ANDA Submissions  
Refuse-to-Receive 
Standards 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
 
December 2016 
Generics 
 
Revision 2  Contains Nonbinding Recommendations 
ANDA Submissions  
Refuse-to-Receive 
Standards 
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 
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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) 
 
December 2016 
Generics 
 
Revision 2 
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  GENERAL POLICY ........................................................................................................ 3 
A.  Form FDA 356h (356h) .................................................................................................................. 4 
B.  Submission, Format, and Organization ....................................................................................... 4 
C.  Non-Payment of GDUFA Obligations .......................................................................................... 4 
D.  Lack of a Designated U.S. Agent for a Foreign Applicant ......................................................... 5 
E.  Citing a Pending Suitability Petition as a Basis of Submission .................................................. 5 
IV.  REVIEWS FOR API ........................................................................................................ 6 
A.  Starting Material ............................................................................................................................ 6 
B.  Sterility Assurance Data ................................................................................................................ 6 
V.  PRODUCT QUALITY DEFICIENCIES ....................................................................... 6 
A.  Inactive Ingredients ....................................................................................................................... 6 
B.  Inadequate Stability ....................................................................................................................... 9 
C.  Packaging Amount Considerations ............................................................................................ 10 
D.  Batch Records .............................................................................................................................. 10 
E.  Method Validation/Verification Reports ................................................................................... 10 
F.  Special Consideration for Transdermal Patches ....................................................................... 11 
G.  Scoring and Conditions of Use .................................................................................................... 12 
H.  Microbiology Considerations ...................................................................................................... 13 
VI.   BIOEQUIVALENCE AND CLINICAL DEFICIENCIES ......................................... 14 
A.  Failed In Vivo BE Studies ........................................................................................................... 14 
B.  Alternate BE Studies.................................................................................................................... 14 
C.  Q1/Q2 Sameness Requirement for Consideration of an In Vivo BE Study Waiver .............. 15 
D.  Inadequate Dissolution Data (In Vitro Studies) ........................................................................ 15 
E.  Miscellaneous Factors .................................................................................................................. 16 
VII.  DISPUTE OF A REFUSE-TO-RECEIVE DECISION .............................................. 17 
APPENDIX A:  EXAMPLES OF MINOR DEFICIENCIES ................................................... 1  Contains Nonbinding Recommendations 
ANDA Submissions  Refuse-to-Receive Standards 
1
Guidance for Industry  
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
I.  INTRODUCTION  
 
This guidance is intended to assist applicants preparing to submit to FDA abbreviated new drug 
applications (ANDAs) and prior approval supplements (PASs) to ANDAs for which the 
applicant is seeking approval of a new strength of the drug product.2  The guidance highlights 
deficiencies that may cause FDA to refuse to receive (RTR) an ANDA.3  An RTR decision 
indicates that FDA determined that an ANDA is not substantially complete.4  A substantially 
complete ANDA is an ANDA that on its face is sufficiently complete to permit a substantive 
review.5 
 
This guidance is not meant to be a comprehensive list of the deficiencies that may or will lead to 
an RTR determination by FDA.  Instead, this guidance identifies certain deficiencies and certain 
recurrent deficiencies that in FDAs experience have led FDA to RTR an ANDA.  This guidance 
also describes how FDA will assess deficiencies identified during FDAs filing review to 
determine whether an ANDA should be received.  We note that industry is aware of many of the 
standards described in this guidance because FDA has historically applied many of these 
standards in its RTR determinations.   
 
FDAs guidance documents, including this guidance, generally do not establish legally 
enforceable responsibilities.  Instead, guidances describe FDAs current thinking on a topic and 
should be viewed only as recommendations, unless specific regulatory or statutory requirements 
are cited.  
                                                 
1 This guidance has been prepared by the Office of Generic Drugs in the Center for Drug Evaluation and Research at 
the Food and Drug Administration.  
2 For purposes of this guidance, the use of the term ANDA will mean ANDAs and new-strength PAS 
submissions. 
3 An RTR determination should not be confused with a refuse-to-approve determination. 
4 21 CFR 314.101(b)(1).  
5 21 CFR 314.3(b).   
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  Contains Nonbinding Recommendations 
The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required.6  
 
 
II.  BACKGROUND 
Pursuant to the enactment of the Generic Drug User Fee Amendments of 2012 (GDUFA),7 the 
Office of Generic Drugs (OGD) is tasked with a number of activities, including the development 
of enhanced refusal to receive standards for ANDAs and other related submissions by the end 
of year 1 of the program....8  Enhanced RTR standards are important because the practice of 
submitting an ANDA that is not sufficiently complete to permit a substantive review and then 
repairing it in the course of an extended review period that needs several cycles of FDA 
response and applicant repair is inherently inefficient and wasteful of resources.  In addition, 
ANDAs that are not sufficiently complete to permit a substantive review generate extra reviews 
and letters.   
FDA evaluates each submitted ANDA individually to determine whether the ANDA can be 
received.  The receipt of an ANDA means that FDA made a threshold determination that the 
ANDA is a substantially complete application, that is, an ANDA that on its face is sufficiently 
complete to permit a substantive review.9  Sufficiently complete means that the ANDA contains 
all the information required under section 505(j)(2)(A)  of the Federal Food,  Drug, and  
Cosmetic Act (FD&C Act) and does not contain a deficiency described in 21 CFR 314.101(d) 
and (e).10   
Our regulations at 21 CFR 314.101 provide the regulatory authority by which FDA may in 
certain cases, and will in others, RTR an ANDA that does not satisfy the criteria for a threshold 
determination that the application is substantially complete .11   
 
 
 
                                                 
6 At various points in this guidance, it is noted that when a particular type of deficiency in an ANDA is seen, FDA 
will RTR the ANDA.  It is important to understand that these statements do not create legal obligations, on 
applicants or on FDA, but rather are included for purposes of transparency.  This means that FDA, in the normal 
course, 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 in the 
normal course find the application not sufficiently complete to permit a substantive review and  RTR it. 
7 Generic Drug User Fee Amendments of 2012 (GDUFA) (Public Law 112-144, Title III). 
8 See Generic Drug User Fee Act Program Performance Goals and Procedures:  
http://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM282505.pdf. 
9 See 21 CFR 314.101(b)(1) and 314.3(b). 
10 21 CFR 314.3(b). 
11 See 21 CFR 314.101(d)-(e). 
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  Contains Nonbinding Recommendations 
 
Between Fiscal Years (FY) 2013 to 2015, FDA refused to receive 379 ANDAs for reasons other 
than failure to pay a GDUFA fee.  Of all original ANDA submissions, FDA refused to receive: 
 
  14% in FY 2013 
  10% in FY 2014 
  14% in FY 201512 
 
In FY 2015, the five most frequent bases for an RTR determination were (in order of frequency): 
inadequate stability data; incomplete information request response; inadequate dissolution; drug 
product was not qualitatively and quantitatively the same (Q1/Q2 same) as the reference listed 
drug (RLD); and failure to respond to information request within the prescribed timeframe).  .   
 
