European Medicines Agency

Pre-Authorisation Evaluation of Medicines for Human Use

London, 01 June 2006

Doc. Ref. EMEA/CHMP/SWP/4447/00 corr 2 1*

COMMITTEE FOR MEDICINAL PRODUCTS FOR HUMAN USE

(CHMP)

GUIDELINE ON THE ENVIRONMENTAL RISK ASSESSMENT OF MEDICINAL

PRODUCTS FOR HUMAN USE

DISCUSSION IN THE SAFETY WORKING PARTY Jun 1999 -Nov 2000

TRANSMISSION TO THE CPMP January 2001

RELEASE FOR CONSULTATION January 2001

DEADLINE FOR COMMENTS July 2001

DISCUSSION IN THE SAFETY WORKING PARTY Oct 2002 - June 2003

TRANSMISSION TO THE CPMP June 2003

RE-RELEASE FOR CONSULTATION July 2003

DEADLINE FOR COMMENTS January 2004

DISCUSSION IN THE SAFETY WORKING PARTY Feb 2004 – Nov 2004

TRANSMISSION TO THE CHMP January 2005

RE-RELEASE FOR CONSULTATION January 2005

DEADLINE FOR COMMENTS April 2005

AGREED BY SAFETY WORKING PARTY May 2006

ADOPTION BY CHMP 01 June 2006

DATE FOR COMING INTO EFFECT 01 December 2006

1
Section 2, paragraph 5, removes the ambiguity of the word “exempt” which was meant to refer to the
content of the ERA dossier and not to the legal requirement for an ERA dossier. Section 8, paragraph
2, addition of the word “studies” after ERA to clarify similarly that the guideline refers to the absence
of ERA studies, not to the absence of the ERA dossier itself (expert report as a minimum).
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E-mail: mail@emea.eu.int http://www.emea.eu.int
EMEA 2006 Reproduction and/or distribution of this document is authorised for non commercial purposes only provided the EMEA is acknowledged
 GUIDELINE ON THE ENVIRONMENTAL RISK ASSESSMENT OF MEDICINAL
PRODUCTS FOR HUMAN USE

TABLE OF CONTENTS

TABLE OF CONTENTS ...................................................................................................................... 2

EXECUTIVE SUMMARY ................................................................................................................... 3

1 INTRODUCTION....................................................................................................................... 3

2 SCOPE AND LEGAL BASIS .................................................................................................... 3

3 GENERAL PRINCIPLES .......................................................................................................... 4

4 PHASE I: ESTIMATION OF EXPOSURE ............................................................................. 4

4.1 SCREENING FOR PERSISTENCE, BIOACCUMULATION AND TOXICITY ...................................... 4
4.2 CALCULATION OF THE PREDICTED ENVIRONMENTAL CONCENTRATION (PEC)..................... 4
4.3 ACTION LIMITS ........................................................................................................................ 5
5 PHASE II: ENVIRONMENTAL FATE AND EFFECTS ANALYSIS ................................. 5
5.1 TIER A: INITIAL ENVIRONMENTAL FATE AND EFFECTS ANALYSIS .......................................... 6
5.2 OUTCOME OF TIER A FATE AND EFFECTS ANALYSIS ............................................................... 7
5.3 TIER B: EXTENDED ENVIRONMENTAL FATE AND EFFECTS ANALYSIS ..................................... 7
5.4 OUTCOME OF TIER B FATE AND EFFECTS ANALYSIS ............................................................... 9
6 PRECAUTIONARY AND SAFETY MEASURES TO BE TAKEN FOR
ADMINISTRATION, DISPOSAL AND LABELLING .......................................................... 9

7 SCIENTIFIC ADVICE FROM THE CHMP ......................................................................... 10

8 THE ENVIRONMENTAL RISK ASSESSMENT REPORT ............................................... 10

9 NOTE ......................................................................................................................................... 11

10 LIST OF ABBREVIATIONS................................................................................................... 11

11 ANNEX ...................................................................................................................................... 12

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EXECUTIVE SUMMARY

The purpose of this guideline is to describe the assessment of potential environmental risks of human
medicinal products. It specifies the scope and legal basis for assessment. It outlines general
considerations and the recommended step-wise procedure of assessment. The general outline of the
Environmental Risk Assessment Report is given, and, when risks cannot be excluded, this guideline
outlines precautionary and safety measures to be considered.

