Information Letter Regarding Important Safety Aspects to Optimize
Critical aspects regarding the application of GLP ... · Critical aspects regarding the application...
Transcript of Critical aspects regarding the application of GLP ... · Critical aspects regarding the application...
![Page 1: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/1.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
Critical aspects regarding the Critical aspects regarding the application of GLP Principles to application of GLP Principles to
new compounds such as new compounds such as biotechnology products biotechnology products
MariaMaria Mercede BrunettiMercede Brunetti
RTC RTC SpASpA ,, PomeziaPomezia , Rome, Italy, Rome, Italyee--mail:mail: mercebrmercebr @@rtcrtc .it.it
CoordinatorCoordinator --GLP group of GIQARGLP group of GIQAR
![Page 2: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/2.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
INTRODUCTION
• Introduction
• Applicable GLP Principles & guidelines
• Conclusions - Final considerations
• Examples (cases)
![Page 3: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/3.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
INTRODUCTION
Biopharmaceutical vs conventional products
• Biological & structural properties of product
� macromolecules (proteins, complexbiopolymers) vs small molecules (organic)
� biological/biotechnology-derived vsorganic synthesis
![Page 4: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/4.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
• Study types: in vitro test /analytical methods
� Test & reference items� Analytical aspects
� characterisation� analysis of doses� analysis of biological matrixes
(TK/PK, immunogenicity)
Biopharmaceutical vs conventional products
INTRODUCTION
![Page 5: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/5.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
GLP (OECD, 1997)
Applicable GLP Principles
GLP (Italy, 2007)
![Page 6: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/6.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
OECD Advisory Document No.: 14, 2004
Applicable GUIDELINES (1)
![Page 7: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/7.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
Applicable GUIDELINES (2)
ICH 6S, 1998
Farmacogenomics, 2005
Immunogenicity, 2008
![Page 8: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/8.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
FDA - Bioanalytical method validation, 2001
Workshop - AAPS/FDA, 2007
Immunoassay, 2004
FDA Warning letters
Applicable GUIDELINES (3)
![Page 9: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/9.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
OECD Advisory Document No.: 14, 2004
![Page 10: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/10.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
PURPOSE: To facilitate the proper application and interpretation of the GLP Principles for the organisation and management of in vitro studies
• standard regulatory tests
• new methods/areas ( ...omics)
• high trough-put screening tests
OECD Advisory Document No.: 14
![Page 11: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/11.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
APPLICATION
• Standard in vitro studies
OECD Advisory Document No.: 14
![Page 12: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/12.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
• in vitro methods (part of in vivo studies)APPLICATION
OECD Advisory Document No.: 14
![Page 13: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/13.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
EXAMPLES(cases)
![Page 14: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/14.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
CASE - 1a
•Test item protein (vaccine, Ab)
•Type of study 13 wks in...
•Study Plan includes the evaluation of immunogenicity(in responsive specie)
![Page 15: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/15.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
CASE - 1b
• REFERENCE ITEM ?
• ELISA TEST ?
![Page 16: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/16.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
CASE-1c: reference item
Ab: Antibody/reference item
• Preparation• Purification• Quantitation and ...
![Page 17: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/17.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
Ab: Preparation
• Must be prepared in a GLP study ?
CASE-1d: reference item
![Page 18: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/18.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
Ab : Purification
GLP - characterisation & labelling:
• identity , concentration, storage condition , preparation date, expiry/retest date
CASE - 1e: reference item
![Page 19: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/19.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
Ab: Quantitation and...
Ex.: in mg of protein/ml -Lowry
CASE-1f: reference item
GLP - characterisation & labelling:
• identity , concentration, storage condition , preparation date, expiry/retest date
Characterisation: meaning, extension ?
![Page 20: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/20.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
FDA Guidance - Bioanalytical Method Validation (2001) - in house STD:• source and lot number, expiration date, certificate of analysis when available, and/or evidence of identity and purity
Characterisation: meaning, extension ?
