EDQM Certificates of Suitability: Cooperation Among Inspectorates

in Europe And Beyond

EDQM Certificates of Suitability: Cooperation Among Inspectorates

in Europe And Beyond

14th International Conference of Drug Regulatory Authorities – Pre-ICDRA

Meeting

Dr Susanne KeitelEuropean Directorate for the Quality of Medicines & HealthCare

Council of Europe

Dr Susanne Keitel, November 2010©2010 EDQM, Council of Europe, All rights reserved 2

ContentContent

• The Council of Europe and EDQM• The Certification Procedure• The EDQM Inspection Program• International Collaboration• Inspection Statistics• Outlook

Dr Susanne Keitel, November 2010©2010 EDQM, Council of Europe, All rights reserved 3

The Council of EuropeThe Council of Europe

• Founded on 5 May 1949 by 10 countries • An international organisation in Strasbourg which

comprises 47 countries of Europe. • The primary aim of the Council of Europe is to

create a common democratic and legal area throughout the whole of the continent, ensuring respect for its fundamental values: human rights, democracy and the rule of law.

Dr Susanne Keitel, November 2010©2010 EDQM, Council of Europe, All rights reserved 5

The EDQMThe EDQMThe European Directorate for the Quality of Medicines & HealthCare (EDQM), a Directorate of the Council of EuropeOur vision is to be a leader in protecting public health byestablishing high quality standards for:• medicines for human and veterinary use, blood transfusion and organ transplantation;

• the safe and appropriate medication;• participating in programmes targeted towards the protection of consumer health.

Dr Susanne Keitel, November 2010©2010 EDQM, Council of Europe, All rights reserved 6

The Certification ProcedureThe Certification Procedure• One out of three options to submit the quality

documentation for an API in EU licensing procedures

• Referred to in the EU pharmaceutical legislation

• Open for substances covered by a Ph.Eur. Monograph

• Certifies that impurities can be adequately controlled by the monograph(s)

• Includes inspections

Dr Susanne Keitel, November 2010©2010 EDQM, Council of Europe, All rights reserved 7

The Certification Procedure (cont.)The Certification Procedure (cont.)

Additional benefits:

• Centralised assessment of APIs: attractive to applicants and National Competent Authorities

• Identification of potential divergent practices by national assessors may contribute to more consistent assessment approaches across Europe

Dr Susanne Keitel, November 2010©2010 EDQM, Council of Europe, All rights reserved 8

The Certificate of Suitability (CEP)The Certificate of Suitability (CEP)

• Certifies that the quality of a given substance can be suitably controlled by the Ph.Eur. monograph -with additional tests, if necessary (stated on the CEP).

• It DOES NOT certify that a batch or batches of the substance complies with the Pharmacopoeia monograph.

• It IS NOT a GMP certificate

GMP Requirements for APIGMP Requirements for API• Active substance must be produced according to EU

GMP (Directives 2001/83/EC and 2001/82/EC)

• It is the responsibility of the MAH to ensure EU GMP compliance of the active substance manufacturer

• Declaration from the MAH Qualified Person(s) (QPs) in the MA (and any subsequent variation(s))

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Challenges in A Globalised WorldChallenges in A Globalised World

• Complex and fragmented supply chain with a growth in adulteration/counterfeiting activities

• Shift of API manufacture away from Europe• Large number of API manufacturers involved,

including increasing trade with intermediates, API starting materials and presence of alternative sources

• Increasing need for on-site verification of GMP compliance?

EDQM Inspection ProgramEDQM Inspection Program• Part of the Certification Procedure, based on a

mandate given by the European Commission

• Maybe performed before or after a CEP is granted

• Aim: to verify compliance with submitted dossierEU GMP Part IIEU GMP Annexes (e.g. Annex 1 / sterile manufacture)

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Selection of SitesSelection of Sites• Done in accordance with EU Commission guidance

(EMEA/INSP/GMP/313538/ 2006)• request from the assessors• sterile substances• may be several triggers involved• re-inspection• regulatory environment of the manufacturing site• inspection by equivalent authority

• Based on a risk-based approach => NO routine inspections!

Dr Susanne Keitel, November 2010©2010 EDQM, Council of Europe, All rights reserved 13

Legal Framework Legal Framework

• The Competent Authority may inspect an API manufacturer in order to ensure that the manufacturing authorisation holder of a medicinal product has fulfilled its obligations under Article 46 (f) and/or Article 50 (f) of the below mentioned Directives (Article 111 of Directive 2001/83/EC and Article 80 of Directive 2001/82/EC)

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EDQM Inspection ProgramEDQM Inspection Program• Draft annual program circulated to Member States

for comments and presented to GMP/GDP Inspectors Working Group at EMA for discussion.

• Program adopted by Certification Steering Commitee.

