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...
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
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INTRODUCTION
• Introduction
• Applicable GLP Principles & guidelines
• Conclusions - Final considerations
• Examples (cases)
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INTRODUCTION
Biopharmaceutical vs conventional products
• Biological & structural properties of product
� macromolecules (proteins, complexbiopolymers) vs small molecules (organic)
� biological/biotechnology-derived vsorganic synthesis
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• 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
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GLP (OECD, 1997)
Applicable GLP Principles
GLP (Italy, 2007)
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OECD Advisory Document No.: 14, 2004
Applicable GUIDELINES (1)
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Applicable GUIDELINES (2)
ICH 6S, 1998
Farmacogenomics, 2005
Immunogenicity, 2008
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FDA - Bioanalytical method validation, 2001
Workshop - AAPS/FDA, 2007
Immunoassay, 2004
FDA Warning letters
Applicable GUIDELINES (3)
OECD OECD EventEvent , Villa , Villa TuscolanaTuscolana , Frascati (Roma), , Frascati (Roma), ItalyItaly , , AprilApril 10 10 –– 11,11, 2008 2008
OECD Advisory Document No.: 14, 2004
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
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APPLICATION
• Standard in vitro studies
OECD Advisory Document No.: 14
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• in vitro methods (part of in vivo studies)APPLICATION
OECD Advisory Document No.: 14
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EXAMPLES(cases)
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CASE - 1a
•Test item protein (vaccine, Ab)
•Type of study 13 wks in...
•Study Plan includes the evaluation of immunogenicity(in responsive specie)
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CASE - 1b
• REFERENCE ITEM ?
• ELISA TEST ?
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CASE-1c: reference item
Ab: Antibody/reference item
• Preparation• Purification• Quantitation and ...
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Ab: Preparation
• Must be prepared in a GLP study ?
CASE-1d: reference item
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Ab : Purification
GLP - characterisation & labelling:
• identity , concentration, storage condition , preparation date, expiry/retest date
CASE - 1e: reference item
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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 ?
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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
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CASE-1i: ELISA TEST
• set up• validation• analysis
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CASE-1l: ELISA TEST
SET UP ad hoc per studio
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CASE-1m: ELISA TEST
VALIDATION• Precision• Accuracy• LOQ (L/U) & range• Calibration curve• Matrix & buffer effects• Stability (freezing)
• acceptancecriteria
• reagents in house
• stability
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ANALYSES
• Storage ofsamples
CASE-1n: ELISA TEST
• acceptancecriteria
• reagents in house
• stability
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CASE-2: control matrix
� Characterisation ?
� Stability/retest date ?
� endogenous product ?
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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)
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CASE - 3b
2 TYPES of TEST
• set up• validation• analysis
A: immunogenicity(test item + reference item - biosimilar)
B: kinetic (test item + reference item - biosimilar)
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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)
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CASE - 4a
• Test item DNA vaccine
• Type of studyrepeated toxicity
• Study Plan includes: biodistribution and evaluation ofimmunogenicity(in responsive strain)
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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
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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 ?
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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
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CASE - 5
� qualitative, quantitative andsemiquantitative analyses(PCR, FACS, ELISA, Multiplex, …)
Type of test: Biomarkers (exploratory)
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• SCIENTIFIC PERSONNEL (SD)
• PERSONNEL - Technicians
Human Factors: manual activities, variability
FINAL CONSIDERATION
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FINAL CONSIDERATION
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FINAL CONSIDERATION
RELATE WITH AUTHORITIESRELATE WITH AUTHORITIESRELATE WITH AUTHORITIESRELATE WITH AUTHORITIES
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THANKS to :
S. Cinelli & I. Andreini