ANDA Submissions   
Refuse-to-Receive 
Standards: 
Questions and Answers 
Guidance for Industry 
 
 
 
DRAFT GUIDANCE
 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to http://www.regulations.gov.  Submit written 
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) Elizabeth Giaquinto Friedman 240-
402-7930.  If the contact is no longer available, please contact the Director of the Office of 
Generic Drug Policy, Office of Generic Drugs, CDER. 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
 
 
 
 
October 2017  Generics 
ANDA Submissions   
Refuse-to-Receive 
Standards: 
Questions and Answers 
Guidance for Industry 
 
Additional copies are available from: 
Office of Communications, Division of Drug Information  
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: 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) 
 
October 2017 
Generics 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  QUESTIONS AND ANSWERS ....................................................................................... 2 
A.  Scope ................................................................................................................................................ 2 
B.  Responding to Deficiencies and RTR Determinations ..................................................................... 3 
C.  General Deficiencies ........................................................................................................................ 6 
D.  Drug Master File (DMF) Review and Deficiencies ......................................................................... 8 
E.  Product Quality Deficiencies ........................................................................................................... 9 
F.  BE and Clinical Deficiencies ......................................................................................................... 14  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  ANDA Submissions  Refuse-to-Receive Standards: 
2  Questions and Answers 
1
3  Guidance for Industry  
4   
5   
6  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
7  Administration (FDA or Agency) on this topic.  It does not establish any rights for any person and is not 
8  binding on FDA or the public.  You can use an alternative approach if it satisfies the requirements of the 
9  applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff responsible 
10  for this guidance as listed on the title page.   
11   
12   
13   
14   
15  I.  INTRODUCTION 
16   
17  This draft guidance is intended to assist applicants preparing to submit to FDA abbreviated new 
18  drug applications (ANDAs) and certain prior approval supplements (PASs) to ANDAs.2  This 
19  guidance provides answers to questions we have received from applicants regarding the guidance 
20  for industry, ANDA SubmissionsRefuse-to-Receive Standards (RTR Standards guidance)3 and 
21  the filing review process, in general.  The questions and answers address general issues about the 
22  organization of an ANDA, filing decisions made by FDA, the review of and deficiencies related 
23  to Drug Master Files (DMFs), product quality, and bioequivalence (BE) and clinical reviews, and 
24  are intended to clarify the deficiencies that may cause FDA to refuse to receive (RTR) an 
25  ANDA.  An RTR decision indicates that FDA has determined that an ANDA is not a 
26  substantially complete application (i.e., that the ANDA, on its face, is not sufficiently complete 
27  to permit a substantive review).4   
28   
29  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
30  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
31  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
                                                 
1 This guidance has been prepared by the Office of Generic Drugs in the Center for Drug Evaluation and Research 
(CDER) at the Food and Drug Administration.  
2 For purposes of this guidance, the use of the term ANDA will mean ANDAs and PAS submissions to ANDAs, as 
described in the introduction. 
3 The RTR Standards final guidance was issued in September 2014 (see Guidance for Industry on [ANDA] 
SubmissionsRefuse-to-Receive Standards; Availability, 79 FR 55813, September 17, 2014).  A revised final 
guidance was posted to FDAs web site on May 26, 2015, which contained minor changes to clarify text, improve 
readability, and reference the Office of Pharmaceutical Quality, which was established after the original guidance 
posted in September 2014.  A subsequent revised final version was posted to FDAs website on December 21, 2016.  
This most recent revised guidance contains further clarifications of policy and minor changes in policy to benefit 
applicants.  
4 21 CFR 314.101(b)(1) and 314.3(b). 
1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
32  the word should in Agency guidances means that something is suggested or recommended, but 
33  not required.5 
34   
35   
36  II.  BACKGROUND 
37   
38  Pursuant to the enactment of the Generic Drug User Fee Amendments of 2012 (GDUFA),6 the 
39  Office of Generic Drugs (OGD) is tasked with a number of activities, including the development 
40  of enhanced refusal to receive standards for ANDAs and other related submissions by the end 
41  of year 1 of the program....7  Enhanced RTR standards are important because the practice of 
42  submitting an ANDA that is not sufficiently complete to permit a substantive review and then 
43  repairing it in the course of an extended review period that needs several cycles of FDA 
44  response and applicant repair is inherently inefficient and wasteful of resources.  In addition, 
45  ANDAs that are not sufficiently complete to permit a substantive review generate extra reviews 
46  and letters.   
47   
48  FDA evaluates each submitted ANDA individually to determine whether the ANDA can be 
49  received.  The receipt of an ANDA means that FDA made a threshold determination that the 
50  ANDA is a substantially complete application, that is, an ANDA that on its face is sufficiently 
51  complete to permit a substantive review.8  Sufficiently complete means that the ANDA contains 
52  all the information required under section 505(j)(2)(A)  of the Federal Food, Drug, and Cosmetic 
53  Act (FD&C Act) and does not contain a deficiency described in 21 CFR 314.101(d) and (e).9   
54   
55  Our regulations at 21 CFR 314.101 provide the regulatory authority by which FDA may in 
56  certain cases, and will in other cases, RTR an ANDA.10   
57   
58   
59  III.  QUESTIONS AND ANSWERS 
60   
61  A.  Scope  
62   
63  Q1:  To which generic drug product submissions do this guidance and the RTR 
64  Standards guidance apply? 
65   
                                                 