1 INTRODUCTION
An Environmental Risk Assessment (ERA) shall accompany an application for a marketing
authorisation for a medicinal product for human use. This guideline describes how to evaluate
potential risks of the medicinal product to the environment. The guideline also includes considerations
for potential precautionary and safety measures to be taken, and recommendations for the
Environmental Risk Assessment Report.

2 SCOPE AND LEGAL BASIS

In accordance with Article 8(3) of Directive 2001/83/EC, as amended, the evaluation of the potential
environmental risks posed by medicinal products should be submitted, their environmental impact
should be assessed and, on a case-by-case basis, specific arrangements to limit the impact should be
considered. In any event this impact should not constitute a criterion for refusal of a marketing
authorisation.
An environmental risk assessment (ERA) is required for all new marketing authorisation applications
for a medicinal product through a centralised, mutual recognition, decentralised or national procedure.
For type II variations, the evaluation of the environmental impact should be made if there is an
increase in the environmental exposure, e.g. a new indication may result in a significant increase in the
extent of the use. For extension applications according to Annex II of Commission Regulation (EC)
No 1085/2003, an environmental risk assessment is also required if there is a potential increase in the
environmental exposure, e.g. an extension application of an oral medicinal product to include a dermal
patch.
An ERA is not required for renewals or Type IA/IB variations.
In the case of products containing vitamins, electrolytes, amino acids, peptides, proteins,
carbohydrates and lipids as active pharmaceutical ingredient(s), an ERA should be provided. This
ERA may consist of a justification for not submitting ERA studies, e.g. due to their nature they are
unlikely to result in a significant risk to the environment. The same applies to vaccines and herbal
medicinal products
In all cases, except for Type I variations and renewal applications, an environmental risk assessment
or a justification for its absence should be provided in Module 1.6 of the Marketing Authorisation
Application (MAA, see section 8).
Directive 2001/83/EC, as amended, relates to those risks to the environment arising from the use,
storage and disposal of medicinal products and not to risks arising from the synthesis or manufacture
of medicinal products. This guideline is focused on environmental risks associated with the use of
medicinal products.
This guideline does not apply to medicinal products consisting of genetically modified organisms
(GMOs). Applicants are referred to the guideline on “Environmental Risk Assessment for Human
Medicinal Products containing, or consisting of, genetically modified organisms (GMOs) (Module
1.6.2). (EMEA/CHMP/BWP/135148/04)”
For marketing authorisation applications for radio-pharmaceutical precursors for radio-labelling and
radio-pharmaceuticals, additional requirements on emission standards for radiation set by Council
Directives 96/29/Euratom and 97/43/Euratom should be taken into account.

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3 GENERAL PRINCIPLES
Assessment of the potential risks to the environment is a step-wise, phased procedure, consisting of
two phases. The first phase (Phase I) estimates the exposure of the environment to the drug substance.
Based on an action limit the assessment may be terminated. In the second phase (Phase II),
information about the fate and effects in the environment is obtained and assessed. Phase II is divided
in two parts, Tier A and B (see Table I).
Certain substances, such as highly lipophilic compounds and potential endocrine disruptors, may need
to be addressed irrespective of the quantity released into the environment.
Table 1: The phased approach in the environmental risk assessment
Stage in Stage in risk Objective Method TEST / DATA
regulatory assessment REQUIREMENT
evaluation

Phase I Pre-screening Estimation of Action limit Consumption data,

exposure logKow.

