What’s most recent in EDQM Inspections - EDQM pdf/Andrew McMath - EDQM... · What’s most recent in EDQM Inspections ? IPA-EDQM-IPC Technical Conference Mumbai, 28 – 29 January

What’s most recent in EDQM Inspections ?

What’s most recent in EDQM Inspections ?

IPA-EDQM-IPC Technical ConferenceMumbai, 28 – 29 January 2010

Dr Andrew McMathScientific Officer

Certification of Substances DivisionAndrew McMath 29/01/10 ©2010 EDQM, Council of Europe, All rights reserved

AgendaAgenda

• EU requirements and EDQM inspection program

• How to prepare for an inspection• Statistics: activity review, compliance

trends• Main Deficiencies

Andrew McMath 29/01/10 ©2010 EDQM, Council of Europe, All rights reserved

Responsibility of the MA holderResponsibility of the MA holder• 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 (QP) in the marketing application (and subsequent variation)


EDQM Inspection ProgramEDQM Inspection Program• In application of Directives 2001/82/EC and

2001/83/EC as amended, the European Commission gave a mandate to the EDQM to establish an annual program for inspections

• Inspections are performed inside and outside Europe and involve manufacturing sites and brokers/distributors holding CEP(s)


EDQM Inspection ProgramEDQM Inspection Program• Part of the Certification Procedure• Maybe performed before or after the CEP is granted• Aim: to verify the compliance with

submitted dossierEU GMP Part IIEU GMP Annexes (e.g. Annex 1 / sterile manufacture)


AS manufacturer’s responsibility in CEP application

AS manufacturer’s responsibility in CEP application

• Declaration that API is produced according to EU GMP (Directives 2001/83/EC and 2001/82/EC)

• Declaration on willingness to be inspected• Refusal for an inspection can constitute

grounds to suspend a CEP (see PA/PH/CEP (08) 17, R1)


PrequisitePrequisite• GMP compliance should be effective at the moment of the application• Compliance to the dossier should be effective at any time; in case some changes have been implemented in the process, specifications, methods they should be submitted to EDQM in accordance to the renewal/revision policy http://www.edqm.eu/en/Revisions-amp-Renewals-663.html


The EU GMPs for API: ICH Q7The EU GMPs for API: ICH Q7• Quality Management• Personnel• Buildings and Facilities• Process Equipment• Documentation and Records• Materials Management• Production and In-Process Controls


The EU GMPs for API: ICH Q7The EU GMPs for API: ICH Q7

• Packaging and Identification Labelling of APIs and Intermediates

• Storage and Distribution• Laboratory Controls• Validation / Qualification• Change Control• Rejection and Reuse of Materials• Complaints and Recalls


The EU GMPs for API: ICH Q7The EU GMPs for API: ICH Q7• Contract Manufacturers (incl. Labs)• Agents, Brokers, Traders, Distributors,

Repackers, and Relabellers• Specific Guidance for APIs Manufactured

by Cell Culture/Fermentation• APIs for Use in Clinical Trials• Glossary


EDQM Inspection ProgramEDQM Inspection Program• The draft annual program is circulated to the

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

• The program is finally adopted by the Certification Division’s Steering Commitee.

• The final program is circulated to all EEA Member States Competent Authorities


Selection of the sitesSelection of the sites

• Done in accordance with EU Commission guidance (EMEA/INSP/GMP/313538/ 2006)– request from the assessors– sterile substances– inspection by equivalent authority– several triggers involved– regulatory environment of the manufacturing site

• Based on a risk-based approach


How the system worksHow the system works• Inspection performed by team usually composed of

an EDQM inspector and an inspector coming from an EU/EEA or MRA National Competent AuthorityN.B. the EDQM does not appoint auditors to carry out inspections (see recent news on web-site)

• The compliance to the submitted dossier and to the EU Good Manufacturing Practices is verified

• An inspection report is issued within 6 weeks• Immediate actions are taken in case of major or

critical deficienciesAndrew McMath 29/01/10 ©2010 EDQM, Council of Europe, All rights reserved

Preparing for an EDQM inspection-preliminary information requestPreparing for an EDQM inspection-preliminary information request• Questions are asked regarding the

– Inspection and audit history – Amount of substances produced– Planned shutdowns– Other questions as relevant

• Data provided are used to endorse the relevance of an inspection in the current year• Not replying considered as concealment of facts and increases the relevance of a prompt inspection


Notification of InspectionNotification of Inspection• By express mail and email• Usually, exact dates and substance are

mentioned• In most cases, only one substance is

concerned• Not accepting the inspection at the scheduled

dates is considered a refusal of inspection, followed by the suspension of the concerned CEP and/or closure of application


Some important points beforethe inspectionSome important points beforethe inspection• EDQM informs local Inspectorate about the dates and scope of the inspection• EDQM welcomes the presence of local inspectors as observers• An inspection schedule is sent to the company about one week before inspection starts


