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An environmental risk assessment (ERA) is now required for all new pharmaceutical product marketing authorisation applications. The author outlines the steps to this procedure.
Concerns regarding the fate and effect of pharmaceuticals in the environment have been increasing following the detection of pharmaceuticals in sewage treatment plant (STP) effluents, surface waters, seawater, groundwater and even drinking water.1,2 Monitoring studies have demonstrated that drug residues in treated wastewater and surface waters are widespread,2 and concerns have further strengthened after residues of the analgesic and anti-inflammatory drug substance diclofenac were held responsible for the unusually high death rate among three species of vulture in India and Pakistan in 2004.3 In response, regulatory agencies have issued detailed guidance on how pharmaceuticals should be assessed for possible adverse effects in the environment and have introduced the requirement for a environmental risk assessment (ERA). An ERA is required for all new marketing authorisation applications for a medicinal product; for type II variations, an ERA should be submitted if there is an increase in environmental exposure; for type IA/IB variations and renewal applications, an ERA is not required. An assessment of potential risks to the environment of medicinal products is a step-wise, phased procedure that may be terminated when sufficient information/data is available to either indicate that the medicinal product is unlikely to pose a risk to the environment, or to identify and sufficiently characterise the potential risks.
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An ERA was first required for veterinary pharmaceuticals in accordance with EU Directive 92/18/EEC and the corresponding note for guidance was issued by the European Medicines Agency (EMA) in 1998. In 2001, the requirement for an ERA was described for human pharmaceuticals in Directive 2001/83/EC. A guidance document was first issued in January 2005 (first draft) and finalised in June 2006.4 In comparison, in the US ERAs for veterinary and human pharmaceuticals have been required by the FDA since 1980 and 1998, respectively.
This article will describe the ERA for human pharmaceuticals in Europe and will present the steps to be taken during the phased procedure of assessing environmental risk.
The main route of entry of human pharmaceuticals into the environment is through uptake in the patient followed by excretion and disposal via wastewater. Hospital wastewater, wastewater from manufacturing sites and landfill leachates may also contain significant concentrations of pharmaceuticals.1 Pharmaceuticals that are not degraded or bound in the sewage treatment plant are released in treatment effluents, subsequently contaminating surface water and possibly ground water. Pharmaceuticals that bind to sewage sludge may also end up in the environment when sludge is spread on land, after which soil, groundwater and surface water may be contaminated.
Existing literature about the ecotoxicological effects of human pharmaceuticals deals predominantly with acute toxicity in standardised tests with aquatic organisms; however, because of continuous, low level exposure, chronic effects are considered more relevant. Therefore, the guidance for environmental risk assessment prepared by the EMA contains the requirement of chronic ecotoxicity studies.4
The guidance document on environmental risk assessment contains the data requirements that should be fulfilled in an ERA,4 but the specific data requirements are not as straightforward as they seem because the choice of the appropriate test is subject to expert judgement. Moreover, certain types of chemicals are, in principle, exempt (e.g., electrolytes, vitamins, amino acids, peptides, proteins, carbohydrates and lipids, vaccines and herbal medicinal products), but these exemptions may be overruled by the specific mode of action (e.g., when the substance has an intended endocrine mode of action).
An ERA consists of two phases: Phase I, which is a screening phase, and Phase II, which may be triggered by the results of Phase I, and in turn consists of two tiers. Phase I is generally thought to be a nontesting phase (with testing taking place in Phase II), but this is not necessarily the case. The non-testing data collected in Phase I include a calculation of the predicted environmental concentration in surface water (PECsurfacewater) of the active substance (based on the maximum daily dose), as well as an assessment of the mode of action and observations extracted from the toxicology database on the active substance. In addition, the logPow of the active substance should be made available. If the logPow value passes the trigger value of 4.5, an assessment is needed to determine whether the substance is Persistent, Bioaccumulative and Toxic (PBT); this is where testing may be necessary. The different steps taken in Phase I and the considered triggers are outlined below.
A predicted environmental concentration in surface water (PECsurfacewater) of ≥0.01 μg/L triggers a Phase II assessment. Calculation of the PECsurfacewater is based on the maximum daily dose and uses a default market penetration factor of 1%. This factor may be refined when epidemiological data are available (i.e., prevalence of the indication), but authorities will only accept such refinement under the assumption that the new drug product will have a 100% market share; however, this is not described in the guidance.
Potential concerns at levels <0.01 μg/L
If the PECsurfacewater is below 0.01 μg/L, no further requirements apply (in principle) unless concern exists for environmental effects at concentrations below the trigger value of 0.01 μg/L. This, for instance, is the case for highly lipophilic compounds, which may accumulate via the food chain, and endocrine active substances, which in the ng/L concentration range may affect fish reproduction.
The mode of action of the active substance should be considered to identify potential concerns. Furthermore, any data from the toxicological database demonstrating that population relevant parameters, such as growth, reproduction and survival, may be affected at low concentrations should be addressed. This assessment should be performed with caution because the receptors and physiology of mammals and aquatic (in)vertebrates may differ substantially. Consequently, the mode of action of the pharmaceutical, which was designed for mammalian physiology, may differ in aquatic (in)vertebrates.1–2,5 If any specific concerns exist, as is evident for endocrine active substances, the standard test requirements listed in Phase II may not apply per se — a tailored strategy should be considered in such a case. A detailed description of such strategy goes beyond the scope of the present paper and is not further elaborated here.
