Blood Products - World Health Organization

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Blood Products - World Health Organization Powered By Docstoc
					Assurance qualité des produits sanguins
    et autres produits biologiques

                          Dr Ana Padilla
                Assurance Qualité des Médicaments
             Médicaments Essentiels et Produits de Santé
                 Organization Mondiale de la Santé
                     Web site addresses

  2 | HSS/EMP/QSM: Séminaire francophone 2011
    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-hepatitis B                               Anti-botulism toxin
         Anti-rabies
         Anti-tetanus                                Other biological products
         Anti-rhesus (anti-D)
                                                      Anticoagulant & fibrinolysis biological
   Albumin                                           therapeutic products
   In vitro biological diagnostic devices (IVDs):
           Priority: Support of international regulations

     3 | HSS/EMP/QSM: Séminaire francophone 2011
    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

 4 | HSS/EMP/QSM: Séminaire francophone 2011
        Blood Products & related Biologicals

 WHO standard setting functions*:
     Develop/establish/provide WHO Biological Reference Preparations

     Develop/adopt/provide evidence based WHO Guidelines on Quality
      Assurance and Control of specific products or procedures

     Support enforcement and implementation of WHO Norms and
      Standards:strengthen technical/regulatory capacity of NRAs & NCLs

     Support operational strategies to improve access to quality products

(*) Consistent with the WHO mandate through the Expert Committee on Biological Standardization

     5 | HSS/EMP/QSM: Séminaire francophone 2011
Blood Products and related Biologicals
          Target Audiencies
   National/Regional Regulatory Authorities

   National/Regional Control and National/Regional Reference Laboratories

   Blood Establishments and Plasma Fractionators

   Manufacturers of animal derived blood products

   Manufacturers of in vitro diagnostic tests

   Public Health Departments/Public Healt Officers/Ministries of Health

   Medical Professionals, Health Workers
   Procurement agencies and NGO’s

6 | HSS/EMP/QSM: Séminaire francophone 2011
Produits Sanguins d'origine Humain
  Human Blood Derived Products
Blood Plasma: a valuable human resource

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

   8 | HSS/EMP/QSM: Séminaire francophone 2011
   Blood Products: Life-Saving Medicines
                                  WHA Resolution 63.12
 Blood and blood components                     Plasma derivatives
     – Whole blood collected into
                                                   Plasma for "fractionation“, further
       containers, anticoagulant to
                                                   purification of plasma proteins, e.g.
       prevent clotting, cold chain
                                                        • Blood Coagulation Factors,
     – Blood components, obtained
                                                           e.g. Factor VIII for treatment of
       from whole blood by separation
                                                           hemophilia A
       (centrifuge or apheresis):
                                                        • Specific Immunoglobulins,
         • Red blood cells: Oxygen
                                                           e.g. anti-hepatitis B, anti-rabies,
                                                           anti-tetanus, anti-D
         • Platelets: Hemostasis, preventing
                                                        • IM and IV normal IgG
                                                        • Albumin,
         • Plasma: clotting factors,
                                                           involved in the regulation of body
           immunoglobulins etc.
                                                           fluids, used for resuscitation
         • Cryoprecipitate , FVIII source

  9 | HSS/EMP/QSM: Séminaire francophone 2011
           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

10 | HSS/EMP/QSM: Séminaire francophone 2011
Blood/Plasma                            Blood
   donation                           Components                         Patients

                                   Plasma for      Plasma-Derived
                                  Fractionation    Medicinal Product

DONATION                          COMPONENTS
                                                   VIRAL               TREATMENT
INFORMATION                       PREPARATION

 Good Manufacturing Practices
11 | HSS/EMP/QSM: Séminaire francophone 2011
             Assuring Blood/Plasma Safety:
                                    “Layers of Safety”

1. Donor selection criteria (epidemiological data)
2. Deferral procedures: national registries to avoid use of
   collections from previously unsuitable donors
3. Laboratory testing for infectious disease markers:
   selection of kits and validation

