Guidance for Industry 

Nonclinical Studies for the 

Safety Evaluation of 

Pharmaceutical Excipients 

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) 

May 2005 

Pharmacology/Toxicology 

J:\!GUIDANC\5544fnlcln2.doc 

4/15/2005 
Guidance for Industry

Nonclinical Studies for the 

Safety Evaluation of 

Pharmaceutical Excipients 

Additional copies are available from: 

Office of Training and Communications

Division of Drug Information, HFD-240

Center for Drug Evaluation and Research

Food and Drug Administration 

5600 Fishers Lane 

Rockville, MD 20857

(Tel) 301-827-4573

http://www.fda.gov/cder/guidance/index.htm 

or 

Office of Communication, Training, and

Manufacturers Assistance, HFM-40 

Center for Biologics Evaluation and Research 

Food and Drug Administration 

1401 Rockville Pike, Rockville, MD 20852-1448 

(Tel) 800-835-4709 or 301-827-1800

http://www.fda.gov/cber/guidelines.htm

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) 

May 2005 

Pharmacology/Toxicology 
TABLE OF CONTENTS 

I. INTRODUCTION............................................................................................................. 1

II. BACKGROUND ............................................................................................................... 1

III. SUBMISSION OF SAFETY DATA................................................................................ 2

A. Over-the-Counter Products ..........................................................................................................3

B. Generic Products............................................................................................................................3

C. New Drug or Biological Product Application..............................................................................3

D. Requests for Additional Safety Data ............................................................................................4

E. Exceptions.......................................................................................................................................4

IV. RECOMMENDED STRATEGIES TO SUPPORT MARKETING OF NEW 

EXCIPIENTS IN DRUG PRODUCTS........................................................................... 4

A. Safety Pharmacology .....................................................................................................................4

B. Potential Excipients Intended for Short-Term Use ....................................................................5

C. Potential Excipients Intended for Intermediate Use...................................................................6

D. Potential Excipients Intended for Long-Term Use .....................................................................6

E. Potential Excipients for Use in Pulmonary, Injectable, or Topical Products...........................7

F. Photosafety Data ............................................................................................................................8

V. SUMMARY ....................................................................................................................... 8
Contains Nonbinding Recommendations 

Guidance for Industry1

Nonclinical Studies for the Safety Evaluation 

of Pharmaceutical Excipients

This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It 

does not create or confer any rights for or on any person and does not operate to bind FDA or the public. 

You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 

and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for 

implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate 

number listed on the title page of this guidance. 

I. INTRODUCTION 

This document provides guidance concerning development of safety profiles to support use of 

new excipients as components of drug or biological products. It is intended for use by reviewers 

within both the Center for Drug Evaluation and Research (CDER) and the Center for Biologics 

Evaluation and Research (CBER) and by interested individuals in industry. It is also intended to 

foster and expedite the development of new excipients, communicate to pharmaceutical and 

excipient manufacturers current CDER and CBER recommendations on the nonclinical safety 

data that should be generated to support excipient development, and increase uniformity within 

CDER and CBER as to expectations for the nonclinical safety evaluation of excipients. 

FDA’s guidance documents, including this guidance, do not establish legally enforceable 

responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should 

be viewed only as recommendations, unless specific regulatory or statutory requirements are 

cited. The use of the word should in Agency guidances means that something is suggested or 

recommended, but not required. 

II. BACKGROUND 

In this guidance, the phrase new excipients means any inactive ingredients that are intentionally 

added to therapeutic and diagnostic products, but that: (1) we believe are not intended to exert 

therapeutic effects at the intended dosage, although they may act to improve product delivery 

(e.g., enhance absorption or control release of the drug substance); and (2) are not fully qualified 

by existing safety data with respect to the currently proposed level of exposure, duration of 

exposure, or route of administration. Examples of excipients include fillers, extenders, diluents, 

 

1

 This guidance has been prepared by the Center for Drug Evaluation and Research (CDER) and the Center for 

Biologics Evaluation and Research (CBER) at the Food and Drug Administration. 

1
Contains Nonbinding Recommendations 

wetting agents, solvents, emulsifiers, preservatives, flavors, absorption enhancers, sustainedrelease matrices, and coloring agents. Within the context of this guidance, the term excipient

applies to macromolecular substances such as albumin, or substances such as amino acids and 

sugars that are used in drug and biological products. It does not, however, apply to process or 

product-related impurities (e.g., degradation products, leachates, residual solvents) or extraneous 

contaminants. 

