GLP Annual Meeting - belgian glp monitoring authority

Transcription

SCIENTIFIC INSTITUTE OF PUBLIC HEALTH Bureau of Quality Assurance 16th GLP Annual Meeting Brussels, 9 November 2011 HEAD OFFICE
Rue Juliette Wytsmanstraat 14
1050 Brussels | Belgium
T +32 2 642 51 11
F +32 2 642 50 01
SITE UCCLE | SITE UKKEL
Rue Engelandstraat 642
1180 Brussels | Belgium
T +32 2 373 31 11
F +32 2 373 32 82
www.wiv-isp.be
www.glp.be
Science at the service of Public health, Food Chain Safety and Environment
GLP Annual Meeting 2011 Programme 08h15 ‐ 09h00 Registration of the participants 09h00 ‐ 09h05 Welcome word (P. Cliquet ‐ QA Manager, WIV‐ISP) p. 3 09h05 ‐ 09h20 Belgian GLP programme, 2011‐2012 (G. Jacobs ‐ GLP Coordinator, WIV‐ISP) p. 5 09h20 ‐ 09h40 Feedback from EC and OECD meetings (M. Schmahl ‐ EC Enterprise and Industry DG) p. 9 09h40 ‐ 09h50 Inspections in China (M. Baeten, WIV‐ISP) p. 15 09h50 ‐ 10h30 Good Clinical Laboratory Practice (E. Berteloot, Janssen Pharmaceutica, R&DQA) p. 17 10h30 ‐ 10h50 Coffee break 10h50 ‐ 11h30 Use of electronic systems in a GLP environment (E. Vanheule, Ablynx) p. 29 11h30 ‐ 12h10 Archiving Anno 2011 (M. Smets, MERAK) p. 51 12h10 ‐ 13h45 Lunch (walking dinner) 13h45 ‐ 14h30 CROs and GLP multisite studies – challenges with Sponsor‐conducted phases (L. Gillbanks, Covance, UK) p. 61 14h30 ‐ 14h50 Coffee break 14h50 ‐ 16h15 Technical issues (GLP inspectors, WIV‐ISP) p. 65 List of participants p. 71 16th GLP Annual Meeting
16th Annual GLP meeting
Welcome word
BQA-GLP Monitorate
Brussels, 9 November 2011
Rue Juliette Wytsmanstraat 14 | 1050 Brussels | Belgie
T +32 2 642 5230| email: BKZ@WIV-ISP.fgov.be | site web: www.GLP.be; https://intranet.WIVISP.fgov.be/
Programme
09h00-09h05 : Welcome word (P. Cliquet, WIV-ISP)
09h05-09h20 : Belgian GLP programme, 2011-2012
(G. Jacobs, WIV-ISP)
09h20-09h40 : Feedback from EC & OECD meetings
(M. Schmahl, EC Enterprise and Industry DG)
09h40-09h50 : Inspections in China (M. Baeten, WIV-ISP)
09h50-10h30 : GCLP (E. Berteloot, Janssen Pharmaceutica, R&DQA)
10h30-10h50 : Coffee break
2
Programme
10h50-11h30 : Use of electronic systems in a GLP environment
(E. Vanheule, Ablynx)
11h30-12h10 : Archiving Anno 2011 (M. Smets, MERAK)
12h10-13h45 : Walking dinner
3
Scientific Institute of Public Health
p. 3 of 76
16th GLP Annual Meeting
Programme
13h45-14h30 : CROs and multisite studies with Sponsorconducted study phase(s) (L. Gillbanks, Covance)
14h30-14h50
14h30
14h50 : Coffee break
14h50-16h15 : Technical issues (GLP inspectors, WIV-ISP)
4
Practical information
•
Certificate of attendance
•
Satisfaction inquiry
•
Badges recuperation at the end of the meeting
•
Smoking: only outside the building
•
Lunch: walking dinner at another room
•
A draft agenda of next year inspections is available for
discussion
Slides of speakers will be placed on www.glp.be (documents)
•
5
Team of GLP Inspectors,
update
•
QA Manager : P. Cliquet
•
GLP Coordinator: G. Jacobs
•
GLP inspectors:
•
E. Mairiaux
•
A.M. Vanherle
•
S. Carbonnelle
•
V. Draguet
•
A. Schoonjans
•
M. Baeten
6
p. 4 of 76
Belgian GLP programme, 2011-2012
Belgium
BQA-GLP Monitorate
T +32 2 642 5230| email: BKZ@iph.fgov.be | site web: www.GLP.be; https://intranet.iph.fgov.be/
GLP inspections 2011 of
Belgian test facilities
• 18 Test Facilities in the Belgian GLP programme
• 7 full GLP inspections performed
• 2 contract archives visited
• Merak
• Iron
I
M
Mountain
t i
• 3 pre-inspections
• Immune Health
• Galephar
• Bayer Crop Science
• 2 test facilities left the programme
• Philip Morris
• Thrombogenics
2
GLP Joint inspections
EPA_US(June 2011)
The Netherlands (June 2011)
•
•
3
p. 5 of 76
Contacts with Receiving
Authorities
Requests to verify the GLP status of test facilities in the OECD
•
database
Request to verify the GLP status of an analytical certificate
Questions about GLP principles
•
•
•
Informing about Non-compliance notifications
Test facility inspection reports
•
Discussion with Receiving Authorities about interpretation of
•
principles and observed non-compliances
Invitations to attend inspection
•
4
Training courses
•
Belgian training course, May 2011
•
•
•
•
•
test item/system characterisation,
study plan and report,
archiving,
g,
computer validation
Malaysia: training course, June 2011
•
computer validation (EM)
Meetings & workshops:
•
Croatia: TAIEX GLP workshop
•
•
December 2010_Zagreb
Germany: 16th DGGF International Meeting
•
September 2011_Berlin
p. 6 of 76
Training of inspectors
•
OECD training course for GLP inspectors
•
•
Jerusalem (Israel)
• S. Carbonnelle
• A. Schoonjans
j
• M. Baeten
GAMP computer validation
•
Barcelona (Spain)
• G. Jacobs
GLP working groups
•
•
EC GLP working group, March 2011
OECD GLP working group, April 2011
OECD Discussion forum
•
Include government and industry representatives from
international trade associations and quality groups.
•
Key area 1:
The discussion group will ask members to flag inconstancies in
the way international inspectorates view some areas of GLP
compliance. Members of the group will be asked to provide clear
examples of differences in approach taken by international
inspectorates and how these impact on their members.
p. 7 of 76
•
Key area 2:
Discussion group members should be asked to flag any
concerns they have about the application of GLP to emerging
technologies. They should be encouraged to clearly identify why
the current principles are likely be difficult to apply to the new
methodologies/ technologies.
•
The discussion group will limit its self to matters which relate to
the above topics. Key areas of discussion will be reviewed on an
annual basis.
•
•
•
•
•
•
•
•
•
•
•
European Federation of Pharmaceutical Industries and Associations (EFPIA)
(Europe) (WG contact Guido Jacobs, Belgium)
FARMAINDUSTRIA (Spain) (WG contact Ignacio Moreno)
Association of the British Pharmaceutical Industry. (ABPI) (UK) (WG contact
Andrew Gray)
French Association for Quality Assurance (SoFAQ) (France) (WG contact
Dominique Abdon)
B iti h A
British
Association
i ti
off R
Research
hQ
Quality
lit A
Assurance (BARQA) (UK) (WG contact
t t
Andrew Gray)
Danish Quality Assurance Group (DKGQA)(Denmark) (WG contact Annette
Hansen)
Swedish Association of Research Quality Assurance (SARQA) (Sweden) (WG
contact Annette Hansen)
German Society for Good Research Practice (DGGF e. V.) (Germany) (WG
contact Wolf Bulling)
Swiss Professional Association of Quality Assurance (SPAQA) (Switzerland)
(WG contact Christoph Moor)
Dutch Association of Research Quality Assurance (DARQA) (Netherlands) (WG
Contact Rob Jaspers)
IT Group for Quality Assurance in Research ( GIQAR) (Italy) (WG contact Bonette
Francesco)
Chinese test facility inspections
•
See presentation of Martijn Baeten
p. 8 of 76
GLP: feedback from EU and
OECD meetings
Maik Schmahl
Chemicals unit –
Brussels, 9/11/2011
Classification & Labelling, Specific Products, Competitiveness
EU GLP WORKING GROUP Helsinki 2011
• Technical issues group on 2 March
• Plenary GLP working group on 3 March
Co-operation with receiving authorities
• Registration / authorisation: GLP claim verification
procedure applies in case of compliance checks and
testing proposals.
