International conference Quality of Active Pharmaceutical Ingredients Hyderabad, September 2009 API Inspections: the EDQM experience – 7 September 2009 Florence Benoit-Guyod, EDQM Inspector Certification of substances Division, EDQM

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 2 The Certification Procedure Intended to be applied for the assessment of the quality of pharmaceutical substances with regards to the criteria of the Ph. Eur. monograph(s) It ensures that all possible impurities and contamination can be fully controlled by the requirements of the monograph(s) Additional benefits: centralised assessment for 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

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 3 Inspection An inspection may be part of the Certification Procedure The inspection is performed either before or after the CEP is granted The inspection aim is to verify the compliance with the submitted dossier and with the EU GMP Part II For sterile substances compliance with Annex 1 EU GMP

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 4 Role of the National Competent Authority The Competent Authority may carry out an inspection of an active substance manufacturer in order to ensure that a 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)

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 5 Conditions for an inspection When requested by a member State, EMEA, European Commission or EDQM (if there are grounds for suspicion of non- compliance, need to verify data submitted) When requested by the manufacturer itself

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 6 Responsibility of the manufacturer In the CEP procedure the manufacturer has to declare: - Compliance to Good Manufacturing Practices (GMP) - Willingness to be inspected

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 7 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)

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 8 EDQM Inspection Program The draft program is circulated to the Member States for comments and presented to the GMP/GDP Inspectors Working Group at EMEA for discussion. The program is finally adopted by the CEP Steering Commitee. The final program is circulated to all EEA Member States Competent Authorities

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 9 Selection of the sites Done in accordance with the EMEA guidance EMEA/INSP/GMP/313538/ 2006 According to a risk-based approach: - main criteria: request from the assessors - sterile substances - inspection by equivalent authority - several triggers involved - regulatory environment of the manufacturing site

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 10 How the system works Inspection performed by team composed of an EDQM inspector and an inspector coming from an EU/EEA or MRA National Competent Authority The compliance to the submitted dossier and to the EU Good Manufacturing Practices Part II is verified An inspection report is issued within 6 weeks Immediate actions are taken in case of major or critical deficiencies

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 11 Inspection Outcome According to the inspection results the Company is quoted as compliant, borderline or non compliant. Companies found compliant may be re- inspected/re-evaluated within 3-5 years depending on the numbers and classification of deficiencies found. Companies found borderline may be re- inspected earlier (about 2 years)

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 12 Inspection follow-up The company must 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

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 13 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, stating the compliance with the CEP and with the GMP A GMP Certificate may be issued by the participating Inspectorate (EMEA/INS/GMP/871/04)

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 14 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 on-going CEP application is rejected Suspension is endorsed by an Ad Hoc Committee All PhEur Member States/Observers/Partners, EMEA, EU Commission and local Inspectorate are informed

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 15 Negative Outcome Information published on the EDQM website (CEP database and Certification webpages) Holder and manufacturer are informed and a possibility of hearing is given Statement of GMP non-compliance is issued by the EEA Inspectorate

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 16 Suspension of the CEP With effect of 2009 the CEPs are suspended for a period of two years Company is requested to apply within this timeframe for a re-inspection 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

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 17 Statistics

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 18 Statistics : locations

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 19 Statistics 2008

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 20 General compliance trends Non compliant sites: 2007: 18% 2008: 21% 2009: 35% (updated to June) This is the result of the ability of EDQM to identify sites with higher risk of non- compliance and to focus on them

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved Review 28 inspections performed 2 refusals of inspection 6 sites non GMP compliant Results: 16 CEPs were suspended and 9 dossiers blocked (the current policy is now to withdraw the application)

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved Review (end June) 17 sites inspected (9 China, 7 India, 1 Hungary) 6 sites non compliant 4 sites borderline (follow-up on going) CEPs suspended: 8 Dossier closed: 2 CEPs withdrawn after suspension due to negative re-inspection: 2 Outcome: 35% of the sites were found non compliant; an additional 18% has a borderline level of compliance

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved main GMP deficiencies

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 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

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 25 Conclusions Experience shows that the inspection remains a powerful tool to detect non compliant manufacturers Finished product manufacturers must improve their ability to select API manufacturers who comply to the EU GMP Part II

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 26 Perspectives Further develop the risk-based approach when elaborating the programme Reinforce collaboration and sharing of information with EU and International Inspectorates

Florence Benoit-Guyod, Sept ©2009 EDQM, Council of Europe, All rights reserved 27 THANK YOU FOR YOUR ATTENTION