German Environment Agency

Environmental risk assessment of VMPs:

Background and state of the art

Workshop „How to achieve an appropriate Environmental Risk Assessment of Veterinary Medicinal Products”

Jutta Klasen

Federal Environment Agency, Germany

Brussels, 07 June 2017

Do veterinay medicinal products pose

a risk to the environment?

2Workshop „How to achieve an appropriate ERA of veterinary medicinal products“, Brussels, 07 June 2017

Exposure of the environment

3

Active pharmaceutical substances used in veterinary medicinal products

(VMPs) and their metabolites are released into the environment.

Workshop „How to achieve an appropriate ERA of veterinary medicinal products“, Brussels, 07 June 2017

surface waterAquaculture

groundwater

soil

Intensively rearedanimales(poultry, cattle, pig)

dungPasture-raised(horse, cattle, sheep)

Companion aminals generally no significant exposure of theenvironment expected

Fate and occurence of VMPs in the environment

4Workshop „How to achieve an appropriate ERA of veterinary medicinal products“, Brussels, 07 June 2017

Typical fate & behavior of different groups Detections fromagricultural use

Sulfonamides: mobile (very low potential to adsorb,good to moderate degradation in soil)

Various sulfonamidesin groundwater in Germany

Tetracyclines: remain in soils(immobile in soils, moderate degradation in soil)

Various tetracyclinesin soils in Germany

Macrocyclic lactones: remain in soils(immobile in soils, persistent in soil)

No systematicmonitoring dataavailable

β-Lactames: detection unlikely(low potential to adsorb, fast degradation in soil)

No detections in soilsor groundwater

Effects of VMPs in the environment – antibiotics

5

Antibiotics:

• Impact on development and spreading of antibiotic resistance

in the environment

• Impact on algae and plants

e.g. enrofloxacin and ciprofloxacin are toxic to cyanoaphyta

and to duckweed (Lemna minor) [Ebert et al. ET&C, 2011]

• Impact on terrestrial plants (emergence, survival, growth)

e.g. florfenicol: NOEC (growth)= 0.06 mg/kg;

tylosintartrate: NOEC (growth) = 16 mg/kg [Richter et al. ESEU, 2016]

Workshop „How to achieve an appropriate ERA of veterinary medicinal products“, Brussels, 07 June 2017

photos: D. Maletzki, U. Kühnen (UBA)

Effects of VMPs in the environment - parasiticides

6Workshop „How to achieve an appropriate ERA of veterinary medicinal products“, Brussels, 07 June 2017

Effects after 1, 2 and 3 weeks:LC50 = 0.88 mg ivermectin/kg dung dw

[Hempel et al. 2006; Römbke et al. 2007]

photos: ECT GmbH, Flörsheim

very toxic on aquatic crustacean and on dung insects

impact on aquatic and soil ecosystems

Example: impact of ivermectin on dung beetle development.

Effects on dung

fauna have caused

concerns about dung

degradation and the

usability of meadows

(impairment of

ecosystem services).

Environmental risk assessment of VMPs

7Workshop „How to achieve an appropriate ERA of veterinary medicinal products“, Brussels, 07 June 2017

Legal framework

8

• Directive 2001/82/EC as amended:

• An ERA needs to be submitted for all new applications irrespective

of the underlying legal basis, i.e. also for generics

• ERA is part of the benefit risk balance, a non-authorization because

of a serious risk for the environment would be possible

• Risk mitigations measures can be included in product literature

• ERA is part of the pharmacovigilance requirements

• ERA has to follow VICH guidelines 6 (Phase I) and 38 (Phase II)

• Additional EMA documents (guidelines, guidance documents, etc.)

• Experimental ERA mainly based on standardized OECD studies

Workshop „How to achieve an appropriate ERA of veterinary medicinal products“, Brussels, 07 June 2017

Tiered ERA approach (acc. to CVMP/VICH-guidelines)

9Workshop „How to achieve an appropriate ERA of veterinary medicinal products“, Brussels, 07 June 2017

Phase I – Exposure assessment

No experimental studies required

Initial calculation of a Predicted Environmental Concentration (PEC)

Comparison with trigger value:100 µg/kg soil (terrestrial animals),

1 µg/l (aquatic animals); parasiticides always require Phase II ERA

Phase II- Fate analysis

experimental data on fate (metabolism, sorption, degradation)

Phase II – Effect analysis

experimental data on effects on organisms in water, sediment and soil

Tier A – base data set

Tier B – extended data set

derivation of a Predicted No Effect Concentration (PNEC)

Risk characterisation: exposure (PEC) (no)effect (PNEC)

PBT assessment

Risk mitigation in case PEC/PNEC ≥ 1 or PBT

Experiences with the current legislation

10Workshop „How to achieve an appropriate ERA of veterinary medicinal products“, Brussels, 07 June 2017

Experiences with the current legislation

Workshop „How to achieve an appropriate ERA of veterinary medicinal products“, Brussels, 07 June 2017 11

Existing (‚legacy‘) products: VMPs were approved before the requirement

for an ERA was introduced into the legislation.