• Implications of the GLP requirement for restriction
dossiers and the designation of substances of very
high concern still need to be worked out
• In case of study audit requests:
ECHA contacts
=> REACH competent authority of (lead) registrant
=> GLP monitoring authority
p. 9 of 76
• ECHA accepts GLP data from 3rd countries that are
full OECD adherents and provisional adherents
where laboratory inspections have taken place jointly
with an OECD GLP monitoring authority.
• Other data can be accepted if the laboratory has
been inspected prior to the performance of the study
by an EU or the Norwegian (EEA), Swiss, Japanese
or Israel monitoring authorities (MRA).
• On a case-by-case basis, inspections by other OECD
GLP monitoring authorities outside of their national
territory may also be recognised.
• ECHA
asked to be informed about severe problems
identified during inspections
warned
d off a possibly
ibl hi
high
h number
b off contacts
t t via
i
the REACH competent authorities because of the
high number of dossiers under evaluation
announced that it may send further technical
questions to the GLP monitoring authorities.
• Will continue to participate in the EU
GLP working group meetings
• Possibly separate meetings with the
GLP monitoring authorities active in its
area and the responsible Commission
service.
p. 10 of 76
• In 2010, the Committee on Human Medicinal Products
(CHMP) requested four study audits linked to two test
facilities in the USA and one in India.
• In 2011, there has so far been one study audit request
regarding a facility in Canada.
CHMP has later withdrawn the study audit requests,
requests but the
agency did recommend to the Canadian monitoring authority
to include the laboratory in its monitoring programme.
• Standard operating procedure for requesting study audits
is working well
• GLP again on agenda of one of the next safety working
parties in order to raise awareness.
Pesticides
• In general, all studies submitted to EFSA for
active substances and plant protection products
should be GLP studies.
• In 2010, EFSA prepared 73 conclusions on active
substances, involving around 30.000 GLP
studies.
• The role of EFSA in this process is that of a peer
reviewer, while the rapporteur Member State is
bearing the responsibility for the initial
evaluation.
Pesticides
• The decision of EFSA to take its own initiative
regarding GLP in the area of plant protection
products was welcomed. Preferably, EFSA
should have a reason for requesting study audits.
• EFSA was encouraged to select specific studies
which are of interest to it and to communicate the
names of the studies to the GLP monitoring
authority undertaking scheduled inspections.
• Inspectors then could look at these studies
during an inspection instead of picking out
studies at random.
p. 11 of 76
Representation at OECD after the Lisbon Treaty
• The Commission informed that it will be inscribed by
the Delegation of the European Union to the OECD
as EU and not as EC anymore
• The Lisbon Treaty also requires an enhanced prior
coordination
Commission will in the future coordinate the positions of the
EU Member States (and if applicable of the External Action
Service) regarding questions from the OECD Secretariat on
the participation of third countries in the OECD GLP working
group and its activities.
Commission will also provide a standard reply regarding the
EU legislation in force to the Member States for use in the
OECD questionnaires.
New members and new Member States
• Bulgaria is still waiting for the first
laboratory to apply for an inspection.
• Latvia announced that it already has a
laboratory in its programme, which
should be revisited soon with the help of
GLP inspectors from another Member
State.
• Turkey announced that its GLP
programme will be fully operational by
the end of 2011.
OECD GLP WORKING GROUP,
PARIS, 5 to 7 April 2011
• Four countries had become OECD members
since the last meeting: Chile, Israel,
Slovenia and Estonia.
• Brasil and India had very recently become
full adherents to the OECD Council's Mutual
Acceptance of Data Decision.
• On-site evaluation of Argentina: in
conformity. Monitoring authority OAA is
currently only responsible for pesticides,
industrial chemicals and biocides.
p. 12 of 76
OECD GLP WG
• Malaysia: The two monitoring authorities of Malaysia declared
that they are ready for an evaluation visit in the near future.
• Thailand indicated that it would apply for an evaluation visit in
January 2012.
• Taiwan informed that it has been evaluated by the US EPA,
which came to the conclusion that its GLP monitoring
EPA's.
programme is compatible to EPA
s. However, OECD waits for
mainland China.
• Russia is an OECD accession country and said to be ready to
start building up two GLP monitoring programmes (one for
medicinal and veterinary products, the other for all other types of
chemicals). Whole process could take 2 to 3 years before an
evaluation visit can be organised.
OECD GLP WG: guideline on
bioanalytical method validation
• FDA and EMA had worked together
• FDA representative came to the
conclusion
co
c us o that
t at the
t e document
docu e t prepared
p epa ed
by EMA is very reasonable and that no
additional OECD guidance needs to be
developed.
• The other members of the working
group agreed.
OECD GLP WG: Position paper on
accreditation and GLP
• Following a proposal from the European
Union, a small working group was set
up to draft an internal document, which
should not be spread to the wider public
before further discussion.
• The EU will be the convenor of the subgroup, and will be joined by Australia,
Denmark (DANAK), Spain (ENAC),
Italy, Japan, Sweden (SWEDAC),
Singapore, Slovakia and US EPA.
p. 13 of 76
OECD GLP WG: other issues
•
Training course for GLP inspectors: 58 participants from 29
countries had registered until March for the next OECD GLP training
course in Israel
•
Discussion group to consider harmonisation issues resulting from the
2008 industry event, in particular in the light of technical progress.
Nominated EU industry representative organisations include:

European Federation of Pharmaceutical Industries and Associations (EFPIA)
The European Chemical Industry Council. (CEFIC)
French Association for Quality Assurance (SoFAQ)
British Association of Research Quality Assurance (BARQA)
DKG –Denmark
SARQA - Sweden
FARMAINDUSTRIA (Spain)
German Society for Good Research Practice (DGGF e. V.)
Association of the British Pharmaceutical Industry. (ABPI)
Dutch Association of Research Quality Assurance (DARQA)
Any questions ?
Disclaimer :
This presentation does not constitute any formal
commitment on behalf of the European Commission and
represents the views and opinions of its author only.
p. 14 of 76
Inspection programme in
China
BQA-GLP Monitorate
GLP inspections 2011 of
Chinese test facilities
• 7 Test Facilities in the Belgian GLP program
• 5 full GLP inspections done
p
by
y Belgium
g
• Visit of new candidates for a GLP-inspection
• Gaiton – Hope
• Suzhou Xishan Zhongke Drug Research & Development
Co., Ltd.- Chemicals Safety Testing Center
• CDSER_Shanghai Institute of Materia Medica
• Meeting with new candidates for a GLP-inspection by Belgium
• Joinn Laboratories
• Ningbo Center of Chemical Safety Evaluation
2
Chinese test facilities
-
FMC,Chemical Technology Consulting Co, Shanghai
-
NutriChem Beijing
-
Pilarquim (Shanghai) Co
Co., LTD
-
Laprode Analysis Co., LTD
-
Covance, Shanghai
-
-
-
-
-
CRO: analytical & chemical testing
CRO: physical-chemical testing, analytical and clinical chemistry testing
and stability tests
CRO: physical-chemical studies
CRO: physical-chemical studies
CRO: toxicity studies, analytical and clinical chemistry testing
-
Wuxi AppTec Shanghai
-
Wuxi AppTec Suzhou
-
-
CRO: ADME studies, toxicokinetic and pharmacokinetic studies, hERG
assay and biomarker studies
CRO: toxicology and mutagenicity studies
3
p. 15 of 76
Inspection in non-MAD Country
•
On request of Belgian/or European sponsor, intending to do a
registration in Belgium/European Agency (EMA, ECHA, EFSA).
•
Focus on Test facility inspection. Study audits at random. By
preference pre-inspection by QA sponsor or consultant.
•
Asking for audits on sponsor specific studies remains
responsibility of receiving authority!
