Guidance for Industry
Environmental Assessment of Human
Drug and Biologics Applications
 
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
July 1998
CMC 6
Revision 1 Guidance for Industry
Environmental Assessment of Human
Drug and Biologics Applications
Copies of this guidance are available from the Office of Training and Communications,
Division of Communications Management, Drug Information Branch, HFD-210, 5600 Fishers
Lane, Rockville, MD  20857 (Phone 301-827-4573) or from the Internet at
http://www.fda.gov/cder/guidance/index.htm.
Copies also are available from the Office of Communication, Training and Manufacturers
Assistance, HFM-40, CBER, FDA, 1401 Rockville Pike, Rockville, MD 20852-1448, or from the
Internet at http://www.fda.gov/cber/guidelines.htm.  Copies also may be obtained by fax from 1-
888-CBERFAX or 301-827-3844 or from Voice Information at 800-835-4709 or 301-827-1800.
  
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Center for Biologics Evaluation and Research (CBER)
July 1998
CMC 6
Revision 1 TABLE OF CONTENTS
I. INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
II. WHAT TYPES OF ACTIONS ARE SUBJECT TO CATEGORICAL
EXCLUSION? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
III. WHEN IS AN EA REQUIRED? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
A. NDAs, Abbreviated Applications, and Supplements . . . . . . . . . . . . . . . . . . . 3
B. Applications for Substances that Occur Naturally in the Environment . . . . 5
C. Extraordinary Circumstances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
IV. PREPARING AN EA FOR SUBMISSION TO CDER or CBER . . . . . . . . . . . . . . . 9
A. Content and Format . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
B. Specific Guidance  Environmental Issues . . . . . . . . . . . . . . . . . . . . . . . . . 13
C. Data Summary Table . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
D. Test Methods and Report Formats . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 26
E. Confidential and Nonconfidential Information . . . . . . . . . . . . . . . . . . . . . . . 26
F. Master Files for Drugs and Biologics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 28
ATTACHMENT A:  NO INCREASED USE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
ATTACHMENT B:  INCREASED USE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 30
ATTACHMENT C:  40 CFR 1508.27 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
ATTACHMENT D:  EA FORMAT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32
ATTACHMENT E:  SAMPLE DATA SUMMARY TABLE . . . . . . . . . . . . . . . . . . . . . . . 33
ATTACHMENT F:  CONFIDENTIAL/NONCONFIDENTIAL . . . . . . . . . . . . . . . . . . . . 34
ATTACHMENT G:  GLOSSARY OF TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
i GUIDANCE FOR INDUSTRY1 
Environmental Assessment of Human Drug 
and Biologics Applications
I. INTRODUCTION
The National Environmental Policy Act of 1969 (NEPA) requires all Federal agencies to assess
the environmental impacts of their actions and to ensure that the interested and affected public is
informed of environmental analyses.  The Food and Drug Administration (FDA) is required under
NEPA to consider the environmental impacts of approving drug and biologics applications as an
integral part of its regulatory process.  FDA's regulations in 21 CFR part 25 specify that
environmental assessments (EAs) must be submitted as part of certain new drug applications
(NDAs), abbreviated applications, applications for marketing approval of a biologic product,
supplements to such applications, investigational new drug applications (INDs) and for various
other actions (see 21 CFR 25.20), unless the action qualifies for categorical exclusion.  
Under the President's reinventing government (REGO) initiatives, announced in April 1995, FDA
reevaluated and revised its environmental regulations to reduce the number of EAs required to be
submitted by industry and, consequently, the number of findings of no significant impact
(FONSIs) prepared by the Agency under NEPA.  FDA issued for public comment a notice of
proposed rulemaking on April 3, 1996 (61 FR 14922) (republished May 1, 1996 (61 FR 19476)),
that proposed additional categorical exclusions for those actions that have been identified as
normally not having a significant effect, individually or cumulatively, on the quality of the human
environment.   The final rule was published on July 29, 1997 (62 FR 40569), and became effective
August 28, 1997.  All applications or petitions requesting Agency action (e.g., NDAs, abbreviated
new drug applications (ANDAs), INDs, biologics license applications (BLAs), supplements to
such applications) must be accompanied by either an EA or a claim of categorical exclusion. 
Failure to provide (1) a claim of categorical exclusion or (2) an adequate EA, is sufficient grounds
for refusing to file or approve the application (21 CFR 314.101(d)(4), 601.2(a) and (c), and
25.15(a)).  An EA that is adequate for filing is one that addresses the relevant environmental
issues.  An EA adequate for approval is one that contains sufficient information to enable the
Agency to determine whether the proposed action may affect significantly the quality of the
human environment.  This guidance provides information on when an EA should be submitted; it
also makes recommendations on how to prepare EAs for submission of drug or biologics
applications to the Center for Drug Evaluation and Research (CDER) and the Center for
     1 This guidance has been prepared under the direction of the Chemistry Manufacturing Controls Coordinating
Committee, Center for Drug Evaluation and Research (CDER), and the Center for Biologics Evaluation and Research
(CBER) at the Food and Drug Administration.  This guidance represents the Agency's current thinking on environmental
assessments.  It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. 
An alternative approach may be used if such approach satisfies the requirements of the applicable statute, regulations, or
both. Biologics Evaluation and Research (CBER).  Topics covered include (1) when categorical
exclusions apply, (2) when to submit an EA, (3) the content and format of EAs, (4) specific
guidance for the environmental issues that are most likely to be associated with human drugs and
biologics, (5) test methods, (6) an applicant's treatment of confidential information submitted in
support of an EA, and (7) master files for drugs and biologics.
This guidance, which is based on the July 1997 final rule, will remain in effect until superseded by
new regulations or new guidance.  The guidance is intended to supersede CDER's Guidance for
Industry For the Submission of an Environmental Assessment in Human Drug Applications and
Supplements, which was published in November 1995.  Information in this guidance, along with
information in the Code of Federal Regulations (CFR) at 21 CFR part 25 and 40 CFR parts 1500-
1508 and the FDA Environmental Assessment Technical Handbook (NTIS Publication Number
PB 87 175345/AS), which provides information on acceptable test methods, represents the core
information available from CDER and CBER to assist industry in preparing an EA.
    
II. WHAT TYPES OF ACTIONS ARE SUBJECT TO CATEGORICAL
EXCLUSION?
Certain classes of actions are subject to categorical exclusion and, therefore, ordinarily do not
require the preparation of an EA because, as a class, these actions, individually or cumulatively,
do not significantly affect the quality of the human environment (21 CFR 25.5(c)).  However, as
required under 21 CFR 25.21 and 40 CFR 1508.4, FDA will require "at least an EA" for any
specific action that ordinarily would be excluded if extraordinary circumstances indicate that the
specific proposed action may significantly affect the quality of the human environment.2   See
section III.C for additional information regarding extraordinary circumstances.
Submissions to CDER or CBER that ordinarily are excluded categorically under the regulations
include actions on (1) NDAs, abbreviated applications, applications for marketing approval of a
biologic product, and supplements to such applications if FDA's approval of the application does
not increase the use of the active moiety; (2) NDAs, abbreviated applications, and supplements to
such applications if FDA's approval of the application increases the use of the active moiety, but
the estimated concentration of the substance at the point of entry into the aquatic environment
will be below 1 part per billion (ppb); (3) NDAs, abbreviated applications, applications for
marketing approval of a biologic product, and supplements to such applications for substances
that occur naturally in the environment when the approval of the application does not alter
significantly the concentration or distribution of the substance, its metabolites, or degradation
products in the environment; (4) INDs; and (5) applications for marketing approval of a biologic
product for transfusable human blood or blood components and plasma.  An applicant is eligible
2 Regulations would require an EIS (environmental impact statement)  when "evaluation of data or information
in an EA or otherwise available to the agency leads to a finding by the responsible agency official that a proposed action
may significantly affect the quality of the human environment (21 CFR 25.22(b)).
2 to file a claim of categorical exclusion from the requirement to submit an EA if the action meets
the criteria of at least one categorical exclusion.  
A person submitting an application or petition of a type subject to categorical exclusion under 21
CFR 25.31 is not required to submit an EA if the person states that the action requested qualifies
for categorical exclusion, citing the particular categorical exclusion that is claimed, and states that
to the applicants knowledge, no extraordinary circumstances exist (21 CFR 25.15(d)).  An
applicant ordinarily need not provide data to demonstrate that the action qualifies for categorical
exclusion.  CDER and CBER can rely on other information submitted in an application to
evaluate the appropriateness of a claim for categorical exclusion.  In the limited instances when it
may be necessary, CDER or CBER will request additional information as needed to establish to
their satisfaction that the criteria for categorical exclusion have been met.
