Contains Nonbinding Recommendations 
     
ANDA Submissions  
Amendments to 
Abbreviated New Drug 
Applications Under 
GDUFA 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
    
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
July 2018 
Generics  Contains Nonbinding Recommendations 
 
ANDA Submissions  
Amendments to 
Abbreviated New Drug 
Applications Under 
GDUFA
  
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) 
 
 
July 2018 
Generics 
  Contains Nonbinding Recommendations 
TABLE OF CONTENTS 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  CATEGORIES OF GDUFA AMENDMENTS .............................................................. 3 
A.  Major Amendments ....................................................................................................................... 3 
C.  Unsolicited Amendments ............................................................................................................... 5 
IV.  REVIEW GOALS ............................................................................................................. 5 
A.  Amendments to ANDAs ................................................................................................................ 5 
1. Major Amendments .......................................................................................................................... 5 
2. Minor Amendments .......................................................................................................................... 7 
3. Unsolicited Amendments .................................................................................................................. 7 
B.  Amendments to PASs .................................................................................................................... 8 
1. Major Amendments .......................................................................................................................... 8 
2. Minor Amendments .......................................................................................................................... 9 
3. Unsolicited Amendments ................................................................................................................ 10 
C.  Amendments to ANDAs and PASs Submitted Prior To and During GDUFA I .................... 11 
V.  APPLICATION OF REVIEW GOALS ....................................................................... 11 
A.  Changes to Classifications or Review Goals .............................................................................. 11 
B.  Deferred Amendments................................................................................................................. 13 
C.  Amendments Submitted Before and After October 1, 2017 .................................................... 13 
D.  Amendments Submitted to Tentatively Approved Applications ............................................. 14 
1. Requests for Final Approval .......................................................................................................... 14 
2. Amendments Other Than Requests for Final Approval ................................................................. 15 
E.  Amendments Submitted in Response to Changes in the DMF ................................................ 15 
VI.  SUBMISSION AND RECEIPT OF AMENDMENTS ................................................ 15 
VII.  REQUESTS FOR RECONSIDERATION OF MAJOR AMENDMENT 
CLASSIFICATION STATUS ................................................................................................... 16 
APPENDIX A:  MAJOR DEFICIENCIES .............................................................................. 17 
APPENDIX B:  EXCERPTED TEXT FROM GUIDANCE FOR INDUSTRY, MAJOR 
MINOR, AND TELEPHONE AMENDMENTS TO ABBREVIATED NEW DRUG 
APPLICATIONS, REV. 2 (DEC. 2001) ..................................................................................... 25  Contains Nonbinding Recommendations 
ANDA Submissions  Amendments to Abbreviated New Drug 
Applications Under GDUFA  
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 explain to applicants how the review goals established as part of the 
Generic Drug User Fee Amendments Reauthorization of 2017 (GDUFA II) apply to amendments 
to either abbreviated new drug applications (ANDAs) or prior approval supplements (PASs) 
submitted to the Food and Drug Administration under section 505(j) of the Federal Food, Drug, 
and Cosmetic Act (FD&C Act) (21 U.S.C. 355(j)).2  This guidance describes amendment 
classifications and categories and explains how amendment submissions may affect an 
applications review goal dates.  The guidance also describes how FDA should assess3 
amendments submitted to ANDAs and PASs received prior to October 1, 2017, which is the 
GDUFA II review goals effective date.   
 
This guidance finalizes the October 2017 draft guidance for industry ANDA Submissions  
Amendments to Abbreviated New Drug Applications Under GDUFA.  This final guidance 
supersedes the December 2001 guidance for industry Major, Minor, and Telephone Amendments 
                                                 
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 Although not directly within the scope of this guidance, we remind applicants of the patent certification 
requirements applicable to ANDA amendments in 21 CFR 314.96(d)(1).  See also 81 FR 69580, 69591-96, and 
69636-39 (October 6, 2016).    
3 To reinforce the policy and procedural changes set forth in the Manual of Policies and Procedures (MAPP) 5241.3 
Good Abbreviated New Drug Application Assessment Practices, the Office of Generic Drugs and the Office of 
Pharmaceutical Quality will use the term assessment in place of review.  MAPP 5241.3, available on the Manual of 
Policies and Procedures (CDER) web page at 
https://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ManualofPoliciesProc
edures/default.htm, defines assessment as the process of both evaluating and analyzing submitted data and 
information to determine whether the application meets the requirements for approval and documenting that 
determination.  MAPP 5241.3 at 3.   
  1  Contains Nonbinding Recommendations 
to Abbreviated New Drug Applications (2001 amendments guidance, see Appendix B) 4 and the 
July 2014 draft guidance for industry ANDA Submissions  Amendments and Easily Correctable 
Deficiencies Under GDUFA, both of which will be withdrawn.  The 2001 amendments guidance 
contained descriptions of major and minor amendments; these descriptions were considered 
during the GDUFA II negotiations and incorporated into the GDUFA Reauthorization 
Performance Goals and Program Enhancements Fiscal Years 2018-2022 (GDUFA II 
Commitment Letter or GDUFA II Goals).5  Excerpted text from that guidance, specifically, the 
sections describing major and minor amendment types is contained in Appendix B of this 
guidance for reference.  
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required.  
 
 
II.  BACKGROUND 
 
GDUFA II was signed into law on August 18, 2017,6 to facilitate timely access to quality, 
affordable generic medicines.  Under the GDUFA II Commitment Letter that accompanied the 
legislation, FDA agreed to certain review goals and procedures for amendments under 
assessment as of or received on or after the GDUFA II effective date (i.e., October 1, 2017).7   
 
The GDUFA II Commitment Letter reflects significant changes in the classification of and 
review goals for amendments to ANDAs and PASs under the Generic Drug User Fee 
Amendments of 2012 (GDUFA I).  Under GDUFA I, amendments were classified into a 
complex Tier system based on the following factors: whether the amendment was solicited (i.e., 
submitted in response to a complete response letter (CRL)) or unsolicited (i.e., submitted on the 
applicants own initiative); whether the amendment was major or minor (as defined in the 
guidance for industry ANDA Submissions  Amendments and Easily Correctable Deficiencies 
Under GDUFA); the number of amendments submitted to the ANDA or PAS; and whether an 
inspection was necessary to support the information contained in the amendment. 
 
GDUFA II simplified the amendment review goals and no longer subjects them to a Tier system; 
however, GDUFA II review goals are still dependent on several factors, as described in section 
                                                 
4 We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
Drugs guidance web page at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm. 
5 The GDUFA II Commitment Letter is available at 
http://www.fda.gov/downloads/ForIndustry/UserFees/GenericDrugUserFees/UCM525234.pdf.  
6 FDA Reauthorization Act of 2017 (Public Law 115-52 Title III). 
7 The application of GDUFA II goals to amendments with a Target Action Date or GDUFA I goal date is discussed 
in section IV of this guidance. 
  2  Contains Nonbinding Recommendations 
IV of this guidance.  In general, GDUFA II amendments will be designated as either standard or 
priority,8 be classified as either major or minor, and receive a goal date based on the factors 
discussed in this guidance, including whether a preapproval inspection is needed.   
 
