EBF Survey: Quality Systems in Macromolecule Analysis

EBF
EBF Survey:
Quality Systems in
Macromolecule Analysis
Peter van Amsterdam
(Solvay Pharmaceuticals,
on behalf of EBF)

EBF
PvA - EBF Quality Survey, Seattle 224-Jun-09
Contents
1. EBF
2. Quality Systems
3. Survey
4. Outcome

EBF
 History
 Members
 Scope
 Organisation
E
B
F European Bioanalysis Forum

EBF
History
Oct 12th 2006 – Brussels
 In a “EU-DVDMDG type meeting”, over 10 EU companies,
together with some CROs, joined to discuss mostly ISR in an
open and stimulating atmosphere.
 At the end of the meeting a number of companies, formally
launched the idea of a broader European BA Organization
 Subsequent meetings in Berlin and Basel saw an increasing
number of participants and proved a keen interest among EU
bioanalysts in such an organization
E
B
F

EBF
Members (June 2009)
1. Abbott
2. Actelion Ltd
3. Active Biotech
4. Almirall
5. Astellas
6. AstraZeneca
7. Bayer Schering Pharma AG
8. Boehringer-Ingelheim
9. Ferring Pharmaceuticals A/S
10. Grünenthal GmbH
11. GSK
12. F. Hoffmann-La Roche
13. Johnson & Johnson
14. H. Lundbeck A/S
15. Merck&Co
16. Merck Serono
17. Novartis Pharma AG
18. Novo Nordisk
19. Nycomed
20. Schering-Plough
21. Orion Corp. Orion Pharma
22. Pfizer
23. Sanofi-Aventis
24. Servier
25. Shire Pharmaceuticals
26. Solvay Pharmaceuticals
27. UCB Pharma
E
B
F

EBF
Scope
 Our focus is bioanalysis within pharmaceutical R&D
 Bioanalysis is defined as :
– quantification of small and large MW drug and metabolites
in body fluids and tissues
– quantification of PD and safety biomarkers amenable to
conventional bioanalytical techniques (binding assays,
chromatographic assays)
– bioanalytical characterization of biologicals
 Identified areas for discussion are :
– Science
– Procedures
– Business tools and Technology
– Regulations
E
B
F

EBF
How are we organized ?
 Steering committee meetings:
– Philip Timmerman (Johnson & Johnson),
– Berthold Lausecker (F. Hoffmann-La Roche )
– Margarete Brudny-Klöppel (Bayer Schering Pharma AG )
– Peter van Amsterdam (Solvay Pharmaceuticals)
– Silke Lüdtke (Boehringer-Ingelheim)
 Closed meetings:
– For member companies only
– Frequency and venue: twice per year (winter and early
summer) in Basel area
 Open meetings:
– Including CRO, regulatory bodies, academia, vendors,
others
– Frequency and venue: yearly (December) in Barcelona
E
B
F

EBF
 OECD & FDA GLP
 ISO
 CAP/CLIA
 BMV
Q
U
A
L
I
T
Y
Quality Systems

EBF
Quality systems as described in the survey
GLP Work is performed in compliance with OECD and/or FDA GLP
GLP-like In agreement with the general principles of GLP and/or run in a GLP
compliant facility without claiming compliance.
BMV Bioanalytical Method Validation. Adherence to applicable parts of FDA's
BMV guideline on small molecules and e.g. relevant literature on BMV of
LBAs
Clin Quality systems used in clinical laboratories or in general labs performing
diagnistics tests. Often referred to as CLIA or CAP/CLIA certified (US).
Similar sytems are applicable in EU (with country specific flavors and
accronyms)
CAP = College of American Pathologists. CLIA = Clinical Laboratory
Improvement Amendments
Other Use the cells in the column when none of the above quality systems is
applicable and indicate your quality system in the comments field (QMS,
ISO17025, … )
None No systems in use nor in place: 'free research'
Q
U
A
L
I
T
Y

