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Assurance qualité des produits sanguins et autres produits biologiques Dr Ana Padilla Assurance Qualité des Médicaments Médicaments Essentiels et Produits.

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Presentation on theme: "Assurance qualité des produits sanguins et autres produits biologiques Dr Ana Padilla Assurance Qualité des Médicaments Médicaments Essentiels et Produits."— Presentation transcript:

1 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

2 HSS/EMP/QSM: Séminaire francophone 2011 2 |2 | Web site addresses

3 HSS/EMP/QSM: Séminaire francophone 2011 3 |3 | Blood Products & related Biologicals Animal-derived immunoglobulins Anti-rabies Anti-venoms Anti-tetanus toxin Anti-diphteria toxin Anti-botulism toxin Human blood derived products Blood components (red cells, platelets, plasma) Blood Coagulation Factors Polyvalent Immunoglobulins (IV, IM) Specific Immunoglobulins Anti-hepatitis B Anti-rabies Anti-tetanus Anti-rhesus (anti-D) Albumin In vitro biological diagnostic devices (IVDs): Priority: Support of international regulations Other biological products Anticoagulant & fibrinolysis biological therapeutic products

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

5 HSS/EMP/QSM: Séminaire francophone 2011 5 |5 | 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

6 HSS/EMP/QSM: Séminaire francophone 2011 6 |6 | 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 NGOs

7 Produits Sanguins d'origine Humain Human Blood Derived Products

8 HSS/EMP/QSM: Séminaire francophone 2011 8 |8 | Blood Plasma: a valuable human resource Medicinal products derived from human donations of blood and plasma play a critical role in health care

9 HSS/EMP/QSM: Séminaire francophone 2011 9 |9 | 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 Plasma derivatives 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 the regulation of body fluids, used for resuscitation

10 HSS/EMP/QSM: Séminaire francophone 2011 10 | 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

11 HSS/EMP/QSM: Séminaire francophone 2011 11 | TRACEABILITY FROM DONOR TO PATIENT COMPONENTS PREPARATION DONATION INFORMATION FRACTIONATION VIRAL INACTIVATION TREATMENT Good Manufacturing Practices Blood/Plasma donation Plasma for Fractionation Blood Components Plasma-Derived Medicinal Product Patients

12 HSS/EMP/QSM: Séminaire francophone 2011 12 | 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 Assuring Blood/Plasma Safety : Layers of Safety

13 HSS/EMP/QSM: Séminaire francophone 2011 13 | 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 Good Manufacturing Practices (GMP)*: an essential tool for improvement of safety * WHO Guidelines available:

14 HSS/EMP/QSM: Séminaire francophone 2011 14 | Plasma Contract Fractionation Programs (Need for GMP implementation) GMP Licensing GMP Licensing Quality Assurance Program across countries PLASMA SUPPLIER FRACTIONATOR Nat.Reg. Authority Nat.Reg. Authority GMP- common principles

15 HSS/EMP/QSM: Séminaire francophone 2011 15 | WHO Guidelines and Recommendations WHO Guidelines and Recommendations WHO Guidelines on viral inactivation and removal procedures intended to assure the viral safety of human blood plasma products WHO Recommendations for the production, control and regulation of human plasma for fractionation WHO Guidelines on good manufacturing practices for blood establishments


17 HSS/EMP/QSM: Séminaire francophone 2011 17 | 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 Overall Goals (WHA Resolution 63.12) The Achilles project

18 Préparations de Référence Internationale OMS (Étalons Internationals)

19 HSS/EMP/QSM: Séminaire francophone 2011 19 | 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 - Complex molecular structure - Cannot be characterized by physicochemical criteria alone Biological assay

20 HSS/EMP/QSM: Séminaire francophone 2011 20 | 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

21 HSS/EMP/QSM: Séminaire francophone 2011 21 | WHO Biological Reference Preparations A tool for comparison of results worldwide WHO IS/IRP 2ndary Ref. Material Regulatory Authorities Manufacturers and Blood Establishments Product Users