FDA considers each submission to an application under review to be an amendment.  These 
submissions will be classified based on the content submitted and issued a goal date consistent 
with that classification.  The types of amendments and review goals described in this guidance 
only apply to submissions that have been received for assessment (i.e., review goals do not apply 
to submissions pending filing review). Information Requests (IRs) and Discipline Review Letters 
(DRLs) neither stop the review clock nor add to the GDUFA II goal.9  Accordingly, a response 
to an IR or DRL generally will not be classified as a major or minor amendment and will not 
receive a goal date.  If a response to an IR or DRL contains information not requested by FDA, 
or if FDA determines that the information provided requires a more thorough assessment, FDA 
will classify the submission as a major or minor amendment with a corresponding goal date.  See 
section V of this guidance.  Similarly, amendments that are administrative in nature and do not 
require a scientific assessment (i.e., administrative amendments) will generally not affect the 
goal date.  See section III.C of this guidance. 
 
 
III.  CATEGORIES OF GDUFA AMENDMENTS     
   
As stated in the GDUFA II Commitment Letter, major and minor amendments were originally 
described in the 2001 amendments guidance.10  This guidance provides further description of 
these amendments and is consistent with the 2001 amendments guidance.  The sections below 
provide general descriptions and examples of the types of deficiencies that would classify an 
applicants response to these deficiencies as a major or minor amendment,11 as provided for in 
the 2001 guidance.  In addition, FDA has developed a non-exhaustive list of examples of major 
deficiencies, which is available in Appendix A12   
 
A.  Major Amendments 
 
                                                 
8 The terms standard and priority are defined in the GDUFA II Commitment Letter, note 8.  See also, section 
505(j)(11)(A) of the FD&C Act and the Manual of Policies and Procedures 5240.3: Prioritization of the Review of 
Original ANDAs, Amendments, and Supplements, as revised, which describes how the review of original ANDAs 
ANDA amendments, and ANDA supplements will be prioritized. 
9 GDUFA II Commitment Letter at 11.  See also draft guidance for industry Information Requests and Discipline 
Review Letters Under GDUFA.  When final, this guidance will represent FDAs current thinking on this topic. 
10 See GDUFA II Commitment Letter at 26.   
11  Note that descriptions of major and minor in this guidance apply only to the classification of major and minor 
amendments and are distinguishable from major or minor issues that FDA staff may identify as filing deficiencies 
during filing review. 
12 An appendix containing examples of minor deficiencies is not included in this guidance because, in general, 
deficiencies not classified as major will be classified as minor deficiencies.   
  3  Contains Nonbinding Recommendations 
Examples of actions that, if requested or taken in response to deficiencies, would result in major 
amendments include:  
   
  Manufacturing a new batch of drug product for any reason (e.g., a composition change or 
reformulation, a change in the source of a drug substance, a change in the manufacturing 
site, the need for a new bioequivalence (BE) study, a new in vitro study for a specific 
product, a change in a major manufacturing process, a new strength of the product, 
unacceptable impurities or impurity levels, unacceptable excipients found during 
assessment, failed stability data, or a change in the container-closure system (other than 
solid oral dosage forms)) 
 
  Performing a new BE study whether or not related to the manufacture of a new batch or 
different formulation of the drug product 
 
  Developing new analytical procedures13 and providing full validation data 
 
FDA has the discretion to consider the responses to additional deficiencies not included in either 
this list or appendix A as major amendments as long as the major amendment classification 
receives concurrence by the appropriate division director.  This classification does not reflect the 
time it takes an applicant to respond to the complete response letter (CRL) but is based on a 
determination by FDA that the content of the information or data provided will require extensive 
assessment.    
 
B.  Minor Amendments  
 
Minor amendments are those not classified as major or are a response to a deficiency that could 
be adequately resolved through an information request (IR) or discipline review letter (DRL).  
Minor amendments often consist of responses to deficiencies that are more easily addressed than 
those in a major amendment and typically require less extensive assessment by FDA.  Examples 
of minor amendments include responses to: 
 
  Minor deficiencies in the drug master file (DMF) 
  
  Incomplete dissolution data 
 
  Labeling deficiencies that have not been adequately addressed in response to an 
information request14 
 
                                                 
13 This language is intended to align with terminology used by the International Conference on Harmonisation and 
revisions to the Code of Federal Regulations.   
14 The 2001 amendments guidance included minor problems regarding good manufacturing practices as an example 
of a minor deficiency.  FDAs current thinking is that, in general, any good manufacturing practice or facility 
deficiency is, in fact, a major deficiency.  See appendix A of this guidance.  
  4  Contains Nonbinding Recommendations 
C.  Unsolicited Amendments 
 
An unsolicited amendment is an amendment with information not requested by FDA, except for 
those amendments considered routine or administrative and that do not require scientific 
assessment.15  The unsolicited amendment will be classified as either major or minor based on 
the content of the amendment.  For example, if an unsolicited amendment contains information 
that addresses any of the major deficiencies identified in this guidance, the unsolicited 
amendment will be classified as major.  
 
 
IV.  REVIEW GOALS 
 
The GDUFA II Commitment Letter identifies the review goals for amendments submitted to 
ANDAs and PASs.16  These review goals are based in part on whether the ANDA or PAS is 
subject to standard review or priority review and whether the amendment is classified as major 
or minor.  Further, the review goals consider whether the submission requires a preapproval 
inspection, and if a priority submission does require a preapproval inspection, whether the 
applicant submitted a timely, complete, and accurate pre-submission facility correspondence 
(PFC).17 
  
A.  Amendments to ANDAs  
 
1.  Major Amendments 
 
a.  ANDA amendments subject to standard review 
 
FDA will review and act on18 90 percent of standard major ANDA amendments within 8 months 
of the amendment submission date19 if FDA does not require a preapproval inspection.20  FDA 
will review and act on 90 percent of standard major ANDA amendments within 10 months of the 
amendment submission date if FDA requires a preapproval inspection.21   
 
                                                 
15 GDUFA II Commitment Letter at 28. 
16 The review goals identified in this guidance apply to amendments to original ANDAs or PASs that are submitted 
either on or after October 1, 2017, or per the GDUFA I bridging scheme described in section IV.C. 
17 See the draft guidance for industry ANDAs: Pre-Submission of Facility Information Related to Prioritized Generic 
Drug Applications (Pre-Submission Facility Correspondence) (PFC Guidance).  When final, this guidance will 
represent FDAs current thinking on this topic.  
18 To act on an application means FDA will issue a CRL, an approval letter, a tentative approval letter, or a refuse-
to-receive letter. 
19 The submission date is the date the amendment arrives in the appropriate FDA electronic portal.  See the guidance 
for industry Providing Regulatory Submissions in Electronic Format  Receipt Dates.      
20 GDUFA II Commitment Letter at 4. 
21 Id.  
  5  Contains Nonbinding Recommendations 
Example:  On November 27, 2017, an applicant submits an amendment in response to a 
CRL that identified major deficiencies in its ANDA.  FDA determines that the 
amendment is subject to a standard review.  The amendment contains information on a 
new facility that requires a preapproval inspection.  FDA classifies the amendment as a 
major amendment requiring a preapproval inspection and sets a 10-month review goal.  
Therefore, the review goal for this amendment is September 26, 2018. 
 
