What s most recent in EDQM Inspections? IPA-EDQM-IPC Technical Conference Mumbai, 28 29 January 2010 Dr Andrew McMath Scientific Officer Certification of Substances Division
Agenda EU requirements and EDQM inspection program How to prepare for an inspection Statistics: activity review, compliance trends Main Deficiencies
Responsibility 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 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 Program Part of the Certification Procedure Maybe performed before or after the CEP is granted Aim: to verify the compliance with submitted dossier EU GMP Part II EU GMP Annexes (e.g. Annex 1 / sterile manufacture)
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)
Prequisite 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 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 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 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 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 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 works Inspection performed by team usually composed of an EDQM inspector and an inspector coming from an EU/EEA or MRA National Competent Authority N.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 deficiencies
Preparing for an EDQM inspectionpreliminary 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 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 before the 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 the inspection 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 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-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 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 reinspected/re-evaluated within 2-5 years depending on the numbers and classification of deficiencies found.
Inspection 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 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 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 ongoing 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 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 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 1999-2009
Statistics 2004-2008: locations 100% 90% 80% 70% 60% 50% 40% 30% Elsewhere EEA Other Asian countries China India 20% 10% 0% 2004 2005 2006 2007 2008
Statistics 2009
2008 main GMP deficiencies Repartition of deficiencies - 2008 Quality related matters (chapt.1, 3, 6, 12, 13, 15, 16) 27% Laboratory controls (chapt.11) 9% Materials management, Storage & distribution, Packaging (chapt.7,10, 9, 17) 18% Compliance to CEP dossier & EP 6% Production & IPC, Rejection & reuse of materials (chapt.8 &14) 5% Process equipment (chapt.5) 21% Buildings & facilities (chapt.4) 14%
2008 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
Conclusions 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
Perspectives 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
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