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
i

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
 This guidance has been prepared under the direction of the Chemistry Manufacturing Controls Coordinating 1 

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.

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
 Regulations would require an EIS (environmental impact statement) when "evaluation of data or information 2

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

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. See 2

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
3

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 applicant’s 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. 
4

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 = 10 μg/kg (conversion factor) 9

* 1.214 x 10 liters per day entering publicly owned treatment works (POTWs), 11

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
5

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
6

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 FDAregulated 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
FDA may clarify the environmental information that must be submitted to the Agency in marketing 3

applications for specific drug or biologic products derived from plants or animals (e.g., paclitaxel, 61 FR 58694).

7

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
8

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
9

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
10

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
11

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
12

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
13

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.
Figure 1

Tiered Approach to Fate and Effects Testing

Determine environments of Potential Concern

Atmospheric, Aquatic and/or Terrestrial

Investigate Depletion

Mechanism(s)

Microbial

Inhibition Test STOP

rapid

complete

Microbial

Inhibition Test

No rapid, complete

depletion mechanism

Log Kow > 3.5 Consider Initiating

Chronic Toxicity Testing

Tier 3

Log Kow <3.5 or Log Kow > 3.5 with justification

TIER 1

Acute Toxicity

1 species

LC or EC < 1000

50 50

MEEC

STOP

Tier 3

No Observed Effects

at MEEC

Observed Effects

at MEEC

TIER 2

Acute Toxicity

Base Set

Aquatic &/or

Terrestrial

LC or EC > 1000

50 50

MEEC

LC or EC > 100

50 50

MEEC

STOP

Tier 3

No Observed Effects

at MEEC

Observed Effects

at MEEC

LC or EC < 100

50 50

MEEC

TIER 3

Chronic Toxicity

Aquatic &/or

Terrestrial

LC or EC > 10 & No Observed Effects

 at MEEC 50 50

MEEC

STOP

LC or EC < 10 or Observed Effects

 at MEEC 50 50

MEEC

Consult CDER/CBER

Note: MEEC = EEC or EIC whichever is greater

14
15

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
16

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 (Kow) is an indicator of a

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 (Koc) of a substance to

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
17

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 t1⁄2 (pH 5-9): # 24 hours

Aerobic Biodegradation t1⁄2: # 8 hours

Soil Biodegradation t1⁄2: # 5 days

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
18

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 FDAregulated 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
19

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 EECaquatic 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
20

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
21

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-observedeffects 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 EC50 

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 EC50 or LC50 divided by the MEEC is greater than or equal to 1000, no

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.
22

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 EC50 or LC50 for the most sensitive organism in the base set divided

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 EC50

or LC50 divided by the MEEC is less than 100, Tier 3 testing should be

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 (Kow). A high octanol/water partition

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
23

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 EC50 or LC50 divided by the MEEC is

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 EC50 or LC50 divided by the MEEC is less than 10 or there

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
24

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.
25

! 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). 
26

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 standalone 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
27

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).
28

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.
In context of Attachments A and B, substitute directly means that the drug or biologic product (i.e., active 4

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 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 directly for that approved product. An active moiety 4

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.
30

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.
31

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.
32

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
33

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 ) ow

1

Vapor Pressure or Henry's Law Constant

Sorption/Desorption (K ) oc

1

DEPLETION MECHANISMS 

Hydrolysis

Aerobic Biodegradation

Soil Biodegradation 

Photolysis 

Metabolism

ENVIRONMENTAL EFFECTS2

Microbial Inhibition

Acute Toxicity

Chronic Toxicity

Depending on dissociations constant(s), water solubility and octanol/water partition coefficient may have to be 1

determined at pH 5 and 9, in addition to pH 7 or Koc may have to be determined in acidic and/or alkaline soil in addition

to neutral soil. See section IV.B.1.a.ii for guidance.

Identify organism(s) and report results, e.g., NOEC, MIC, EC LC in ppm of active moiety. 2

50, 50
34

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

Proposed Action

b. CAS Number X

c. Molecular Formula X

d. Molecular Weight X

e. Structural Formula X
EA FORMAT ITEM SUBSECTION NONCONFIDENTIAL CONFIDENTIAL

35

6. Environmental a. Assessing Toxicity to For example: For example:

Issue Environmental Organisms 

(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

* Substances expected to enter or * Specific toxicology/

(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
EA FORMAT ITEM SUBSECTION NONCONFIDENTIAL CONFIDENTIAL

36

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 
37

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.
38

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 (t1⁄2): Time required to reduce by one-half the concentration of a material.

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 (EC50): The concentration of material to which organisms are

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 (LC50): The concentration of material to which organisms are

exposed that is estimated to be lethal to 50 percent of the test organisms. The LC50 is usually

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 (Kow): The ratio of a chemical's solubility in n-octanol and

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 Kow is used as an

estimate of the tendency of the chemical to bioaccumulate or adsorb to soil or sediments.
39

Parts per billion (ppb): One unit of chemical (usually expressed as mass) per 1,000,000,000

(10 ) units of medium (e.g., water) or organism (e.g., tissue) in which it is contained. For water 1 9

μg/L = 1 ppb; for tissue 1 μg/kg = 1 ng/g = 1 ppb.

Parts per million (ppm): One unit of chemical (usually expressed as mass) per 1,000,000 (10 )

6

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 μg/g = 1 ppm.

Parts per trillion (pptr): One unit of chemical (usually expressed as mass) per

1,000,000,000,000 (10 ) units of medium (e.g., water) or organism (e.g., tissue) in which it is 12

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.