 
III.  GENERAL POLICY  
 
FDA considers the nature (e.g., major or minor) of the deficiencies, including the number of 
deficiencies in the ANDA, in determining whether an ANDA is incomplete on its face.13  During 
FDAs filing review of a submitted ANDA, FDA will determine if there are any major or minor 
deficiencies.  Generally, a major deficiency is one that in FDAs judgment is significant in nature  
such as certain deficiencies found in 21 CFR 314.101(d) or 21 CFR 314.101(e);14 other major 
deficiencies are discussed in this and other guidances.  Numerous minor deficiencies (discussed 
below) also constitute a major deficiency.  A major deficiency will result in a determination by 
FDA that the ANDA is incomplete on its face under 21 CFR 314.101(d)(3), and FDA will 
therefore RTR an ANDA containing a major deficiency.   
 
A minor deficiency is one that in FDAs judgment is minor in nature and can be easily 
remedied.15  As a result, FDA will allow the applicant a prescribed time period (described below 
in this section) to provide a response to such deficiencies.  In particular, if FDA determines that 
an ANDA contains fewer than ten minor deficiencies (i.e., nine deficiencies or fewer), FDA will 
notify the applicant of the deficiencies, by phone, fax, or through the primary method for 
communication, which is email.  FDA, in its discretion, provides applicants with the opportunity 
to correct minor deficiencies or amend the ANDA, within seven (7) calendar days.16   If within 7 
calendar days the requested information is not received, FDA will RTR the ANDA.  However, if 
                                                 
12 See FY 2015 Performance Report to Congress for the Generic Drug User Fee Amendments, available at 
http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/UserFeeReports/PerformanceReports/U
CM493026.pdf.  
13 21 CFR 314.101(d)(3). 
14 Pursuant to 21 CFR 314.101(d), FDA may not consider an ANDA to be received if any of the deficiencies 
under that regulation applies.  FDA will determine on a case-by-case basis whether a deficiency under certain 
provisions of  314.101(d) is a major or minor deficiency, in accordance with the principles described in this 
guidance. 
15 Though the focus of this guidance is to highlight major deficiencies, select minor deficiencies are listed in 
Appendix A  the list is not a comprehensive list of minor deficiencies. 
16 The response period will begin the day after notification is provided.  If the 7th calendar day falls on a Saturday, 
Sunday, or Federal holiday, the deadline for amending the ANDA to correct the deficiencies will be the next day 
that is not a Saturday, Sunday, or Federal holiday. 
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  Contains Nonbinding Recommendations 
FDA determines that an ANDA contains ten or more minor deficiencies or one or more major 
deficiencies, FDA will not consider the ANDA to be  a substantially complete application under 
21 CFR 314.101(b)(1).  In such cases, FDA will notify the applicant that FDA considers the 
ANDA not to have been received.  If the applicant decides to submit additional materials to 
correct the deficiencies, the resulting amended ANDA will be considered a new ANDA 
submission, received as of the date the amended ANDA is submitted (if deemed substantially 
complete), and the applicant will be required to pay a new ANDA fee.  If an ANDA is not 
received and the applicant takes no action, FDA may consider the ANDA withdrawn after 1 
year.17  An ANDA applicants failure to take action after a refuse-to-receive decision on an 
ANDA may be considered a request by the applicant to withdraw the ANDA, unless the 
applicant requests an extension of time in which to resubmit the ANDA.18  There may be 
circumstances, however, under which an exception to, or a waiver of, a regulatory requirement 
may be granted.  FDA will consider the merits of such circumstances on a case-by-case basis.19 
 
The following sections discuss deficiencies that FDA considers to be major deficiencies.  A 
selection of minor deficiencies is provided in Appendix A.  
 
A.  Form FDA 356h (356h) 
 
An ANDA must contain a completed application form (i.e., Form FDA 356h).  If this form is not 
included, or is not signed, which indicates that the applicant is not attesting to the material 
contained in the application, FDA will RTR the ANDA.20 
 
B.  Submission, Format, and Organization  
 
The ANDA should be formatted according to the eCTD format, and it should be submitted 
electronically for GDUFA metric goals to apply to the ANDA.21  Under Section 745A(a) of the 
FD&C Act, electronic submissions of applications to FDA will be required at least 24 months 
after the issuance of the final guidance for industry, Providing Regulatory Submissions in 
Electronic Format  Certain Human Pharmaceutical Product Applications and Related 
Submissions Using the eCTD Specifications (the eCTD guidance), which published on May 5, 
2015.  Accordingly, the electronic submission of ANDAs in a format specified by FDA is 
required as of May 5, 2017.22   
 
C.  Non-Payment of GDUFA Obligations 
 
                                                 
17 21 CFR 314.101(b)(3)(iii). 
18  Abbreviated New Drug Applications and 505(b)(2) Applications; Final Rule, 81 FR 69580, 69622 (October 6, 
2016). 
19 21 CFR 314.99(b). 
20 21 CFR 314.101(d)(1). 
22 To ensure receipt of an electronic submission, please follow the current eCTD specifications as provided in 
FDAs Data Standards Catalog available at  
http://www.fda.gov/downloads/ForIndustry/DataStandards/StudyDataStandards/UCM340684.xls.  
22 To ensure receipt of an electronic submission, please follow the current eCTD specifications as provided in 
FDAs Data Standards Catalog available at  
http://www.fda.gov/downloads/ForIndustry/DataStandards/StudyDataStandards/UCM340684.xls.  
4 
  Contains Nonbinding Recommendations 
FDA will RTR an ANDA in certain cases if there are outstanding user fee obligations23:   
 
  If an applicant fails to pay the GDUFA ANDA or PAS fee within 20 calendar days of 
submitting the application 24 
  If an ANDA references a Type II active pharmaceutical ingredient (API) Drug Master 
File (DMF) that is not on the public available for reference list because of non-payment 
of the GDUFA DMF fee 25 
  If an ANDA references a facility that is on the facility arrears list for failure to pay the 
GDUFA facility fee(s)26  
  If the applicant is the owner of or is affiliated with the owner of a facility on the facility 
arrears list27 
  If the applicant is listed on the backlog arrears list28 
  If the applicant is affiliated with an applicant on the backlog arrears list.29 
In all of these cases, FDA will RTR an ANDA for nonpayment of GDUFA user fee obligations.  
Upon satisfaction of all applicable user fee obligations, CDERs Office of Management will 
issue a formal correspondence to the applicant indicating the adjusted receipt date (i.e., the date 
on which all outstanding user fee obligations were satisfied in full) for which the ANDA is 
eligible. 
 
