Environmental Risk Assessment and New Drug Development
Published on 03rd August
In our globalized world, human pharmaceutical residues and traces of other (chemical) down-the-drain contaminants have become an environmental concern. Following the detection of (pharmaceutical) drug residues in drinking and surface waters , regulatory agencies around the world, including the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA), have developed detailed guidance on how pharmaceutical products should be assessed for possible adverse environmental effects.
Hence, an Environmental Risk Assessment or ERA is required as part of the clinical development, regulatory submission and marketing authorization of pharmaceuticals. This is mandatory for drugs both for the treatment of human diseases as well as veterinary use.
Using fate, exposure and effects data, an environmental risk assessment or ERA evaluates the potential risk of (new) medicinal compounds and the environmental impact they cause.
Despite the available guidance from regulatory agencies, regulatory policy is complex, and a number of aspects related to ERA remain unclear because they are not yet well defined. Furthermore, the specific requirements are not always straightforward. Moreover, while some types of chemicals are exempt (e.g., vitamins, electrolytes, peptides, proteins), such exemption may be overruled when a specific mode of action (MOA) involves endocrine disruption and modulation.
In this white paper, which focuses on human pharmaceuticals rather than veterinary pharmaceuticals, the author reviews topics ranging from regulations and environmental chemistry to exposure analysis and environmental toxicology. He also addresses key aspects of an ERA.
The effective functioning of a modern, healthy society increasingly demands developing novel therapeutic agents for the treatment of human and veterinary disease as well as the new and emerging technologies that form the foundation for advancement. A proper understanding of environmental health and safety risks that may have been introduced into the environment as part of developing these new medicines is an important part of this process.
To understand these risks, Environmental Risks Assessments or ERAs are designed to systematically organize, evaluate and understand relevant scientific information. The purpose of such assessment is to ascertain if, and with what likelihood, individuals are directly or indirectly exposed to (novel) medicinal compounds, (bio) pharmaceutical products or active pharmaceutical ingredients in our immediate environment, as well as the consequences of such exposure. The information can then be used to assess if the use of these agents may result in unintended health-related impairment or harm as the result of such exposure, as well as the impact these agents may have on a globalized world. 
Exposure may occur if humans come into contact with (novel) medicinal compounds, (bio) pharmaceutical products or active pharmaceutical ingredients. And while therapeutic agents may be intended to cause some measure of harm – for example, chemotherapeutic agents in the treatment of patients with various forms of cancer designed to “kill” malignant cells – unintended environmental exposure may, in turn, cause unintended serious adverse events. In many cases, such exposure may be limited to trace levels of the active pharmaceutical ingredient.
Over the past 30 years, the impact of such exposure, as well as its implications, have become clearer. Because early analytical equipment was not very sensitive, traces of (novel) therapeutic and medicinal compounds, (bio) pharmaceuticals and active pharmaceutical ingredients were not easily detected in the environment until the 1990s. The result was that the impact of these agents in the environment was generally considered nonexistent and unimportant.
However, since the late 1940s, scientists have been aware of the potential that a variety of chemicals are able to mimic endogenous estrogens and androgens. 
The first accounts indicating that hormones were not completely eliminated from municipal sewage, wastewater and surface water were not published until 1965, by scientists at Harvard University,  and it was not until 1970 that scientists, concerned with wastewater treatment, probed to what extent steroids are biodegradable, because hormones are physiologically active in very small amounts. 
However, the first report specifically addressing the discharge of medicinal compounds, pharmaceutical agents or active pharmaceutical ingredients into the environment was published in 1977 by scientists from the University of Kansas. 
Despite these and many other early findings, the subject of medicinal compounds such as steroids and other pharmaceutical residues in wastewater did not gain significant attention until the 1990s, when the occurrence of hermaphroditic fish was linked to natural and synthetic steroid hormones in wastewater. 
In numerous studies and reports, researchers hypothesized and confirmed that effluent discharge in the aquatic environment, such as municipal sewage, wastewater systems as well as surface waters, contained either a substance or (multiple) substances, including natural and synthetic hormones, that are estrogenic to fish, affecting their reproductive systems. 
