ERA in EU required for previously registered APIs, but negative result doesn't mean marketing authorization denial

Validation Times, Jan, 2008 by Joseph Pickett

An environmental risk assessment (ERA) is required in the European Union (EU) for new active pharmaceutical ingredients (APIs), and new uses of previously registered APIs. ERAs are governed by the June 2006 guidance document and the EU's Technical Guidance Document (TGD) for risk assessment, according to Manu Sharma, Gradient Corporation, Cambridge, MA.

Sharma spoke at a Jan. 16 Expertbriefings.com audio conference entitled: "Cost-Effective Compliance with EU Pharmaceutical Environmental Risk Assessment Requirements."

He said the objective of an ERA is to assess environmental risks from API societal use, and to protect population level impacts. A tiered testing assessment approach is used to understand API environmental fate and effects, he said. A key question is: Is the predicted environmental concentration (PEC) less than the predicted no effects concentration (PNEC)?

Phase I on the assessment is similar to FDA categorical exclusion calculations. Phase II is triggered if the PEC exceeds 0.01 ug/L. This translates to a dose threshold of >2 mg/d assuming a default market penetration of 1%. The dose threshold can be higher for low market penetration drugs. Epidemiological data can be used to justify an alternative value.

The conclusion, said Sharma, is that Phase II if API dosage is greater than 2 mg/d unless lower default market penetration can be justified.

The purpose of Phase II of the ERA is to identify risks to aquatic receptors and activated sludge microorganisms. It should be determined if additional tests are needed. GLP studies using OECD protocols are preferred. All relevant data should be taken into account.

Recommendations for Phase II Tier A tests, he said, are:

* Fate tests: Adsorption/desorption, ready biodegradability, aerobic and anaerobic transformation in sediments if not readily biodegradable, and

* Effects tests: Activated sludge respiration inhibition, algae growth inhibition, fish early life stage toxicity.

The goal of Phase II Tier B testing is to assess risks to aquatic receptors, terrestrial receptors, and bioaccumulation effects. There are few prescriptive criteria, and testing in this area refers heavily to the EU TGD. "Substantial room for expert judgment is allowed," said Sharma.

A key question is: Is there a mass-based categorical exclusion similar to FDA's? The agency's categorical exclusion is about 44,000 kg per year. EMEA's exclusion is dose-based, with a default of 2 mg/d. Even if Phase II is not triggered, a PBT assessment is required for many APIs. If the testing is necessary, it can cost up to $400,000 and take six to 18 months to complete.

Are there ways to save money to expedite the ERA process, Sharma asked? One possible way, he explained, is through physicalchemical properties data generated during drug development. He cautioned that some laboratories are pushing for data generation using OECD methods.

He said that mathematical screening models can be used to determine the value of conducting tests. TGD-prescribed screening models can be used for PBT assessments.

Models such as OECD 308 may be used, but the cost is high ($150,000) and it is time consuming to conduct a sediment degradation test. Test data is used to define whether a sediment assessment is needed.

If an ERA concludes there are significant risks to the environment, a marketing authorization denial is not necessarily issued. Generally, Sharma said, the worst case is the inclusion of labels and an explanation regarding environmental effects with the drug.

"In some cases, marketing authorization has been granted when some tests are ongoing," he stated.

By Joseph Pickett, Managing Editor