III. WHEN IS AN EA REQUIRED?
Preparation of an environmental assessment ordinarily is required unless the proposed action
qualifies for an exclusion under 21 CFR 25.30 or 25.31.  An EA would also be required if
extraordinary circumstances indicate that the specific proposed action may significantly affect the
quality of the human environment (21 CFR 25.21).  
Detailed information is provided below for the most common situations when actions would not
qualify for categorical exclusion. 
A. NDAs, Abbreviated Applications, and Supplements
Note: Section 1, below, should be used to assess increased use of a biological product as
referenced in 21 CFR 25.31(a).  Section 2 does not apply to biologics license applications
(BLAs) because BLAs are not included in the categorical exclusion on which this section
is based (21 CFR 25.31(b)).  BLAs should be evaluated for whether they are eligible for
categorical exclusion using 21 CFR 25.31(a) or (c) or other appropriate categorical
exclusions found in 21 CFR 25.30 and 25.31. 
NDAs, abbreviated applications, and supplements to such applications would not qualify
for categorical exclusion if FDA's approval of the application increases the use of the
active moiety and the estimated concentration of the substance at the point of entry into
the aquatic environment will be 1 ppb or greater. 
1. Increased Use
Increased use of an active moiety may occur if the drug will be administered at
higher dosage levels, for longer duration, or for different indications than were
previously in effect, or if the drug is a new molecular entity.   The term use also
encompasses disposal of FDA-regulated articles by consumers.  
3 Attachment A contains examples of actions that would not be considered to
increase the use of a drug and Attachment B contains examples of actions that
would be considered to increase the use of a drug or biologic.  These lists are not
inclusive.  An applicant is encouraged to contact the appropriate Center if  any
questions arise as to whether a particular action is considered to increase the use of
a drug or biologic.  
2. Estimating the Concentration of a Substance at the Point of Entry into the
Aquatic Environment
The expected introduction concentration (EIC) of an active moiety into the aquatic
environment should be calculated as follows:
EIC-Aquatic (ppb) = A x B x C x D  where
A = kg/year produced for direct use (as active moiety)
B = 1/liters per day entering POTWs*
C = year/365 days
D = 109 g/kg (conversion factor)
* 1.214 x 1011 liters per day entering publicly owned treatment works (POTWs),
Source: 1996 Needs Survey, Report to Congress.  Information regarding the Needs
Survey is available on the Internet at http://www.epa.gov/owm.  It is updated
periodically.
This calculation assumes:
! All drug products produced in a year are used and enter the publicly owned
treatment works (POTW) system.
! Drug product usage occurs throughout the United States in proportion to
the population and amount of waste water generated.
! There is no metabolism. 
 
The estimate of the kilogram/year active moiety should be based on or include (1)
the highest quantity of the active moiety expected to be produced for direct use in
any of the next five years.  Produced for direct use means the quantity intended for
use in humans during a given year (i.e., excludes any quantity produced for
inventory buildup), (2) the quantity used in all dosage forms and strengths included
in the application, and (3) the quantity used in an applicant's related applications. 
Related applications include those for other dosage forms using the same active
moiety and for products using different forms of the active moiety (e.g., level of
hydration, salt, free acid/base).  All concentrations should be reported as the
4 concentration of active moiety, rather than the salt or complex.
 
  The calculation of the expected introduction concentration (EIC) of an active
moiety entering into the aquatic environment from patient use can consider the
extent of metabolism of the active moiety to less pharmacologically active or
inactive compounds, if that information is available.  The pharmacological activity
of metabolites relative to the active moiety should be considered when calculating
the EIC.  The weighted contribution of the metabolite to the EIC should be
calculated (e.g., kg/year active moiety x 10% x 0.5 for a metabolite found at a 
level of 10% and that has half the pharmacological activity of the active moiety). 
If the pharmacological activity of the metabolite is unknown, it can be assumed to
be the same as the active moiety. 
An alternative calculation should be used if the drug product is intended for use in
a specific geographic location (e.g., use an alternative value for the amount of
liters per day entering POTWs  term B in the EIC calculation above).  
Moreover, if an alternative calculation is used to estimate localized use, or for any
other reason, the calculation and the source and basis for the alternative calculation
should be provided when filing an EA or a claim of categorical exclusion and
would be subject to review.
 
B. Applications for Substances that Occur Naturally in the Environment
NDAs, abbreviated applications, applications for marketing approval of a biologic product
and supplements to such applications for substances that occur naturally in the
environment would not qualify for categorical exclusion under 21 CFR 25.31(c) when
FDA's approval of the application alters significantly the concentration or distribution of
the substance, its metabolites, or degradation products in the environment.  This might be
the case when the use and disposal occur in a geographic area where the substance does
not naturally occur.  However, the application may be eligible for a categorical exclusion
under other provisions in 21 CFR 25.31.
In addition to drug and biologic products derived from natural sources or from biological
systems, substances can be considered naturally occurring even if they are chemically
synthesized.  The Agency will consider the form in which the FDA-regulated article will
exist in the environment when determining whether the drug or biologic is a naturally
occurring substance.  For example, a modified active moiety (e.g., salt) that does not
occur naturally could be considered a naturally occurring substance if it is established that,
in vivo and in the environment, the active moiety exists in a form that is found naturally. 
Biological and biotechnological products will be similarly evaluated.  For example, a
protein or DNA comprising naturally occurring amino acids or nucleosides, but having a
sequence different from that of a naturally occurring substance, will normally qualify as a
5 naturally occurring substance after consideration of metabolism.  The same principle
would apply to synthetic peptides and oligonucleotides and living and dead cells and
organisms.  CDER and CBER may rely on other information submitted in an application
(e.g., information about metabolism, excretion, and stability; viability (if applicable); and
physical and/or chemical characteristics of the product) in determining whether the FDA-
regulated article would be considered a naturally occurring substance.
CDER and CBER will evaluate on a case-by-case basis the appropriateness of categorical
exclusions claiming that the quantity of the naturally occurring substance that is expected
to enter the environment as a result of an action will not alter significantly the
concentration or distribution of the substance, its metabolites, or degradation products in
the environment.
C. Extraordinary Circumstances
As stated in 21 CFR 25.21 and 40 CFR 1508.4, FDA will require at least an EA for any
specific action that ordinarily would be categorically excluded if extraordinary
circumstances indicate that the specific proposed action could significantly affect the
quality of the human environment.  Extraordinary circumstance can be shown by data
available either to the Agency or the applicant and can be based on the production, use, or
disposal from use of the FDA-regulated article.  Data available to the Agency can include
public information, information submitted in the application, and data available to the
Agency on the same or similar products.
1. Actions for which available data establish that there is a potential for
serious harm to the environment at the expected level of exposure.
FDA considers harm to the environment to include not only toxicity to
environmental organisms but also environmental effects other than toxicity, such as
lasting effects on ecological community dynamics.
2. Actions that adversely affect a species or the critical habitat of a species
determined under the Endangered Species Act or the Convention on
International Trade in Endangered Species of Wild Fauna and Flora to be
endangered or threatened, or wild fauna or flora that are entitled to special
protection under some other Federal law.
Actions that adversely affect a species or the critical habitat of a species
determined under the Endangered Species Act to be endangered or threatened,
wild fauna or flora listed in the Convention on International Trade in Endangered
Species of Wild Fauna and Flora (CITES), or wild fauna or flora that are entitled
to special protection under some other Federal law or international treaty to which
the United States is a party would be considered an extraordinary circumstance,
and an EA should be submitted unless there are specific exemptions relating to the
6 pharmaceutical substances or FDA action.  An example of an exception would be
when a species is afforded special protection under Federal law or international
treaty, but the pharmaceutical is derived only from nonwild specimens. If nonwild
specimens are exempted from Federal law or treaty, the action would be eligible
for categorical exclusion as indicated in section III.C.3.a.  Both direct effects (e.g.,
pharmaceuticals derived from fauna or flora, see section III.C.3) and indirect
effects (e.g., adverse effects from manufacturing site emissions) should be
considered.
Under the U.S. Endangered Species Act (ESA), Congress declared, "[T]he United
States has pledged itself as a sovereign state in the international community to
conserve to the extent practicable the various species of fish or wildlife and plants
facing extinction, pursuant to the Convention on International Trade in
Endangered Species of Wild Fauna and Flora" (16 U.S.C. 1531(a)(4)(F)). 
Identification as an endangered or threatened species does not preclude the use of
such fauna or flora.  However, under the ESA, if a species has been determined to
be endangered or threatened, a Federal agency is required to consult with the
Secretary of Interior or the Secretary of  Commerce to ensure that the agency's
actions are not likely to jeopardize the continued existence of  endangered or
threatened species or their critical habitats (16 U.S.C. 1536).  