•
One study/study type/SD
•
All documents (including raw data) must be available in English
4
Certificate for Belgian Test
facility vs. Chinese Test Facility
Although a Chinese test facility can be found in compliance after
an inspection, this is not a guarantee for the Test Facilities that
their data will be accepted by the OECD member contries. Each
receiving authority may decide to send additional GLPp
to verify
y the accuracy
y of their compliance
p
status for a
inspectors
specific study.
•
5
p. 16 of 76
Good Clinical Laboratory Practice (GCLP)
09 NOV 2011
Ellen Berteloot, ir., MBA
Program Manager Clinical Labs R&DQA
ONE TEAM Making the Difference for Patients WORLDWIDE
Agenda
Agenda
• Clinical Trials – Clinical Labs
• The ‘Jungle’ of GCLP documents: Historical Overview
• Compliance Expectations – Regulatory Authority Inspections
• Sponsor Overview
• Patient Safety
• Reliability/Integrity of data
• Planning of the Work
• Informed Consent - Confidentiality
Good Clinical Laboratory Practices - Ellen Berteloot, ir., MBA
09 NOV 2011
3
p. 17 of 76
Clinical Trials
GCP
- Clinical Labs
- GCLP
Clinical Trials and compliance to ICH GCP
• All trial aspects should be conducted according to GCP
regulations
09 NOV 2011
5
Set-up of a Clincal Study
SPONSOR
1
ICH GCP
Investigator
Site
(Hospital)
Investigator
Site
(Hospital)
Clinical
Laboratory
Investigator
Site
(Hospital)
Investigator
Site
(Hospital)
Clinical
Laboratory
MONITOR
Clinical
Laboratory
Clinical
Laboratory
Clinical
Laboratory
09 NOV 2011
6
p. 18 of 76
Clinical Trials and compliance to ICH GCP
• All trial aspects should be conducted according to GCP
regulations
• This includes analysis/evaluation of samples collected
as part of a clinical trial (laboratory work)
• Laboratory analysis/evaluations has long been regarded as a
‘only a small part’ of the whole clinical study
09 NOV 2011
7
09 NOV 2011
8
Clinical Labs: scope of work
• Clinical Chemistry
• Hematology – Coagulation
• Microbiology
• Urinanalysis
• Immuno-assays, including Biomarker Testing
• Bioanalytical testing
• Bio-equivalence testing
• Pharmacogenomic testing
•…
What do we ‘take away’ from GCP guidelines
to translate into laboratory environment?
• ‘Pure’ GCP’s remain too vague with respect to sample
analysis to ensure practical implementation in laboratories
• Of major importance is:
– The need to ensure patient safety
– The need to ensure reliability and integrity of data
09 NOV 2011
9
p. 19 of 76
GCLP’s: the hybrid of…
• Good Clinical Practices: in se too vague
• Good Laboratory Practices: refer to the analysis of samples
from non-clinical studies
• Guidance documents from other organizations/accrediting
bodies (CAP, CLIA, ISO,…)
E.g. ISO 15189 provides insights on particular requirements
for quality and competence for Medical Laboratories
09 NOV 2011
10
GCLP’s: the hybrid of…
• Provides laboratories with specific guidelines on how to
‘implement’ the GCP regulations into a laboratory
environment
• Again… to ensure (1) patient safety (2) reliability and
integrity of the data generated by laboratories
analysing/evaluating samples collected as part of a clinical
trial
09 NOV 2011
11
The ‘Jungle’ of GCLP documents:
Historical Overview
p. 20 of 76
The ‘jungle’ of GCLP documents:
Historical overview (1)
• BARQA 2003: Good Clinical Laboratory Practice, A quality
system for Laboratories that undertake the Analyses of
Samples from Clinical trials
• US NIH DAIDS 2008, 2011: DAIDS Guidelines for Good
Clinical Laboratory Practice Standards
• ICMR 2008: Guidelines for Good Clinical Laboratory
Practices
• WHO 2009: Good Clinical Laboratory Practice
09 NOV 2011
13
The ‘jungle’ of GCLP documents:
Historical overview (2)
• MHRA 2009 : Good Clinical Practice, Guidance on the
maintenance of regulatory compliance in laboratories that
perform the analysis or evaluation of clinical trial samples
• EMA (2010 draft): Reflection paper on guidance for
laboratories that perform the analysis or evaluation of clinical
trial samples
• …and many more…
09 NOV 2011
14
And even before these GCLP documents…
• US CLIA regulation 42 CFR 493
• CAP standard
• ISO 15189 clinical laboratory standard
• CPA standard
-> These requirements characterize GCLP from the perspective
of a quality-driven, top-down management controlled
process and are the most frequently encountered clinical
laboratory standards by sponsors of clinical research
09 NOV 2011
15
p. 21 of 76
Comparing all these documents…
• Philosophy in writing the guidelines is the same,
details vary…
• Patient Safety
• Intergrity and Reliability of data
09 NOV 2011
16
Compliance Expectations
Regulatory Authority Inspections
Compliance expectations for Clinical Labs
• US: enforced CLIA licensure or CAP accreditation
• EU: ISO 15189 mandated (e.g. Germany) or in near future
(e.g.
(e
g by 2012
0
France),
a ce), Belgium:
egu
BELAC
C accreditation
acc ed tat o
• UK: CPA accreditation
09 NOV 2011
18
p. 22 of 76
Regulatory Authority GCLP inspections
• Belgium:
– GLP inspections for labs in non-clinical studies
– No formal GCLP inspections yet
• UK:
– MHRA GLP inspectors additionally have a GCP Laboratory
Inspection Scheme (inspection every 2 years)
– own GCLP guidance document as an expectation for labs
09 NOV 2011
19
09 NOV 2011
21
Sponsor Overview
Sponsor Overview
• Clinical trials conducted according to GCP’s
• Laboratory part conducted according to GCLP’s: e.g.
– Patient safety
e ab ty and
a d integrity
teg ty of
o data
– Reliability
– Planning of the Work
– Informed Consent – Confidentiality
–…
p. 23 of 76
Patient Safety
Patient Safety
• Any issues that may impact patient safety should be
reported without delay
• Normal ranges and alert/panic values should be
established prior to start of analysis
• Content of the Results and observations should be
reviewed/QC’d in a timely manner by an appropriately
qualified person to identify anomalous or out of spec data
• Reporting mechanism/communication lines should be
established beforehand
09 NOV 2011
23
Reliability/Integrity of data
p. 24 of 76
Reliability/Integrity of data
• External Accreditation/Performance/Proficiency
testing schemes – demonstrate competency
• Analytical methods/systems used should be appropriately
documented, validated, controlled and approved to
demonstrate fitness for purpose
• Repeat Analysis & Reporting of repeat analysis results
• Quality Control procedures
09 NOV 2011
25
Planning of the Work
Planning of the Work
• “Protocol”: all laboratory information should be documented
prior to initiation of the work
– Within the full clinical trial protocol
– In a separate document (Analytical plan, Statement of Work,
contract…)
– Signed! Analytical project manager, sponsor, (investigator)
• Content
C t t off the
th Analytical
A l ti l Plan
Pl
– Designed to provide sufficient detail and instructions for those
undertaking the work
– Identification of the work, information concerning sponsor and
trial facility, dates, analytical process, records, quality audit,…
• SOPs:
– Covering e.g. Repeat Analysis & reporting,…
09 NOV 2011
27
p. 25 of 76
Informed Consent - Confidentiality
Informed Consent - Confidentiality
• Work in support of clinical trials should be covered by the
consent given by the trial subjects
• Handling trial materials, collection of data and reporting of
results should be designed to maintain subject
confidentiality and study blinding/coding
09 NOV 2011
29
Thank You - Questions?