5At various points in this guidance, it is noted that when a particular type of deficiency is identified in an ANDA, 
FDA will RTR the ANDA.  These statements are included for purposes of transparency, and do not create legal 
obligations, on applicants, or on FDA.  This means that FDA generally will RTR an ANDA on the grounds 
described in this guidance.  This guidance does not preclude the possibility that an ANDA applicant may be able to 
demonstrate, in particular circumstances, that the regulatory requirements for receiving an ANDA have been met 
even when, as described in this guidance, FDA would generally find that the ANDA is not a substantially complete 
application and RTR the submission. 
6 Generic Drug User Fee Amendments of 2012 (GDUFA) (Public Law 112-144, Title III). 
7 See Generic Drug User Fee Act Program Performance Goals and Procedures:  
http://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM282505.pdf.  
8 See 21 CFR 314.101(b)(1) and 314.3(b). 
9 21 CFR 314.3(b). 
10 See 21 CFR 314.101(d)-(e). 
2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
66    This guidance and the RTR Standards guidance apply to original abbreviated new drug 
67  applications (ANDAs) and certain prior approval supplements (PASs) to ANDAs 
68  consistent with our current practices, including those in which the applicant is seeking 
69  approval of a new strength11, reformulation of a drug product that does not require a new 
70  original ANDA submission, return of a discontinued product to the market, and Rx-to-
71  OTC switches for all conditions of use.12   
72   
73  B.  Responding to Deficiencies and RTR Determinations 
74   
75  Q2:  Does an applicant have an opportunity to correct deficiencies identified during the 
76  filing review? 
77   
78  The guidance for industry, ANDA SubmissionsRefuse-to-Receive Standards, 
79  memorializes many of the standards that FDA historically has applied in its RTR 
80  determinations and sets forth several minor deficiencies that may be corrected and major 
81  deficiencies that may result in an RTR determination.  FDA, in its discretion, may 
82  provide applicants with the opportunity to correct deficiencies that are minor in nature as 
83  identified in an Information Request (IR) within seven calendar days.  If the applicant 
84  successfully corrects the minor deficiencies within seven calendar days, the ANDA 
85  submission will be received and retain the original submission date. 
86   
87  If information is missing, the type of data missing determines FDAs RTR decisions.  If 
88  FDA determines a deficiency is major, but that deficiency could be corrected quickly, it 
89  does not obviate the fact that the ANDA lacked that data in the first instance.  This would 
90  result in an RTR determination and the ANDA, if resubmitted, would not retain the 
91  original submission date.   
92   
93  Q3:  An applicant receives an IR listing minor deficiencies identified during the filing 
94  review.  The IR states that the response is due within seven calendar days.  What 
95  happens if the applicant fails to submit the responses within this time frame? 
96   
97  If an ANDA applicant receives an IR from FDA listing minor deficiencies identified 
98  during the filing review, and the requested information is not submitted and received 
99  within seven calendar days, FDA will RTR the ANDA.  Responses to IRs should 
100  completely address all outstanding issues identified in the IR.  Responses to IRs should 
101  be formatted and submitted following current electronic Common Technical Document 
102  (eCTD) specifications, submission structure recommendations, file format, and version 
103  recommendations (see guidance for industry on Providing Regulatory Submissions in 
104  Electronic Format  Certain Human Pharmaceutical Product Applications and Related 
105  Submissions Using the eCTD Specifications). 
                                                 
11 A PAS for a new strength includes a change in strength of a solid oral dosage form product, ; change in 
concentration for a parenteral dosage-form product; change in vial size, fill volume, and/or package size to a 
parenteral dosage-form product (i.e., total drug content); change in concentration of an oral liquid, ophthalmic, otic, 
transdermal, or topical drug product,    
12 Once this guidance is finalized, FDA will revise the introduction to this guidance and the RTR Standards 
Guidance so that the PASs that currently are subject to filing review and within the scope of these guidances are 
clearly identified. 
3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
106   
107  Q4:  An applicant receives an RTR determination and provides a response to some of the 
108  deficiencies.  Will the response be accepted as a resubmission? 
109   
110  No, FDA will not accept a partial response to an RTR determination.  If FDA issues an 
111  RTR determination, an applicant may either correct all deficiencies identified therein by 
112  resubmission of a complete ANDA (i.e., a new application that remedies the major 
113  deficiencies and any and all minor deficiencies identified in the RTR letter) or withdraw 
114  the application under 21 CFR 314.99.  (If the applicant takes no action, FDA may 
115  consider the ANDA withdrawn after one year.)13  
116   
117  If the applicants response to RTR determination is incomplete or otherwise inadequate 
118  and therefore does not remedy FDAs determination that the ANDA is not a substantially 
119  complete application, FDA will RTR the resubmission.   
120   
121  Q5:  An applicant receives an RTR determination.  The applicant resubmits the ANDA 
122  and provides a response to each deficiency, but the applicant receives a subsequent 
123  RTR determination.  Why did FDA RTR the resubmission? 
124   
125    FDA may RTR a resubmission for multiple reasons including, but not limited to, the 
126  failure to provide a comprehensive response to the deficiencies identified in the RTR 
127  letter and failure to follow the current recommendations relevant to filing (e.g., 
128  recommendations set forth in RTR guidances and in product-specific bioequivalence 
129  guidances) in effect at the time of resubmission.  
130   
131  Q6:  An applicant receives an RTR determination and seeks assistance in developing a 
132  resubmission.  Will FDA assist the applicant in responding to the deficiencies? 
133   
134    FDA does not provide specific guidance to applicants on how to remedy an ANDA that 
135  has received an RTR determination.  If an applicant has concerns regarding the content of 
136  an RTR determination letter, the applicant should contact FDA via the email address 
137  identified in the correspondence.  If an applicant has general questions about generic drug 
138  development (e.g., quantitative and qualitative (Q1/Q2) issues),14 FDA recommends that 
139  the applicant submit a controlled correspondence to FDA at genericdrugs@fda.hhs.gov.15  
140  An applicant may submit questions and request general information regarding the 
141  preparation of submissions in electronic format to esub@fda.hhs.gov.  
142   
143  Q7:  How long does an applicant have to request reconsideration of an RTR 
144  determination? 
145   
                                                 