3. Use of Fauna or Flora
FDA intends to examine closely the proposed actions for FDA-regulated articles
obtained from fauna and flora and will use the extraordinary circumstances
provision to require an EA in any instance in which it appears from an examination
of the proposed action that the action may jeopardize the continued existence of a
species.  The following sections discuss CDER's  and CBER's current position on
when the use of fauna or flora normally would constitute an extraordinary
circumstance for which an EA should be submitted to support the application.3
a.  Cultivated Specimens
Actions involving drug or biologic products derived from cultivated plants
(e.g., plantation, nursery stock) or bred or domestic animals (e.g.,
laboratory breed, cows, pigs) are not normally considered an extraordinary
circumstance that would require an EA for an action that is normally
categorically excluded (see section III.C.2 for a possible exception).
b. Wild Specimens
3 FDA may clarify the environmental information that must be submitted to the Agency in marketing
applications for specific drug or biologic products derived from plants or animals (e.g., paclitaxel, 61 FR 58694).
7 i. NDAs, abbreviated applications, applications for marketing
approval of a biologic product, or certain supplements to
such applications.
NDAs, abbreviated applications and applications for marketing
approval of a biologic product where the drug or biologic product
is derived from plants or animals taken from the wild, supplements
to such applications that relate to changes in the source of the wild
biomass (e.g., species, geographic region where biomass is
obtained), or supplements to such applications that are considered
to increase the use of an active moiety or biologic substance (see
Attachment B) and which will cause more harvesting than what was
described in the original EA would be considered an extraordinary
circumstance, and an EA should be submitted.
ii. INDs
INDs generally involve relatively small quantities of a drug or
biologic product and treatment of a limited number of patients. 
Many INDs never result in the filing of an NDA or application for
marketing approval of a biologic product, which would allow for
the wide-spread commercial sale of the product.  CDER and CBER
will evaluate INDs on a case-by-case basis where the drug or
biologic product is derived from wild plants or animals to determine
whether the extraordinary circumstance provision in 21 CFR 25.21
is invoked.  
To facilitate Center review, when submitting a claim of categorical
exclusion for actions where the drug or biologic product is derived from
plants or animals, CDER and CBER request that the applicant provide the
following information with the claim, or specifically identify where the
information can be located (e.g., page number of application):  (1)
biological identification (i.e., common names, synonyms, variety, species,
genus and family); (2) a statement as to whether wild or cultivated
specimens are used; (3) the geographic region (e.g., country, state,
province) where the biomass is obtained; and (4) a statement indicating
whether the species is (a) determined under the Endangered Species Act or
the Convention on International Trade in Endangered Species of Wild
Fauna and Flora (CITES) to be endangered or threatened, (b) entitled to
special protection under some other Federal law or international treaty to
which the United States is a party, or (c) the critical habitat of a species
that has been determined to be endangered or threatened under the
Endangered Species Act or the Convention on International Trade in
Endangered Species of Wild Fauna and Flora (CITES) or is entitled to
8 special protection under some other Federal law or international treaty to
which the United States is a party.  CDER and CBER will use this
information to evaluate whether the claim of categorical exclusion is
appropriate.
4. Production and Disposal Sites
FDA has found that regulated articles produced and disposed of in compliance
with all applicable emission requirements do not significantly affect the
environment and has determined it is unnecessary to review a company's
compliance with Federal, State, and local environmental laws.  In addition, both
CDER and CBER routinely require as part of their safety evaluations that live
organisms be inactivated following production and prior to release into the
environment if there is a reasonable possibility that the living system may be
harmful to the environment.  Therefore, CDER and CBER will not routinely
request submission of manufacturing and disposal information in an EA.  
However, if information available to the Agency or the applicant establishes that
the general or specific emission requirements promulgated by Federal, State, or
local environmental protection agencies do not address unique emission
circumstances and the emissions may harm the environment, this would be
sufficient grounds for requesting manufacturing or disposal information in an EA. 
Actions that threaten a violation of Federal, State, or local law or requirements
imposed for the protection of the environment may constitute a significant impact
(40 CFR 1508.27(b)(10)). 
5. Significant Effects as Defined in 40 CFR 1508.27
The Council on Environmental Quality has provided a definition of "significantly"
to aid in determining if an action may significantly affect the quality of the human
environment.  These examples should be considered when evaluating whether
extraordinary circumstances exist that may warrant submission of at least an EA
(See Attachment C).
IV. PREPARING AN EA FOR SUBMISSION TO CDER or CBER
A. Content and Format
This section describes the basic information that should be submitted in an EA if an EA is
required.  Attachment D contains an outline of the format for an EA.  Alternative formats
may be used, but the applicant should recognize that use of a standard format, such as
described in this guidance, promotes efficiency in the review process. 
1. Date
9 The EA should include the date the EA was originally prepared and the date(s) of
any subsequent amendments.
2. Name of Applicant or Petitioner
The EA should identify the applicant who is submitting the application.
3. Address
The EA should contain the address where all correspondence is to be directed.
 
4. Description of Proposed Action
a. Requested Approval
The description of the requested approval should include the drug or
biologic application number (if available), the drug or biologic product
name, the dosage form and strength, and a brief description of the product
packaging.  For example, "XYZ Pharmaceuticals has filed an NDA
pursuant to section 505(b) of the Federal Food, Drug, and Cosmetic Act
for TRADE NAME (established name), 250 mg and 500 mg, packaged in
OHDPE bottles.  An EA has been submitted pursuant to 21 CFR part 25."
b. Need for Action
The EA should briefly describe the drug's or biologic's intended uses in the
diagnosis, cure, mitigation, treatment, or prevention of disease.
c. Locations of Use
The EA should identify the location(s) where the product will be used. 
Depending on the type of product and its use, the locations of use are
typically identified as hospitals, clinics and/or patients in their homes.  If
use is expected to be concentrated in a particular geographic region, this
fact should be included.
d. Disposal Sites
Unless other disposal methods by the end user are anticipated, it is
sufficient to state that at U.S. hospitals, pharmacies, or clinics, empty or
partially empty packages will be disposed of according to hospital,
pharmacy, or clinic procedures and/or that in the home, empty or partially
empty containers will typically be disposed of by a community's solid waste
management system, which may include landfills, incineration, and
10 recycling, although minimal quantities of the unused drug could be
disposed of in the sewer system.
5. Identification of Substances that are the Subject the Proposed Action
The EA should contain information that allows for the accurate location of data 
about the substance in the scientific literature and for identification of closely
related compounds.  At a minimum, the information listed below should be
provided, if available.  For many biological products, format items 5.a.iii, b, c, and
d will not apply.  Other information, such as the international nonproprietary name
(INN) or nonsystematic or semisystematic chemical names should be included if
deemed useful in the identification of the compounds.  
Usually this information need only be provided for the drug or biologic substance,
but the same information also should be provided for the form of the active
ingredient in the drug or biologic product if it is different from the drug or biologic
substance (e.g., a salt formed in situ from a free base) or for a pharmacologically
active related substance formed by conversion from a pharmacologically inactive
parent compound (e.g., a prodrug product is converted to the pharmacologically
active form).
a. Nomenclature
  i. Established Name (U.S. Adopted Name-USAN)
ii. Brand/Proprietary Name/Tradename
iii. Chemical Names or Genus/Species of Biologic Product
(e.g., virus)
! Chemical Abstracts (CA) Index Name (inverted
form)
! Systematic Chemical Name (uninverted form) 
b. Chemical Abstracts Service (CAS) registration number
c. Molecular Formula
d. Molecular Weight
e. Structural (graphic) Formula/Amino Acid Sequence
6. Environmental Issues
11 The type of information provided will vary depending on the environmental issues
associated with the particular action.  In general, the EA should include a succinct
description of the environmental issues.  The affected environment and the
environmental effects and their significance should be discussed.  Data and
analyses to support the discussions should be provided as appropriate.  Specific
guidance is provided in section IV.B for the environmental issues that are most
likely to be associated with human drugs and biologics.  For environmental issues
not specifically addressed in section IV.B (e.g., those included in sections III.C.4
and 5), applicants are encouraged to consult the appropriate Center prior to
preparing the EA.  
7. Mitigation Measures
Describe measures taken to avoid or mitigate any potential adverse environmental
effects associated with the proposed action.  If no adverse environmental effects
have been identified, it should be so stated and indicated that, therefore, no
mitigation measures are needed.  See section IV.B.2.b for additional information
regarding the discussion of mitigation measures for actions involving fauna and
flora.
8. Alternatives to the Proposed Action
If no potential adverse environmental effects have been identified for the proposed
action, the EA should state this.  If potential adverse environmental effects have
been identified for the proposed action, the EA "shall discuss any reasonable
alternative course of action that offers less environmental risk or that is
environmentally preferable to the proposed actions" (21 CFR 25.40(a)).  The
discussion should include the no-action alternative and measures that FDA or
another government agency could undertake as well as those the applicant or
petitioner would undertake.  The EA should include a description of those
alternatives that will enhance the quality of the environment and avoid some or all
of the adverse environmental effects of the proposed action.  The environmental
benefits and risks of the proposed action and the environmental benefits and risks
of each alternative should be discussed.  See section IV.B.2.c for additional
information regarding the discussion of alternatives for actions involving fauna and
flora.  
