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 2 24-Jun-09

Contents

1. EBF

2. Quality Systems

3. Survey

4. Outcome


History

Members

Scope

Organisation

E

B

F European Bioanalysis Forum


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


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


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


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


OECD & FDA GLP

ISO

CAP/CLIA

BMV

Q

U

A

L

I

T

Y

Quality Systems


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


Design

Response

Analysis

Survey

S

U

R

V

E

Y


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


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


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


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


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


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


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


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


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


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


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


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


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


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







Questions & Answers

O

U

T

C

O

M

E


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



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



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



Conclusion …

O

U

T

C

O

M

E







Questions & Answers

O

U

T

C

O

M

E


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


Changes from validation to application

Conclusion …..

O

U

T

C

O

M

E







Questions & Answers

O

U

T

C

O

M

E


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


Differences between Drug BM

Immunogenicity

Conclusion …..

O

U

T

C

O

M

E







Questions & Answers

O

U

T

C

O

M

E


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


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


Differences between techniques

Conclusions …..

O

U

T

C

O

M

E


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


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

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