13 21 CFR 314.101(b)(3). 
14 See, generally, guidance for industry ANDA Submissions  Refuse-to-Receive Standards. We update guidances 
periodically.  To make sure you have the most recent version of a guidance, check the FDA Drugs guidance 
webpage at: https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.  
15 See guidance for industry Controlled Correspondence Related to Generic Drug Development. If the applicants 
general question pertains to a drug product for which the applicant has submitted an ANDA that was subsequently 
refused for receipt, the applicant should reference the RTR determination in the controlled correspondence. 
4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
146    The Agency believes that seven calendar days provides an applicant sufficient time to 
147  review FDAs regulatory action and determine whether the applicant would like to pursue 
148  a request for reconsideration.  It also ensures that applicants submit requests for 
149  reconsideration of recent Agency regulatory actions.  Like minor deficiencies, any 
150  matters that will be challenged should be reviewed, analyzed, and addressed within seven 
151  calendar days.   
152   
153  The Agency recognizes that an applicant will require some time to identify, coordinate, 
154  and compile the information necessary to submit a response to the RTR determination; 
155  however, in an effort to streamline reviews and enable timely inspections, the Agency 
156  needs to define an acceptable time frame in which to challenge an RTR determination.  
157  For example, if an applicant receives an RTR determination 60 days after the application 
158  is submitted and submits a successful request for reconsideration one month after the 
159  RTR determination was made, the Agency will have lost one month of application review 
160  time and the Agencys ability to ensure timely inspections may be jeopardized.      
161   
162  Q8:  If an applicant requests reconsideration of an RTR determination, should the 
163  applicant resubmit the ANDA including responses to the deficiencies identified in 
164  the RTR correspondence with the request for reconsideration? 
165   
166    The applicant may either submit only a request for reconsideration or a request for 
167  reconsideration with the resubmitted ANDA (i.e., a new submission that provides a 
168  comprehensive response to the deficiencies identified in the RTR letter).  If an applicant 
169  only submits a request for reconsideration, the applicant does not pay an additional 
170  GDUFA fee and the ANDA will remain in RTR status, meaning that no technical review 
171  will commence.   
172   
173  If an applicant prefers to resubmit the ANDA while the request for reconsideration is 
174  pending, the applicant should provide a resubmission and remit any applicable user 
175  fees.16  This will initiate the filing review for the ANDA as resubmitted.  The applicant 
176  should identify that the resubmission is related to a pending request for reconsideration 
177  on the resubmission cover page.  To facilitate review, submit all supporting information 
178  provided for the request for reconsideration in the resubmission, along with complete 
179  responses to any other deficiencies identified in the RTR correspondence.  While the 
180  FDA is evaluating the request for reconsideration, the ANDA will remain in RTR status 
181  and no technical review will commence.  The applicant will be notified when a decision 
182  on the request for reconsideration has been made.    
183     
184  Q9:  Will FDA accept an unsolicited filing amendment submitted during filing review to 
185  correct a deficiency identified by the ANDA applicant? 
186   
187    FDA will not review any unsolicited amendment submitted by the applicant, other than 
188  an administrative amendment identifying a change in contact information or ownership, 
189  while the ANDA is pending filing review.17  For example, an amendment containing data 
                                                 
16 See Section 744B(a)(3)(E) of the FD&C Act.  
17 FDA will note the submission of any amendments containing patent certifications during filing review. 
5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
190  that should have been included in the original submission will not be reviewed during the 
191  filing review or considered when making the determination of whether the ANDA is a 
192  substantially complete application.    
193   
194  Q10:  How does the GDUFA Amendment Tier structure impact the filing review?   
195   
196  The Amendment Tier program associated with GDUFA I will generally not impact the 
197  filing review.  FDA will communicate minor filing deficiencies that may be remedied to 
198  an applicant.  The applicants response to these deficiencies is not considered a solicited 
199  amendment, which is an amendment submitted in response to a complete response letter 
200  that sets a new goal date for the ANDA.18  The applicants submission of a response to 
201  minor deficiencies identified during the filing review will not impact the GDUFA 
202  performance goal date for the ANDA, provided that adequate responses to such minor 
203  deficiencies are received within seven calendar days.  The reauthorization of GDUFA 
204  does not include the Amendment Tier program.19 The types of amendments and review 
205  goals associated with the GDUFA II apply only to submissions that have been received 
206  for review (i.e., review goals do not apply to submissions pending filing review).   
207     
208  C.  General Deficiencies 
209     
210  Q11:  If a typographical error (or typo) is the basis for a major deficiency resulting in 
211  an RTR determination, will FDA rescind its RTR decision if the applicant identifies 
212  the typographical error and provides a corrected submission? 
213   
214    FDA will not rescind the RTR determination if a typographical error is the basis for a 
215  major deficiency and the applicant informs FDA of the error and provides a corrected 
216  submission.  When compiling an ANDA, applicants should ensure that all relevant data 
217  and information necessary to support the substantive review is correctly transcribed into 
218  appropriate sections of the ANDA.  When performing a filing review, the Agency will 
219  assume that the information transcribed in an ANDA is correct.  The Agency must move 
220  expeditiously through the filing process to ensure that FDA is able to meet its 
221  commitment to review and act on ANDAs within specified GDUFA performance metric 
222  goal dates.   
223   
224  A typographical error that may result in a major deficiency due to an applicants lack of 
225  quality control is not limited to a numerical value; the error may involve an alphabetical 
226  letter, symbol, or other text.   
227   
228  Example: In guidance, FDA recommends that ANDAs contain the initiation date 
229  for each stability study conducted, along with individual pull dates (removal from 
230  the storage chamber and preferably identified in MM/DD/YYYY or 
                                                 