9. List of Preparers
The EA should include the name, job title, and qualifications (e.g., educational
degrees) of those persons preparing the assessment and should identify any persons
or agencies consulted.  Contract testing laboratories should be included in the list
of consultants, although this may be included in a confidential appendix. 
Curriculum vitae can be included in lieu of a description of an individual's
12 qualifications.
  
10. References
The EA should include a list of citations for all referenced material and standard
test methods used in generating data in support of the EA.  Copies of referenced
articles that are not generally available and that are used to support specific claims
in the EA document should be attached in a nonconfidential appendix.  
11. Appendices
Both confidential and nonconfidential appendices can be included.  See section
IV.E for additional information about the treatment of confidential information.  A
list of the appendices should be included in the EA summary document with a
designation of confidential or nonconfidential following each of the listings. 
Typically, the nonconfidential appendices include data summary tables and copies
of referenced articles that are generally unavailable or that were used to support 
specific claims in the EA.  Proprietary or confidential information, such as use
estimates and test reports, should be included in the confidential appendices.
B. Specific Guidance  Environmental Issues
1. Assessing Toxicity to Environmental Organisms
If an EA is required, it normally should focus on characterizing the fate and effects
of the compound of interest in the environment (1) when FDA's approval of the
application increases the use of an active moiety and the estimated concentration
of the active moiety at the point of entry into the aquatic environment is 1 ppb or
greater (see section III.A); (2) when the substance occurs naturally in the
environment and FDA's approval of the application alters significantly the
concentration or distribution of the substance, its metabolites, or degradation
products in the environment (see section III.B); or (3) in some cases, when data
available to the Agency or applicant establish that at the expected level of
exposure, there is the potential for serious harm to the environment (see section
III.C.1).  The provided information should focus on the fate and effects of the
active moiety and/or structurally related substances (SRSs), rather than on
excipients, for example.
The Centers encourage the use of a logical, tiered approach to testing so that
adequate information is available to assess the potential environmental fate and
effects of pharmaceuticals while minimizing the cost to industry.  Figure 1 provides
an illustration of a tiered approach.  Alternative, scientifically justified approaches
also can be used.
13 Figure 1
Tiered Approach to Fate and Effects Testing
Determine environments of Potential Concern
Atmospheric, Aquatic and/or Terrestrial
rapid
Investigate Depletion Microbial
Mechanism(s) Inhibition Test STOP
complete
No rapid, complete
depletion mechanism
Microbial
Inhibition Test
Log Kow > 3.5 Consider  Initiating Tier 3
Chronic Toxicity Testing
Log Kow <3.5 or Log Kow > 3.5 with justification
No Observed Effects STOP
at MEEC
TIER 1 LC  or EC       > 1000
Acute Toxicity 50 50
1 species MEEC Observed Effects Tier 3
at MEEC
LC  or EC      < 1000
50 50
MEEC
No Observed Effects STOP
TIER 2 at MEEC
Acute Toxicity
Base Set LC  or EC       > 100
50 50
Aquatic &/or MEEC Observed Effects Tier 3
Terrestrial at MEEC
LC  or EC       < 100
50 50
MEEC
TIER 3
STOP
Chronic Toxicity LC  or EC       > 10  & No Observed Effects
Aquatic &/or      5  0          5 0                  at MEEC
MEEC
Terrestrial
LC  or EC      < 10  or Observed Effects
     5  0          5 0                  at MEEC
MEEC
Consult CDER/CBER
Note:  MEEC = EEC or EIC whichever is greater
14 Information submitted for fate and effects can include specific data generated on
the test substance or relevant information on analogous compounds from the
submitter or from peer-reviewed literature as appropriate.  Actual experimental
data regarding base parameters are generally preferable to computer modeling;
however, in some circumstances computer modeling may be appropriate.   FDA
should be consulted if a company believes computer modeling is appropriate and
wishes to use modeling in an EA.
a. Environmental Fate of Released Substances
i. Identification of Substances of Interest
The actual substances that will enter or exist in the environment
(i.e., atmospheric, aquatic, terrestrial) can include the parent
compound (i.e., drug or biologic substance) or SRSs such as the
dissociated parent compound, metabolites, or degradants.  The EA
should list the drug or biologic substance and the predominant
SRSs expected to enter or exist in the environment; provide the
name, chemical structure and CAS number when possible; and
provide a rationale for the decision as to which substance(s) will be
studied.  Predominant SRSs should be considered those greater
than 10 percent of dose. 
In most cases, fate (and effects) information should be provided on
the parent (or active) drug or biologic substance, as representative
of substances entering the environment.  Such information is
relevant to SRSs when the SRSs possess the same fundamental
structure as the parent drug or biologic substance and are
comparably or more polar.  At a minimum, the EA should contain a
discussion of the potential fate and effects of the predominant SRSs
based on their structural differences and/or similarities to the parent
compound (e.g., due to a functional group change, the metabolite
should be more soluble than the parent compound, or the SRS is
more polar).  Computerized structure-activity relationship modeling
programs may be useful in supporting extrapolation of fate and
effects information from the parent (or active) drug or biologic
substance to the SRS.  Relevant available pharmacologic activity
and toxicity information should be provided for the SRSs.  Specific
toxicity-activity information for SRSs may be included in a
confidential appendix.  Additional environmental information on a
predominant SRS may be warranted, following consultation with
the appropriate Center, if the fate of the compound is expected to
differ from the parent compound, or there is an indication that the
15 SRSs effect on the environment would be substantially greater than
from the parent drug or biologic substance.
ii. Physical and Chemical Characterization
The following tests should be conducted to determine if the
compound is most likely to amass predominantly in aquatic,
terrestrial, and/or atmospheric environments:
! Water Solubility
! Dissociation Constant(s)
! Octanol/Water Partition Coefficient
! Vapor Pressure or Henry's Law Constant 
If there is a scientific basis for not performing a test, the
justification should be included in the EA (e.g., water solubility was
not determined because the compound is hydrolytically unstable). 
For a test compound that associates or dissociates in water, water
solubility and the octanol/water partition coefficient may have to be
determined at pH 5 and 9 as well as pH 7.  
The octanol/water partition coefficient (K ) is an indicator of a
ow
nonionized compound's potential to adsorb to the organic fraction
of soil, sediment, or biosolids (i.e., sludge) in addition to being an
indicator of a compound's lipophilicity.  It is not as good a predictor
for inorganic chemicals, metal organic complexes, dissociating,
ionic organic compounds, or compounds with other mitigating
structural features such as molecular size.  Further study of the
sorption and/or desorption properties (K ) of a substance to
oc
biosolids should be considered if log K  is greater than 3 or other
ow
properties indicate that sorption or desorption may occur.
iii. Environmental Depletion Mechanisms
Depletion mechanisms should be investigated to determine if there
is degradation of the compound in the environment(s) of interest.  It
is usually sufficient to provide basic supporting information that
identifies the potential for a compound to be removed from the
environment by a depletion mechanism (e.g., photolysis or
hydrolysis based on information developed for analytical methods
validation or from stability studies).  It is unnecessary to go to
16 extraordinary effort to identify a depletion mechanism once the
typical depletion mechanisms (i.e., hydrolysis, photolysis,
biodegradation) have been investigated or to continue investigating
other potential depletion mechanisms once one has been identified.
If the depletion mechanism is being used to reduce the expected
introduction concentration or to eliminate effects testing, a formal,
detailed analysis of the depletion mechanism should be provided
(e.g., according to a standard test method, rate determination,
analysis of expected exposure time in the environment).
 
Consideration should be given to the nature and extent of the
degradation.  If a rapid, complete depletion mechanism is identified
(degradants are relatively simple, polar by-products), no testing to
determine the environmental effects of the compound should be
performed except for a microbial inhibition test or other appropriate
test to assess the potential for the compound to disrupt waste
treatment processes.  Based on the estimated time prior to emission
from a treatment facility, the following would be considered rapid
depletion mechanisms: 
Hydrolysis t  (pH 5-9): # 24 hours
12
Aerobic Biodegradation t :   # 8 hours
12
Soil Biodegradation t :   # 5 days
12
Direct and indirect photolysis, although significant under laboratory
conditions, may not be as rapid a depletion mechanism in the
environment due to significant variation in light intensity (e.g.,
related to weather, latitude, depth penetration) and duration of
exposure.  Efforts to characterize photolysis as a depletion
mechanism should take these factors into consideration.  
iv. Environmental Concentrations
Expected Introduction Concentration (EIC):  The environmental
introduction concentrations into those environments (i.e., aquatic,
terrestrial, atmospheric) where the substance(s) of interest is most
likely to amass (see section IV.B.1.a.ii) should be estimated.  A
method of calculating the expected introduction concentration of a
substance into the aquatic environment is described in section
III.A.2.  The calculation of the expected introduction concentration
(EIC) entering into the aquatic environment from patient use, in
addition to considering metabolism as described in section III.A.1, 
may include consideration of the environmental depletion
17 mechanisms that occur in the waste treatment process (e.g.,
adsorption, degradation, hydrolysis), if the information is available
(see section IV.B.1.a.iii).