Not all excipients are inert substances; some have been shown to be potential toxicants. The 

Federal Food, Drug, and Cosmetic Act of 1938 (the Act) was enacted after the tragedy of the 

elixir of sulfanilamide in 1937 in which an untested excipient was responsible for the death of 

many children who consumed the pharmaceutical. The Act required manufacturers to perform

safety testing of pharmaceuticals and submit new drug applications (NDAs) demonstrating safety 

before marketing. Since that time, the Agency has become aware that certain other excipients 

used in commerce can cause serious toxicities in consumers of prescription and over-the-counter 

(OTC) drug products in the United States and other countries. 

This guidance describes the types of toxicity data that the Agency uses in determining whether a 

potential new excipient is safe for use in human pharmaceuticals. It discusses recommended 

safety evaluations for excipients proposed for use in OTC and generic drug products, and 

describes testing strategies for pharmaceuticals proposed for short-term, intermediate, and longterm use. It also describes recommended excipient toxicity testing for pulmonary, injectable, and 

topical pharmaceuticals.

III. SUBMISSION OF SAFETY DATA 

Most, if not all, drug products could not be made without the use of excipients. Tablets, 

capsules, suspensions, and others all require one or more excipients in their formulations. 

Excipients may also have functions, for example, in sustained release preparations or in 

enhancing drug penetration through the skin. 

It is important to perform risk-benefit assessments on proposed new excipients in drug products 

and to establish permissible and safe limits for these substances. This requires evaluation of a 

safety database. With proper planning, however, it is often possible to assess the toxicology of 

an excipient in a relatively efficient manner. For example, sponsors can develop new excipients 

concurrently with safety evaluation of new drug and biological products by adding groups of 

animals that receive the excipient to studies that would have been conducted anyway to develop 

a drug substance. The Centers recognize that existing human data for some excipients can 

substitute for certain nonclinical safety data, and an excipient with documented prior human 

exposure under circumstances relevant to the proposed use may not require evaluation in the full 

battery of toxicology studies outlined in this guidance. For example, the Centers will continue to 

consider factors such as use in previously approved products or GRAS status as a direct food 

additive. Under some circumstances (e.g., similar route of administration, level of exposure, 

patient population, and duration of exposure) experience associated with the prior use may 

adequately qualify an excipient. However, it may be necessary for the safety database associated 

with that excipient to be brought up to current standards (e.g., submission of additional genetic 

2
Contains Nonbinding Recommendations 

toxicology data). The available information that supported the prior use will be considered in 

light of any proposed new use by the appropriate review division. It is important to note that the 

inclusion of an excipient in a USP/NF monograph or other non-FDA document is not an 

indication that the substance has been reviewed by the FDA and found safe for use. 

A. Over-the-Counter Products 

For products marketed under OTC drug monographs, 21 CFR 330.1(e) requires: “The product 

contains only suitable inactive ingredients which are safe in the amounts administered and do not 

interfere with the effectiveness of the preparation or with suitable tests or assays to determine if

the product meets its professed standards of identity, strength, quality, and purity. Color 

additives may be used only in accordance with section 721 of the act and subchapter A of this 

chapter.” It is the manufacturer’s responsibility to comply with these requirements and to have 

appropriate supporting data in its files. The provisions of § 330.1(e) do not apply to OTC 

products marketed under NDAs or abbreviated new drug applications (ANDAs). Some 

excipients used in NDA-approved drug products may not be safe for use in OTC products (e.g., 

some toxic excipients used in cancer chemotherapeutics). 

B. Generic Products 

Requirements for submitting safety information on excipients in ANDAs for generic products are 

stated in 21 CFR 314.94(a)(9). Under this regulation, drug products intended for parenteral, 

ophthalmic, or otic use should contain the same excipients in the same concentrations as the 

reference listed drug product, with the exception of buffers, antioxidants, and preservatives, 

provided that the applicant identifies and characterizes the differences and provides information 

demonstrating that the differences do not affect the safety of the proposed drug product. For 

other routes of administration (e.g., topical dermal, oral), there is no requirement that the 

excipients in the final formulations be the same as those in the reference listed drug product, 

although the applicant must demonstrate that the inactive ingredients do not affect the safety or 

efficacy of the proposed drug product (21 CFR 314.94(a)(9)(ii)). However, we recommend that 

the applicant identify and characterize the differences in excipients and provide information 

demonstrating that the differences do not affect the safety of the proposed drug product. 