In time, scientists confirmed that these adverse effects, and implications of endocrine disruption and modulation, were caused by residues of estrogenic human pharmaceuticals. 
After discovering hermaphroditic fish in and near water-treatment facilities, scientists identifying the estrogenic compounds that were most likely associated with this occurrence confirmed that substances such as ethynylestradiol, originating from pharmaceutical use, generated a similar effect in caged fish exposed to levels as low as 1 to 10 ng 1−1 and that positive responses may even arise at 0.1 to 0.5 ng 1−1. 
Although it was now recognized that the therapeutic agent or active pharmaceutical ingredient itself was biologically active, experts generally believed that there was only a limited environmental impact during manufacturing; and because these therapeutic agents were only manufactured in relatively small amounts, they were not concerned about the potential environmental risk of pharmaceutical residues and trace contaminants. 
Today, with pharmacotherapy a common part of our daily life, many concerned citizens realize that pharmaceutical residues and trace contaminants may represent an increased environmental risk with potential consequence for human and animal health. 
And although the concentrations of these residues rarely exceed the level of parts per billion (ppb), limiting acute toxicity, the emergence of these residues and traces in the environment fundamentally changed the way we look at the (potential) risk of these active pharmaceutical ingredients in the ecosystem. 
But regulators have also come to understand that environmental risk assessment developed for non-medicinal chemical containment cannot necessarily be applied to (novel) medicinal compounds, (bio) pharmaceutical products or active pharmaceutical ingredients. They understand that protecting the environment, while at the same time improving human and animal health, requires a better understanding of how to protect the environment (the ecosystem) as well as the active pharmaceutical ingredient in its own regulated environment.
5.0 Value for society
The issue of medicinal compounds, (bio) pharmaceutical agents and active pharmaceutical ingredients in our environment is complex. This complexity is, in part, derived from the medicinal value of these compounds and the general acceptance that patient use – and therefore the excretion of active pharmaceutical ingredients into the environment and, as a result, the potential of harmful effects to the ecosystem and human health – rather than other methods of release, is the primary reason why we find traces of these agents in our environment. 
There is no doubt that modern medicines developed by research-based pharmaceutical companies have brought tremendous value. For example, the development of antibiotics generated enormous gains in public health through the prevention and treatment of bacterial infections. In the 20th century, the use of antibiotics aided the unprecedented doubling of the human life span. 
Before the development of insulin in the late 1920s and early 1930s, people diagnosed with diabetes (type 1) were not expected to survive. In 1922, children with diabetes rarely lived a year after diagnosis. Five percent of adults died within two years, and less than 20% lived more than 10 years. But since insulin became available, the drug has become a daily routine for people with diabetes, creating a real survival benefit and making the difference between life and death. 
Pharmaceutical agents have also drastically impacted social life. The introduction of the pill in the early 1960s, for example, affected women’s health, fertility trends, laws and policies, religion, interpersonal relations, family roles, women’s careers, gender relations and premarital sexual practices, offering a host of contraceptive and non-contraceptive health benefits. 
It can be said that the emergence of the women’s rights movement of the late 1960s and 1970s is directly related to the availability of the pill and the control over fertility it enabled: It allowed women to make personal choices about life, family and work. 
The development of novel targeted anticancer agents, including antibody-drug conjugates or ADCs, have resulted in a new way of treating cancer and hematological malignancies with fewer adverse events, longer survival and better quality of life (QoL).
In the end, the economic impact of pharmaceutical agents, some hailed as true miracles, has been remarkable, contributing to our ability to cure and manage (human) disease and allowing people to live longer, healthier lives.
At the same time, the (clinical) use of (novel) medicinal or (bio) pharmaceutical agents and their underlying active ingredients can also harbor a number of risks for the environment.
6.0 Understanding environmental risk
In the development of novel therapeutic agents, intensive pre-clinical investigations yield a vast amount pharmacological and toxicological data. During the discovery and (early) development of therapeutic agents, researchers are paying close attention to target specificity and pathways to understand how an innovative drug compound may have beneficial efficacy in the treatment of human or veterinary diseases. Because adverse events are undesirable, drug developers often focus on therapeutics with a well-understood mechanism of action (MOA) and low toxicity (often measured in ng/L). 