Phase II Tier A Screening Initial prediction of Risk Assessment Base set aquatic
risk toxicology and fate

Phase II Tier B Extended Substance and Risk Assessment Extended data set on
compartment-specific emission, fate and
refinement and risk effects
assessment

4 PHASE I: ESTIMATION OF EXPOSURE

In phase I, the estimation should be based only on the drug substance, irrespective of its route of
administration, pharmaceutical form, metabolism and excretion.

4.1 Screening for Persistence, Bioaccumulation and Toxicity

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 TGD2.

4.2 Calculation of the Predicted Environmental Concentration (PEC)

In Phase I the PEC calculation is restricted to the aquatic compartment. The initial calculation of PEC
in surface water assumes:
 A fraction of the overall market penetration (market penetration factor: Fpen) within the range of
existing medicinal products. The Applicant may use the default value or refine the Fpen 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 sewage treatment plant (STP).
 Metabolism in the patient is not taken into account.
The following formula should be used to estimate the PEC in the surface water:

2
European Chemicals Bureau (2003) Technical Guidance Document in support of Commission Directive
93/67/EEC on Risk Assessment for new notified substances, Commission Regulation (EC) No 1488/94 on Risk
Assessment for existing substances and Directive 98/8/EC of the European Parliament and of the Council
concerning the placing of biocidal products on the market.
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 DOSEai * Fpen
PECSURFACEWATER = ------------------------------------------------------------------------------
WASTEWinhab * DILUTION

Table 2: Default values for PECSURFACEWATER calculation in Phase I

Parameter Symbol Value Unit Origin Remarks
Input
• Maximum daily dose DOSEai [mg.inh-1.d-1] A The highest
consumed per inhabitant recommended
dose should be
used
• Fraction of market Fpen 0.01(*) [--] D Default
penetration
• Amount of wastewater WASTEWinhab 200 [L.inh-1.d-1] D From TGD
per inhabitant per day
• Dilution factor DILUTION 10 [--] D From TGD

Output PECSURFACEWATER [mg.L-1] O

• Local surface water
concentration
A = information from Applicant, D = Default value, O = Output * see note
4.3 Action limits

If the PECSURFACEWATER value is below 0.01 µg/L(3), and no other environmental concerns are apparent,
it is assumed that the medicinal product is unlikely to represent a risk for the environment following
its prescribed usage in patients.
If the PECSURFACEWATER value is equal to or above 0.01 µg/L, then a Phase II environmental fate and
effect analysis should be performed as described below (section 5).
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.

5 PHASE II: ENVIRONMENTAL FATE AND EFFECTS ANALYSIS

The recommended Phase II assessment is conducted by evaluating the PEC/PNEC ratio based on
relevant environmental testing (“base set of data”) and predicted environmental concentration (Tier
A). If potential environmental impact is indicated, further testing might be needed to refine PEC
(predicted-environmental-concentration) and PNEC (predicted-no-effect -concentration) values in Tier
B.
Experimental studies should preferably follow the test protocols issued by the European Commission,
Organization for Economic Co-operation and Development (OECD) or the International Organization
for Standardization (ISO). It is recognised that there are acceptable test guidelines and approaches and
methods, other than those described in this section, which are capable of providing an equivalent
environmental risk assessment. Their use should be justified in the Environmental Risk Assessment
Report. Studies should be conducted in compliance with Good Laboratory Practices.
All relevant data should be taken into account, e.g. data on physical-chemical properties, primary and
secondary pharmacodynamics, toxicology, metabolism, excretion, degradability, and persistence of the
drug substance and/or relevant metabolites.

3
The present action limit is based mainly on acute toxicity data and may therefore be revised in future versions
of the guideline when a sufficient amount of chronic data is available.
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5.1 Tier A: Initial environmental fate and effects analysis
The assessment in Tier A should be based on the drug substance unless otherwise justified, e.g. if the
drug substance is a pro-drug.