Some drug or biologic substance and/or active moiety may enter
the terrestrial environment when biosolids from waste water
treatment facilities, which contain adsorbed material, are applied to
land.   Application of biosolids to land is subject to regulation by
the Environmental Protection Agency (EPA) or an appropriate
State authority.  Biosolids are generally subjected to some form of
aerobic or anaerobic digestion in the waste treatment facility.  The
EIC for the terrestrial compartment should be estimated if, based on
the available physical or chemical properties of the compound,
significant quantities of the active moiety are expected to adsorb to
biosolids.  The calculation used will depend on the typical
treatment, disposal, and application processes.  Currently,
approximately 6.8 million tons of biosolids (dry basis) are generated
per year with 54 percent of that quantity being applied to land.  The
remaining biosolids are incinerated, landfilled or disposed of by
other means.  Depletion mechanisms (e.g.,  biodegradation,
hydrolysis) that occur in the waste treatment process can be
considered when calculating the EIC for the terrestrial
compartment, if the information is available.  Additional
information regarding land application of biosolids is available from
EPA's Office of Wastewater Management (on the Internet at
http://www.epa.gov/owm/bio.htm).
The concentration expected in the atmospheric compartment need
not be routinely calculated for pharmaceutical products
administered through inhalation because, for the majority of these,
the active moiety or other compound of interest is not released into
the air.  However, the EIC should be considered for products that
are released primarily into the air (e.g., medical gases).  
CDER and CBER have defined use to encompass disposal of FDA-
regulated articles by consumers. Normally, the EIC from disposal
need not be calculated since the majority of pharmaceutical
products will be totally consumed, and any residual waste will
typically be disposed of in landfills or at incineration facilities that
are regulated by the EPA or appropriate State agencies.  These
agencies have considered the environmental impacts from the
operation of these facilities in their licensing process and require
controls (e.g., scrubbers, lined landfills, migration tests) to limit the
release of materials into the environment.  The EIC for disposal
18 should be calculated if significant quantities of material are
expected to be disposed of other than by landfill, incineration or
other procedures regulated by the EPA or appropriate State
agencies.
Expected Environmental Concentration (EEC):  The expected
environmental concentration (EEC), sometimes referred to as the
predicted environmental concentration (PEC), is the concentration
of the active moiety or other compound of interest that organisms
would be exposed to in the environment (e.g., surface water) after
consideration of, for example, spatial or temporal concentration or
depletion factors such as dilution, degradation, sorption and/or
bioaccumulation.  Adjustments to the expected introduction
concentration may be made, based on spatial and temporal
concentration or depletion factors, to provide an expected
environmental concentration.  Supporting information and/or
discussion should be provided to explain the factors used in
calculating the expected environmental concentration.  The
concentration should be provided for each environmental
compartment (aquatic, terrestrial, atmospheric) expected to be
affected based on the physical and/or chemical characterization of
the compound of interest.  In the majority of cases, the EEC for the
aquatic environment would be expected to be significantly less than
the EIC for the aquatic environment due to dilution.  Based on
dilution factors for POTWs available from the EPA, applying a
dilution factor of 10 to the EIC-aquatic to estimate the EEC-
aquatic is normally appropriate.  
v. Summary
A summary discussion of the environmental fate of the substance(s)
of interest should be provided for each environmental compartment
based on the information and data provided in the EA, and the
environmental compartment(s) in which the substance is expected
to predominantly amass should be identified.  In some
circumstances, transport between environmental compartments
should be considered when determining the fate of the substance(s)
of interest in the environment.  
Aquatic Environment:  In general, pharmaceutical substances are
expected to enter predominantly into the aquatic environment and,
therefore, the focus of any effects studies most likely will be on
aquatic organisms.  If the substance(s) of interest rapidly degrades
(see section IV.B.1.a.iii) or adsorbs completely and irreversibly to
19 biosolids, then fate and effects in the aquatic environment should
not usually be considered.
Terrestrial Environment:  In general, substances enter the
terrestrial environment  predominantly from biosolids removed from
waste water treatment plants that are subsequently applied to land. 
Therefore, effects on the terrestrial environment are more likely if a
compound adsorbs to biosolids (see section IV.B.1.a.ii).  Biosolids
are generally subjected to some form of aerobic or anaerobic
digestion in the waste treatment facility; only a fraction of the
biosolids may be applied to land, while the remainder is incinerated
or land filled.  Fate and effects testing in the terrestrial environment
should be considered if testing indicates that the substance(s) of
interest will significantly adsorb to biosolids (e.g., K  $ 1000).
oc
Atmospheric Environment:  In general, substances that do not
adsorb readily to soils, have a high vapor pressure, and have a low
water solubility, are likely to volatilize significantly from the aquatic
or terrestrial environments, although actual volatilization rates will
depend on environmental conditions (e.g., dispersion away from the
evaporation site) and on factors that can lessen or enhance the
effective vapor pressure or behavior of the chemical at a liquid-air
or solid-air interface.  The atmospheric compartment may be of
interest for medical gases.  But, based on the polarity of the
majority of compounds at relevant aquatic environmental
conditions, it is unlikely that there would be substantive partitioning
from the aquatic to the atmospheric environment for other
pharmaceuticals.   Any potential for a substance to volatilize and
recycle into the aquatic or terrestrial environments should be
discussed based on the information and data available for the
substance.
b. Environmental Effects of Released Substances
Tiered approach to environmental effects testing (see below,
Microbiological Inhibition Testing through Tier 3 Testing and Figure 1):  If
no rapid, complete depletion mechanism has been identified, it should be
assumed that the compound will persist in the environment for some time
and, therefore, the toxicity of the released substances to environmental
organisms should be evaluated.  The fate of the substance should be
considered when designing the studies.  For those compounds that enter
the atmospheric environment, testing should be designed based on the
extent to which the substance recycles into the aquatic or terrestrial
environments.  All toxicity test results for the drug or biologic substance
20 should be reported in terms of the quantity and/or concentration of the
active moiety.  When using this tiered approach to effects testing, it is
important to design the test conditions appropriately so that a no-observed-
effects concentration is determined.
Microbial Inhibition Testing:  A microbial inhibition test or other
appropriate test (e.g., respiration inhibition testing) should be performed to
assess the substance(s) of interest's potential to inhibit microorganisms and
subsequently disrupt waste treatment processes.
Assessment Factors:  The assessment factors are intended to provide a
consistent regulatory basis for determining when additional ecotoxicity
testing should be performed (tiered approach).  They are directly related to
the amount of valid ecotoxicity data available.  If the LC   or  EC  or other
50 50
appropriate test endpoint divided by the maximum expected environmental
concentration  (MEEC: EIC or EEC, whichever is greater) is less than the
assessment factor, additional testing should be performed.  The use of EC
50 
or test end point other than the LC should be limited to those test
50 
organisms for which the LC  is not the test endpoint.
50 
TEST TIER ASSESSMENT FACTOR
1 1000 (see below) 
2  100 (see below)
3    10 (see below)
Alternative scientifically justified approaches also can be used.
Tier 1 Testing:  Acute ecotoxicity testing should be performed on a
minimum of one suitable test organism (see base set for Tier 2 testing).  If
the EC   or  LC  divided by the MEEC is greater than or equal to 1000, no
50 50
further testing should be conducted unless sublethal effects are observed at
the MEEC.  If the EC   or  LC  divided by the MEEC is less than 1000,
50 50
Tier 2 testing should be performed.  Sublethal effects (observed effects) at
the MEEC indicate that chronic toxicity testing (Tier 3) should be
performed.  The use of the assessment factor of 100 could be used for Tier
1 testing if there is evidence (e.g., Tier 2 testing on a similar compound) to
support that the single test organism used would be expected to be the
most sensitive of the base set test organisms.  If the compound is expected
to partition to both the aquatic and terrestrial environments, usually testing
of an aquatic test organism is sufficient since CDER has routinely observed
lower toxicity results reported for aquatic test organisms as compared to
terrestrial test organisms.