Example:  On July 24, 2019, an applicant submits an amendment in response to a Risk 
Evaluation and Mitigation Strategy (REMS) modification request.  FDA determines that 
the amendment is subject to a standard review.  FDA classifies the amendment as a major 
amendment that does not require a preapproval inspection and sets an 8-month review 
goal.  Therefore, the review goal for this amendment is March 23, 2020.  
 
b.  ANDA amendments subject to priority review22 
 
FDA will review and act on 90 percent of priority major ANDA amendments within 6 months of 
the amendment submission date if preapproval inspection is not required.23  FDA will also 
review and act on 90 percent of priority major ANDA amendments within 8 months of the 
amendment submission date if (1) preapproval inspection is required and (2) the applicant 
submits a complete and accurate PFC that remains unchanged at the time of the amendment 
submission no later than 60 days prior to the amendment submission date.24  Finally, FDA will 
review and act on 90 percent of priority major ANDA amendments within 10 months of the 
amendment submission date if (1) preapproval inspection is required and (2) the applicant fails to 
submit a PFC no later than 60 days prior to the amendment submission date, the PFC is 
incomplete or inaccurate, or the facility information changes between the submission of the PFC 
and the submission of the amendment.25  
 
Example:  On September 20, 2018, an applicant submits an amendment in response to a 
CRL that identified major deficiencies in its ANDA.  FDA determines that the 
submission is subject to a priority review.  The applicant submitted a complete and 
accurate PFC on July 19, 2018.  The applicant subsequently added a new facility and 
placed information about the new facility in its September 20, 2018, submission.  FDA 
classifies the amendment as a major amendment requiring a preapproval inspection and 
                                                 
22 As described in this section and in section IV.B.b below, the GDUFA II Commitment Letter provides a timeline 
for the submission of PFCs (i.e., 2 months prior to the amendment submission).  The FDA Reauthorization Act of 
2017 at section 801 requires submission of PFCs no later than 60 days prior to the submission of the original 
ANDA.  To ensure that PFCs for amendments are submitted consistent with PFCs for original submissions, FDA 
has adopted the timing required in the FDA Reauthorization Act of 2017.  For the most current thinking on the 
submission of PFCs, see the PFC guidance, supra note 21.  
23 GDUFA II Commitment Letter at 4.  
24 Id. at 4-5. 
25 Id. at 5. 
  6  Contains Nonbinding Recommendations 
sets a 10-month review goal.  Therefore, the review goal for this amendment is July 19, 
2019.26 
  
2.  Minor Amendments 
 
FDA will review and act on 90 percent of standard and priority minor ANDA amendments 
within 3 months of the amendment submission date.27   
 
Example:  On March 8, 2019, an applicant submits an amendment in response to a CRL 
that identified minor deficiencies in its ANDA.  FDA determines that the amendment is 
subject to a priority review.  FDA classifies the amendment as a minor amendment and 
sets a 3-month review goal.  The review goal for this amendment is June 7, 2019.   
 
Table 1: Summary of Performance Goals to Major and Minor Amendments to ANDAs 
 
Submission Type  Performance Goal 
Standard major  90% reviewed within 8 months of the submission date if preapproval 
amendment to an  inspection is not required 
ANDA  90% reviewed within 10 months of the submission date if preapproval 
inspection is required 
Priority major  90% reviewed within 6 months of the submission date if preapproval 
amendment to an  inspection is not required 
ANDA  90% reviewed within 8 months of the submission date if: 
(1) A preapproval inspection is required; 
(2) The applicant submits a complete and accurate PFC no later than 60 
days prior to the amendment submission date; and  
(3) The PFC remains unchanged at the time of the amendment submission  
90% reviewed within 10 months of the submission date if: 
(1) A preapproval inspection is required and  
(2) The applicant fails to submit a complete and accurate PFC no later 
than 60 days prior to the amendment submission date or 
(3) Information in a complete and accurate submitted PFC changes  
Standard or priority 
minor amendment  90% reviewed within 3 months of the submission date 
to an ANDA 
 
3.  Unsolicited Amendments 
 
FDA will generally review and act on an unsolicited ANDA amendment submitted during the 
review cycle by the later of either (1) the goal date for the original submission or solicited 
amendment being amended or (2) the goal date assigned under the review goals for standard and 
                                                 
26 If the September 20, 2018, submission did not contain a new facility and the complete and accurate PFC 
submitted on July 19, 2018, remained unchanged, FDA would have set an 8-month review goal.   
27 GDUFA II Commitment Letter at 5. 
  7  Contains Nonbinding Recommendations 
priority review ANDAs.28  FDA will generally review and act on unsolicited ANDA 
amendments submitted between review cycles by the later of (1) the goal date for the subsequent 
solicited amendments or (2) the goal date assigned under the review goals for standard or priority 
ANDAs.29,30   
 
Example:  On August 1, 2018, an applicant submits an ANDA, which contains a request 
for a priority designation, 60 days after the submission of a complete and accurate PFC.  
FDA determines that the application is subject to a priority review and sets an 8-month 
review goal.  The review goal for this ANDA is March 31, 2019. 
 
On October 15, 2018, the applicant submits an amendment containing a change in 
manufacturing site, but the applicant did not submit a PFC.  FDA decides that the subject 
drug still meets the priority designation associated with the original ANDA.  However, 
because the amendment contains a change to the manufacturing site information 
submitted in the original PFC, FDA classifies the amendment as a major amendment 
requiring a preapproval inspection and sets a 10-month review goal, which extends the 
review goal of this ANDA.  The review goal for this ANDA and amendment is August 
14, 2019.   
 
Example:  On August 5, 2019, an applicant submits an ANDA.  FDA determines that the 
application is subject to a standard review and sets a 10-month review goal.  The review 
goal for this ANDA is June 4, 2020. 
 
On February 4, 2020, the applicant submits an amendment containing a REMS 
modification.  FDA classifies the amendment as a minor amendment and sets a 3-month 
review goal.  The review goal for this amendment is subsumed into the review of the 
ANDA.  Accordingly, the review goal for this ANDA and amendment remains June 4, 
2020. 
 
