Environmental Assessment for Pharmaceuticals - FDA Perspective Charles E. Eirkson III Center for Veterinary Medicine U

1. Environmental Assessment for Pharmaceuticals - FDA PerspectiveCharles E. Eirkson IIICenter for Veterinary MedicineU.S. Food and Drug Administration NCAC SOT: Emerging Issues in Water Contamination April 15, 2010

2. Topics • Legal • Regulatory • Science • Risk Management • Wrap-up/summary

3. Agency’s Roles and Priorities Primary Federal agency for regulating pharmaceuticals and personal care products • Foods • Human Drugs • Animal Drugs • Cosmetics • Medical Devices

4. Statutes & Regulations Primary Statutory authorities • Food, Drug, & Cosmetic Act of 1938 • Public Health Service Act of 1944 Supplemental authority • National Environmental Policy Act (NEPA) of 1969 Regulatory responsibilities • Title 21 Code of Federal Regulations

5. FDA Implementation of NEPA Council on Enviromental Quality 40 CFR, Part 1500 - 1508 1) Categorical Exclusions 2) Environmental Assessments (EA) 3) Environmental Impact Statements (EIS) FDA Regulations NEPA regs -- 21 CFR Part 25

6. Categorical Exclusion Classes of actions that individually or cumulatively do not significantly affect the quality of the human environment are ordinarily excluded from the requirement to prepare an EA or EIS

7. Categorical Exclusions • Action on original and abbreviated new human and animal drug if there is no increase in use of the active moiety • Action on a human and animal drug for a naturally occurring substance if no significant change in environmental exposure • Investigation of a new human and animal drug

8. Categorical exclusions con’t Human approval Predicted WWTP effluent introductory concentrations (EIC) of < 1 ppb Estimate based on high-end projected sales and worse-case, end-of-pipe effluent discharges Based upon retrospective analysis of EAs

9. Categorical Exclusion con’tVeterinary approvals • non-food animals • Rx drugs for therapeutic use in terrestrial species Extraordinary circumstances trump a claim of categorical exclusion.

10. Extraordinary circumstances • At the expected level of exposure there is the potential for serious harm to the environment • Adverse effect on species or the critical habitat of an endangered or threatened species

11. FDA Actions that may* need EA Approval of: • New Drug Application (NDA), • Biologics License Application (BLA), • New Animal Drug Application (NADA) • Device Pre-Market Approval (PMA) Action on: • Investigational New Drug Application (IND) • Investigational New Animal Drug Application (INAD) • Investigational Device Exemption (IDE) * Unless Excluded by 21 CFR 25.31

12. Agency’s Roles and Priorities • Review claims for categorically exclusion • Review the EA submitted by the sponsor • Determine appropriate action • Finding of No significant Impact (FONSI) • Environmental Impact Statement (EIS)

13. FDA EA • Concise public document • Use and Disposal (not manufacturing) • Sufficient evidence and analysis • FONSI or EIS • Aids an agency's compliance with NEPA • Facilitates preparation of EIS • Includes: • need for the action • alternatives • list of agencies and persons • Identifies potential mitigations

14. EA Availability Most actions are categorically excluded • published in the Federal Register Many actions have EAs • published in the Federal Register • public display/available in FDA Document Management Branch • 113 + EAs for new animal drugs and feed additives on line at: www.fda.gov/AnimalVeterinary/DevelopmentApproval Process/EnvironmentalAssessments/default.htm

15. FDA Scenarios

16. Risk = exposure to a chance of loss (or of losing something we value) Current and Future Environmental Assessments Risk = Hazard x Exposure

17. EA Focus • Ecosystem protection • Laboratory studies on invertebrates, fish, plants at different trophic levels • Measurement endpoints: mortality, immobilization, reproduction, growth, functional responses • Biogeochemical cycling (nitrogen, carbon transformation)

18. Guidance CDER guidance Environmental Assessment of Human Drug and Biologics Applications (July 1998)http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm070561.pdf CVM guidance Environmental Impact Assessment for Veterinary Medicinal Products (VMP) Phase I (Sept. 1998) http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM052424.pdf Phase II (January 2006) http://www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM052500.pdf

20. Veterinary Phase I Guidance harmonized - EU, Japan, US, Australia legal and exposure criteria exempt from full risk analysis extensive in vivo metabolism aquaticintroduction concentration < 1 g/L terrestrial introduction concentration < 100 g/Kg

21. Veterinary Phase II Guidance Risk-quotient method = PEC : PNEC. • Predicted environmental concentration (PEC) • Predicted no effect concentration (PNEC) • Assessment Factor (AF) • Three Tiers (A,B,C) as needed

