“If you had asked me 10 years ago if I’d be speaking on this topic, I would have said no,” said Merck’s Keith Silverman, PhD, MPH, speaking on “Environmental Risk Assessment of Pharmaceuticals” at the AAPS 2010 annual meeting in New Orleans. For a variety of reasons—especially a heightened media interest—the issue of how drugs may be impacting humans and the environment has become something that the entire industry, Merck included, is paying much more attention to. Silverman—Merck’s director of product stewardship and science—noted that on his staff, there are now three risk assessors whose sole job is to conduct environmental risk assessments for pharmaceuticals in development.
Silverman sought to put the issue into context, given that much of the media scrutiny has been “sensationalized.” First, how are drugs entering the environment? The primary pathway is normal patient use (and excretion via waste), he said. Unused medicines have become a large issue in Europe, and now in the U.S., but are not as significant as patient use. Finally, while manufacturing effluent has recently been identified as a pathway for potential environmental contamination, it is relatively minor in comparison, Silverman said. “The predominant mass loading is from patient use,” he said.
What does Silverman make of the sensationalized headlines, which cite instances of various drugs (from ibuprofen to Prozac) being found in drinking water? The problem, he said, is that analytical technologies to detect trace drug compounds have dramatically improved, while our ability to assess the risk of those trace elements has not. “People are equating detection in surface water with risk,” he said. “But we’re not seeing risk assessments and exposure assessments being done. Our analytical detection has been phenomenal, but what’s it’s done is make people forget about the risk assessment.”
Nevertheless, Silverman said that there is a tremendous amount of research being done in industry, academia, and government in relation to analytical chemistry as well as toxicology. One of the key areas under study refers to the “fate” of the compound. In other words, “what kind of degradation do we see in waste treatment plants and the environment?” Silverman asked. “And then what happens to them in the environment?”
Merck, Silverman noted, conducts both “acute” and “chronic” toxicology assessments on its compounds, and is increasing its focus on biodegradation of drug products.
Regulatory Picture
Most countries have clear requirements for assessing the potential environmental impact of drug products, Silverman said, while others, including emerging nations, are developing them. There is little consistency, however, in these many schemes around the world.
In the U.S., Silverman said, FDA requires manufacturers to submit an Environmental Risk Assessment (ERA, or EA) with every marketing application, whether a new product or a supplemental application that may have an increase in environmental exposure (such as a higher dosage).
A categorical exclusion provision is allowed if the drug: does not significantly affect the quality of the human environment; is in clinical trials; or is a new drug with a market volume less than 44,000 kg per year. There are, however, extraordinary circumstances which give FDA the right to require an EA—for example, for a compound that is considered hormonally active.
EU guidelines, on the other hand, are more comprehensive than those in the U.S., but they’re also very open to interpretation, Silverman noted. The EMA and other authorities generally require an environmental risk assessment with each application. But this assessment is not grounds for a denial of the marketing approval—“that’s pretty interesting,” Silverman said.
Some member states are pressuring the EMA to change this and make the environmental risk criteria part of regulators’ risk-benefit decision-making process. In addition, some are saying that if a drug has a less-than-stellar environmental profile, it is a factor that may be considered into country-specific pricing and reimbursement schemes.
As in the U.S., in Europe an environmental assessment is required for all new medicinal products, and supplemental applications with an increase in the environmental exposure. Exemption rules are similar to those in the U.S., he said.
EU guidelines do differ from FDA guidelines in terms of “action triggers” that may require an EA. “They are really looking at the exposure to the environment from patient use, not from unused products or manufacturing waste,” he said. “Any drug that’s administered in greater than 2 mg per day triggers an ERA.” Environmental concentration calculations for the assessment are derived based on percentages of the eligible patient population likely to use a product.
Praise for Canada
Both U.S. and EU regulations for environmental risk assessments can stand an upgrade, Silverman implied, and they need to emphasize potential risk factors earlier in the development process. “Any smart environmental framework has to compliment the drug discovery process,” he said. “My team has to provide the ERA by the time we provide a marketing application. That means we start all our testing at least a year and a half to two years earlier.” That means testing starts typically in early Phase 1.
A smart regulatory framework must also help companies integrate the ERA into the business, Silverman added. Merck has developed systems and frameworks for addressing new and existing compounds “for any country we wish to go into,” he said. A key to this preparedness is maintaining a close relationship between Silverman’s team and Regulatory Affairs, as well as with those conducting specific preclinical and clinical studies.
Merck’s approach goes beyond what is expected in the U.S. and EU, and is more aligned with what has been developed in Canada. Traditionally, Canada has had little regulation regarding environmental impact of drug products. It had no provisions under its Food and Drug Act, so regulations fell under the country’s Environmental Protection Act—a “cradle-to-grave assessment” designed around industrial chemicals with poor applicability to pharma, Silverman noted.
Within the past few years, however, Canada has launched an Environmental Assessment Working Group (EAWG) to address the issue. The group is comprised of regulators, nongovernmental associations, physicians and scientists, and representatives of the pharmaceutical, food, cosmetic, and other industries.
In June 2010, the EAWG released a draft of new regulations, which is now still open to comment. At its core, the regulation establishes a framework for manufacturers to consult with the government early in the product lifecycle, and the EA is included as part of the common technical document when a marketing application is filed. “There’s a lot of transparency and consistency in the new Canadian system,” Silverman stated. “It ties the EA process into the Pre-Notification Consultation,” requiring a robust early set of data on potential environmental impact of the product.
When Canadian authorities are presented with the manufacturer’s early findings, they will either deliver a Letter of No Suspicion of Toxicity or, if there were suspicion, work with the manufacturer to put in place a risk management program.
The action trigger in the Canadian proposal is a Predicted Environmental Concentration (PEC) action limit. Merck data, and data found in industry databases such as PhRMA PhACT and MISTRA, suggest that many if not most hormone products fall outside action limits, and thus EAWG has stipulated that hormones automatically require a full environmental risk assessment. Antibiotics are also a concern, but will be reviewed on a case-by-case basis.
In a nutshell, Silverman said, Canada has done it right. It got the right stakeholders together and has put a framework together that aligns with a typical drug development timeline, and includes an early interaction period with the government authorities.