Ellen Berteloot, ir., MBA
Program Manager Clinical Labs R&DQA
ONE TEAM Making the Difference for Patients WORLDWIDE
p. 26 of 76
Abbreviations
•
BARQA: British Association of Research Quality Assurance
•
CAP: College of American Pathologists
•
CLIA: Clinical Laboratory Improvement Amendments
•
CPA: Clinical Pathology Accreditation
•
EMA: European Medicines Agency
•
GCLP: Good Clinical Laboratory Practice
•
GCP: Good Clinical Practice
•
ICMR: Indian Council of Medical Research
•
ISO: International Organization for Standardization
•
MHRA: Medicines and Healthcare products Regulatory Agency
•
NIH DAIDS: National Institute of Health Division of AIDS supported Clinical Trials
•
SOP: Standard Operating Procedure
•
WHO: World Health Organization
09 NOV 2011
31
p. 27 of 76
p. 28 of 76
Use of electronic systems in a
GLP environment
Eline Vanheule
Principal Investigator
Annual GLP meeting Brussels
Nanobodies® Inspired by nature
9 november 2011
Introduction - General
Drug discovery and development company based in Ghent, Belgium
A pioneer in next generation biologics - Nanobodies®
>25 programmes in the R&D pipeline
7 Nanobody products in the clinic - 3 Phase II, 1 in Phase I/II and 3 Phase I
First clinical proof
proof-of-concept
of concept for a Nanobody achieved in May 2011
6 additional potential clinical “proof-of-concepts” by end of 2013
Exclusive rights to >550 patent applications and granted patents
Partnerships with 4 leading pharmaceutical companies
>280 staff
Cash at 30 June 2011of €92.6M
www.ablynx.com
2
Introduction - Ablynx’s Nanobodies
Camelidae family has both forms
CH1
CL
VH
VL
CH2
CH3
VHH
CH2
CH3
Conventional antibody
Heavy-chain antibody
Heavy and light chains
Both chains required for antigen
binding and stability
Only heavy chains
Full antigen binding capacity
and very stable
www.ablynx.com
VHH
Ablynx’s Nanobody®
Based on the smallest
functional fragment of a
naturally occurring
heavy-chain antibody
3
p. 29 of 76
Ablynx’s internal and funded programmes
Target
Selection
Lead
Lead
Identification Optimization
Pre-clinical
Phase I
Phase II
Phase III
Registration
IND
Launch
Haematology/
ALX-0081 (vWF)
Thrombotic disorders ALX-0681/0081 (vWF)
ATN-103 (TNFα)
PF-05230905 (TNFα)
ALX-0061 (IL-6R)
Immunology/
Infection/
Inflammation
Musculoskeletal
ALX-0141 (RANKL)
Neurology
ALX-0171 (RSV)
Pulmonary
disease
ALX-0651 (CXCR4)
Oncology
Ablynx-led programme
Partner-led programme
Various
The three Merck Serono programmes are in
co-discovery and co-development with Ablynx
www.ablynx.com
4
Introduction - Pharmacology Department
Ablynx
Pharmacology
Pharmacodynamics
Bioanalytics
GLP Unit
Toxicology
Pharmacokinetics
www.ablynx.com
5
Introduction – Scope
GLP group of the Pharmacology Department
Pre-clinical safety studies (Pharmaceuticals)
• bioanalytical analyses to support toxicokinetics/pharmacokinetics
• biomarker analyses to support pharmacodynamics
• toxicokinetic calculations and evaluation
Clinical bioanalysis (PK/PD) and PK evaluation
www.ablynx.com
6
p. 30 of 76
Introduction – Techniques
GLP group of the Pharmacology Department
ELISA technique
Electronic system for
• document management: ADMS based on OpenText
• data processing: E-workbook/Biobook (IDBS)
www.ablynx.com
7
Introduction of electronic data processing at Ablynx
Regulatory documentation
GLP Group
Clinical assay development
(Pharmacology)
“free research” (Discovery)
Challenge: find one system that fits all requirements
www.ablynx.com
8
Introduction - Requirements
Flexible and good overall solution for all departments
• ability to work in a strictly regulated GxP and flexible R&D
environment
Ability to process and share data, collaborate on
experiments and search the results
Excellent, fast, ... search capabilities
Only authorized individuals can make data entries
Data entries cannot be deleted
Audit trail, changes can be tracked
www.ablynx.com
9
p. 31 of 76
Introduction - 2 major systems
ADMS
Biobook
Electronic storage of
regulatory /
approved documents
Data capture and
data processing
in the lab
www.ablynx.com
10
Overview
Ablynx Document Management System (ADMS)
•
•
•
•
•
use
version control
access rights
upload documents
search
• workflows
www.ablynx.com
11
ADMS – Use
Centralisation of regulatory/approved documents
Automated review and approval cycle
Version control
Searching capabilities
Audit trail
Information sharing:
• with other departments
• with other programs via links
ADMS
www.ablynx.com
Biobook
12
p. 32 of 76
ADMS – Version Control
Every version of a document within the ADMS will remain available
Minor/Major versioning will be used, linked to the workflow:
• review of a document will result in an augmented minor version
• approval of a document will result in an augmented major version
Version numbering will be automated to prevent duplication of version
numbers using the following format:
• major version: X.0 (where X is the major version number)
• minor version: 0.x (where x is the minor version number)
Versions of a document can be reserved for editing and released
afterwards as a new minor version
www.ablynx.com
13
ADMS- Access Rights
Access rights
Access rights
Coordinator (C)
Author (A)
X
x
x
See content
X
x
x
Modify
X
x
x
x
See
Edit attributes
Add items
x
x
Reserve
Delete Empty folders
Edit permissions
x
x
Viewer (V)
x
x
www.ablynx.com
14
ADMS - Folder Taxonomy and Access Rights
NON-GLP
GLP
Fold
er
Sub fold
er 1
NP0010
GLP general
Sub folder 2
System validation
Sub folder 3
Sub folder 4
Sub folder 5
Equipment
Buffers
Temperature monitoring
AXXX
Study number X
Phase GLP number X
Phase GLP number X
PHDPT PHDPT‐
ADM‐
‐GLP
GLP
A
Computer systems
Personnel qualification
Supporting documentation
Sub folder 6
Correspondence
Shipment
Method validation plan
Reagents and test items
Data
Deviations
C
PHDP
T‐
MGM
T‐GLP
PHDP
T‐
PHDPT‐
ADM MGM PHDPT
T
A
V
V
V
A
C
A
V
V
V
A
C
A
V
V
V
A
C
A
V
V
V
A
C
A
V
V
V
A
C
A
V
V
V
A
A
C
C
A
A
V
V
V
V
V
V
A
C
V
V
A
C
A
V
V
V
A
A
C
C
A
A
V
V
V
V
V
V
A
C
A
V
V
V
A
C
A
V
V
V
Correspondence
Shipment
A
A
C
C
A
A
V
V
V
V
V
V
Method validation plan
A
Method validation report
GLP method validation X
C
A
A
V
V
V
V
Reagents and test items
A
C
A
V
V
V
Data
Deviations
A
A
C
C
A
A
V
V
V
V
V
V
Method validation report
A
C
A
V
V
V
www.ablynx.com
15
p. 33 of 76
ADMS – Upload Documents
Only the person with the right permission (author) can upload a
document in a folder
Categories is a mandatory field
www.ablynx.com
16
ADMS – Upload Documents
Categories = 4 meta-data sets
important for the search funtion!
