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International API Inspection Pilot Program

Olivier GrossScientific AdministratorEMEA

DIA International Conference

Quality of Active Pharmaceutical Ingredients

5th – 7th September 2009

Any views expressed are those of the author and should not be understood as those of EMEA or its scientific committees

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27 EU Member States and 42 national authorities

5 operational MRAPartners

3 EEA countries

1 “Advanced MRA” (ACCA)partner

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GMP Inspections within EMEA (1)

No inspectors at EMEA, only coordination of inspections done by the 27 Member States

Different type of inspections for APIs and FP

- Pre-authorisation Inspections

- Post-Authorisation Inspections

- Re-inspections every 2-3 years

Most of the inspections coordinated by EMEA are not in EEA

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GMP Inspections within EMEA (2)

In EEA, EMEA relies on the inspections performed by EEA authorities of their manufacturing sites on their territories every 2-3 years

EMEA relies also on inspections carried out by MRA countries (Switzerland, Australia, New Zealand, Canada, Japan)

Quarterly meetings of GMP Inspectors Working Group

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Main GMP inspection challenges in EU (1)

Ensure continued protection of Public Health with scarce resources and budgets

Increasing regulatory requirements and expectations with

more and more global operations.

Concerns about the supply chain in the legal and illegal sector with a growth in counterfeit activity

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Main GMP inspection challenges in EU (2)

More and more complex supply chains and a fundamental shift of the manufacturing sites of APIs outside EU leading to an increasing European and international and focus on the quality of APIs

For each product a large numbers of API manufacturers involved, intermediates, API starting materials, alternative sources

Responsibility of the GMP compliance of the API manufacturer relies with the QP of the Finished Product.

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International Collaboration activities (1)

Number of mechanisms for international partnership between EU and other countries

- EEA countries, accession countries, EDQM, WHO, PIC/S

- Mutual Recognition Agreements (MRA)- Confidentiality arrangements: FDA, Japanese

MHLW, Canada,- EU - US Transatlantic administrative simplification

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International Collaboration activities (2)

IT exchange tools :

May 2007 launch of EudraGMP databaseGMP information on inspections performed by EU and MRA

partners

further release to include a module for sharing inspection plans

US FDA Compliance status database (COMSTAT)

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Background for the project (1)

Global supply chain for APIs / Global regulatory environment (ICH)

Increasing demand for international collaboration on inspection work sharing on a risk-based approach

Quality issues in 2008 for products with API manufactured outside EU (e.g. heparin)

New EU legislative proposals expected to impact approaches to GMP API inspections

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Background for the project (2)

Need of better use of International inspectional resources allowing an increase inspectional coverage outside participating regions

Coordination/collaboration/information between authorities on sites of common interest can contribute to risk based approaches and improve inspection efficiency.

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The project : Starting up

Authorities performing significant number of inspections of APIs outside of their territories approached by EMEA end 2007EU : France, Germany, Ireland, Italy, United Kingdom

MRA : Australian TGA

Council of Europe : EDQM

US : FDA

All agreed to participate in a pilot phase to last for 18 months with recommendation for future action

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The project : Tools of the program (1)

Objectives developed into :Update on a pilot project to collaborate on international GMP

inspection activities http://www.emea.europa.eu/Inspections/docs/43043807enrev1.pdf

Rules of engagement and procedures for participating authorities (active pharmaceutical ingredients/active substances)

http://www.emea.europa.eu/Inspections/docs/41432308en.pdf

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The project : Tools of the program (2)

Confidentiality agreements signed between the participating authorities to allow sharing of inspection plans

Template spreadsheet for exchange of inspection planning's, retrospective and prospective, defined.

APIs –Jurisdiction- Name of the site –Address-Zip Code- City- state/Province—Country- Last inspection- C/NC- Planned inspection-Category-Sterile-

.

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The project : Running of the program (1)

Use of a common GMP standard = ICH Q7

Each involved authority responsible for any follow-up actions (e.g. administrative or enforcement)

Always right to perform “own” inspections

All authorities to ensure if possible an agreed conclusion in case of joint inspection

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The project : Running of the program (2)

Organisation of bilateral and general teleconferences to built up the program and define a strategy for the sites of common interest :

July 2008 : AFSSAPS, IMB, EDQM, EMEA, MHRA, TGA, USFDA, ZLG

September 2008 : AFSSAPS, IMB, EDQM, EMEA, MHRA, TGA, USFDA, ZLG

December 2008 : EDQM, EMEA, USFDA,

March 2009 : EMEA, USFDA

April 2009 : EMEA , TGA

April 2009 : TGA, USFDA

May 2009 : EDQM , TGA

July 2009 : AIFA, AFSSAPS, IMB, EDQM, EMEA, MHRA, TGA, USFDA

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The project : Running of the program (3)

Main activities to be developed within the program based on the sharing of inspections planning:

- Sharing of inspection reports of passed inspections

- Sharing of inspection reports of future inspections with or without scope extension

- Joint inspection with or without scope extension.

