GLP Annual Meeting 2011 syllabus

Science at the service of Public health, Food Chain Safety and Environment

SCIENTIFIC INSTITUTE OF PUBLIC HEALTH

Bureau of Quality Assurance

16th

GLP Annual Meeting Brussels, 9 November 2011

www.wiv-isp.be www.glp.be

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

GLP Annual Meeting 2011

Programme 08h15 ‐ 09h00 Registration of the participants

09h00 ‐ 09h05 Welcome word p. 3 (P. Cliquet ‐ QA Manager, WIV‐ISP)

09h05 ‐ 09h20 Belgian GLP programme, 2011‐2012 p. 5 (G. Jacobs ‐ GLP Coordinator, WIV‐ISP)

09h20 ‐ 09h40 Feedback from EC and OECD meetings p. 9 (M. Schmahl ‐ EC Enterprise and Industry DG)

09h40 ‐ 09h50 Inspections in China p. 15 (M. Baeten, WIV‐ISP)

09h50 ‐ 10h30 Good Clinical Laboratory Practice p. 17

(E. Berteloot, Janssen Pharmaceutica, R&DQA)

10h30 ‐ 10h50 Coffee break

10h50 ‐ 11h30 Use of electronic systems in a GLP environment p. 29 (E. Vanheule, Ablynx)

11h30 ‐ 12h10 Archiving Anno 2011 p. 51 (M. Smets, MERAK)

12h10 ‐ 13h45 Lunch (walking dinner)

13h45 ‐ 14h30 CROs and GLP multisite studies – challenges with Sponsor‐conducted phases p. 61 (L. Gillbanks, Covance, UK)

14h30 ‐ 14h50 Coffee break

14h50 ‐ 16h15 Technical issues p. 65 (GLP inspectors, WIV‐ISP)

List of participants p. 71

16th Annual GLP meeting

Welcome word

BQA-GLP Monitorate

Brussels, 9 November 2011

Rue Juliette Wytsmanstraat 14 | 1050 Brussels | BelgieT +32 2 642 5230| email: [email protected] | site web: www.GLP.be; https://intranet.WIV-ISP.fgov.be/

09h00-09h05 : Welcome word (P. Cliquet, WIV-ISP)

09h05-09h20 : Belgian GLP programme, 2011-2012

(G. Jacobs, WIV-ISP)

Programme

2

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

10h50-11h30 : Use of electronic systems in a GLP environment

(E. Vanheule, Ablynx)

11h30-12h10 : Archiving Anno 2011 (M. Smets, MERAK)

Programme

3

12h10-13h45 : Walking dinner

16th GLP Annual Meeting

Scientific Institute of Public Health Brussels, 9 November 2011 p. 3 of 76

13h45-14h30 : CROs and multisite studies with Sponsor-

conducted study phase(s) (L. Gillbanks, Covance)

14h30-14h50 : Coffee break

Programme

4

14h30 14h50 : Coffee break

14h50-16h15 : Technical issues (GLP inspectors, WIV-ISP)

Practical information

• Certificate of attendance

• Satisfaction inquiry

• Badges recuperation at the end of the meeting

5

• 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)

Team of GLP Inspectors, update

• QA Manager : P. Cliquet

• GLP Coordinator: G. Jacobs

• GLP inspectors:

6

• E. Mairiaux

• A.M. Vanherle

• S. Carbonnelle

• V. Draguet

• A. Schoonjans

• M. Baeten




Belgian GLP programme, 2011-2012 Belgium

BQA-GLP Monitorate


Rue Juliette Wytsmanstraat 14 | 1050 Brussels | BelgieT +32 2 642 5230| email: [email protected] | 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

• MerakI M t i

2

• Iron Mountain• 3 pre-inspections

• Immune Health• Galephar• Bayer Crop Science

• 2 test facilities left the programme• Philip Morris • Thrombogenics

GLP Joint inspections

• EPA_US(June 2011)• The Netherlands (June 2011)

3



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

4

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

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 MeetingGermany: 16th DGGF International Meeting• September 2011_Berlin



Training of inspectors

• OECD training course for GLP inspectors• Jerusalem (Israel)

• S. Carbonnelle• A. Schoonjansj• 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.