Automatically generates number when all attributes above are filled in
www.ablynx.com
17
ADMS – Search
Only search on documents that can be viewed
Advanced search allows to search on several parameters
• different combinations are possible
• you can save searches that you will run regularly
www.ablynx.com
18
p. 34 of 76
ADMS – Workflows
Review workflow
Approval without e-sign and with mandatory attributes
Approval with e-sign and with mandatory attributes
www.ablynx.com
19
ADMS – Workflows
Signature = electronic version of a scanned signature
www.ablynx.com
20
Overview
Biobook
• general introduction
• pipette database
• sample database
• sample analysis
• studyy report
p
www.ablynx.com
21
p. 35 of 76
Biobook – General Introduction
Electronic system for data capture and processing in
the lab
Links between different workflows
• e.g. pipette reference in sample analysis workflow
Fast data processing by pre
pre-established
established formulas
• all workflows are designed by Ablynx
QC and approval with electronical signatures
Audit trail
www.ablynx.com
22
Biobook – Pipette Database
Due date passed: 0 and coloured red
Due date between 1 and 14: couloured orange
www.ablynx.com
23
Biobook – Sample Database
Study Set-up Table
www.ablynx.com
24
p. 36 of 76
Select Matrices Table
Select Species
(human, rat, mouse, dog, ...)
www.ablynx.com
25
Subjects Table
Timepoints Table
www.ablynx.com
26
Composition Sample Name
www.ablynx.com
27
p. 37 of 76
Mapping Table
www.ablynx.com
28
Mapping Table
www.ablynx.com
29
Biobook – Sample Analysis
ELISA technique
Standard curve – QC samples - Samples
• OD values
• %CV and %RE
• reported concentration
Equipment identification
www.ablynx.com
30
p. 38 of 76
Set-up Assay
www.ablynx.com
31
Set-up assay detailed
www.ablynx.com
32
Buffers
Lab disposables
Number/Name of plates
www.ablynx.com
33
p. 39 of 76
Plate Layout - Lab workflow
www.ablynx.com
34
Freezer timecheck samples
Date of coating/analysis
www.ablynx.com
35
Assay
Parameters
www.ablynx.com
36
p. 40 of 76
Available samples – link to Sample database
www.ablynx.com
37
Instrumentation
www.ablynx.com
38
Pipettes – link to Pipette database
www.ablynx.com
39
p. 41 of 76
Standard curve and QCs
www.ablynx.com
40
Plate Summary
www.ablynx.com
41
OD Values
www.ablynx.com
42
p. 42 of 76
Standard curve data
www.ablynx.com
43
Standard Curve
QCs
www.ablynx.com
44
Published Standard Results – Plate validity – assay
parameters
• input in study report
www.ablynx.com
45
p. 43 of 76
Published Sample/QC Results
• input in study report
www.ablynx.com
46
Reshuffle: extract search result data from several
tables containing data on pipettes
www.ablynx.com
47
Biobook – Study Report
Summary of results from Sample Analysis Workflow
This workflow captures all required results from the
different workflows into tables
Statistics
• interinter and intra
intra- plate statistics required for regulatory
purpose
Those tables will be pasted in the study (phase) report
www.ablynx.com
48
p. 44 of 76
Assay Parameters-report
www.ablynx.com
49
Overview Sample analysis data
Overview Plate Validity
www.ablynx.com
50
Biobook – Sample Analysis Workflow
Overview QC data
www.ablynx.com
51
p. 45 of 76
Overall statistics QC concentrations
Inter plate QC Statistics
www.ablynx.com
52
Intra plate QC statistics
www.ablynx.com
53
Overview standard curves / statistics
www.ablynx.com
54
p. 46 of 76
PK reporting table
www.ablynx.com
55
Lists of
•
•
•
•
samples
samples re-analysed
samples per plate
results per analysis day
Comparisons between sample analysis, re-analysis, ...
Audit trail
www.ablynx.com
56
Overview
Biobook
• general introduction
• pipette database
• sample database
• sample analysis
• studyy report
p
Archiving
Validation
Advantages/disadvantages
www.ablynx.com
57
p. 47 of 76
Archiving
Logical seperation
electronic records marked as archived
Access rights are changed
• everybody has view rights
• only Archivist and Test Facility Management have author
rights
www.ablynx.com
58
Overview
Biobook
•
•
•
•
•
general introduction
pipette database
sample database
sample analysis
p
studyy report
Archiving
Validation
Advantages/disadvantages
www.ablynx.com
59
Validation
Validation Plan: describes the different steps in the validation
project, the responsibilities (supplier/client) and the timelines
IQ - Installation Qualification
• Server and client installation
• Executed by the developer, witnessed by the client
OQ - Operational
p
Qualification
• OQ of the core system, test scripts supplied by the developer,
executed by the client
• OQ of the Workflows, test scripts supplied by the developer,
executed by the client
PQ - Performance Qualification
• Simulate Study in BioBook and compare with previous results,
obtained with Excel spreadsheets
• Train GLP people and setup proper SOP or INS
www.ablynx.com
60
p. 48 of 76
Overview
Biobook
• General Introduction
• Pipette Database
• Sample Database
• Sample Analysis
• Study
y Report
p
Archiving
Validation
Advantages/Disadvantages
www.ablynx.com
61
Advantages/Disadavantages
Advantages
•
•
•
•
•
•
•
audit trail
version control
electronic review/approval cycle
fast data processing
search
information sharing with other departments
safe resources linked to paper process
Disadvantages
• costs – to be balanced versus resource savings
• intensive development programme
• intensive validation programme
www.ablynx.com
62
p. 49 of 76
p. 50 of 76
INFORMATION MANAGEMENT
Annual GLP Meeting
Brussels, 9th of November 2011
“Archiving Anno 2011”
Mireille Smets ‐ Business Unit Manager Merak nv
Who is Merak ?
Established in 1977
A privately held Belgian company
+/‐ 85 employees
10 million € turnover in 2010
Sites – In Belgium – 6 : Antwerp (2) , Mechelen (2) and Brussels (2)
– In The Netherlands ‐ 1 : Amsterdam
– In Switserland – 2 : Zürich • “Information Management”
•
•
•
•
•
Who is Merak ?
• Certified:
– ISO 9001 since 1994
– ISO/IEC 27001 since 2008
– ISO 14001 since 2011
• Audited/Compliant:
– PCI DSS
– Audited Strategic Documents Storage
– GLP/GMP
p. 51 of 76
Merak’s philosophy
• Merak is a partner, not just a supplier
•
Think together to define the best/optimal solution
•
Service as it is … 24h/24h
•
An optimal records management is as good as the speed of the retrieval of the record
What is the definition of “an archive” ?
Dictionnary “Van Dale”
p (
,
“A collection of data from the past (documents, registers etc … ) one wishes to keep or is required to keep”
“A repository of archived documents”
Type of Information carriers
Papyrus Æ
dates back since 3000 BC
Microfilm Æ
dates back since beginning 20th century
Digital Æ
has entered in the eighties
p. 52 of 76
Pro & Contra of Information carriers
Type of Information
Carrier
Pro Contra
Easy to use, A habit, Durability guaranteed
depending on quality
Volume
Paper
Durability guaranteed
(up to 100 years) depending on quality
Accessibility, Availability
Microfilm
Digital
Flexible, Availability is high, system must be
24h/24h up running
Continuous
development, limited
lifetime
What kind of Information does exist?
Slides
Final reports
Wet tissues
Samples
Microfilms
Paper records
p
Records of all inspections by Quality Assurance Certificates of Analysis
y
Computer media
Study related documents and communication
Photos
Paraffin blocks
Records of qualifications, training, experience and job description of personnel
Records and reports of maintenance and calibration of apparatus
Historical files of all Standard Operating Procedures (SOP’s)
Why do we keep information ?
A retention period of archived records and materials is in place :
“The retention period defines the minimal period of time that data must be retained and must be available”
The retention period is a decision made my the authorised owner of the archives
Obligation required and defined by national legislation
Company’s internal policies on retention
Company’s know how to keep
evidence
p. 53 of 76
Approach on archiving
Internal approach: External approach:
•Archive: a designated area or facility of the own company for the secure
storage and retention of records and materials
•Contract Archive Services: external organizations that supply support/services focused on the archiving activity
Supported with:
Managed by:
•Archivist: an individual designated to be responsible for the management of the archive, e.g for the operations and procedures for archiving
•Contracts, SLA’s;
•Access Arrangements;
•Conditions of storage;
•Inspections by Quality Assurance (QA)
Main concerns on the archiving process
•Location of the archives
•Confidentiality
•Availability
•Traceability
Traceability
•Continuity of staff
•Follow‐up on the destruction process
•Continuity
•New developments
•Transparency of cost structure
Listed up in OECD guidelines
Focus
Management of Archives
Internal
Versus
External
Internal Archive Management
External Archive Management
• Budget for investment;
• Fixed costs;
• Predefined capacity;
• Service during working hours;
• Staff policy;
• Doubt on continuity
• Limited budget investment;
• Variable costs;
• Flexible capacity;
• Service 24h/24h;
• Stability in staff policy;
• Scale advantages
p. 54 of 76
Scope of OECD 15
•OECD Principles:
‐ Good Laboratory Practice (GLP)
‐ Good Manufacturing Practice (GMP)
•OECD °15,, Advisory document of the working group on GLP:
y
gg p
“Establishment and control of archives that operate in compliance with the principles of GLP”
•Scope of OECD°15: “This document is intended for use by test facilities that are required to operate in compliance with the Principles of GLP, for organizations that supply support e.g. contract archives and for sponsors, GLP compliance monitoring authorities and receiving authorities.”