18 See GDUFA Program Performance Goals and Procedures (GDUFA I Commitment Letter) available at 
https://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM282505.pdf.  
19 See GDUFA Reauthorization Performance Goals and Program Enhancement Fiscal Years 2018-2022 (GDUFA II 
Commitment Letter) available at 
https://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM525234.pdf.  
6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
231  YYYY/MM/DD format) for each stability time point, so FDA can verify that each 
232  study covers the recommended six-month (180-day) minimum hold time.  If the 
233  applicant provides a date that does not confirm a 180-day hold time as a result of 
234  a typographical error, FDA will RTR the ANDA.  A demonstration by the 
235  applicant that the basis of the RTR was caused by a typographical error will not 
236  be sufficient to rescind the RTR determination for this type of deficiency.   
237   
238  Example: In guidance, FDA recommends that ANDAs contain information 
239  concerning Long-Term Storage Stability coverage in the applicable row of the 
240  Study Information Bioequivalence table.  These data are necessary to ascertain 
241  adherence to appropriate storage temperatures and duration.  If the applicant 
242  provides a date or temperature (including temperature range) that does not 
243  confirm proper storage conditions or duration as a result of a typographical error, 
244  FDA will RTR the ANDA.  A demonstration by the applicant that the basis of the 
245  RTR was caused by a typographical error will not be sufficient to rescind the RTR 
246  determination for this type of deficiency.   
247   
248  Example: In guidance, FDA recommends that a threshold value for a particular 
249  variable should be >60 units.  In the ANDA, the applicant uses a symbol that 
250  indicates it does not meet the threshold value (e.g., <60 units).  As a result of this 
251  typographical error, FDA will RTR the ANDA.  A demonstration by the applicant 
252  that the basis of the RTR was caused by a typographical error will not be 
253  sufficient to rescind the RTR determination for this type of deficiency.   
254   
255  Q12:  Will FDA RTR an ANDA that does not contain a patent certification that is 
256  consistent with the regulations? 
257   
258    FDA will treat as a minor deficiency an applicants failure to include a patent 
259  certification or statement that is consistent with section 505(j)(2)(A)(vii) and (viii) of the 
260  FD&C Act and 21 CFR 314.94(a)(12) and 314.96(d).   
261   
262  Q13:  Will FDA RTR an ANDA if the submission contains a section or information in a 
263  language other than English and the applicant does not provide an English 
264  translation? 
265   
266    FDA will identify untranslated content, which must be translated into English,20 in an IR.  
267  Failure to provide the requested translations will result in an RTR.  Moreover, it is 
268  incumbent upon the applicant to ensure that any and all untranslated content in the 
269  ANDA submission, including all sections of the document (e.g., headers, titles), is 
270  translated into English.  Therefore, should FDA discover additional untranslated content 
271  in the ANDA submission after an IR response has been submitted, the ANDA will be 
272  refused for receipt.    
273   
                                                 
20 See 21 CFR 314.101(d)(5). 
7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
274    FDA will accept an ANDA with the English translation on a page next to the original 
275  text.  FDA recommends that the translation be printed in size 12 type to facilitate review.  
276  The applicant should use its best judgment in determining how to fit the necessary 
277  information on a page without impacting the reviewers ability to read the information. 
278   
279  Q14:  If the point of contact for the ANDA is out of the office, how will the applicant 
280  receive filing deficiencies from FDA?   
281   
282    FDA will notify the point of contact for the ANDA (i.e., the applicants responsible 
283  official for applicants located in the U.S. or the U.S. Agent, if applicable), as identified 
284  on the Form FDA 356h in the ANDA file via the primary method for communication for 
285  deficiencies, which is secure email.  Once notified, the applicant has seven calendar days 
286  to satisfactorily correct the identified deficiencies.  In the event that FDA receives an out-
287  of-office message when communicating deficiencies by email to the point of contact, 
288  FDA will not contact any person not identified on Form FDA 356h.  FDA recommends 
289  that applicants provide an email address on the Form FDA 356h that is checked regularly, 
290  even if the designated point of contact is out of the office, to ensure that all 
291  communications from FDA are received in a timely manner. 
292   
293    We recommend that applicants notify the Agency of any change in the point of contact 
294  for the ANDA as soon as practicable by submitting an administrative amendment to the 
295  ANDA file. 
296   
297  D.  Drug Master File (DMF) Review and Deficiencies  
298   
299  Q15:  Will FDA RTR an ANDA referencing a Type II active pharmaceutical ingredient 
300  (API) DMF that has not been listed on the Available for Reference List21 as of the 
301  date the ANDA is submitted to FDA? 
302   
303  FDA will RTR an ANDA that relies on a Type II API DMF that has not been deemed 
304  available for reference22 at the time the filing review for such ANDA is completed.  In 
305  determining whether a Type II API DMF is available for reference by an ANDA, FDA 
306  will consider those materials submitted by the relevant DMF holder as of the date that the 
307  ANDA is submitted to FDA. 
308   
309  Q16:  Will FDA review a Type IV DMF for the formulation of flavoring agents, coloring 
310  agents, and/or imprinting inks that are referenced in an ANDA during the filing 
311  review? 
312   
                                                 