5.1.1 Physical-chemical properties and fate

The Tier A screening data set provides for information on physical-chemical properties and on the fate
of a substance in the environment.
To investigate the fate of the substance in the STP a ready biodegradability test should be conducted.
The fate of substances, which are not readily biodegradable, should be investigated in a water
sediment study. If the KOW indicates a potential for bioaccumulation, a specific risk assessment should
be conducted as mentioned in Section 4.1. The sorption behaviour of substances in sewage sludge is
described through the adsorption coefficient (KOC), which is defined as the ratio between the
concentration of the substance in the sewage sludge’s organic carbon and the concentration of the
substance in the aqueous phase at adsorption equilibrium. It is assumed that a substance with a high
KOC value is retained in the STP and may reach the terrestrial compartment with land spreading of
sewage sludge.

5.1.2 Aquatic effect studies

For the Tier A assessment approach, a standard long-term toxicity test set on fish, daphnia and algae is
proposed to determine the predicted no-effect concentration (PNECWATER). The purpose of this
analysis is to predict the concentration of the substance for which adverse effects are not expected to
occur. Guidance on the assessment of adverse effects is given in the TGD. The Applicant should
justify the test species used.
Table 3: Physical-chemical, fate and effects studies recommended in Phase II Tier A
Study Type Recommended Protocol

Adsorption - Desorption Using a Batch Equilibrium OECD 106/ OECD 121/OPPTS

Method 835.1110*
Ready Biodegradability Test OECD 301
Aerobic and Anaerobic Transformation in Aquatic OECD 308
Sediment Systems
Algae, Growth Inhibition Test OECD 201
Daphnia sp. Reproduction Test OECD 211
Fish, Early Life Stage Toxicity Test OECD 210
Activated Sludge, Respiration Inhibition Test OECD 209
* One study is generally sufficient.

Blue-green algae (Cyanophyta) are recommended for effects testing of antimicrobials, as they are
more sensitive indicator organisms than green algae. Short-term testing is generally not applicable for
human pharmaceuticals since continuous exposure of the aquatic environment via STP effluents is
assumed.
Substances with anti-microbial activity may affect microbial communities. The microbial community
most likely exposed to the highest concentrations of the substance(s) is the activated sludge
community. In order to evaluate anti-microbial effects of anti-microbial substances, the activated
sludge respiration inhibition test (OECD 209) should be used.

5.1.3 Calculation of PNEC using assessment factors

The predicted no effect concentration (PNEC) is calculated by applying an assessment factor (AF) to
the no-observed-effect-concentration(s) (NOEC) from relevant effects studies. The AF is an
expression of the degree of uncertainty in the extrapolation from the test data on a limited number of
species to the actual environment.

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The PNECWATER is based on the lowest NOEC result from the base set long-term toxicity tests. The
PNECMICROORGANISM is based on the NOEC result of the anti-microbial effect study. The
PNECGROUNDWATER is based on the NOEC result of the test with Daphnia sp.
To calculate the PNEC from the long-term toxicity tests and the anti-microbial effect study a default
AF of 10 is applied. This AF accounts for:
• inter-species variations of differences in sensitivity
• intra-species variability
• laboratory data to field impact extrapolation.

5.1.4 Groundwater assessment

An exposure assessment for groundwater is required. Entry into the groundwater is considered via
bank filtration, except for substances with an average KOC >10000 L/kg or for substances that are
readily biodegradable or for substances that have a DT90 of <3 days. A simple estimation is
PECGROUNDWATER= 0.25 * PECSURFACEWATER. The PECGROUNDWATER should be compared to the
PNECGROUNDWATER.