D.  Lack of a Designated U.S. Agent for a Foreign Applicant 
 
FDA will RTR an ANDA if a foreign applicant does not designate a U.S. agent.  If the person 
signing the application form (i.e., Form FDA 356h) does not reside or have a place of business 
within the United States, the application form is required to contain the name and address of, and 
be countersigned by, an attorney, agent, or other authorized official who resides or maintains a 
place of business within the United States.30   
 
E.  Citing a Pending Suitability Petition as a Basis of Submission 
 
If an applicant submits a copy of, or refers to, a pending suitability petition, FDA will RTR the 
ANDA because it lacks a legal basis for the submission.31  An ANDA can rely on a suitability 
petition as a basis of submission only after the petition has been approved by FDA.  ANDAs can 
be submitted for drug products that differ from the listed drug, provided that a suitability petition 
requesting a change is submitted pursuant to section 505(j)(2)(C) of the FD&C Act and in 
                                                 
23 See Generic Drug User Fee Amendments of 2012; Public Law 112-144, Title III.  See also 
http://www.fda.gov/ForIndustry/UserFees/GenericDrugUserFees/ucm319567.htm and the guidance for industry 
Generic Drug User Fee Amendments of 2012:  Questions and Answers Related to User Fee Assessments. 
24 Section 744B(g)(3) of the FD&C Act.  
25 Section 744B(g)(2) of the FD&C Act.  
26 Section 744B(g)(4)(A)(ii) of the FD&C Act.  
27 Section 744B(g)(4)(A)(i) of the FD&C Act.  
28 Section 744B(g)(1) of the FD&C Act.  
29 Id. 
30 21 CFR 314.94(a)(1) (incorporating by reference 21 CFR 314.50(a)(1), (3), (4), and (5)). 
31 21 CFR 314.101(d)(3). 
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  Contains Nonbinding Recommendations 
accordance with 21 CFR 314.93 and 10.30, and the suitability petition is approved by FDA.  The 
changes (from the RLD) that can be requested in a suitability petition are: 
 
  Change in route of administration 
  Change in dosage form 
  Change in strength 
  One active ingredient is substituted for one of the active ingredients in a listed 
combination drug  
 
An applicant who wishes to rely on an approved suitability petition as the basis of submission for 
an ANDA can do so by identifying the listed drug cited in the approved petition as the basis for 
the ANDA, subject to the limitation described in 21 CFR 314.93(f)(2).32  In addition, the docket 
number and a copy of FDAs correspondence approving the petition must be included in the 
ANDA submission.33,  
 
 
IV.  REVIEWS FOR API 
 
A.  Starting Material 
 
FDA will RTR an ANDA if the active pharmaceutical ingredient (API) review, whether in an 
ANDA or in a referenced drug master file (DMF), reveals that the starting material for the API is 
not justified according to the principles in the ICH Q11 guidance.34,35 
 
B.  Sterility Assurance Data 
 
FDA will RTR an ANDA if the API review, whether in an ANDA or a referenced DMF, reveals 
that sterility assurance data are missing for a sterile API.36 
 
 
V.  PRODUCT QUALITY DEFICIENCIES  
 
A.  Inactive Ingredients37  
 
1.  Inactive Ingredients Exceeding the Inactive Ingredient Database Limit 
 
FDA will RTR an ANDA if the submission proposes to use an inactive ingredient at a level that 
exceeds any of the inactive ingredient database (IID) listings without the justification described 
                                                 
32 21 CFR 314.94(a)(3)(i). 
33 21 CFR 314.94(a)(3)(iii). 
34 See International Conference on Harmonisation (ICH) (2012), Q11 Development and Manufacture of Drug 
Substances (Chemical Entities and Biotechnological/Biological Entities). 
35 21 CFR 314.50(d)(1)(i). 
36 21 CFR 314.50(d)(1)(i) and 21 CFR 314.50(d)(1)(ii). 
37 In general, although considered supportive, GRAS certification, FEMA certification, DMF authorization, or 
composition are not considered sufficient justification to support safety of an inactive ingredient or level at which it 
is used in the drug product.  
6 
  Contains Nonbinding Recommendations 
below.38,39  Applicants can justify inactive ingredient levels by reference to the IID, which is a 
listing of inactive ingredients and their maximum levels of use (per dosage unit or percent 
composition), arranged by either route of administration or dosage form.40  An inactive 
ingredient is considered justified, for receipt purposes, if the proposed level is at or below the 
amount indicated in the IID for the corresponding route of administration of the drug product.  If 
an applicant wishes to use an inactive ingredient at a level per unit that is higher than what is 
proposed in the IID, options are available to facilitate receipt of the ANDA: 
 
  Submit complete pharmacology/toxicology information.   
 
In the draft guidance, FDA described the type of pharmacology/toxicology information that 
should be submitted for ANDA submissions that propose to use an inactive ingredient at a 
level that exceeds any of the IID listings to avoid FDA refusing-to-receive the ANDA.  After 
additional consideration, FDA believes that this issue bears further evaluation, and the 
Agency is not prepared to offer its current thinking on this subject at this time.  The Agency 
anticipates addressing this issue in a separate guidance.   
 
  Cite a specific example of a CDER-approved drug product.  
 
Applicants should cite a specific example of a CDER-approved drug product that contains 
the inactive ingredient at or above the proposed level of use41 for the appropriate route of 
administration. 
 
  Refer to an FDA controlled correspondence response.   
 
Applicants should refer to a controlled correspondence in which FDA issued a response 
indicating that the proposed level of use is acceptable for receipt purposes.42  Applicants 
should calculate the maximum daily intake (MDI) for the inactive ingredient and provide the 
name of the RLD, if applicable.  No more than three inactive ingredient queries should be 
submitted per controlled correspondence.   
 
Inactive ingredient justification for oral liquid drug products should not be based on a listed 
percentage in the IID.  This is because the components of liquid dosage forms are generally 
expressed in terms of milligrams per milliliter (%w/v), and as a result, the amount of inactive 
ingredient delivered per dose cannot be properly ascertained by simply comparing the %w/v 
composition of a particular inactive ingredient to a threshold percentage in the IID.  Instead, the 
                                                 
38 If the inactive ingredient is determined to be a novel inactive ingredient for the corresponding route of 
administration of the drug product (unless it is a physical mixture of components found in the IID and within 
acceptable IID maximum levels), FDA will RTR the ANDA.  Use of a novel inactive ingredient will generally 
require submission as a 505(b)(2) application. 
39 21 CFR 314.94(a)(9)(ii). 
40 See http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm.  
41 That is, amount per dosage unit or maximum daily intake (MDI) that is based on the calculated maximum daily 
dose (MDD) of the active ingredient in the drug product. 
42 Controlled correspondences are submitted via e-mail through GenericDrugs@fda.hhs.gov.  See 
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm120610.htm for 
more information. 
7 
  Contains Nonbinding Recommendations 
applicant should calculate the amount of inactive ingredient that is delivered per dose or per day 
(MDI) based on dosing recommendations indicated in the RLD label.  In addition, the applicant 
should justify the calculated amount based on an amount-per-unit IID listing that corresponds to 
an oral dosage form (e.g., solid oral dosage form).  Alternatively, for the ANDA to be considered 
for receipt, one of the previously discussed options in this section can be used.    
 