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Scenario a: inspection report sharing

API manufacturer in

third country

EU willing to inspect and to

share the report with US

US willing to inspect

INSPECTIONAPI 1

INSPECTIONAPI 1

a: US delegates to EU

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Scenario b: inspection report sharing with expanded scope

API manufacturer in

third country

US willing to inspect AP1 +

AP2 and share the report with EU

EU willing to inspect API 2

INSPECTIONAPI 1

INSPECTIONAPI 2

b: EU ask US to expand scope

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Scenario c: collaborative inspection

API manufacturer in third country

Joint inspected by

EU + US

EU willing to inspect

US willing to inspect

Decision of joint inspection

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The project : Key Performance Indicators

Increased transparency and visibility of inspections

Decrease in “duplicate inspections” inspections of the same product or sites carried out by more than one authority within a similar time period

Overall (pre-approval and surveillance/post-approval/GMP) increase in number of sites of API inspected relative to 2006-2008 figures

Increase in number of inspections performed of value to more than one authority

Positive assessment of the deliverables

Regulatory capacity building in countries with emerging API industry.

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The Project : Retrospective data

Retrospective inspection data (2006-2007-2008) provided by :

EDQM (124), USFDA (215), AFSSAPS (55), TGA (47), MHRA (31), and EMEA (63) . Total 535 API manufacturing sites outside the participating countries

91 (17 %) API manufacturing sites were inspected in the last 3 years by more than one of the above mentioned inspectorates.  

- 74 were inspected by two different inspectorates from which 30 sites where inspected within 6-7 month - 16 were inspected by 3different inspectorates - 1 was inspected by 4 different inspectorates

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The project : Results in 2009 (1)

EMEA 99

EDQM 125

FDA 42

TGA 174

AFSSAPS 9

AIFA 4

ZLG 3

IMB 2

MHRA 31

Total 489 sites shared 489

Inspection Reports Done 6

Requested 14

Proposed 12

Total 32

Joint Inspections Done 6

Confirmed 2

Asked 10

Proposed 2

Total 20

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The project : Results in 2009 (2)

489 sites identified and shared

103 Sites common to at least 2 participants identified for possible cooperation

NCA Nb of Sites Nb of Hits %Collaboratio

n

EMEA 99 53 50 % 10 IR + 11 JI

EDQM 125 45 36 % 9 IR + 6 JI

TGA 147 87 60 % 15 IR + 13 JI

FDA 42 28 66 % 8 IR + 8 JI

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The project : Next steps

Regular teleconferences and e-mail exchanges for the development of the program, the organisation of joint inspections and sharing of inspection reports.

Improving process monitoring:Gather more data on site inspections planning (all sites, APIs)

Reporting tools (e.g. feedback form)

Reliance on each other’s inspections will increase resource available to cover more sites

Enlarge the number of participants

Enlarge the scope after ending the first 18-month cycle

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Conclusion

Working together is challenging

Need to have recognition of each other’s environments, organisation, expertise

Significant collaborative work underway

Cooperation of Regulatory authorities is in the interest of Public Health worldwide.

Communication will be the key to success

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European Medicines Agency 7, Westferry CircusCanary WharfLondon E14 4HBUnited Kingdom

Tel: +44 (0) 20 7418 8400Fax: +44 (0) 20 7418 8416GMP@emea.europa.euqdefect@emea.europa.euGMPINS@emea.europa.eu

www.emea.europa.eu

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AbbreviationsEMEA- European Medicines AgencyCVMP - Committee for Medicinal Products for Veterinary useCHMP - Committee for Medicinal Products for Human useCOMP - Committee for Orphan Medicinal Products HMPC - Committee for Herbal Medicinal Products PDCO – Committee for Paediatric Medicinal ProductsMS – Member StatesEU – European UnionEEA – European Economic AreaEDQM – European Directorate for the Quality of Medicines and HealthcareMRA – Mutual Recognition AgreementsPIC/S - Pharmaceutical Inspection Cooperation SchemeWHO - World Health OrganisationAPI- Active Pharmaceutical Ingredient (term active substance used in EEA)ICH/VICH International Conference on Harmonisation/Veterinary equivalent