Guidance for Industry
 

Submission of Summary 

Bioequivalence Data for ANDAs 

DRAFT GUIDANCE
 

This guidance document is being distributed for comment purposes only. 

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

publication in the Federal Register of the notice announcing the availability of the draft 

guidance. Submit comments to the Division of Dockets Management (HFA-305), Food and 

Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should 

be identified with the docket number listed in the notice of availability that publishes in the 

Federal Register. 

For questions regarding this draft document, contact (CDER) Aida L. Sanchez 240-276-8782. 

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

April 2009 

OGD
 
 

Guidance for Industry 

Submission of Summary 

Bioequivalence Data for ANDAs 

Additional copies are available from: 

Office of Communication
 

Division of Drug Information
 

Center for Drug Evaluation and Research
 

Food and Drug Administration 

10903 New Hampshire Ave., Bldg. 51, Room 2201
 

Silver Spring, MD 20993-0002
 

(Tel) 301-796-3400
 

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

U.S. Department of Health and Human Services 

Food and Drug Administration 

Center for Drug Evaluation and Research (CDER) 

April 2009 

OGD
 
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 (IR) Drug Products.......................................................................................4
 

B. Extended-Release (ER) Drug Products — Nonrelease Controlling Excipients........................6
 

C. Extended-Release (ER) Drug Products — Release Controlling Excipients..............................7
 

D. Semisolid Dosage Forms................................................................................................................8
 

E. Other Complex Dosage Forms......................................................................................................9
 

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1 Guidance for Industry1
 

2 

3 Submission of Summary Bioequivalence Data for ANDAs 

4 

5 

6 This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current 

7 thinking on this topic. It does not create or confer any rights for or on any person and does not operate to 

8 bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of 

9 the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA 

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

11 the appropriate number listed on the title page of this guidance. 

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 new 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 ANDA applicants 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 (§ 320.1(g)). 

25 

26 This guidance provides information on the following subjects: 

27 • the types of ANDA submissions covered by the BE data rule 

28 • a recommended format for summary reports of BE studies 

29 • the types of formulations FDA considers to be the same drug product formulation for 

30 different dosage forms based on differences in composition. 

31 

32 This guidance does not address which formulations FDA considers the same drug product 

33 formulation based on differences in methods of manufacture. 

34 

1 This guidance has been prepared by the Division of Bioequivalence in the Office of Generic Drugs, Office of 

Pharmaceutical Science, Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration 

(FDA). 

2

 See the final rule “Requirements for Submission of Bioequivalence Data” published in the Federal Register on 

January 16, 2009 (the BE data rule). 

3

 The BE data rule amended the Agency’s bioequivalence regulations in 21 CFR parts 314 and 320. 

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35 The guidance is applicable to BE studies conducted for ANDAs during both preapproval and 

36 postapproval periods. 

37 

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

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

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

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

42 recommended, but not required. 

43 

44 

45 II. BACKGROUND 

46 

47 The Federal Food, Drug, and Cosmetic Act (the Act) and FDA regulations require that ANDA 

48 applicants submit, among other things, information showing that the applicant’s drug product is 

49 bioequivalent to the approved product designated by FDA as the reference listed drug (RLD) 

50 (section 505(j)(2)(A)(iv) of the Act (21 U.S.C. 355(j)(2)(A)(iv)); §§ 314.94(a)(7) and 

51 320.21(b)(1)). In the past, ANDA applicants have submitted only the BE studies that 

52 demonstrate that a generic product meets BE criteria,4 but have not typically submitted additional 

53 BE studies conducted on the same drug product formulation, including studies that do not show 

54 the product meets bioequivalence criteria. 