Inactive ingredients that are included in powders for oral suspension should be justified as 
described in the preceding paragraph, with calculations of amounts delivered per dose based on 
the dry powder composition (i.e., prior to reconstitution). 
 
When justifying inactive ingredients for semi-solid and topical dosage forms, applicants can 
refer to listed percentages in the IID.  However, the percent concentration of each inactive 
ingredient should be converted into an amount expressed in one of the following forms:  mg/mL, 
mg/g, mL/mL, etc. 
 
2.    Changes to Non-Exception Inactive Ingredients in Parenteral, Ophthalmic, and 
Otic Products 
 
FDA will RTR an ANDA if certain concerns with respect to non-exception inactive ingredients 
are not addressed in the ANDA.43  
 
Parenteral drug products generally must contain the same inactive ingredients and in the same 
concentration as the RLD.44  However, specific changes (from the RLD drug product) are 
permitted for certain inactive ingredients (i.e., preservatives, buffers, and antioxidants), which 
are considered exception inactive ingredients.  Applicants should identify and characterize the 
differences and should submit information demonstrating that the differences do not affect the 
safety or efficacy of the proposed drug product.45  This justification is a critical aspect of the 
exception inactive ingredient allowance and should be provided in the ANDA to support the 
proposed exception inactive ingredient change. 
 
For all other inactive ingredients, an ANDA whose subject is a parenteral drug product must be 
qualitatively and quantitatively the same (Q1/Q2 same) as the RLD, with certain allowable 
differences permitted under 21 CFR 314.94(a)(9)(iii).46  Before submitting an ANDA, the 
applicant can submit a controlled correspondence to request a Q1/Q2 evaluation of proposed 
formulations to minimize the risk of FDA refusing-to-receive the ANDA.47  Even if an inactive 
ingredient is determined to be quantitatively the same as the RLD, the proposed concentration 
should be justified with reference to the IID in the event that it falls within the upper limit of the 
Q1/Q2 threshold.  In other words, if an inactive ingredient is demonstrated to be quantitatively 
                                                 
43 21 CFR 314.94(a)(9)(ii). 
44 21 CFR 314.94(a)(9)(iii). 
45 Id. 
46 Id. (Also, quantitative sameness generally is interpreted by OGD to mean a concentration that is within 95-105% 
of the RLD concentration.  That is, sameness as discussed herein does not suggest an exact value, but rather a range 
of values).   
47 As with other inactive ingredient queries, FDA requests that the applicant submit no more than three proposed 
formulations for evaluation per controlled correspondence.  See, guidance for industry Controlled Correspondence 
Related to Generic Drug Development.  
8 
  Contains Nonbinding Recommendations 
the same as the RLD (same implies 95% but 105% of the RLD concentration or amount) yet 
exceeds the IID limit for the applicable route of administration, FDA will RTR the ANDA.48 
 
An ANDA concerning an ophthalmic drug product should be Q1/Q2 the same as the RLD with 
respect to all of its components, or include data from appropriate BE studies.49  Despite a similar 
allowance (to parenteral products) provided for ophthalmic drug products in 21 CFR 
314.94(a)(9)(iv), FDA has determined that, as a scientific matter, any qualitative or quantitative 
deviations from the RLD should be accompanied by an appropriate in vivo BE study or studies.   
 
For otic drug products, differences with respect to the types of inactive ingredients listed in 21 
CFR 314.94(a)(9)(iv) are permitted, provided that these differences are identified and 
characterized and information is submitted demonstrating that these differences do not affect the 
safety or efficacy of the proposed drug product. 
 
B.  Inadequate Stability  
 
1.  Number of Batches and Length of Studies 
 
FDA will RTR an ANDA if certain batch size and study recommendations are not satisfied.50,51  
The applicant should provide three pilot-scale batches or two pilot-scale and one small-scale 
batch with both accelerated and long-term data provided for each batch covering a period of no 
less than 6 months (180 days), with data from three time points (e.g., 0, 3, and 6 months).52  
However, if 6 months of accelerated data show a significant change53 or failure of any attribute 
in one or more batches, the applicant should also include 6 months of intermediate54 stability 
studies at the time of submission.  
 
The initiation date for each of the stability studies, along with individual pull dates (removal 
from the storage chamber) for each stability time point should also be provided as part of the 
data to verify that each study covers the recommended 6-month (180 days) minimum hold time. 
 
                                                 
48 The assumption should not be made that any listed IID concentration incorporates the 105% Q1/Q2 allowance. 
49 See 21 CFR 320.22(b)(1).  An applicant proposing to submit an ANDA for a non-Q1/Q2 same ophthalmic drug 
product is strongly urged to contact the Division of Bioequivalence for guidance prior to submitting an application. 
50 ANDAs submitted and date-stamped by the Agency prior to June 20, 2014 (the date of implementation of FDA 
stability guidance), will be evaluated for filing review purposes using ANDA stability recommendations in place 
prior to June 20, 2014. 
51 21 CFR 314.50(d)(1)(i) and 21 CFR 314.50(d)(1)(ii). 
52 Guidance for industry ANDAs:  Stability Testing of Drug Substances and Products.  See also FDAs guidance for 
industry ANDAs:  Stability Testing of Drug Substances and Products, Questions and Answers.   
53 The ICH guidance for industry entitled Q1A(R2) Stability Testing of New Drug Substances and Products defines 
significant change as one or more of the following (as appropriate for the dosage form):  (1) a 5% change in assay 
from its initial value, or failure to meet the acceptance criteria for potency when using biological or immunological 
procedures; (2) a degradation products exceeding its acceptance criterion; (3) failure to meet the acceptance criteria 
for appearance, physical attributes, and functionality test (e.g., color, phase separation, resuspendibility, caking, 
harness, dose delivery per actuation); however, some changes in physical attributes (e.g., softening of suppositories, 
melting of creams) may be expected under accelerated conditions; (4) failure to meet acceptance criterion for pH; 
and (5) failure to meet the acceptance criteria for dissolution for 12 dosage units. 
54 Intermediate storage condition testing does not apply to drug products intended for storage in a refrigerator. 
9 
  Contains Nonbinding Recommendations 
2.  Container Orientation 
 
FDA will RTR an ANDA if both worst-case scenario and non-worst-case stability data adhering 
to the recommendations described in section V.B.1 and this section are not submitted for the 
described drug product batches:  liquids, solutions, semi-solids, and suspensions.55   
  
C.  Packaging Amount Considerations 
 
FDA will RTR an ANDA if the ANDA does not package a minimum (threshold) amount of the 
finished drug product in the container/closure systems that are proposed for marketing, as 
discussed in FDAs guidance for industry ANDAs:  Stability Testing of Drug Substances and 
Products, Questions and Answers.56  Also as discussed in the guidance, the threshold amount 
that should be packaged is governed by the specific dosage form (e.g., solid oral dosage forms, 
oral powders/solutions/suspensions, parenteral drug products, ophthalmic/otic drug products, 
transdermal patches, and topicals such as creams/lotions/gels and inhalation solutions/nasal 
sprays) of the finished drug product that is the subject of the ANDA submission.   
 
