EBF EBF Survey: Quality Systems in Macromolecule Analysis Peter van Amsterdam (Solvay Pharmaceuticals, on behalf of EBF)
May 10, 2015
EBF
EBF Survey:
Quality Systems in
Macromolecule Analysis
Peter van Amsterdam (Solvay Pharmaceuticals,
on behalf of EBF)
EBF PvA - EBF Quality Survey, Seattle 2 24-Jun-09
Contents
1. EBF
2. Quality Systems
3. Survey
4. Outcome
EBF PvA - EBF Quality Survey, Seattle 3 24-Jun-09
History
Members
Scope
Organisation
E
B
F European Bioanalysis Forum
EBF PvA - EBF Quality Survey, Seattle 4 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 5 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 6 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 7 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 8 24-Jun-09
OECD & FDA GLP
ISO
CAP/CLIA
BMV
Q
U
A
L
I
T
Y
Quality Systems
EBF PvA - EBF Quality Survey, Seattle 9 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 10 24-Jun-09
Design
Response
Analysis
Survey
S
U
R
V
E
Y
EBF PvA - EBF Quality Survey, Seattle 11 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 12 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 13 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 14 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 15 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 16 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 17 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 18 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 19 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 20 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 21 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 22 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 23 24-Jun-09
BM Validation BM Analysis
0
10
20
30
40
50
60
70
80
90
100
GLP GLP-
like
Clin BMV Other None SOP QA
Validation
Application
O
U
T
C
O
M
E
EBF PvA - EBF Quality Survey, Seattle 24 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 25 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 26 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 27 24-Jun-09
Changes over phases: pre-clinical to clinical
Quantitative Assays
0
10
20
30
40
50
60
70
80
90
100
GLP GLP-
like
Clin BMV Other None SOP QA
Pre-clincal
Early Clinical
Late Clinical
O
U
T
C
O
M
E
EBF PvA - EBF Quality Survey, Seattle 28 24-Jun-09
Changes over phases: pre-clinical to clinical
Immunogenicity
0
10
20
30
40
50
60
70
80
90
100
GLP GLP-
like
Clin BMV Other None SOP QA
Pre-clincal
Early Clinical
Late Clinical
O
U
T
C
O
M
E
EBF PvA - EBF Quality Survey, Seattle 29 24-Jun-09
Changes over phases: pre-clinical to clinical
Conclusion …
O
U
T
C
O
M
E
EBF PvA - EBF Quality Survey, Seattle 30 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 31 24-Jun-09
Changes from validation to application
0
10
20
30
40
50
60
70
80
90
100
GLP GLP-
like
Clin BMV Other None SOP QA
Validation
Application
O
U
T
C
O
M
E
EBF PvA - EBF Quality Survey, Seattle 32 24-Jun-09
Changes from validation to application
Conclusion …..
O
U
T
C
O
M
E
EBF PvA - EBF Quality Survey, Seattle 33 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 34 24-Jun-09
Drug BM Immunogenicity
0
10
20
30
40
50
60
70
80
90
100
GLP GLP-
like
Clin BMV Other None SOP QA
Quantitative
Biomarkers
Immunogenicity
O
U
T
C
O
M
E
EBF PvA - EBF Quality Survey, Seattle 35 24-Jun-09
Differences between Drug BM
Immunogenicity
Conclusion …..
O
U
T
C
O
M
E
EBF PvA - EBF Quality Survey, Seattle 36 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 37 24-Jun-09
Differences between techniques:
Quantitative Assays
0
10
20
30
40
50
60
70
80
90
100
GLP GLP-
like
Clin BMV Other None SOP QA
Own LBA
Kit LBA
LC-MS
Multiplexing
Bioassay
Biochemical
Other
O
U
T
C
O
M
E
EBF PvA - EBF Quality Survey, Seattle 38 24-Jun-09
Differences between techniques:
Immunogenicity
0
10
20
30
40
50
60
70
80
90
100
GLP GLP-
like
Clin BMV Other None SOP QA
Screening
Confirmation
AB typing
Neutr. Functional
Neutr. Prolifiration
O
U
T
C
O
M
E
EBF PvA - EBF Quality Survey, Seattle 39 24-Jun-09
Differences between techniques
Conclusions …..
O
U
T
C
O
M
E
EBF PvA - EBF Quality Survey, Seattle 40 24-Jun-09
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 PvA - EBF Quality Survey, Seattle 41 24-Jun-09
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