EDQM Certificates of Suitability: Cooperation Among Inspectorates ...

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


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.


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.


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


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


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))


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)


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!


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)


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


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


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


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


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.



Principles:

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



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



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


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


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


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


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


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


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

EDQM Certificates of Suitability: Cooperation Among Inspectorates ...

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