EBF
 Design
 Response
 Analysis
Survey
S
U
R
V
E
Y

EBF
Design & History
 Quantitative Assays & Immunogenicity
 Biopharmaceuticals & Biomarkers
 Pre-clinical & Clinical phases
 Tabular fashion: easy data entry
 Version 1. Designed by EBF-IGM SC
– distributed during fall 2008 within EBF
– discussed during EBF-IGM meeting on 3-dec-08
 Version 2. EBF-IGM members version
– distributed 13-Mar-09 within EBF
– distributed 20-Apr-09 within LBABFG (US)
– reminder 26-May-09 within LBABFG (WW)
S
U
R
V
E
Y

EBF
Quantitative Assays: Biopharmaceuticals &
Biomarkers
GLP GLP-like Clin BMV Other None Yes No Yes No
In-house developed
immunoassay
Commercial
immunoassay (kit)
Instrumental (LC-
MS)
Multiplexing
(Luminex, MSD)
Bioassay
Biochemical assay
Other
QA
involvement
?
Quality System SOP
driven?
Comments
S
U
R
V
E
Y

EBF
Immunogenicity: Biopharmaceuticals
GLP GLP-like Clin BMV Othe
r
Non
e
Yes No Yes No
Screening assay
Confirmation
assay
AB (sub)typing
Neutralisation
assay
Neutralisation
assay (functional)
QA
involveme
nt?
Quality System SOP
driven?
Comments
S
U
R
V
E
Y

EBF
Response
 16 from EBF-IGM
– 20 members att
– Pharma companies only
 5 + 6 from LBABFG
– US (400+) + ROW (~400) members
– Pharma + CROs
 EBF outcome representative for EU industry
 LBABFG: number to small to draw region or business type
specific conclusions
 All data merged: 27 surveys x 8 quality levels x 2 stages x (7
quantitative assays x 5 areas + 5 immunogenicity assays x 3
areas) = 21600
S
U
R
V
E
Y

EBF
Analysis
 Merge 27 surveys (adding up all the x’s)
 For each type of assay, express Quality System use as
percentage of the total (ex BMV) assay use
 BMV as percentage of total
 SOP use: percentage Yes of Yes + No
 QA involvement: percentage Yes of Yes + No
S
U
R
V
E
Y
GLP GLP-like Clin BMV Other None Yes No Yes No
In-house developed
immunoassay
SOP
driven?
QA
involvement
?
Quality System

EBF
Outcome
 General aspects
 Questions & Answers
– Differences between Novel & Known
biomarkers?
– Changes over phases: pre-clinical to clinical?
– Changes from validation to application?
– Differences between Drug <-> BM <->
Immunogenicity?
– Differences between techniques?
O
U
T
C
O
M
E

EBF
Quantitative Assays: Relative Use per Type
0
5
10
15
20
25
30
35
Pre-clinical Early
Clinical
Late Clinical Novel BM Known BM
Own LBA
Kit LBA
LC-MS
Multiplexing
Bioassay
Biochemical
Other
O
U
T
C
O
M
E

EBF
Immunogenicity: Relative Use per Type
0
5
10
15
20
25
30
35
Pre-clinical Early Clinical Late Clinical
Screening
Confirmation
AB typing
Neutr. Functional
Neutr. Prolifiration
O
U
T
C
O
M
E

EBF
 Differences between Novel & Known biomarkers?
 Changes over phases: pre-clinical to clinical?
 Changes from validation to application?
 Differences between Drug  BM  Immunogenicity?
 Differences between techniques?
Questions & Answers
O
U
T
C
O
M
E

EBF
Biomarkers: Novel  Known
 Novel Biomarker: An analyte that is measured by
an in vitro test or specialized technology which is
NOT available as a routine clinical lab test
 Known Biomarker: An analyte that is measured by
an in vitro test or specialized technology which is
available as a routine clinical lab test
O
U
T
C
O
M
E

