WHO Norms and Standards:
Blood Products & related Biologicals
Dr Ana Padilla
Blood Products & related Biologicals
WHO/HIS/EMP/RHT
Outline

Blood Products and related Biologicals

Introduction

RWHA63.12: availability, safety and quality of blood products

Blood and Blood Components are Essential Medicines:


The need for national blood regulatory systems
WHO Biological Reference preparations
Blood Products & related Biologicals
Human blood derived products
Animal-derived immunoglobulins

Blood components (red cells, platelets, plasma)

Anti-rabies

Blood Coagulation Factors

Snake 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)
Albumin

Other biological products
Anticoagulant & fibrinolysis biological
therapeutic products
In vitro biological diagnostic devices (IVDs):
Priority: blood safety, public health, support harmonization of international regulations
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Introduction (1)
The overall goal is to promote and enhance the quality, availability,
and safety of blood products and associated in vitro diagnostic
devices (IVDs).
Prevention of the transmission of blood-borne infections and emerging
agents worldwide is paramount.
Specific strategies are considered where needed
Introduction (2)
The blood products and related biologicals programme is providing Member
States with the tools needed
- to meet international validated standards for production and control of
those products
- to promote enforcement and implementation of appropriate production
processes and effective quality assurance regulations
- to support technical capacity building where needed
Introduction (3)
Quality assurance and regulatory tools to achieve the goals:
 WHO Guidelines for the manufacture and control of blood products;
 WHO International biological reference preparations (international standards,
reference panels);
 Regular evaluation of transmission of blood-borne emerging infectious agents with
the collaboration of WHO disease control Departments and the WHO Blood
Regulators Network (BRN) and other specialized expert groups;
 International coordination of standards setting organizations and promotion of the
biological standardization principles;
Blood Products: Life-Saving Medicines
WHA Resolution 63.12
Blood products are defined as
therapeutic substances derived from
human blood, including whole blood,
labile blood components and plasmaderived medicinal products (WHA 63.12,
adopted 2010).
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 derived products
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 regulation of
body fluids
WHO Essential Medicines List
 Human derived blood products
– Blood and Blood components
• Whole blood, red blood cells, platelets, fresh frozen plasma
– Blood Coagulation Factors: FVIII, PCC
– Human Normal Immunoglobulin (IV and IM)
– Anti-D immunoglobulin
– Anti-tetanus immunoglobulin
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TRACEABILITY
FROM DONOR TO PATIENT
Blood
donation
Blood
Components
Plasma for
Fractionation
DONATION
INFORMATION
donor population•
donor selection•
collection process•
10
GMP
BE
|
COMPONENTS
PREPARATION, e.g.
production process•
testing•
process control•
release •
storage & transport•
Patients
Plasma-Derived
Medicinal Product
FRACTIONATION, e.g.
production process •
technology impact •
viral inactivation•
QC & release •
storage & transport•
GMP PP
Blood establishment: production processes
Suitability of plasma depends on meeting
production standards for blood collection
and component manufacturing
Control of
processes
required for
production of all
blood
components in
blood
establishments
Resolution WHA 63.12*
The Need for Blood Regulation
• Regulatory oversight serves to ensure that blood
collectors, plasma derivatives manufacturers and
care providers
– have control of the entire process (donor to patient)
– monitor the safety and quality of products, and
– take appropriate action if adverse events occur
• Regulation assures that blood standards are met
and is needed to assure that unused plasma is
suitable for fractionation but itself depends on
empowerment through a legislative framework
Resolution WHA63.12*
The Need for Blood Regulation – I
• 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.”
*Availability, quality and safety of blood products, May 2010
Resolution WHA63.12*
The Need for Blood Regulation – II
• 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
*Availability, quality and safety of blood products, May 2010
Resolution WHA63.12
Availability, safety and quality of blood products
 Points out the need to support improvements in the
availability, safety and quality of blood products
 In particular, the Resolution draws attention to the large
volumes of human plasma, that have been separated from
whole blood, and currently go to waste
 Yet, the plasma wasted could be used as a starting
material for the manufacture of essential plasma-derived
medicinal products unavailable today for treatment of local
populations
Improving Access to Safe Blood Products
Whole Blood and Blood Components as
Essential Medicines
TRACEABILITY
FROM DONOR TO PATIENT
Blood
donation
Blood
Components
Plasma for
Fractionation
DONATION
INFORMATION
donor population•
donor selection•
collection process•
GMP BE
COMPONENTS
PREPARATION, e.g.
production process•
testing•
process control•
release •
storage & transport•
Patients
Plasma-Derived
Medicinal Product
FRACTIONATION, e.g.
production process •
technology impact •
viral inactivation•
QC & release •
storage & transport•
GMP PP
Blood and Blood Components are Essential Medicines:
Product Characteristics (I)
Under internationally recognized standards, blood/blood components share
fundamental features of medicines:
– Manufacturing processes akin to other medicines, e.g.
• Raw material qualification (i.e. donor selection and testing), in-process
quarantines, quality controls (e.g. temperature monitoring, visual inspection),
product release, expiration dating, traceability, etc.
– Administration only on a doctor’s order or prescription
– Defined medical indications and contra-indications
– Labeling for identity, content and intended use
Additionally, blood/blood components delivered contain recognized medicines
(e.g. anticoagulants, buffers, preservative solutions, etc.)
Blood and Blood Components are Essential Medicines:
Product Characteristics (II)
• Examples of international product standards for the
manufacture of blood components include:
 WHO Technical Report Series, No. 840, 1994, Annex 2
“Requirements for the collection processing and quality
control of blood, blood components and plasma
derivatives”
WHO Catalogue of International Biological Reference
Preparations
Council of Europe, EDQM “Guide to the preparation, use
and quality assurance of blood components – 16th Ed.”
National laws (e.g. Australia, Canada, Germany, Japan,
Switzerland, USA etc.)
Importance of Listing Blood and Blood Components
as Essential Medicines (I)
• Having Blood and BC on WHO’s Model List of Essential
Medicines (EML), would help governments to justify increased
efforts in blood donor recruitment and blood collection, which
would improve medical care in the population.
– If the medicine is deemed “essential,” steps will be taken to
increase awareness, assure availability, and thereby prevent
deaths and disabilities from blood shortages
• Listing of Blood and BC on WHO's EML would be especially
important to address unmet needs for effective treatment of
hemorrhage and anemia in many developing countries
Importance of Listing Blood and Blood Components
as Essential Medicines (II)
In considering listing of Blood and BC as Essential Medicines,
WHO and MS should take notice of the needs:
– To establish and strengthen National Blood Regulatory
Systems through education and technical support to
regulators of medicines and blood operators
– To promote establishment of adequate blood system
infrastructures
– To assist Member States to avoid potential unintended
consequences to existing blood systems
WHO available tools
www.who.int/bloodproducts