To qualify the dosage units that are packaged toward the applicable threshold, the following 
three recommended criteria for each container/closure configuration should be satisfied: 
 
  Stability data (as described in section V.B.1 of this guidance). 
 
  Container/closure system information should be submitted in ANDA section 3.2.P.7.  
If bracketing or matrixing is used, an ANDA should include the container/closure 
system information applicable to configurations that were excluded from stability 
studies because of bracketing or matrixing.  
 
  Container and carton (if applicable) labeling for each packaging configuration 
containing dosage units to be counted in the overall packaged total should be 
provided in section 1.14.1 of the ANDA.  
 
D.  Batch Records 
 
FDA will RTR an ANDA if blank and executed batch records are not provided, regardless of 
whether commercial scale-up is proposed.57  For example, both commercial (blank) and executed 
(pilot) batch records for the pilot batches that are manufactured to support an ANDA should be 
submitted, along with any accompanying reconciliation sheets.   
 
E.  Method Validation/Verification Reports 
 
                                                 
55 See 21 CFR 314.94(a)(9)(i) stating that ANDAs must include chemistry, manufacturing, and controls information 
required under 21 CFR 314.50(d)(1). 
56 21 CFR 314.50(d)(1)(ii).         
57 21 CFR 314.50(d)(1)(ii)(b). 
10 
  Contains Nonbinding Recommendations 
FDA will RTR an ANDA if method validation/verification reports are not provided.58  It is 
critical that method validation/verification reports for all analytical methods be provided in 
sections 3.2.S.4.3 and 3.2.P.5.3 of the ANDA, for both the drug substance (API) and drug 
product, respectively.  That is, for drug products for which a relevant official United States 
Pharmacopeia (USP) drug product monograph exists, verification59 of the USP analytical 
procedures should be provided.  Verification should also be submitted for methods used from 
outside sources, such as a Type II API DMF holder, unless the methods have been fully validated 
in house.  For any in-house methods used, validation of the analytical procedure should be 
submitted in either of the appropriate sections of the ANDA (i.e., sections 3.2.S.4.3 or 3.2.P.5.3).  
In-house methods used in lieu of USP methods should be compared to the USP method to 
support a demonstration that the in-house method is sufficient. 
 
In addition, for ANDAs not submitted electronically60, the applicant should submit three copies 
of the method validation/verification package for the API, the drug product, or both.61  
 
F.  Special Consideration for Transdermal Patches 
 
FDA will RTR an ANDA for a transdermal patch if the ANDA does not address certain special 
considerations.62,63   
 
  Matrix Systems 
 
ANDAs for matrix transdermal systems should be supported by stability data on three 
batches of drug product manufactured from three distinct laminates, where each batch of 
laminate is made using different lots of API, adhesives, backing, and/or other critical 
elements in the drug product.  If an applicant is seeking approval for multiple strengths of a 
particular drug product, the applicant can choose to use a bracket approach by manufacturing 
three batches of the highest and lowest strengths and at least one batch of each of the 
bracketed strengths.  An example is given below. 
  Laminate Batch # 1 (pilot-scale):  All strengths (highest, lowest, and bracketed) 
-
  Laminate Batch # 2 (pilot-scale):  Highest and lowest strengths 
-
  Laminate Batch # 3 (pilot- or small-scale):  Highest and lowest strengths 
-
 
  Reservoir Systems 
                                                 
58 21 CFR 314.50(d)(1) and 314.94(a)(9)(i). 
59 EP (European Pharmacopoeia)/BP (British Pharmacopoeia)/JP (Japanese Pharmacopoeia) methods may be 
allowed, for which, in many cases, verification (versus full validation) may suffice.  
60 On May 5, 2017, the electronic submission of ANDAs in a format specified by FDA will be required.  See 
discussion in section III.B. 
61 21 CFR 314.50(e)(2)(i).  
62 21 CFR 314.50(d)(1). 
63 In addition to the considerations identified in this section, FDA has provided recommendations on the submission 
of studies evaluating the adhesive performance of a Transdermal Delivery System (TDS) or topical patch in support 
of an ANDA  in the guidance for industry Assessing Adhesion with Transdermal Delivery Systems and Topical 
Patches for ANDAs.   The recommendations provided in the guidance will supersede the recommendations related 
to adhesion studies provided in individual product-specific recommendations published before the guidance was 
issued.  Accordingly, FDA will RTR an ANDA for failure to follow the recommendations in the guidance once the 
final guidance is issued.   
11 
  Contains Nonbinding Recommendations 
 
Applicants are strongly encouraged to consult the Office of Lifecycle Drug Products, within the 
Office of Pharmaceutical Quality before making a decision to develop a reservoir transdermal 
system product.  ANDAs for reservoir transdermal systems should be supported by stability data 
on three batches of drug product manufactured from three distinct reservoir gels.  Each batch of 
drug product should use different lots of API, adhesives, gel excipients, backing membrane, rate 
controlling membrane, and/or other critical elements in the drug product.  If multiple strengths of 
a reservoir transdermal system are prepared from reservoir gels containing different 
concentrations of API, three batches of each strength should be manufactured.  A bracket 
approach is usually not acceptable.  
 
G. Scoring and Conditions of Use  
 
1.  Functional Scoring Configurations That Are Inconsistent With the RLD 
 
FDA will RTR an ANDA if there are inconsistencies in the scoring configuration between the 
RLD and the test product and those inconsistencies have not been reviewed and approved by 
FDA before submission of the ANDA.  Scoring configurations often facilitate dose titration and 
other patient-specific regimens that would be imprecise because of the difficulty of splitting an 
unscored tablet (for more information, see FDAs guidance for industry Tablet Scoring:  
Nomenclature, Labeling, and Data for Evaluation (Tablet Scoring guidance)).  FDAs Tablet 
Scoring guidance recommends that the scoring configuration of generic drug products should be 
the same as the RLD and so demonstrate that the test product can be administered in a manner 
consistent with the dosing recommendations of the RLD.   
 
Inconsistencies in scoring configuration between the RLD and the test product may not facilitate 
this demonstration.  For example, if an RLD 10 mg tablet is scored to enable administration of a 
5 mg dose (and a 5 mg dose is supported by the label) and the test product is unscored and does 
not offer a 5 mg strength, an ANDA applicant will be unable to demonstrate that the test product 
can be administered in a manner consistent with the dosing recommendations of the RLD.   
 
