Environmental Risk Assessment of pharmaceuticals in Europe

1. The prioritisation and environmental
risk assessment of pharmaceuticals :
Experiences in Europe
Graham Merrington, David Taylor,
Melanie Gross, Dean Leverett
SETAC Asia-Pacific - Adelaide 2014 1

2. SETAC Asia-Pacific - Adelaide 2014 2
Outline
 The ERA process in Europe
 Phase 1
 Phase 2
 Problems with the European Medicines Agency
guidance
 Data inefficiencies
 Member State inconsistencies
 Flaws ........in the process
 Prioritisation processes
 Conclusions and recommendations

3. Environmental Risk Assessment of
human pharmaceuticals in Europe
 Legislation - Directive 2001/83/EC.
 Requires an ERA for market authorisation applications.
 Applies to all new medicinal products.
 Except vitamins, electrolytes, peptides, proteins, lipids &
carbohydrates, vitamins and herbal remedies.
 Applies to new applications for existing products where there
is an increase in the environmental exposure.
 Non Statutory Guidance 2006.
 Guideline on the environmental risk assessment of medicinal
products for human use [EMEA/CHMP/SWP/4447/0].
 Supplemented by Q&A document (2010) required for clarification
of certain aspects in guideline, which were open to interpretation.
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4. EMA Guidance on Environmental Risk
Assessment of Human Pharmaceuticals
EMEA/CHMP/SWP/4447/00
STAGE PURPOSE OBJECTIVE METHOD
Phase 1 Pre Screening Estimation of exposure
Action Limit
PEC > 0.01μg/l
Phase 2
Tier A
Screening Initial prediction of risk
Risk
Assessment
Phase 2
Tier B
Risk
Assessment
Substance/compartment -
specific refinement and
risk assessment
Risk
Assessment
Additional test data
needed dependant
on risk evaluation
TIER B - TERRESTRIAL TESTS OECD
Aerobic & anaerobic trans. in soil 307
216
Soil Micro organisms: Nitrogen
Transformation Test
Terrestrial Plants, Growth Test 208
Earthworm, Acute Toxicity Tests 207
Collembola, Reproduction Test ISO11267
TIER A - TEST REQUIREMENTS OECD
Absorption/Desorption Equilibrium 106
Ready Biodegradability 301
308
Aerobic & Anaerobic Transformation in
Aquatic Sediment Systems
Algae - Growth Inhibition 201
Daphnia sp. Reproduction 211
Fish, Early Life Stage Toxicity Test 210
Activated Sludge Respiration Inhibition 209

