IPA-EDQM Mumbai 12/2007 ©2007 EDQM, Council of Europe 1 Certification (CEP/CoS) and inspection system Corinne Pouget Certification of Substances Division.

IPA-EDQM Mumbai 12/2007 ©2007 EDQM, Council of Europe

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Certification (CEP/CoS) Certification (CEP/CoS) and inspection systemand inspection system

Corinne Pouget Certification of Substances Division

EDQM & HealthCare


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OverviewOverview

• Scope and running the systemScope and running the system• The EDQM inspection programmeThe EDQM inspection programme• Update and key figuresUpdate and key figures• Perspectives 2008Perspectives 2008


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Scope and running the Scope and running the systemsystem


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The Certification procedureThe Certification procedure

• To show for a pharmaceutical substance:To show for a pharmaceutical substance:– Suitability of the Ph. Eur. Monograph to control Suitability of the Ph. Eur. Monograph to control

the quality of a substancethe quality of a substance– Compliance with European regulatory Compliance with European regulatory

requirementsrequirements

• Created in 1994, scope enlargedCreated in 1994, scope enlarged• Managed by EDQMManaged by EDQM• Harmonisation and centralisation of workHarmonisation and centralisation of work


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Legal backgroundLegal background

• Directives 2001/83/EC and 2001/82/ECDirectives 2001/83/EC and 2001/82/EC Ph Eur monographs are mandatory (specific and Ph Eur monographs are mandatory (specific and

general)general) Need to demonstrate that a specific monograph is Need to demonstrate that a specific monograph is

suitable to control the quality of the active substancesuitable to control the quality of the active substance Where there is a monograph in Ph Eur:Where there is a monograph in Ph Eur:

- CEP ‘deemed to replace the relevant section of the module’ CEP ‘deemed to replace the relevant section of the module’ (3.2.S)(3.2.S)

- CEP holder must give assurance in writing to the applicant…CEP holder must give assurance in writing to the applicant…no change since CEP granted by EDQMno change since CEP granted by EDQM

Prevention of TSE risksPrevention of TSE risksDemonstration of compliance preferably by a CEPDemonstration of compliance preferably by a CEP


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Legal background (2)Legal background (2)

• Note for guidance : « Note for guidance : « Summary of Summary of requirements for active substances requirements for active substances “(“(CHMP/QWP/297/97 rev. 1 EMEA/CVMP/1069/02CHMP/QWP/297/97 rev. 1 EMEA/CVMP/1069/02):):– CEPCEP– ASMFASMF– Full information in Marketing ApplicationFull information in Marketing Application

• Resolution AP-CSP(07) 1 Resolution AP-CSP(07) 1 of the of the Council of Europe: Procedural aspectsCouncil of Europe: Procedural aspects


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Scope of the procedureScope of the procedure

• Substances covered by a specific PhEur monograph: Substances covered by a specific PhEur monograph: Active, excipients, herbal drugs / herbal preparationsActive, excipients, herbal drugs / herbal preparations

• TSE risk products TSE risk products (SM, intermediates, reagents,..)(SM, intermediates, reagents,..)

• Not applicableNot applicable for biotechnological products, products for biotechnological products, products from human tissues, semi-finished or finished products, from human tissues, semi-finished or finished products, substances not included in Ph. Eursubstances not included in Ph. Eur


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Scope (2)Scope (2)

• Open to any manufacturer of active substance / Open to any manufacturer of active substance / expicient whatever the geographical originexpicient whatever the geographical origin

• Centralised evaluationCentralised evaluation• Facilitates management of Marketing ApplicationsFacilitates management of Marketing Applications• CEP accepted in all EP countries (36) + others CEP accepted in all EP countries (36) + others

(eg Canada, Australia, Morocco, Tunisia, New (eg Canada, Australia, Morocco, Tunisia, New Zealand..)Zealand..)


