Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 1 Conference on Sustainable Development and...

Conference Uppsala, 10-11 Nov 2009 Jean-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 futureDr Jean-Marc Vidal

European Medicines Agency (EMEA)

Acknowledgement to Kornelia Grein and Jordi Torren


OutlineOutline

• EMEA mission & Pharmaceutical legislation

• Guideline principles: Evaluation and Precautions

• Role of the EMEA and Environment Protection

• Summary & Conclusion


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

productsTo advise on research and development

programmes

EMEA Mission Statement


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.

…


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)

Conference Uppsala, 10-11 Nov 2009 Jean-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.


ERA Veterinary Medicines

• CVMP guidance from 1996 superseded by CVMP guidance from 1996 superseded by CVMP-VICH guidelinesCVMP-VICH guidelines::

– Phase I (VICH GL6) (July 2000)Phase I (VICH GL6) (July 2000)– Phase II (VICH GL38) (October 2005)Phase II (VICH GL38) (October 2005)

• CVMP guideline in supporting VICH GLs CVMP guideline in supporting VICH GLs 6 & 38 (EMEA/CVMP/ERA/418282/2005-6 & 38 (EMEA/CVMP/ERA/418282/2005-Rev.1)Rev.1)– Finalised in 2008 + Q&A documentFinalised in 2008 + Q&A document


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


The CHMP Guideline

CHMP – Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use

(CHMP/SWP/4447/00)


Excretion

Sewage

Disposal

Surface waterSoil

Landfill site

Waste

Ground water

Sewage treatment plant

Drinking water

Storage

Air

Entry paths into the environment for most medicinal products when prescribed to patients

Incineration

(Air)

Entry Paths into the Environment


Stage in regulatory evaluation

Stage in risk assessment

Objective MethodTest /Data requirements

Phase I Pre-screeningEstimation of exposure

Action limit

Consumption data

logKOW

Phase II Tier A ScreeningInitial 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

Step-Wise Approach


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 >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


Phase I calculation

Parameter Symbol Value Unit

Maximum daily dose DOSEai mg*inh-1d-1

Market penetration Fpen 0.01(default)

Amount waste water WASTEWinhab 200 (default) L*inh-1d-1

Dilution factor DILUTION 10 (default)

Predicted concentration PECSURFACE WATER (OUTPUT) mg*L-1

Calculation of the Predicted Environmental Concentration (PEC)

PECSURFACE WATER =DOSEai * Fpen

WASTEWinhab * DILUTION


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


Phase I threshold

Action limits

PECSURFACEWATER <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

PECSURFACEWATER 0.01 g/L

Phase II environmental fate and effect analysis


Phase IIA

Tier A - Recommended assessment approach

Physical-chemical properties and fate

Aquatic effect studies

Calculation of PNEC using assessment factors

Groundwater assessment


Aquatic Effect Studies

Aquatic invertebrates speciesDaphnia magna

Algae

Fish species

Bluegill

Zebrafish

Trout


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


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.


Role of EMEA and Role of EMEA and

Precautions of use of Precautions of use of

PharmaceuticalsPharmaceuticals

Role of EMEA and Role of EMEA and

Precautions of use of Precautions of use of

PharmaceuticalsPharmaceuticals


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.


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 waterGroundwaterDrinking water

Drug Delivery Systems, Dermal Patch


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.


Considerations for the Future (1/3)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

•



• 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

•



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)



• 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”?


ConclusionsConclusions

• 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


Acknowledgements

Kornelia Grein (EMEA, Veterinary medicines)

Jordi Torren (EMEA, Veterinary medicines)

Klaus Olejniczak (BfARM, DE)

John Jensen, (NERI, DK)

Thank you !

Conference Uppsala, 10-11 Nov 2009Jean-Marc Vidal (EMEA) 1 Conference on Sustainable Development and...

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