Consideration should be given to the prior indication and patient population for which use of the 

excipient was previously deemed safe. Alternatively, new or additional information to support 

the proposed new use should be referenced. 

C. New Drug or Biological Product Application 

It is important that a new or inadequately qualified inactive ingredient proposed for use in any 

product to be marketed pursuant to an NDA, biologics license application (BLA), or ANDA be 

supported by adequate data. These data can be placed in the application directly or in a drug 

master file (DMF). This guidance describes the nonclinical data we recommend be submitted to 

verify that a proposed excipient is safe in the amounts administered if relevant prior human use 

cannot be adequately documented. 

3
Contains Nonbinding Recommendations 

D. Requests for Additional Safety Data 

We may request additional safety data if we determine that the proposed conditions of use are 

not fully supported by the available data. We may request a pharmacokinetic profile for 

excipients that are extensively absorbed or biotransformed. When applicable, drug-excipient 

interaction studies may also be requested. The proposed conditions of use of a new excipient 

(e.g., use in pediatric patients)2

 may affect the need for toxicology data. The sponsor is 

encouraged to contact the appropriate review division for guidance. 

E. Exceptions 

We recognize that every excipient is unique and that scientifically valid reasons may exist for 

modifying and deleting certain preclinical studies listed in this guidance for a given combination 

of excipient and proposed use. For example, it may be justifiable for the safety evaluation of 

excipients deemed necessary for the delivery of lifesaving therapies to be abbreviated (relative to 

the evaluation of excipients for use in products for low morbidity indications) or completed postapproval. As another example, excipients that are large polymers that differ from previously 

characterized excipients only in molecular weight (chain length) can be adequately characterized 

in an abbreviated manner using less safety data, provided that the new excipient and the 

previously studied excipient are sufficiently similar with regard to physical state, 

pharmacokinetics, and levels of unreacted monomers and other impurities. We will consider 

such excipients on a case-by-case basis. The sponsor is encouraged to contact the appropriate 

review division to receive specific guidance when necessary. 

IV. RECOMMENDED STRATEGIES TO SUPPORT MARKETING OF NEW 

EXCIPIENTS IN DRUG PRODUCTS 

We recommend that all pivotal toxicology studies be performed in accordance with state-of-theart protocols and good laboratory practice regulations. The following recommendations are 

primarily intended for excipients for which adequate prior human exposure has not been 

documented. 

A. Safety Pharmacology 

We recommend that all potential new excipients be appropriately evaluated for pharmacological 

activity using a battery of standard tests (see ICH guidance S7A).3

 These evaluations can be 

performed during the course of toxicology studies or as independent safety pharmacology 

studies. It is useful for these data to be obtained at an early point during the safety evaluation of 

an excipient, since, if the excipient is found to be pharmacologically active, this information can 

influence subsequent development. Appropriate regulatory guidance can be given by the 

responsible review division. 

 

2 Concerning use in pediatric patients, see the CDER draft guidance for industry Nonclinical Safety Evaluation of

Pediatric Drug Products. When final, this guidance will represent the FDA’s current thinking on this topic. For the 

most recent version of a guidance, check the CDER guidance page at http://www.fda.gov/cder/guidance/index.htm.

3

 ICH guidance for industry S7A Safety Pharmacology Studies for Human Pharmaceuticals

4
Contains Nonbinding Recommendations 

B. Potential Excipients Intended for Short-Term Use 

We recommend that the safety evaluation of potential new excipients that are intended for use in 

products that are limited by labeling to clinical use of 14 or fewer consecutive days per treatment 

episode and are infrequently used include at least the following: 

1. Acute toxicology studies performed in both a rodent species and a mammalian nonrodent 

species by the route of administration intended for clinical use (see CDER guidance for 

industry Single Dose Acute Toxicity Testing for Pharmaceuticals). It is not necessary to 

determine the LD50 of an excipient.4

 It may be appropriate to omit acute toxicology 

studies from the safety evaluation of a new excipient under certain circumstances. For 

example, if repeat-dose toxicology studies are performed in which the high dose is the 

limit dose (e.g., 2 g/kg or 2 percent of the diet) and little or no toxicity is observed at that 

dose, it can be assumed that the acute toxicity has been adequately evaluated. In some

cases, a dose-escalation study is considered an acceptable alternative to a single-dose 

design (see ICH guidance M3).5

2. It is recommended that the absorption, distribution, metabolism, and excretion of the 

excipient be studied following administration by the clinically relevant routes to the same

species that are used in the nonclinical safety studies (see ICH guidelines S3A and S3B).6

3. It is recommended that excipients be evaluated in the standard battery of genetic 

toxicology studies discussed in ICH guidance S2B.7

4. It is recommended that 1-month repeat-dose toxicology studies be performed in both a 

rodent species and a mammalian nonrodent species by the route of administration 

intended for clinical use. It is important that the studies include complete clinical 

pathology, histopathology, and toxicokinetic analysis. 