•“The guidance contained within this document should equally apply to the contract archive facilities”
The archive facility
OECD°15 on the archive facilities: “The archive facility should be suitably designed and constructed to accommodate the archived records and materials”
Request on Access control (physically and virtually)
• Prevention of unauthorized access • Virus protection against hacking into the computerized archive facility
Internal archive management
•No customized access control specifically for the archive facility
•Need for extra investments to secure computerized archive facility
External archive management
•Electronic entry system – badge control by handing over the information
•Presence of QA+ frequent audits & inspections →Information Security Management System (ISMS) by ISO/IEC 27001
Construction of the archive facility ‐ Preventive
•Protection against water e.g. risk of flooding
•Protection against fire and explosions
•Prevention against the entry of rodent
•Presence of back‐up electrical power for all critical equipment e.g. temperature, humidity, refrigerators, freezers
•Archive facility located in the same building
•No customized fire prevention and protection
•No customized prevention (even little) of the entry of rodent
•No presence of back up electrical power
•Solid construction of building especially adapted to archiving activity
•Customized fire prevention system (Sprinkler system) in compliance with NFPA 13
•Frequent rodent and pest control •Presence of back up electrical power e.g. power generators, mobile unit humidity, mobile unit cooling/heating, back up supply of CO₂ gas, presence of back up freezers
p. 55 of 76
The archive conditions
OECD°15 on the archive conditions:
“Storage conditions should be designed to preserve and not adversely affect the quality and integrity of retained records and materials.”
Storage conditions required for particular materials:
•Frozen or refrigerated
•Frozen or refrigerated
•Dust free
•Free from magnetic interference (electronic media)
•Need for implementation of environmental monitoring procedures •Need for calibration of monitoring systems
•Chain of custody
The archive conditions (2)
•Not always evident to store different records and materials separately
•No electromagnetic vault
•Lack of sufficient monitoring procedures External archive management
•Climatized environment regarding different storage requests e.g. separate storage of paper, microfilms, wet tissues, blocks, slides, tapes etc …
•Storage of electronic media in a vault protected against magnetic influences
•Presence of calibrated data loggers
•Presence of at least two independent alarm systems
•Procedures defined in SOP’s
Disaster Recovery
OECD°15 on Disaster Recovery:
“Test facilities and contract archives should have procedures in place to minimize damage to archived records and materials caused by adverse events.”
Which kind of adverse events do exist:
•Fire and electrical failure
•Weather‐related damage e.g. flooding
•Theft and sabotage
•Disaster recovery especially for records and materials is not core business
•Less focus on archiving aspect in Disaster Recovery Plan
•Own responsibility if disaster occurs Scientific Institute of Public Health
•Presence & tested of Disaster Recovery Plan customized for archiving activity
•Plan includes emergency contacts, location of necessary equipment and records that should be made
•Regular monitoring and testing of Disaster Recovery Plan
p. 56 of 76
Security
OECD°15 on Security:
“The archive facility should be both physically and operationally secure to prevent unauthorized access and changes to or loss of retained records and materials.”
Security guidelines requested :
•Access restricted to staff
•Need to accompany visitors
•Records of visitations
•Restriction of access to electronic records
•Measures to prevent alteration and deletion (read‐only access)
Security (2)
• Access not always restricted to archive staff
• Digital records part of the entire IT infrastructure
•Accidental loss or damage of records
•Access to archive facility only by authorized staff members
•Access to digital records via use of digipass and token
•Destruction of all records only by authorized persons
•Audits and inspections →
ISMS → ISO certifications
•Procedures defined in SOP’s
Track & Trace
OECD °15 on Placement of records and materials into archive facility:
Archiving in timely manner
•Archive staff = responsible for integrity of records and materials
•Indexing to facilitate orderly storage and rapid retrieval
•SOP’s to define procedures
•Importance of location in archive facility
•Archiving is own responsibility for 100%
•All archived records and materials centralized in one archive location
•No distinction made between different types of records and materials
•No anonymous treatment
•Possible loss of records and materials
•Specifications of records and materials require different storage locations
•Random distribution in archive facility
•Anonymous treatment → unique barcode
•Easy retrieval by customized indexing
•Online consultation of inventories
•Responsible for integrity of archives
p. 57 of 76
Retrieval & Disposal
OECD °15 on Retrieval and disposal of archived records and materials
Establishment of SOP’s to define circumstances of removal or destruction
•Description of who is authorized to request removal or destruction of records and materials
i l
•Register movement and manipulation of documents and materials •Mechanisms to track movements of records and materials
•Verification of records and materials after return to archive facility
•Approval from authorized persons in case of destruction
Retrieval & Disposal (2)
•Difficulties in retrieving records and materials
d
d t i l
•Establishment of SOP’s
•Authorization procedure
•Records of removal of documents and materials
• SOP’s define procedures for each type of record or material
t i l
•Control of every manipulation
•Badge control for exchange of records and materials
•Flexibility – 24h/24h
•Anonymous treatment of records and materials – unique barcode •History of manipulations available
•Errors are reported every minute – 24h
•Approval for destruction only from authorized persons
Retention
OECD °15 on retention of electronic records:
Implications:
•Long‐term retention → influences choice of storage medium to prevent loss of data
•Readable during the entire retention period
•Migration from computerized system to storage medium to place in physical archive e.g. magnetic tape, CD, …
•Adapted storage conditions: protection against magnetic fields, extreme temperatures, …
p. 58 of 76
Retention (2)
•Permanent investments to guarantee readability
•No optimal storage conditions for electronic media
•No protection against magnetic influences
•Responsibility of IT personnel
•Cloud archiving: Confidentiality? Integrity? Availability?
•Guaranteed readability •Frequent audits and inspections →
ISMS ISO/IEC 27001 certified
•Optimal storage conditions: monitoring of temperature and humidity
•Electromagnetic vault to protect from electromagnetic influences
Continuity
New developments
Location
‐Single Point of Contact
‐Guidelines concerning the inventory and the request of documents
‐Permanent training personnel
‐Expansion of information flow
‐Paper vs. Digital
‐Growth of organization ‐(De)central
‐Construction of the building
‐Climatized environment
‐Security (against fire, theft,...)
‐Risk of flooding
Confidentiality
Destruction
SUMMARY
‐who
who may authorize
may authorize
‐Check of approval
‐Follow up of destruction process‐
shredding
‐Certificate of actual destruction
‐Limited access
‐Control exchange of documents
‐Possibility to seal vital information
Availability
‐24h/24h service
‐ what after working hours?
Traceability‐ Chain of custody
‐(non) vital documents
‐Intolerance of mistakes
‐Tracing speed
‐Manual tracing desired
‐Digital tracing using barcodes
‐Digital tracing using barcodes + control
Availability logistics
‐Car park (shuttle between archive facility and customer)
‐Presence of staff
‐Timely delivery of originals or digital copy
Conclusion
•
•
•
•
•
•
•
analyse all options in detail
KISS
know how in information management
know how in information management
professional management of information
transparancy in costs is necessary
set up a needs analysis and implement correct
monitor and check quality at all times
p. 59 of 76
Thank you for your attention
Always welcome at Merak !
www.merak.be
p. 60 of 76
CROs & GLP Multisite Studies
- challenges with Sponsor-Conducted Phases
Belgian GLP Authority Annual Meeting
Linzi Gillbanks – QA Manager
November 2011
CONFIDENTIAL
Presentation Overview
• Incidence of GLP multisite (MS) studies with
Sponsor-conducted phases
• Common types of sponsor-conducted phases
• The “theoretical” approach
– How things might work in theory
• The reality
– How things tend to work in real life
• Challenges from the CRO perspective
CONFIDENTIAL
2
Incidence of MS Studies With Sponsor-Conducted Phases
• Sample of studies from Covance Master Schedule
conducted in Harrogate over the last 3 months
No of GLP
studies
No. MS Studies
% of MS
studies
No. MS studies
with Sponsor
Phase
% of MS
studies with
Sponsor Phase
284
96
34%
30
11%
• Most common Sponsor-conducted phases:
• Formulations analysis
• Bioanalysis (TK samples)
• Pathology peer review
3
CONFIDENTIAL
p. 61 of 76
Typical Requests We Make To Sponsors Who Are
To Conduct a MS Study Phase
• Request identification of PI for the assigned phase
• Request evidence of GLP credentials for the test site
– National Monitoring Programme “certificate”
– Evidence of inspection (eg by US FDA)
• Inspection results and acceptability of resulting actions
– Note that we would rarely request to conduct an on site audit of the
Sponsor’s facilities!