As a result, only a small number of pharmaceuticals will be classified as highly and acutely toxic, requiring new approaches to identify pharmaceutical agents in robust environmental hazard and risk assessments. 
7.0 Pharmaceutical risk assessment
While non-medicinal and chemical entities produced in significant commercial quantities require an environmental risk assessment based on a minimum set of hazard data to assess and manage risks to humans and the environment, such an approach does not necessarily apply to (novel) therapeutic agents. One reason is that the health and wellbeing of humans should never be assessed and managed on the basis of risk alone. Regulators generally require drug developers or sponsors to undertake a comprehensive assessment of the potential risks and benefits of a proposed therapeutic agent, which may demonstrate significant risk to the patient. However, these risks are largely offset by the medicinal benefits of such agents.
Regulators around the world require a systematic and transparent assessment of the (potential) of environmental risk in addition to a (novel) medicinal agent’s quality, safety and efficacy, and relevance as part of regulatory decision-making. 
8.0 Environmental risk and regulatory requirements in the United States
The legal mandate of protecting the environment in the United States consists of the National Environmental Policy Act of 1969 (NEPA), which requires all federal agencies to assess the environmental impact of their actions and the impact on the environment, and the Federal Food, Drug and Cosmetic Act (FFDCA) of 1938 (amended in 1976).
This legal framework further determines that the regulation of pharmaceuticals in the environment is the responsibility of the United States Environmental Protection Agency or EPA and the United States Food and Drug Administration (FDA), which is required to consider the environmental impact of approving novel therapeutic agents and biologics applications as an integral part of the regulatory process.
The FDA has required environmental risk assessments for (novel) medicinal compounds, (bio) pharmaceutical agents and active pharmaceutical ingredients for veterinary use (since 1980) as well as the treatment of human diseases (since 1998).
As such, the FDA regulations in 21 CFR part 25 identify which Pharmaceutical Environmental Risk Assessment or PERA is required as part of a New Drug Application or NDA, abbreviated application, Investigational New Drug application or IND. 
The same regulations (21 CFR 25.30 or 25.31) identify categorical exclusions for a number of products and product categories – including vitamins, electrolytes, peptides, proteins, etc. – that do not require the preparation of an environmental risk assessment or ERA because, as a class, these agents, individually or cumulatively, do not significantly affect the quality of the (human) environment.
In addition, and in contrast to the categorical exclusion, these regulations also identify cases when such an exemption may be overruled as the result of a specific mode of action (MOA) involving endocrine disruption and modulation. 
9.0 Required ERA
Under the applicable regulations, NDAs, abbreviated applications and supplements to such applications do not qualify for a categorical exclusion if the FDA’s approval of the application results in an increased use of the active moiety or active pharmaceutical ingredient, as a result of higher dose levels, use of a longer duration, for a different indication than was previously approved, or if the medicinal agent or drug is a new molecular entity and the estimated concentration of the active therapeutic agent at the time of entry into the aquatic environment is expected to be 1 part per billion (ppb) or greater.
Furthermore, a categorical exclusion is not applicable when approval of an application results in a significantly altered concentration or distribution of a (novel) therapeutic agent, the active pharmaceutical ingredient, its metabolites or degradation products in the environment.
Regulations also refer to so-called extraordinary circumstances (stated in 21 CFR 25.21 and 40 CFR 1508.4) where a categorical exclusion does not exist. This may be the case when a specific product significantly affects the quality of the (human) environment and the available data establishes that there is a potential for serious harm. Such environmental harm may go beyond toxicity and may include lasting effects on ecological community dynamics. Hence, it includes adverse effects on species included in the United States Endangered Species Act (ESA) as well as other federal laws and international treaties to which the United States is a party. In these cases, considered extraordinary circumstances, an environmental risk assessment is required unless there are specific exemptions relating to the active pharmaceutical ingredient.
