(Vaccines, cytokines, growth factors,endocrines)
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QSM/EMP/HSS
(Blood products, in vitro diagnostics)
Blood Products & related Biologicals
Human blood derived products
Animal- derived sera

Blood components (red cells, platelets, plasma)

Anti-rabies

Blood Coagulation Factors

Anti-venoms (snake bites)

Polyvalent Immunoglobulins (IV, IM)

Anti-tetanus toxins

Specific Immunoglobulins

Anti-diphteria toxins

Anti-botulism toxins






Anti-hepatitis B
Anti-rabies
Anti-tetanus
Anti-rhesus (anti-D)
Albumin
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
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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
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Blood Products & related Biologicals
Strategic Plan (approved at 57th ECBS, 2006)

WHO Essential Medicines List:
o Animal derived sera (IgS):
Snake antivenom and anti-rabies immunoglobulins
o Human blood derived products:
GMP production of plasma for fractionation

WHO Biological Reference Standards for regulation and
control of in vitro (biological) diagnostic tests
o Standardization of traditional and new technologies
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WHO Essential Medicines List (I)

Animal derived blood products
–
–
Snake anti-venom immunoglobulins
Anti-rabies imunoglobulins
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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
Antivenom sera are essential to prevent
long-term disability & death
n
Courtesy Prof D Warrell, Nuffield Department of Clinical Medicine, Oxford
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Component 1: Global Quality Assurance Guidance

Development of WHO Guidelines on the Production, Control
and Regulation of animal plasma-derived immunoglobulins
(encompassing e.g. control of starting materials and largescale implementation and control of manufacturing steps)

Elaborated in parallel to, and as a result of, WHO Regional
and Bi-Regional Workshops
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Countries represented
Jakarta, May 2008
SEARO
Bangladesh
India
Indonesia
Nepal
Thailand
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WPRO
Australia
Cambodia
Japan
Malaysia
Papua New Guinea
China
Philippines
Vietnam
Countries represented
Addis Ababa, July 2008
AFRO
Benin, Cameroon, Côte d'Ivoire,
Democratic Republic of Congo
Ghana, Guinea, Kenya
Mali, Niger, Nigeria
South Africa, Senegal
Tanzania, Uganda
Zimbabwe
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EMRO
Egypt
Morocco
Pakistan
Saudi Arabia
Tunisia
Fragility of production systems in developing world
The document has been
discussed in the field:
FINAL REVISED UPDATED VERSION
WHO/BS/08.2088
Bi-Regional Workshops in
Aisa and Africa:
- Jakarta, May 2008
- Addis Ababa, June 2008
Global experts consultation
ENGLISH ONLY
EXPERT COMMITTEE ON BIOLOGICAL
STANDARDIZATION (ECBS)
Geneva, 13 to 17 October 2008
Proposed WHO Guidelines for the Production,
Control and Regulation of Snake Antivenom
Immunoglobulins
ADOPTED BY ECBS on 17 October 2008
Adoption requested to the
59th ECBS (2008)
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NOTE:
This document has been prepared for the purpose of inviting
comments on the proposals contained therein, and for the preparation of the materials
to be considered by the Expert Committee on Biological Standardization. Comments
proposing modifications for this text MUST be received by 1 October 2008 and
should be addressed to the attention of Dr Ana Padilla, World Health Organization, at
the following e-mail address [email protected], with copy to [email protected],
or by fax at the number +41 22 791 4889.
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
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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.
2007)
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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
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Literature
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Literature
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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
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
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Capacity building for snake venoms
production and antivenoms
preclinical evaluation:
a proposal to strenghten national capacities
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.
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Consequences…

The antivenoms produced using low quality, or nonrepresentative 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.
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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.
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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.
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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 noncommercial 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
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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.
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WHO Essential Medicines List (II)
 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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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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The ‘Achilles’ project:
a WHO initiative to assure safety and
availability of blood products in
developing countries
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.
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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
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What
is the
situation ?
What
are global
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)
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WHO“Achilles”
“Achilles” project:
project:
The
Expected
ProjectOutcomes
Goals

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
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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
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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
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
WHO “Achilles” project (*)
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
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WHO “Achilles”
“Achilles” project:
WHO
project:
Expected Outcomes
Outcomes
Expected
 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
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WHO Biological Reference Preparations
Global Measurement Standards
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
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WHO Biological Reference Preparations
Strategic Plan

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!"
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WHO Biological Reference Preparations
Blood Products and related Biologicals
120
Number of
preparations
100
80
60
40
20
0
Blood Safety and
Blood Coagul. and
General
Thrombotic Agents
Hematology
In vitro Diagnostic Tests
Therapeutic products
Immunological
Reagents
Total
52
15
10
75
0
20
7
27
Medical field application
WHO Catalogue of Biological Reference Preparations: www.who.int/bloodproducts
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Web site addresses
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Priority Projects for Biological Reference Preparations
WHO Collaborating Centres' Meeting (29-30 January 2007)
WHO Recommendations: Annex 2, WHO TRS, No 932, 2005
2007
2008
2009
ECBS
HCV RNA (3rd)*
2007
Anti-Syphilitic (2nd)*
2007
Anti-HBs
(2nd)*
2008
Anti-HBc*
2008
HIV-1 gt1 (2nd)**
2009
HIV-2 RNA*
2009
HBV gt2**
2009
Anti-HCV**
2009
Anti-T. cruzi**
2009
1the
Consultation
Feasibility studies
Collaborative study
*IS
**Panel
anti-HIV antibody panel will also be extended; 2two panels for HBsAg- and NAT-tests
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WHO IVD Standardization
Priorities 2009

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
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Migration Flows from Latin America
Chagas disease
Spain 2005
Canada 2001
216,975
Canada 2001
216,975
>1 million
Legal 640,000
Europe 1985-1992
>1 million
Legal 640,000
Europe 1985-1992
Spain 2005
250,000
250,000
Japan 1990
150,000
Japan 1994
1990
250,000
150,000
Japan 1994
250,000
USA
Up 1989:2,459,000
USA
90s: legal 7,036,000
Up 1989:2,459,000
Up 2005: legal 7,486,643
90s: legal 7,036,000
Undocumented
Up 2005:2000:
legal 5,6
7,486,643
million
2006: 8,9 million
Undocumented
2000: 5,6 million
2006: 8,9 million
Australia 1990
80,000
Australia 2005/2006
1990
65,707
80,000
Australia 2005/2006
65,707
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Technical capacity of National
Regulatory Authorities
Blood Products Regulations
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
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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
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WHO Working Groups
WHO CC for
Biological Standards
& Quality Assurance
Research
& Public Health
Institutions
National/Regional
Reg. Authorities
Experts Partners
& Collaborations
WHO ECBS
Expert Advisory Panels
Other Standard
setting Organizations
(e.g.BIPM, EDQM, ISO)
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WHO Consultations
Industry:
Manufacturers
Associations
Intnal Scientific
Societies
(e.g. ISTH, ISBT, IFCC)
Web site addresses
www.who.int/bloodproducts
www.who.int/biologicals
www.who.int/medicines
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