Submission of Summary Bioequivalence Data for Abbreviated New Drug Applications

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Guidance for Industry
Submission of Summary
Bioequivalence Data for ANDAs
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
May 2011
Generics

Guidance for Industry
Submission of Summary
Bioequivalence Data for ANDAs
Additional copies are available from:
Office of Communications
Division of Drug Information, WO51, Room 2201
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave.
Silver Spring, MD 20993-0002
Phone: 301-796-3400; Fax: 301-847-8714
druginfo@fda.hhs.gov
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
May 2011
Generics

Contains Nonbinding Recommendations
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TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
III. 	SUBMISSION OF ALL BIOEQUIVALENCE STUDIES ........................................... 2
A. 	What Types of ANDA Submissions Must Include All BE Studies? .......................................... 3
B. 	What Format Should Be Used for a Summary Report? ............................................................ 3
IV. 	SAME DRUG PRODUCT FORMULATION................................................................ 3
A. 	Immediate-Release Drug Products............................................................................................... 4
1. 	Immediate-Release Formulations Considered to Be the Same……………………………..….4
2. 	Immediate-Release Formulations Considered Not to Be the Same……………………………5
3. 	Immediate-Release Formulations - Other………………………………………………..……6
B. 	Extended-Release Drug Products—Nonrelease Controlling Excipients................................... 6
1. 	Extended-Release Formulations Considered to Be the Same (Nonrelease Controlling Excipients)…6
2. Extended -Release Formulations Considered Not to Be the Same
(Nonrelease Controlling Excipients)……………………………………………………………………...…..………. 7
3. Extended-Release Formulations - Other (Nonrelease Controlling Excipients)………...………..……7
C. 	Extended-Release Drug Products—Release Controlling Excipients......................................... 8
1. Extended-Release Formulations Considered to Be the Same (Release Controlling Excipients)……..8
2. Extended-Release Formulations Considered Not to Be the Same (Release Controlling Excipients)...8
3. Extended-Release Formulations - Other (Release Controlling Excipients)..........................................8
D. 	Semisolid Dosage Forms................................................................................................................ 8
E. 	Other Complex Dosage Forms...................................................................................................... 9

Contains Nonbinding Recommendations
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Guidance for Industry1
Submission of Summary Bioequivalence Data for ANDAs
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5 	This guidance represents the Food and Drug Administration’s (FDA’s) current thinking on this topic. It
6 	does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
7 	You can use an alternative approach if the approach satisfies the requirements of the applicable statutes
8 	and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for
9 	implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate
10 	number listed on the title page of this guidance.
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I. 	INTRODUCTION
This guidance is intended to assist applicants who are submitting abbreviated new drug
applications (ANDAs) in complying with FDA’s requirements for the submission of
bioequivalence (BE) data. FDA’s final rule on “Requirements for Submission of Bioequivalence
Data” (the BE data rule) requires an ANDA applicant to submit data from all BE studies the
applicant conducts on a drug product formulation submitted for approval, including studies that
do not demonstrate that the generic product meets the current bioequivalence criteria.2 All BE
studies conducted on the same drug product formulation must be submitted to the Agency as
either a complete study report or a summary report of the BE data.3 The amended regulations
include a definition of same drug product formulation (section 320.1(g)).
This guidance provides information on the following subjects:
• 	Types of ANDA submissions covered by the BE data rule.
• 	Recommended format for summary reports of BE studies.
• 	Types of formulations the Agency considers to be the same drug product
formulation for different dosage forms based on differences in composition.
This guidance does not address which formulations the Agency considers to be the same drug
product formulation based on differences in methods of manufacture.
1 This guidance has been prepared by the Division of Bioequivalence, Office of Generic Drugs, Office of
Pharmaceutical Science, in the Center for Drug Evaluation and Research (CDER) at the Food and Drug
Administration.
2 See the final rule, “Requirements for Submission of Bioequivalence Data,” that was published in the Federal
Register on January 16, 2009.
3 The BE data rule amended the Agency’s bioequivalence regulations in 21 CFR parts 314 and 320.
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The guidance is applicable to BE studies conducted for ANDAs during both preapproval and
postapproval periods.