• 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 i ti f R h Q lit A (BARQA) (UK) (WG t t• British Association of Research Quality Assurance (BARQA) (UK) (WG contact 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 BonetteFrancesco)

Chinese test facility inspections

• See presentation of Martijn Baeten



GLP: feedback from EU and OECD meetings

Maik Schmahl Brussels, 9/11/2011Chemicals unit –Classification & Labelling, Specific Products, Competitiveness

EU GLP WORKING GROUP Helsinki 2011

• Technical issues group on 2 March• Plenary GLP working group on 3 March

EU GLP WORKING GROUP Helsinki 2011Co-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• 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




• 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

d f ibl hi h b f t t iwarned of a possibly high number of contacts via the REACH competent authorities because of the high number of dossiers under evaluationannounced 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 thePossibly separate meetings with the GLP monitoring authorities active in its area and the responsible Commission service.




• In 2010, the Committee on Human Medicinal Products(CHMP) requested four study audits linked to two testfacilities in the USA and one in India.

• In 2011, there has so far been one study audit requestregarding a facility in Canada.

CHMP has later withdrawn the study audit requests but theCHMP has later withdrawn the study audit requests, but theagency did recommend to the Canadian monitoring authorityto include the laboratory in its monitoring programme.

• Standard operating procedure for requesting study auditsis working well

• GLP again on agenda of one of the next safety workingparties 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.



EU GLP WORKING GROUP Helsinki 2011Representation 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 theCommission 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.

EU GLP WORKING GROUP Helsinki 2011New members and new Member States

• Bulgaria is still waiting for the firstlaboratory to apply for an inspection.

• Latvia announced that it already has alaboratory in its programme, whichshould be revisited soon with the help ofshould be revisited soon with the help ofGLP inspectors from another MemberState.

• Turkey announced that its GLPprogramme will be fully operational bythe 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• 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.



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 programme is compatible to EPA's. However, OECD waits forprogramme 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 that the document prepared co c us o t at t e docu e t p epa edby 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 publicshould not be spread to the wider public before further discussion.

• The EU will be the convenor of the sub-group, and will be joined by Australia, Denmark (DANAK), Spain (ENAC), Italy, Japan, Sweden (SWEDAC), Singapore, Slovakia and US EPA.



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.




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

• Visit of new candidates for a GLP-inspection by Belgium

2

p y g• Gaiton – Hope• Suzhou Xishan Zhongke Drug Research & DevelopmentCo., 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

Chinese test facilities

- FMC,Chemical Technology Consulting Co, Shanghai- CRO: analytical & chemical testing

- NutriChem Beijing- CRO: physical-chemical testing, analytical and clinical chemistry testing

and stability testsPilarquim (Shanghai) Co LTD

3

- Pilarquim (Shanghai) Co., LTD- CRO: physical-chemical studies

- Laprode Analysis Co., LTD- CRO: physical-chemical studies

- Covance, Shanghai- CRO: toxicity studies, analytical and clinical chemistry testing

- Wuxi AppTec Shanghai- CRO: ADME studies, toxicokinetic and pharmacokinetic studies, hERG

assay and biomarker studies- Wuxi AppTec Suzhou

- CRO: toxicology and mutagenicity studies



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. Bypreference pre-inspection by QA sponsor or consultant.

4

• Asking for audits on sponsor specific studies remainsresponsibility of receiving authority!

• One study/study type/SD

• All documents (including raw data) must be available in English

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 thattheir data will be accepted by the OECD member contries. Eachreceiving authority may decide to send additional GLP-inspectors to verify the accuracy of their compliance status for a

5

p y y pspecific study.



