Guidance for Industry

Variations in Drug Products that

May Be Included in a Single ANDA

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

December 1998

OGD 2
Guidance for Industry

Variations in Drug Products that

May Be Included in a Single ANDA

Comments and suggestions regarding this document should be submitted within 90 days of

publication in the Federal Register of the notice announcing the availability of the guidance. All

comments should be identified with the docket number provided at the beginning of the notice.

Submit comments to the Dockets Management Branch (HFA-305), Food and Drug

Administration, 5630 Parklawn Dr., rm. 1061, Rockville, MD 20852. 

After the comment period closes, comments should be provided in writing to the Center for Drug

Evaluation and Research (CDER), Food and Drug Administration, 5600 Fishers Lane, Rockville,

Md. 20857.

Additional copies are available from:

Office of Training and Communications 

Division of Communications Management

The Drug Information Branch, HFD-210

5600 Fishers Lane, Rockville, MD 20857

(Tel) 301-827-4573

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

U.S. Department of Health and Human Services

Food and Drug Administration

Center for Drug Evaluation and Research (CDER)

December 1998

OGD 2
i

TABLE OF CONTENTS

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

II. GENERAL CONSIDERATIONS ....................................... . 1

A. Reference Listed Drugs (RLDs) ................................... . 1

B. Multiple Bioequivalence Studies .................................. . 2

C. Different Excipients ............................................ . 2

D. Different Dosage Forms ......................................... . 3

E. Pharmacy Bulk Packages ........................................ . 3

F. Different Strengths or Concentrations ............................. . 3

G. Different Container Sizes and Configurations ....................... . 3

III. SPECIFIC DOSAGE FORMS ......................................... . 4

A. Solid Oral Dosage Forms ........................................ . 4

B. Parenteral Products ............................................ . 5

C. Transdermal Products .......................................... . 6
This guidance has been prepared by the Office of Generic Drugs in the Center for Drug Evaluation and 1

Research (CDER) at the Food and Drug Administration. This guidance represents the Agency's current thinking on

variations in drug products that may be included in a single abbreviated application. 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 statue, regulations, or both. 

GUIDANCE FOR INDUSTRY1

Variations in Drug Products that May Be Included in a Single 

Abbreviated New Drug Application

I. INTRODUCTION

This guidance is intended to provide information to applicants on certain specific variations of a

drug product that should be included in a single abbreviated new drug application (ANDA) and

describe the general factors to be considered when determining whether single or multiple

ANDAs should be submitted. 

Prior to October 1, 1990, applicants were to submit separate ANDAs for each drug dosage form

and for each variation (e.g., strength or color) within a dosage form. Historically, applications

were separated for ease of review and postapproval tracking. On October 1, 1990, the Office of

Generic Drugs (OGD) issued the Interim Policy and Procedure Guide (PPG) 20-90. This guide

permitted certain variations of solid oral dosage forms and injectables to be submitted within a

single abbreviated application. On June 7, 1995, PPG 20-90 was amended to allow certain

variations to be submitted as supplements.

This guidance incorporates the policies and procedures in PPG 20-90, clarifies the practice of

including variations of products in a single application, and reduces the burden on industry for

submitting and maintaining separate applications for certain variations of the same drug product.

II. GENERAL CONSIDERATIONS

To minimize disruption of the review of pending applications, OGD recommends that applications

that have already been submitted but not approved be maintained as submitted. To aid in

administrative tracking, OGD also suggests that applications submitted before December 31,

1998, continue to follow the policies described in OGD PPG 20-90. For applications submitted

after December 31, 1998, OGD recommends that applicants refer to this guidance to determine

whether one or more ANDAs should be submitted for variations of a specific drug product

dosage form.

A. Reference Listed Drugs (RLDs)
2

To determine which variations of a product should be included in a single abbreviated

application, the initial consideration is whether there are separate NDAs as reference listed

drugs (RLDs) or whether there is a single NDA as a RLD. (For example, when the same

drug product is used for two separate indications, that product might have two separate

NDAs as RLDs.) Generally, when there is a separate NDA as a reference listed drug for a

specific drug product there should be a separate abbreviated application for that NDA. 

However, as described in sections B through G of this guidance, this will not always be

the case.

B. Multiple Bioequivalence Studies

Separate ANDAs should be submitted when, because of certain variations in the drug

product (e.g., formulations, shapes), an in vivo bioequivalence study cannot be waived (21

CFR 320). Examples of this situation include:

C Formulation Differences. Two products should not be included in the same

application if two strengths of a capsule have differences in formulation or if there

are questions about absorption of the products so that an in vivo bioequivalence

waiver would not be granted for the lower strength, even if a bioequivalence study

was performed on the higher strength (21 CFR 320.22(d)(2)).

C Multiple combinations of strengths, shapes, and colors for oral solids. Where there

are such multiple combinations, separate in vivo bioequivalence studies should be

performed and separate applications should be submitted (21 CFR 320.22(d)(4)). 

More specific guidance on this can be found in Section III, Specific Dosage Forms.

There are instances when a single ANDA can be submitted even if the application includes

more than one bioequivalence study. For example, if there are five strengths of a product

and there is acceptable proportionality of inactive ingredients, but the Division of

Bioequivalence (DBE) has suggested separate bioequivalence studies on the lowest and

highest strengths, all five strengths may be included in the same application. In this case,

the studies are not related to a difference in formulation but have been recommended to

ensure the equivalence of a product across a wide range of strengths. 