B.  Amendments to PASs 
 
1.  Major Amendments  
 
a.  PAS amendments subject to standard review 
 
FDA will review and act on 90 percent of standard major PAS amendments within 6 months of 
the amendment submission date if preapproval inspection is not required.31  FDA will review 
and act on 90 percent of standard major PAS amendments within 10 months of the amendment 
submission date if preapproval inspection is required.32   
                                                 
28 Id. at 8. 
29 Id.  
30 See section V.B for a discussion on FDAs practice of deferred review of unsolicited amendments. 
31 GDUFA II Commitment Letter at 6. 
32 Id.  
  8  Contains Nonbinding Recommendations 
 
Example:  On March 3, 2020, an applicant submits an amendment in response to a CRL 
to a PAS for a new strength that identified the need for a new BE study.  FDA determines 
that the amendment is subject to a standard review.  FDA classifies the amendment as a 
major amendment that does not require a preapproval inspection and sets a 6-month 
review goal.  The review goal for this amendment is September 2, 2020.   
 
b.  PAS amendments subject to priority review 
 
FDA will review and act on 90 percent of priority major PAS amendments within 4 months of 
the amendment submission date if preapproval inspection is not required.33  FDA will review 
and act on 90 percent of priority major PAS amendments within 8 months of the amendment 
submission date if (1) preapproval inspection is required and (2) the applicant submits a PFC no 
later than 60 days prior to the PAS submission date and the PFC is found to be complete and 
accurate and remains unchanged at the time of PAS submission.34  FDA will review and act on 
90 percent of priority major PAS amendments within 10 months of the amendment submission 
date if (1) preapproval inspection is required and (2) the applicant does not submit a PFC no later 
than 60 days prior to amendment submission or the facility information contained in the PFC 
changes prior to the PAS submission date or is found to be incomplete or inaccurate.35 
 
Example:  On March 26, 2020, an applicant submits an amendment in response to a CRL 
that identified minor deficiencies in a PAS.  The amendment adds a new facility.  FDA 
determines that the amendment is subject to a priority review.  The applicant submitted a 
complete and accurate PFC 60 days prior to submission of the amendment.  FDA 
classifies the amendment as a major amendment requiring a preapproval inspection and 
sets an 8-month review goal.  The review goal for this amendment is November 25, 
2020.36 
 
2.  Minor Amendments  
 
FDA will review and act on 90 percent of standard and priority minor PAS amendments within 3 
months of the amendment submission date.37   
 
Example:  On May 1, 2020, an applicant submits an amendment in response to a CRL 
that identified minor deficiencies in a PAS.  FDA classifies the amendment as a minor 
amendment and sets a 3-month review goal.  The review goal for this amendment is July 
31, 2020.   
                                                 
33 Id.  
34 Id. at 7. 
35 Id.  
36 If FDA identifies a facility in the March 26, 2020, submission that was not identified in the complete and accurate 
PFC, FDA will set a 10-month review goal.  
37 GDUFA II Commitment Letter at 7.  
  9  Contains Nonbinding Recommendations 
 
On June 10, 2020, the applicant submits an unsolicited amendment.  FDA classifies the 
unsolicited amendment as a minor amendment and sets a 3-month review goal, extending 
the review goal for the current review.  The review goal for both amendments is 
September 9, 2020. 
 
Table 2: Summary of Performance Goals to Major and Minor Amendments to PASs 
 
Submission Type  Performance Goal 
Standard major  90% reviewed within 6 months of the submission date if preapproval 
amendment to a  inspection is not required 
PAS  90% reviewed within 10 months of the submission date if preapproval 
inspection is required 
Priority major  90% reviewed within 4 months of the submission date if preapproval 
amendment to a  inspection is not required 
PAS  90% reviewed within 8 months of the submission date if: 
(1) A preapproval inspection is required;  
(2) The applicant submits a complete and accurate PFC no later than 60 
days prior to the amendment submission date; and  
(3) The PFC remains unchanged at the time of amendment submission  
90% reviewed within 10 months of the submission date if:  
(1) A preapproval inspection is required and 
(2) The applicant fails to submit a complete and accurate PFC no later 
than 60 days prior to the date of the amendment submission or 
(3) Information in a complete and accurate submitted PFC changes  
Standard or priority 
minor amendment  90% reviewed within 3 months of the submission date 
to a PAS 
 
3.  Unsolicited Amendments  
 
Like unsolicited amendments to ANDAs, FDA will generally review and act on unsolicited PAS 
amendments submitted during the review cycle by the later of (1) the goal date for the original 
submission/solicited amendment, or (2) the goal date assigned in accordance with the above 
goals for standard and priority review PASs.  FDA will generally review and act on unsolicited 
PAS amendments submitted between review cycles by the later of (1) the goal date for the 
subsequent solicited amendments, or (2) the goal date assigned in accordance with the above 
goals for standard or priority PASs.38 
 
Example:  On November 26, 2019, an applicant submits an unsolicited amendment for a 
new formulation.  The amendment is submitted after FDA issued a CRL that identified 
minor deficiencies in a PAS, but the amendment does not respond to that CRL.   
 
                                                 
38 See section V.B for a discussion on FDAs practice of deferred review of unsolicited amendments. 
  10  Contains Nonbinding Recommendations 
On January 15, 2020, the applicant submits an amendment in response to the CRL.  FDA 
classifies (1) the amendment in response to the CRL as a minor amendment with a 3-
month review goal and (2) the unsolicited amendment as a major amendment requiring a 
preapproval inspection with a 10-month review goal.  Because the longest goal date (i.e., 
the 10-month goal) applies, the review goal for both amendments is November 14, 2020.   
 
C.  Amendments to ANDAs and PASs Submitted Prior To and During GDUFA I 
 
As described in Section II above, any amendment submitted to an ANDA or a PAS under 
GDUFA I was subject to classification under the Tier system with varying review goals.  The 
GDUFA II Commitment Letter includes the following provisions for amendments to applications 
with GDUFA I goals and for amendments to applications that did not receive GDUFA I goal 
dates (i.e., ANDAs and PASs submitted prior to the start of cohort year 3 of GDUFA I (i.e., 
October 1, 2014)):39   
 
  FDA will continue to assess amendments to ANDAs and PASs submitted prior to 
October 1, 2017, that have been assigned a GDUFA I review goal date and will act on 
those submissions by the GDUFA I goal date.   
 
  FDA will review and act on 90 percent of ANDA amendments with Target Action Dates 
(TADs)40 by the goal date.  For these submissions, FDA will convert the TAD to a 
GDUFA II goal date.41   
 
  FDA will review and act on 90 percent of amendments pending with FDA as of October 
1, 2017, that were not subject to GDUFA I goal dates and either (a) were not previously 
assigned TADs (i.e., the submission did not have a GDUFA I goal date or a TAD) or (b) 
were previously assigned TADs that came due prior to October 1, 2017, but remain under 
review as of October 1, 2017 (i.e., FDA did not take action by the TAD and the 
submission remains under review with FDA), by GDUFA II amendment goal dates that 
FDA will assign on October 1, 2017.42  
 
 
V.  APPLICATION OF REVIEW GOALS 
 
A.  Changes to Classifications or Review Goals 
 
All initial amendment classifications and any changes to those classifications will be made at 
FDAs discretion.  A CRL will advise the applicant whether the applicants response to the CRL 
                                                 
39 See GDUFA II Commitment Letter at 9-10. 
40 Under GDUFA I, a TAD represents FDAs aspirational deadline for action on either a pre-GDUFA I Year 3 
original ANDA or a CRL amendment or equivalent IR to an original ANDA. 
41 See GDUFA II Commitment Letter at Attachment A. 
42 For any goal date assigned by FDA on October 1, 2017, the goal will not be later than July 31, 2018.  GDUFA II 
Commitment Letter at 10. 
  11  Contains Nonbinding Recommendations 
will be classified as a major or minor amendment.  However, FDA may change its classification 
of the CRL response or its initial classification of an unsolicited amendment based on the content 
of the amendment (e.g., if the amendment proposes a new strength in the response to the CRL), 
including any information not identified by the applicant in the cover letter of the CRL response.  
The decision to change an amendments classification will be made by the regulatory project 
manager and the ANDA assessment team, in consultation with the appropriate FDA division 
director.  
 