Conversely, if the ANDA product (e.g., 10 mg) is manufactured with a score mark and the RLD 
10 mg tablet is unscored and the label indicates no recommended dose lower than 10 mg, the test 
product offers the potential for delivering a dose (5 mg) that is not reflected in the label, which 
would be considered a new dosing regimen.  As a result, an ANDA applicant will be unable to 
demonstrate that the test product would be administered only in a manner consistent with the 
dosing recommendations of the RLD.   
   
2.  Fill Volumes for Parenteral Drug Products That Differ From the RLD 
 
FDA will RTR an ANDA whose subject is a parenteral drug product if its fill volume deviates 
from the RLD drug product and the deviation is not permitted.64,65   ANDA parenteral 
(injectable) drug products should contain the same concentration and total drug content per 
                                                 
64 That is, alterations beyond overfill allowances that are within USP recommendations in a relevant drug product 
monograph. 
65 See generally 21 CFR 314.50(d)(1). 
12 
  Contains Nonbinding Recommendations 
container as the RLD.  Therefore, a deviation from the fill volume (total drug content) of the 
RLD parenteral drug product may constitute a change in strength.  A change in strength must 
first be approved via the suitability petition process (see section III.F of this guidance) before it 
can be proposed in an ANDA submission.   
 
3.  Differences in Packaging and/or Labeling That May Be Associated With the 
Safe/Effective Use of the Drug Product   
 
FDA will RTR an ANDA on a case-by-case basis if the ANDA contains differences in 
packaging and/or labeling from the RLD that may be associated with safe/effective use of the 
drug product.66  Generally, if the RLD is packaged with certain labeling in a manner to ensure its 
proper administration, the test product should be packaged and labeled similarly.  For example, 
an RLD product may incorporate labeling on its packaging that contains a combination of visual 
and/or typographical aids, beyond the direct label text, to facilitate patient compliance and safety.  
Blister packaging is an example of such packaging, whereby certain drug products communicate 
crucial patient information directly on the blister carton (and/or the blister itself) to both improve 
patient compliance and reduce the incidence of harm or injury that may result from improper 
administration of the drug product.  A blister carton may also better allow any supplemental 
patient information to be attached directly to it, which in turn ensures that each patient receives 
the necessary drug product information upon dispensing from a pharmacy.  Such a proposed 
product should generally be packaged similarly to the RLD to account for these considerations.   
 
4.  Other Inconsistencies  
 
FDA will RTR an ANDA if the ANDA contains certain other inconsistencies.  In accordance 
with 21 CFR 314.94(a)(4), an ANDA must include a statement that the conditions of use 
prescribed, recommended, or suggested in the labeling proposed for the drug product have been 
previously approved for the RLD.  However, there are certain exceptions (e.g., for labeling 
differences permitted pursuant to an approved suitability petition that is cited as an ANDAs 
basis of submission (see section III.F for further details)).  Any other proposed condition-of-use 
changes would not be acceptable.  Examples of proposed condition-of-use changes may include, 
but are not limited to, citing a sprinkle capsule dosage form as a basis of submission but 
producing a capsule that cannot be administered in the same manner as the RLD, or proposing 
alterations to either the amount of active ingredient delivered per dose or the dosing regimen 
such that neither are consistent with those described in the RLD labeling. 
 
H. Microbiology Considerations 
 
Generally, FDA will RTR an ANDA if it contains certain deficiencies related to microbiology 
considerations.   
 
An ANDA should contain all sterility assurance validation studies for terminally sterilized drug 
products and aseptically filled drug products, as described below67: 
                                                 
66 21 CFR 314.94(a)(8). 
67 21 CFR 314.50(d)(1). 
13 
  Contains Nonbinding Recommendations 
 
1.  Terminally sterilized drug products 
 
  Validation of production terminal sterilization process  
  Validation of depyrogenation of product containers and closures  
  Validation of container-closure package integrity  
 
2.  Aseptically filled drug products 
 
  Validation of the sterilizing grade filters (bacterial retention studies) 
  Validation of the sterilization of sterile bulk drug or product contact equipment, 
components, containers, and closures 
  Validation of the depyrogenation of product containers and closures 
  Validation of the aseptic filling process/line/room (media fills/process simulations) 
  Validation of container-closure package integrity 
 
In addition, an ANDA should include at the time of submission, at minimum, summaries of 
validation studies. 
  
 
VI.   BIOEQUIVALENCE AND CLINICAL DEFICIENCIES  
 
As a general matter, ANDA applicants should refer to FDAs Product Specific 
Recommendations for Generic Drug Development website for Bioequivalence (BE) guidances 
regarding recommended in vivo and/or in vitro BE and other recommended studies.68   
 
A.  Failed In Vivo BE Studies 
 
FDA will RTR an ANDA if only a failed in vivo BE study is submitted.69  FDA regulations 
require applicants to submit information on failed BE studies.70  Typically, a failed study is one 
that does not satisfy the 90% confidence interval (CI) criterion (e.g., falls outside of the 0.8-1.25 
acceptance criterion limits) for either the area under curve (AUC) or peak plasma concentration 
(Cmax) parameter.  If this occurs for highly variable drug products, the applicant may submit a 
study using a replicate study design and analyze data using a reference-scaled average (RSA) 
approach for the failed parameter.  Applicants should refer to FDAs Product Specific 
Recommendations for Generic Drug Development website for BE guidances or submit BE 
guidance requests for proposed products to Generic Drugs@fda.hhs.gov.  
 
B.  Alternate BE Studies 
 
                                                 
68 FDAs BE recommendations for specific products can be found at 
http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm075207.htm. 
69 It is also recommended that a brief CMC summary of any failed studies be included in the Pharmaceutical 
Development report. 
70 21 CFR 314.94(a)(7)(i). 
14 
  Contains Nonbinding Recommendations 
FDA will RTR an ANDA if the ANDA contains one or more in vivo studies that were not 
recommended in the BE guidance, without adequate justification.71  Adequate justification 
should include justification for an approach that deviates from FDA posted guidance, including 
data (Module 2.7 and Module 5) and appropriate references.  Applicants should refer to FDAs 
Product Specific Recommendations for Generic Drug Development website for BE guidances 
or submit BE guidance requests for proposed products to Generic Drugs@fda.hhs.gov.   
 
C.  Q1/Q2 Sameness Requirement for Consideration of an In Vivo BE Study Waiver 
 
Certain drug products may be eligible for a waiver from conducting in vivo BE studies typically 
required to support an ANDA.  For example, in accordance with 21 CFR 320.22(b)(1), parenteral 
drug products, in addition to both ophthalmic and otic solutions, may be eligible for a waiver of 
BE studies, provided that their formulations are considered Q1/Q2 same as the RLD.72  If such a 
drug product is determined not to be Q1/Q2 same as the RLD, FDA will RTR the ANDA based 
on the determination that the drug product is ineligible for a waiver because of permissible 
formulation differences.73 
 
For ophthalmic solutions, it is critical to also complete and include the BE table Comparative 
Physicochemical Data of Ophthalmic Solution Drug Products74 in Module 2.7 of the ANDA 
submission to further support the waiver request.  This table captures key information/data 
relevant to both the test product and the RLD.  If this table is omitted, FDA will RTR the ANDA 
despite a determination that the test formulation is Q1/Q2 same as the RLD.75 
 
D.  Inadequate Dissolution Data (In Vitro Studies) 
 
For any recommended dissolution study, it is critical that appropriate comparison data (i.e., test 
product and RLD) be provided.76  If there is evidence within the ANDA that the appropriate 
dissolution studies were not conducted or a supplemental study is omitted, FDA will RTR the 
ANDA.   
 