• Request information about test site QA audit activities to support the
phase to be conducted
– and request confirmation of audit results
• Request details of phase from PI to enable incorporation of information
into the study plan
• Request PI provides confirmation that they will conduct phase in
accordance with study plan and applicable GLP regulations
• Request that PI notify our SD of study plan, and SOP, deviations
• Request QA and PI statements when reporting the phase
CONFIDENTIAL
4
What Are Typical Responses Obtained?
• The requests we make to Sponsor test sites and
PIs are compatible with OECD guidance for
conduct of MS studies
– but whilst some Sponsors will oblige ……… often
these requests are not fully met
– appears to be a significant difference in responses
obtained from other CROs
• In the following slides we will consider some of
the responses we receive when making
requests of Sponsor test sites ……………..
CONFIDENTIAL
5
Request to identify a PI for the assigned phase
• Differences in opinion as to what constitutes a study
“phase”:
– Pathology Peer review
– Statistical analysis
• Where Sponsor does not agree that the above
constitute a “phase”,
p
, they
y are reluctant to identifyy an
individual as PI
• International differences in national authority
interpretation will often drive this difference in
opinion
– but a difficult issue for the CRO if their national authority
have clearly stated their expectation
6
CONFIDENTIAL
p. 62 of 76
Request evidence of GLP credentials for the test site
• Might think this would be fairly simple. But ……..
– Sponsor claims to be GLP compliant when they are not
• Misunderstanding of what GLP is
• At least one example where Sponsor believed they were a “GLP facility”
following a consultant’s audit!
– No evidence of regulatory inspection history in countries where
“certificate” or similar is not provided
• Eg US
• Or history exists, but Sponsor unwilling to share information regarding the
issues raised, and responses provided to regulator
– In the absence of the above, would Sponsor accept an on site
inspection by CRO QA?
• Many would not
7
CONFIDENTIAL
Request information about test site QA audit activities
• Request generally met favourably
– Some information provided
• If regular collaboration, most Sponsors will not
want to respond on a study specific basis
– Information will be provided and kept on file by CRO
– Updated periodically by Sponsor
S
• A significant number of Sponsors are reluctant to
provide results of audits to CROs
– Will simply state that all OK (no visibility to issues)
– US based Sponsors particularly reluctant
8
CONFIDENTIAL
Requesting Information to Include in the Study Plan
• In order to have only a single study plan, it is necessary for
the SD to include details of all phases in their study plan
– Surprising reluctance of Sponsors to provide information
– Reluctance even to provide reference to local documentation eg
analytical method
• Concern about setting a precedent for their own in house studies
• Sponsor PIs may also resist requests to confirm they will
conduct
d t th
their
i phase
h
according
di tto th
the study
t d plan
l and
d
referenced regulations
– Sponsor staff unaccustomed to a need to respond to external
requests?
• Communications regarding plan and SOP deviations are
also relatively uncommon
– Unlikely that we are informed by all Sponsor PIs
– Often deviations are discussed between PI and Study Monitor (as
both are at the same location), whereas the lines of communication
should be between PI and SD
9
CONFIDENTIAL
p. 63 of 76
Request for PI and QA Statements for Sponsor Phase
• Recent example
– Refusal to provide a PI statement specifically defining regulations
under which study was conducted
– Refusal to provide QA statement detailing elements of phase
inspected
• US-based Sponsor did not consider these were necessary for us
– “other CROs have had no problem with this”!!!!!!! ……. an oft used comment
• Limited flexibilityy of their standard report
p format
– and unwillingness to change to accommodate our request
• This is unusual (most Sponsors realise we need these
documents)
– but underlines how expectations can be very different, particularly in
some countries, even though we communicate expectations in
advance
– often a belief that Sponsor QA = Lead QA
CONFIDENTIAL
10
Who Does the CRO Side With?!
• The Regulator?
• The Sponsor?
11
CONFIDENTIAL
Conclusions
• A CRO has two “masters”
– The Sponsor
– The National Regulator
• The GLP MS study, with a Sponsor-conducted
phase,
h
b
brings
i
allll elements
l
t ttogether
th
• When these “masters” are of different nationality,
expectations for GLP MS studies can differ
markedly
– impossible for the CRO to accommodate all expectations
– whose lead does the CRO follow?!
12
CONFIDENTIAL
p. 64 of 76
Technical issues
BQA-GLP Monitorate
Q1_Can the Document Controller hold
a position as QA personnel?
For example, the responsibilities of the Document Controller shall be as
follows:
1.
Maintains Master List of Documents (number of copies distributed,
location of the distributed documents...etc.)
2.
Maintain Equipment List (validation of computerized systems,
maintenance/calibration
i t
/ lib ti off equipments,
i
t location
l
ti off the
th equipments,
i
t
number of equipments...etc)
3.
Maintain Master Schedule
4.
Control of documents (SOP numbering & indexing, distribution of latest
version of SOPs & removal of superseded versions)
5.
Ensure all SOPs are according SOP of SOPs (format)
6.
Prompt specific authors for the review of their SOPs when the review
date is approaching)
7.
Maintain list of expiring dates of chemicals
Q1_Answer: Can the Document
Controller hold a position as QA
personnel?
•
QA should always remain independent from the work he has to
verify.
p. 65 of 76
Q2_Legibility of handwritten raw data
•
•
•
A copy of an handwritten raw data file is transferred to another
test site for statistical/PK calculations
The raw data in the table are introduced in an Excel file for
further calculation
Due to the bad readability of the handwritten numbers
• Sometimes a 5 was introduced as a 6, 0 as 5, 2 as 9, 1 as 7
• Who’s responsible for those mistakes?
• How to avoid those mistakes?
Q2_Answer: Legibility of handwritten
raw data
•
II,1.4.3: all study personnel are responsible for the quality of
their data: make study personnel aware of the problem
•
II, 8.3.: all data generated should be recorded legibly by the
individual entering the data. Archive the handwritten raw data
together with the Excel file
•
II, 9.2.4: QA should certify that the report reflects correctly the
raw data: include QC control of input, mail Excel files back to
study personnel for confirmation of input.
Q3_Characterisation
•
A batch of an inorganic mineral is subdivided in 3 parts
characterisation:
a: batch particles between 2-25 µm
b: all particles greater than 10 µm
c: all particles between 1
1-10
10 µm
•
The batch (a) is used for the in vivo inhalation study
Part (b) and part (c) are used for in the vitro inhalation study
•
Is the SD allowed to include the 3 studies into one study plan?
•
p. 66 of 76
Q3_Answer: Characterisation
•
•
The belgian MA prefers 3 study plan to avoid confusion
But the receiving authority can prefer one study report in some
cases
•
In this case the characterisation of the 3 parts should be clearly
d
described
ib d iin th
the reportt tto avoid
id misinterpretation
i i t
t ti off th
the d
data
t
Q4_How to act as QA here?
For a measurement sequence of an analytical instrument results
and background information are available as far as printable
(pdf/hardcopy) (so far, so good…)
Detailed data (e.g. injection volume, highly relevant for the result)
are only available if QA contacts an analytical person with the
necessary access rights; with this “inhibition threshold” and time
pressure often there is no inspection at all
Only way out: print out these details, if not: no OK from QA. There
is no special QA access rights in the software, which apart from
that is validated
Shouldn`t all data which are defined to be important for the
evaluation be totally accessible for the QA audit directly and not
by the detour described?
Q4_Answer: How to act as QA here?