4. Implementation of GMPs in blood/plasma
     collection establishments

12 | HSS/EMP/QSM: Séminaire francophone 2011
       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 available:
   13 | HSS/EMP/QSM: Séminaire francophone 2011
Plasma Contract Fractionation Programs
    (Need for GMP implementation)
                                GMP- common principles
              Nat.Reg.                                         Nat.Reg.
              Authority                                        Authority

                            Quality Assurance Program

             SUPPLIER                                        FRACTIONATOR
                                          across countries

14 | HSS/EMP/QSM: Séminaire francophone 2011
      WHO Guidelines and Recommendations

                          WHO Guidelines on good manufacturing
                          practices for blood establishments

                         WHO Recommendations for the production, control
                         and regulation of human plasma for fractionation

                          WHO Guidelines on viral inactivation and removal
                          procedures intended to assure the viral safety
                          of human blood plasma products

15 | HSS/EMP/QSM: Séminaire francophone 2011
Overall Goals (WHA Resolution 63.12)
        The “Achilles” project

 To raise quality standards in blood establishments (BE)

 To reduce risk of transmission of infectious diseases

 Effective regulatory systems for blood products worldwide

 To make safe blood products available to patients

 17 | HSS/EMP/QSM: Séminaire francophone 2011
     Préparations de Référence
    Internationale OMS (Étalons
             Definition of Biologicals (WHO)
                                               Biological sources
                         Crude, semi purified extracts or purified fractions
                              of microbial, animal or human tissues

                                                 Produced by biological processes
                                                        Traditional/ Recombinant DNA/
                                                         Other biological technologies

             Biological assay
     - Complex molecular structure
     - Cannot be characterized by physicochemical criteria alone

19 | HSS/EMP/QSM: Séminaire francophone 2011
      WHO Biological Reference Standards*
        Global measurement standards
 Tool for comparison of biological
  measurement results worldwide

 Facilitate transfer of laboratory
  science into worldwide clinical practice

 Underpin apropriate clinical dosage

 Facilitate convergence of international
  regulations (e.g. blood products; blood
  safety related IVDs)
*Established by the Expert Committee on Biological Standardization

   20 | HSS/EMP/QSM: Séminaire francophone 2011
  WHO Biological Reference Preparations
          A tool for comparison of results worldwide


                                     Ref. Material     and Blood

                                                     Product Users

21 | HSS/EMP/QSM: Séminaire francophone 2011
Analytical                   Standards required by CTS
                                                                        WHO standards available
Sensitivity                       EU IVD Directive
HIV1p24 Ag                                      2 IU/ml                     1st WHO IS, 1992 (1000IU/ml)
Anti-HBS                                10 IU (detection limit)             2nd WHO IS, 2008 (100IU/ml)
                                 0.5 ng/ml (French or UK-standard)
                                                                     2nd WHO International Standard for HBsAg:
                                  0.130 IU (WHO HBsAg 2nd IS)
HBsAg                               (new CTS published, 2009)
                                                                                   33 IU/ampoule
                                                                            WHO dilutional reference panel

Anti-HBc                                         None                        WHO 1st IS, 2008 (50IU/ml)
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                          Analytical sensitivity (IU/ml)          HCV RNA 3rd IS (2007): 5.19 log10/ml
HBV                          defined on WHO standards                HBV DNA 2nd IS (2006): 6.0 log10/ml
HIV genotype panel                                                             10 different genotypes
WHO International Standards for Blood Grouping Reagents (minimum potency reagents)

      22 | HSS/EMP/QSM: Séminaire francophone 2011
     WHO Biological Reference Preparations
                 Blood Products and related Biologicals
                                                    120           60% of total IS or Ref Panels
                                                                  established between 1999-2009
                           Number of preparations





                                                      0    Blood Safety and      Coagul.Factors/     Immunological
                                                          General Hematology   Thrombolytic Agents     Reagents
               In vitro Diagnostic Tests                          55                   13                 10          78
               Therapeutic products                               0                    25                 11          36
WHO Catalogue of Biological Reference Preparations:

    23 | HSS/EMP/QSM: Séminaire francophone 2011

24 | HSS/EMP/QSM: Séminaire francophone 2011
    WHO Biological Reference Standards*
      Development & Establishment
1. Selection of candidate materials                            7. Characterization of final product

2. Characterization of candidate                               8. Stability studies (incl. statistical
   materials                                                      analysis)
3. Dilution of materials                                       9. WHO international collaborative
   (dilution matrix)
                                                                  study (incl. statistical analyses)
4. Inactivation (if needed)
                                                               10. WHOCC & Working Groups
5. Freeze-drying
                                                               11. Report to ECBS and decision
6. Feasibility studies                                         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.