If FDA determines that a preapproval inspection is required for any facility referenced in the 
ANDA during the assessment of an unsolicited or solicited minor amendment, FDA will classify 
the submission as a major amendment and set a review goal of 10 months from the submission 
date.   
 
Example:  On November 13, 2017, an applicant submits an amendment in response to a 
CRL that identified minor deficiencies in an ANDA.  FDA determines that the 
amendment is subject to standard review.  The amendment includes a new a facility that 
requires a preapproval inspection.  FDA classifies the amendment as a major amendment 
requiring a preapproval inspection and sets a 10-month review goal.  The review goal for 
this amendment is September 12, 2018.   
 
Example:  On August 24, 2018, an applicant submits an amendment in response to a CRL 
that identified minor deficiencies in an ANDA.  The amendment contains information on 
a new strength.  FDA determines that the amendment is subject to a standard review and 
that no preapproval inspection is required.  FDA classifies the amendment as a major 
amendment and sets an 8-month goal.  The review goal for this amendment is April 23, 
2019.    
 
If an applicant does not submit a response to an IR or DRL within the time frame requested by 
FDA, FDA may reissue the contents of an IR or DRL as a deficiency in a CRL on completion of 
the current review cycle.  If an applicant submits a response to an IR or DRL within the 
requested time frame, but the response contains information requiring a more extensive 
assessment than is typically required for an applicants response to such deficiencies (e.g., the 
applicant provides more information than anticipated by FDA when the deficiency was issued), 
the amendment will be classified as a minor or major amendment and the review goal will be 
adjusted accordingly from the submission date. 
 
Example:  During the assessment of a standard ANDA, FDA determines that an applicant 
failed to identify all facilities in the Form FDA 356h.  FDA issues an IR to the applicant 
asking it to update the FDA Form 356h.  On November 19, 2018, the applicant submits a 
timely response to the IR and provides an updated FDA Form 356h.  FDA determines 
that the newly identified facility requires a preapproval inspection.  FDA changes the 
classification of the IR response to a standard major amendment requiring a preapproval 
inspection and sets a 10-month review goal from the submission date.  The review goal 
this amendment is September 18, 2019. 
 
  12  Contains Nonbinding Recommendations 
Notification of a change in classification and change in the review goal will be provided to the 
applicant after FDA determines that this change is appropriate. 
 
B.  Deferred Amendments 
 
FDA has historically exercised, and continues to exercise, discretion in determining whether to 
accept or defer an unsolicited amendment submitted during the review cycle.  FDA will 
generally accept an unsolicited amendment submitted during the review cycle and adjust the goal 
date for the application.  However, FDA may defer assessment of the unsolicited amendment if 
the discipline assessments are close to completion and either (1) the submitted amendment 
contains a significant amount of new information to be assessed or (2) the amendment is 
submitted after the relevant assessments have been completed and while an IR, DRL, or CRL is 
being prepared because the submission of an amendment at these times causes inefficiencies in 
FDAs assessment.  This discretion to assess or defer such amendments enables FDA to timely 
assess all GDUFA submissions.  The review goal for unsolicited amendments is discussed in 
sections IV.A.3 and IV.B.3 of this guidance.   
 
Example:  FDA is assessing an original ANDA with a goal date of November 13, 2018.  
On October 15, 2018, the applicant submits an unsolicited amendment containing a new 
source for the active pharmaceutical ingredient.  The product quality assessment is 
complete, and FDA identified minor deficiencies for inclusion in a CRL.  FDA 
determines that it will defer assessment of the unsolicited amendment until the applicant 
submits a response to the CRL.   
 
FDA issues the CRL on November 1, 2018.  The applicant submits its response to the 
CRL on December 30, 2018.  FDA classifies the amendment in response to the CRL as a 
minor amendment with a 3-month review goal and classifies the unsolicited amendment 
as a major amendment requiring a preapproval inspection with a 10-month review goal.  
Because the longest goal date applies (i.e., the 10-month goal), the review goal for both 
amendments is October 29, 2019. 
 
C.  Amendments Submitted Before and After October 1, 2017 
 
In certain situations, an applicant may submit a new amendment to an existing amendment (i.e., 
the applicant amends a previously submitted amendment that is under FDA assessment).  In 
these instances, submitting the additional amendment may extend the goal date.  If an applicant 
submits an amendment on or after October 1, 2017, to an amendment under review that is subject 
to a TAD or GDUFA I review goal, FDA will assess both amendments by either the TAD or 
GDUFA I review goal or the GDUFA II review goal, whichever is longer, to facilitate 
assessment and ultimately decrease the number of review cycles. 
 
Example:  On June 8, 2017, an applicant submits an amendment in response to a CRL 
that identified major deficiencies in an ANDA.  FDA determines that the amendment is 
subject to a standard review.  FDA classifies the amendment as a major amendment 
requiring a preapproval inspection and sets a 10-month review goal.  The review goal for 
this amendment is April 7, 2018.   
  13  Contains Nonbinding Recommendations 
 
On February 16, 2018, the applicant submits an unsolicited amendment.  FDA determines 
that the unsolicited amendment is subject to standard review.  FDA classifies the 
amendment as a minor amendment and sets a 3-month review goal, which extends the 
current review goal.  The review goal for both amendments is extended to May 15, 2018.  
 
D.  Amendments Submitted to Tentatively Approved Applications 
 
As described in sections IV.A.3 and IV.B.3 of this guidance, unsolicited amendments submitted 
off-cycle are generally not assessed and are not assigned a goal date until the applicant submits a 
solicited amendment.  FDA will, however, assess unsolicited amendments to ANDAs that have 
received tentative approval (TA), as described below. 
 
1.  Requests for Final Approval  
 
A request for final approval with no new data, information, or other changes to the ANDA 
generally requires 90 days for FDA assessment.  Accordingly, these requests for final approval 
should be submitted no later than 90 days prior to the date on which an applicant seeks final 
approval (i.e., a 90-day goal date will be set upon FDAs receipt of the request).  It is therefore 
incumbent on the applicant to accurately plan the request for final approval.  If a request for final 
approval is submitted fewer than 90 days prior to the earliest lawful approval date, FDA may not 
approve the ANDA by the earliest lawful approval date because of inadequate assessment time.   
 