22 HSS/EMP/QSM: Séminaire francophone 2011 22 | Analytical Sensitivity Standards required by CTS EU IVD Directive WHO standards available Immunoassays HIV1p24 Ag2 IU/ml1 st WHO IS, 1992 (1000IU/ml) Anti-HBS10 IU (detection limit)2 nd WHO IS, 2008 (100IU/ml) HBsAg 0.5 ng/ml (French or UK-standard) 0.130 IU (WHO HBsAg 2nd IS) (new CTS published, 2009) 2 nd WHO International Standard for HBsAg: 33 IU/ampoule WHO dilutional reference panel Anti-HBcNoneWHO 1 st IS, 2008 (50IU/ml) Anti-HIV subtype panelWHO Ref. Panel: 6 different subtypes NAT assays (qualitative and quantitative) HIV Analytical sensitivity (IU/ml) defined on WHO standards HIV-1 RNA 2nd IS (2005): 5.56 log10/ml HCVHCV RNA 3rd IS (2007): 5.19 log10/ml HBVHBV DNA 2nd IS (2006): 6.0 log10/ml HIV genotype panel 10 different genotypes WHO International Standards for Blood Grouping Reagents (minimum potency reagents)

23 HSS/EMP/QSM: Séminaire francophone 2011 23 | WHO Biological Reference Preparations Blood Products and related Biologicals WHO Catalogue of Biological Reference Preparations: 60% of total IS or Ref Panels established between 1999-2009

24 HSS/EMP/QSM: Séminaire francophone 2011 24 | Documents

25 HSS/EMP/QSM: Séminaire francophone 2011 25 | WHO Biological Reference Standards* Development & Establishment 7.Characterization of final product 8.Stability studies (incl. statistical analysis) 9.WHO international collaborative study (incl. statistical analyses) 10. WHOCC & Working Groups 11. Report to ECBS and decision 12. Storage and distribution 1.Selection of candidate materials 2.Characterization of candidate materials 3.Dilution of materials (dilution matrix) 4.Inactivation (if needed) 5.Freeze-drying 6.Feasibility studies *Recommendations for the preparation, characterization and establishment of international and other biological reference standards (revised 2004); Annex 2, WHO TRS, No 932, 2005.

26 HSS/EMP/QSM: Séminaire francophone 2011 26 | 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

27 HSS/EMP/QSM: Séminaire francophone 2011 27 | ECBS: HIV (IVD Technologies) WHO International Standard or Reference Panel UsersCurrentTest Test developers, manufacturers, regulators, blood establishments, fractionators, reference laboratories, diagnostic laboratories HIV-1 p24 antigen, 1 st IS (IU)Serology Anti-HIV, 1 st Ref Panel (no unitage) (HIV-1 subtypes: A, B, C, CRF_01, O; HIV-2) HIV-1 RNA 2 nd IS (IU)NAT HIV-1 RNA Genotype 1 st Ref Panel (no unitage) (A,B,C,D, AE, F, G, AG-GH, groups N & O) HIV-2 RNA 1st IS (IU) -

28 HSS/EMP/QSM: Séminaire francophone 2011 28 | ECBS: Hepatitis Viruses (IVD Technologies) WHO International Standard or Reference Panel UsersCurrentTest Test developers, manufacturers, regulators, blood establishments, fractionators, reference laboratories, diagnostic laboratories Hepatitis B surface antigen, 2 nd IS (IU) - adw2Serology Anti-Hepatitis B virus core antibodies (IU) HBsAg genotype reference panel Hepatitis A virus RNA 1 st IS (IU)NAT Hepatitis B virus DNA 2 nd IS (IU) – genotype A2 Hepatitis B virus DNA Genotype 1 st Reference Panel Genotypes A, B, C, D, E, F, G (no unitage) - Hepatitis C virus RNA 2 nd IS (IU) Current IS both for HBsAg and HBV DNA are genotype A2: 1% of HBV infections worldwide

29 Immunoglobulines d'origine animal Produits thérapeutiques d'origine animal

30 HSS/EMP/QSM: Séminaire francophone 2011 30 | WHO Essential Medicines List Animal derived blood products – Snake anti-venom immunoglobulins

31 A - Collection of venoms B – Horse Immunization Protocols C – Starting material of animal derived sera D – Fractionation & Purification process SNAKE ANTIVENOM IMMUNOGLOBULINS VERY POOR REGULATORY CONTROL: Technology in the public domain

32 HSS/EMP/QSM: Séminaire francophone 2011 32 | WHO Guidelines and Recommendations ANIMAL DERIVED BLOOD PRODUCTS ANIMAL DERIVED BLOOD PRODUCTS 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)

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

34 HSS/EMP/QSM: Séminaire francophone 2011 34 | WHO Guidelines WHO Database: Medically Important Snakes Distribution maps, pictures & antivenoms

35 HSS/EMP/QSM: Séminaire francophone 2011 35 | 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 NGOs Objective is to use the web site to distribute accurate data that can be used to plan improvements to existing supply and distribution.

36 HSS/EMP/QSM: Séminaire francophone 2011 36 | Web site addresses E-mail addresses:;

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