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Confidentiality respectedConfidentiality respected

• CEP dossiers submitted directly by CEP dossiers submitted directly by manufacturersmanufacturers

– No applicant part (≠ ASMF)No applicant part (≠ ASMF)

• Independently of any marketing applicationIndependently of any marketing application

• Archived in a specific restricted area Archived in a specific restricted area (EDQM)(EDQM)

• Assessment on the premises of EDQMAssessment on the premises of EDQM


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Who is involved?Who is involved?The different stakeholders and their roles are defined in Terms of The different stakeholders and their roles are defined in Terms of Reference (PA/PH/CEP (01) 1 (see EDQM web-site)Reference (PA/PH/CEP (01) 1 (see EDQM web-site)

• Steering Committee Steering Committee – 11 members : representative bodies of EU and Ph. Eur countries11 members : representative bodies of EU and Ph. Eur countries

• Assessors from 16 countries Assessors from 16 countries – About 80: chemical purity, TSE, toxicologists, for herbal drugs, About 80: chemical purity, TSE, toxicologists, for herbal drugs,

sterilitysterility• Technical Advisory Boards (TAB)Technical Advisory Boards (TAB)

Chemical TABChemical TABTSE TABTSE TAB

• Certification DivisionCertification Division


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Steering CommitteeSteering Committee

• Appointment of assessors

• Appointment of Technical Advisory Boards (TABs) and their Chairmen

• Policy

• Co-ordination of issues between the parties represented


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Technical advisory board’s (TAB) role

• Assist assessors in case of doubt or disagreement

• Technical guidance

• Technical/scientific problems and seek advice for SC


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Assessors and Certification Assessors and Certification DivisionDivision

• Independent AssessorsIndependent Assessors – evaluation of dossiers evaluation of dossiers

• Certification Division Certification Division (EDQM scientific and (EDQM scientific and administrative staff)administrative staff)

– execution of the procedure and co-ordinationexecution of the procedure and co-ordination


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The EDQM Inspection The EDQM Inspection programmeprogramme


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EDQM Inspection programmeEDQM Inspection programme

In application of Directive 2001/83/EC as In application of Directive 2001/83/EC as amended (Article 111) and Directive 2001/82/EC amended (Article 111) and Directive 2001/82/EC as amended (Article 80):as amended (Article 80):

MandateMandate is given to EDQM (by EC) to establish is given to EDQM (by EC) to establish an annual programme for inspections:an annual programme for inspections:– Manufacturing sites and brokers/distributors holding Manufacturing sites and brokers/distributors holding

CEPs CEPs – Inspections inside and outside EUInspections inside and outside EU– Authorities notified of issues arisingAuthorities notified of issues arising


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EDQM inspection programmeEDQM inspection programme

• In line with EMEA ‘trigger document’:In line with EMEA ‘trigger document’:– If requested during assessment If requested during assessment – Sterile substancesSterile substances– CEP held by brokers/traders/distributorsCEP held by brokers/traders/distributors– To join a scheduled national inspection To join a scheduled national inspection – On justified requests from manufacturersOn justified requests from manufacturers

• Adopted by the CEP Steering CommitteeAdopted by the CEP Steering Committee


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Inspection progressInspection progress

• Lasts about 3 days Lasts about 3 days • Team of 2 inspectors (of Ph. Eur member states)Team of 2 inspectors (of Ph. Eur member states)

– Local inspector invited in Local inspector invited in nonnon-Ph. Eur countries-Ph. Eur countries– EDQM representativeEDQM representative

• References:References:– ICH Q7A (+annex 1 of EU guideline for sterile subst.) and any other ICH Q7A (+annex 1 of EU guideline for sterile subst.) and any other

relevant GMP documentsrelevant GMP documents– Certification DossierCertification Dossier

• Visit of the manufacturing facilities (process flow)Visit of the manufacturing facilities (process flow)• Study of production and QA management documentsStudy of production and QA management documents• Conclusions presented orally to the company at the end of the Conclusions presented orally to the company at the end of the

inspectioninspection


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Follow-up of an inspectionFollow-up of an inspection