A request for final approval with substantive changes to an ANDA, changes in the status of the 
manufacturing and/or testing facilities compliance with current good manufacturing practices, 
or that adds new facilities will be classified as a major or minor amendment based on the content 
in the submission and will be assigned the appropriate review goal date.  The submission of 
multiple amendments prior to final approval may also delay the issuance of the final approval 
letter.  Applicants should assess the changes made to the application and updates to approval 
requirements or recommendations (e.g., reference listed drug (RLD) labeling updates or updates 
to the United States Pharmacopeia monograph)43 since the TA and consider the possible review 
goals that would be assigned to their request for final approval when determining the appropriate 
timing for submission of their request.  This will help ensure that final approval is granted in a 
timely fashion to permit earliest lawful marketing. 
 
Example:  On November 4, 2019, an applicant submits a request for full approval to a 
tentatively approved ANDA.  The request contains information about a new 
manufacturing site.  FDA determines that the amendment is subject to a standard review 
and that the new manufacturing site requires a preapproval inspection.  FDA classifies the 
request for full approval as a major amendment requiring preapproval inspection and sets 
a 10-month review goal.  The review goal for this amendment is September 3, 2020. 
                                                 
43 As new requirements are issued and recommendations are provided that impact received or tentatively approved 
ANDAs, applicants should amend their applications, as appropriate, to ensure FDA is able to take action in a timely 
manner. 
  14  Contains Nonbinding Recommendations 
   
2.  Amendments Other Than Requests for Final Approval 
 
If an applicant submits multiple amendments between the TA and when the applicant requests 
final approval, these amendments will be classified as unsolicited, and, in general, FDA will set a 
review goal consistent with the criteria outlined in section IV of this guidance.  However, for 
certain amendments, FDA may delay assessment if the earliest lawful final approval date is not 
for several years.  For example, FDA may delay assessment of a labeling update that does not 
require a change in patent certification for an ANDA with paragraph III certifications to patents 
that will not expire for 5 years.  FDA will not delay assessment of ANDA amendments 
submitted to applications under the Presidents Emergency Plan for Aids Relief (PEPFAR) that 
have received TA because PEPFAR products that have been tentatively approved are eligible for 
purchase with PEPFAR funds in developing countries.  For amendments that FDA will assess 
upon submission, including amendments to ANDAs for PEPFAR products, FDA will set a goal 
date consistent with the criteria outlined in section IV of this guidance.   
 
Example:  On October 5, 2017, an applicant submits an unsolicited amendment to a 
tentatively approved ANDA for a PEPFAR product.  The amendment contains 
information on a new container-closure system.  FDA classifies the amendment as a 
minor amendment and sets a 3-month review goal.  The review goal for this amendment 
is January 4, 2018.        
 
E.  Amendments Submitted in Response to Changes in the DMF 
 
Changes made to a DMF referenced in an ANDA that may impact the safety, efficacy, quality, or 
substitutability of the drug product (e.g., new facilities added by the DMF holder that need to be 
addressed by the applicant in an amendment to the ANDA) may be considered unsolicited 
amendments to the ANDA and therefore may extend existing review goals or may result in a 
CRL being issued to the ANDA.   
 
 
VI.  SUBMISSION AND RECEIPT OF AMENDMENTS 
 
Any amendment submitted to FDA should identify on the first page that it is an amendment.  To 
facilitate processing, FDA recommends that the applicant provide the following information on 
the first page of the submission, as appropriate: 
 
  A statement indicating whether the amendment is unsolicited or in response to an 
assessment from FDA  
 
  The discipline from which the IR/DRL was issued or the disciplines from which 
the CRL was issued 
 
  The amendment classification (major or minor) as identified by FDA in a CRL 
 
  If unsolicited, the amendment classification proposed by the applicant 
  15  Contains Nonbinding Recommendations 
 
  A statement indicating that the application should be classified as priority 
(including a justification for that classification) 
 
  A statement indicating that the applicant is requesting priority review for the 
amendment (including a justification for that request)  
 
  A statement indicating if and when a PFC was submitted in preparation for the 
amendment   
 
  A statement indicating if the amendment is addressing a change in the DMF 
 
  A statement indicating whether the amendment contains any manufacturing or 
facilities changes (e.g., new facilities or changes that are of the type identified on 
the FDA Form 356h, including changes in responsibilities for facilities already 
listed in the ANDA) 
 
The regulatory project manager will issue the applicant an acknowledgment letter to confirm 
submission of the amendment.  Most acknowledgment letters will be issued before the technical 
assessment of that amendment begins.44  The acknowledgment letter will not state whether a 
preapproval inspection is required but will instead state two possible goal dates: the goal date 
with an inspection and the goal date without. 
 
 
VII.  REQUESTS FOR RECONSIDERATION OF MAJOR AMENDMENT 
CLASSIFICATION STATUS 
 
Applicants may request reclassification of their major amendment status via a teleconference 
with FDA.  FDA will schedule and conduct the teleconference and decide 90 percent of such 
reclassification requests within 30 calendar days of the date of FDAs receipt of the request for a 
teleconference.45  This goal applies only if an applicant accepts the first scheduled teleconference 
date offered by FDA.46  Requests for reclassification should be submitted to the ANDA, with a 
copy to the appropriate signatory authority and to ANDAReconsideration@fda.hhs.gov.   
 
Following final decision of a request for reconsideration at the division level, an applicant may 
pursue formal dispute resolution above the division level following the guidance for industry 
Formal Dispute Resolution:  Appeals Above the Division Level.   
                                                 
44 If a previous amendment was subject to priority review, but a subsequent amendment is subject to standard 
review, FDA will notify the applicant of this change in classification within 14 days of receipt of the solicited 
amendment.  GDUFA II Commitment Letter at 12. 
45 See GDUFA II Commitment Letter at 12-13.  See also the draft guidance for industry Requests for 
Reconsideration at the Division Level Under GDUFA.  When final, this guidance will represent FDAs current 
thinking on this topic. 
46 Id. 
  16  Contains Nonbinding Recommendations 
APPENDIX A:  MAJOR DEFICIENCIES 
 
This appendix contains a non-exhaustive list of examples of deficiencies that the Food and Drug 
Administration (FDA) may consider major.  During either the course of submission assessment 
or the inspection of any facility referenced in a submission, data integrity issues related to any 
discipline(s) below may be found.  If FDA, through further investigation or follow up, 
determines that the data supporting the submission are unreliable, FDA may consider the issue a 
major deficiency. 
 