55 

56 The BE data rule amended FDA’s regulations to require that ANDA applicants submit data from 

57 all BE studies the applicant conducts on the drug product formulation submitted for approval 

58 (§§ 314.81(b)(2)(vi), 314.94(a)(7), 314.96(a)(i), and 320.21(b)(1) and (c)). The FDA believes 

59 that data from any additional BE studies may be important in our determination of whether a 

60 product is bioequivalent to the RLD, and are relevant to our evaluation of generic products in 

61 general.5

 These data will (1) increase our understanding of generic drug development and how 

62 changes in components and composition may affect formulation performance, and (2) promote 

63 further development of science-based bioequivalence policies. 

64 

65 

66 III. SUBMISSION OF ALL BIOEQUIVALENCE STUDIES 

67 

68 FDA regulations, as amended by and clarified in the BE data rule, require that a complete report 

69 be submitted for the BE studies upon which the applicant relies for approval, and either a 

70 complete or summary report be submitted for each additional study conducted on the same drug 

71 product formulation (§§ 314.81(b)(2)(vi), 314.94(a)(7), 314.96(a)(i), and 320.21(b)(1) and (c)). 

72 This requirement includes both in vivo and in vitro testing conducted to demonstrate 

73 bioequivalence. The regulations also provide that, if a summary report is submitted, and the 

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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74 Agency believes that there may be bioequivalence issues or concerns with the drug product, the 

75 Agency may request that a complete report be prepared and submitted to FDA. 

76 

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 (§ 314.94) 

83 • ANDA amendments (§ 314.96(a)) 

84 • ANDA supplements that require BE studies under § 320.21(c) 

85 • ANDAs submitted under a suitability petition (§ 314.93) 

86 • ANDA annual reports (§ 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, please refer to the Office of Generic Drugs (OGD) 

91 Web page.6

 The Division of Bioequivalence has developed model data summary tables in a 

92 concise format consistent with the ICH Common Technical Document (CTD). The tables, under 

93 the heading “Model Bioequivalence Data Summary Tables,” are available in Word and PDF 

94 formats. The FDA recommends that these table formats be used to organize the data for 

95 summary reports required by the BE data rule. 

96 

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 § 320.1(g), 

102 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 § 320.1(g) applies regardless of whether the 

110 products are manufactured at the same or different manufacturing sites.7 

111 

6

 The OGD Web page address is http://www.fda.gov/cder/ogd/index.htm. 7

 See the preamble of the BE data rule, FDA response to comment 15. 

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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 • minor differences in composition that are unlikely to have any detectable impact on 

116 formulation quality and performance between the formulations being compared. These 

117 differences would result in formulations that meet the definition of same drug product 

118 formulation, and for which BE studies must be submitted (§§ 314.81(b)(2)(vi), 

119 314.94(a)(7), 314.96(a)(i), and 320.21(b)(1) and (c)). 

120 • differences in composition that are likely to result in a significant difference in 

121 formulation quality and performance between the formulations being compared. These 

122 differences would result in formulations that do not meet the definition of same drug 

123 product formulation, and for which BE studies need not be submitted. 

124 

125 

126 A. Immediate-Release (IR) Drug Products 

127 

128 1. IR Formulations Considered the Same 

129 

130 Minor differences that result in product formulations that are considered the same 

131 include: 

132 

133 • A difference in an ingredient intended to affect the color or flavor of the drug 

134 product 

135 • A different approved ingredient of the printing ink 

136 • A difference in the technical grade and/or specification of an excipient (e.g., 

137 Avicel PH102 vs. Avicel PH200) 

138 • A difference in particle size or polymorphic form of the drug substance or 

139 excipients. 

140 

141 Formulations with different amounts of excipients are considered the same drug product 

142 formulation if: 

143 • for an individual excipient, the difference in weight between the formulations being 

144 compared is less than or equal to the percentage shown in Table 1 and 

145 • the cumulative total of all excipient weight differences is less than or equal to 10 

146 percent. 

147 

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Table 1. IR Formulations — Differences in Excipient Weights 

Excipient 

Difference (≤) in Excipient 

Weights Between Two 

Formulations1 

Filler 10 

Disintegrant 

Starch 

Other 

6 

2 

Binder 3 

Lubricant 

Calcium (Ca) or Magnesium (Mg) Stearate 

Other 

0.5 

2 

Glidant 

Talc 

Other 

2 

0.2 

Film Coat 2 

149 1 Percentage of difference between the formulation proposed for marketing and another 

150 experimental formulation. 