• Final program circulated to all EEA Member States’ Competent Authorities

Dr Susanne Keitel, November 2010©2010 EDQM, Council of Europe, All rights reserved 15

How The System WorksHow The System Works• Inspection performed by team, usually composed of

EDQM inspector and inspector coming from EU/EEA or MRA National Competent Authority

• Compliance with submitted dossier and EU GMP verified

• EDQM informs local inspectorate about date and scope of inspection and welcomes participation of local inspectors as observers

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EDQM and the EMAEDQM and the EMA• GMP/GDP Inspectors’ Working Group

• Discussion of EU Regulations, GMPs, GDPs• Management of MRAs in the field of GMP• Management of the Community Procedures

• EudraGMP database access• International API Inspection Pilot Program (2007)

• Gathers authorities performing significant number of API inspections outside their territories: FR, DE, IE, IT, UK, EDQM, AU, US

• Aim: to make best use of inspectorates’ resources• Based on sharing inspection reports or/and performing joint

inspections

Dr Susanne Keitel, November 2010©2010 EDQM, Council of Europe, All rights reserved 17

EDQM and GMP InspectoratesEDQM and GMP Inspectorates• Inspections performed by team composed of

EDQM inspector and inspector from EU/EEA or *MRA National Competent Authority

AustriaCzech RepublicDenmark FinlandFrance Germany GreeceHungaryIrelandItaly

LatviaNetherlandRomaniaUKSwedenSpain*Switzerland*Australia+ WHO

Dr Susanne Keitel, November 2010©2010 EDQM, Council of Europe, All rights reserved 18

API Pilot ProjectAPI Pilot Project

• Overall objective is to see whether greater international collaboration and information sharing can help:– to better distribute inspection capacity, – allowing more sites to be monitored and – reducing unnecessary duplication.

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API Pilot ProjectAPI Pilot Project

Principles:

• Sharing of inspection reports of conducted inspections• Sharing information on inspection planning• Joint inspection with or without scope extension.

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API Pilot ProjectAPI Pilot Project

Involved Authorities:• EU: France, Germany, Ireland, Italy, United Kingdom• Council of Europe: EDQM• MRA: Australia (TGA)• US: FDA

Current Status:• Interim Report available

(http://www.ema.europa.eu/docs/en_GB/document_library/Report/2010/10/WC500097431.pdf)

• Collaboration to continue

Dr Susanne Keitel, November 2010©2010 EDQM, Council of Europe, All rights reserved 21

API Pilot ProjectAPI Pilot Project

Benefits for EDQM:- Broader coverage of manufacturing sites by using

external inspection reports- suspension/restoration of CEPs (sterile) based on inspection/re-inspection

performed by Germany- Joint inspections with TGA

- Extension of the inspection’s scope (i.e. covering an API subject to the CEP procedure) saved resources

- International networking / confidence building

Dr Susanne Keitel, November 2010©2010 EDQM, Council of Europe, All rights reserved 22

EDQM Inspection Statistics2004-2009

EDQM Inspection Statistics2004-2009

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

2004 2005 2006 2007 2008 2009

ElsewhereEEAAsia otherChinaIndia

Dr Susanne Keitel, November 2010©2010 EDQM, Council of Europe, All rights reserved 23

Statistics 1999-2010 (Exp)Statistics 1999-2010 (Exp)

0

5

10

15

20

25

30

35

Number of EDQM inspections per yearOutside EU/EEA EU/EEA

Dr Susanne Keitel, November 2010©2010 EDQM, Council of Europe, All rights reserved 24

Statistics 2004-2010 (Exp)Statistics 2004-2010 (Exp)

EDQM40%

France9%

Germany11%

Finland3%

Switzerland5%

Italy3%

Romania9%

Denmark4%

Sweden3%

Spain4% Norway

3%

UK3%

Greece3%

EDQM Inspections 2010 - Repartition of the number of inspector-days

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2009 Review2009 Review• 29 sites inspected by EDQM• 32 sites covered by exchange of information with

other inspectorates• 10 found non-compliant with EU GMP• 3 sites borderline (follow-up on going)• CEPs suspended: 11• Dossiers closed: 2• CEPs withdrawn after suspension due to negative

re-inspection: 3• 3 CEPs suspended for two manufacturing sites due

to refusal to be inspected

Dr Susanne Keitel, November 2010©2010 EDQM, Council of Europe, All rights reserved 26

OutlookOutlook• Further develop risk-based approach when elaborating

programme• Reinforce collaboration and sharing of information with

EEA and international inspectorates in order to optimise inspection ressources through:– (Pilot) program for exchange of information on API (EMA)– GMDP Inspectors’ Working Group: EEA members – Committee of officials of PIC Scheme (PIC/S)– Confidentiality agreement with PIC/S, TGA Australia, USFDA– Confidentiality agreement with WHO being finalised– EUDRA GMP database

Dr Susanne Keitel, November 2010©2010 EDQM, Council of Europe, All rights reserved 27

Thank you for your attention!Thank you for your attention!