5.2 Outcome of Tier A fate and effects analysis

At the end of Tier A, information from the screening data set is available comprising long-term
toxicity data for algae, Daphnia and fish, data on microbial inhibition and information on the rate of
adsorption (KOC). The PECSURFACEWATER has been refined with information on the sales forecast of the
product.
 If the ratio PECSURFACEWATER: PNECWATER for the drug substance is below 1, then further testing in
the aquatic compartment will not be necessary and it can be concluded that the drug substance
and/or its metabolites are unlikely to represent a risk to the aquatic environment.
 If the ratio PECSURFACEWATER : PNECWATER is above 1, further evaluation, preferably on the fate of
the drug substance and/or its metabolites in the aquatic environment are needed in Tier B.
 If the ratio PECGROUNDWATER : PNECGROUNDWATER is above 1, further evaluation, preferably on the
fate of the drug substance and/or its metabolites in the aquatic environment are needed in Tier B.
 If the ratio PECSURFACEWATER : PNECMICROORGANISM is above 0.1, further evaluation of the fate and
the effects of the drug substance and/or its metabolites on micro-organisms are needed in Tier B.
 If the n-octanol/water partition coefficient indicates the transfer of the drug substance from the
aquatic environment into organisms and a potential to bioaccumulate (KOW >1000), then the
bioconcentration factor should be considered in Tier B. Additional criteria for the need of a
bioconcentration study are given in the TGD.
 If the adsorption/desorption data indicates the affinity for the drug substance to bind to sewage
sludge in the STP (KOC > 10 000 L/kg) an environmental assessment of the drug substance in the
terrestrial compartment should be conducted, unless the substance is readily biodegradable. The
terrestrial risk assessment complements the aquatic risk assessment and does not replace it.
 If a substance is not ready biodegradable and if the results from the water sediment study (OECD
308) demonstrate significant shifting of the drug substance to the sediment, effects on sediment
organisms should be investigated in Tier B. The criterion for sediment studies is met if more that
10% of the substance at any time point after or at 14 days is present in sediment. A detailed
strategy for further testing in order to refine the PNEC for the aquatic compartment can be found
in the TGD.
5.3 Tier B: Extended environmental fate and effects analysis
If in Tier A a potential risk for the medicinal product to the environment has been identified, then a
Tier B assessment should be conducted.
In Tier B, the refined risk assessment may be performed using the refined PEC and the PNEC for the
parent compound, as well as using the dedicated PEC and PNEC for the relevant (≥ 10% of amount

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excreted) metabolic fractions.
Refinement of the risk assessment using data on transformation of the substance within the
environment (i.e. the water/sediment systems) is not further considered here and is subject to expert
judgement.
A specific risk assessment should be conducted for a drug substance with a logKow > 4.5 (see section
4.1)

5.3.1 Environmental fate analysis and PECSURFACEWATER refinement

In Tier B the PECSURFACEWATER may be also refined with information from:
STP modelling using the SimpleTreat model described in the European Union System for the
Evaluation of Substances (EUSES, http://ecb.jrc.it/) by incorporating:
 adsorption of substances to sewage sludge in STPs, using the data from the estimation of the
adsorption coefficient (OECD 106),
 test for ready biodegradability in the STP (OECD 301).

The local surface water concentration can be refined as:

Elocalwater * Fstp water

PECSURFACEWATER = --------------------------------------------------------------------------------
WASTEWinhab * CAPACITYstp * FACTOR * DILUTION
Where

Elocalwater = DOSEai * Fexcreta * Fpen * CAPACITYstp

Table 4 summarises the parameters and default values recommended for the calculation of
PECSURFACEWATER in Phase II. Worst-case estimates should be used.
Table 4: Parameters and defaults for PECSURFACEWATER calculation in Phase II
Parameter Symbol Value Unit Origin Remarks
Input
• Amount of wastewater WASTEWinhab 200 [L.inh-1.d-1] D From TGD
per inhabitant per day
• Capacity of local CAPACITYstp 10000 [inh] D From TGD
sewage treatment plant
(STP)
• Fraction of emission Fstpwater [--] C Calculated by
directed to surface water SimpleTreat
• Dilution factor DILUTION 10 [--] D From TGD
• Factor taking the FACTOR [--] C From TGD
adsorption to suspended §2.3.8.3
matter into account
• Local emission to Elocalwater [mg d-1] A
wastewater of the
relevant residue
Output
• Local surface water
concentration PEClocalwater [mg.L-1] O
A = information from Applicant; D = Default, C = Calculated, O = Output

