Risk Assessment Of Medicinal Products Research Articles

Evaluation of the EMA log kow trigger for fish BCF testing based on data for several human pharmaceuticals

In the European Medicines Agency (EMA) “Guideline for Environmental Risk Assessment of Medicinal Products for Human Use,” a fish bioconcentration factor (BCF) study is triggered in Phase I for pharmaceuticals having log Kow >4.5, to support Persistence, Bioaccumulation and Toxicity (PBT) screening, and in Phase II to assess secondary poisoning and bioaccumulation (‘B’) potential when log Kow ≥3. The standard sampling schedule outlined in OECD Test Guideline 305 (TG305) may require assessment of approximately 200 fish following exposure to low- and high-test concentrations and a negative control. We report experimental log Kow and BCF values for 64 human pharmaceuticals that were used to evaluate the current BCF testing trigger of log Kow ≥3, and whether a single BCF exposure concentration allows accurate classification of bioaccumulation potential. Our data support raising the BCF testing trigger to log Kow ≥4, and use of a single test concentration. The resulting reduction in the use of fish is consistent with the 3 R s principle and did not adversely affect classification accuracy. An assessment of potential risk of secondary poisoning was also conducted for three drugs classified as either B or vB, and no risks were identified.

Elements to assess the quality of information of case reports in pregnancy pharmacovigilance data—a ConcePTION project

To assess the risk of exposure to a medicinal product during pregnancy in an individual case report, the necessary information should be present, complete and clearly described. Previously designed grading tools were not developed for pregnancy pharmacovigilance data. This study aims to identify the elements that are necessary to assess of the quality of information for risk assessment of medicinal products used during pregnancy. This is a first step in the development of a validated method to assess the clinical quality of case reports in pregnancy pharmacovigilance data. Potential information elements were determined by means of an expert focus group discussion and a survey based on its outcome. This provided an overview of possible information elements to be selected. For the final selection of the elements, a second survey and subsequent focus group discussion was used. Twenty-one information elements within seven categories were identified: information related to the association itself, the event, exposure to the medicinal product, maternal factors, pregnancy, labour, and the child. This study identified elements considered necessary in the assessment of quality of information of case reports in pregnancy pharmacovigilance data, via an extensive four-step process.

Occurrence of Levonorgestrel in Water Systems and Its Effects on Aquatic Organisms: A Review.

Levonorgestrel is one of the active ingredients of oral contraceptives detected in the aquatic environment at concentrations in the order of ng/L. During the past decade, a wealth of new information about levonorgestrel has been produced, with several studies having reported negative effects in the reproduction and growth of aquatic organisms after exposure to this emerging contaminant of concern. In the present study, the data about its levels in water and its effects on aquatic organisms were integrated and used to perform an updated preliminary aquatic risk assessment for levonorgestrel based on the guideline for Environmental Risk Assessment of Medicinal Products for Human Use from the European Medicines Agency. The aim was to investigate if this pharmaceutical has a risk for adverse effects on aquatic organisms (i.e. for organisms residing in surface water and groundwater). The results evidenced that levonorgestrel is likely to pose an environmental risk to surface water (risk quotient >1). Based on these results, a more refined risk assessment for this pharmaceutical is needed. Besides, our findings highlight the need for investigation under the adverse outcome pathway (AOP) framework, as well as for further studies about toxicological interactions between levonorgestrel and other synthetic steroids.

Local environmental risk assessment of anticancer drugs in a developing country

Anticancer drugs used in cancer treatment are excreted unchanged or as metabolites by feces and urine in hospitals and households. These drugs enter the municipal sewage system but wastewater treatment plants are not capable of removing all of these micro pollutants. In many countries such as Brazil, sanitation departments do not provide service, nor have access to all of the population, therefore most sewage is still released into untreated receiving bodies. This study analyzes the consumption of anticancer drugs in a Brazilian hospital located in one of the 10 municipalities with the best sanitation index in the country. It estimates its environmental risk in aquatic matrixes by the European Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use. Among the 20 drugs analyzed, the three most consumed (cyclophosphamide, 5-fluoruracil, and cytarabine) show a predicted environmental concentration value greater than the action limit of 0.01 µg/L recommended by the guideline. The risk assessment was performed on all pharmaceuticals consumed to get a greater awareness of risk. Results do not indicate local environmental risk but, considering that the study was performed under the best sanitation scenario, it cannot be extrapolated in the other municipalities. The study highlights that development of suitable methodologies should be considered to perform environmental risk assessment of pharmaceuticals in developing countries sanitation conditions.

