Pharmaceuticals in the Environment Changing Public Perception and Regulatory Guidance

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Pharmaceuticals in the EnvironmentChanging
Public Perception and Regulatory Guidance

• Alex Constan, PhD
• Worldwide Safety Sciences
• Pfizer Global Research and Development, Groton, CT

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The Perfect Storm

• Multiple drugs have been detected in the
  effluents of domestic wastewater treatment
  plants, lakes/rivers, ground water, and drinking
  water
• Advances in analytical chemistry have led to a
  dramatic increase in the number of
  pharmaceuticals detected
• Sources Patient excretion (primary) disposal
  unused
• The bioactivity and pseudo-persistence of these
  drugs have resulted in widespread media
  speculation about the potential for chronic
  effects to humans and environmental species
• Environmental risk assessment initiatives (EU,
  Canada, Japan) for drug registration are evolving
  in a precautionary manner in response to the above

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Media Coverage of PIE
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Number of Papers with Quantitative Concentration
Data
Data published through December, 2004.
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Summary of PIE Analytical Data
Concentrations Detected (ppb)
Notes All concentrations in µg/L (parts per
billion, ppb) ND samples assumed to be zero to
calculate averages LOD Limit of Detection
Data published through December, 2004.
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Environmental Assessments

• Environmental assessments (EA) or an exclusion
  are submitted as part of an NDA and MAA filing
• Address the potential for environmental risk from
  post consumer use of a drug
• Involve development and application of
  environmental fate and effect data
• Multiple factors influencing regulatory
  requirements/guidances for EA in drug
  registration
• Current worldwide requirements for EA are not
  harmonized
• FDA tiered approach (guidance may be revised)
  EA trigger 44,000
  kg/yr (PEC 1ppb)
• EMEA (EU) draft guidance re-released Jan 2005
  ERA trigger 2 mg
  dose (PEC 0.01ppb)
• Canada and Japan developing guidelines

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EU (EMEA) Phased Approach to Environmental Risk
Assessments (ERA)
Phase I Initial Assessment

• Estimate exposure
• Unlikely environmental risk if max daily dose lt
  2mg
• PECSURFACEWATER of 0.01 ppb
• Action limits may not be applicable if atypical
  ecotox effects

Phase II Environmental Fate and Effect

• Tier A Screening
• Base set of aquatic tox fate studies for PBT
  properties
• Action limits PEC/PNEC gt1 or log P gt 3 ? Tier B
• Tier B Primary Assessment
• Bioaccumulation/bioconcentration studies (OECD
  305)
• Further characterization of aquatic compartment
• Case-by-case refinement of PEC for alternative
  approaches

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Potential Implications in EU
If possibility of environmental risks cannot be
excluded, precautionary and safety measures could
include

• Product labeling of potential environmental risks
• Package insert for product storage and disposal
• Formulary preferences
• Post-approval monitoring
• Potential for restricted use (i.e., hospital use)

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Concerns with EMEA Draft Guidance

• PEC calculation (exposure) does not include
  metabolism (excreted amount of unchanged
  compound)
• Does not fully utilize mammalian pharmacology,
  toxicology, metabolism data, and environmental
  biochemistry physiology assessment to allow for
  a science-based EA/ERA testing strategy.
  Instead, maintains emphasis on box checking and
  default action limits.
• Decrease in log P action limit may unnecessarily
  characterize compounds as bioaccumulative even
  though they may be extensively metabolized or
  biodegraded

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Looking Ahead

• Proactive effort by industry to assess
  environmental risks and contribute to development
  of a science-based approach to environmental risk
  assessments for pharmaceuticals
• Increased development of drugs for lipophilic
  targets/receptors

Upcoming Meetings to Discuss EA/ERA Process

• IBC Conference - Amsterdam (Oct 3-4, 2005)
  Pharmaceuticals in the Environment
• EMEA Conference London (Oct 27-28, 2005)
  ERA for Human Veterinary
  Medicinal Product
• SETAC Mtg. Symposium on PIE Baltimore (Nov
  13-17, 2005)
• SOT Mtg. Symposium on PIE San Diego (Mar 5-9,
  2006)
• DIA Conference/Workshop Stockholm (May 2006)
  Environmental Assessment of Human Medicines