The mandate
 WHA 63.12 on availability, quality and safety of blood products

The tools (internationally agreed standards)
 Assessment criteria for national blood regulatory systems
 WHO Guidelines on GMP for blood establishments
 WHO Guidelines on Production, control & regulation plasma for
fractionation
 WHO Guidelines on Viral Inactivation and Removal procedures
 WHO catalogue of biological reference materials: blood products and blood
safety IVDs (on-going development and establishment)

Collaboration with government organizations: national regulatory authorities,
national blood programmes and Inspectorate
 Training experience strengthening implementation of regulatory systems
 Wide international expert networks: ECBS, BRN, WHOCC, others
 Worldwide network of National Regulatory Authorities (ICDRA)
Overview of activities undertaken by
WHO to assess the need to support
local production of quality recovered
plasma by blood establishments in
LMIC* as a means to improve access to
safe blood products
*LMIC: Low and middle income countries
What we have learned (1)
• Significant volumes of plasma are discarded in multiple
countries with no/poor access to PDMP
• Such plasma, when meeting GMP requirements could
be used to treat patients with bleeding disorders and
primary immunodeficiencies if fractionated
• Need for cost-benefit analysis in blood establishments
and opportunities for technology transfer and potential
fractionation of plasma
What we have learned (2)
• Implementation and upgrading of production standards for
recovered plasma in blood establishments can lead to an
upgrade in the overall blood establishment and benefit to
public health
• Public health benefit includes:
– provision of better epidemiology data for the population
– reduction in transmission of infectious diseases by blood
transfusion (e.g., HIV and hepatitis) from red blood cells,
platelets and plasma transfused as blood components
Cost-benefit analysis is essential
What we have learned (3)
• The precise selection of viral test kits should take into
account several scientifically-based aspects including:
– Specificity/sensitivity of tests, including that of local
tests
– Donor characteristics (e.g. first time vs repeat donors)
– Local epidemiological situations (e.g. viral genotypes)
– Evolution of testing technologies
– Understanding the risks and knowing the limitations of
the assays
• Importance of international standards & reference
preparations developed and established by WHO
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
Examples of contract fractionation programmes
• A contract fractionation programme in large countries such as
Brazil and Iran, with government commitment, allows
reduction by about 30-40% in the cost of similar amount of
imported products
• Products made from local plasma may induce lower imported
price, due to competition
• Closer collaboration and coordination between NRA of the
plasma fractionator and NRA of the plasma supplier
(convergence of regulation) is needed
Plasma Contract Fractionation Programs
- Need for GMP implementation in BE GMP- common principles
Quality Assurance Program
PLASMA
SUPPLIER
GMP
Licensing
Nat.Reg.
Authority
Licensing
GMP
Nat.Reg.
Authority
FRACTIONATOR
across countries
WHO Biological Reference Preparations
WHO Biological Reference Materials
The WHO International Biological Reference Preparations (IBRP)
serve as reference sources for biologically defined activity
expressed in an internationally agreed unit or specific level of
reactivity.
Regulators define requirements for blood therapeutic products
and blood safety IVD related requirements on the basis of these
preparations allowing international harmonisation/convergence of
regulations.
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
