1. Environmental Assessment for Pharmaceuticals - Environmental Assessment for Pharmaceuticals - FDA Perspective Charles E. Eirkson III Center for Veterinary Medicine U.S. Food and Drug Administration NCAC SOT: Emerging Issues in Water Contamination April 15, 2010

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

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

4. Statutes & Regulations Primary Statutory authorities Food, Drug, & Cosmetic Act of 1938 Food, Drug, & Cosmetic Act of 1938 Public Health Service Act of 1944 Public Health Service Act of 1944 Supplemental authority National Environmental Policy Act (NEPA) of 1969 National Environmental Policy Act (NEPA) of 1969 Regulatory responsibilities Title 21 Code of Federal Regulations 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 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 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 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 dischargesEstimate based on high-end projected sales and worse-case, end-of-pipe effluent discharges Based upon retrospective analysis of EAsBased upon retrospective analysis of EAs

9. Categorical Exclusion con’t Veterinary approvals non-food animals non-food animals Rx drugs for therapeutic use in terrestrial species 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 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 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), New Drug Application (NDA), Biologics License Application (BLA), Biologics License Application (BLA), New Animal Drug Application (NADA) New Animal Drug Application (NADA) Device Pre-Market Approval (PMA) Device Pre-Market Approval (PMA) Action on: Investigational New Drug Application (IND) Investigational New Drug Application (IND) Investigational New Animal Drug Application (INAD) Investigational New Animal Drug Application (INAD) Investigational Device Exemption (IDE) Investigational Device Exemption (IDE) * Unless Excluded by 21 CFR 25.31

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

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

14. EA Availability Most actions are categorically excluded published in the Federal Register published in the Federal Register Many actions have EAs published in the Federal Register published in the Federal Register public display/available in FDA Document Management Branch public display/available in FDA Document Management Branch 113 + EAs for new animal drugs and feed additives on line at: 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 = Hazard x Exposure Current and Future Environmental Assessments Risk = exposure to a chance of loss (or of losing something we value)

17. EA Focus Ecosystem protection Ecosystem protection Laboratory studies on invertebrates, fish, plants at different trophic levels Laboratory studies on invertebrates, fish, plants at different trophic levels Measurement endpoints: mortality, immobilization, reproduction, growth, functional responses Measurement endpoints: mortality, immobilization, reproduction, growth, functional responses Biogeochemical cycling (nitrogen, carbon transformation) 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/GuidanceCompliance RegulatoryInformation/Guidances/ucm070561.pdf http://www.fda.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/ucm070561.pdf http://www.fda.gov/downloads/Drugs/GuidanceCompliance RegulatoryInformation/Guidances/ucm070561.pdf CVM guidance Environmental Impact Assessment for Veterinary Medicinal Products (VMP) Phase I (Sept. 1998) http://www.fda.gov/downloads/AnimalVeterinary/Guidance ComplianceEnforcement/GuidanceforIndustry/UCM052424. pdf Phase II (January 2006) http://www.fda.gov/downloads/AnimalVeterinary/Guidance ComplianceEnforcement/GuidanceforIndustry/UCM052500. pdf

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

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

22. Base Set Data Requirements Physical-chemical studies - Water Solubility - Dissociation Constant - UV-Visible Absorption Spectrum - Melting Temperature - Vapour Pressure - Octanol/Water Partition 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. Surface water EndpointAF algae (96 h) EC50100 algae (96 h) EC50100 invertebrate (48 h) EC501000 invertebrate (48 h) EC501000 fish (96 h) LC501000 fish (96 h) LC501000 Veterinary TIER A Assessment Soil earthworm (chronic)NOEC10 earthworm (chronic)NOEC10 higher plants (3 species)EC50100 higher plants (3 species)EC50100 micro-organisms (28 days)< 25% of control micro-organisms (28 days)< 25% of control Dung (pasture animals) dung fly EC50100 dung fly EC50100 dung beetle EC50100 dung beetle EC50100

24. Surface waterEndpointAF algae (96 h)NOEC10 algae (96 h)NOEC10 invertebrate (21 d)NOEC 10 invertebrate (21 d)NOEC 10 fish (28 d)NOEC 10 fish (28 d)NOEC 10 sediment species (varies)NOEC10 sediment species (varies)NOEC10Soil earthworm no recommendation earthworm no recommendation higher plants (more species) NOEC10 higher plants (more species) NOEC10 micro-organisms (100 days)< 25% of control micro-organisms (100 days)< 25% of controlBioaccumulation BCF > 1000 l/kg  investigate secondary poisoning BCF > 1000 l/kg  investigate secondary poisoning Veterinary TIER B Assessment

25. Veterinary TIER C Assessment Refined Risk Analysis Specialized environmental fate modeling Specialized environmental fate modeling Probabilistic exposure analyses Probabilistic exposure analyses Specialized Laboratory and/or Field Testing Pulsed exposure studies Pulsed exposure studies Microcosm and mesocosm studies Microcosm and mesocosm studies In-stream studies In-stream studies Risk Management Use restrictionsUse restrictions Mandatory treatment requirementsMandatory treatment requirements Effluent discharge limitsEffluent 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) 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) Effluent treatment stipulated on the drug product label (e.g., settling ponds, activated carbon) “No discharge” to surface waters “No discharge” to surface waters Water quality benchmark development and reporting Water quality benchmark development and reporting

27. Possible Data for Application to Human Exposure Possible Data for Application to Human Exposure

28. Human Drug Development Nonclinical Data Collected Safety Pharmacology Safety Pharmacology Toxicokinetics and Pharmacokinetics Toxicokinetics and Pharmacokinetics Repeated Dose Toxicity Repeated Dose Toxicity Genotoxicity (in vitro; in vivo) Genotoxicity (in vitro; in vivo) Carcinogenicity Carcinogenicity Reproductive and Developmental Toxicology Reproductive and Developmental Toxicology Immunotoxicity Immunotoxicity Other Studies: Other Studies: Phototoxicity, antigenicity, juvenile animal toxicity, mechanistic studies, studies on metabolites and impuritiesPhototoxicity, 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:Characterize potential toxic effects prior to clinical studies: Pediatric Patients Pediatric Patients Peri- and Postnatal Population Peri- and Postnatal Population Pregnant Women/Women of Childbearing Age Pregnant Women/Women of Childbearing Age Estimate the maximum recommended starting dose (MRSD) and dose range for first-in-human clinical trials.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.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 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 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 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 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 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 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 240-276-8173charles.eirkson@fda.hhs.govAcknowledge: Suzanne Fitzpatrick, Ph.D. FDA, Office of the Commissioner Ranaan Bloom, Ph.D. and Emily A. McVey, Ph.D. FDA, CDER, Office of Pharmaceutical Science