assurance qualité des produits sanguins et autres produits biologiques dr ana padilla assurance...

Assurance qualité des produits sanguins Assurance qualité des produits sanguins et autres produits biologiqueset autres produits biologiques

Dr Ana Padilla Assurance Qualité des Médicaments

Médicaments Essentiels et Produits de SantéOrganization Mondiale de la Santé

HSS/EMP/QSM: Séminaire francophone 20112 |

Web site addressesWeb site addresses

http://www.who.int/bloodproducts

http://www.who.int/bloodproducts/snakeantivenoms

http://www.who.int/bloodproducts/catalogue


Blood Products & related BiologicalsBlood 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 In vitro biological diagnostic devices (IVDs): Priority: Support of international regulations

Other biological products Anticoagulant & fibrinolysis biological therapeutic products

Other biological products Anticoagulant & fibrinolysis biological therapeutic products


Blood Products & related BiologicalsBlood 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


Blood Products & related BiologicalsBlood 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


Blood Products and related BiologicalsBlood Products and related Biologicals Target AudienciesTarget 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

Produits Sanguins d'origine HumainProduits Sanguins d'origine Humain

Human Blood Derived ProductsHuman Blood Derived Products



Blood Plasma: a valuable human resourceBlood Plasma: a valuable human resource

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


Blood Products: Life-Saving MedicinesWHA Resolution 63.12

Blood Products: Life-Saving MedicinesWHA 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


WHO List of Essential Medicines 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


TRACEABILITYTRACEABILITY FROM DONOR TO PATIENTFROM DONOR TO PATIENT

TRACEABILITYTRACEABILITY FROM DONOR TO PATIENTFROM DONOR TO PATIENT

COMPONENTS PREPARATION

DONATIONINFORMATION

FRACTIONATIONVIRAL INACTIVATION

TREATMENT

Good Manufacturing Practices

Blood/Plasma donation

Plasma for Fractionation

Blood Components

Plasma-Derived Medicinal Product

PatientsPatients


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




GMP implementation in Blood/Plasma Establishments: a key element to

Quality and safety of plasma for fractionationPlasma contract fractionation programs

Supporting access to blood plasma products

Good Manufacturing Practices (GMP)*: an essential tool for improvement of safety

*WHO Guidelines available: www.who.int/bloodproducts


Plasma Contract Fractionation Programs(Need for GMP implementation)

Plasma Contract Fractionation Programs(Need for GMP implementation)

GM

PL

ice

ns

ing GM

PL

ice

ns

ing

Quality Assurance Program

across countries

PLASMASUPPLIER FRACTIONATOR

Nat.Reg.Authority

Nat.Reg.Authority

GMP- common principles


WHO Guidelines and RecommendationsWHO Guidelines and Recommendationshttp://www.who.int/bloodproducts/en/

WHO Guidelines and RecommendationsWHO Guidelines and Recommendationshttp://www.who.int/bloodproducts/en/

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

WHO Recommendations for the production, controland regulation of human plasma for fractionation

WHO Guidelines on good manufacturing practices for blood establishments


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

Préparations de Référence Préparations de Référence Internationale OMS (Étalons Internationale OMS (Étalons

Internationals) Internationals)



Definition of Biologicals (WHO) Definition of Biologicals (WHO) Definition of Biologicals (WHO) Definition of Biologicals (WHO)

Biological sourcesCrude, semi purified extracts or purified fractions

of microbial, animal or human tissues

Produced by biological processesProduced by biological processes Traditional/ Recombinant DNA/

Other biological technologies

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

Biological assay Biological assay


WHO Biological Reference Standards*WHO Biological Reference Standards*Global measurement standardsGlobal 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


WHO Biological Reference Preparations

A tool for comparison of results worldwide

WHOIS/IRP

2ndary Ref. Material

Regulatory

Authorities

Manufacturers

and Blood Establishments

Product Users


Analytical Sensitivity

Standards required by CTSEU IVD Directive

WHO standards available

Immunoassays

HIV1p24 Ag2 IU/ml1st WHO IS, 1992 (1000IU/ml)

Anti-HBS10 IU (detection limit)2nd WHO IS, 2008 (100IU/ml)

HBsAg0.5 ng/ml (French or UK-standard)