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
The Federal Food, Drug, and Cosmetic Act (the FD&C Act) and FDA regulations require that an
ANDA applicant submit, among other things, information showing that the applicant’s drug
product is bioequivalent to the approved product designated by FDA as the reference listed drug
(RLD) (section 505(j)(2)(A)(iv) of the FD&C Act (21 U.S.C. 355(j)(2)(A)(iv); sections
314.94(a)(7) and 320.21(b)(1)). In the past, ANDA applicants submitted only the BE studies that
demonstrated that a generic product met BE criteria,4 but they did not typically submit additional
BE studies conducted on the same drug product formulation, including studies that did not show
the product met bioequivalence criteria.
The BE data rule amended FDA’s regulations to require that an ANDA applicant submit data
from all BE studies the applicant conducts on the drug product formulation submitted for
approval (sections 314.81(b)(2)(vi), 314.94(a)(7), 314.96(a)(i), and 320.21(b)(1) and (c)). We
believe that data from any additional BE studies may be important in our determination of
whether a product is bioequivalent to the RLD and are relevant to our evaluation of generic
products in general. 5 These data will increase our understanding of generic drug development
and how changes in components and composition may affect formulation performance, as well
as promote further development of science-based bioequivalence policies.
III. 	SUBMISSION OF ALL BIOEQUIVALENCE STUDIES
FDA regulations, as amended by and clarified in the BE data rule, require that a complete report
be submitted for the BE studies upon which the applicant relies for approval and either a
complete or summary report be submitted for each additional study conducted on the same drug
product formulation (sections 314.81(b)(2)(vi), 314.94(a)(7), 314.96(a)(i), and 320.21(b)(1) and
(c)). This requirement includes both in vivo and in vitro testing conducted to demonstrate
bioequivalence. The regulations also provide that, if a summary report is submitted—and the
Agency believes that there may be bioequivalence issues or concerns with the drug product—the
Agency may request that a complete report be prepared and submitted to FDA.
4 Currently 90 percent confidence interval limits of 80 to 125.
5 This view was endorsed by FDA’s Advisory Committee for Pharmaceutical Science at a meeting held on
November 16, 2000. See 68 FR 61640 at 61647, October 29, 2003.
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A. 	What Types of ANDA Submissions Must Include All BE Studies?
Under the BE data rule, ANDA applicants are required to submit information from all BE studies
conducted on the same formulation of the drug product contained in the following submissions:
• 	ANDAs (section 314.94).
• 	ANDA amendments (section 314.96(a)).
• 	ANDA supplements that require BE studies under section 320.21(c).
• 	ANDAs submitted under a suitability petition (section 314.93).
• 	ANDA annual reports (section 314.81(b)(2)(vi)).
B. 	What Format Should Be Used for a Summary Report?
90 	For a suggested format for summary reports, go online to FDA’s Generic Drugs: Information for
Industry web page. The Division of Bioequivalence has developed model data summary tables
in a concise format consistent with a
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common technical document (CTD) formatted application.
The tables are located under the heading “Generic Drug Development, Abbreviated New Drug
Application (ANDA) Submissions, and Review Information.” The Agency recommends that
these table formats be used to organize the data for summary reports required by the BE data
rule.
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IV. 	SAME DRUG PRODUCT FORMULATION
FDA amended the regulations to require an applicant to submit data from all BE studies
conducted on the same formulation of the drug product submitted for approval. In section
320.1(g), FDA added a definition of the term same drug product formulation:
Same drug product formulation means the formulation of the drug product submitted for
approval and any formulations that have minor differences in composition or method of
manufacture from the formulation submitted for approval, but are similar enough to be
relevant to the FDA’s determination of bioequivalence.
The definition of same drug product formulation in section 320.1(g) applies regardless of whether
the products are manufactured at the same or different manufacturing sites. 6
In the following sections, we discuss differences in composition to consider when comparing drug
product formulations. For immediate-release (IR) and extended-release (ER) drug products, we
discuss:
• 	Minor differences in composition that are unlikely to have any detectable impact on
formulation quality and performance between the formulations being compared. These
6 See the preamble of the BE data rule, FDA response to comment 15.
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differences would result in formulations that meet the definition of same drug product
formulation and for which BE studies must be submitted (sections 314.81(b)(2)(vi),
314.94(a)(7), 314.96(a)(i), and 320.21(b)(1) and (c)).