21 Type II API DMFs for which applicable fees have been paid and that have been found complete are listed on an 
Available for Reference list on FDAs Web site available at: 
http://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM332875.pdf.  FDA encourages 
applicants to consult the Available for Reference list to confirm that FDA has determined that a Type II API 
DMF is available for reference. 
22 Available for reference indicates that the DMF fee has been paid within the required payment period and the DMF 
has not failed an initial completeness assessment.  See sections 744B(a)(2)(D) and 744B(g)(2) of the FD&C Act. 
8  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
313  FDA will review a Type IV DMF for flavoring and coloring agents and imprinting inks 
314  that are referenced in an ANDA to determine if the formulation or information on the 
315  formulation is readily available therein.  Information will be considered readily available 
316  if the Right of Reference letter clearly indicates the exact location of the relevant 
317  information within the DMF, including 1) the page number and the date of submission to 
318  the DMF if such DMF is a paper or a hybrid submission or 2) the eCTD sequence 
319  number and submission date if such DMF number is fully electronic (i.e., electronically 
320  submitted in eCTD format).  If any of the information identified in numbers 1 or 2 above 
321  is missing from the Right of Reference letter, FDA will contact the applicant to request 
322  submission of a revised Right of Reference letter that includes the missing information.  
323  The applicant may have the supplier or DMF holder submit the information directly to 
324  FDA.  If the requested information is not provided within seven calendar days from 
325  notification, FDA will RTR the ANDA. 
326   
327  Q17:  Will FDA review a Type IV DMF for an excipient to determine whether it contains 
328  pharmacology/toxicology (pharm/tox) data to support its use in a proposed drug 
329  product? 
330   
331    FDA will review a Type IV DMF for an excipient to determine whether it contains 
332  pharm/tox data to support its use in a proposed drug product, provided the pharm/tox data 
333  is readily available therein. Information will be considered readily available if the Right 
334  of Reference letter clearly indicates the exact location of the relevant information within 
335  the DMF, including 1) the page number and the date of submission to the DMF if such 
336  DMF is a paper or a hybrid submission or 2) the eCTD sequence number and submission 
337  date if such DMF number is fully electronic (i.e., electronically submitted in eCTD 
338  format).  If any of the information identified in numbers 1 or 2 above is missing from the 
339  Right of Reference letter, FDA will contact the applicant to request submission of a 
340  revised Right of Reference letter that includes the missing information.  Alternately, the 
341  applicant may have the supplier or DMF holder submit the information directly to FDA.  
342  If the requested information is not provided within seven calendar days from notification, 
343  FDA will RTR the ANDA. 
344   
345  E.  Product Quality Deficiencies 
346   
347  1.  Stability Data 
348     
349  Q18:  Will FDA RTR an ANDA that fails to use two API lots to manufacture three batches 
350  of each strength of a proposed product? 
351   
352    Yes, FDA will consider an applicants failure to use two API lots to manufacture three 
353  batches of each strength of a proposed product a major deficiency.   
354   
355  Q19:  Will FDA RTR an ANDA if the applicant fails to provide certain stability study 
356  information to support worst-case orientation? 
357   
9  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
358  FDA will RTR the ANDA if the applicant fails to provide the recommended stability 
359  study information.  An applicant should provide three pilot-scale batches or two pilot-
360  scale and one small-scale batch with both accelerated and long-term data provided for 
361  each batch covering a period of no less than six months (i.e., 180 days), in all cases, in 
362  the upright orientation and, for liquids, solutions, semi-solids, and suspensions in the 
363  worst-case orientation as well.  For each of these batches, the applicant should provide 
364  three time points (e.g., 0, 3, and 6 months) that cover the recommended hold time (i.e., 6 
365  months) for the data for both worst-case and non-worst-case orientations.   
366   
367  If an ANDA contains stability data for studies conducted under intermediate conditions, 
368  the applicant should provide the full complement (i.e., 6 months worth) of failed 
369  accelerated data at three time points (e.g., 0, 3, and 6 months) and repeat the intermediate 
370  stability study for each of the three batches of the strength for whichever batch failed, 
371  including intermediate data in both the worst-case and upright orientations.23  The 
372  recommendation for the submission of intermediate data for all three batches if an 
373  applicants accelerated data show a significant change or failure of any attribute in one or 
374  more batches also applies to drug products for which orientation is not a consideration 
375  and that do not require worst-case orientation data.24 
376   
377  2.  Packaging Configurations 
378   
379  Q20:  Will FDA RTR an ANDA if the proposed packaging is inconsistent with the 
380  condition(s) of use approved for the reference listed drug (RLD)? 
381   
382  Yes, FDA will RTR an ANDA if the proposed packaging is inconsistent with the 
383  condition(s) of use approved for the RLD.  For example, if the RLD is approved for a 14-
384  day course of treatment, repeated at a specific interval, and is marketed in 14-count 
385  packages, the ANDA should propose marketing containers that are consistent with the 
386  approved condition(s) of use.   
387   
388  3.  Batch Records 
389   
390  Q21:  The guidance for industry ANDA Submissions - Refuse to Receive Standards states 
391  that FDA will RTR an ANDA if batch records are not provided.  Should an 
392  applicant submit commercial (i.e., blank) batch records if no scale-up is proposed? 
393   
394    An applicant should submit the commercial (i.e., blank) batch records, even if the 
395  applicant does not propose scale-up for the commercial batches.  The submission of the 
396  commercial batch records is in addition to the executed batch records submitted pursuant 
397  to 21 CFR 314.50(d)(1)(ii)(b). 
398   
399  Q22:  Will FDA RTR an ANDA that references batch records previously submitted by an 
400  applicant in another ANDA? 
                                                 