• Report sent to the companyReport sent to the company• Company requested to address deficiencies Company requested to address deficiencies • When positive inspectors’ opinion:When positive inspectors’ opinion:

EDQM Attestation of InspectionEDQM Attestation of Inspection GMP certificate drafted by the EU leader GMP certificate drafted by the EU leader

inspectorinspector


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Rationale for suspension of Rationale for suspension of CEPs CEPs • In case of In case of major/criticalmajor/critical GMP deficiency(ies) GMP deficiency(ies)

The company does not operate with a sufficient level of The company does not operate with a sufficient level of compliance compliance

• If major deviation(s) compared to the dossierIf major deviation(s) compared to the dossier Failure in the declarations and commitmentsFailure in the declarations and commitments

Decision to suspend the CEP (board) Decision to suspend the CEP (board) and/or to block applicationsand/or to block applications


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In case of suspension of a CEPIn case of suspension of a CEP

• Holder (and manufacturer) notified:Holder (and manufacturer) notified:– justification, conditions for restoration, possibility for justification, conditions for restoration, possibility for

hearinghearing

• All relevant authorities informed, incl.All relevant authorities informed, incl. EMEA EMEA Working groups + EU CommissionWorking groups + EU Commission

• Public information: EDQM website + CEP on-linePublic information: EDQM website + CEP on-line


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Frequent findings Frequent findings noticed by inspectorsnoticed by inspectors

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Frequent findingsFrequent findings

• Few critical deviationsFew critical deviations• About 25% were major deviationsAbout 25% were major deviations• In some cases combination of major/minor lead to In some cases combination of major/minor lead to

a critical situationa critical situation• 110 inspections carried out - 15 defective110 inspections carried out - 15 defective !! Selected sites, suspected to be non-compliant Selected sites, suspected to be non-compliant

before inspection (eg. request from assessors)before inspection (eg. request from assessors) These figures cannot be extrapolated for a statistical These figures cannot be extrapolated for a statistical

overview of the status of the API sites overview of the status of the API sites


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Frequent deviationsFrequent deviationsBased on 110 inspections Based on 110 inspections incl. 9% traders , 3% TSE subst; sterile excludedincl. 9% traders , 3% TSE subst; sterile excluded))

• Process equipment (15%)Process equipment (15%) ++• Materiel management (12%)Materiel management (12%) ==• Documentation and records (11%)Documentation and records (11%) --• Buildings & facilities (10%)Buildings & facilities (10%) ==• Quality management, Lab controls (8%)Quality management, Lab controls (8%) --• Production and IPC (7%)Production and IPC (7%) ==• Compliance with CEP dossier (7%)Compliance with CEP dossier (7%) ++• Packaging & labelling, validation (4%)Packaging & labelling, validation (4%) --


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Frequent deviationsFrequent deviations

• Process equipment:Process equipment:• Identification of equipment insufficient Identification of equipment insufficient • Handling of closed equipment not satisfactoryHandling of closed equipment not satisfactory• Cleaning procedures poorly defined or appliedCleaning procedures poorly defined or applied• Non-calibrated apparatus for IPCNon-calibrated apparatus for IPC

• Material management:Material management:• Lack of qualification of suppliersLack of qualification of suppliers• ‘‘Critical’ suppliers not well definedCritical’ suppliers not well defined• Incomplete tracing-back of animal-origin materialsIncomplete tracing-back of animal-origin materials


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Frequent deviations (2)Frequent deviations (2)

• Documentation and records:- Lack of procedures, or insufficient details - Weak management of the documentation system- Contradiction between procedures and reality- Incomplete batch records

• Batch release:- Insufficiently described (written procedures)- Unclear (weakness of adequate checks)- Responsibilities unclear (no defined or inappropriate responsible

person)


