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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.

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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
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

implemented for more than 50 years mandated by member states
- implemented for more than 50 years - mandated by Member States

International Biological Standardization

by WHO

WHO is expected to be both a driving force

and a key reference point on biological

standardization issues

blood products related biologicals
Blood Products & related Biologicals

Animal- derived sera


Anti-venoms (snake bites)

Anti-tetanus toxins

Anti-diphteria toxins

Anti-botulism toxins

Human blood derived products

Blood components (red cells, platelets, plasma)

Blood Coagulation Factors

Polyvalent Immunoglobulins (IV, IM)

Specific Immunoglobulins

Anti-hepatitis B



Anti-rhesus (anti-D)


Other related productsAnticoagulant & fibrinolysis biological therapeutic products

  • In vitro biological diagnostic devices Priority: IVDs applied to the control of blood and blood products safety
quality assurance and safety blood products and related biologicals
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


blood products related biologicals strategic plan approved at 57 th ecbs 2006
Blood Products & related Biologicals Strategic Plan (approved at 57th ECBS, 2006)
  • WHO Essential Medicines List:
      • Animal derived sera (IgS):
        • Snake antivenom and anti-rabies immunoglobulins
      • Human blood derived products:
        • GMP production of plasma for fractionation
  • WHO Biological Reference Standards for regulation and control of in vitro (biological) diagnostic tests
      • Standardization of traditional and new technologies
who essential medicines list i
WHO Essential Medicines List (I)
  • Animal derived blood products
    • Snake anti-venom immunoglobulins
    • Anti-rabies imunoglobulins

The Meeting urged WHO to:

Improve availability of antisera bybuilding 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
Antivenom sera are essential to prevent long-term disability & death


Courtesy Prof D Warrell, Nuffield Department of Clinical Medicine, Oxford

component 1 global quality assurance guidance
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 large-scale implementation and control of manufacturing steps)
  • Elaborated in parallel to, and as a result of, WHO Regional and Bi-Regional Workshops

Fragility of production systems in developing world

The document has been discussed in the field:

Bi-Regional Workshops in Aisa and Africa: - Jakarta, May 2008 - Addis Ababa, June 2008

Global experts consultation

Adoption requested to the 59th ECBS (2008)

antivenom is the only specific antidote to snake venom
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

clinical assessment need of efficacy test reported by dr thapa nepal
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)
major issues about antivenom preparations
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


Technology in the public domain (not protected by intelectual property)

A - Collection of venoms

B – Horse Immunization


C – Starting material of animal derived sera

D – Fractionation &

Purification process

3 major instruments to inform about potency and efficacy of antivenoms
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

Capacity building for snake venoms production and antivenoms preclinical evaluation:

a proposal to strenghten national capacities

venoms production basic problems
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.
  • The antivenoms produced using low quality, or non-representative 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.
  • 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.
component 2 national regional capacity building on venoms production
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.
components of the who proposal proposed who consultation 2009
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 non-commercial 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
expected outcomes
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.
who essential medicines list ii
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

blood plasma a valuable human resource
Blood Plasma: a valuable human resource

Medicinal products derived from human donations of blood and plasma play a critical role in health care


The ‘Achilles’ project:

a WHO initiative to assure safety and availability of blood products in developing countries

what is the global situation


What is the global situation ?
  • 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.
what is the global situation33
What is the global situation ?


  • 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
what is the global situation34

What are the problems?

What is the global situation ?
  • 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)
who achilles project expected outcomes
WHO “Achilles” project: Expected Outcomes

The “Achilles” project: Project 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

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

traceability from donor to patient







Medicinal Product

Plasma for








Good Manufacturing Practices

plasma contract fractionation programs need for gmp implementation
Plasma Contract Fractionation Programs(Need for GMP implementation)








GMP- common principles



Quality Assurance Program



across countries

who achilles project action plan demonstration project
WHO “Achilles” projectAction Plan (demonstration project)

WHO “Achilles” 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

who achilles project expected outcomes40
WHO “Achilles” project: Expected Outcomes

WHO “Achilles” project: Expected Outcomes

  • 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

WHO Biological Reference Preparations

Global Measurement Standards

who biological reference preparations global measurement standards
WHO Biological Reference PreparationsGlobal 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
who biological reference preparations strategic plan
WHO Biological Reference PreparationsStrategic 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!"
who biological reference preparations blood products and related biologicals
WHO Biological Reference PreparationsBlood Products and related Biologicals

WHO Catalogue of Biological Reference Preparations:

Priority Projects for Biological Reference Preparations WHO Collaborating Centres' Meeting (29-30 January 2007)


Feasibility studies

Collaborative study

WHO Recommendations: Annex 2, WHO TRS, No 932, 2005



1the anti-HIV antibody panel will also be extended; 2two panels for HBsAg- and NAT-tests

who ivd standardization priorities 2009
WHO IVD StandardizationPriorities 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

international conference of drug regulatory authorities icdra recommendations bern 2008
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
quality assurance safety blood products and related biologicals programme overview
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


WHO Working Groups


Reg. Authorities

WHO Consultations

Experts Partners

& Collaborations

WHO CC for Biological Standards & Quality Assurance


Expert Advisory Panels





& Public Health


Other Standard

setting Organizations


Intnal Scientific




Web site addresses