21 Tier 2 Testing:  Acute ecotoxicity testing should be performed on the
minimum base set of aquatic and/or terrestrial organisms.  The aquatic base
set usually consists of (1) a fish acute toxicity test, (2) an aquatic
invertebrate acute toxicity test, and (3) an algal species bioassay.  The
terrestrial base set usually consists of (1) plant early growth tests, (2)
earthworm toxicity tests, and (3) soil microbial toxicity tests.  Usually only
an earthworm toxicity study is indicated if the substance binds tightly to
soil.  A rodent acute toxicity is not included in the terrestrial base set since
there is usually a significant quantity of mammalian (e.g., mouse, rat, dog,
monkey, human) toxicity testing performed, both acute and chronic, to
support the underlying applicacton and to demonstrate the safety of the
drug or biologic product.  Consultation with CDER or CBER is suggested
prior to initiating any terrestrial studies. 
If the EC or  LC  for the most sensitive organism in the base set divided
50  50
by the MEEC is greater than or equal to 100, no further testing should be
conducted unless sublethal effects are observed at the MEEC.  If the EC
50
or LC  divided by the MEEC is less than 100, Tier 3 testing should be
50
performed.  Sublethal effects (observed effects) at the MEEC indicate that
chronic toxicity testing (Tier 3) should be performed.
Tier 3 Testing:  Chronic toxicity testing should be considered if the
compound has the potential to bioaccumulate or bioconcentrate, if
indicated based on Tier 1 and/or Tier 2 testing, or if there are other
indications that the compound undergoes biotransformation to more toxic
compounds.
Bioaccumulation, or bioconcentration, is a complex, dynamic process that 
depends on the availability, persistence, and physical and/or chemical
properties of a compound in the environment.  In general, pharmaceuticals
tend not to be very lipophilic and are produced and/or used in relatively
low quantities compared to industrial chemicals.  In humans, the majority
of pharmaceuticals are metabolized to some extent to SRSs that are more
polar, less toxic, and less pharmacologically active than the parent
compound.  This suggests that there is a low potential for bioaccumulation
or bioconcentration of pharmaceuticals; however, because of the length of
time it takes to conduct chronic toxicity studies, applicants are encouraged
to identify as early as possible compounds that are candidates for these
studies.  
A primary indicator of the potential for bioaccumulation is a compound's
octanol/water partition coefficient (K ).  A high octanol/water partition
ow
coefficient indicates that the compound will tend to be lipophilic.  Chronic
toxicity testing should be considered if log K  of a compound is greater
ow
22 than or equal to 3.5 under relevant environmental conditions (e.g., pH 7),
and a justification should be provided if chronic toxicity testing is not
performed.  Structural features (e.g., molecular size, polarity) that limit
passage across biological membranes or the lack of bioavailability to
environmental organisms (e.g., strong adsorption to soil) are mitigating
factors that could be considered when determining if bioaccumulation
(bioconcentration) would be a concern for compounds with a K  greater
ow
than or equal to 3.5.  It may be important to obtain acute toxicity data for
the organism to be tested to set the concentrations for the chronic studies
properly.  If the preparer of an EA is considering initiating chronic toxicity
studies, consultation with CDER or CBER is recommended to ensure that
such studies are appropriate and properly designed.  
For chronic toxicity testing, if the EC   or  LC  divided by the MEEC is
50 50
greater than or equal to 10, no further testing should be conducted unless
sublethal effects are observed at the MEEC.  CDER or CBER should be
consulted if the EC   or  LC  divided by the MEEC is less than 10 or there
50 50
are sublethal effects at the MEEC.
  
Test Methods and Test Organisms:  Studies should be performed using test
organisms and methods that have been identified by the FDA
Environmental Assessment Technical Handbook, the EPA (40 CFR 797),
the Organization for Economic Cooperation and Development (OECD), or
other peer-reviewed literature, as appropriate, for use in environmental
studies.  If the drug or biologic product is intended to act upon an
environmental organism (e.g., antiparasitic, antibiotic), information
regarding the toxicity to the target organism(s) should be included.
c. Summary
A summary discussion of the environmental fate and effect of the
substance(s) of interest should be provided.  Discussion of the affected
environments (aquatic, terrestrial, or atmospheric) should be included.  The
toxicity test results should be compared to the MEEC and the difference
between the values discussed (e.g., in terms of the assessment factor,
> 1000, > 100).  It also may be appropriate to relate the toxicity test results
to other estimated environmental concentrations (see section IV.B.1.a.iv).  
2. Use of Fauna or Flora
If an EA is to be submitted for an action because the use of fauna or flora is the
environmental issue (see section III.C.2 or 3), the EA should include specific
information regarding the source of the fauna or flora, the mitigation measures
associated with the harvesting of the resources, and a discussion of the reasonable
23 alternatives.
 
a. Use of Resources
Information relating to the source of the plant or animal, such as biological
identification, government oversight of harvesting, geographic region
where biomass is obtained, and harvesting methods and techniques should
be included in the EA.  The EA should include, but not be limited to, the
following types of information:
! Biological identification (i.e., common names, synonyms, variety,
species, genus, and family).
! A statement as to whether wild or cultivated specimens are used.
! The geographic region (e.g., country, state, province) where
biomass is obtained and whether harvesting occurred on public or
private land.
! A brief description of government oversight of the harvesting
including, if applicable, the identity of the authority permitting
harvesting and identity of authorities consulted regarding the
harvesting.  Submission of copies of permits or harvesting
regulations relating to the specific species is helpful.  For species
covered under CITES, CDER or CBER could request copies of
relevant permits.
! A brief description of the applicant's oversight of the harvesting.
! A statement indicating whether the species is (1) determined under
the Endangered Species Act or the Convention on International
Trade in Endangered Species of Wild Fauna and Flora (CITES) to
be endangered or threatened, (2) entitled to special protection
under some other Federal law or international treaty to which the
United States is a party, or (3) the critical habitat of a species that
has been determined to be endangered or threatened under the
Endangered Species Act or the Convention on International Trade
in Endangered Species of Wild Fauna and Flora (CITES) or is
entitled to special protection under some other Federal law or
international treaty to which the United States is a party.
! A statement describing the part of plant or animal used and whether
it is a renewable resource.
24 ! A detailed description of the method of harvest including such
information as the type of harvesting (e.g., clear cut, gleaning from
timber stands destined for clear cutting, salvaging, pruning),
frequency of harvest, whether the harvesting technique will affect
the ecosystem (and if so, how), and whether the harvesting is
conducted in accordance with government regulations or guidances
(include citations to applicable regulations or guidances).
! Bulk weight or other appropriate measure of biomass needed to
yield one kilogram of active moiety or biologic substance, the
amount that has been harvested to date to support the proposed
Agency action for the product, and the amount expected to be
harvested in the future.
! The amount of biomass needed to produce the active moiety or
biological substance used to treat the average patient.  This should
be provided in terms easy to understand (e.g., 2-3 trees per patient). 
The expected patient population and number of kilograms of active
moiety or biologic substance needed per year should be provided.
! An estimate of the total number of plants or animals in the
geographic region where the biomass is obtained.
! Any uses of the plant or animal other then for the proposed use
(humans, food source, habitat for fauna).
! Plant or animal growth rate and/or life span and, if applicable, the
rate of  reproduction/regeneration.
! A discussion of whether the harvesting provides for sustained yield
(e.g., percentage of sustainable harvest needed to supply annual
needs based on the proposed use and any prior approved uses).
b. Mitigation Measures
Mitigation measures taken before (e.g., developing a process that uses a
renewable part of a plant), during (e.g., limiting/selecting specimens to be
harvested), and after harvesting (e.g., reforestation) should be included in
the discussion of mitigation measures (see 40 CFR 1508.20). 
25 c. Alternatives to the Proposed Action
A discussion must be provided of the reasonable alternatives that were
considered when deciding which biomass source would be used to produce
the active moiety or biologic substance (21 CFR 25.40(a)).  All alternatives
that were considered (e.g., other species, wild or cultivated sources,
chemical synthesis) should be discussed.  A brief discussion of the factors
(e.g., environmental effects) that were considered in deciding whether or
not the alternative would be used should be provided. The no-action (i.e.,
no approval) alternative should also be discussed.  It should be indicated if
any of the alternatives not currently used are planned for use in the future.
C. Data Summary Table
To facilitate review, the EA, if appropriate, should include a data summary table in a
nonconfidential appendix (EA format item 11).  Attachment E provides an example of a
suitable data summary table.
D. Test Methods and Report Formats
Test methods and report formats are provided in the FDA Environmental Assessment
Technical Handbook.  Equivalent tests, such as those provided by the EPA (40 CFR 796
and 797), the Organization for Economic Cooperation and Development (OECD), or
other validated, peer-reviewed methods can be used.   Environmental fate studies should
be compliant with either FDA's current Good Manufacturing Practice (cGMP) regulations
(21 CFR 211.194) or FDA's Good Laboratory Practice (GLP) regulations (21 CFR part
58).  The reports submitted in support of fate testing should include a description of the
test method sufficient for a reviewer to determine the scientific merit of the methodology. 