C. Different Excipients

Any product variations because of differences in excipients (e.g., absorption enhancers or

hydrophobic agents) or other changes in formulation that may significantly affect

absorption of the active drug ingredient or active moiety should be submitted in separate

applications. This would include products with differences in excipients where separate
3

bioequivalence studies are recommended.

Topical products with differences in excipients where separate in vivo demonstration of

bioequivalence is recommended should be submitted in separate applications.

D. Different Dosage Forms

Different dosage forms should be submitted in separate applications. (See the FDA

publication, Approved Drug Products with Therapeutic Equivalence Evaluations.)

E. Pharmacy Bulk Packages

Pharmacy bulk packages should always be submitted as separate applications. Strengths

or fill volumes for pharmacy bulk packages that can share a single application should be

determined based on the RLD.

F. Different Strengths or Concentrations

Different strengths or concentrations of a drug product or combination product, if they are

the same dosage form, intended for the same route of administration, and have the same

indications, should be submitted in one original application when their qualitative

composition is the same. (See Section IV for additional guidance.)

G. Different Container Sizes and Configurations

Except for pharmacy bulk packages, products utilizing different container sizes,

configurations, and materials (e.g., glass or plastic) of one finished pharmaceutical product

intended to be used for the same route of administration and for the same indications

(consistent with the RLD) may usually be included in a single application, within certain

limitations.

In general, separate applications should be submitted for special packaging systems. In

this context, special packaging may describe novel or technologically new container

closure systems or packaging to serve the special needs of the intended population. A

major consideration in deciding if single or multiple ANDAs would be recommended is

whether significantly different manufacturing processes for which there is little experience

would be used in the special packaging. Because of the range of possibilities that special

packaging provides, such applications will generally be treated on a case-by-case basis. If

applicants are considering novel or nontraditional processes for packaging, it is suggested

that the specific situations should be discussed with OGD prior to submitting applications.

Different packaging formats in which the drug delivery device is integral to the use of the

product usually should be submitted as separate applications. In this case the
4

manufacturing process for the packaging format may be a consideration. Examples

include syringes, aerosol or pressurized (powered) dispensers versus manually operated

pump dispensers, and product-loaded swabs versus applicator bottles or separate solutions

and applicators. Unit and bulk packed product-loaded swabs, however, could be included

in a single application.

III. SPECIFIC DOSAGE FORMS

The considerations for more prevalent specific dosage forms are detailed below. For dosage

forms not specifically covered, please refer to Section II - General Considerations. The

recommendations in Section III are intended to provide the applicant with sufficient information

to determine whether separate applications should be submitted for other dosage forms. If there

are still questions, the OGD should be contacted for assistance.

A. Solid Oral Dosage Forms

The chart below is a restatement of the information set forth in PPG 20-90. Applicants

should limit the number of variations in a single application. Limiting the variations makes

the review process simpler and allows more accurate tracking of postapproval changes. 

Only the following combinations of strengths, color, and shapes should be included in a

single application.

SOLID ORAL DOSAGE FORMS

One strength

One color

One shape = Single application

One strength

One color

Multiple shapes = Single application

One strength

Multiple colors

One shape = Single application

Multiple strengths

One color

One shape = Single application

Multiple shapes = Only one color per shape per strength should

be submitted in a single application. Different

combinations should be submitted in separate
5

applications.

B. Parenteral Products

Each application for a parenteral product should be limited to a common formulation. 

When more than one strength of a product exists, some small formulation differences may

be included in a single application. A common example of such a difference is the amount

of inactive ingredient needed to produce tonicity. Preserved and nonpreserved

formulations, however, are considered to be different formulations, and separate

applications would be recommended.

Varying fill volumes (e.g., 2, 5, and 20 mL vial sizes) may be included in the same

application, but drug products with different container materials or packaging systems

should be submitted as separate applications. 

PARENTERAL SOLUTIONS AND SUSPENSIONS 

One formulation 

One strength = Single application

One formulation

Multiple strengths = Single application

Multiple formulations

(e.g., preserved or unpreserved)

One strength = Multiple applications*

One formulation

One strength

Multiple fill sizes = Single application**
6

One formulation

One strength

One or multiple fill sizes, 

Multiple packaging types, 

or container materials = Multiple applications, depending on the

number of package types and/or container

materials used

*Some small formulation differences, such as the amount of an inactive ingredient

needed to maintain tonicity, may be included in a single application with different

strengths. Additionally, each application should be limited to a single dosage form.

** Except Pharmacy bulk packages. Pharmacy bulk packages should always be

submitted as separate applications.

PARENTERAL STERILE SOLIDS

One formulation

One or multiple fill quantities

Single container/closure system = Single application

One formulation

One or multiple fill quantities

Multiple container/closure 

systems = Multiple applications 

Multiple formulations = Multiple applications

C. Transdermal Products

The method of manufacture of a transdermal product usually determines whether one or

more applications would be recommended. For example, if the active ingredient is

contained in the patch adhesive, the same application should not contain submission data

for a product where the active ingredient is contained in a reservoir. Transdermal systems

of the same size which release different amounts of the active ingredient through a

membrane should be submitted in separate ANDAs, because each strength uses different

manufacturing procedures and controls. However, transdermal products in which the

active ingredient is in the same component of the patch, but product strength depends

upon the patch size, should be in a single application.