 25 | HSS/EMP/QSM: Séminaire francophone 2011
                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

  26 | HSS/EMP/QSM: Séminaire francophone 2011
          ECBS: HIV (IVD Technologies)
                              WHO International Standard or Reference Panel
Test              Current                                        Users
Serology          HIV-1 p24 antigen, 1st IS (IU)
                                                                Test developers,
                  Anti-HIV, Ref Panel (no unitage)              manufacturers,
                  (HIV-1 subtypes: A, B, C, CRF_01, O; HIV-2)   regulators, blood
NAT               HIV-1 RNA 2nd IS (IU)                         fractionators,
                  HIV-1 RNA Genotype 1st Ref Panel (no unitage) reference laboratories,
                  (A,B,C,D, AE, F, G, AG-GH, groups N & O)      diagnostic laboratories
                  HIV-2 RNA 1st IS (IU) -

 27 | HSS/EMP/QSM: Séminaire francophone 2011
      ECBS: Hepatitis Viruses (IVD Technologies)
                          WHO International Standard or Reference Panel
Test              Current                                       Users
Serology          Hepatitis B surface antigen, 2nd IS (IU) - adw2      Test developers,
                  Anti-Hepatitis B virus core antibodies (IU)          manufacturers,
                  HBsAg genotype reference panel
NAT               Hepatitis A virus RNA 1st IS (IU)                    establishments,
                  Hepatitis B virus DNA 2nd IS (IU) – genotype A2      fractionators,
                  Hepatitis B virus DNA Genotype 1st Reference Panel   reference
                  Genotypes A, B, C, D, E, F, G (no unitage) -         laboratories,
                  Hepatitis C virus RNA 2nd IS (IU)
Current IS both for HBsAg and HBV DNA are genotype A2: 1% of HBV infections worldwide

   28 | HSS/EMP/QSM: Séminaire francophone 2011
Immunoglobulines d'origine animal
Produits thérapeutiques d'origine animal
                WHO Essential Medicines List

             Animal derived blood products

               –    Snake anti-venom immunoglobulins

 30 | HSS/EMP/QSM: Séminaire francophone 2011
VERY POOR REGULATORY CONTROL: Technology in the public domain

                           A - Collection of venoms

  B – Horse Immunization     C – Starting material of   D – Fractionation &
         Protocols            animal derived sera       Purification process
         WHO Guidelines and Recommendations


   WHO Guidelines on production, control and regulation of
    snake antivenom immunoglobulins

   WHO Database: clinically important venomous snakes
    species and its worldwide geographical distribution together
    with antivenoms for treatment of snakebite envenomings

   WHO website hosting both the Guidelines and database
    (maps, pictures, products, manufacturers)

   Cost-effective study to support access to antivenoms (2012)

32 | HSS/EMP/QSM: Séminaire francophone 2011
     WHO Database: Medically Important Snakes
      Distribution maps, pictures & antivenoms

  Red or orange question marks (?)                  Allocation to CATEGORY 1 shown in red
(Indicates expected presence not yet                (Indicates common, widespread species
confirmed due to lack of exploration              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)
   33 | HSS/EMP/QSM: Séminaire francophone 2011
WHO Database: Medically Important Snakes
Distribution maps, pictures & antivenoms

                                                                      WHO Guidelines
 34 | HSS/EMP/QSM: Séminaire francophone 2011
                 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.

35 | HSS/EMP/QSM: Séminaire francophone 2011
                     Web site addresses

    E-mail addresses:;

 36 | HSS/EMP/QSM: Séminaire francophone 2011

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