A Persistent, Bioaccumulative and Toxic (PBT) assessment is triggered for substances with logPow >4.5. A substance is classified as a PBT substance if all three criteria (persistence, bioaccumulation and toxicity) are met. These criteria have been defined in the Technical Guidance Document6 and the ECHA guidance in support of REACH.7 It should be noted that the PBT assessment is not described as being part of the Phase II assessment, nor does it trigger a Phase II assessment. Under REACH, substances with a PBT classification are candidates for substitution, but it is not yet clear in what way medicinal products with a PBT classification are dealt with.
Phase I summary
In summary, data collected in Phase I determine if a Phase II assessment is required. This is the case if the calculated PECsurfacewater is ≥0.01 μg/L, or if concern exists that environmental effects may occur at concentrations <0.01μg/L (e.g., due to endocrine disruption or accumulation in the food chain).
Phase II is subdivided into two Tiers (Tier A and Tier B). Environmental fate and effects testing starts off using standardised test protocols in Tier A; Tier B may be triggered by data collected and/or generated in Tier A. Again, the logPow value should be considered; if this value is 3, a bioconcentration study in fish is triggered in Tier B.
Tier A: data requirements
Fate data generated in Tier A include the adsorption to sludge and soil, and biodegradation. If the substance is found to have an affinity to bind to sewage sludge in the STP (Koc>10000 L/kg), an environmental assessment of the substance in the terrestrial compartment is required in Tier B — unless the substance is readily biodegradable. This approach is based on the expectation that biodegradable substances are not likely to end up in the environment. If the substance is not readily biodegradable and binds to sludge, it may end up in the terrestrial environment because of the spreading of sludge on agricultural soil. Furthermore, if a substance is not readily biodegradable, a water-sediment study should be performed to study the distribution of the substance in the aquatic environment. If significant migration to the sediment compartment is demonstrated (i.e., 10% of administered amount), the effects on sedimentdwelling organisms should be studied in Tier B.
Environmental effect studies in Tier A include an algal growth inhibition test, Daphnia magna reproduction test, fish early life stage test and activated sludge respiration inhibition test. It should be noted that the fish early life stage test is unlikely to respond adequately to all pharmaceutical modes of action, and a lifecycle or partial lifecycle test in fish may be more relevant in some cases.5 It is recommended that the responsible authority is consulted when doubts exist.
Tier B: requirements
Environmental fate studies in Tier B may include a bioconcentration study in fish and/or degradation in soil; effects studies may include testing with terrestrial organisms such as soil microflora, earthworms, springtails and plants.
Using the results from the effect studies performed in Tier A, predicted no effect concentrations (PNECs) are derived for the surface water, STP and groundwater compartments, and compared with calculated PEC values (PECsurfacewater , PECgroundwater). If one or more of the PEC/PNEC ratios exceeds the pre-defined trigger values (1 for surface water and groundwater compartments, and 0.1 for the STP), a Tier B assessment should be conducted. This Tier B assessment may include a refinement of the PEC values using data on, for example, excretion from humans, adsorption to sludge (Koc from Tier A) and/or a refined market penetration factor. In addition, data on transformation of the substance in the environment, such as photodegradation or data from the water-sediment study, may be used.
Based on the outcome of the ERA, specific arrangements to limit the impact of the pharmaceutical on the environment should be considered; for example, product labelling and the inclusion of directions for safe disposal and storage in the package leaflet for patient use. In all cases, the impact should not constitute a criterion for refusal of a marketing authorisation of human pharmaceuticals; however, it should be noted that this is not the case for veterinary pharmaceuticals, where a risk to the environment does lead to refusal of a marketing authorisation.
Experience in ERA for human pharmaceuticals is rather limited because the guidance has only existed since 2006 and some of the aspects of the assessment remain unclear. For instance, metabolites are only briefly addressed in Phase II, but the extent to which metabolites should be considered has not been defined. Likewise, the test requirements are limited to invertebrates and fish — higher organisms, such as birds, are not addressed and this is considered as a gap in the assessment. An update of the guidance document was originally scheduled for the end 2009; however, it was decided not to update the guidance, but to instead provide a document containing frequently asked questions and answers. So far, this document has not yet been received.
D.F. de Roode is Regulatory Affairs Manager at NOTOX B.V. Tel. +31(0)73 640 67 00 Fax: +31(0)73 640 67 99 Email: email@example.com
1. O.A.H. Jones, N. Voulvoulis and J.N. Lester, Environmental Technology, 22(12), 1383–1394 (2001).
2. K. Fent, A.A. Weston and D. Caminada, Aquatic Toxicology, 76(2), 122–159 (2006).
3. J.L. Oaks et al., Nature, 427(6975), 630–633 (2004).
4. European Medicines Agency, Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use (EMEA/CHMP/SWP/4447/00), June 2006. www.ema.europa.eu
5. M. Crane, C. Watts and T. Boucard, Science of the Total Environment, 367(1), 23–41 (2006).
6. European Commission, Technical guidance document in support of Commission Directive 93/67/EEC on risk assessment for new notified substances and Commission Regulation (EC) No 1488/94 on risk assessment for existing substances, 2003.
7. European Chemicals Agency, Guidance on information requirements and chemical safety assessment (Chapter R.7b:L endpoint specific guidance), 2008. http://echa.europa.eu