Good Clinical Laboratory Practice (GCLP)09 NOV 2011

Ellen Berteloot, ir., MBA

ONE TEAM Making the Difference for Patients WORLDWIDE

Program Manager Clinical Labs R&DQA

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

09 NOV 2011Good Clinical Laboratory Practices - Ellen Berteloot, ir., MBA 3



Clinical Trials - Clinical LabsGCP GCLPGCP - GCLP

Clinical Trials and compliance to ICH GCP

• All trial aspects should be conducted according to GCP regulations


InvestigatorSite

(Hospital)

Set-up of a Clincal Study

ClinicalLaboratory

InvestigatorSite

(Hospital)

SPONSOR

ICH GCP


Laboratory

InvestigatorSite

(Hospital)

ClinicalLaboratory

ClinicalLaboratory

MONITORInvestigator

Site(Hospital)

ClinicalLaboratory

ClinicalLaboratory



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


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




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 • 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


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


The ‘Jungle’ of GCLP documents:Historical OverviewHistorical Overview



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 StandardsClinical Laboratory Practice Standards

• ICMR 2008: Guidelines for Good Clinical Laboratory Practices

• WHO 2009: Good Clinical Laboratory Practice


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 EMA (2010 draft): Reflection paper on guidance for laboratories that perform the analysis or evaluation of clinical trial samples

• …and many more…


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




Comparing all these documents…

• Philosophy in writing the guidelines is the same, details vary…

• Patient Safety

• Intergrity and Reliability of data


Compliance ExpectationsRegulatory Authority InspectionsRegulatory 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. by 2012 France), Belgium: BELAC accreditation(e g by 0 a ce), e g u C acc ed tat o

• UK: CPA accreditation




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


Sponsor Overview

Sponsor Overview

• Clinical trials conducted according to GCP’s

• Laboratory part conducted according to GCLP’s: e.g.– Patient safety

– Reliability and integrity of datae ab ty a d teg ty o data

– Planning of the Work

– Informed Consent – Confidentiality

– …




Patient Safety

Patient Safety

• Any issues that may impact patient safety should bereported without delay

• Normal ranges and alert/panic values should beestablished prior to start of analysis

• Content of the Results and observations should bereviewed/QC’d in a timely manner by an appropriatelyqualified person to identify anomalous or out of spec data

• Reporting mechanism/communication lines should beestablished beforehand


Reliability/Integrity of data



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 purposedemonstrate fitness for purpose

• Repeat Analysis & Reporting of repeat analysis results

• Quality Control procedures


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)

C t t f th A l ti l Pl• Content of the Analytical Plan– 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,…




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 subjectresults should be designed to maintain subjectconfidentiality and study blinding/coding


Thank You Questions?Thank You - Questions?

Ellen Berteloot, ir., MBAProgram Manager Clinical Labs R&DQA

ONE TEAM Making the Difference for Patients WORLDWIDE



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






Use of electronic systems in a GLP environment

Nanobodies® -Inspired by nature

GLP environment

Eline VanheulePrincipal Investigator

Annual GLP meeting Brussels9 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-of-concept for a Nanobody achieved in May 2011

www.ablynx.com

First clinical proof 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

2

Introduction - Ablynx’s Nanobodies

Camelidae family has both forms

VH

VLCL

CH1

VHH

VHH

C 2

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Conventional antibody

Heavy and light chainsBoth chains required for antigen binding and stability

Heavy-chain antibody

Only heavy chainsFull antigen binding capacity and very stable

CH3

CH2HH

Ablynx’s Nanobody®

Based on the smallest functional fragment of a naturally occurring heavy-chain antibody

CH3

CH2



Ablynx’s internal and funded programmes

LaunchIND

ALX-0081 (vWF)ALX-0681/0081 (vWF)

Immunology/Infection/Inflammation

Haematology/Thrombotic disorders

ALX-0061 (IL-6R)

ATN-103 (TNFα)PF-05230905 (TNFα)

RegistrationPhase IIILeadOptimization Phase ITarget

SelectionLead

IdentificationPre-clinical Phase II

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Ablynx-led programmePartner-led programme

ALX-0141 (RANKL)

Neurology

Oncology

Various

Pulmonary disease

Musculoskeletal

ALX-0651 (CXCR4)

ALX-0171 (RSV)

The three Merck Serono programmes are in

co-discovery and co-development with Ablynx

Introduction - Pharmacology Department

Ablynx

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Pharmacology

ToxicologyGLP UnitPharmacodynamics Bioanalytics Pharmacokinetics

Pre-clinical safety studies (Pharmaceuticals)• bioanalytical analyses to support toxicokinetics/pharmacokinetics