10.0 Naturally Occurring Substances
Based on the current regulations, a drug or biologic may be considered to be a “naturally occurring” substance if it comes from a natural source or is the result of a biological process. This applies even if such a product is chemically synthesized. The regulators consider the form in which an active ingredient or active pharmaceutical agent exists in the environment to determine if a medicinal compound or biologic is a naturally occurring substance. Biological and (bio) pharmaceutical compounds are also evaluated in this way.
According to the Guidance for Industry, a protein or DNA containing naturally occurring amino acids or nucleosides with a sequence different from that of a naturally occurring substance will, after consideration of metabolism, generally qualify as a naturally occurring substance. The same principle applies to synthetic peptides and oligonucleotides as well as living and dead cells and organisms. 
11.0 Preparing an Environmental Risk Assessment
If an environmental risk assessment is required, the FDA requires drug developers and/or sponsors to focus on characterizing the fate and effects of the active pharmaceutical ingredient in the environment as laid out in the Guidance for Industry, Environmental Assessment of Human Drugs and Biologics Applications (1998). 
This is generally the case if the estimated concentration of the active pharmaceutical ingredient being considered reaches, at the point of entry into the aquatic environment, a concentration ≥1 PPB; significantly alters the concentration or distribution of a naturally occurring substance, its metabolites or degradation products in the environment; or, based on available data, it can be expected that an increase of the level of exposure may, potentially, lead to serious harm to the environment. 
To guarantee that satisfactory information is available, the 1998 Guidance for Industry lays out a tiered approach for toxicity testing to be included in an environmental risk assessment. [Figure I] 
Furthermore, if potential adverse environmental impacts are identified, the environmental risk assessment should, in accordance with 21 CFR 25.40(a), include a discussion of reasonable alternatives designed to offer less environmental risk or mitigating actions that lower the environmental risk.
12.0 A Tiered Approach
The fate and effects testing is based on a tiered approach:
12.1 Tier 1
This step does not require acute ecotoxicity testing to be performed if the EC50 or LC50 divided by the maximum expected environmental concentration (MEEC) is ≥1,000, unless sublethal effects are observed at the MEEC. If sublethal effects are observed, chronic testing as indicated in tier 3 is required. 
12.2 Tier 2
In this step, acute ecotoxicity testing is required to be performed on a minimum of aquatic and/or terrestrial organisms. In this phase, acute ecotoxicity testing includes a fish acute toxicity test, an aquatic invertebrate acute toxicity test and analgal species bioassay.
Similar to tier 1, tier 2 does not require acute ecotoxicity testing to be performed if the EC50 or LC50 for the most sensitive organisms included in the base test, divided by the maximum expected environmental concentration (MEEC) is, in this tier, ≥100, unless sublethal effects are observed at the MEEC. However, as in the case of tier 1, if sublethal effects are observed, chronic testing as indicated in tier 3 is required. 
12.3 Tier 3
This tier requires chronic toxicity testing if the active pharmaceutical ingredient has the potential to bioaccumulate or bioconcentrate, or if such testing is required based on tier 1 or tier 2 test results. 
13.0 Bioaccumulation and Bioconcentration
Bioaccumulation and bioconcentration are complex and dynamic processes depending on the availability, persistence and physical/chemical properties of an active pharmaceutical ingredient in the environment. 
Bioaccumulation and bioconcentration refer to an increase in the concentration of the active pharmaceutical ingredient in a biological organism over time, compared with the concentration in the environment. In general, compounds accumulate in living organisms any time they are taken up and stored faster than they are metabolized or excreted. The understanding of this dynamic process is of key importance in protecting human beings and other organisms from the adverse effects of exposure to a (novel) medicinal compound, (bio) pharmaceutical agent or active pharmaceutical ingredient, and it is a critical consideration in the regulatory process. 
According to the definition in the Guidance for Industry, active pharmaceutical ingredients are generally not very lipophilic and are, in comparison to industrial chemicals, produced in relatively low quantities. Furthermore, the majority of active pharmaceutical ingredients generally metabolize to Slow Reacting Substances or SRSs that are more polar, less toxic and less pharmaceutically active than the original parent compound. This suggests a low potential for bioaccumulation or bioconcentration. 