A.  Pharmaceutical Quality Deficiencies  
 
1.  Drug Master File (DMF) 
 
a.  Inadequate selection or justification of starting materials 
 
b.  Toxicological studies are needed to qualify an unqualified impurity 
 
c.  Reference to a secondary DMF which has not been assessed, is currently 
inadequate, or requires submission of a technical dossier from a third-party 
supplier with significant additional manufacturing information 
 
d.  Failure to provide adequate analytical procedures or method validation which 
would require significant new procedure development 
 
e.  Insufficient physical or chemical characterization data to demonstrate structure, 
form, or drug substance sameness (especially for complex active pharmaceutical 
ingredients (APIs)) in the DMF 
 
f.  Major change in drug substance manufacturing process with inadequate 
supporting data 
 
g.  API batch inadequacies that require manufacture of a new API batch 
 
2.  Drug Product 
 
a.  Toxicological studies47 are needed to qualify an unqualified impurity 
 
b.  Need new API source 
 
                                                 
47 Preclinical studies should not be required to support approvability of an ANDA.  Published and publicly available 
preclinical data to support the effectiveness of a requested change, impurity, or level of excipient can be submitted 
to an ANDA as justification.  The adequacy of this data will be assessed by FDA.  The need for new preclinical 
studies suggests that an ANDA may not be the appropriate submission pathway for the proposed drug product.  See 
54 FR 28872 at 28880 (July 10, 1989).  See also, draft guidance for industry Determining Whether to Submit an 
ANDA or 505(b)(2) Application.  When final, this guidance will represent FDAs current thinking on this topic. 
  17  Contains Nonbinding Recommendations 
c.  Post-receipt addition of new API source  
 
d.  A new strength of the finished dosage form added after receipt 
 
e.  Need new manufacturing site for finished dosage form  
 
f.  Unacceptable physical properties for drug product (e.g., see guidances for 
industry Size, Shape, and Other Physical Attributes of Generic Tablets and 
Capsules and Tablet Scoring: Nomenclature, Labeling, and Data for Evaluation)   
 
g.  Need full-term stability data to establish expiration dating (failing accelerated, 
intermediate stability data) 
 
h.  Need new system for product performance (current system is not delivering the 
proper dose (e.g., auto injectors)) 
 
i.  Need substantial revision to proposed analytical procedures (proposed procedure 
is not stability-indicating or is not discriminating enough to address product 
quality) 
 
j.  Need to identify or include critical quality attributes (CQAs) or methods for 
controlling them (e.g., CQAs related to nasogastric (NG) tube administration, 
abuse deterrence properties, as indicated in the reference listed drug (RLD) 
labeling) 
 
k.  Failure to provide environmental assessment for plant-derived products, when 
needed 
 
l.  Insufficient data to demonstrate drug substance sameness (especially for complex 
APIs) 
 
m. Insufficient data to support use-related risk analysis and any human factors 
studies associated with the proposed product 
 
n.  Insufficient data to support drug/device compatibility and sustainability for the 
proposed product 
 
o.  Need for safety assessment of extractables and leachables, inadequate assessment 
of extractables and leachables, or submission of that assessment in an unsolicited 
amendment 
 
3.  Process 
 
a.  Major change in drug product manufacturing process (e.g., change from wet to 
dry granulation) 
 
  18  Contains Nonbinding Recommendations 
b.  Change in specification that would require changes to the manufacturing process 
 
c.  Significant differences between the manufacturing process proposed for 
commercial batches and exhibit batches 
 
d.  Size of exhibit batches is less than the minimum requirement, unless justified 
 
e.  Change in or lack of information about the form of the drug substance during drug 
product manufacturing, which could adversely affect CQAs of the drug product 
 
f.  Product quality adversely affected by interaction of API and excipients during 
manufacturing 
 
g.  Product quality adversely affected by inadequately scaling up manufacturing 
process (e.g., process parameters) 
 
h.  Commercial manufacture at risk by scaling up any unit operation >10 times  
 
i.  Requirement to manufacture a new batch (e.g., stability failure) 
 
j.  Significant differences between process descriptions, in-process controls, or scale-
up information in Module 2 and Module 3 
 
k.  Need for safety assessment of extractables and leachables, inadequate assessment 
of extractables and leachables, or submission of the assessment in an unsolicited 
amendment 
 
4.  Microbiology 
 
a.  For terminally sterilized products, failure to provide sterilization validation data to 
support the terminal sterilization of the drug product 
 
b.  For aseptically filled products, failure to provide validation data to support the 
sterilization of the equipment or components utilized in production of the drug 
product 
 
c.  For aseptically filled products, failure to provide sterilization validation for the 
method proposed for sterilizing the drug solution (either drug substance or drug 
product) prior to aseptic filling (e.g., sterilizing filtration bacterial retention 
validation results) 
 
d.  For aseptically filled products, failure to provide media fill process simulation 
data supporting the use of the appropriate filling line/machine 
 
e.  For multi-dose products, failure to provide antimicrobial effectiveness test results 
 
  19  Contains Nonbinding Recommendations 
f.  Failure to provide depyrogenation validation data for the container-closure 
system, when appropriate 
 
g.  Absence of finished product release or stability specifications, or excessively high 
specification acceptance criteria with no adequate justification (e.g., high bacterial 
endotoxins limit) 
 
h.  Failure to provide suitability studies (previously referred to as validation studies 
for generic drug products), when appropriate, for finished product release/stability 
testing methods (e.g., bacterial endotoxins testing, sterility testing, or container 
closure integrity testing) 
 
i.  Reference to a DMF that is inadequate with respect to certain microbiological 
quality issues such as failure to provide sterilization validation information 
 
5.  Biopharmaceutics 
 
a.  Proposed in vitro release (e.g., dissolution) method or related analytical 
procedure, including development report and validation, is inadequate or lacking 
(i.e., new method or procedure is required) 
 
b.  Data supporting the proposed in vitro release acceptance criteria (e.g., in vitro in 
vivo correlation (IVIVC), data or in silico physiologically based pharmacokinetics 
(PBPK) modeling) is inadequate 
 
c.  Failure to include an in vivo study (e.g., bioequivalence, IVIVC, vasoconstrictor 
assay) when it is required for a post-approval change48  
 
6.  Facilities49 
 
a.  Deficiencies that indicate one or more facilities were found inadequate at the time 
of action 
 
b.  Deficiencies that indicate the submission failed to identify facilities required to be 
listed in the application 
 
B.  Bioequivalence Deficiencies  
 
                                                 
48 See guidances for industry SUPAC-MR: Modified Release Solid Oral Dosage Forms; Scale-Up and Post-
Approval Changes: Chemistry, Manufacturing and Controls, In Vitro Dissolution Testing, and In Vivo 
Bioequivalence Documentation, and Immediate Release Solid Oral Dosage Forms Scale-Up and Postapproval 
Changes: Chemistry, Manufacturing, and Controls, In Vitro Dissolution Testing, and In Vivo Bioequivalence 
Documentation.  
49 In addition to the deficiencies identified in this section, FDA will classify any amendment that provides for a new 
facility that requires comprehensive evaluation as a major amendment.  
  20  Contains Nonbinding Recommendations 
1.  Bioequivalence (BE) 
 
a.  Inadequate or insufficient in vivo studies (e.g., pharmacokinetic (PK), 
pharmacodynamic (PD), or clinical) or in vitro BE studies (e.g., in vitro NG tube 
and gastronomy tube (G tube) testing) requiring submission of new studies.  
Examples include but are not limited to: failed study(ies); sampling times did not 
capture C adequately; exclusion of study outliers; wrong reference standard 
max 
used; metabolite data not supportive; T /T  issues; and other PK or statistical 
max lag
issues 
 