23 See guidances for industry, ANDA Submissions  Refuse to Receive Standards, ANDAs: Stability Testing of Drug 
Substances and Products, and ANDAs: Stability Testing of Drug Substances and Products, Questions and Answers. 
24 See guidance for industry ANDAs: Stability Testing of Drug Substances and Products, Questions and Answers. 
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401   
402    Yes, FDA will RTR an ANDA that references batch records previously submitted by an 
403  applicant in another ANDA.  When an applicant submits individual ANDAs for drug 
404  products containing the same active ingredient, each ANDA should have its own 
405  independent basis for approval.25 
406   
407  4.  Over-the-Counter Drug Products 
408   
409  Q23:  Will FDA RTR an ANDA for an over-the-counter (OTC) two-piece, hard gelatin 
410  capsule product that does not contain information indicating that it is sealed using 
411  an acceptable tamper-evident technology in conformance with tamper-evident 
412  packaging requirements?  
413   
414              Yes, FDA will RTR an ANDA for an OTC two-piece hard gelatin capsule product that is 
415  not sealed using an acceptable tamper-evident technology because that product fails to 
416  conform to the tamper-evident packaging requirements for OTC products in 21 CFR 
417  211.132.  The regulations require, for products covered by 21 CFR 211.132, that an OTC 
418  two-piece hard gelatin capsule product for retail sale be sealed using an acceptable 
419  tamper-evident technology. 
420   
421  Q24:  Will FDA RTR an ANDA for a partial Rx-to-OTC switch that references  data in 
422  the applicants approved ANDA for the prescription drug product? 
423   
424    In general, an applicant submitting an ANDA for an Rx-to-OTC switch where fewer than 
425  all conditions of use were switched to OTC status (partial Rx-to-OTC switch) may 
426  reference data on the proposed product from an approved ANDA or ANDA that has been 
427  received for the prescription drug product that the ANDA applicant also owns instead of 
428  conducting new in vivo and in vitro studies to establish BE to the RLD for the OTC 
429  product.  However, each Rx-to-OTC switch is unique and the requirements for ANDA 
430  applicants are based on the characteristics of the OTC RLD including formulation, 
431  packaging, conditions of use, among others, and any other requirements specific to OTC 
432  products.  For example, if the OTC RLD has a different formulation from the Rx RLD, 
433  the ANDA applicant will likely need to produce new batches and new BE data.  Certain 
434  changes in packaging may also result in ANDA applicants needing to produce new 
435  batches, with this packaging change also potentially requiring additional data to support 
436  BE.  An applicant that is referencing an approved ANDA should provide BE summary 
437  tables in Module 2.7 in the proposed ANDA.   
438   
439  In order to avoid an RTR determination, an applicant may submit a controlled 
440  correspondence regarding the ability to reference an existing ANDA in a new ANDA for 
441  a partial Rx-to-OTC switch.   
442   
443  5.  Inactive Ingredients26 
                                                 
25 21 CFR 314.101(d)(3). 
26 OGDs Division of Filing Review (DFR) reviews the list of inactive ingredients and determines whether the 
inactive ingredients were identified in the Inactive Ingredient Database (IID) and justified for the proposed use 
11  Contains Nonbinding Recommendations 
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444   
445   
446  Q25:   If an application references a general listing from the Inactive Ingredient Database 
447  (IID) and does not include a justification for the grade of excipient, will FDA 
448  identify the lack of justification as a deficiency at filing? 
449   
450    FDA will RTR an ANDA that lacks a justification in its original ANDA submission for 
451  the grade of an inactive ingredient when referencing a nonspecific or different grade of an 
452  inactive ingredient that is available in various grades.27  An ANDA that references a 
453  general IID listing or an IID listing for a different grade of an inactive ingredient but fails 
454  to provide any justification for the specific grade is not a substantially complete 
455  application because FDA has no basis on which to review the safety of the specific grade 
456  of the inactive ingredient in the proposed drug product.   
457   
458  An applicant using a specific grade of an inactive ingredient should justify the use of that 
459  grade, and may not cite to a different grade or a nonspecific listing as support for the 
460  safety of the inactive ingredient in the proposed drug product without providing 
461  additional justification.  Grades of an inactive ingredient may differ in chemical or 
462  physical properties and may affect the safety profile of a drug product.  Some inactive 
463  ingredients have grades or variations that may not have undergone a full safety evaluation 
464  in a previously approved product.  Some variations may rely, in part, on a finding of 
465  safety for an approved drug product that contains a similar grade of the inactive 
466  ingredient.  The applicants justification should identify the differences between the 
467  grades of the inactive ingredient and address any implication of the change in grade on 
468  the safety of the proposed drug product using a data-driven approach.  Whether the safety 
469  of a proposed grade of the inactive ingredient, in the context of the currently proposed 
470  drug product, is supported by a different grade of the inactive ingredient included in a 
471  previously approved drug product will be evaluated during the technical review of the 
472  ANDA. 
473   
474    An applicant may submit a controlled correspondence during product development 
475  regarding the specific grade of an inactive ingredient that the applicant proposes to use in 
476  the proposed drug product and reference the correspondence in the ANDA.  
477   
478  Q26:  Will FDA RTR an ANDA that fails to provide an IID reference for an inactive 
479  ingredient for the particular route of administration for the proposed drug product 
480  or that provides an IID reference for the inactive ingredient for a different route of 
481  administration than the route of administration for the proposed drug product? 
482   
                                                                                                                                                             