• biomarker analyses to support pharmacodynamics

• toxicokinetic calculations and evaluation

Introduction – Scope GLP group of the Pharmacology Department

www.ablynx.com

Clinical bioanalysis (PK/PD) and PK evaluation

6



ELISA technique

Electronic system for • document management: ADMS based on OpenText

Introduction – TechniquesGLP group of the Pharmacology Department

www.ablynx.com

• data processing: E-workbook/Biobook (IDBS)

7

Introduction of electronic data processing at Ablynx

Regulatory documentation

GLP Group

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Clinical assay development (Pharmacology)

“free research” (Discovery)

Challenge: find one system that fits all requirements

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

www.ablynx.com

Excellent, fast, ... search capabilities

Only authorized individuals can make data entries

Data entries cannot be deleted

Audit trail, changes can be tracked

9



Introduction - 2 major systems

ADMS Biobook

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Electronic storage of regulatory / approved documents

Data capture and data processing in the lab

Overview

Ablynx Document Management System (ADMS)• use• version control• access rights• upload documents• search

www.ablynx.com

• workflows

11

ADMS – Use

Centralisation of regulatory/approved documents

Automated review and approval cycle

Version control

Searching capabilities

Audit trail

www.ablynx.com

Information sharing:• with other departments• with other programs via links

12

ADMS Biobook



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 versionnumbers using the following format:

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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

13

ADMS- Access Rights

Access rights Coordinator (C) Author (A) Viewer (V)

See X x x

See content X x x

Modify X x

Access rights

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Edit attributes x x

Add items x x

Reserve x x

Delete Empty folders

x

Edit permissions

x

ADMS - Folder Taxonomy and Access Rights

Folder

Sub folder 1

Sub folder 2

Sub folder 3

Sub folder 4

Sub folder 5

Sub folder 6

PHDPT ‐GLP

PHDPT‐ADM‐GLP

PHDPT‐

MGMT‐GLP

PHDPT‐ADM

PHDPT‐

MGMT

PHDPT

NP0010GLP

generalSystem

validationEquipment A C A V V V

Computer systems A C A V V VPersonnel qualification

A C A V V V

Supporting documentation

Buffers A C A V V V

Temperature monitoring A C A V V V

AXXX Study number X A C A V V V

Phase GLP number X Correspondence A C A V V V

GLP NON-GLP

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Phase GLP number X Correspondence A C A V V VShipment A C A V V V

Method validation plan

A C A V V V

Reagents and test items

A C A V V V

Data A C A V V VDeviations A C A V V V

Method validation report

A C A V V V

GLP method validation X

A C A V V V

Correspondence A C A V V VShipment A C A V V V

Method validation plan A C A V V V

Reagents and test items A C A V V V

Data A C A V V VDeviations A C A V V V

Method validation report A C A V V V



ADMS – Upload Documents

Only the person with the right permission (author) can upload a document in a folderCategories is a mandatory field

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ADMS – Upload Documents

www.ablynx.com

Categories = 4 meta-data sets important for the search funtion!

Automatically generates number when all attributes above are filled in

17

ADMS – Search

Only search on documents that can be viewedAdvanced search allows to search on several parameters

• different combinations are possible• you can save searches that you will run regularly

www.ablynx.com 18



ADMS – Workflows

Review workflow

Approval without e-sign and with mandatory attributes

Approval with e-sign and with mandatory attributes

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ADMS – Workflows

Signature = electronic version of a scanned signature

www.ablynx.com 20

Overview

Biobook• general introduction• pipette database• sample database• sample analysis• study report

www.ablynx.com

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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-established formulas

www.ablynx.com

Fast data processing by pre established formulas• all workflows are designed by Ablynx

QC and approval with electronical signatures

Audit trail

22

Biobook – Pipette Database

www.ablynx.com 23

Due date passed: 0 and coloured redDue date between 1 and 14: couloured orange

Biobook – Sample Database

Study Set-up Table

www.ablynx.com 24




Select Matrices Table Select Species(human, rat, mouse, dog, ...)

