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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
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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
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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)
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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
12
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)
13
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
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Summary: Experiences with the current situation
15
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
17
“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
www.umweltbundesamt.de/en/topics/chemicals/pharmaceuticals
www.umweltbundesamt.de/themen/chemikalien/arzneimittel