Transcript Guidelines - National Institute for Biological Standards and Control

Development of Biological Reference
Preparations for Blood Safety-related IVDs
- WHO Strategic Plan -
SoGAT XX, Warsaw, Poland
12-13 June 2007
Michael Chudy, WHO; Geneva, Switzerland
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M. Chudy | 12 June 2007
Biological Standardization
 WHO is mandated by it's Member States to "…develop,
establish and promote international standards for
biological products."
 In practice, biological products cover
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Vaccines
Blood and blood products
Biological therapeutics
In vitro diagnostic devices
M. Chudy | 12 June 2007
Quality Assurance and Safety of Biological Products
WHO Norms & Standards: Expert Committee on Biological Standardization
Biological Products
(Vaccines, blood products, other biologicals
and in vitro diagnostic devices)
NSB/IVB/FCH
(Vaccines, cell regulators)
QSD/PSM/HTP
(Blood products, in vitro diagnostic devices)
Immunizations, Vaccines & Biologicals
Medicines, Policy and Standards
Department (IVB);
Department (PSM*);
Family and Community Health Cluster (FCH) Health Technology and Pharmaceuticals Cluster
(HTP)
(*) Expert Committee for Pharmaceutical Preparations
(*) Expert Committee for Essential Medicines
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WHO Biological Reference Preparations
 Recommendations for the preparation, characterization
and establishment of international and other biological
reference standards (revised 2004)
Annex 2, WHO TRS, No 932, 2005.
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WHO Biological Reference Preparations
 International Standard [expressed in IU]
 Reference Reagent
 International Reference Panel
– Endorsed and adopted by Expert Committee on Biological
Standardization (decision making body)
– Catalogue on the website
www.who.int/medicines
www.who.int/bloodproducts/ivd/infectious_markers
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Establishment of
WHO Biological Reference Preparations *
1. Selection of candidate materials
7. Characterization of final product
2. Characterization of candidate
materials
8. Stability studies (incl. statistical
analysis)
3. Feasibility studies
4. Inactivation (if needed)
5. Dilution of materials (dilution
matrix)
6. Freeze-drying
9. International collaborative study
(incl. statistical analyses)
10. Report to WHO
11. ECBS decision
12. Storage and distribution
(maintenance)
*Recommendations for the preparation, characterization and establishment
of international and other biological reference standards (revised 2004); Annex 2, WHO TRS, No 932, 2005.
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WHO Biological Reference Preparations:
IVD Strategic Plan (5 years)
For blood safety-related IVDs:
 Serological test platforms
 NAT assays
 Other tests
Meeting of the WHO Collaborating Centres for Biological
Standards and Standardization (NIBSC, CBER, PEI) in
Jan 2007 organized by WHO QSD/PSM
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Meeting of WHO Collaborating Centres for
Biological Standards and Standardization
 WHO Biological Reference Preparations: Review of current situation
and new proposals
 Role of epidemiological data worldwide
 New test platforms and emerging technologies
 Define priority projects
 Ways forward for collaboration (WHO CC-Network model)
– Would strengthen the collaboration between the WHO CCs, and between
WHO CCs and WHO
– Respect interests of CCs
– Synergize activities
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WHO Biological Reference Preparations:
Current Situation and Proposals
Pathogens with impact on blood safety
√ √ √ √

HIV
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HBV √
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Other hepatitis viruses
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B19V
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Bacteria and parasites (causative agents for syphilis, malaria, Chagas disease)
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Arthropod-borne agents (WNV, dengue virus)
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Prion agents √ √ √ √
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Other blood-borne agents (bacteria, leishmania, HHV-8)
√√√
√ √
, HCV
√
√ √ √
, HTLV1/2, CMV
√
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√ NAT; √ Serology; √ Other
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√
Testing for Syphilitic Infection
 Treponema pallidum
 Blood screening test in many countries
 Anti-syphilitic serum, WHO 1st IS (#HS) nearly exhausted
 Proposal for replacement:
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IgG preparation (plasma pool of samples from latent syphilis patients)
IgM/IgG preparation (plasma pool of samples from acute syphilis patients)
Collaborative study is completed
Report to ECBS in October 2007
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Testing for Malarial Infection
 Plasmodium falciparum, P. malariae, P. ovale, P. vivax
 Endemic in more than 100 countries
 Donor testing to reduce the deferral period/loss of donors (non-endemic areas)
 Direct parasite detection
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Giemsa- or Wright's-stained thick and thin blood film (gold standard method)
Time expensive, need experienced hands
 Antigen detection
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No sufficient sensitivity
 NAT testing
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Pro and cons (e. g. DNA vs RNA!)