www.ablynx.com 25


Subjects Table

www.ablynx.com 26

Timepoints Table


Composition Sample Name

www.ablynx.com 27




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

www.ablynx.com

Equipment identification

30




Set-up Assay

www.ablynx.com 31


Set-up assay detailed

www.ablynx.com 32


Buffers

www.ablynx.com

Lab disposables

Number/Name of plates

33




Plate Layout - Lab workflow

www.ablynx.com 34


Freezer timecheck samples

www.ablynx.com

Date of coating/analysis

35


Assay Parameters

www.ablynx.com 36




Available samples – link to Sample database

www.ablynx.com 37


Instrumentation

www.ablynx.com 38


Pipettes – link to Pipette database

www.ablynx.com 39




Standard curve and QCs

www.ablynx.com 40


Plate Summary

www.ablynx.com 41


OD Values

www.ablynx.com 42




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




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 • inter- and intra- plate statistics required for regulatory

www.ablynx.com 48

inter and intra plate statistics required for regulatory purpose

Those tables will be pasted in the study (phase) report




Assay Parameters-report

www.ablynx.com 49


Overview Sample analysis data

www.ablynx.com 50

Overview Plate Validity

Biobook – Sample Analysis Workflow

Overview QC data

www.ablynx.com 51




Overall statistics QC concentrations

www.ablynx.com 52

Inter plate QC Statistics


Intra plate QC statistics

www.ablynx.com 53


Overview standard curves / statistics

www.ablynx.com 54




PK reporting table

www.ablynx.com 55


Lists of• samples• samples re-analysed• samples per plate• results per analysis day

www.ablynx.com 56

Comparisons between sample analysis, re-analysis, ...

Audit trail

Overview


www.ablynx.com

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Archiving

Validation

Advantages/disadvantages

57



Archiving

Logical seperationelectronic records marked as archived

Access rights are changed• everybody has view rights

www.ablynx.com

• only Archivist and Test Facility Management have author rights

58

Overview


www.ablynx.com

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Archiving

Validation

Advantages/disadvantages

59

Validation

Validation Plan: describes the different steps in the validation project, the responsibilities (supplier/client) and the timelinesIQ - Installation Qualification

• Server and client installation • Executed by the developer, witnessed by the client

OQ - Operational Qualification

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p• 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 clientPQ - Performance Qualification

• Simulate Study in BioBook and compare with previous results, obtained with Excel spreadsheets

• Train GLP people and setup proper SOP or INS



Overview

Biobook• General Introduction• Pipette Database• Sample Database• Sample Analysis• Study Report

www.ablynx.com

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ArchivingValidationAdvantages/Disadvantages

61

Advantages/Disadavantages

Advantages• audit trail• version control• electronic review/approval cycle• fast data processing• search

www.ablynx.com

• 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

62





INFORMATION MANAGEMENT

Annual GLP MeetingBrussels, 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




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”

“A collection of data from the past (documents, p ( ,registers etc … ) one wishes to keep or is required to keep”

“A repository of archived documents”


Papyrus dates back since 3000 BC

Microfilm dates back since beginning 20th century

Type of Information carriers

Digital has entered in the eighties




Type of InformationCarrier

Pro Contra

PaperEasy to use, A habit, Durability guaranteed

Volume

Pro & Contra of Information carriers

Paper Durability guaranteeddepending on quality

MicrofilmDurability guaranteed(up to 100 years) depending on quality

Accessibility, Availability

DigitalFlexible, Availability is high, system must be24h/24h up running

Continuousdevelopment, limitedlifetime


What kind of Information does exist?

Microfilms

Wet tissues

Paper records

Samples

Slides

Certificates of Analysis

Final reports

Records of all inspections by Quality Assurance

Paraffin blocks

Computer media Photos

p y

Study related documents and communication

Historical files of all Standard Operating Procedures (SOP’s)

Records and reports of maintenance and calibration of apparatus

Records of qualifications, training, experience and job description of personnel


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”

Why do we keep information ?

