setac asia pacific 2014 - pharmaceutical era [gm2]

SETAC Asia-Pacific - Adelaide 2014 1

The prioritisation and environmental risk assessment of pharmaceuticals : Experiences in Europe

Melanie Gross, Dean Leverett

Graham Merrington, David Taylor,

2SETAC Asia-Pacific - Adelaide 2014

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

Outline


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.

STAGE PURPOSE OBJECTIVE METHOD

Phase 1 Pre Screening Estimation of exposureAction 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

OECDTIER B - TERRESTRIAL TESTS

ISO11267Collembola, Reproduction Test

207Earthworm, Acute Toxicity Tests

208Terrestrial Plants, Growth Test

216Soil Micro organisms: Nitrogen Transformation Test

307Aerobic & anaerobic trans. in soil

Additional test data needed dependant on risk evaluation

106Absorption/Desorption Equilibrium

209Activated Sludge Respiration Inhibition

210Fish, Early Life Stage Toxicity Test

211Daphnia sp. Reproduction

201Algae - Growth Inhibition

308Aerobic & Anaerobic Transformation in Aquatic Sediment Systems

301Ready Biodegradability

OECDTIER A - TEST REQUIREMENTS

EMA Guidance on Environmental Risk Assessment of Human Pharmaceuticals EMEA/CHMP/SWP/4447/00


Phase 1 Pre ScreeningAssessment 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 ≥ 0.01g l-1 must proceed to Phase 2. All pharmaceuticals with a daily dose ≥ 2 mg ai proceed to Phase 2.

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.”



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.


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).


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.


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.

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.SETAC Asia-Pacific - Adelaide 2014 10

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.


Prioritisation of PharmaceuticalsAn 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.SETAC Asia-Pacific - Adelaide 2014 12


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

setac asia pacific 2014 - pharmaceutical era [gm2]

Science

data availability of

data confidentiality

tier b assessment requiredkow

new api

tier aresults

europe phase

new product

new applications