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

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

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1 Guidance for Industry1

2 Submission of Summary Bioequivalence Data for ANDAs
3
4
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.
11
12
13
14 I. INTRODUCTION
15
16 This guidance is intended to assist applicants who are submitting abbreviated new drug
17 applications (ANDAs) in complying with FDA’s requirements for the submission of
18 bioequivalence (BE) data. FDA’s final rule on “Requirements for Submission of Bioequivalence
19 Data” (the BE data rule) requires an ANDA applicant to submit data from all BE studies the
20 applicant conducts on a drug product formulation submitted for approval, including studies that
21 do not demonstrate that the generic product meets the current bioequivalence criteria.2 All BE
22 studies conducted on the same drug product formulation must be submitted to the Agency as
23 either a complete study report or a summary report of the BE data.3 The amended regulations
24 include a definition of same drug product formulation (section 320.1(g)).
25
26 This guidance provides information on the following subjects:
27
28 • Types of ANDA submissions covered by the BE data rule.
29
30 • Recommended format for summary reports of BE studies.
31
32 • Types of formulations the Agency considers to be the same drug product
33 formulation for different dosage forms based on differences in composition.
34
35 This guidance does not address which formulations the Agency considers to be the same drug
36 product formulation based on differences in methods of manufacture.
37

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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38 The guidance is applicable to BE studies conducted for ANDAs during both preapproval and
39 postapproval periods.
40
41 FDA’s guidance documents, including this guidance, do not establish legally enforceable
42 responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should
43 be viewed only as recommendations, unless specific regulatory or statutory requirements are
44 cited. The use of the word should in Agency guidances means that something is suggested or
45 recommended, but not required.
46
47 II. BACKGROUND
48
49 The Federal Food, Drug, and Cosmetic Act (the FD&C Act) and FDA regulations require that an
50 ANDA applicant submit, among other things, information showing that the applicant’s drug
51 product is bioequivalent to the approved product designated by FDA as the reference listed drug
52 (RLD) (section 505(j)(2)(A)(iv) of the FD&C Act (21 U.S.C. 355(j)(2)(A)(iv); sections
53 314.94(a)(7) and 320.21(b)(1)). In the past, ANDA applicants submitted only the BE studies that
54 demonstrated that a generic product met BE criteria,4 but they did not typically submit additional
55 BE studies conducted on the same drug product formulation, including studies that did not show
56 the product met bioequivalence criteria.
57
58 The BE data rule amended FDA’s regulations to require that an ANDA applicant submit data
59 from all BE studies the applicant conducts on the drug product formulation submitted for
60 approval (sections 314.81(b)(2)(vi), 314.94(a)(7), 314.96(a)(i), and 320.21(b)(1) and (c)). We
61 believe that data from any additional BE studies may be important in our determination of
62 whether a product is bioequivalent to the RLD and are relevant to our evaluation of generic
63 products in general.5 These data will increase our understanding of generic drug development
64 and how changes in components and composition may affect formulation performance, as well
65 as promote further development of science-based bioequivalence policies.
66
67 III. SUBMISSION OF ALL BIOEQUIVALENCE STUDIES
68
69 FDA regulations, as amended by and clarified in the BE data rule, require that a complete report
70 be submitted for the BE studies upon which the applicant relies for approval and either a
71 complete or summary report be submitted for each additional study conducted on the same drug
72 product formulation (sections 314.81(b)(2)(vi), 314.94(a)(7), 314.96(a)(i), and 320.21(b)(1) and
73 (c)). This requirement includes both in vivo and in vitro testing conducted to demonstrate
74 bioequivalence. The regulations also provide that, if a summary report is submitted—and the
75 Agency believes that there may be bioequivalence issues or concerns with the drug product—the
76 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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77 A. What Types of ANDA Submissions Must Include All BE Studies?

