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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

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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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- 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

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Blood Products & related Biologicals biologicals (WHO/HQ)

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

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Quality Assurance and Safety: biologicals (WHO/HQ)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


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Blood Products & related Biologicals Strategic Plan biologicals (WHO/HQ)(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

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    WHO Essential Medicines List (I) biologicals (WHO/HQ)

    • Animal derived blood products

      • Snake anti-venom immunoglobulins

      • Anti-rabies imunoglobulins

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    The Meeting urged WHO to: biologicals (WHO/HQ)

    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

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    Antivenom sera are essential to prevent biologicals (WHO/HQ)long-term disability & death


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

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    Component 1: Global Quality Assurance Guidance biologicals (WHO/HQ)

    • 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

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    Countries represented biologicals (WHO/HQ)Jakarta, May 2008

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    Countries represented biologicals (WHO/HQ)Addis Ababa, July 2008

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    Fragility of production systems in developing world biologicals (WHO/HQ)

    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)

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    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 to Snake Venom(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 to Snake Venom

    • 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 to Snake Venom

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    Literature to Snake Venom

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    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

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    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 Antivenomsbuilding for snake venoms production and antivenoms preclinical evaluation:

    a proposal to strenghten national capacities

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    Venoms production: Basic problems Antivenoms

    • 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… Antivenoms

    • 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.

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    Consequences… 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.

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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 production(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

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    Expected outcomes production

    • 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) production

    • 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 production

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

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    The ‘Achilles’ project: production

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

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    Background production

    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.

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    What is the global situation ? production


    • 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 are the problems? production

    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)

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    WHO “Achilles” project: productionExpected 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

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    Good Manufacturing Practices (GMP): productionan 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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    Medicinal Product

    Plasma for








    Good Manufacturing Practices

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    Plasma Contract Fractionation Programs production(Need for GMP implementation)








    GMP- common principles



    Quality Assurance Program



    across countries

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    WHO “Achilles” project productionAction 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

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    WHO “Achilles” project: productionExpected 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

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    WHO Biological Reference Preparations production

    Global Measurement Standards

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    WHO Biological Reference Preparations productionGlobal 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 productionStrategic 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 productionBlood Products and related Biologicals

    WHO Catalogue of Biological Reference Preparations: www.who.int/bloodproducts

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    Web site addresses production

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    Priority Projects for Biological Reference Preparations productionWHO 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

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    WHO IVD Standardization productionPriorities 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 productionChagas disease

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    Technical capacity of National Regulatory Authorities production

    Blood Products Regulations

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    International Conference of Drug Regulatory Authorities production (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 Biologicals.


    Reg. Authorities

    WHO Consultations

    Experts Partners

    & Collaborations

    WHO CC for Biological Standards & Quality Assurance


    Expert Advisory Panels





    & Public Health


    Other Standard

    setting Organizations

    (e.g.BIPM, EDQM, ISO)

    Intnal Scientific


    (e.g. ISTH, ISBT, IFCC)

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    Web site addresses Biologicals.