EBF
Novel  Known Biomarkers
From: Ronald R. Bowsher - Challenges in Validating Test Kits for Quantification of
Biomarkers – Presented at BIOVAL 2004
Clinical
Assays
Safety
Assessments
PK
Assessments
Drug
Assays
Novel
Biomarker
Assays
Natural History
Biologic Activity / PD
Safety
Surrogates
Routine
Biomarkers
CLIA GLP
Novel
Biomarkers?
O
U
T
C
O
M
E

EBF
Novel BM  Known BM
0
10
20
30
40
50
60
70
80
90
100
GLP GLP-
like
Clin BMV Other None SOP QA
Novel BM
Known BM
O
U
T
C
O
M
E

EBF
BM Validation  BM Analysis
0
10
20
30
40
50
60
70
80
90
100
GLP GLP-
like
Validation
Application
O
U
T
C
O
M
E

EBF
Differences between Novel & Known
biomarkers
 Conclusion:
Overall, on average, the is little to no difference in
how pharma validates and runs methods for novel
and for known biomarkers
O
U
T
C
O
M
E

EBF
Questions & Answers
O
U
T
C
O
M
E

EBF
Changes over phases: pre-clinical to clinical
Expectations:
 Pre-clinical phase: GLP (e.g. toxicokinetics)
 Early Clinical: part of the assays may be of
‘research’ nature
 Late Clinical: more contracted out, more focus on
proof, safety & efficacy, BEq, …
O
U
T
C
O
M
E

EBF
Quantitative Assays
0
10
20
30
40
50
60
70
80
90
100
GLP GLP-
like
Pre-clincal
Early Clinical
Late Clinical
O
U
T
C
O
M
E

EBF
Immunogenicity
0
10
20
30
40
50
60
70
80
90
100
GLP GLP-
like
Pre-clincal
Early Clinical
Late Clinical
O
U
T
C
O
M
E

EBF
 Conclusion
…
O
U
T
C
O
M
E

EBF
Questions & Answers
O
U
T
C
O
M
E

EBF
Changes from validation to application
0
10
20
30
40
50
60
70
80
90
100
GLP GLP-
like
Validation
Application
O
U
T
C
O
M
E

EBF
Changes from validation to application
 Conclusion
…..
O
U
T
C
O
M
E

EBF
Questions & Answers
O
U
T
C
O
M
E

EBF
Drug  BM  Immunogenicity
0
10
20
30
40
50
60
70
80
90
100
GLP GLP-
like
Quantitative
Biomarkers
Immunogenicity
O
U
T
C
O
M
E

EBF
Differences between Drug  BM 
Immunogenicity
 Conclusion
…..
O
U
T
C
O
M
E

EBF
Questions & Answers
O
U
T
C
O
M
E

EBF
Differences between techniques:
Quantitative Assays
0
10
20
30
40
50
60
70
80
90
100
GLP GLP-
like
Own LBA
Kit LBA
LC-MS
Multiplexing
Bioassay
Biochemical
Other
O
U
T
C
O
M
E

EBF
Differences between techniques:
Immunogenicity
0
10
20
30
40
50
60
70
80
90
100
GLP GLP-
like
Screening
Confirmation
AB typing
Neutr. Functional
Neutr. Prolifiration
O
U
T
C
O
M
E

EBF
Differences between techniques
 Conclusions
…..
O
U
T
C
O
M
E

EBF
Acknowledgement
 For filling in the survey:
 For discussion & review: All EBF members
ABC Labs Novartis
Active Biotech Novo Nordisk
Amgen Pfizer
Anapharm Questpharm
Astellas Roche
Astra-Zeneca Sanofi-Aventis
Bayer Schering Schering-Plough
Boehringer-Ingelheim Shire
Ferring Solvay Pharmaceuticals
Genzyme Vimta
Johnson & Johnson Wyeth
Merck-Serono Xendo

EBF
And …
 EBF website (under development)
– http://www.europeanbioanalysisforum.eu
 EBF 2nd Open Conference:
The Broadening Scope of Validation
– 2 – 4 December 2009, Barcelona, Spain
– http://www.bioanalysis-forum.com

EBF Survey: Quality Systems in Macromolecule Analysis

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