5. It is recommended that the reproductive toxicology of the excipient be evaluated as 

discussed in ICH guidelines S5A and S5B,8

 including: (1) assessment of potential to 

affect fertility or early embryonic development to implantation; (2) teratology in both a 

 

4

 53 FR 39650 (October 11, 1988)

5

 ICH guidance for industry M3 Nonclinical Safety Studies for the Conduct of Human Clinical Trials for 

Pharmaceuticals (http://www.fda.gov/cder/guidance/index.htm)

6

 ICH guidelines for industry S3A Toxicokinetics: The Assessment of Systemic Exposure in Toxicity Studies and S3B

Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution Studies 

(http://www.fda.gov/cder/guidance/index.htm)

7

 ICH guidance for industry S2B Genotoxicity: A Standard Battery for Genotoxicity Testing of Pharmaceuticals 

(http://www.fda.gov/cder/guidance/index.htm)

8

 ICH guidelines for industry S5A Detection of Toxicity to Reproduction for Medicinal Products and S5B Detection

of Toxicity to Reproduction for Medicinal Products: Addendum on Toxicity to Male Fertility 

(http://www.fda.gov/cder/guidance/index.htm)

5
Contains Nonbinding Recommendations 

rodent species and a mammalian nonrodent species; and (3) effects on prenatal and 

postnatal development, including maternal function. The most efficient way to address 

these different developmental landmarks is use of a single-study rodent assay (as defined 

in ICH guidance S5A) to assess all phases of reproductive toxicity, in conjunction with a 

teratology study in a nonrodent species, provided that the available data predict the 

excipient has minimal toxicity. 

C. Potential Excipients Intended for Intermediate Use 

We recommend that the nonclinical safety evaluation of potential new excipients that are 

intended for use in drug products that are labeled for clinical use of more than 2 weeks but less 

than or equal to 3 months per treatment episode include at least the following: 

1. All studies from Section IV.A. and B. in this guidance, with the exception of the 1-month 

toxicology studies. Note: If toxicity or significant biological activity is observed in 

short-term studies, 1-month toxicology studies may be useful for establishing dosages to 

be used in 3-month studies. 

2. We recommend that 3-month repeat-dose toxicology studies be performed in both a 

rodent species and a mammalian nonrodent species by the appropriate route of 

administration. It is important that the studies include complete clinical pathology, 

histopathology, and toxicokinetic analysis. 

3. We may ask for additional studies (e.g., studies involving parenteral administration). 

This request is usually driven by questions raised in the completed studies. 

D. Potential Excipients Intended for Long-Term Use 

We recommend that the safety evaluation of potential new excipients that are intended for use in 

drug products labeled for clinical use of more than 3 months in a given patient (either as a single 

treatment episode or as a result of multiple courses of therapy to treat a chronic or recurrent 

condition) include at least the following: 

1. All studies from Section IV.A., B., and C. of this guidance. Note that 1-month and 3-

month toxicology studies are not essential, but may provide useful dosage selection data. 

2. We recommend that a 6-month repeat-dose toxicology study be performed in a rodent 

species by the appropriate route. It is important that the study include complete clinical 

pathology, histopathology, and toxicokinetic analysis. We recommend that studies that 

involve excipients of low toxicity in general use the limit dose as the highest dose for 

testing. 

3. It is important that a chronic toxicology study be performed in a mammalian nonrodent 

species by the appropriate route. If toxicity and pharmacologic effect were absent in 

state-of-the-art subchronic studies, a 6-month study may be sufficient. When toxicity is 

detected in shorter duration studies, or in rodents, a chronic study in nonrodents of 9 to12 

6
Contains Nonbinding Recommendations 

months may be appropriate. The sponsor is encouraged to contact the appropriate review 

division for guidance. 