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5.3.2 Extended effects analysis

5.3.2.1 Water sediment effects

Effects on a sediment dwelling organism (Hyalella sp; Lumbriculus sp. or Chironomus sp.) should be
investigated and compared to the PECSEDIMENT if the results from the water sediment study (OECD
308) demonstrate significant shifting of the drug substance to the sediment.

5.3.2.2 Specific effects on micro-organisms

If in Tier A, a risk for micro-organisms is identified, further evaluation of the fate and effects of the
drug substance and/or its metabolites on micro-organisms are needed in Tier B.
The exposure concentration in the aeration tank of the SimpleTreat model (PECAERATION TANK) should
be used to refine the risk quotient for micro-organisms. To determine the PNECMICROORGANISMS a
number of standardized tests on single microbial species are given in the TGD (e.g. Pseudomonas
putida). If the ratio PECAERATION TANK: PNECMICROORGANISMS is >1, further analyses of anti-microbial
effects should be conducted in Tier B.

5.3.3 Terrestrial environmental fate and effects analysis

When indicated (KOC >10000 L/kg), unless readily biodegradable, the concentration of the medicinal
product in the terrestrial compartment should be calculated. STP modelling to obtain a PECSLUDGE is
performed using the SimpleTreat model in EUSES (http://ecb.jrc.it/). Methodologies, such as
described in the TGD, should preferably be used for risk assessment including PECSOIL calculation.
In general, a base set of tests investigating biodegradation in soil, toxicity to soil invertebrates and
acute effects on terrestrial plants and micro organisms should be conducted (Table 5).
Table 5: Terrestrial fate and effects studies recommended in Phase II Tier B:
Study Type Recommended Protocol
Aerobic and anaerobic transformation in soil OECD 307
Soil Micro organisms: Nitrogen Transformation Test OECD 216
Terrestrial Plants, Growth Test OECD 208
Earthworm, Acute Toxicity Tests OECD 207
Collembola, Reproduction Test ISO 11267

5.4 Outcome of Tier B fate and effects analysis

At the end of Tier B, information from the refined data set is available comprising information on
route(s) of excretion and qualitative and quantitative information on excreted compounds, and
possibly additional long-term toxicity data, additional data on microbial inhibition, and additional
information on the biodegradability of the substance.

6 PRECAUTIONARY AND SAFETY MEASURES TO BE TAKEN FOR

ADMINISTRATION, DISPOSAL AND LABELLING
When the possibility of environmental risks cannot be excluded, precautionary and safety measures
may consist of:
 An indication of potential risks presented by the medicinal product for the environment.
 Product labelling, Summary Product Characteristics (SPC), Package Leaflet (PL) for patient use,
product storage and disposal.
Labelling should generally aim at minimising the quantity discharged into the environment by
appropriate mitigation measures.
Appropriate disposal of unused pharmaceuticals, e.g. when shelf life has expired, is considered
important to reduce the exposure of the environment. In order to enhance environmental protection, it
is therefore recommended that – even for medicinal products that do not require special disposal
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measures - package leaflets (patient information leaflets) should include the following general
statement:
“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.

7 SCIENTIFIC ADVICE FROM THE CHMP

The applicant may request scientific advice on issues related to environmental risk assessment and on
possible precautionary and safety measures to be taken with respect to the use and disposal of a
medicinal product.