Critical review on the Environmental Risk Assessment of medicinal products for human use in the centralised procedure

In this article we analyse the Environmental Risk Assessment (ERA) of 59 medicinal products for human use authorised in the EU through the centralised procedure between 2011 and 2012, to establish whether company submissions are compliant with the European Medicines Agency (EMA) guideline and complete in terms of data and study reports provided. The most frequent questions raised by EU regulatory authorities are described, together with an evaluation of the presence and quality of ERA-related information in published regulatory assessment documents. The results of this review show recent improvement in ERA-related data presented in regulatory assessment documents available to the public while also highlighting a need to develop further guidance on environmental issues in order to assist applicants improve their ERA dossiers and overcome current shortcomings.

Assessment of the environmental fate and effects of the PPARgamma receptor agonist, pioglitazone

The environmental fate and effects of pioglitazone prescribed for the treatment of type 2 diabetes were evaluated in an environmental risk assessment following the European Medicines Agency (EMA) “Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use”; EMEA/CHMP/SWP/4447/00. A predicted environment concentration (PEC) for surface water was estimated at 0.023 μg L −1, (action limit of 0.01 μg L −1) triggering a comprehensive battery of laboratory evaluations. Pioglitazone and its major metabolites were determined not to significantly adsorb to sewage solids, were not persistent in the aquatic environment, did not bioaccumulate and were non-toxic to aquatic organisms. Pioglitazone does not pose an unacceptable risk to groundwater supplies, with concentrations not anticipated to be a risk to aquatic organisms or human drinking water supplies. Pioglitazone does not pose a risk of secondary poisoning.

Environmental risk assessment of human pharmaceuticals in the European Union: A case study with the β‐blocker atenolol

β-Adrenergic receptor blockers (β-blockers) are applied to treat high blood pressure, ischemic heart disease, and heart rhythm disturbances. Due to their widespread use and limited human metabolism, β-blockers are widely detected in sewage effluents and surface waters. β-Adrenergic receptors have been characterized in fish and other aquatic animals, so it can be expected that physiological processes regulated by these receptors in wild animals may be affected by the presence of β-blockers. Because ecotoxicological data on β-blockers are scarce, it was decided to choose the β-blocker atenolol as a case study pharmaceutical within the project ERAPharm. A starting point for the assessment of potential environmental risks was the European guideline on the environmental risk assessment of medicinal products for human use. In Phase I of the risk assessment, the initial predicted environmental concentration (PEC) of atenolol in surface water (500 ng L−1) exceeded the action limit of 10 ng L−1. Thus, a Phase II risk assessment was conducted showing acceptable risks for surface water, for groundwater, and for aquatic microorganisms. Furthermore, atenolol showed a low potential for bioaccumulation as indicated by its low lipophilicity (log KOW = 0.16), a low potential for exposure of the terrestrial compartment via sludge (log KOC = 2.17), and a low affinity for sorption to the sediment. Thus, the risk assessment according to Phase II-Tier A did not reveal any unacceptable risk for atenolol. Beyond the requirements of the guideline, additional data on effects and fate were generated within ERAPharm. A 2-generation reproduction test with the waterflea Daphnia magna resulted in the most sensitive no-observed-effect concentration (NOEC) of 1.8 mg L−1. However, even with this NOEC, a risk quotient of 0.003 was calculated, which is still well below the risk threshold limit of 1. Additional studies confirm the outcome of the environmental risk assessment according to EMEA/CHMP (2006). However, atenolol should not be considered as representative for other β-blockers, such as metoprolol, oxprenolol, and propranolol, some of which show significantly different physicochemical characteristics and varying toxicological profiles in mammalian studies.