Following a proper understanding of this process, tier 3 chronic toxicity testing is required if an active pharmaceutical ingredient has the potential to bioaccumulate or bioconcentrate. A primary indicator is the octanol/water partition coefficient (Kow). If, for example, the logarithm of the octanol/water partition coefficient (Kow) is high, the active pharmaceutical ingredient tends to be lipophilic. If the coefficient is ≥3.5 under relevant environmental conditions, such as a pH of 7, chronic toxicity testing is required.
Tier 3 does not require further testing if the EC50 or LC50 divided by the maximum expected environmental concentration (MEEC) is ≥10, unless sublethal effects are observed at the MEEC.
In accordance with the Guidance for Industry, a drug developer or sponsor should include a summary discussion of the environmental fate and effect of the active pharmaceutical ingredient in an environmental risk assessment. The environmental risk assessment should also include a discussion of the affected aquatic, terrestrial or atmospheric environments. 
14.0 Special Consideration: Environmental Impact Statement
Following the filing of an environmental risk assessment for gene therapies, vectored vaccines and related recombinant viral or microbial products, the FDA will evaluate the information and, based on the submitted data, determine whether the proposed (novel) medicinal compound, (bio) pharmaceutical agent or active pharmaceutical ingredient may significantly affect the environment and if an Environmental Impact Statement (EIS) is required. According to 21 CFR 25.52, if an EIS is required, it will be available at the time the product is approved. Furthermore, if required, an EIS includes, according to 40 CFR 1502.1, a fair discussion of the environmental impact as well as information to help decision-makers and the public find reasonable alternatives that help in avoiding or minimizing adverse impacts or enhance environmental quality. 
However, if the FDA determines that an EIS is not required, a Finding of No Significant Impact (FONSI) will, according to 21 CFR 25.41(a), explain why this is not required. This statement will include either the environmental risk assessment or a summary as well as reference to underlying documents supporting the decision. 
15.0 European requirements
In Europe, environmental risk assessments were, in accordance EU Directive 92/18/EEC and the corresponding note for guidance issued by the European Medicines Agency (EMA), first required for (novel) medicinal agents for veterinary use in 1998. The requirement for an environmental risk assessment for (novel) medicinal agents, (bio) pharmaceuticals and active pharmaceutical ingredients for the treatment of human disease was first described in 2001 in Directive 2001/83/EC.
Subsequent to an initial guiding document published in January 2005, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) issued its final guidance for the assessment of environmental risk of medicinal products for human use in 2006. 
After the discovery of pharmaceutical residues and trace contaminants in the environment, regulators in the European Union require that an application for marketing authorization of a (novel) medicinal or (bio) pharmaceutical agent is accompanied by an environmental risk assessment.
This requirement is spelled out in the revised European Framework Directive relating to medicinal products for human use. It applies for new registrations as well as repeat registrations for the same medicinal agent if the approval of such an extension or application leads to the risk of increased environmental exposure.
In Europe, the objective of the environmental risk assessment is to evaluate, in a step-wise, phased procedure, and as part of the Centralized Procedure by the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP), the potential environmental risk of (novel) medicinal compounds, (bio) pharmaceutical agents and/or active pharmaceutical ingredients. Such an assessment will be executed on a case-by-case basis.
16.0 Phase I
In this process, Phase I estimates the exposure of the environment to the drug substance and is only focused on the active pharmaceutical ingredient or drug substance/active moiety, irrespective of the intended route of administration, pharmaceutical form, metabolism and excretion.
This phase excludes amino acids, proteins, peptides, carbohydrates, lipids, electrolytes, vaccines and herbal medicines, because regulators believe that these biologically derived products are unlikely to present a significant risk to the environment. 
The exemption for these biologically derived biopharmaceuticals is generally interpreted as an exemption for all biopharmaceutical agents manufactured via live organisms and that have an active ingredient that is biological in nature. 