The BE guidances discussed in this section contain important details about the types of 
dissolution studies appropriate for the RLD and test products, along with information on waiver 
of an in vivo BE data requirement for any additional strengths for which approval is sought.77  In 
addition, these BE guidances may reference dissolution methods available through FDAs Web 
site that are specific to a particular drug product.78   
 
                                                 
71 21 CFR 314.94(a)(7). 
72 In such instances, bioequivalence is considered to be self-evident.   
73 21 CFR 314.94(a)(7). 
74 BE tables can be found on FDAs Web site at the following location: 
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/Approv
alApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM120957.pdf. 
75 21 CFR 314.94(a)(7). 
76 21 CFR 314.50(d)(1). 
77 See 21 CFR 320.22(d)(2)(ii). 
78 For examples of FDA-recommended dissolution methods, see 
http://www.accessdata.fda.gov/scripts/cder/dissolution/index.cfm. 
15 
  Contains Nonbinding Recommendations 
Other suggested types of comparative (i.e. test product and RLD) supplemental dissolution 
studies include: 
 
  Alcohol dose-dumping  
  Half-tablet dissolution for modified-release drug products with functional score 
marks79 performed for each strength of test and RLD in the recommended media, or 
quality control (QC) media if there is no recommendation (alcohol dose-dumping 
studies are not recommended for half-tablet dissolution studies) 
  Any other product-specific dissolution study described in the BE recommendations 
for the relevant product 
 
E.  Miscellaneous Factors 
 
1.  Study Information BE Table80 
 
FDA will RTR an ANDA if the Study Information BE table is incomplete.81  The Study 
Information BE table compiles important information about study type and site locations and 
should be placed in Module 2.7 of the ANDA (along with the other BE summary tables).  
Applicants should provide the requested information regarding sample storage and long-term 
storage.  Receipt of the ANDA is also predicated on the following information that is captured in 
the table: 
   
  The number of days of long-term storage stability (LTSS) coverage should be equal to or 
more than the number of days for sample storage duration. 
 
  The temperature (C) reported for LTSS coverage should be within or less than the 
temperature range for sample storage.   
 
2.  Waiver of In Vivo BA or BE Studies for BCS Class I Drugs 
 
If the applicant requests a Biopharmaceutics Classification System (BCS) Class 1 BA/BE 
waiver, FDA will RTR the ANDA if any of the data needed to support such a waiver request are 
missing from the ANDA at the time of submission.82  Applicants should refer to FDAs guidance 
for industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release 
Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System for details 
regarding waivers of any required in vivo bioavailability (BA) or BE studies for a BCS Class 1 
drug substance.  
                                                 
79 A functional score mark enables delivery of a dose that is supported by RLD labeling. 
80 A copy of this BE table can be found on FDAs Web site at the following location:  
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/Approv
alApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM120957.pdf. 
81 21 CFR 314.94(a)(7). 
82 21 CFR 314.94(a)(7). 
16 
  Contains Nonbinding Recommendations 
 
3.  Office of Bioequivalence and Office of Pharmaceutical Quality Receipt 
Evaluations 
 
FDA will RTR an ANDA, in certain cases, based on the recommendations of DBE, the Division 
of Clinical Review (DCR), and/or the Office of Pharmaceutical Quality.  Deficiencies in these 
modules are generally associated with, but not limited to, various concerns with an in vivo BE or 
clinical endpoint BE study, or statistical data and/or design. 
     
4.    Drug-Device Combination Products 
 
On a case-by-case basis and in consideration of preliminary evaluations performed by consultant 
offices, FDA will RTR an ANDA for a drug-device combination product if a device used to 
deliver the drug is not sufficiently similar to the device used to deliver the RLD.  Any device 
used to deliver the drug should be similar enough to that used with/for the RLD so as to ensure, 
at a minimum, safe and proper administration of the product without the need for retraining by a 
health care professional and to ensure that its performance characteristics, operating principles, 
and critical design attributes will result in a product that will perform the same as the RLD under 
the conditions of use described in the labeling.  In addition, the patient instructions in the 
labeling, as it concerns use of the device, should meet the same labeling requirement for 
ANDAs.83 
 
5.    Missing Case Report Forms  
 
FDA will RTR an ANDA if a clinical study conducted does not contain copies of individual case 
report forms for patients enrolled in the study.84  Applicants should provide a random selection 
of at least 10% of all case report forms for any study that enrolls patients.  Applicants should also 
include all case report forms for subjects removed from study analysis for any reason.  In 
addition, applicants should provide copies of individual case report forms for each patient who 
died during a clinical study or who did not complete the study because of an adverse event, 
whether believed to be drug-related or not, including patients receiving reference drugs or 
placebo, consistent with 21 CFR 314.50(f)(2).  
 
 
VII.  DISPUTE OF A REFUSE-TO-RECEIVE DECISION 
 
If an applicant disagrees with or wishes to discuss an RTR decision, the applicant should submit 
its concerns first to the email address identified in the RTR letter.  If FDAs subsequent response 
does not resolve the matter, a teleconference can be scheduled with the applicant, a Division of 
Filing Review (DFR) Team Leader, DFR Supervisor, and, if needed, the appropriate division 
director.  If the matter still remains unresolved, the applicant can use the dispute resolution 
procedure (see 21 CFR 314.103 and guidance for industry Formal Dispute Resolution: Appeals 
Above the Division Level).   
                                                 
83 Section 505(j)(2)(A)(v) of the FD&C Act and 21 CFR 314(a)(8)(iv).84 21 CFR 314.101(d)(3). 
84 21 CFR 314.101(d)(3). 
17 
  Contains Nonbinding Recommendations 
APPENDIX A:  EXAMPLES OF MINOR DEFICIENCIES 
 
1.  An ANDA is required to contain either an environmental assessment (EA) or a claim of 
categorical exclusion.85  Pursuant to 21 CFR 25.15(a) and in reference to FDAs guidance for 
industry Environmental Assessment of Human Drug and Biologics Applications (EA 
guidance), all applications or petitions requesting FDA action require the submission of 
either (1) an EA or (2) a claim of categorical exclusion, as defined in 21 CFR 25.31.86  A 
claim of categorical exclusion shall include a statement of compliance with the categorical 
exclusion criteria and shall state that to the applicants knowledge, no extraordinary 
circumstances exist.87  If FDA does not receive an EA or claim of categorical exclusion made 
by the applicant within 7 calendar days of notification of the omission(s), FDA will RTR the 
ANDA. 
   