Company’s tasks before theinspectionCompany’s tasks before theinspection• Provide SMF/fill in a questionnaire provided by EDQM• These document(s) should be carefully filled in,

preferably from experienced staff and cross-checked by QA. They are core document(s) for the preparation of the inspection

• Send invitation letter by surface mail and scanned by email (for visa application)

• Organise, in collaboration with EDQM, hotels and transfers


Financial AspectsFinancial Aspects• Flat rate fee of € 5000 for each inspection,

independent on the duration of the inspection• Companies who requested an inspection are

charged with € 9000


Inspection follow-upInspection follow-up• Inspection report sent within 6 weeks• Company’s reply within 1 month (from the

receipt of the inspection report)• No corrective action plan should be submitted

before the inspection report was sent• Replies should be fully documented• Commitments should reflect what has or will

actually be done


Inspection OutcomeInspection Outcome• According to the inspection results the

Company is quoted as compliant, borderline or non compliant.

• Borderline status is only a provisional status: after assessment of the corrective action plan, the outcome modified to compliant or non-compliant.

• Companies found compliant may be re-inspected/re-evaluated within 2-5 years depending on the numbers and classification of deficiencies found.


Inspection follow-upInspection follow-up• The company should reply to the deficiencies

found within one month from the receipt of the inspection report

• The replies should be fully documented and reflect actual measures in place

• Discrepancies with the certification dossier are specifically addressed and managed by the revision process at DCEP


Positive OutcomePositive Outcome• In case of positive conclusion of the inspection,and

if any expected changes for CEP revision have been submitted, an inspection attestation is delivered by EDQM, stating the compliance with the CEP-dossier and with the appropriate EU GMP rules

• A GMP Certificate should be issued by the participating EEA Inspectorate, if applicable (EMEA/INS/GMP/871/04)


Negative OutcomeNegative Outcome• In case of critical/major GMP deficiencies or in

case of major deviation compared to the dossier (failure in the declarations and commitments), the corresponding CEP is suspended and/or an on-going CEP application is cancelled

• Suspension is endorsed by an Ad Hoc Committee• All Ph Eur Member States, EMA, EU Commission

and the local Inspectorate are informed


Negative OutcomeNegative Outcome• Information published on the EDQM website

(CEP database and Certification webpages)• Holder and manufacturer are informed • A possibility of hearing is given• Statement of GMP non-compliance is issued

by the EEA Inspectorate• The company must inform their customers

(MAH)


Suspension of the CEPSuspension of the CEP• CEPs are suspended for a period of two

years (NEW! see PA/PH/CEP (08) 17, R1 2009)

• Company is requested to apply within this timeframe for a re-inspection (otherwise final cancellation of CEP)

• Based on a valid justification, the company may ask for an extension of this period

• Lifting the suspension can only be done after an inspection with positive outcome


Statistics 1999-2009Statistics 1999-2009


Statistics 2004-2008: locationsStatistics 2004-2008: locations

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

2004 2005 2006 2007 2008

Elsewhere

EEA

Other Asian countries

China

India


Statistics 2009Statistics 2009


2008 main GMP deficiencies2008 main GMP deficienciesRepartition of deficiencies - 2008

Compliance to CEP dossier & EP

6%

Production & IPC, Rejection & reuse of

materials (chapt.8 &14)5%

Buildings & facilities (chapt.4)

14%Process equipment (chapt.5)

21%

Materials management, Storage & distribution, Packaging (chapt.7,10,

9, 17)18%

Quality related matters (chapt.1, 3, 6, 12, 13,

15, 16)27% Laboratory controls

(chapt.11) 9%


2008 main GMP deficiencies2008 main GMP deficiencies• Quality related matters

– Validation of processes, qualification of equipment, quality review, change control

• Process equipment, buildings and facilities– Cleanliness, maintenance

• Materials management – Traceability, key starting material vendor approval,

storage


ConclusionsConclusions• Experience shows that the inspection remains a

powerful tool to detect non compliant manufacturers and increases the safety for the patients

• API manufacturers should take their responsibilities with regards to GMP compliance

• Finished product manufacturers need to improve their ability to select API manufacturers who comply to the EU GMP guidelines


PerspectivesPerspectives• To further develop the risk based approach on

elaborating the inspection program• Develop a GMP assessment of sites to be

re-inspected in order to optimize resources• To reinforce collaboration/exchange with

European/International Inspectorates and GMP/GDP Inspectors Working Group

• Exchange of information and/or performing joint inspections and ‘mutual recognition’ within the frame of the API pilot project launched by EMA


THANK YOU FOR

YOUR ATTENTION !

THANK YOU FOR

YOUR ATTENTION !


Documents

What’s most recent in EDQM Inspections - EDQM pdf/Andrew McMath - EDQM... · What’s most recent in EDQM Inspections ? IPA-EDQM-IPC Technical Conference Mumbai, 28 – 29 January