151 

152 Illustrative examples: 

153 

154 • If the amount of a filler excipient in an experimental formulation (A) is 105 

155 milligrams (mg) and the same filler excipient in the formulation proposed to be 

156 marketed (B) is 100 mg, the difference in the excipient weight is 5 percent. These 

157 two formulations would be considered the same, because the difference in weights of 

158 the filler excipient is less than 10 percent. 

159 

160 • In the case of multiple excipient changes, if an experimental formulation (A) contains 

161 95 mg of a filler excipient and 103 mg of a disintegrant, and the formulation proposed 

162 for marketing (B) contains 100 mg of the same filler and 100 mg of the same 

163 disintegrant, the difference in weight for the filler is 5 percent, and the difference in 

164 weight for the disintegrant is 3 percent. The cumulative change is 8 percent, less than 

165 10 percent for all excipient differences. Therefore, these formulations would be 

166 considered the same. 

167 

168 2. IR Formuations Considered Not the Same 

169 

170 A difference that results in product formulations that are not considered the same would 

171 include the addition or deletion of an excipient (with the exception of a difference in an 

172 ingredient intended to affect the color or flavor of the drug product, or a difference in an 

173 ingredient of the printing ink). 

174 

175 Formulations with different amounts of the same excipients are not consideredthe same 

176 drug product formulation if: 

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177 • for an individual excipient, the difference in excipient weight between the 

178 formulations being compared exceeds the percentages shown in Table 1, or 

179 • the cumulative total of all excipient weight differences exceeds 10 percent. 

180 

181 Illustrative examples: 

182 

183 • If the amount of a filler excipient in an experimental formulation (A) is 115 mg and 

184 the filler excipient in the formulation proposed for marketing (B) is 100 mg, the 

185 difference in the excipient weight would be 15 percent. These two formulations 

186 would not be considered the same, because the difference in weights of the filler 

187 excipient is greater than 10 percent. 

188 

189 • In the case of multiple excipient changes, if an experimental formulation (A) contains 

190 90 mg of a filler excipient and 106 mg of a disintegrant, and the formulation proposed 

191 for marketing (B) contains 100 mg of the filler and 100 mg of the disintegrant, the 

192 difference in weight for the filler is 10 percent, and the difference in weight for the 

193 disintegrant is 6 percent. The cumulative change would be 16 percent. Therefore, 

194 these formulations would not be considered the same, and any studies conducted with 

195 Formulation A would not need to be submitted. 

196 

197 

198 B. Extended-Release (ER) Drug Products — Nonrelease Controlling Excipients 

199 

200 1. ER Formulations Considered the Same (Nonrelease Controlling Excipients) 

201 

202 Minor differences that result in product formulations that are considered the same 

203 include: 

204 

205 • A difference in an ingredient intended to affect the color or flavor of the drug 

206 product 

207 • A different approved ingredient of the printing ink 

208 • A difference in the technical grade and/or specification of a nonrelease controlling 

209 excipient (e.g., Avicel PH102 vs. Avicel PH200) 

210 • A difference in particle size or polymorphic form of the drug substance or 

211 excipients. 

212 

213 Formulations with different amounts of the same nonrelease controlling excipients are 

214 considered the same drug product formulation if: 

215 • for an individual excipient, the difference in excipient weight between the 

216 formulations being compared is less than or equal to the percentages listed in Table 

217 2, and 

218 • the cumulative total of all excipient weight differences is less than or equal to 10 

219 percent. 