78
79 Under the BE data rule, ANDA applicants are required to submit information from all BE studies
80 conducted on the same formulation of the drug product contained in the following submissions:
81
82 • ANDAs (section 314.94).
83 • ANDA amendments (section 314.96(a)).
84 • ANDA supplements that require BE studies under section 320.21(c).
85 • ANDAs submitted under a suitability petition (section 314.93).
86 • ANDA annual reports (section 314.81(b)(2)(vi)).
87
88 B. What Format Should Be Used for a Summary Report?
89
90 For a suggested format for summary reports, go online to FDA’s Generic Drugs: Information for
91 Industry web page. The Division of Bioequivalence has developed model data summary tables
92 in a concise format consistent with a common technical document (CTD) formatted application.
93 The tables are located under the heading “Generic Drug Development, Abbreviated New Drug
94 Application (ANDA) Submissions, and Review Information.” The Agency recommends that
95 these table formats be used to organize the data for summary reports required by the BE data
96 rule.
97
98 IV. SAME DRUG PRODUCT FORMULATION
99
100 FDA amended the regulations to require an applicant to submit data from all BE studies
101 conducted on the same formulation of the drug product submitted for approval. In section
102 320.1(g), FDA added a definition of the term same drug product formulation:
103
104 Same drug product formulation means the formulation of the drug product submitted for
105 approval and any formulations that have minor differences in composition or method of
106 manufacture from the formulation submitted for approval, but are similar enough to be
107 relevant to the FDA’s determination of bioequivalence.
108
109 The definition of same drug product formulation in section 320.1(g) applies regardless of whether
110 the products are manufactured at the same or different manufacturing sites.6
111
112 In the following sections, we discuss differences in composition to consider when comparing drug
113 product formulations. For immediate-release (IR) and extended-release (ER) drug products, we
114 discuss:
115
116 • Minor differences in composition that are unlikely to have any detectable impact on
117 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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118 differences would result in formulations that meet the definition of same drug product
119 formulation and for which BE studies must be submitted (sections 314.81(b)(2)(vi),
120 314.94(a)(7), 314.96(a)(i), and 320.21(b)(1) and (c)).
121
122 • Differences in composition that are likely to result in a significant difference in
123 formulation quality and performance between the formulations being compared. These
124 differences would result in formulations that do not meet the definition of same drug
125 product formulation and for which BE studies need not be submitted.
126
127 A. Immediate-Release Drug Products
128
129 1. Immediate-Release Formulations Considered to Be the Same
130
131 Minor differences that result in product formulations that are considered to be the same include
132 the following:
133
134 • A difference in an ingredient intended to affect the color or flavor of the drug product.
135
136 • A different approved ingredient of the printing ink.
137
138 • A difference in the technical grade and/or specification of an excipient (e.g., Avicel
139 PH102 versus Avicel PH200).
140
141 • A difference in particle size of the drug substance or excipients.
142
143 Formulations with different amounts of excipients are considered to be the same drug product
144 formulation if:
145
146 • For an individual excipient, the difference in weight between the formulations being
147 compared is less than or equal to the percentage shown in Table 1, and
148
149 • The cumulative total of all excipient weight differences is less than or equal to 10
150 percent.
151

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152 Table 1. Immediate-Release Formulations—Differences in Excipient Weights

153
Difference (≤) in Excipient
Excipient Weights Between Two
Formulations*
Filler 10
Disintegrant
Starch 6
Other 2
Binder 3
Lubricant
Calcium or Magnesium Stearate 0.5
Other 2
Glidant
Talc 2
Other 0.2
Film Coat 2
154 * Percentage of difference between the formulation proposed for marketing and another experimental
155 formulation.
156
157 Illustrative examples of IR formulations considered to be the same are provided below:
158
159 • If the amount of a filler excipient in an experimental formulation (A) is 105 mg and
160 the same filler excipient in the formulation proposed to be marketed (B) is 100 mg,
161 the difference in the excipient weight is 5 percent. These two formulations would be
162 considered the same because the difference in weight of the filler excipient is less
163 than 10 percent.
164
165 • In the case of multiple excipient changes, if an experimental formulation (A) contains
166 95 mg of a filler excipient and 103 mg of a disintegrant and the formulation proposed
167 for marketing (B) contains 100 mg of the same filler excipient and 100 mg of the
168 same disintegrant, the difference in weight for the filler excipient is 5 percent and the
169 difference in weight for the disintegrant is 3 percent. The cumulative change is 8
170 percent, which is less than 10 percent for all excipient differences. Therefore, these
171 formulations would be considered the same.
172
173 2. Immediate-Release Formuations Considered Not to Be the Same
174
175 A difference that results in product formulations that are considered not to be the same would
176 include the addition or deletion of an excipient (with the exception of a difference in an
177 ingredient intended to affect the color or flavor of the drug product or a difference in an
178 ingredient of the printing ink).
179
180 Formulations with different amounts of the same excipients are considered not to be the same
181 drug product formulation if:
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183 • For an individual excipient, the difference in excipient weight between the
184 formulations being compared exceeds the percentages shown in Table 1, or
185
186 • The cumulative total of all excipient weight differences exceeds 10 percent.
187
188 Illustrative examples of IR formulations considered not to be the same are provided below:
189
190 • If the amount of a filler excipient in an experimental formulation (A) is 115 mg and
191 the filler excipient in the formulation proposed for marketing (B) is 100 mg, the
192 difference in the excipient weight would be 15 percent. These two formulations
193 would not be considered the same because the difference in weight of the filler
194 excipient is greater than 10 percent.
195
196 • In the case of multiple excipient changes, if an experimental formulation (A) contains
197 90 mg of a filler excipient and 106 mg of a disintegrant and the formulation proposed
198 for marketing (B) contains 100 mg of the filler excipient and 100 mg of the
199 disintegrant, the difference in weight for the excipient is 10 percent and the difference
200 in weight for the disintegrant is 6 percent. The cumulative change would be 16
201 percent. Therefore, these formulations would not be considered the same, and any
202 studies conducted with formulation A would not need to be submitted.
203
204 3. Immediate Release Formulations - Other
205
206 Studies performed on experimental formulations containing different polymorphic forms of the
207 drug substance also should be submitted.
208
209 B. Extended-Release Drug Products—Nonrelease Controlling Excipients
210
211 1. Extended-Release Formulations Considered to Be the Same (Nonrelease
212 Controlling Excipients)
213
214 Minor differences that result in product formulations that are considered to be the same include
215 the following:
216
217 • A difference in an ingredient intended to affect the color or flavor of the drug product.
218
219 • A different approved ingredient of the printing ink.
220
221 • A difference in the technical grade and/or specification of a nonrelease controlling
222 excipient (e.g., Avicel PH102 versus Avicel PH200).
223
224 • A difference in particle size of the drug substance or excipients.
225
226 Formulations with different amounts of the same nonrelease controlling excipients are considered
227 to be the same drug product formulation if:
228