WHO Biological Reference Preparations
Blood Products and related Biologicals
130 Reference preparations:
65% IS/Ref Panels established between
2000-2012:
60% new preparations (36% BS, 22% HT, 30% IP/IM)
40% replacements (19% BS, 67% HT, 14% IP/IM)
http:// www.who.int/bloodproducts
Documents
http:// www.who.int/bloodproducts
Testing strategies and national control of
blood safety related in vitro-diagnostic
tests, a priority
- First line detection of infectious agents
- Crucial for the prevention of transmission of
blood-borne pathogens
- Significant impact on appropriate control of
safety of blood and blood products
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: impact on blood safety, public health issues and international regulations
ECBS: HIV (IVD Technologies)
http://www.who.int/bloodproducts/catalogue/en
WHO International Standard or Reference Panel
Test
Current
Serology
HIV-1 p24 antigen, 1st IS (IU)
1st
Anti-HIV, Ref Panel (no unitage)
(HIV-1 subtypes: A, B, C, CRF_01, O; HIV-2)
NAT
HIV-1 RNA 2nd IS (IU)
HIV-1 RNA Genotype 2nd Ref Panel (no unitage)
(A,B,C,D, AE, F, G, AG-GH, groups N & O)
HIV-1 Circulating Recombinant Forms (CRFs)
RNA 1st Reference Panel (no unitage)
HIV-2 RNA 1st IS (IU)
Users
Test developers,
manufacturers,
regulators, blood
establishments,
fractionators,
reference laboratories,
diagnostic laboratories
ECBS: Hepatitis related reference standards
http://www.who.int/bloodproducts/catalogue/en
Test
Serology
WHO International Standard or Reference Panel
Current
Users
Hepatitis B surface antigen (HBsAg), 2nd IS (IU)+dilutional panel Test developers,
manufacturers,
HBsAg genotypes, 1st Reference Panel (15 members)
Hepatitis B virus “e” antigen (HBeAg), 1st IS (IU)
Anti-Hepatitis B virus “e” antibodies (anti-HBeAg), 1st IS (IU)
Anti-Hepatitis B virus core antibodies, 1st IS (IU)
Hepatitis B immunoglobulin, 2nd IS (IU)
NAT
Hepatitis A virus RNA 1st IS (IU)
Hepatitis B virus DNA 2nd IS (IU)
Hepatitis B virus DNA Genotype 1st Reference Panel
Genotypes A, B, C, D, E, F, G (8 members)
Hepatitis C virus RNA 2nd IS (IU)
Hepatitis D virus (HDV) RNA 1st IS (IU)
regulators,
blood
establishments,
fractionators,
reference
laboratories,
diagnostic
laboratories
Immunotherapy; Hemostasis/Thrombosis
− Blood group reagents
– Blood Coagulation Factors*
• (e.g. FactorVIII, IX, vWF, PCC)
–
Human immunoglobulins
• (e.g. anti-D, hepatitis B, rabies, tetanus, rubella, varicella zoster etc.)
– Protease inhibitors
• (AT, C1esterase inh; alpha1-antitrypsin)
– Albumin
– Other blood related biologicals
• (e.g. Unfractionated and LMW Heparin; Streptokinase; Urokinase; Tissue
Plasminogen Activator)
(*)Plasma Reference Materials applied to the Diagnosis of Blood Coagulation Disorders
Main achievements
– The required IBRPs for the detection of microbial agents with an impact on
the regulation and control of the safety of blood and blood products have
been established.
– The development of WHO reference panels designed for the determination
of efficiency of Hepatitis and HIV diagnostic kits to detect the
genotypes/subtypes prevalent in the different regions was high priority.
– The reference panels as well as the international standards have been a
fundamental tool in the on-going development and improvement of assays
for the control of quality and safety of blood products.
Coordination of setting standards activities required
– WHO CC plans of work in the development of IVD IRPs
• Updates on emerging/re-emerging pathogens
• New test strategies & emerging technologies
• Selection of priority projects supporting IVD & blood safety
regulations
– 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: ISO,
BPM, European Commission etc.
http:// www.who.int/bloodproducts
Web site addresses
http://www.who.int/bloodproducts
http://www.who.int/bloodproducts/catalogue