0.130 IU (WHO HBsAg 2nd IS)(new CTS published, 2009)

2nd WHO International Standard for HBsAg: 33 IU/ampoule

WHO dilutional reference panel

Anti-HBcNoneWHO 1st IS, 2008 (50IU/ml)

Anti-HIV subtype panel WHO 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 panel10 different genotypes WHO International Standards for Blood Grouping Reagents (minimum potency reagents)


WHO Biological Reference PreparationsBlood Products and related Biologicals

WHO Biological Reference PreparationsBlood Products and related Biologicals

0

20

40

60

80

100

120N

um

ber

of

pre

par

atio

ns

In vitro Diagnostic Tests 55 13 10 78

Therapeutic products 0 25 11 36

Blood Safety and General Hematology

Coagul.Factors/ Thrombolytic Agents

Immunological Reagents

Total

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

60% of total IS or Ref Panels

established between 1999-2009


DocumentsDocuments


WHO Biological Reference Standards*WHO Biological Reference Standards*Development & EstablishmentDevelopment & Establishment

WHO Biological Reference Standards*WHO Biological Reference Standards*Development & EstablishmentDevelopment & Establishment

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

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 *Recommendations for the preparation, characterization and establishment

of international and other biological reference standards (revised 2004); Annex 2, WHO TRS, No 932, 2005.


In vitro diagnostic devices (IVDs)*Medical devices used in vitro for the examination of human specimens

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


ECBS: HIV (IVD Technologies) http://www.who.int/bloodproducts/en/

ECBS: HIV (IVD Technologies) http://www.who.int/bloodproducts/en/

WHO International Standard or Reference Panel

TestCurrentUsersSerologyHIV-1 p24 antigen, 1st IS (IU)

Test developers, manufacturers, regulators, blood establishments,fractionators ,

reference laboratories, diagnostic laboratories

Anti-HIV, 1st Ref Panel (no unitage)(HIV-1 subtypes: A, B, C, CRF_01, O; HIV-2)

NATHIV-1 RNA 2nd IS (IU)

HIV-1 RNA Genotype 1st Ref Panel (no unitage)(A,B,C,D, AE, F, G, AG-GH, groups N & O)

HIV-2 RNA 1st IS (IU) -


ECBS: Hepatitis Viruses (IVD Technologies) http://www.who.int/bloodproducts/en/

ECBS: Hepatitis Viruses (IVD Technologies) http://www.who.int/bloodproducts/en/

WHO International Standard or Reference Panel

TestCurrentUsersSerologyHepatitis B surface antigen, 2nd IS (IU) - adw2 Test developers,

manufacturers, regulators, blood establishments,

fractionators, reference laboratories, diagnostic laboratories

Anti-Hepatitis B virus core antibodies (IU)HBsAg genotype reference panel

NATHepatitis A virus RNA 1st IS (IU)

Hepatitis B virus DNA 2nd IS (IU) – genotype A2Hepatitis B virus DNA Genotype 1st Reference Panel

Genotypes A, B, C, D, E, F, G (no unitage) -

Hepatitis C virus RNA 2nd IS (IU)

Current IS both for HBsAg and HBV DNA are genotype A2: 1% of HBV infections worldwide

Immunoglobulines d'origine animal Immunoglobulines d'origine animal Produits thérapeutiques d'origine animalProduits thérapeutiques d'origine animal


WHO Essential Medicines List WHO Essential Medicines List

Animal derived blood products

– Snake anti-venom immunoglobulins


A - Collection of venoms

B – Horse ImmunizationProtocols

C – Starting material of animal derived sera

D – Fractionation &Purification process

SNAKE ANTIVENOM IMMUNOGLOBULINS VERY POOR REGULATORY CONTROL: Technology in the public domain


WHO Guidelines and RecommendationsWHO Guidelines and RecommendationsWHO Guidelines and RecommendationsWHO Guidelines and Recommendations

ANIMAL DERIVED BLOOD PRODUCTSANIMAL 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)


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

www.who.int/bloodproducts/snakeantivenoms


WHO Guidelines


www.who.int/bloodproducts/snakeantivenoms


WHO web site: Target AudiencesWHO 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.


Web site addressesWeb site addresses




E-mail addresses: [email protected]; [email protected]