Assessment – Inspection – QC Laboratories Pr Pierre-Antoine Bonnet DLC - AFSSAPS

1. Assessment – Inspection – QC Laboratories Pr Pierre-Antoine Bonnet DLC - AFSSAPS Interregional Seminar for Quality Control Laboratories involved in WHO Prequalification Programme and/or participating in respective sampling and testing projects, Nairobi, Kenya, 23-25 September 2009

2. AFSSAPS Historical Background • March 1993 : Creation of the Agence du médicament which gathers for Medicines for the first time within the same structure : • Assessment (ex-direction de la pharmacie et du médicament –DPhM- Ministry of Health) • Quality Control Laboratories (ex-laboratoire national de la santé-LNS- Ministry of Health) • Inspection (creation of a centralised GMP inspection)

3. AFSSAPS Historical Background • 1998 : creation of Afssaps • Extension of the Competences : from Medicines to the overall Health Products including Medical Devices and Cosmetics • Complete separation of the functions of production and contrôle for all Health Products for Human Use

4. AFSSAPS Main Specificities 1. The General Director takes in the State name all health decisions relevant to Health Product Quality & Safety 2. The Agency gathers three scientific competence poles on Evaluation (on dossiers), Quality Control Laboratories (on products) and Inspection (on sites), allowing global and rapid health security management and decisions on Health Products for human use. 3. Afssaps has an enlarged knowledge of all health products for human use (evaluation, control, inspection, vigilances), on all the chain (from clinical trials to market surveillance)

5. AFSSAPS Supervision of the Quality of Medicines OVERALL EVALUATION OF THE QUALITY OF MEDICINES DEMEB DIE ASSESSMENT INSPECTION DLC MANUFACTURINGSITES DOSSIERS LABORATORY CONTROL CONTROL PRODUCTS

6. Market surveillance of Health Products Annual Programmes - Shared programmes between Assessment, Inspection and QC Laboratories - Risk-analyses based programmes On time Surveillance surveys - in line with any relevant health product related problem - to propose relevant management and decisions

7. Market surveillance of Health Products Follow up of Quality Control Laboratories expertise In case of OOS or relevant problem: All issues are discussed and shared within regular inter-directions meetings (one per month for Chemical Medicines) with inputs from: - QC Laboratories Scientists - Pharmacopoeia Supervisors - Assessors - GMP and Forensic Inspectorates Common decisions and follow-up are proposed and put in place

8. Risk-oriented control programmesApplication to Generics Qualitative evaluation: Input from the different concerned parties: Assessment, Inspection, Laboratory control List of axes of particular interest - Follow up of former identified problems - Specific therapeutic classes - Specific pharmaceutical tests - Stability concerns - Control of labelling, packaging - Relevance to maintain a certain level of non-specific controls, controls of new groups… - Inputs from the MA Working Group on Generics…

9. Laboratory Control of Generics

10. LABORATORY CONTROLSFOLLOW-UP The Follow-up is insured upon a large concertation between all AFSSAPS concerned parties Regular meetings (monthly) between: Assesors, Inspectorates, Quality Control laboratories All detected problems (OOS, analytical remarks, follow up of any motivated control) are discussed and assessed Sharing of any consistent information • Common and concerted approach • Centralised and coordinated interaction with the MAH • Collective decision

11. AFSSAPS follow-up actions further to OOS controls of Generics 174 Actions for a total of 2097 medicinal products analysed, i.e. 1 action for 12 controlled products

12. API Laboratory Control • Programme Surveys • Inter-directions / Pharmacopoeia planning meetings Focus on sensitive, instable APIs, multi-sources… • Focus on specified parameters : API dosage Related impurities Residual solvents…. • Referentials: EP monographs (whenever possible) • Motivated Controls • Sampling further to GMP inspection • Focused and oriented analyses according to specific request

13. Example: The Heparine case HEPARINES ALERT QUALITY France Sweden

14. QC RESULTS

15. QC RESULTS – INSPECTION - EVALUATION • QUALITY CONTROL : market surveillance dedicated to heparins • PHARMACOPOEIA : UP-DATING EP MONOGRAPHS • INSPECTION : INSPECTION IN FRANCE AND CHINA (with EDQM) EUROPEAN COOPERATION (GMDP IWG) • EVALUATION : UP-DATING OF M.A. DOSSIERS • QUALITY • VIRAL SAFETY

16. Cooperative risk analysis forAnnual QC programmes EMEA/INS/S&T/5291/2005 Sampling and testing of CAP objectives and description of the programme « In the future products may be selected based on a risk analysis based on findings at assessment, GMP inspections, submitted variations… Criteria could include risks identified for active substance, patient profiles, poor stability, production process, pharmaceutical form and data from previous controls. »

17. Risk-oriented control programmes EDQM/OMCLs Quantitative model Occurrence-related factors Generic, Product with sensitive stability Complexity of product, Recently licensedproduct.. Exposure-related factors Dispensing level of product… Harm-related factors Route of administration, Low therapeutic index, Vulnerable target population, Long duration of treatment… EMEA/INS/S&T/120857/2008 Sampling and testing of CAPs: Development of risk based approach for the selection of products

18. Risk-oriented control programmesApplication to European Authorised Medicines Quotation tables by the QC labs

19. Risk-oriented control programmes • Comprehensive • Quotation criteria with • benefits from: • - Assessment expertise • - Pharmacovigilance reports • - Inspection findings • - QC laboratories results

20. EVALUATION – INSPECTION – QUALITY CONTROLAPPLICATION TO COSMETICS Alert on Toothpastes containing Diethylene glycol DEG • Alerts from Panama, USA, Canada • Information to the public (all over the problem case) • Sampling on the French Market and different distribution sites • Laboratory QC : Control of 123 products on July-August 2007 • GC/MS (FDA) July 2007 / OOS for values above 0,1% • Microbiological control • 19 00S samples concerning 11 products • Risk assessment: Acute and chronic DEG intake • Health Safety Policy Decision: DEG forbidden in toothpastes, Recall of products • 2008: DEG forbidden at the European level (Annex II of the Directive) Follow-up in 2009: New Market surveillance (sampling and testing)

21. EVALUATION – INSPECTION – QUALITY CONTROLAPPLICATION TO COSMETICS

22. Assessment – Inspection – QC Laboratories • Close collaboration between scientific advisors and experts in evaluation, inspection and QC Labs requires time and organisation • Exchange of information is essential for good management of Health products quality and safety issues • Coordinated approach allows special focus on dedicated issues and comprehensive treatment and solutions • Transversal collaboration is essential for sound implementation of referentials and regulation

23. Assessment – Inspection – QC Laboratories Thank you for your attention Asanta sana kwa kusikiliza