GLP - characterisation & labelling:
• identity , concentration, storage condition , preparation date, expiry/retest date
CASE-1h: reference item
![Page 21: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/21.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
CASE-1i: ELISA TEST
• set up• validation• analysis
![Page 22: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/22.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
CASE-1l: ELISA TEST
SET UP ad hoc per studio
![Page 23: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/23.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
CASE-1m: ELISA TEST
VALIDATION• Precision• Accuracy• LOQ (L/U) & range• Calibration curve• Matrix & buffer effects• Stability (freezing)
• acceptancecriteria
• reagents in house
• stability
![Page 24: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/24.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
ANALYSES
• Storage ofsamples
CASE-1n: ELISA TEST
• acceptancecriteria
• reagents in house
• stability
![Page 25: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/25.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
CASE-2: control matrix
� Characterisation ?
� Stability/retest date ?
� endogenous product ?
![Page 26: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/26.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
CASE - 3a
• Test item: recombinant protein (therapeutic use )
• Type of study: repeated toxicity
• Study Plan includes:� evaluation of immunogenicity
(immuno-response present/absent )
� kinetic analysis (non-chromatographic methods)
![Page 27: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/27.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
CASE - 3b
2 TYPES of TEST
• set up• validation• analysis
A: immunogenicity(test item + reference item - biosimilar)
B: kinetic (test item + reference item - biosimilar)
![Page 28: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/28.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
CASE - 3c
☯ ELISA test in house ☯ Commercial Ab - surrogate
(mono or policlonal ?)
(antigen : test item in vivo study and/or reference item -biosimilar)
☯ Response: YES/NO (cut point definition)
A: immunogenicity - qualitative/semiquantitative(test item + reference item - biosimilar)
![Page 29: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/29.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
CASE - 4a
• Test item DNA vaccine
• Type of studyrepeated toxicity
• Study Plan includes: biodistribution and evaluation ofimmunogenicity(in responsive strain)
![Page 30: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/30.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
CASE - 4b
A: biodistribution: PCR(Sponsor - non GLP site in a multisite study-OK phase I)
B: immunogenicity humoral and cell-mediated (validation ? acceptance criteria ? scientific publications ?)
2 TYPE of TEST
![Page 31: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/31.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
CASE - 4c
Semiquantitative analysis
☯ Humoral immunogenicity test� Reference item: commercial monoclonal Ab -
surrogate (calibration curve , QC)
� “ Test item ” : OGM (Balb 3T3/...antigen) - supplied by the Sponsor (through University)
Verification at receipt - acceptance (FACS- surrogate)
� Results analyses: criteria ?
![Page 32: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/32.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
CASE - 4d
☯ cell-mediated immunogenicity test� Primary cells (splenocytes) conjugated or not with
peptide + fluorochrome (antigen - high and low concentration)
� Inoculum in treated mice: fluorescence measurement in samples (FACS)
� Results analyses: criteria ?
GLP: enough internal preliminary test/s ?
Semiquantitative analysis
![Page 33: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/33.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
CASE - 5
� qualitative, quantitative andsemiquantitative analyses(PCR, FACS, ELISA, Multiplex, …)
Type of test: Biomarkers (exploratory)
![Page 34: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/34.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
• SCIENTIFIC PERSONNEL (SD)
• PERSONNEL - Technicians
Human Factors: manual activities, variability
FINAL CONSIDERATION
![Page 35: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/35.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
FINAL CONSIDERATION
![Page 36: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/36.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
FINAL CONSIDERATION
RELATE WITH AUTHORITIESRELATE WITH AUTHORITIESRELATE WITH AUTHORITIESRELATE WITH AUTHORITIES
![Page 37: Critical aspects regarding the application of GLP ... · Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products ... immunogenicity)](https://reader031.fdocuments.in/reader031/viewer/2022022607/5b8368fa7f8b9a940b8d05da/html5/thumbnails/37.jpg)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
THANKS to :
S. Cinelli & I. Andreini