 Antibody testing
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1st IS P. falciparum DNA, #04/176 (ECBS 2006)
Antibody Reference Panel (proposal)
Effective indicator of infection
Negative result no guarantee that donor is not infected
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Chagas Disease
 American Trypanosomiasis
 Protozoan parasite Trypanosoma (T.) cruzi
 First described by Carlos Chagas in 1909
 Morphologically distinct stages
– Insect-stage: epimastigote
– Host-stage: Trypomastigote/amastigote
 >100 strains classified into two groups (T. cruzi I and T. cruzi II)
 Chronic asymptomatic carrier state in infected individuals
 Endemic in Latin America
 Non-endemic areas: issue due to emigration (e.g. USA, Spain, France)
 16–18 million infected cases; >80 million people at risk
 T. cruzi DNA detected in mummies from Chile and Peru (7050 BC-1050 AD)
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T. cruzi Infection
Main routes of parasite transmission
 By bloodfeeding bugs (sub-family Triatominae); the
faeces of the insects contain parasites which can enter
the wound left after the bloodmeal, usually when it is
scratched or rubbed
 Transfusion with infected blood (whole blood and
components);
 Tissue and organ transplantations
 Congenital (from infected mother to fetus)
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Testing for T. cruzi Infection
 Diagnosis is complex due to low parasitemia in later
stages
 Microscopic examination of T. cruzi in blood, lymph fluid,
cerebrospinal fluid
 Xenodiagnosis (uninfected bugs are fed on an individual
suspected of having the disease; investigation of blood
smear microscopically several weeks later)
 PCR (limited sensitivity due to low T.cruzi level in chronic
stages)
 Serological tests detecting antibodies are well-suited
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Testing for T. cruzi Infection:
Serological Tests for Detecting Antibodies
 Screening tests (initial tests)
– Indirect hemagglutination assay (IHA)
– Enzyme-linked immunosorbent assay (ELISA)
 Confirmatory tests (supplemental tests)
– Indirect immunoflourescence assay (IFA)
– Radio-immuno-precipitation assay (RIPA)
– Immunoblot/Western blot
 Rapid tests
Antigens used for ELISA tests
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Whole parasite lysates or semipurified antigenic fractions (epimastigote stage)
Trypomastigote excretory-secretory antigens (TESAs; major component trans-sialidase)
Cocktail of recombinant proteins
Synthetic peptides
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Testing for T. cruzi Infection:
Blood Donation Screening
 Endemic areas
– In most counties for more than 10 years
– Prevalence of T. cruzi-infected blood is higher than of HIV, HBV and HCV
– Transfusion-transmitted rest-risk differs from country to country
 Non-endemic areas
– USA
• >12 million immigrants from endemic regions
• ARC pilot studies since end of Jan 2007 with ORTHO test
– Spain
• Recommendation to test donors from endemic regions (not for excl. source plasma)
• To reduce the deferral period/loss of donors
– France
• Evaluation of screening tests (blood centre in Tours)
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Testing for T. cruzi Infection
 Problems with serological tests
– Indeterminate results and false-positive results
• Other T. spec
• Other infectious diseases: e.g. leishmaniasis, malaria, syphilis
• Autoimmune disorders
– Lack of sensitivity of some assays
 No global reference materials for serological tests available
 Need for establishing of appropriate BRPs/already ECBS endorsed
 WHO Consultation on 2-3 July 2007, WHO/HQ Geneva
 Reference Preparations for both screening and clinical diagnostics
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Epidemiological Information
WHO Collaborating Centres' Meeting (29-30 January 2007)
Points for discussion
 Changes of prevalence data of infectious agents
(variability, new variants, mutants)
 Emerging/re-emerging agents: investigation to assess the
relevance on blood and blood product safety
 Coordination and information exchange between the
WHO CCs and with other groups (e.g. WP-TTID/ISBT)
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New Tests and Emerging Technologies
WHO Collaborating Centres' Meeting (29-30 January 2007)
 New generations of ELISA systems/platforms
 New NAT approaches
 Emerging technologies:
– Chip technology (microarray)
– Nanotechnology-based assays
 Suitability of existing WHO Biological Reference
Preparations
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Priority Projects for Biological Reference Preparations
WHO Collaborating Centres' Meeting (29-30 January 2007)
2007
2008
2009
ECBS
HCV RNA (3rd)*
2007
Anti-syphilitic (2nd)*
2007
Anti-HBs
(2nd)*
2008
Anti-HBc*
2008
HIV-1 gt (2nd)**
2009
HIV-2 RNA*
2009
HBV gt1**
2009
Anti-HCV**
2009
Anti-T. cruzi**
2009
1two
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panels for HBsAg- and NAT-tests;
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Consultation
Feasibility studies
Collaborative study
*IS
**Panel
Future Projects for Biological Reference Preparations
WHO Collaborating Centres' Meeting (29-30 January 2007)
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New proposals (ECBS endorsement is needed):
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For further discussion:
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Anti-HTLV-1/2 antibody panel
Anti-Plasmodium species antibody panel
HIV-2 genotype panel
HCV genotype panel
B19V genotype panel
Anti-CMV antibody standard
WNV RNA preparation/pan panel for arthropod-borne flaviviruses RNA
HCV core antigen preparation
Preparations for anti-HHV-8 antibodies and HHV-8 DNA
TSE blood preparations
Blood-borne bacteria panel
Anti-Leishmania antibody panel
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Ways Forward for Collaboration
WHO Collaborating Centres' Meeting (29-30 January 2007)
 To monitor progress
– Annual face-to-face meetings
– Teleconferences
 Need to establish a network of WHO CCs for IVD-related
biological standardization representing all the WHO
Regions
– To ensure complementary and focused expertise at global level
 Master form sheet for future BRP proposals
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M. Chudy | 12 June 2007
Meeting of WHO Collaborating Centres for
Biological Standards and Standardization
Meeting Report:
Development of WHO Biological Reference
Preparations for blood safety-related in vitro
diagnostic tests
Shortly on the website:
www.who.int/bloodproducts/ivd/infectious_markers
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WHO Biological Reference Preparations
 Validation, quality control and comparability of IVD tests
(analytical sensitivity)
 Tool for identifying unsuitable diagnostic kits
 Tool for global regulation and harmonization in the IVD area
 Tool for regulatory bodies, manufacturers, product users
(physicians/scientists) to communicate in a "common language"
 Underpin the appropriate diagnoses of the disease
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WHO Collaborating Centres
for Biological Standards and Standardization
 WHO CCs: NIBSC, CBER, PEI
 WHO CCs represent the greatest know how and
experience in establishing global measurement standards
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Characterization of source materials
Freeze-drying procedure
Organizing collaborative studies
Custodian/distribution of reference materials
 In collaboration with manufacturers, regulatory bodies,
blood transfusion services, WHO CCs involved in
diagnostics of blood-borne infections, scientific experts,…
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