based on the IID.  Accordingly, FDA will RTR an ANDA if the proposed limits for a particular inactive ingredient 
exceed those identified in the IID without justification supporting this higher level.  Also, for an IID listing that 
differs from the proposed  inactive ingredient in nomenclature, molecular weight, viscosity, grade, etc., applicants 
should provide justification for citing the IID listing as the basis for its proposed level of use.  Absent such 
justification, DFR will RTR an ANDA for a proposed product that contains  the new inactive ingredient.  
27 For some inactive ingredients available in various grades, the IID may contain a listing for the inactive ingredient 
with grade unspecified (i.e., the IID listing is nonspecific).   
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483    FDA will generally consider an applicants failure to provide an IID reference for an 
484  inactive ingredient for the particular route of administration for the proposed drug 
485  product or an applicants provision of an IID reference for an inactive ingredient for a 
486  different route of administration than the route of administration for the proposed drug 
487  product (e.g., referencing an IID listing for an inactive ingredient for an oral route of 
488  administration for a sublingual or buccal tablet) as a minor deficiency, provided FDA is 
489  able to validate the level of use.28  If FDA cannot validate the level of use and the 
490  applicant has not provided justification for its level of use within the original ANDA 
491  submission, then FDA will RTR the ANDA.     
492   
493  Generic drug products should use inactive ingredients that have previously been included 
494  in an FDA-approved product at or below the proposed maximum daily exposure, in a 
495  similar clinical context, and by the same route of administration.  Applicants should 
496  consider the safety of inactive ingredients in their generic drug product.  A justification 
497  may include supportive information from the IID, a controlled correspondence response 
498  from OGD, published literature, evidence of safe use in FDA-approved drug products 
499  with a similar context of use, or other relevant and science-based safety information.  If a 
500  justification cites published literature, the applicant should submit a copy of the 
501  publication(s) in its ANDA.   
502   
503  If an inactive ingredient is unqualified for the corresponding route of administration of 
504  the proposed drug product (unless it is a physical mixture of components that are not 
505  novel), FDA will RTR the ANDA because there is no prior evidence of safe use in an 
506  FDA-approved drug product.  An inactive ingredient without prior evidence of safe use in 
507  an FDA-approved drug product is considered novel.  Use of a novel excipient generally 
508  will require submission of a new drug application (NDA) under section 505(b) of the 
509  FD&C Act. 
510   
511  6. Impurity Data 
512   
513  Q27:   The guidance for industry ANDA Submissions  Refuse to Receive for Lack of 
514  Justification of Impurity Limits indicates that FDA will RTR an ANDA that fails to 
515  provide justification for certain impurities above specified thresholds. How does 
516  FDA review ANDAs at filing to determine if sufficient justification is provided in the 
517  application? 
518     
519  During the filing review, FDA will determine if the ANDA: 1) proposes limits in drug 
520  substances and drug products for specified identified impurities that are above 
521  qualification thresholds; (2) proposes limits for specified unidentified impurities that are 
522  above identification thresholds; and/or (3) proposes limits for unspecified impurities 
523  (e.g., any unknown impurity) that are above identification thresholds.  If any of these 
524  factors are met, FDA will review the ANDA to determine if the applicant has provided a 
525  justification for these proposals.     
526   
                                                 
28 Level of use is used in this guidance to describe the amount per dosage unit as represented in the IID.   
13  Contains Nonbinding Recommendations 
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527  If the ANDA does contain a justification, the application will be received, assuming there 
528  are no deficiencies leading to an RTR determination.  The sufficiency of the justification 
529  will be reviewed during the technical review of the ANDA.  If the ANDA does not 
530  contain a justification for the proposed limits, FDA will RTR the application.   
531   
532  7.  Dissolution Testing 
533   
534  Q28:  What is the proper location for comparative (test product and RLD) half-tablet 
535  dissolution data? 
536    
537  FDA recommended half-tablet dissolution test data should be contained in Module 2.7 of 
538  the ANDA.  The failure to perform the recommended half-tablet dissolution studies (i.e., 
539  test product and RLD) or the failure to correctly place such dissolution data in Module 
540  2.7 is considered a major deficiency. 
541   
542  8.  Scoring and Conditions of Use 
543   
544  Q29:  Will FDA RTR an ANDA containing a statement that the score mark is non-
545  functional? 
546   
547    The scoring configuration of a generic drug product generally should be the same as the 
548  RLD to demonstrate that the test product can be administered in a manner consistent with 
549  the dosing recommendations of the RLD.  An applicant should include a comparison of 
550  the test product to the RLD for any proposed scoring configuration of the generic drug 
551  product.  FDA will RTR an ANDA that contains as justification an applicants statements 
552  that the score mark is non-functional when the RLD labeling contains dosing 
553  recommendations consistent with the dose delivery enabled by the score mark. 
554      
555  F.  BE and Clinical Deficiencies 
556   
557  Q30:  Will FDA RTR an ANDA if the ANDA deviates from the recommendations 
558  identified in a product-specific guidance (or BE guidance)? 
559   
560    As a general matter, ANDA applicants should consult the BE recommendations for 
561  specific products on FDAs Web page for product-specific recommendations on 
562  conducting recommended in vivo and/or in vitro studies for generic drug development29.  
563  FDA will RTR an ANDA that deviates from any study or standard described or 
564  recommended in a product-specific recommendation without providing justification (i.e., 
565  a demonstration that the alternate approach proposed by the applicant meets applicable 
566  statutory and regulatory requirements) for the deviation.  For example, if an applicant 
567  does not perform dissolution testing in all types of media as recommended in the product-
568  specific recommendation, the applicant should provide a justification for its testing 
569  methods to avoid a major deficiency determination.  In general, dissolution test methods 
570  for particular products are provided in FDAs product-specific BE recommendations. 
571   
                                                 
