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 ProductsNonrelease 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 ProductsRelease 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 Industry  
1 
2  Submission of Summary Bioequivalence Data for ANDAs 
3   
4   
5  This guidance represents the Food and Drug Administrations (FDAs) 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 FDAs requirements for the submission of 
18  bioequivalence (BE) data.  FDAs 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 Agencys 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  FDAs guidance documents, including this guidance, do not establish legally enforceable 
42  responsibilities.  Instead, guidances describe the Agencys 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 applicants 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 FDAs 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 submittedand the 
75  Agency believes that there may be bioequivalence issues or concerns with the drug productthe 
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 FDAs 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 FDAs 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 FDAs 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 FormulationsDifferences 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:  
182   
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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 ProductsNonrelease 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 FormulationsDifferences 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 ProductsRelease 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. 
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