Yet, not all biologically derived biopharmaceuticals are (easily) biodegradable, and scientists have detected modified natural products, including plasmids, in the environment. Furthermore, some protein structures, including prions, are very environmentally stable and resistant to degradation, allowing them to persist in the environment.  Hence, this approach requires future scientific justification.
In Phase I, following the directions included in the European Chemicals Bureau (2003) Technical Guidance Document, an active pharmaceutical ingredient or drug substance/active moiety with a logKow >4.5 requires further screening for persistence, bioaccumulation and toxicity, or a PBT assessment.
For example, based on the OSPAR Convention and REACH Technical Guidance, highly lipophilic agents and endocrine disruptors are referred to PBT assessments.
Phase I also includes the calculation of the Predicted Environmental Concentration or PEC of active pharmaceutical ingredients, which, in this phase, is restricted to the aquatic environment, and a so-called “action limit” requiring additional screening.
The “action limit” threshold for the PEC in surface water (PECsurface water), for example, is calculated by using the daily dose of an active pharmaceutical ingredient, the default values for wastewater production per capita, and the estimated sale and/or distribution of the active pharmaceutical ingredient if there is evidence of metabolism and no biodegradation or retention following sewage treatment is observed.
17.0 Phase II
Phase II, divided into two parts, tier A and tier B, assesses the fate and effects of novel medicinal compounds, (bio) pharmaceutical agents or active pharmaceutical ingredients in the environment.
Following the assessment of the PEC/PNEC ratio based on relevant environmental fate and effects data (Phase IIA), further testing may be needed to refine PEC and PNEC values in phase II tier B. A PEC/PNEC ratio of This process helps regulators to evaluate potential adverse effects independently of the benefit of the (novel) medicinal compound, (bio) pharmaceutical agent or active pharmaceutical ingredient, or the direct or indirect impact on the environment.
|Stage in regulatory evaluation||Stage in risk assessment||Objective||Method||TEST / DATA REQUIREMENT|
|Phase I||Pre-screening||Estimation of exposure||Action limit||Consumption data, logKow|
|Phase II Tier A||Screening||Initial prediction of risk||Risk assessment||Base set aquatic toxicology and fate|
|Phase II Tier B||Extended||Substance and compartment-specific refinement and risk assessment||Risk assessment||Extended data set on emission, fate and effects|
Table 1: The Phased Approach in Environmental Risk Assessment in Europe
18.0 Outcome of fate and effects analysis
In all cases, the medicinal benefit for patients has relative precedence over environmental risks. This means that even in the case of an unacceptable (residual) environmental risk caused by a novel medicinal compound, pharmaceutical agent or active pharmaceutical ingredient, after third-tier considerations, prohibition of a new active pharmaceutical ingredient is not taken into consideration.
If European regulators determine that the possibility of environmental risk cannot be excluded, mitigating, precautionary and safety measures may require the development of specific labeling designed to address the potential risk, as well as adding adequate information in the Summary of Product Characteristics (SPC), Package Leaflet (PL) for patient use, product storage and disposal. The information on the label, SPC and PL should also include information on how to minimize the discharge of the product into the environment and how to deal with disposal of unused product, such as in the case of shelf-life expiration.
In extreme cases, a recommendation may be included for restricted in-hospital or in-surgery administration under supervision only, a recommendation for environmental analytical monitoring, or a requirement for ecological field studies.  
19.0 Combined effects
Often overlooked by regulators is the fact that the regulatory frameworks such as the European REACH Regulation, the Water Framework Directive (WFD) and the Marine Strategy Framework Directive (MSFD) mainly focus on toxicity assessment of individual chemicals or active pharmaceutical ingredients.
This poses a problem for the proper execution of environmental risk assessments and regulation because the effect of contaminant mixtures with multiple chemical agents and active pharmaceutical ingredients, irregardless of their source, is a matter of growing, and recognized, scientific concern. 
To solve this problem, scientists are working on experimental, modeling and predictive environmental risk assessment approaches using combined effect data, the involvement of biomarkers to characterize Mode of Action, and toxicity pathways and efforts to identify relevant risk scenarios related to combined effects of pharmaceutical residues, trace contaminants as well as non-medicinal (industrial) chemicals. 
