Transcript Quality Assurance and Safety of Blood Products & Related Biologicals An update Dr Ana Padilla Blood Products & related Biologicals Quality Assurance and Safety: Medicines Essential.

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
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
2 | EMP TBS, November 2010
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
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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 Plasma: a valuable human resource
Medicinal products derived from
human donations of blood and plasma
play a critical role in health care
5 | HSS/EMP/QSM: 14 June 2010
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
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Good
Manufacturing Practices
| EMP TBS, November 2010
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
*WHO Guidelines: Final document adopted by ECBS and ECSPP 2010
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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
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)

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
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The
“Achilles”
project
WHO
“Achilles” project
Action Plan
(demonstration
Work
Plans(*) project)

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
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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: http://www.who.int/bloodproducts/brn/BRN_TermsofReference.pdf
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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:
http://www.who.int/bloodproducts/brn/BRN_TermsofReference.pdf
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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
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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.
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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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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
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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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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)
0.5 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
None
WHO 1st IS, 2008 (50IU/ml)
Immunoassays
HIV1p24 Ag
Anti-HBS
HBsAg
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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WHO Biological Reference Preparations
A tool for comparison of results worldwide
Regulatory
Authorities
WHO
IS/IRP
2ndary
Ref. Material
Manufacturers
Product Users
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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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WHO IVD Standardization
2nd WHO CC* Meeting: 17-19 February 2009

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
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WHO Biological Reference Standards
Priority: blood safety-related IVDs
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
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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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Documents
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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
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PEI New Areas of Responsibility since 2007
Advanced Therapy
Medicinal Products
gene therapy
cells and vectors
- therapy:
cardio-vascular disease
infectious disease
cancer
monogeneic inherited
disease
- preventive vaccine
somatic
cell therapy
pancreatic islet cells,
chondrocytes
xenotransplantation
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tissueengineered
products
tissue repair,
substitution:
autologous
chondrocyte
transplantation (ACT),
manipulated stem
cells
tissue
preparations
(classical)
musculo-skeletal
tissues, amnion,
heart valves,
skin,
cornea,
blood vessels
haematopoietic
stem cells
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
30 | EMP TBS, November 2010
WHO Essential Medicines List

Animal derived blood products
–
–
Snake anti-venom immunoglobulins
Anti-rabies immunoglobulins
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Poor quality and poor regulatory control
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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
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.
TBS,Snake
November
Antivenoms
2010 Website
34
34| EMPWHO
| November 7, 2015
 http://www.who.int/bloodproducts/
snake_antivenoms/snakeantiveno
mguide/en/index.html
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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)
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www.who.int/bloodproducts/snakeantivenoms
WHO Database
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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
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