5. Phase 1 Pre Screening
Assessment of Exposure (PEC)
 % market penetration [Fpen]: 1% unless published data exists.
 Data is required on disease incidence, simple marketing data or
projections are not acceptable.
 Waste water: 200 Litres/inhabitant/day
 Dilution factor: 10
 Any ai with a PEC of ≥ 0.01g l-1 must proceed to Phase 2.
 All pharmaceuticals with a daily dose ≥ 2 mg ai proceed to Phase 2.
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6. Phase 2 Tier A
Results and Required Actions
Tier A Result ACTION
PECSurface Water / PNECWater < 1.0 No further aquatic testing required
PECSurface Water / PNECWater > 1.0 Tier B Assessment required
PEC / PNECGroundwater > 1.0 Tier B Assessment required
PECSurface Water / PNECMicroorganism > 0.1 Tier B Assessment required
Kow > 1000 Tier B Bioaccumulation study (TGD)
Log Koc > 10000 (unless readily degradable) Tier B Soil Organism Tests
If >10% shifts to sediment in 14d Tier B Sediment Dweller Test
“In some cases, the action limit may not be applicable. Some drug substances
may affect the reproduction of vertebrate or lower animals at concentrations
lower than 0.01 μg/L. These substances should enter Phase II and a tailored
risk assessment strategy should be followed that addresses its specific
mechanism of action. In these cases, the Applicant should justify all actions taken.”
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7. Problems with the implementation
of existing EMA guidance
 Despite the existence of clear guidance there is still
disparity in the way ERAs are evaluated between
EU member state authorities.
 The procedures involved frequently lead to
inefficient duplication of effort .
 This can sometimes lead to animal
studies being duplicated.
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8. Inefficiencies with Phase 2 Data
 Availability of data for new and generic API is likely
to be very different in volume and quality.
 Data will always need to be generated for a new API.
 For generics, some data may be available in literature, but in
many cases data gaps still need to be filled.
 BUT MAs are granted product by product .
 Companies with same generic API in different
products need to submit separate ERAs.
 Data confidentiality and no formal data sharing mechanism
mean an API can undergo several isolated, but similar ERAs.
 Same data gaps can be filled several times (duplication).
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9. Inconsistent Evaluation by
European Member States
 Example 1:
 Guidance allows for justification of absence of an
ERA, if the introduction of a new product will not
increase the environmental exposure.
 Such waivers are accepted by some MS for
generic Marketing Approval Applications (MAAs)
on basis that a new product will simply displace
other established products with API & dose.
 Other more conservative MS categorically reject
such waivers.
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10. Inconsistencies in Evaluation by
European Member States
 Example 2:
 Completion of a full ERA is required by some MS
prior to granting of MA, whilst others allow ERA to
be completed as post-authorisation commitment.
 One company submitted waiver to one MS → MA granted
with ERA required as post-authorisation commitment.
 Same company submitted partial ERA to another MS (full
ecotox, but incomplete fate data due to delays in testing)
→ MA withheld until full data package submitted.
 This is despite the fact that environmental impact does
not constitute a criterion for refusal of MA.
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11. Flaws with the existing situation
 The Directive forbids the results of the ERA being
used in the assessment of the Marketing Approval.
 The absence of this requirement currently undermines
public confidence.
 If PEC/PNEC ratio is exceeded the registrant should be
required to justify the socioeconomic case as with veterinary
pharmaceuticals.
 PECs are calculated separately for each product.
 New PEC calculations should include all the existing API in
the environment or the risk will be underestimated.
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12. Flaws with the existing situation
 All biopharmaceuticals appear to be exempt.
 Many will have short half lives but this may not be universal.
 “Except vitamins, electrolytes, peptides, proteins, lipids & carbohydrates,
vitamins and herbal remedies”. [EMEA/CHMP/SWP/4447/0]
 There is no requirement to provide ERAs for the
existing (ca.3000) products on the EU market.
 The impact of pharmaceuticals in the environment cannot be
properly assessed in the absence of such data.
 Prioritisation and cost sharing would be necessary.
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13. Prioritisation of Pharmaceuticals
An Unresolved Technical Challenge
 The optimum approach is to rank in order of risk ratio.
 This requires an estimate of both PEC and PNEC.
 Predicted Exposure (tonnage released + modelling).
 Actual Exposure (monitoring).
 Estimated or measured NOECs.
 Data on pharmaceuticals however is very limited.
 Estimated sales data is produced but is highly confidential.
 There are high potency/low volume & low potency/high volume compounds.
 Monitoring data is scarce & limited to a few compounds.
 Satisfactory NOEC values exist for only a few compounds.
 QSAR data is unreliable.
 Current prioritisations are not robust.
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14. Conclusions & Recommendations
 The current EU scheme for pharmaceutical ERA is greatly
improved & represents current best practice. However there is
scope for improvement:
 Co-ordination between regulators in Member States needs improvement.
 A mechanism is needed to enable data to be shared to avoid duplication.
 The ERA should form part of the data used to evaluate the MAA.
 The PEC values used should reflect all the API in the environment not just
from the product under consideration.
 The current exemption for biopharmaceuticals should be reviewed in the
light of increasing knowledge.
 An efficient and equitable mechanism is needed to produce ERAs for
existing pharmaceuticals.
 More research is needed to provide a valid prioritisation procedure
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