clotrimazole, fluconazole, and miconazole, the antibiotics sulfamethoxazole and
trimethoprim, the proton pump inhibitors omeprazole and its metabolite 4-hydroxy
omeprazole sulfide (OM14), the synthetic hormone norethisterone, and the antidepressant venlafaxine.
(b) Environmental Aspects in the Registration of Pharmaceuticals
The legal basis for the registration, production, distribution, and use of medicinal
products in the EU member states is governed by the Directive 2001/83/EC. In
accordance with their provisions, any medical product should get an official authorization previous to its marketing, which is issued by the European Medicines
Agency (EMA) after the proper completion of a registry process. According to
Article 8(3) of the aforesaid directive, applicants must submit a dossier containing
the necessary information to ensure the safety and therapeutic and clinical efficacy of
the pharmaceutical product. As part of this authorization file, information regarding
the potential risks of the drug to the environment is required. Therefore, companies
wishing to register a new drug have to provide an Environmental Risk Assessment
(ERA) [21, 22]. The norm has as well some exceptions (i.e., magistral formulas,
research products, radionuclides, blood derivatives, or natural constituents like
electrolytes, carbohydrates, lipids, amino acids, peptides, proteins, etc.). Medicinal
products consisting of genetically modified organisms have specific requirements
as well.
To facilitate and harmonize the ERA procedures, the EMA has elaborated the
corresponding guidelines, which have been conveniently updated [23].
According to the EMA guideline 2019 [23], the overall process is depicted in
Fig. 1 and includes a risk assessment and a specific hazard assessment. The risk
assessment is focused on the environmental occurrence (exposure) and ecotoxic
potential effects of the product on the exposed organisms. For some specific
biological effects and substances (i.e., endocrine disruptors, antibiotics, etc.), additional aspects have to be considered. In turn, the hazard assessment refers to intrinsic
properties of the products considered harmful for the living organisms exposed
regardless of the concentration and specifically to the persistence, bioaccumulation,
and toxicity (in short, PBT) characteristics. For full details the interested readers are
addressed to the above referred EMA guideline [23].
Briefly, the procedure includes two phases (Fig. 2). In general, Phase I consists of
a decision tree mostly addressed to differentiate among products that require a
further assessment (Phase II) or those that not. This is done on the basis of the
predicted environmental concentration (PEC) in surface water of the product estimated from its predicted use. If PEC ! 0.01 μg/L, the product enters Phase II;
otherwise the process is finished. Phase II is a tiered process, starting with the study
of physico-chemical properties, environmental fate and ecotoxicity, and a Predicted
No Effect Concentration (PNEC). Among other aspects like potential risk to the
groundwater and the soil, or the possibility of secondary poisoning in across the
trophic chain, Tier A examines the risk ratio PEC/PNEC in surface water, and if it
exceeds 1, a Tier B with PNEC refinement is performed. The PBT hazard assessment, carried out (if necessary) in parallel to the risk assessment, aims at evaluating
The Journey of Human Drugs from Their Design at the Bench to Their Fate in Crops
15
trimethoprim, the proton pump inhibitors omeprazole and its metabolite 4-hydroxy
omeprazole sulfide (OM14), the synthetic hormone norethisterone, and the antidepressant venlafaxine.
(b) Environmental Aspects in the Registration of Pharmaceuticals
The legal basis for the registration, production, distribution, and use of medicinal
products in the EU member states is governed by the Directive 2001/83/EC. In
accordance with their provisions, any medical product should get an official authorization previous to its marketing, which is issued by the European Medicines
Agency (EMA) after the proper completion of a registry process. According to
Article 8(3) of the aforesaid directive, applicants must submit a dossier containing
the necessary information to ensure the safety and therapeutic and clinical efficacy of
the pharmaceutical product. As part of this authorization file, information regarding
the potential risks of the drug to the environment is required. Therefore, companies
wishing to register a new drug have to provide an Environmental Risk Assessment
(ERA) [21, 22]. The norm has as well some exceptions (i.e., magistral formulas,
research products, radionuclides, blood derivatives, or natural constituents like
electrolytes, carbohydrates, lipids, amino acids, peptides, proteins, etc.). Medicinal
products consisting of genetically modified organisms have specific requirements
as well.
To facilitate and harmonize the ERA procedures, the EMA has elaborated the
corresponding guidelines, which have been conveniently updated [23].
According to the EMA guideline 2019 [23], the overall process is depicted in
Fig. 1 and includes a risk assessment and a specific hazard assessment. The risk
assessment is focused on the environmental occurrence (exposure) and ecotoxic
potential effects of the product on the exposed organisms. For some specific
biological effects and substances (i.e., endocrine disruptors, antibiotics, etc.), additional aspects have to be considered. In turn, the hazard assessment refers to intrinsic
properties of the products considered harmful for the living organisms exposed
regardless of the concentration and specifically to the persistence, bioaccumulation,
and toxicity (in short, PBT) characteristics. For full details the interested readers are
addressed to the above referred EMA guideline [23].
Briefly, the procedure includes two phases (Fig. 2). In general, Phase I consists of
a decision tree mostly addressed to differentiate among products that require a
further assessment (Phase II) or those that not. This is done on the basis of the
predicted environmental concentration (PEC) in surface water of the product estimated from its predicted use. If PEC ! 0.01 μg/L, the product enters Phase II;
otherwise the process is finished. Phase II is a tiered process, starting with the study
of physico-chemical properties, environmental fate and ecotoxicity, and a Predicted
No Effect Concentration (PNEC). Among other aspects like potential risk to the
groundwater and the soil, or the possibility of secondary poisoning in across the
trophic chain, Tier A examines the risk ratio PEC/PNEC in surface water, and if it
exceeds 1, a Tier B with PNEC refinement is performed. The PBT hazard assessment, carried out (if necessary) in parallel to the risk assessment, aims at evaluating
The Journey of Human Drugs from Their Design at the Bench to Their Fate in Crops
15