4. If appropriate (see ICH guideline S1A),9

 one of the following approaches may be used to 

evaluate carcinogenic potential: 

a. Two-year carcinogenicity bioassays in two appropriate species by the relevant 

routes.10

b. A 2-year carcinogenicity study in one rodent species plus an alternative study 

(e.g., appropriate use of neonatal or transgenic animals) in a different rodent 

species. We encourage discussion with the appropriate review division of the 

usual choice for that alternative assay. 

c. Submission of documentation providing scientific justification that 

carcinogenicity data are not necessary. For example, based on negative genetic 

toxicology data (see ICH guidance S2B for recommended assays), limited 

systemic exposure, absence of accumulation based on nonclinical and clinical 

pharmacokinetic data, negative histopathology data from chronic toxicology 

studies performed at the maximum feasible dose (MFD) (absence of preneoplastic 

lesions and other toxicologic effects), and knowledge of other excipients in the 

same class, it may be reasonable to forego carcinogenicity testing. Decisions 

concerning the adequacy of this approach would be made on a case-by-case basis, 

using a weight-of-evidence approach. In other cases, adequately performed cell 

transformation assays or one 2-year bioassay in the rat or one transgenic assay, if

negative, may be sufficient to contribute to the weight-of-evidence assessment to 

address the carcinogenic potential of the excipient. It is strongly encouraged that 

application of the approach described herein be undertaken in consultation with 

appropriate review division staff. 

E. Potential Excipients for Use in Pulmonary, Injectable, or Topical Products 

We recommend that the safety evaluation of potential new excipients that are intended for use in 

injectable, topical (dermal, intranasal, intraoral, ophthalmic, rectal, or vaginal), or pulmonary 

drug products include the following:11

 

9

 ICH guideline for industry S1A The Need for Long-term Rodent Carcinogenicity Studies of Pharmaceuticals 

(http://www.fda.gov/cder/guidance/index.htm)

10 It may be most cost-effective to evaluate excipients for carcinogenicity through inclusion in bioassays that are 

conducted in support of therapeutic ingredients. In such cases, it may be appropriate for the carcinogenicity 

assessment of an excipient to be limited to administration of a single dose of the excipient per species (addition of a 

single arm to each bioassay), provided that the dose was either the maximum tolerated dose (MTD) or the maximum

feasible dose (MFD). 

11 For cases in which a new excipient is being developed in relation to a specific product, sponsors are encouraged to

consult with the appropriate review division to determine if additional guidance is available. 

7
Contains Nonbinding Recommendations 

1. All studies from Section IV.A., B., C., or D., as appropriate, using the appropriate route 

of administration. Studies that include the to-be-marketed formulation of the drug 

product are preferred, if this information is available at the time of excipient evaluation. 

2. Sensitization study (e.g., guinea pig maximization study or murine local lymph node 

assay). Consult CDER guidance for industry Immunotoxicology Evaluation of 

Investigational New Drugs for more information. 

3. For excipients intended for injectable use, the following considerations may be 

appropriate: 

a. An in vitro hemolysis study could be performed at the intended concentration for 

I.V. administration (bolus and/or infusion) to determine the hemolytic potential. 

b. The plasma concentrations of creatinine kinase determined at the intended 

excipient concentration for I.M. or S.C. administration can provide information on 

potential muscle damage. 

c. An evaluation of protein binding in relation to local site tolerability could be 

done. 

4. Excipients intended for topical use may need support from toxicology studies by both the 

intended clinical route and the oral or parenteral route if clinical pharmacokinetic studies 

conducted under conditions of maximum exposure show patients would experience 

systemic exposure to the excipient or its metabolite, particularly if limited systemic 

exposure were observed in nonclinical studies conducted by the clinical route of 

administration. The developer of a potential new excipient is invited to contact the 

appropriate review division to discuss whether or not this is appropriate for a specific 

excipient. 

5. For topical dermal products and ophthalmic products, it may be appropriate to conduct an 

ocular irritation study. 

F. Photosafety Data 

We recommend that excipients be evaluated regarding the need for photosafety testing as 

described in the CDER guidance for industry Photosafety Testing. Either the excipient or the 

complete drug product could be tested. We encourage consulting the appropriate drug review 

division prior to initiation of studies. 

V. SUMMARY 

Acknowledging the need to develop new excipients, we have proposed a flexible approach that 

attempts to consider both the type of use the excipient will have in approved products and the 

biological activity and physical properties of the molecular entity. It is recognized that during 

8
Contains Nonbinding Recommendations 

9

the course of data evaluation, the reasons for additional data or the potential to eliminate some 

studies may become apparent. In such cases, we recommend consultation with appropriate 

review division staff to avoid delays in use of the excipient.