Test performance and test reporting for environmental effects studies should meet FDA's
GLP standards.  Guidance on test reporting formats is included in the FDA Environmental
Assessment Technical Handbook or 40 CFR parts 796 and 797.  Raw test data (e.g.,
copies of notebook pages,  HPLC chromatograms for each assay) should not be included
in the EA.  
E. Confidential and Nonconfidential Information
Some of the information that is submitted in an EA may be available elsewhere in an
application or in a publicly available document.  This information may be incorporated by
reference in the EA (21 CFR 25.40(d)).  However, the EA summary document, the
document that contains the information recommended in section IV.A, should be a stand-
alone document that contains a summary of the public information that is incorporated by
reference and, to the extent possible, a summary of the confidential information that is
either incorporated by reference or included in confidential appendices to the EA (21 CFR
25.51(a)).  The EA will be made public by the FDA as required by regulations issued by
26 the Council on Environmental Quality.  Therefore, the EA should contain, if appropriate,
three distinct parts: (1) the EA summary document (see section IV.A), which is
nonconfidential; (2) nonconfidential appendices; and (3) appendices with confidential
information used to support the EA.  Confidential data and information  pertinent to the
environmental review of a proposed action should be included in confidential appendices
whenever possible to facilitate review of the EA.  All confidential appendices should be at
the end of the environmental assessment document.  References to nonconfidential and
confidential appendices may be included in the EA summary document, as appropriate.  
The EA summary document, nonconfidential appendices, and FONSI are made available
for public inspection to the extent allowed by applicable laws (21 CFR 25.50(a) and (b)). 
Attachment F provides general guidance as to which information can be included in
confidential appendices of the EA.  It is the applicant's responsibility to clearly identify the
information in the EA that it believes is confidential.   
F. Master Files for Drugs and Biologics
CDER and CBER do not take action on drug master files (DMFs) or master files (MFs) 
(i.e., they do not approve or disapprove submissions to a DMF (21 CFR 314.420(a)) or
MF).  Therefore, NEPA does not apply, and no EA needs to be submitted for a master
file.  
However, if an EA is required for the particular application, certain information that is
included in a master file may be needed to address the relevant environmental issue(s).  In
these instances, the applicant seeking marketing approval should include the
nonconfidential information in the EA summary document, rather than provide reference
to the master file.  The master file holder may be the applicant or an independent
manufacturer who wants to limit the applicant's access to proprietary information.  A
master file reference may be provided for the confidential information, although this
information must be summarized to the extent possible and included in the EA for public
release.  To expedite review of the EA, CDER and CBER prefer that copies of
confidential information from master files be submitted in confidential appendices to the
EA, whenever possible.  If a letter of authorization is provided to reference confidential
information in a master file, the specific type of information that is being referenced, the
submission date, and page number where the information can be located should be stated. 
References to master files should be included in a confidential appendix since such
references are considered confidential commercial information under the Freedom of
Information Act (FOIA).
27  
REFERENCES
1. FDA, "National Environmental Policy Act; Revision of Policies and Procedures; Final
Rule," Federal Register, July 29, 1997 (62 FR 40569).
2. FDA, "National Environmental Policy Act; Proposed Revision of Policies and Procedures;
Proposed Rule," Federal Register, April 3, 1996 (61 FR 14922); (republished May 1,
1996 (61 FR 19476)).
3. Rand, G., and S. Petrocelli, Fundamentals of Aquatic Toxicology, Hemisphere Publishing
Corporation, 1987.
 4. Zeeman, M., and J. Gilford, "Ecological Hazard Evaluation and Risk Assessment Under
EPA's Toxic Substances Control Act (TSCA): An Introduction," Environmental
Toxicology and Risk Assessment, ASTM STP 1179, Wayne G. Landis, Jane S. Hughes,
and Michael A. Lewis, Eds., American Society for Testing and Materials, Philadelphia:
1993, pp. 7-21.
 
28 ATTACHMENT A:  NO INCREASED USE
The following are types of actions that are not considered to result in increased use of an active
moiety if approved by the Agency:
! Chemistry, manufacturing and control supplements ( 314.70, 601.12).
! Abbreviated applications.
! Lower doses than previously approved for the same indication (i.e., total daily dose).
! Shorter duration of use than previously approved for the same indication (e.g., number of
days).
! Exclusion of a patient population in the labeling (e.g., by age, gender, complicating
medical conditions).
! A prodrug for which the active metabolite is an approved product in the United States and
which is intended to substitute directly4 for that approved product.  An active moiety
which is the active metabolite of an approved prodrug in the United States would be
considered similarly.
! New dosage forms that substitute directly for an approved product.
! Product reformulations in which the labeled amount of active moiety/biologic substance
remains constant.
! Packaging changes/dosage form product line extensions that substitute directly for an 
approved product (e.g., new delivery system, addition of a different vial fill size).
! Combination drugs in which the single product substitutes directly for two approved
products that would be administered separately.
4 In context of Attachments A and B, substitute directly means that the drug or biologic product (i.e., active
moiety or biologic substance) will be used for the same indication, at the same or lower dosage levels (i.e., total daily
dose), and for the same or shorter duration of use (e.g., number of days) as previously approved by the Agency for the
same active moiety or biologic substance.
29 ATTACHMENT B:  INCREASED USE
 
The following are types of actions that are considered to result in increased use of an active
moiety if approved by the Agency:
! New molecular entities.
! A new indication for a drug that was previously approved.  This includes those actions
requesting approval of off-label uses and switches from a second-line to first-line
indication.
! L to OTC switches.
! Higher doses than were previously approved (i.e., total daily dose).
! Longer duration of use than previously approved (e.g., number of days).
! Inclusion of a patient population in the labeling that had previously been specifically
excluded (e.g., by age, gender, complicating medical conditions).
! New dosage forms/routes of administration that increase the amount of active
ingredient/biologic substance used.  For example, the use of the active moiety or biologic
substance for the same indication will normally increase if a switch is made from an
injectable dosage form to an oral dosage form.
30 ATTACHMENT C:  40 CFR 1508.27
 1508.27  Significantly.
"Significantly" as used in NEPA requires considerations of both context and intensity:
(a) Context.  This means that the significance of an action must be analyzed in several contexts
such as society as a whole (human, national), the affected region, the affected interests, and the
locality.  Significance varies with the setting of the proposed action.  For instance, in the case of a
site-specific action, significance would usually depend upon the effects in the locale rather than in
the world as a whole.  Both short- and long-term effects are relevant.
(b)  Intensity.  This refers to the severity of impact.  Responsible officials must bear in mind that
more than one agency may make decisions about partial aspects of a major action.  The following
should be considered in evaluating intensity:
(1) Impacts that may be both beneficial and adverse.  A significant effect may exist even if the
Federal agency believes that on balance the effect will be beneficial.
(2) The degree to which the proposed action affects public health or safety.
(3) Unique characteristics of the geographic area such as proximity to historic or cultural
resources, park lands, prime farmlands, wetlands, wild and scenic rivers, or ecologically
critical areas.
(4) The degree to which the effects on the quality of the human environment are likely to be
highly controversial.
(5) The degree to which the possible effects on the quality of the human environment are
highly uncertain or involve unique or unknown risks.
(6) The degree to which the action may establish a precedent for future actions with
significant effects or represents a decision in principle about a future consideration.
(7) Whether the action is related to other actions with individually insignificant but
cumulatively significant impacts.  Significance exists if it is reasonable to anticipate a
cumulatively significant impact on the environment.  Significance cannot be avoided by
terming an action temporary or by breaking it down into small component parts.
(8) The degree to which the action may adversely affect districts, sites, highways, structures,
or objects listed in or eligible for listing in the National Register of Historic Places or may
cause loss or destruction of significant scientific, cultural, or historical resources. 
(9) The degree to which the action may adversely affect an endangered or threatened species
or its habitat that has been determined to be critical under the Endangered Species Act of
1973.
(10) Whether the action threatens a violation of Federal, State, or local law or requirements
imposed for the protection of the environment.