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 keepevidence




Internal approach: External approach:

Approach on archiving

•Archive: a designated area or facility of the own company for the securestorage and retention of records and materials

Managed by:

•Archivist: an individual designated to be responsible for the management of the archive, e.g for the operations and procedures for archiving

•Contract Archive Services: external organizations that supply support/services focused on the archiving activity

Supported with:

•Contracts, SLA’s;•Access Arrangements;•Conditions of storage;•Inspections by Quality Assurance (QA)


•Location of the archives•Confidentiality•Availability•Traceability

Main concerns on the archiving process

Traceability•Continuity of staff•Follow‐up on the destruction process•Continuity•New developments•Transparency of cost structure

Listed up in OECD guidelines


FocusManagement of Archives

InternalVersus

External

Internal Archive Management

• Budget for investment;• Fixed costs;• Predefined capacity;• Service during working hours;• Staff policy;• Doubt on continuity

External Archive Management

• Limited budget investment;• Variable costs;• Flexible capacity;• Service 24h/24h;• Stability in staff policy;• Scale advantages




•OECD Principles:‐ Good Laboratory Practice (GLP)‐ Good Manufacturing Practice (GMP)

•OECD °15, Advisory document of the working group on GLP:

Scope of OECD 15

, y g g 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”


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)

The archive facility

• Prevention of unauthorized access • Virus protection against hacking into the 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

Internal archive management•No customized access control specifically for the archive facility•Need for extra investments to secure computerized archive facility


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

External archive management•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

Internal archive management•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




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

The archive conditions

•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


External archive managementInternal archive management

The archive conditions (2)

•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

•Not always evident to store different records and materials separately•No electromagnetic vault•Lack of sufficient monitoring procedures


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

Disaster Recovery

•Weather‐related damage e.g. flooding•Theft and sabotage

External archive management•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

Internal archive management•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




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

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)

External archive management•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

Internal archive management• Access not always restricted to archive staff• Digital records part of the entire IT infrastructure•Accidental loss or damage of records


Track & TraceOECD °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

External archive management•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

Internal archive management•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




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

i l

Retrieval & Disposal

materials•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


External archive management• SOP’s define procedures for each type of record or

t i l

Internal archive management•Difficulties in retrieving

d d t i l

Retrieval & Disposal (2)

material•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

records and materials•Establishment of SOP’s•Authorization procedure•Records of removal of documents and materials


OECD °15 on retention of electronic records:

Retention

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, …




Retention (2)

External archive management•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

Internal archive management•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?


SUMMARY

New developments‐Expansion of information flow‐Paper vs. Digital‐Growth of organization

Location‐(De)central‐Construction of the building‐Climatized environment‐Security (against fire, theft,...)‐Risk of flooding

Confidentiality‐Limited access‐Control exchange of documents‐Possibility to seal vital information

Destruction‐whomay authorize

Continuity‐Single Point of Contact‐Guidelines concerning the inventory and the request of documents‐Permanent training personnel

Availability‐24h/24h service‐what after working hours?

Availability logistics‐Car park (shuttle between archive facility and customer)‐Presence of staff‐Timely delivery of originals or digital copy

Traceability‐ Chain of custody‐(non) vital documents‐Intolerance of mistakes‐Tracing speed‐Manual tracing desired‐Digital tracing using barcodes‐Digital tracing using barcodes + control

who may authorize‐Check of approval‐Follow up of destruction process‐shredding‐Certificate of actual destruction


Conclusion

• analyse all options in detail• KISS• know how in information managementknow 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




Thank you for your attention

Always welcome at Merak !Always welcome at Merak !

www.merak.be



CROs & GLP Multisite Studies- challenges with Sponsor-Conducted Phases

CONFIDENTIAL

Belgian GLP Authority Annual MeetingLinzi Gillbanks – QA Manager

November 2011

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

CONFIDENTIAL2

• The reality– How things tend to work in real life

• Challenges from the CRO perspective

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 Phase284 96 34% 30 11%

CONFIDENTIAL3

284 96 34% 30 11%

• Most common Sponsor-conducted phases:

• Formulations analysis

• Bioanalysis (TK samples)

• Pathology peer review



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

CONFIDENTIAL4

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

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

CONFIDENTIAL5

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 ……………..