8 THE ENVIRONMENTAL RISK ASSESSMENT REPORT

The Expert Report should be presented in Module 1.6 of the dossier. The report should be based on the
characteristics of the product, its potential environmental exposure, fate and effects, and risk
mitigation strategies as appropriate. The conclusion of the report should be based on sound scientific
reasoning supported by adequate studies. If other relevant data are available they should also be
submitted, e.g. tests focussing on relevant substance specific biological effects.

There may be cases in which the absence of ERA studies could be justified (e.g. marketing
authorisation applications for generic medicinal products or type II variations). In these cases, the
expert should provide a rationale for the absence of ERA studies, taking into consideration a possible
significant increase of environmental exposure to the drug substance.

The Expert Report should include an evaluation of the applicability of the environmental assessment
performed. In particular, the report should provide or justify the absence of:
1. An estimate of the potential environmental exposure (PEC) with an assessment of the underlying
assumptions.
2. An assessment of possible risks to the environment from the point of view of use, and a
presentation and evaluation of data in support of such risk evaluation,
3. An evaluation of precautionary and safety measures to be taken regarding the environmental
release from use in patients, and disposal of unused products or waste materials derived from such
products,
4. Proposals for labelling (SPC, PL) which give an outline of the information that applicants could
provide on precautionary and safety measures to be taken, for the purpose of reducing any risks to
the environment, with regard to the administration to patients and disposal of waste products.
The expert should sign the Expert Report and a curriculum vitae should be provided.

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9 Note

Fpen
A 95 percentile of 0.954 % was calculated as the default penetration factor (Fpen). It is proposed to
use an Fpen of 0.01 (1%) in the risk assessment.
The penetration factor (Fpen) represents the proportion of the population being treated daily with a
specific drug substance. The default penetration factor was derived from a wide range of individual
market penetration factors, which were calculated as follows:

consumption [mg*year-1] * 100

Fpen [%] = ------------------------------------------------------------------------
DDD [mg*d-1*inhab] * inhabitants [inhab] * 365 d*year-1

The following data were used:

- Institut für Medizinische Statistik, Frankfurt/M., (IMS Health): IMS Health maintains a data bank
“Chemical Country Profil” containing statistics for annual German consumption of about 2700
drug substances. This database was considered representative for the drug consumption in the
European Union.
- Defined daily dose values (DDD) values of the World Health Organization (WHO). In total DDD-
values for about 1450 drug substances were available.
- German population: 82 012 000 inhabitants in 2001
For the evaluation of the market penetration factor about 800 drug substances were taken into account.
Those substances were established on the German market in 2001 and a DDD-value was available.

10 LIST OF ABBREVIATIONS
AF Assessment Factor
CHMP Committee for Medicinal Products for Human Use
DDD Defined daily dose value(s)
DT90 Degradation Time for 90% of a substance to be degraded under laboratory conditions
EMEA European Medicines Agency
ERA Environmental Risk Assessment
EUSES European Union System for the Evaluation of Substances
Fpen (Market) Penetration Factor (see note 1)
GMOs Genetically Modified Organisms
ISO International Organization for Standardization
Koc Adsorption Coefficient
MAA Marketing Authorisation Application
NOEC No Observed Effect Concentration
OECD Organization for Economic Co-operation and Development
OPPTS US EPA Office of Prevention, Pesticides and Toxic Substances
OSPAR 1992 Convention for the Protection of the Marine Environment of the North-East
Atlantic (The “OSPAR Convention”)
PEC Predicted Environmental Concentration

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PNEC Predicted No Effect Concentration
PL Package Leaflet
SPC Summary of Product Characteristics
STP Sewage Treatment Plant
TGD EU Technical Guidance Document
WHO World Health Organization

11 ANNEX

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

Excretion Storage Disposal

Air

Sewage Waste Incineration

Landfill site (Air)

Sewage treatment plant

Surface water Ground water

Soil

Drinking water

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