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
Topics

Legal

Regulatory

Science

Risk Management

Wrap-up/summary
Agency’s Roles and Priorities
Primary Federal agency for regulating
pharmaceuticals and personal care
products
 Foods
 Human Drugs
 Animal Drugs
 Cosmetics
 Medical Devices
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
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
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
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
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
Categorical Exclusion con’t
Veterinary approvals


non-food animals
Rx drugs for therapeutic use in
terrestrial species
Extraordinary circumstances
trump a claim of categorical
exclusion.
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
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
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)
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
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
FDA Scenarios
Current and Future
Environmental Assessments
Risk = exposure to a
chance of loss
(or of losing something
we value)
Risk = Hazard x Exposure
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)
Guidance
CDER guidance
Environmental Assessment of Human Drug and Biologics
Applications (July 1998)
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
Figure 1
Tiered Approach to Fate and Effects Testing
D e te r min e e n v ir o n me n ts o f Po te n tia l C o n c e r n
Atmo s p h e r ic , Aq u a tic a n d /o r Te r r e s tr ia l
r a p id
In v e s tig a te D e p le tio n
Me c h a n is m( s )
Mic r o b ia l
In h ib itio n Te s t
c o mp le te
STO P
N o r a p id , c o mp le te
d e p le tio n me c h a n is m
Mic r o b ia l
In h ib itio n Te s t
L o g Kow > 3 .5 C O N SID ERin itia tin g
c h r o n ic to x ic ity te s tin g
Tie r 3
L o g Kow <3 .5 o r L o g K
ow > 3 .5 w ith ju s tific a tio n
N o O b s e r v e d Effe c ts
a t MEEC
TIER 1
Ac u te To x ic ity
1 s p e c ie s
L C o r EC
50
50
> 1000
50
MEEC
L C o r EC
STO P
< 1000
O b s e r v e d Effe c ts
a t MEEC
Tie r 3
N o O b s e r v e d Effe c ts
a t MEEC
STO P
50
MEEC
TIER 2
Ac u te To x ic ity
Ba s e Se t
Aq u a tic &/o r
Te r r e s tr ia l
L C o r EC
50
MEEC
L C o r EC
50
50
> 100
O b s e r v e d Effe c ts
a t MEEC
Tie r 3
< 100
50
MEEC
TIER 3
C h r o n ic To x ic ity
Aq u a tic &/o r
Te r r e s tr ia l
L C o r EC
50
50
L C o r EC
50
MEEC
50
> 1 0 & N o o b s e r v e d Effe c ts
a t MEEC
< 1 0 o r O b s e r v e d Effe c ts
a t MEEC
MEEC
C o n s u lt C D ER
N ot e : MEEC = EEC or EIC w hic he v e r is gre a t e r
STO P
Veterinary Phase I Guidance

harmonized - EU, Japan, US, Australia

legal and exposure criteria

exempt from full risk analysis

extensive in vivo metabolism


aquatic introduction concentration
< 1 g/L
terrestrial introduction concentration
< 100 g/Kg
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
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
Terrestrial effect studies
- Algae
- Daphnia
- Fish
- Micro-organisms
- Terrestrial plants
- Earthworm
Veterinary TIER A Assessment
Surface water
• algae (96 h)
• invertebrate (48 h)
• fish (96 h)
Endpoint
EC50
EC50
LC50
AF
100
1000
1000
Soil
• earthworm (chronic)
• higher plants (3 species)
• micro-organisms (28 days)
NOEC
10
EC50
100
< 25% of control
Dung (pasture animals)
• dung fly
• dung beetle
EC50
EC50
100
100
Veterinary TIER B Assessment
Surface water
• algae (96 h)
• invertebrate (21 d)
• fish (28 d)
• sediment species (varies)
Endpoint
NOEC
NOEC
NOEC
NOEC
AF
10
10
10
10
Soil
• earthworm
• higher plants (more species)
• micro-organisms (100 days)
no recommendation
NOEC
10
< 25% of control
Bioaccumulation
• BCF > 1000 l/kg  investigate secondary poisoning
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
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

Possible Data for Application to
Human Exposure
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
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
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
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
Safe Disposal of Medicines
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
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. and Emily A. McVey, Ph.D.
FDA, CDER, Office of Pharmaceutical Science