220 

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221 

222 Table 2. ER Formulations — Differences in Excipient Weights 

Nonrelease Controlling Excipient 

Difference ( ≤ ) in Excipient 

Weights Between Two 

Formulations1 

Filler 10 

Disintegrant 

Starch 

Other 

6 

2 

Binder 1 

Lubricant 

Calcium (Ca) or Magnesium (Mg) Stearate 

Other 

0.5 

2 

Glidant 

Talc 

Other 

2 

0.2 

Film Coat 2 

223 1 Percentage of difference between another experimental formulation and the formulation 

224 proposed for marketing. 

225 

226 

227 

228 2. ER Formulations Not Considered the Same (Nonrelease Controlling Excipients) 

229 

230 Examples of differences that result in product formulations that are not considered the 

231 same include: 

232 

233 • The addition or deletion of an excipient (except for a difference in an ingredient 

234 intended to affect the color or flavor of the drug product, or a difference in an 

235 ingredient of the printing ink) 

236 • A difference in weight of a nonrelease controlling excipient between the 

237 formulations being compared that exceeds the percentage listed in Table 2 

238 • The cumulative total difference in weights of all nonrelease controlling excipients 

239 exceeds 10 percent. 

240 

241 

242 C. Extended-Release (ER) Drug Products — Release Controlling Excipients 

243 

244 1. ER Formulations Considered the Same (Release Controlling Excipients) 

245 

246 Examples of minor differences that result in product formulations that are considered the 

247 same include: 

248 

249 • A difference in the technical grade and/or specification of the release controlling 

250 excipient(s) (e.g., Eudragit RS 100 vs. Eudragit RL 100) 

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251 

252 • A difference in particle size or polymorphic form of the drug substance or excipients. 

253 

254 • A difference in the amount of release controlling excipient(s), expressed as the 

255 difference in weight of the release controlling excipient(s) in the experimental 

256 formulation compared to the formulation proposed for marketing, of less than or equal 

257 to 10 percent. 

258 

259 2. ER Formulations Not Considered the Same (Release Controlling Excipients) 

260 

261 Examples of differences that result in product formulations that are not considered the 

262 same include: 

263 

264 • The addition or deletion of a release controlling excipient 

265 

266 • A difference in the amount of release controlling excipient(s), expressed as the 

267 difference in weight of the release controlling excipient(s) in the experimental 

268 formulation compared to the formulation proposed for marketing, of greater than 10 

269 percent. 

270 

271 D. Semisolid Dosage Forms 

272 

273 For the purposes of this guidance, formulations of semisolid dosage form products are 

274 considered the same if the experimental formulation is in the same category as the 

275 formulation proposed for marketing (e.g., the formulations being compared are both for 

276 creams) and any differences between formulations are as described below. 

277 

278 • If the difference in the amount of an individual excipient between the experimental 

279 formulation and the formulation intended to be marketed is less than or equal to 5 

280 percent, the two formulations are considered the same. 

281 

282 • If more than one excipient amount is changed, and the cumulative total of differences 

283 in the amount of all excipients is less than or equal to 7 percent, the two formulations 

284 are also considered the same. 

285 

286 • Formulations with differences in particle size distribution of the drug substance, if the 

287 drug is in suspension, are considered the same. 

288 

289 Formulations with differences in technical grade of a structure forming excipient are not 

290 considered the same. 

291 

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292 E. Other Complex Dosage Forms 

293 

294 For other complex dosage forms (such as transdermals, injectable suspensions, and 

295 suppositories), there is limited information regarding quantitative and qualitative changes 

296 that could have a significant impact on the bioavailability of the product. Because of this 

297 lack of information, we consider all experimental formulations that are pharmaceutically 

298 equivalent to the formulation of the complex dosage form product intended to be 

299 marketed to be the same as the reference listed drug. Therefore, the FDA requests 

300 submission of either a summary report or a complete report of all bioavailability or 

301 bioequivalence studies conducted during the development of the drug product. This 

302 information will increase our understanding of the development of the generic product 

303 and how changes in components, composition, and methods of manufacture have affected 

304 formulation performance. Access to this information will also promote further 

305 development of science-based bioequivalence policies for complex dosage forms. 

306 

307 

9