• 	Differences in composition that are likely to result in a significant difference in
formulation quality and performance between the formulations being compared. These
differences would result in formulations that do not meet the definition of same drug
product formulation and for which BE studies need not be submitted.
A. 	Immediate-Release Drug Products
1. 	Immediate-Release Formulations Considered to Be the Same
Minor differences that result in product formulations that are considered to be the same include
the following:
• 	A difference in an ingredient intended to affect the color or flavor of the drug product.
• 	A different approved ingredient of the printing ink.
• 	A difference in the technical grade and/or specification of an excipient (e.g., Avicel
PH102 versus Avicel PH200).
• 	A difference in particle size of the drug substance or excipients.
Formulations with different amounts of excipients are considered to be the same drug product
formulation if:
• 	For an individual excipient, the difference in weight between the formulations being
compared is less than or equal to the percentage shown in Table 1, and
• 	The cumulative total of all excipient weight differences is less than or equal to 10
percent.
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Table 1. Immediate-Release Formulations—Differences in Excipient Weights
Excipient
Difference (≤) in Excipient
Weights Between Two
Formulations *
Filler 	10
Disintegrant
Starch
Other
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2
Binder 	3
Lubricant
Calcium or Magnesium Stearate
Other
0.5
2
Glidant
Talc
Other
2
0.2
Film Coat 	2
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* Percentage of difference between the formulation proposed for marketing and another experimental
formulation.
Illustrative examples of IR formulations considered to be the same are provided below:
• 	If the amount of a filler excipient in an experimental formulation (A) is 105 mg and
the same filler excipient in the formulation proposed to be marketed (B) is 100 mg,
the difference in the excipient weight is 5 percent. These two formulations would be
considered the same because the difference in weight of the filler excipient is less
than 10 percent.
• 	In the case of multiple excipient changes, if an experimental formulation (A) contains
95 mg of a filler excipient and 103 mg of a disintegrant and the formulation proposed
for marketing (B) contains 100 mg of the same filler excipient and 100 mg of the
same disintegrant, the difference in weight for the filler excipient is 5 percent and the
difference in weight for the disintegrant is 3 percent. The cumulative change is 8
percent, which is less than 10 percent for all excipient differences. Therefore, these
formulations would be considered the same.
2. 	Immediate-Release Formuations Considered Not to Be the Same
A difference that results in product formulations that are considered not to be the same would
include the addition or deletion of an excipient (with the exception of a difference in an
ingredient intended to affect the color or flavor of the drug product or a difference in an
ingredient of the printing ink).
Formulations with different amounts of the same excipients are considered not to be the same
drug product formulation if:
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• 	For an individual excipient, the difference in excipient weight between the
formulations being compared exceeds the percentages shown in Table 1, or
• 	The cumulative total of all excipient weight differences exceeds 10 percent.
Illustrative examples of IR formulations considered not to be the same are provided below:
• 	If the amount of a filler excipient in an experimental formulation (A) is 115 mg and
the filler excipient in the formulation proposed for marketing (B) is 100 mg, the
difference in the excipient weight would be 15 percent. These two formulations
would not be considered the same because the difference in weight of the filler
excipient is greater than 10 percent.
• 	In the case of multiple excipient changes, if an experimental formulation (A) contains
90 mg of a filler excipient and 106 mg of a disintegrant and the formulation proposed
for marketing (B) contains 100 mg of the filler excipient and 100 mg of the
disintegrant, the difference in weight for the excipient is 10 percent and the difference
in weight for the disintegrant is 6 percent. The cumulative change would be 16
percent. Therefore, these formulations would not be considered the same, and any
studies conducted with formulation A would not need to be submitted.
3. 	Immediate Release Formulations - Other
Studies performed on experimental formulations containing different polymorphic forms of the
drug substance also should be submitted.
B. 	Extended-Release Drug Products—Nonrelease Controlling Excipients
1. 	Extended-Release Formulations Considered to Be the Same (Nonrelease
Controlling Excipients)
Minor differences that result in product formulations that are considered to be the same include
the following:
• 	A difference in an ingredient intended to affect the color or flavor of the drug product.
• 	A different approved ingredient of the printing ink.
• 	A difference in the technical grade and/or specification of a nonrelease controlling
excipient (e.g., Avicel PH102 versus Avicel PH200).
• 	A difference in particle size of the drug substance or excipients.