29 Available at http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075207.htm.  
14  Contains Nonbinding Recommendations 
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572  Q31:  Will FDA RTR an ANDA if the ANDA does not contain the data sets as 
573  recommended or does not otherwise follow recommendations identified in a 
574  product-specific recommendation? 
575   
576    FDA considers an applicants failure to provide data sets (as distinguished from stability 
577  studies) or definition files (e.g., type of data recommended, format, and file structure) as 
578  recommended in product-specific recommendations to be a minor deficiency.  
579   
580  Certain product-specific recommendations suggest additional information or data to 
581  support the studies recommended therein (e.g., testing the minimum amount of 
582  antimicrobial activity against a microorganism, providing adequate measurements at time 
583  points identified in the guidance).  Failure to submit this additional information to support 
584  the recommended studies would be considered a major deficiency in the absence of a 
585  justification (i.e., a demonstration that the alternate approach proposed by the applicant 
586  meets applicable statutory and regulatory requirements).   
587   
588  As noted in the product-specific recommendations, applicants can use an alternate 
589  approach if it satisfies the requirements of the applicable statutes and regulations.  
590  Applicants who wish to discuss an alternate approach are encouraged to contact OGD by 
591  submitting a controlled correspondence.  The ANDA submission should indicate if the 
592  applicant is proposing to use an alternate approach to certain product-specific 
593  recommendations and identify any discussions with OGD, if applicable, related to the 
594  proposed alternate approach.  The justification for the proposed alternate approach should 
595  be provided in Module 2.7 of the ANDA. 
596   
597  Q32:  Where should an applicant place long-term storage stability (LTSS) data?  Will 
598  failure to provide this information cause FDA to RTR an ANDA? 
599   
600  An applicant should provide LTSS coverage and data location in Bioequivalence 
601  Summary Table 10.  As indicated in the table, the applicant should specify the exact 
602  location of the LTSS study reports and data in Module 5.3.1.4.  The applicant should 
603  state the Module, Section, Subsection, and pages.  We recommend that the applicant also 
604  include a hyperlink in addition to the exact location.   
605   
606  FDA will generally classify an applicants failure to provide LTSS data in Summary 
607  Table 10 as a minor deficiency, provided the applicant has provided LTSS data in 
608  Module 5.3.1.4.  If the applicant fails to provide the LTSS data in Module 5.3.1.4, but 
609  provides the LTSS data in Summary Table 10, this omission will be considered a minor 
610  deficiency.  However, if an applicant fails to include the LTSS data in Summary Table 10 
611  and fails to provide supporting data in Module 5.3.1.4, FDA will RTR the ANDA. 
612   
613  Q33:  Will FDA RTR an ANDA that makes reference to BE data previously submitted by 
614  that applicant in another ANDA? 
615   
616    An applicant may reference BE data submitted in another ANDA, as long as the ANDA 
617  being referenced has been received for review.  FDA recommends that an ANDA 
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Draft  Not for Implementation 
618  referencing an ANDA that has been received provide, at minimum, the BE summary 
619  tables.   
620   
621  Q34:  Should an applicant provide summary tables in an ANDA for other studies? 
622   
623    Depending on the type of study conducted, the applicant should provide appropriate 
624  summary tables for each applicable study within their submission.  To facilitate 
625  submission of this data, FDA has developed summary table templates to be utilized by 
626  applicants and FDA has posted these tables to FDAs Web page.30  Generally, failure to 
627  provide the data in a summary table would be considered a minor deficiency.  However, 
628  if an applicant fails to provide the tables in Module 2 and the underlying data in Module 
629  5, this omission is considered a failure to submit a passing study and would result in an 
630  RTR determination. 
631   
632  Q35:   How should the study reports be submitted in Module 5 to ensure that an ANDA 
633  contains information to support an in vivo BE or clinical endpoint BE study, or 
634  statistical data and/or design?  Would the omission of these reports be considered a 
635  major or minor deficiency?  
636   
637  Clinical study reports should be provided as more than one document pursuant to the 
638  International Conference on Harmonization guideline for industry E3: Structure and 
639  Content of Clinical Study Reports.  Omission of any of these reports would be considered 
640  a minor deficiency.  The individual documents that should be included in a study report 
641  are listed below: 
642   
643    Synopsis 10 (E3 2) 
644    Study report (E3 1, 3 to 15) 
645    Protocol and amendments (E3 16.1.1) 
646    Sample case report forms (E3 16.1.2) 
647    List of IECs or IRBs (E3 16.1.3) and consent forms 
648    List and description of investigators (E3 16.1.4) and sites 
649    Signatures of principal or coordinating investigator(s) or sponsors responsible 
650  medical officer (E3 16.1.5) 
651    Listing of patients receiving test drug(s) from specified batch (E3 16.1.6) 
652    Randomization scheme (E3 16.1.7) 
653    Audit certificates (E3 16.1.8) and reports 
654    Documentation of statistical methods (E3 16.1.9) and interim analysis plans 
655    Documentation of interlaboratory standardization methods of quality assurance 
656  procedures if used (E3 16.1.10) 
657    Publications based on the study (E3 16.1.11) 
658    Important publications referenced in the report (E3 16.1.12) 
659    Discontinued patients (E3 16.2.1) 
                                                 
30 See Abbreviated New Drug Application (ANDA) Forms and Submission Requirements page available at: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplicati
ons/AbbreviatedNewDrugApplicationANDAGenerics/ucm120955.htm.  
16  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
660    Protocol deviations (E3 16.2.2) 
661    Patients excluded from the efficacy studies (E3 16.2.3) 
662    Demographic data (E3 16.2.4) 
663    Compliance and/or drug concentration data (E3 16.2.5) 
664    Individual efficacy response data (E3 16.2.6) 
665    Adverse event listings (E3 16.2.7) 
666    Listing of individual laboratory measurements by patient (E3 16.2.8) 
667    Case report forms (E3 16.3) 
668    Individual patient data listings (Case Report Tabulations) (E3 16.4) 
669    Data tabulations 
o
670    Data tabulations datasets 
671    Data definitions 
672    Annotated case report form 
673    Data listing 
o
674    Data listing datasets 
675    Data definitions 
676    Annotated case report form 
677    Analysis datasets 
o
678    Analysis datasets 
679    Analysis programs 
680    Data definitions 
681    Annotated case report form 
682    Subject profiles 
o
683    IND safety reports 
o
684   
17