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”, they are reluctant to identify an

CONFIDENTIAL6

p , y yindividual 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



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

CONFIDENTIAL7

“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

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

S

CONFIDENTIAL8

– Updated periodically by Sponsor• 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

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 d t th i h di t th t d l d

CONFIDENTIAL9

conduct their phase according to the study plan and 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



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 flexibility of their standard report format

CONFIDENTIAL10

y p– 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

Who Does the CRO Side With?!

• The Regulator?

CONFIDENTIAL11

• The Sponsor?

Conclusions

• A CRO has two “masters”– The Sponsor– The National Regulator

• The GLP MS study, with a Sponsor-conducted h b i ll l t t th

CONFIDENTIAL12

phase, brings all elements together• 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?!




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, i t / lib ti f i t l ti f th i tmaintenance/calibration of equipments, location of the equipments,

number of equipments...etc)3. Maintain Master Schedule4. 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.



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 µmb: all particles greater than 10 µmc: all particles between 1 10 µmc: all particles between 1-10 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?



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 ib d i th t t id i i t t ti f th d tdescribed in the report to avoid misinterpretation of the data

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 theare 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.”



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 studynumber

• Apparatus and software: if technician has to decide according toApparatus 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, butalso generated information should be archived.



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 d thi i t ?What does this requirement 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• 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?



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)



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




Receiving Authorities

European Commission Maik Schmahl [email protected]

Johanna Rose [email protected]




Test Facilities

Ablynx

Marie‐Paule Bouche marie‐[email protected]

Eline Vanheule [email protected]

Kjell Mortier [email protected]

Bram De Rammelaere [email protected]

ATC Patrice Chiap [email protected]

Barbara Campo [email protected]

BAYER

Veerle Habex [email protected]

Sandra Berghman [email protected]

Sofie Tanghe [email protected]

Tinneke Kooi [email protected]

Sophie Persoon [email protected]

Luc Beurms [email protected]

CER Jean‐Luc Beaudart [email protected]

Véronique Misson [email protected]

Cirlam Pieter Deschuytter [email protected]

Marina Dorchain [email protected]

Covance Linzi Gillbanks [email protected]

CRA‐W U10 Vanessa Hérion [email protected]

V. Lecocq [email protected]

O. Pigeon [email protected]

R. Rousseau [email protected]




CRA‐W UG5 D. Vrevos [email protected]

Blandine Gaurois [email protected]

ECTX‐consult Tony Brouwers [email protected]

Fac DGK (Gent) An Maes [email protected]

Ann Spaerkeer [email protected]

Galephar Benedicte Mertens [email protected]

Bernard Cahay [email protected]

Janssen Pharmaceutica NV Hilde Van den Eynde [email protected]

Patricia Engelen [email protected]

Ellen Berteloot [email protected]

Pilarquim Jiang Haiyan

Chou Chengping

Quality Assistance Isabelle Manon Isabelle.manon@quality‐assistance.be

SGS Life Science Services Christian Sulmon [email protected]

Isabelle Parmentier [email protected]

Coralie Quinet [email protected]

Charraf Chebbah [email protected]

Isabelle De Neyer [email protected]

Straticell Aline Chrétien [email protected]

Coralie Bastin [email protected]

Thrombogenics Martine Meurrens [email protected]

Maureen Moerenhout [email protected]




Toxikon Erik Haghedooren [email protected]

Gaby Boonen [email protected]

Thierry Celis [email protected]

Marc De Buyser [email protected]

UCB Pierre Boulanger [email protected]

Françoise Van Bogaert [email protected]

Lynn Stanley [email protected]

UGENT Kris Baert [email protected]

ULG Audrey Renkin [email protected]

VITO‐CARDAM An Van Rompay [email protected]

Ab Borburgh [email protected]




Contract Archives

MERAK Mireille Smets [email protected]

Caroline Sermon [email protected]

Peter Goossens [email protected]

BNC‐Group André Verstraeten averstraeten@bnc‐group.com

France De Smedt fdesmedt@bmc‐group.com