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• Buildings and facilities:Buildings and facilities:– Areas not well defined for storage / quarantine / samplingAreas not well defined for storage / quarantine / sampling– Inadequate protection of environment and production areasInadequate protection of environment and production areas– Systems for air, steam, gases,… not sufficiently qualified and Systems for air, steam, gases,… not sufficiently qualified and

monitoredmonitored

• Quality Management:Quality Management:− Role of QA inadequately resourced, insufficiently describedRole of QA inadequately resourced, insufficiently described− Poor training and knowledge of the QA staffPoor training and knowledge of the QA staff− QA staff not involved in matters related to the quality of productsQA staff not involved in matters related to the quality of products− Weakness of quality reviewWeakness of quality review


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• Laboratory:Laboratory:– Use of non registered methodsUse of non registered methods– Standards not appropriateStandards not appropriate– Equipment not properly qualified/monitoredEquipment not properly qualified/monitored

• Production / IPC:Production / IPC:– Critical parameters insufficiently defined and controlledCritical parameters insufficiently defined and controlled– Equipment inappropriate or badly maintainedEquipment inappropriate or badly maintained– Risks of contamination/cross-contaminationRisks of contamination/cross-contamination– Deviations not sufficiently documented, explained/investigated, no Deviations not sufficiently documented, explained/investigated, no

reporting system in placereporting system in place


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For sterile substancesFor sterile substances

≤ ≤ 10 % of inspections carried out10 % of inspections carried out

1.1. General aspects (clean areas, classification, monitoring) and General aspects (clean areas, classification, monitoring) and processing (reduction of contamination, bio burden monitoring..)processing (reduction of contamination, bio burden monitoring..)

2.2. Personnel (training, clothing) and premises (pipes, air-flow and Personnel (training, clothing) and premises (pipes, air-flow and pressure, warning systems)pressure, warning systems)

3.3. Sterilisation validation, and filtration (integrity, re-use of filters)Sterilisation validation, and filtration (integrity, re-use of filters)

!! New policy for manufacturing sites on the CEP New policy for manufacturing sites on the CEP


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UUpdate and pdate and Key figuresKey figures


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Update on communicationUpdate on communication

• Technical advice procedure (5 meetings in Technical advice procedure (5 meetings in 2007)2007)

• Workshops Workshops

• One-to-one meetingsOne-to-one meetings

• EDQM website redesignedEDQM website redesigned


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« CEP on-line »: is my CEP valid?« CEP on-line »: is my CEP valid?

www.edqm.euwww.edqm.eu


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Full CEP numberFull CEP number

Issue date of the current CEPIssue date of the current CEP

StatusStatusHolder name (on CEP)Holder name (on CEP)


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Contacts with Licensing AuthoritiesContacts with Licensing Authorities

• Transmission of CEP evaluation reportsTransmission of CEP evaluation reports– Upon request from an authorityUpon request from an authority– In the context of a marketing application or any justified In the context of a marketing application or any justified

reasonreason– Copy of the report(s) sent also to the holderCopy of the report(s) sent also to the holder– Reports from 20 dossiers sent in 2007, 44 in 2006 (incl. Reports from 20 dossiers sent in 2007, 44 in 2006 (incl.

15 for TPD/Health Canada)15 for TPD/Health Canada)


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Update on workload and Update on workload and deadlinesdeadlines

• Workload increases:Workload increases:– 320 new applications in 2006, 350 in 2007320 new applications in 2006, 350 in 2007– 500 revisions/renewals in 2006, 600 in 2007500 revisions/renewals in 2006, 600 in 2007

Cumulative number of applications received

18 9

48 52

109

132155

199

420

451

239

280

317305

322

270

0 0 0 0 0 0 0 0

229 233

39 31 33 28 25 2018 9

48 52

109

132155

199 191

218200

249

284 277297

250

0

50

100

150

200

250

300

350

400

450

500

1992199319941995199619971998199920002001200220032004200520062007

number of applications

Total

TSE Doubles

Chemical


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Since beginning of procedureSince beginning of procedure• > 3300 applications> 3300 applications• > 2300 certificates granted> 2300 certificates granted• > 650 substances> 650 substances• > 560 manufacturers from 43 countries> 560 manufacturers from 43 countries