OECD Consensus Document no. 10 The Application of the
Principles of GLP to Computerised System :
•
“QA personnel should have, for review, direct read-only access
to the data stored within a computerised system.”
p. 67 of 76
Q5_Manuals as part of SOP &
archiving
If manuals (e.g. from analytical instruments), are declared to be
part of SOPs:
do the manuals need to be copied together with the current valid
SOP document when transferred to the archive?
or
is it sufficient to state within the SOP that the manuals will stay with
the instrument during the validity period of the SOP and will be
archived at the time of decommissioning?
Answer Q5_Manuals as part of SOP &
archiving
Ideally, SOP should make reference to version number (or issue
date) of the manual.
If SOP is modified but not the manual, only archiving of SOP is
necessary.
If SOP is modified because of changes in the manual (so new
version number!), SOP + manual have to be archived!
For ex. Update of software
Q6_Definition of raw data
What does a GLP inspector expect in a study file?
•
Communication by e-mail: subject should indicate unique study
number
•
Apparatus and software: if technician has to decide according to
what he sees on the screen for his further steps. Print-out of the
screen is needed
•
Calculations based on input as print-out? Not only print-out, but
also generated information should be archived.
p. 68 of 76
Q7_Traceability to international system
unit
Concerning the traceability to the international system of unit (SI), the
requirement of the OECD principles on Good Laboratory Practice is the
following (paragraph 4.2):
"Calibration should, where appropriate, be traceable to national or
international standards of measurement "
Wh t does
What
d
thi
this requirement
i
t suppose ?
1/ The calibration has to be carried out by an accredited calibration
laboratory which produces a calibration certificate with accreditation
reference?
2/ The calibration can be carried out by a calibration laboratory whose
reference standards are traceable to the international system
unit but which is not accredited? In this case it produces a calibration
certificate without accreditation reference.
3/ Or calibration can be done by the test facility itself by the use of
traceable reference standards which are traceable to the
international system unit?
Q7_Answer: Traceability to
international system unit
•
•
•
Some instruments can be sent to an accredited laboratory
(e.g. thermometers) or calibrated on site by the service of an
accredited laboratory (e.g. balances). In this case, the
accredited laboratory will issue a certificate as documentation
of the traceability to the international standards.
It is acceptable that a third party performs a calibration
traceable to national or international standards if it is not
accredited itself. In this case, the test facility has to ensure
that the third party is qualified; e.g. by a supplier audit. As in
the other cases, the certificate of traceability has to be issued
by an accredited laboratory.
It is possible that the test facility calibrates instruments using
reference items purchased from an accredited laboratory. As
in 1), the accredited laboratory will issue a certificate as
documentation of the traceability to the international system
unit. This can be the case for calibration weights or reference
thermometers.
Q8_Verified copies of records as raw
data?
•
Should original records always be archived, or would it be
acceptable to archive only verified copies of records as raw
data?
p. 69 of 76
Q8_Answer: verified copies of records
as raw data?
•
Verified (electronic) copies should be accepted as raw data for
the purpose of monitoring the GLP compliance of test facilities
and studies, provided that the procedure for creating verified
copies is fully transparent and properly validated.
•
However, destruction of original records may pose a risk for the
applicant and/or sponsor since receiving authorities may require
the retention of the original records. (see case under question 2)
p. 70 of 76
List of participants GLP Monitoring Authority WIV‐ISP Guido Jacobs Guido.Jacobs@wiv‐isp.be Patricia Cliquet Patricia.Cliquet@wiv‐isp.be Martijn Baeten Martijn.Baeten@wiv‐isp.be Eric Mairiaux Eric.Mairiaux@wiv‐isp.be Anne‐Marie Vanherle Anne‐Marie.Vanherle@wiv‐isp.be Valérie Draguet Valerie.Draguet@wiv‐isp.be Sophie Carbonnelle Sophie.Carbonnelle@wiv‐isp.be An Schoonjans An.Schoonjans@wiv‐isp.be Vicky Kielbaska Vicky.kielbaska@wiv‐isp.be Caroline Graide Caroline.Graide@wiv‐isp.be Els Collijs Els.Collijs@wiv‐isp.be Scientific Institute of Public Health
p. 71 of 76
List of participants Receiving Authorities European Commission Maik Schmahl Maik.Schmahl@ec.europa.eu Johanna Rose Johanna.rose@ext.ec.europe.eu Scientific Institute of Public Health
p. 72 of 76
List of participants Test Facilities Ablynx Marie‐Paule Bouche marie‐paule.bouche@ablynx.com
Eline Vanheule eline.vanheule@ablynx.com
Kjell Mortier Kjell.mortier@ablynx.com Bram De Rammelaere Bram.derammelaere@ablynx.com
Patrice Chiap p.chiap@ulg.ac.be Barbara Campo actgoquality@gmail.com Veerle Habex veerle.habex@bayer.com Sandra Berghman sandra.berghman@bayer.com
Sofie Tanghe Sofie.tanghe@bayer.com
Tinneke Kooi Tinneke.kooi@bayer.com
Sophie Persoon sophie.persoon@bayer.com Luc Beurms luc.beurms@bayer.com Jean‐Luc Beaudart quality@cergroupe.be Véronique Misson v.misson@cergroupe.be
Pieter Deschuytter pieter.deschuytter@cirlam.com
Marina Dorchain marina.dorchain@cirlam.com Covance Linzi Gillbanks Linzi.Gillbanks@covance.com CRA‐W U10 Vanessa Hérion herion@cra.wallonie.be V. Lecocq labecotox@cra.wallonie.be O. Pigeon pigeon@cra.wallonie.be R. Rousseau rousseau@cra.wallonie.be ATC BAYER CER Cirlam Scientific Institute of Public Health
p. 73 of 76
List of participants CRA‐W UG5 D. Vrevos vrebos@cra.wallonie.be Blandine Gaurois gaurois@cra.wallonie.be ECTX‐consult Tony Brouwers tony.brouwers@ectxconsult.be Fac DGK (Gent) An Maes an.maes@ugent.be
Ann Spaerkeer ann.spaerkeer@ugent.be Benedicte Mertens bmert@galephar.be Bernard Cahay bcaha@galephar.be Hilde Van den Eynde hvdeynde@its.jnj.com
Patricia Engelen pengelen@its.jnj.com Ellen Berteloot ebertel1@its.jnj.com Jiang Haiyan Chou Chengping Quality Assistance Isabelle Manon Isabelle.manon@quality‐assistance.be SGS Life Science Services Christian Sulmon Christian.sulmon@sgs.com
Isabelle Parmentier Isabelle.parmentier@sgs.com Coralie Quinet Coralie.quinet@sgs.com Charraf Chebbah Charaf.chebbah@sgs.com Isabelle De Neyer isabelle.deneyer@sgs.com Aline Chrétien achretien@straticell.com Coralie Bastin cbastin@straticell.com Martine Meurrens martine.meurrens@thrombogenics.com Maureen Moerenhout maureen.moerenhout@thrombogenics.com Galephar Janssen Pharmaceutica NV Pilarquim Straticell Thrombogenics Scientific Institute of Public Health
p. 74 of 76
List of participants Toxikon Erik Haghedooren erik.haghedooren@toxikon.be
Gaby Boonen Gaby.boonen@toxikon.be
Thierry Celis thierry.celis@toxikon.be Marc De Buyser marc.de.buyser@toxikon.be Pierre Boulanger Pierre.boulanger@ucb.com
Françoise Van Bogaert francoise.vanbogaert@ucb.com
Lynn Stanley lynn.stanley@ucb.com UGENT Kris Baert Kris.baert@ugent.be ULG Audrey Renkin Audrey.renkin@ulg.ac.be VITO‐CARDAM An Van Rompay an.vanrompay@vito.be Ab Borburgh ab.borburgh@vito.be
UCB Scientific Institute of Public Health
p. 75 of 76
List of participants Contract Archives MERAK Mireille Smets Caroline Sermon BNC‐Group Mireille.smets@merak.be Caroline.sermon@merak.be Peter Goossens Peter.Goossens@merak.be André Verstraeten averstraeten@bnc‐group.com France De Smedt fdesmedt@bmc‐group.com Scientific Institute of Public Health
p. 76 of 76