20.0 International harmonization
Created in the 1990s, the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) was set up as an agreement between the European Union, the United States and Japan to harmonize different regional and national requirements for registering pharmaceutical agents in order to reduce the need to duplicate testing during the research and development phase of (novel) medicinal compounds, (bio) pharmaceutical agents and active pharmaceutical ingredients. However, to date, and partly as a result of the overlying differences in regulations and directives, environmental risk assessments have, so far, not been included in the harmonization procedures. 
In contrast, the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products, or VICH, similar to the ICH a trilateral set up in 1996 between the European Union, the Unites States and Japan, does include the assessment of ecotoxicity and the evaluation of environmental impact of veterinary medicinal products.
The VICH guideline, intended to provide a common basis for an Environmental Impact Assessment or EIA, offers guidance for the use of a single set of environmental fate and toxicity data and is designed to guide scientists to secure the type of information needed to protect the environment. The guideline, published in 2004 and recommended for implementation in 2005, was developed as a scientifically objective tool to help scientists and regulators extract the maximum amount of information from studies to achieve an understanding of the potential (risk) of specific Veterinary Medicinal Products to the environment. 
21.0 Impact of Environmental Risk Assessment
Although an environmental risk assessment is part of the regulatory approval and marketing authorization process in both the United States and Europe, the actual impact can be different.
In Europe, an adverse environmental risk assessment for (novel) medical compounds, (bio) pharmaceutical agents or active pharmaceutical ingredients for human use does not impact or influence the marketing approval application. EU Directive 2004/27/EC/Paragraph 18 stipulates that the environmental impact should be assessed and, on a case-by-case basis, specific arrangements to limit it should be envisaged. In any event, the impact should not lead to refusal of a marketing authorization.
However, a parallel directive pertaining to veterinary medicine, as laid out in EU Directive 2009/9/EC, stipulates that, in the case of veterinary medicine, an environmental impact assessment should be conducted to assess the potential harmful effects and the kind of harm the use of such a product may cause to the environment, as well as to identify any precautionary measures that may be necessary to reduce such risk.
Furthermore, the directive requires that, in the case of live vaccine strains which may be zoonotic, the risk to humans also needs to be assessed. In the case of veterinary medicine, an environmental impact assessment is part of the overall risk-benefit assessment, and, in the case of a negative result, may potentially lead to a refusal to approve the medicinal compound, (bio) pharmaceutical agent or active pharmaceutical ingredient.
In the United States, the FDA has eliminated environmental assessment requirements for certain types of veterinary drugs when they are not expected to significantly affect the environment. However, a negative assessment, based on unacceptable risk to “food” or “non-food” animals, can result in a refusal of a New Animal Drug Application (NADA) or a Supplemental New Animal Drug Application (SNADA). 
The central questions in the development of (novel) medicinal compounds, (bio) pharmaceutical products or active pharmaceutical ingredients for the treatment of human and veterinary disease is whether a novel agent will have an effect on the environment.
Regulators around the world, including in the United States and Europe, follow different assessment methodologies to ascertain these risks. However, all regulators use fate, exposure and effects data to help them understand if a (novel) medicinal compound, (bio) pharmaceutical agent or active pharmaceutical ingredient harbors a potential environmental risk, causing potential harmful effects on the ecosystem, and how this impacts human and veterinary health.
In all cases, environmental risk assessments are carried out based on scientifically sound premises, relying on established, accepted and universally known facts.
Overall, environmental risk assessments are useful analytical tools, providing critical information contributing to public health, as well as key instruments in guiding environmental policy decision-making.
As such, they play a key role in building a better, healthier world.
August 3, 2017 | Corresponding Authors: Duane Huggett, Ph.D | DOI: 10.14229/jadc.2017.29.08.001
Received: February 24, 2017 | Accepted for Publication: April 28, 2017 | Published online Augu 3, 2017 |
Last Editorial Review: August 3, 2017
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