Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA)

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• Conference on Sustainable Development and
  Pharmaceuticals
• Uppsala, 10-11 November 2009
• EMEAs role in a sustainable development
  todays situation and the future
• Dr Jean-Marc Vidal European Medicines Agency
  (EMEA)
• Acknowledgement to Kornelia Grein and Jordi Torren

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Outline

• EMEA mission Pharmaceutical legislation
• Guideline principles Evaluation and Precautions
• Role of the EMEA and Environment Protection
• Summary Conclusion

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EMEA Mission Statement

• 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

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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.

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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)

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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.

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ERA Veterinary Medicines

• 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)
• Finalised in 2008 QA document

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EU Guidelines

• 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

Ref. EMEA/P/24143/2004
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The CHMP Guideline

• CHMP Guideline on the Environmental Risk
  Assessment of Medicinal Products for Human Use
  (CHMP/SWP/4447/00)

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Entry Paths into the Environment
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Step-Wise Approach
Stage in regulatory evaluation Stage in risk assessment Objective Method Test /Data requirements
Phase I Pre-screening Estimation of exposure Action limit Consumption data logKOW
Phase II Tier A Screening Initial prediction of risk Risk assessment Base set aquatic toxicology and fate
Phase II Tier B Extended Substance and compartment-specific refinement and risk assessment Risk assessment Extended data set on emission, fate and effects
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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 logKOW gt4.5 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

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Phase I calculation
Calculation of the Predicted Environmental
Concentration (PEC)
DOSEai Fpen WASTEWinhab DILUTION
PECSURFACE WATER
Parameter Symbol Value Unit
Maximum daily dose DOSEai mginh-1d-1
Market penetration Fpen 0.01(default)
Amount waste water WASTEWinhab 200 (default) Linh-1d-1
Dilution factor DILUTION 10 (default)
Predicted concentration PECSURFACE WATER (OUTPUT) mgL-1
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Phase I calculation parameters

• The initial calculation of PECSURFACE 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

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Phase I threshold

• Action limits
• PECSURFACEWATER lt0.01 ?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
• PECSURFACEWATER ?0.01 ?g/L
• Phase II environmental fate and effect analysis

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Phase IIA

• Tier A - Recommended assessment approach
• Physical-chemical properties and fate
• Aquatic effect studies
• Calculation of PNEC using assessment factors
• Groundwater assessment

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Aquatic Effect Studies
Algae
Fish species
Bluegill
Aquatic invertebrates species Daphnia magna
Zebrafish
Trout
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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

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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.

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Role of EMEA and Precautions of use of
Pharmaceuticals
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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.

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Drug Delivery Systems, Dermal Patch
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
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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.

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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

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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

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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)

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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?

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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

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Acknowledgements
Kornelia Grein (EMEA, Veterinary
medicines) Jordi Torren (EMEA, Veterinary
medicines) Klaus Olejniczak (BfARM, DE) John
Jensen, (NERI, DK) Thank you !