22. Physical-chemical studies - Water Solubility - Dissociation Constant - UV-Visible Absorption Spectrum - Melting Temperature - Vapour Pressure - Octanol/Water Partition Base Set Data Requirements Environmental fate studies - Soil adsorption/desorption - Degradation in soil - Degradation in aquatic systems - Photolysis (optional) - hydrolysis (optional) Aquatic effect studies - Algae - Daphnia - Fish Terrestrial effect studies - Micro-organisms - Terrestrial plants - Earthworm

23. Veterinary TIER A Assessment • Surface water EndpointAF • algae (96 h) EC50 100 • invertebrate (48 h) EC50 1000 • fish (96 h) LC50 1000 • Soil • earthworm (chronic) NOEC 10 • higher plants (3 species) EC50 100 • micro-organisms (28 days) <25% of control • Dung (pasture animals) • dung fly EC50 100 • dung beetle EC50 100

24. Veterinary TIER B Assessment • Surface waterEndpoint AF • algae (96 h) NOEC 10 • invertebrate (21 d) NOEC 10 • fish (28 d) NOEC 10 • sediment species (varies) NOEC 10 • Soil • earthworm no recommendation • higher plants (more species) NOEC 10 • micro-organisms (100 days) < 25% of control • Bioaccumulation • BCF > 1000 l/kg  investigate secondary poisoning

25. Veterinary TIER C Assessment Refined Risk Analysis • Specialized environmental fate modeling • Probabilistic exposure analyses Specialized Laboratory and/or Field Testing • Pulsed exposure studies • Microcosm and mesocosm studies • In-stream studies Risk Management • Use restrictions • Mandatory treatment requirements • Effluent discharge limits

26. Potential Risk Mitigation Options • Use limitations on drug label (e.g., limit frequency or site of use; specify minimum dilution prior to discharge) • Effluent treatment stipulated on the drug product label (e.g., settling ponds, activated carbon) • “No discharge” to surface waters • Water quality benchmark development and reporting

27. Possible Data for Application to Human Exposure

28. Human Drug Development Nonclinical Data Collected • Safety Pharmacology • Toxicokinetics and Pharmacokinetics • Repeated Dose Toxicity • Genotoxicity (in vitro; in vivo) • Carcinogenicity • Reproductive and Developmental Toxicology • Immunotoxicity • Other Studies: • Phototoxicity, antigenicity, juvenile animal toxicity, mechanistic studies, studies on metabolites and impurities Guidance Document: ICHM3(R2): Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals 28

29. Nonclinical Studies • Characterize potential toxic effects prior to clinical studies: • Pediatric Patients • Peri- and Postnatal Population • Pregnant Women/Women of Childbearing Age • Estimate the maximum recommended starting dose (MRSD) and dose range for first-in-human clinical trials. • Identify parameters for clinical monitoring of potential adverse effects. 29

30. Studies to Evaluate the Safety of Residues of Veterinary Drugs in Human Food • Repeat-Dose (90-Day) Toxicity Testing • Repeat-Dose (Chronic) Toxicity Testing • Developmental Toxicity Testing • Reproductive Toxicity Testing • Microbiological Analysis • Genotoxicity Testing • Carcinogenicity Testing

31. Veterinary Food Safety Acceptable Daily Intake (ADI) • Consider all available oral toxicity data • Select most appropriate NOAEL from the most appropriate study • Benchmark Dose Lower Bound – BMDL also a possible point of departure • Select appropriate safety factor

32. Safe Disposal of Medicines

33. Summary FDA continues to work with its federal partners - EPA, USGS, CDC - and the regulated industry to address the ecological and human health implications of pharmaceutical residues in the environment FDA has human preclinical and clinical data that should be useful for determining safety of pharmaceuticals in water The FDA has extensive risk assessment experience in setting safe concentrations for ‘microconstituents’ in foods and beverages The ADI approach is internationally recognized and can be used in risk assessments for pharmaceuticals in drinking water For a limited number of high risk products, product labeling includes specific drug disposal methods designed to improve risk/benefit balance FDA promotes the safe disposal methods as described in the Federal Drug Disposal Guidelines

34. Thank You Charles E. Eirkson III FDA, CVM , Environmental Safety Team 240-276-8173 charles.eirkson@fda.hhs.gov Acknowledge: Suzanne Fitzpatrick, Ph.D. FDA, Office of the Commissioner Ranaan Bloom, Ph.D. andEmily A. McVey, Ph.D. FDA, CDER, Office of Pharmaceutical Science