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 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
i 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)
1 This guidance has been prepared by the Office of Generic Drugs in the Center for Drug Evaluation and
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.  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
2 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
3 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
4 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**
5 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. 
6