A review programm of these ‚legacy‘ products (substances) was not

implemented.

Sometimes dossiers are incomplete and/or not according to current

standards.

Data on environmental safety are only available for about half of the

environmentally relevant active substances.

For many VMPs in use no or not sufficient data on environmental safety are available.

Pre-market phase – a dissatisfying situation

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Applicant A(Product A )

Applicant B(Product B)

Marketing Application ERA 1

Marketing Application ERA 2

Marketing Application ERA 3

Applicant C(Product C)

Different applicants apply for a marketing authorisation of a medicinal product intended for the same indication and containing the same active substance.

• Multiplication of data / ERAs

• Results of fate and effect studies

may vary. This may lead to

- varying assessments

- different risk mitigation measures

- non harmonised product

information

Not satisfying, neither from a scientific nor from an economic point of view.

Workshop „How to achieve an appropriate ERA of veterinary medicinal products“, Brussels, 07 June 2017

Post market surveillance (pharmacovigilance)

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Obligation to report on environmental problems of every single veterinary medicinal product in the Eco-Pharmacovigilance.

photos: Rönnefahrt (UBA)

How to observe potential environmental effects? Evidence of the causal relationship ?

Pharmacovigilance is not sufficient to ensure the environmental safety of VMPs.

Spreading of manure

Medication

Workshop „How to achieve an appropriate ERA of veterinary medicinal products“, Brussels, 07 June 2017

Substance based surveillance necessary.

Summary and outlook

14Workshop „How to achieve an appropriate ERA of veterinary medicinal products“, Brussels, 07 June 2017

Summary: Experiences with the current situation

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Knoweldge gaps on legacy products exist for ca. 50 % of the relevant

active substances.

Pre-marketing phase:

- Multiplication of data and assessments waste of resources.

- ERA within authorisation procedure of VMPs should be organised

in a more efficient way.

- Need for harmonised ERAs and product information.

Post-marketing surveillance:

The existing pharmacovigilance system is not able to ensure the

environmental safety of medicinal products in use. A product

independent substance review is necessary.

Workshop „How to achieve an appropriate ERA of veterinary medicinal products“, Brussels, 07 June 2017

The way forward: shared use of environmental data

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• Knowledge gaps on legacy products should be filled.

• The best option to safe resources and to avoid unnecessary testing is a shared use of data.

• The ERA of medicinal products within the authorisation procedure should be organised in a more harmonised and more effective way.

Experiences on how to organise a shared use of environmental data exist from other regulatory areas.

Not really a new idea, but still the best ?

Notice to applicants, Vol 6C, 2009

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“Applicants are encouraged to co-operate with other companiesin developing ERA data or sharing existing data.”

4.1 ERA Monographs

“Developing ERA monographs, i.e. documents, in which information on fate and effects of active substances in the environment is summarised that could be used for Phase II assessments of products containing that substance could be considered. This approach would prevent unnecessary repetition of experiments would save resources and would lead to a more harmonized assessment of environmental risks. Monographs could be a valuable instrument for supporting availability of veterinary medicines. As the legislation foresees the presentation of ERAs on individual product application basis the development of ERA monographs, i.e. ERAs on substance basis would be a voluntary initiative.It is up to the industry to make use of the concept and to provide the necessary data to develop such monographs.“

Workshop „How to achieve an appropriate ERA of veterinary medicinal products“, Brussels, 07 June 2017

• What has hampered a voluntary initiative? • Which steps are necessary to improve the situation?

30.06.2017 / Hier steht der Veranstaltungstitel in 12 Punkt 18

Thank your for yourattention !Jutta Klasen

jutta.klasen@uba.de

www.umweltbundesamt.de/en/topics/chemicals/pharmaceuticals

www.umweltbundesamt.de/themen/chemikalien/arzneimittel