Evaluation of the OECD 314B Activated Sludge Die-Away Test for Assessing the Biodegradation of Pharmaceuticals

The European Medicines Agency guideline for the environmental risk assessment of medicinal products provides a step-by-step phased approach to evaluate the potential risks of new medicines to the environment. Phase I ("prescreen") estimates the initial exposure of the new medicine in the environment. Phase II A ("screen") estimates the fate and effects in the environment. The fate screen determines the inherent properties of the new medicinal active ingredient to sorb to sludge, soil, and sediment matrices and its potential to degrade in a sewage treatment plant and in the subsequent water-sediment compartment. Current ERA Guidance (2006) recommends the OECD 301B Ready Biodegradation Test for Phase II Tier A testing without a clear recommendation for Phase II Tier B testing when further refinement may be needed. With the recent approval of the OECD 314B method for activated sludge, there is now an alternative test method that may be better suited for Phase II Tier A testing and to the data needs of the ERA. As a batch test, it fits the needs of a Tier A screen. It is not designed to simulate the operational steps of a sewage treatment plant, such as the OECD 303 tests, and yet provides the following without considerable costs or resources of OECD 303: (1) useful kinetic information in a test that reflects the conditions of the sewage-treatment environment, i.e., realistic biomass solids concentrations and low level test material concentrations to simulate first-order (nongrowth) kinetics, (2) mass balance analysis for CO(2) evolution and for residues found in mixed liquor, (3) use of an abiotic control to assess losses other than those attributed to biotic biodegradation, and (4) biotransformation profile of degradants. This paper presents the results of OECD 301B with that of OECD 314B for activated sludge biodegradation for five Pfizer drug substances. The use of this new method as an alternative to OECD 301B would strengthen the fate testing screen in Phase II Tier A of the EMEA ERA. It would provide a characterization of a substance's potential for biotransformation and mineralization during sewage treatment and provide a means for revising predicted environmental concentration of surface water for amount removed during sewage treatment.

The CHMP guideline on environmental risk assessment of medicinal products for human use: Three years of regulatory experience

The CHMP guideline on environmental risk assessment of medicinal products for human use: Three years of regulatory experience

Human pharmaceuticals in surface waters: Implementation of a prioritization methodology and application to the French situation

Human pharmaceuticals are widely used and can reach surface waters, where they have the potential to exert biological effects on aquatic non-target organisms. Due to the high number of pharmaceutical drugs used in human medicine throughout the world, it is necessary to select the pharmaceuticals to search for, prior to implementing any environmental measurements and any extensive environmental risk assessment (ERA). This paper describes a methodology developed in order to define this selection. The prioritization scheme consists in three tiers. First, a preliminary classification based on the assessment of exposure is implemented. This exposure assessment is determined by calculating predicted environmental concentrations (PECs) for each pharmaceutical according to the European Medicine Evaluation Agency's (EMEA's) environmental risk assessment guidelines [EMEA, 2006. European Medicine Agency Guideline on the Environmental Risk Assessment of Medicinal Products for Human Use. EMEA/CHMP/SWP/4447/00.]. In the second step, the preliminary classification is reviewed on a case-by-case hypothesis basis using all the biological data available: ecotoxicological, pharmacological (mechanism of action (MoA), enzyme modulation, adverse effects) and physicochemical data (log K ow). Finally, an additional step is used to select priority compounds among molecules showing the same chemical structure and the same mechanism of action. We applied this methodology to the French situation and prioritized 120 parent molecules and 30 metabolites. The final prioritization list gathers 40 parent compounds and 14 metabolites. Among the 40 parent molecules, 21 have already been found in the aquatic environment, indicating a good agreement between the theoretical approach and the environmental measurements. Parameters used to construct the effect criteria are discussed for their relevance.