Repartition of manufacturers by zone03/2006

Europe47%

Middle East19%

Asia18%

America15%

Pacific1%

Africa0%


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inspectionsinspections

110 manufacturing sites inspected 110 manufacturing sites inspected • in 22 countries in 22 countries ((incl.incl. China, India, Mexico, Canada, China, India, Mexico, Canada,

Europe)Europe)• 12 cases where major/critical deficiencies led to 12 cases where major/critical deficiencies led to

suspension of CEPssuspension of CEPs– Some being held by European wholesalers/distributorsSome being held by European wholesalers/distributors– cases where ‘sterile ’ grade was refusedcases where ‘sterile ’ grade was refused– some CEPs ‘restored’ already after re-inspection some CEPs ‘restored’ already after re-inspection (CEP revised)(CEP revised)


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DeadlinesDeadlines

• Deadlines improved:Deadlines improved:– New appl.: up to 6 months delay in 2006, 3-New appl.: up to 6 months delay in 2006, 3-

4 months in 20074 months in 2007– Renewals: up to 6 months delay in 2006, 3-Renewals: up to 6 months delay in 2006, 3-

4 months in 20074 months in 2007– Intermediate revisions: on time in 2006 and Intermediate revisions: on time in 2006 and

2007 2007 – Add info: in time in 2006 (4 months) and in Add info: in time in 2006 (4 months) and in

2007 (3 months)2007 (3 months)

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Perspectives 2008Perspectives 2008

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Perspectives for EDQM Perspectives for EDQM inspection programmeinspection programme

• Programme to be continued in application of the Programme to be continued in application of the EU mandateEU mandate

• Follow-up of defective inspections - reinspectionsFollow-up of defective inspections - reinspections• Enlarge experienceEnlarge experience

– >> 35 inspections/year 35 inspections/year– with other inspectorates, groups…with other inspectorates, groups…– And other countriesAnd other countries


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EDQM inspection programme (2)EDQM inspection programme (2)

• Promote inspections of drug substances Promote inspections of drug substances and establish an adequate systemand establish an adequate system– Reinforce collaboration with EU/EMEAReinforce collaboration with EU/EMEA– Collaboration with European/international Collaboration with European/international

inspection working groupsinspection working groups– System for harmonised decisions for System for harmonised decisions for

sites/batches/MA concerned after suspension sites/batches/MA concerned after suspension of CEPsof CEPs


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Procedural aspectsProcedural aspects

• Deadlines:Deadlines:– Reduce delay for new applications (be on time ??)Reduce delay for new applications (be on time ??)– EDQM commits to treat RQs EDQM commits to treat RQs without changeswithout changes on time on time

from 01/01/2008from 01/01/2008

• Electronic submissions:Electronic submissions:– Instructions for applicants to develop electronic Instructions for applicants to develop electronic

applicationsapplications– Prepare for e-CTDPrepare for e-CTD


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Revision of CEPsRevision of CEPs

• Revise the system to reduce administrative Revise the system to reduce administrative work, in cooperation with EMEA QWP:work, in cooperation with EMEA QWP:– Define minor changes which will not lead to a Define minor changes which will not lead to a

revised CEP after approvalrevised CEP after approval– Access to CEP database for Authorities Access to CEP database for Authorities

(history of revisions,..)(history of revisions,..)• Wait for revision of EU RegulationWait for revision of EU Regulation


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THANK YOU FOR YOUR THANK YOU FOR YOUR ATTENTIONATTENTION

IPA-EDQM Mumbai 12/2007 ©2007 EDQM, Council of Europe 1 Certification (CEP/CoS) and inspection system Corinne Pouget Certification of Substances Division.

Documents

ipaedqm mumbai

edqm harmonisation

council of europe

cep slide

finished products

system slide

eur slide

biotechnological products