Formulations with different amounts of the same nonrelease controlling excipients are considered
to be the same drug product formulation if:
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• 	For an individual excipient, the difference in excipient weight between the formulations
being compared is less than or equal to the percentages listed in Table 2, and
• 	The cumulative total of all excipient weight differences is less than or equal to 10
percent.
Table 2. Extended-Release Formulations—Differences in Excipient Weights
Nonrelease Controlling Excipient
Difference ( ≤ ) in Excipient
Weights Between Two
Formulations *
Filler 	10
Disintegrant
Starch
Other
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2
Binder 	1
Lubricant
Calcium or Magnesium Stearate
Other
0.5
2
Glidant
Talc
Other
2
0.2
Film Coat 	2
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*Percentage of difference between the formulation proposed for marketing and another experimental
formulation.
2. 	Extended-Release Formulations Considered Not to Be the Same (Nonrelease
Controlling Excipients)
Examples of differences that result in product formulations that are considered not to be the same
include the following:
• 	The addition or deletion of an excipient (except for a difference in an ingredient
intended to affect the color or flavor of the drug product or a difference in an
ingredient of the printing ink).
• 	A difference in weight of a nonrelease controlling excipient between the formulations
being compared that exceeds the percentage listed in Table 2.
• 	The cumulative total difference in weights of all nonrelease controlling excipients
exceeds 10 percent.
3. 	Extended Release Formulations – Other (Nonrelease Controlling Excipients)
Studies performed on experimental formulations containing different polymorphic forms of the
drug substance also should be submitted.
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C. 	Extended-Release Drug Products—Release Controlling Excipients
1. 	Extended-Release Formulations Considered to Be the Same (Release Controlling
Excipients)
Examples of minor differences that result in product formulations that are considered to be the
same include the following:
• 	A difference in the technical grade and/or specification of the release controlling
excipient(s) (e.g., Eudragit RS 100 versus Eudragit RL 100).
• 	A difference in particle size of the drug substance or excipients.
• 	A difference in the amount of release controlling excipient(s), expressed as the
difference in weight of the release controlling excipient(s) in the experimental
formulation compared to the formulation proposed for marketing, of less than or
equal to 10 percent.
2. 	Extended-Release Formulations Considered Not to Be the Same (Release
Controlling Excipients)
Examples of differences that result in product formulations that are considered not to be the same
include the following:
• 	The addition or deletion of a release controlling excipient.
• A difference in the amount of release controlling excipient(s), expressed as the
difference in weight of the release controlling excipient(s) in the experimental
formulation compared to the formulation proposed for marketing, of greater than 10
percent.
3. 	Extended Release Formulations – Other (Release Controlling Excipients)
Studies performed on experimental formulations containing different polymorphic forms of the
drug substance also should be submitted.
D. 	Semisolid Dosage Forms
For the purposes of this guidance, formulations of semisolid dosage form products are
considered to be the same if the experimental formulation is in the same category as the
formulation proposed for marketing (e.g., the formulations being compared are both for creams)
and any differences between formulations are as described below.
• 	If the difference in the amount of an individual excipient between the experimental
formulation and the formulation intended to be marketed is less than or equal to 5
percent, the two formulations are considered to be the same.
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• 	If more than one excipient amount is changed, and the cumulative total of differences
in the amount of all excipients is less than or equal to 7 percent, the two formulations
are considered to be the same.
• 	Formulations with differences in particle size distribution of the drug substance, if the
drug is in suspension, are considered to be the same.
Formulations with differences in technical grade of a structure forming excipient are considered
not to be the same.
E. 	Other Complex Dosage Forms
For other complex dosage forms (e.g., transdermals, injectable suspensions, and suppositories),
limited information is available regarding quantitative and qualitative changes that could have a
significant impact on the bioavailability of the product. Because of this lack of information, we
consider all experimental formulations that are pharmaceutically equivalent to the formulation of
the complex dosage form product intended to be marketed to be the same as the RLD.
Therefore, the Agency requests submission of either a summary report or a complete report of all
bioavailability or bioequivalence studies conducted during the development of the drug product.
This information will increase our understanding of the development of the generic product and
how changes in components, composition, and methods of manufacture have affected
formulation performance. Access to this information will promote further development of
science-based bioequivalence policies for complex dosage forms.