31 ATTACHMENT D:  EA FORMAT
1. Date
2. Name of Applicant/Petitioner
3. Address
4. Description of Proposed Action
a. Requested Approval
b. Need for Action
c. Locations of Use
d. Disposal Sites
5. Identification of Substances that are the Subject of the Proposed Action
a. Nomenclature
  i. Established Name (U.S. Adopted Name - USAN)
ii. Brand/Proprietary Name/Tradename
iii. Chemical Names or Genus/Species of Biologic Product (e.g., virus)
!! Chemical Abstracts (CA) Index Name
!! Systematic Chemical Name
b. Chemical Abstracts Service (CAS) Registration Number
c. Molecular Formula
d. Molecular Weight
e. Structural (graphic) Formula/Amino Acid Sequence
6. Environmental Issues
7. Mitigation Measures
8. Alternatives to the Proposed Action
9. List of Preparers
10. References
11. Appendices
32 ATTACHMENT E:  SAMPLE DATA SUMMARY TABLE
SAMPLE DATA SUMMARY TABLE
PHYSICAL/CHEMICAL CHARACTERIZATION
Water Solubility1
Dissociation Constant(s)
Log Octanol/Water Partition Coefficient (Log
K )1
ow
Vapor Pressure or Henry's Law Constant
Sorption/Desorption (K )1
oc
DEPLETION MECHANISMS 
Hydrolysis
Aerobic Biodegradation
Soil Biodegradation 
Photolysis 
Metabolism
ENVIRONMENTAL EFFECTS2 
Microbial Inhibition
Acute Toxicity
Chronic Toxicity
1Depending on dissociations constant(s), water solubility and octanol/water partition coefficient may have to be
determined at pH 5 and 9, in addition to pH 7 or K may have to be determined in acidic and/or alkaline soil in addition
oc 
to neutral soil.  See section IV.B.1.a.ii for guidance.
2Identify organism(s) and report results, e.g., NOEC, MIC, EC   LC  in ppm of active moiety.
50, 50
33 ATTACHMENT F:  CONFIDENTIAL/NONCONFIDENTIAL
EA FORMAT ITEM SUBSECTION NONCONFIDENTIAL CONFIDENTIAL
1.Date *** X
2. Name of *** X
Applicant/Petitioner
3. Address *** X
4. Description of a. Requested Approval X
Proposed Action
b. Need for Action X
c. Locations of Use X
d. Disposal Sites X
5. Identification of  a. Nomenclature X
Substances that are the
Subject of the b. CAS Number X
Proposed Action
c. Molecular Formula X
d. Molecular Weight X
e. Structural Formula X
34 EA FORMAT ITEM SUBSECTION NONCONFIDENTIAL CONFIDENTIAL
6. Environmental a. Assessing Toxicity to For example: For example:
Issue Environmental Organisms 
* Substances expected to enter or * Specific toxicology/
(Specific exist in the environment. pharmacological activity data for
environmental issues * Summary discussion of SRSs
identified in section toxicity/activity of predominant * Test reports
IV.B) SRSs relative to the parent * Environmental concentration
(active) compound estimates
* Test results physical/chemical
characterization
* Method of calculating estimates of
environmental concentration
* Supporting information for
spatial/temporal depletion factors
* Environmental effects test results
b. Use of Fauna or Flora For example: For example:
* Biological identification and other * Bulk weight of biomass needed
information relating to species to produce a kg of active moiety
used (e.g., plant growth rate) * Amount harvested
*  Geographic region of the source * The expected patient population
*  Government oversight and kg of active moiety expected
*  Method of harvesting to be used per year
7. Mitigation *** X
Measures
8. Alternatives to the *** X
Proposed Action
9. List of Preparers *** X
35 EA FORMAT ITEM SUBSECTION NONCONFIDENTIAL CONFIDENTIAL
10. References *** X
11. Appendices *** For example: For example:
* Referenced articles not generally * Estimates of the kg of active
available or which are used to moiety to be used/year
support specific claims in the EA * Test reports
document * Letters of authorization to DMFs
* Data summary table 
36 ATTACHMENT G:  GLOSSARY OF TERMS
Active Moiety:  The molecule or ion, excluding those appended portions of the molecule that
cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other
noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule, responsible for
the physiological or pharmacological action of the drug substance (21 CFR  314.108(a)).  The
active moiety is the entire molecule or ion, not the "active site."
Bioaccumulation:  The process by which industrial waste, chemicals, and other substances
gradually accumulate in living tissue.
Bioconcentration:  The process by which industrial waste, chemicals, and other substances
accumulate directly from water into and onto aquatic organisms.
Biological (biologic) product:  Any virus, therapeutic serum, toxin, antitoxin, vaccine, blood,
blood component, derivative, allergenic product, or analogous product applicable to the
prevention, treatment, or cure of a disease or condition of human beings (section 351 of the
Public Health Service Act).
Biomass:  The plant, plant part (e.g., bark,  leaves, flower, seed), animal, or animal part (e.g.,
skin, liver, stomach) that is collected for processing into a drug or biologic.
Drug product:  A finished dosage form, for example, tablet, capsule, or solution, that contains a
drug substance, generally, but not necessarily, in association with one or more ingredients (21
CFR 314.3(b)).
Drug substance:  An active ingredient that is intended to furnish pharmacological activity or
other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease or to
affect the structure or any function of the human body, but does not include intermediates used in
the synthesis of such ingredient (21 CFR 314.3(b)).
Expected environmental concentration (EEC):  The expected concentration of the active
moiety or other structurally related substance of interest that organisms would be exposed to in
the environment (e.g., surface water) after consideration of spatial or temporal concentration or
depletion factors such as dilution, degradation, sorption, bioaccumulation.  This is sometimes
referred to as the predicted environmental concentration (PEC). 
Expected introduction concentration (EIC) for disposal:  The expected introduction
concentration of the active moiety that may enter the environment due to disposal.  Depletion
mechanisms that occur prior to introduction into the environment may be considered in the
calculation as indicated in the text.
37 Expected introduction concentration (EIC) for use:  The expected introduction concentration,
based on fifth-year marketing estimates, of the active moiety that can enter the environment due
to use.  Depletion mechanisms that occur prior to introduction into the environment and human
metabolism may be considered in the calculation as indicated in the text.
Half-life (t ):  Time required to reduce by one-half the concentration of a material.
12
Lowest observed effect concentration (LOEC):  The lowest concentration of a material used in
a toxicity test that has a statistically significant adverse effect on the exposed population of the
test organisms as compared with the controls.
Master file:  A submission of information to the FDA by a person who intends it to be referenced
during the review of an application.  See 21 CFR 314.420 for specific information on drug master
files.
Maximum expected environmental concentration (MEEC):  The expected introduction
concentration (EIC) or expected environmental concentration (EEC), whichever is greater.
Median effective concentration (EC ):  The concentration of material to which organisms are
50
exposed that is estimated to be effective in producing some sublethal response in 50 percent of the
test organisms.  The EC   is  usually  expressed  as  a  time-dependent  variable  (e.g.,  24  hour  EC ).
50 50
Median lethal concentration (LC ):  The concentration of material to which organisms are
50
exposed that is estimated to be lethal to 50 percent of the test organisms.  The LC  is usually
50
expressed as a time-dependent variable (e.g., 24 hour LC ).
50
Minimum inhibitory concentration (MIC):  The lowest concentration of a chemical that
inhibits the visible growth of the test organisms.
New molecular entity:  An active moiety (present as the unmodified base [parent] compound, or
an ester or a salt, clathrate, or other noncovalent derivative of the base [parent] compound) that
has not been previously approved or marketed as the active moiety in the United States for use in
a drug product, either as a single ingredient or as part of a combination product, or as part of a
mixture of stereoisomers. 
No observed effect concentration (NOEC):  The highest concentration of a material used in a
toxicity test that has no statistically significant adverse effect on the exposed population of test
organisms as compared with the controls.
Octanol/water partition coefficient (K ):  The ratio of a chemical's solubility in n-octanol and
ow
water at equilibrium; also expressed as P.  A measurement of a drug's or biologic's lipophilicity
and an indication of its ability to cross cell membranes.  The logarithm of P or K  is used as an
ow
estimate of the tendency of the chemical to bioaccumulate or adsorb to soil or sediments.
38 Parts per billion (ppb):  One unit of chemical (usually expressed as mass) per 1,000,000,000
(109) units of medium (e.g., water) or organism (e.g., tissue) in which it is contained.  For water 1
g/L = 1 ppb; for tissue 1 g/kg = 1 ng/g = 1 ppb.
Parts per million (ppm):  One unit of chemical (usually expressed as mass) per 1,000,000 (106)
units of medium (e.g., water) or organism (e.g., tissue) in which it is contained.  For water 1 mg/L
= 1 ppm; for tissue 1 mg/kg = 1 g/g = 1 ppm.
Parts per trillion (pptr):  One unit of chemical (usually expressed as mass) per
1,000,000,000,000 (1012) units of medium (e.g., water) or organism (e.g., tissue) in which it is
contained.  For water 1 ng/L = 1 pptr; for tissue 1 ng/kg = 1 pptr.
Soil or sediment/water partition coefficient (K ):  The ratio of chemical adsorbed per unit
oc
weight of organic carbon in soil or sediment to the concentration of the chemical in solution at
equilibrium.
Toxicity:  The inherent potential or capacity of a material to cause adverse effects in a living
organism.
39