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229 • For an individual excipient, the difference in excipient weight between the formulations
230 being compared is less than or equal to the percentages listed in Table 2, and
231
232 • The cumulative total of all excipient weight differences is less than or equal to 10
233 percent.
234
235 Table 2. Extended-Release Formulations—Differences in Excipient Weights
236
Difference ( ≤ ) in Excipient
Nonrelease Controlling Excipient Weights Between Two
Formulations*
Filler 10
Disintegrant
Starch 6
Other 2
Binder 1
Lubricant
Calcium or Magnesium Stearate 0.5
Other 2
Glidant
Talc 2
Other 0.2
Film Coat 2
237 *Percentage of difference between the formulation proposed for marketing and another experimental
238 formulation.
239
240 2. Extended-Release Formulations Considered Not to Be the Same (Nonrelease
241 Controlling Excipients)
242
243 Examples of differences that result in product formulations that are considered not to be the same
244 include the following:
245
246 • The addition or deletion of an excipient (except for a difference in an ingredient
247 intended to affect the color or flavor of the drug product or a difference in an
248 ingredient of the printing ink).
249
250 • A difference in weight of a nonrelease controlling excipient between the formulations
251 being compared that exceeds the percentage listed in Table 2.
252
253 • The cumulative total difference in weights of all nonrelease controlling excipients
254 exceeds 10 percent.
255
256 3. Extended Release Formulations – Other (Nonrelease Controlling Excipients)
257
258 Studies performed on experimental formulations containing different polymorphic forms of the
259 drug substance also should be submitted.

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260 C. Extended-Release Drug Products—Release Controlling Excipients

261
262 1. Extended-Release Formulations Considered to Be the Same (Release Controlling
263 Excipients)
264
265 Examples of minor differences that result in product formulations that are considered to be the
266 same include the following:
267
268 • A difference in the technical grade and/or specification of the release controlling
269 excipient(s) (e.g., Eudragit RS 100 versus Eudragit RL 100).
270
271 • A difference in particle size of the drug substance or excipients.
272
273 • A difference in the amount of release controlling excipient(s), expressed as the
274 difference in weight of the release controlling excipient(s) in the experimental
275 formulation compared to the formulation proposed for marketing, of less than or
276 equal to 10 percent.
277
278 2. Extended-Release Formulations Considered Not to Be the Same (Release
279 Controlling Excipients)
280
281 Examples of differences that result in product formulations that are considered not to be the same
282 include the following:
283
284 • The addition or deletion of a release controlling excipient.
285
286 • A difference in the amount of release controlling excipient(s), expressed as the
287 difference in weight of the release controlling excipient(s) in the experimental
288 formulation compared to the formulation proposed for marketing, of greater than 10
289 percent.
290
291 3. Extended Release Formulations – Other (Release Controlling Excipients)
292
293 Studies performed on experimental formulations containing different polymorphic forms of the
294 drug substance also should be submitted.
295
296 D. Semisolid Dosage Forms
297
298 For the purposes of this guidance, formulations of semisolid dosage form products are
299 considered to be the same if the experimental formulation is in the same category as the
300 formulation proposed for marketing (e.g., the formulations being compared are both for creams)
301 and any differences between formulations are as described below.
302
303 • If the difference in the amount of an individual excipient between the experimental
304 formulation and the formulation intended to be marketed is less than or equal to 5
305 percent, the two formulations are considered to be the same.

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306 • If more than one excipient amount is changed, and the cumulative total of differences
307 in the amount of all excipients is less than or equal to 7 percent, the two formulations
308 are considered to be the same.
309
310 • Formulations with differences in particle size distribution of the drug substance, if the
311 drug is in suspension, are considered to be the same.
312
313 Formulations with differences in technical grade of a structure forming excipient are considered
314 not to be the same.
315
316 E. Other Complex Dosage Forms
317
318 For other complex dosage forms (e.g., transdermals, injectable suspensions, and suppositories),
319 limited information is available regarding quantitative and qualitative changes that could have a
320 significant impact on the bioavailability of the product. Because of this lack of information, we
321 consider all experimental formulations that are pharmaceutically equivalent to the formulation of
322 the complex dosage form product intended to be marketed to be the same as the RLD.
323 Therefore, the Agency requests submission of either a summary report or a complete report of all
324 bioavailability or bioequivalence studies conducted during the development of the drug product.
325 This information will increase our understanding of the development of the generic product and
326 how changes in components, composition, and methods of manufacture have affected
327 formulation performance. Access to this information will promote further development of
328 science-based bioequivalence policies for complex dosage forms.