1. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 1 Conference on Sustainable Development and Pharmaceuticals Uppsala, 10-11 November 2009 EMEA´s role in a sustainable development – today´s situation and the future Dr Jean-Marc Vidal European Medicines Agency (EMEA) Acknowledgement to Kornelia Grein and Jordi Torren

2. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 2 Outline EMEA mission & Pharmaceutical legislation Guideline principles: Evaluation and Precautions Role of the EMEA and Environment Protection Summary & Conclusion

3. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 3  To protect and promote public health  Allow rapid access to safe and effective innovative medicines  Facilitating innovation and stimulating research  Mobilising scientific resources from throughout the EU to provide high-quality evaluation of medicinal products  To advise on research and development programmes EMEA Mission Statement

4. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 4 EU Pharmaceutical Legislation Directive 2001/83/EC, as amended: Art 8 (3) The application shall be accompanied by the following particulars and documents, submitted in accordance with Annex I:  … (ca) Evaluation of the potential environmental risks posed by the medicinal product. This impact shall be assessed and, on a case-by-case basis, specific arrangements to limit it shall be envisaged.  (d) Description of the manufacturing method.  (e) Therapeutic indications, contraindications and adverse reactions.  (f) Posology, pharmaceutical form, method and route of administration and expected shelf life.  (g) Reasons for any precautionary and safety measures to be taken for the storage of the medicinal product, its administration to patients and for the disposal of waste products, together with an indication of potential risks presented by the medicinal product for the environment.  …

5. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 5 Additional Specific Legal Requirements Radio-pharmaceuticals  Council Directives 96/29/Euratom and 97/43/Euratom. Genetically Modified Organisms (GMOs)  Directive 2001/18/EC Chemical Legislation  REACH  Water Framework Directive  (GMP)

6. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) The CHMP Guideline CHMP – Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use (CHMP/SWP/4447/00)  Legislative basis: Article 8(3) of Directive 2001/83/EC, as amended  An ERA is REQUIRED for all new MAAs for a medicinal product through a centralised, mutual recognition, decentralised or national procedure.  and for post-marketing submissions (type II variations, line extension). Not renewals for human medicines.

7. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 7 ERA Veterinary Medicines CVMP guidance from 1996 superseded by CVMP-VICH guidelines :CVMP guidance from 1996 superseded by CVMP-VICH guidelines : –Phase I (VICH GL6) (July 2000) –Phase II (VICH GL38) (October 2005) CVMP guideline in supporting VICH GLs 6 & 38 (EMEA/CVMP/ERA/418282/2005- Rev.1)CVMP guideline in supporting VICH GLs 6 & 38 (EMEA/CVMP/ERA/418282/2005- Rev.1) –Finalised in 2008 + Q&A document

8. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 8 Status of Guidelines vs Legal requirements  To be considered as harmonised Community position  If followed by relevant parties such as applicants, marketing authorisation holders, sponsors, manufacturers and regulators will facilitate assessment, approval and control of medicinal products in the EU.  Nevertheless, alternative approaches may be taken, provided that these are appropriately justified EU Guidelines Ref.: EMEA/P/24143/2004

9. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) The CHMP Guideline CHMP – Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use (CHMP/SWP/4447/00)

10. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 10 Entry Paths into the Environment

11. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 11 Stage in regulatory evaluation Stage in risk assessment ObjectiveMethod Test /Data requirements Phase IPre-screening Estimation of exposure Action limit Consumption data logK OW Phase II Tier AScreening Initial prediction of risk Risk assessment Base set aquatic toxicology and fate Phase II Tier BExtended Substance and compartment- specific refinement and risk assessment Risk assessment Extended data set on emission, fate and effects Step-Wise Approach

12. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 12 Phase I principles In phase I, the estimation should be based only on the drug substance, irrespective of its route of administration, pharmaceutical form, metabolism and excretion With reference to the OSPAR Convention, drug substances with a logK OW >4.5 should be screened, in a step-wise procedure, for persistence, bioaccumulation and toxicity according to the EU TGD Certain substances, such as highly lipophilic compounds and potential endocrine disruptors, may need to be addressed irrespective of the quantity released into the environment In Phase I the PEC calculation is restricted to the aquatic compartment

13. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 13 Phase I calculation ParameterSymbolValueUnit Maximum daily doseDOSEaimg*inh -1 d -1 Market penetrationFpen0.01(default) Amount waste waterWASTEWinhab200 (default)L*inh -1 d -1 Dilution factorDILUTION10 (default) Predicted concentrationPEC SURFACE WATER (OUTPUT)mg*L -1 Calculation of the Predicted Environmental Concentration (PEC) PEC SURFACE WATER = DOSEai * Fpen WASTEWinhab * DILUTION

14. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 14 Phase I calculation parameters The initial calculation of PEC SURFACE WATER assumes:  A fraction of the overall market penetration (Fpen). The applicant may refine this fraction by providing reasonably justified market penetration data, e.g. based on published epidemiological data  The predicted amount used per year is evenly distributed over the year and throughout the geographic area  The sewage system is the main route of entry of the drug substance into the surface water  There is no biodegradation or retention of the drug substance in the STP  Metabolism in the patient is not taken into account

15. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 15 Phase I threshold Action limits PEC SURFACEWATER <0.01  g/L and no other environmental concerns apparent  Assume that the medicinal product is unlikely to represent a risk for the environment following its prescribed usage in patients PEC SURFACEWATER  0.01  g/L  Phase II environmental fate and effect analysis

16. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 16 Phase IIA Tier A - Recommended assessment approach Physical-chemical properties and fate Aquatic effect studies Calculation of PNEC using assessment factors Groundwater assessment

17. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 17 Aquatic Effect Studies Aquatic invertebrates species Daphnia magna Alga e Fish species Bluegill Zebrafish Trout

18. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 18 Phase IIB Tier B –Considerations Several options to refinement of PEC and PNEC for the parent compound and/or relevant metabolites (≥ 10% of amount excreted) Environmental transformation, when relevant Information from refined and expanded data set  Route(s) of excretion and metabolites  Long-term toxicity  Microbial inhibition  Biodegradability

19. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 19 ERA Veterinary Medicines Phase II: Candidates: –The active is a new compound for mass medication of food producing animals. –The active is not extensively metabolised in the animal. It is an antimicrobial applied via feed/water herd medication or a parasiticidal substance applied on pasture or it is a fish medicine.

20. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 20 Role of EMEA and Precautions of use of Pharmaceuticals Role of EMEA and Precautions of use of Pharmaceuticals

21. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 21 Product Information Labelling should generally aim at minimising the quantity discharged into the environment by appropriate mitigation measures. PIL: Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to dispose of medicines no longer required. These measures will help to protect the environment. Additional labelling should be employed only when warranted (e.g. radioactive isotope preparations or medicines concentrated in devices) in which circumstances the measures to be taken should be practical and realistic given the anticipated use of the product.

22. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 22 The contraceptive patch product XYcontains 0.75 mg ethinyl estradiol and 6.0 mg norelgestromin hormones in a single patch. The gradual release of hormones over the course of each week (approximately 20 µg/day ethinyl estradiol and 150 µg/day norelgestromin) act much like contraceptive pills do. Surface water Groundwater Drinking water Drug Delivery Systems, Dermal Patch

23. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 23 Examples SPC: 6.6 Instructions for use and handling, and disposal No Concern:  Any unused product or waste material should be disposed of in accordance with local requirements. Concerns (patch Evra):  Apply immediately upon removal from the protective sachet. After use the patch still contains substantial quantities of active ingredients. Remaining hormonal active ingredients of the patch may have harmful effects if reaching the aquatic environment. Therefore, the used patch should be discarded carefully. The disposal label from the outside of the sachet should be peeled open. The used patch should be placed within the open disposal label so that the sticky surface covers the shaded area on the sachet. The disposal label should then be closed sealing the used patch within. Any used or unused patches should be discarded according to local requirements or returned to the pharmacy. Used patches should not be flushed down the toilet nor placed in liquid waste disposal systems.

24. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 24 Considerations for the Future (1/3) Transparency –Summarised data are available in the EPAR but heterogeneous –New template has been agreed will harmonise published data and level of details –Swedish initiatives ! Environmental data –EU funded research e.g. Start-project, brings new knowledge on the fate and concentration of substances in the environment –Technologies to improve treatment of waters in STP

25. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 25 Considerations for the Future (1/3) Transparency –Summarised data are available in the EPAR but heterogeneous –New template has been agreed will harmonise published data and level of details –Swedish initiatives ! Environmental data –EU funded research e.g. Start-project, brings new knowledge on the fate and concentration of substances in the environment –Technologies to improve treatment of waters in STP

26. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 26 Considerations for the Future (2/3) Risk minimisation measures for pharmaceuticals –Product information Risks on environmental described in the SPC, section 5.3 (preclinical data) if concerns –Risk minimisation (disposal): Recommendations for disposal in the SPC and PIL –Risk Management Plan may include recommendation when serious risks to public health (human pharmaceuticals)

27. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 27 Considerations for the Future (3/3) Guidelines –Revision of Guidelines according to the state-of-the art science. Ad-hoc expert groups working both on human (SWP) and veterinary medicines (ERA-WP). –Action limits could be more adapted to the risk of particular products/pharmacological class –Specific Annexes to Guidelines could be envisaged. Legislation –Veterinary medicines legislation under revision. Discussion of “monographs”?

28. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 28 Conclusions Evaluation of the potential risk of medicines to the environment for any new dossier submitted Transparency: Summary data on the environmental assessment are published in the EPAR. Recommendations on precautions for use and disposal is included in the product information where necessary Risk-Benefit (Efficacy and Safety) in the patients should be considered together with Environmental Risks

29. Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) Acknowledgements Kornelia Grein (EMEA, Veterinary medicines) Jordi Torren (EMEA, Veterinary medicines) Klaus Olejniczak (BfARM, DE) John Jensen, (NERI, DK) Thank you !