Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products

Transcription

1 Critical aspects regarding the application of GLP Principles to new compounds such as biotechnology products Maria Mercede Brunetti RTC SpA, Pomezia,, Rome, Italy Coordinator-GLP group of GIQAR

2 INTRODUCTION Introduction Applicable GLP Principles & guidelines Examples (cases) Conclusions - Final considerations

3 INTRODUCTION Biopharmaceutical vs conventional products Biological & structural properties of product macromolecules (proteins, complex biopolymers) vs small molecules (organic) biological/biotechnology-derived vs organic synthesis

4 INTRODUCTION Biopharmaceutical vs conventional products Study types: in vitro test /analytical methods Test & reference items Analytical aspects characterisation analysis of doses analysis of biological matrixes (TK/PK, immunogenicity)

5 Applicable GLP Principles GLP (OECD, 1997) GLP (Italy, 2007)

6 Applicable GUIDELINES (1) OECD Advisory Document No.: 14, 2004

7 Applicable GUIDELINES (2) ICH 6S, 1998 Farmacogenomics, 2005 Immunogenicity, 2008

8 Applicable GUIDELINES (3) FDA - Bioanalytical method validation, 2001 Workshop - AAPS/FDA, 2007 Immunoassay, 2004 FDA Warning letters

9 OECD Advisory Document No.: 14, 2004

10 OECD Advisory Document No.: 14 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

11 OECD Advisory Document No.: 14 APPLICATION Standard in vitro studies

12 OECD Advisory Document No.: 14 APPLICATION in vitro methods (part of in vivo studies)

13 EXAMPLES (cases)

14 CASE - 1a Test item protein (vaccine, Ab) Type of study 13 wks in... Study Plan includes the evaluation of immunogenicity (in responsive specie)

15 CASE - 1b REFERENCE ITEM? ELISA TEST?

16 CASE-1c: reference item Ab: Antibody/reference item Preparation Purification Quantitation and...

17 CASE-1d: reference item Ab: Preparation Must be prepared in a GLP study?

18 CASE - 1e: reference item Ab: Purification GLP - characterisation & labelling: identity, concentration, storage condition, preparation date, expiry/retest date

19 CASE-1f: reference item Ab: Quantitation and... Ex.: in mg of protein/ml - Lowry GLP - characterisation & labelling: identity, concentration, storage condition, preparation date, expiry/retest date Characterisation: meaning, extension?

20 CASE-1h: reference item Characterisation: meaning, extension? 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 GLP - characterisation & labelling: identity, concentration, storage condition, preparation date, expiry/retest date

21 CASE-1i: ELISA TEST set up validation analysis

22 CASE-1l: ELISA TEST SET UP ad hoc per studio

23 CASE-1m: ELISA TEST VALIDATION acceptance criteria reagents in house stability Precision Accuracy LOQ (L/U) & range Calibration curve Matrix & buffer effects Stability (freezing)

24 CASE-1n: ELISA TEST ANALYSES acceptance criteria reagents in house stability Storage of samples

25 CASE-2: control matrix Characterisation? Stability/retest date? endogenous product?

26 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)

27 set up CASE - 3b 2 TYPES of TEST A: immunogenicity (test item + reference item - biosimilar) B: kinetic (test item + reference item - biosimilar) validation analysis

28 CASE - 3c A: immunogenicity - qualitative/semiquantitative (test item + reference item - biosimilar) 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)

29 CASE - 4a Test item DNA vaccine Type of study Study Plan repeated toxicity includes: biodistribution and evaluation of immunogenicity (in responsive strain)

30 CASE - 4b 2 TYPE of TEST 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?)

31 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?

32 CASE - 4d Semiquantitative analysis 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?

33 CASE - 5 Type of test: Biomarkers (exploratory) qualitative, quantitative and semiquantitative analyses (PCR, FACS, ELISA, Multiplex, )

34 FINAL CONSIDERATION SCIENTIFIC PERSONNEL (SD) PERSONNEL - Technicians Human Factors: manual activities, variability

35 FINAL CONSIDERATION

36 FINAL CONSIDERATION RELATE WITH AUTHORITIES

37 THANKS to: S. Cinelli & I. Andreini