2.  An ANDA must contain an accurate and complete English translation of each part of the 
application that is not in English.88  This requirement includes the translation of all sections 
of the document (e.g., headers, titles).  FDA will accept an ANDA with the English 
translation on a blank page next to the original text.  FDA recommends that the translation be 
legible in size 12 font.  The applicant should use its best judgment in determining how to fit 
the necessary information on a page without impacting the reviewers ability to read the 
information. If FDA does not receive English translation of each part of the application that 
is not in English within 7 calendar days of notification of the omission(s), FDA will RTR the 
ANDA. 
 
3.  An ANDA must contain either a daily elemental iron calculation for products that contain 
iron89 or a statement that the amount of elemental iron ingested per day does not exceed 5 
milligram (mg), in accordance with 21 CFR 73.1200(c).    A daily elemental iron calculation 
should be included in module 3.2.P.1 in addition to all other inactive ingredient justification 
data/information.  If FDA does not receive either the calculation or aforementioned statement 
within 7 calendar days of notification of the omission(s), FDA will RTR the ANDA. 
 
4.  An applicant should complete the Pharmacy Bulk Package Sterility Assurance table90 for 
pharmacy bulk packages and place this table in section 1.14.1.4 of Module 1 of the ANDA.   
If FDA does not receive the completed table within 7 calendar days of notification of the 
omission, FDA will RTR the ANDA. 
 
5.  An applicant should include all of the facility information that is listed in Modules 3.2.S.2 
and 3.2.P.3.1 (drug substance and drug product, respectively) of the application in Field 29 of 
the 356h form, using continuation pages for Field 29 when needed.91  FDA will notify the 
applicant if there are any facilities listed in either of the aforementioned modules of the 
                                                 
85 21 CFR 314.101(d)(4). 
86See the EA guidance for information as to which types of drug products require an EA  
87 21 CFR 25.15(a). 
88 21 CFR 314.101(d)(5). 
89 21 CFR 314.50(d)(1)(i). 
90http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/Appr
ovalApplications/AbbreviatedNewDrugApplicationANDAGenerics/UCM352612.pdf. 
91 21 CFR 314.101(d)(1). 
  1  Contains Nonbinding Recommendations 
ANDA that are not captured in Field 29 and/or on its continuation pages.  If FDA does not 
receive a revised 356h form within 7 calendar days of notification of the facility omission(s), 
FDA will RTR the ANDA. 
 
6.  If there is a patent listed in FDAs Approved Drug Products with Therapeutic Equivalence 
Evaluations (commonly referred to as the Orange Book) for the RLD, the ANDA must 
include a patent certification as to that patent, with one exception.  If the patent is a method of 
use patent and the labeling of the RLD includes uses that are not covered by the patent, an 
ANDA applicant may be able to submit92 a patent statement93 explaining that the method of 
use patent does not claim any of the uses in the proposed labeling of the ANDA product.  If 
the applicant submits such a patent statement, the proposed labeling in the ANDA must not 
include methods of use (or indications) that are covered by the use codes in the Orange Book 
for the patent in question.  Where a listed patent claims the drug substance and/or drug 
product and one or more methods of use, the applicant may provide a split certification to 
the patent (i.e., the applicant provides a statement that the applicant is not seeking approval 
for one or more methods of use claimed by the patent based on the use code(s) listed in the 
Orange Book (sometimes referred to as a section viii statement) and a patent certification 
to the remaining claims). If, upon filing review of such an ANDA, OGD determines that the 
labeling submitted in the ANDA does refer to a use described in such use codes, OGD will 
not provide guidance or suggestions as to how the proposed labeling should be amended.  
Instead, OGD will inform the applicant that it must either revise its labeling or withdraw the 
patent statement.  If, within 7 calendar days of being informed of this issue, an applicant fails 
to withdraw the patent statement or revise the proposed labeling so as not to refer to the use 
claimed by the patent, FDA will RTR the ANDA. 
 
7.  The listed drug that is relied on as the ANDAs basis of submission is ordinarily the drug 
product that is designated as the RLD in the Orange Book.94  If a listed drug that is not 
designated the RLD is cited as the basis of submission for an ANDA, FDA will notify the 
applicant of the error.  If the correct information is not submitted within 7 calendar days, 
FDA will RTR the ANDA.  
 
8.  For those ANDAs using APIs that do not make reference to a Type II API DMF, an 
evaluation of the API information presented within Module 3 (drug substance)95 of the 
application will be performed.  Any deficiencies96 will be communicated to the ANDA 
applicant for correction.  If a response to the API deficiencies is not received within 7 
calendar days, FDA will RTR the ANDA.   
 
                                                 
92 Pursuant to section 505(j)(2)(A)(viii) of the FD&C Act and 21 CFR 314.94(a)(12)(iii), and also referred to as a 
Section viii carve-out.  
93 See Abbreviated New Drug Application Regulations; Patent and Exclusivity Provisions; Final Rule, 59 FR 50338, 
50347 (Oct. 3, 1994). 
94 21 CFR 314.94(a)(3). 
95 Specifically, section 3.2.S.2 and its accompanying subsections, though this does not preclude review of the other 
sections and subsections that make up 3.2.S so that the completeness of the API section in its entirety may be 
assessed. 
96 Note that the minor deficiencies found during the API review are not counted against the total for all other ANDA 
deficiencies, as described in the introduction to Section III. 
  2  Contains Nonbinding Recommendations 
9.  In accordance with 21 CFR 314.94(a)(8)(iv), an ANDAs proposed labeling must be the 
same as the labeling approved for the RLD, except for (1) changes required because of 
differences approved under a petition filed under 21 CFR 314.93, or (2) because the drug 
product and the RLD are produced or distributed by different manufacturers.  Differences 
between the applicants proposed labeling and labeling approved for the RLD can include 
differences in expiration date, formulation, bioavailability or pharmacokinetics, labeling 
revisions made to comply with current FDA labeling guidelines or other guidance, or 
omission of an indication or other aspect of labeling protected by patent or accorded 
exclusivity under section 505(j)(5)(F) of the FD&C Act.  Applicants must submit a side-by-
side comparison of the RLD and the proposed labeling.97  In accordance with 21 CFR 
314.94(d)(1)(iii), the content of labeling must be submitted in an electronic format that FDA 
can process, review, and archive.  FDA periodically issues and updates its guidance on how 
to provide electronic submissions.98  If responses to these deficiencies are not received within 
7 calendar days of being informed of these issues, FDA will RTR the ANDA.   
                                                 
97 See 21 CFR 314.94(a)(8)(iv). 
98 See guidance for industry Providing Regulatory Submissions in Electronic FormatContent of Labeling. 
  3