b.  Inadequate physicochemical data for ophthalmic products, oral solutions, or 
injections, as needed 
 
c.  Deficiencies related to device comparability for nasal/inhalation products 
 
d.  Insufficient validation data 
 
e.  Reintegration of chromatograms (including manual reintegration) 
 
f.  Reanalysis of samples (e.g., request reanalysis due to contract/clinical research 
organization (CRO) issue, site issue, analytical issue, or inadequate justification 
for reanalysis of samples) 
 
g.  Insufficient justification for protocol deviations, such as inclusion or exclusion of 
subjects 
 
h.  Submission contains an in vivo study with serious adverse event, death, or 
different safety profile between the test product and RLD 
 
i.  Inadequate in vitro alcohol dose dumping dissolution testing or in vitro half tablet 
dissolution testing 
 
j.  Inadequate in vitro dissolution testing due to aged or expired batches 
 
k.  Information needed to address the impact of significant Office of Study Integrity 
Surveillance inspectional or review findings 
 
l.  Inadequate formulation (e.g., due to safety concerns, capsule size, in vitro alcohol 
dose dumping) 
 
m. Deficiencies related to excipients above inactive ingredient limit 
 
n.  Deficiencies related to sugar alcohol content in a drug product formulation (e.g., 
sugar alcohol content differs significantly from RLD) 
 
  21  Contains Nonbinding Recommendations 
o.  Inadequate due to consult-related deficiencies including, but not limited to: 
insufficient information submitted to address safety issues (e.g., insufficient 
pharmacology/toxicology information to support the safety of the formulation); 
insufficient information to address tablet size, or a change in device/container 
closure; and insufficient information to address changes related to PK studies  
 
p.  Deficiencies related to changes in FDAs guidances for industry that result in 
inadequate or insufficient in vivo and/or in vitro BE studies  
 
q.  Inadequate information provided to support that the alternate method (e.g., 
deviation from recommendations in FDAs guidances for industry) is acceptable 
for demonstrating BE between products 
 
2.  Clinical Review 
 
a.  Failure to show statistical non-inferiority of the proposed product to the reference 
product in the skin irritation, sensitization, and adhesion study with regard to 
irritation potential or adhesive performance for patch products 
 
b.  Failure to show statistical non-inferiority of the proposed products vehicle patch 
to the positive control (e.g., sodium lauryl sulfate) in the skin irritation and 
sensitization study with regard to irritation potentials 
 
c.  Failure to demonstrate BE of the test and reference products in the clinical BE 
endpoint study 
 
d.  Unacceptable clinical endpoint BE study due to incorrect endpoint selection, 
inappropriate dosing regimen selection, inappropriate treatment duration, or study 
population 
 
e.  Failure to demonstrate superiority of the test and reference products over placebo 
in the clinical endpoint BE study 
 
f.  Inadequate information provided to ensure the safety of the proposed formulation 
for all labeled indications and patient populations 
 
g.  Inadequate information provided to support that the efficacy and safety of the 
proposed formulation would not differ from that of the RLD 
 
h.  The surrogate endpoint (or measurement scale/questionnaire) is not generally 
recognized as a validated measure for the indication 
 
i.  Unacceptable study data due to a concern about study conduct or data integrity 
 
3.  Pharmacology/Toxicology 
 
  22  Contains Nonbinding Recommendations 
a.  Inadequate safety justification to ensure the proposed formulations composition 
and specifications would have a similar safety profile as the RLD 
 
i.  Justification may include, but is not limited to nonclinical studies50 
supporting the safety of the proposed drug substance or drug product (e.g., 
safety justification for an unqualified impurity or proposed excipient level, 
genetic toxicology data (in silico, in vitro, in vivo), general toxicology 
data, safety justification for residual solvents or product and process- 
related extractables and leachables) 
 
4.  Clinical Consultation 
 
a.  Inadequate information provided to ensure the safety of the proposed product in 
labeled clinical use would not differ from that of the RLD 
 
b.  Inadequate information provided to support that the safety of the proposed 
formulation would not differ from that of the RLD 
 
c.  Inadequate information to support the safety of the inactive ingredients in the 
labeled population (e.g., safety in pediatric population) or labeled duration of 
dosing (e.g. long term treatment vs short course therapy) 
 
d.  Unknown safety of an inactive ingredient because it has not been used in other 
drug products with similar conditions of use or target populations 
 
e.  Inadequate information to ensure the side effects from a proposed inactive 
ingredient will not exacerbate the adverse events already reported for the RLD 
(e.g., polyethylene glycol (PEG) exacerbating diarrhea) 
 
f.  Potential safety risk due to capsule/tablet size or appearance or potential for 
change in a patients use pattern compared to the RLD 
 
g.  Device or container-closure design issues that may affect safety or efficacy 
 
h.  PK profile (e.g., T ) is different from RLD in a clinically significant way that 
max
may affect safety or efficacy 
 
5.  Statistical 
 
a.  Failure to collect in the study the data required for necessary analyses  
 
                                                 
50 See note 51 regarding what data is permissible to support an ANDA.  For example, a proposed drug product that 
contains a novel excipient (an excipient that has not been used in an FDA-approved drug product, the safety of 
which cannot be established without clinical testing) would not be permitted in an ANDA.   
  23  Contains Nonbinding Recommendations 
b.  Unacceptable study data due to significant discrepancies between datasets or 
presence of spurious data 
 
c.  Lack of pre-specification of the analysis methods and statistical models to be used 
in the protocol and the statistical analysis plan 
 
d.  Failure of study to meet its objective using either the FDA-recommended method 
or a pre-specified, justified alternative method 
 
e.  Failure to resolve through information requests a major issue affecting the 
analysis results or the ability of the FDA assessor to perform the analyses  
 
C.  Risk Evaluation and Mitigation Strategies (REMS) Deficiencies 
 
1.  REMS with Elements to Assure Safe Use (ETASU) 
 
a.  ANDA does not include a required REMS submission 
 
b.  REMS submission included in the ANDA has not been updated to reflect 
approved modifications to the REMS after ANDA submission 
 
c.  REMS submission does not contain elements as required by the REMS for the 
RLD or is missing information 
 
d.  There is no established single shared system REMS finalized for the drug product 
and/or FDA has not waived the single shared system requirement 
 
D.  Labeling Deficiencies  
 
2.  Labeling 
 
a.  Proposed labeling differs from the last approved labeling for the RLD, outside the 
scope of differences allowed under 21 CFR 314.94(a)(8)(iv) 
 
b.  Proprietary name request was denied and a new name was submitted for 
consideration  
   
  24  Contains Nonbinding Recommendations 
APPENDIX B:  EXCERPTED TEXT FROM GUIDANCE FOR INDUSTRY, MAJOR 
MINOR, AND TELEPHONE AMENDMENTS TO ABBREVIATED NEW DRUG 
APPLICATIONS, REV. 2 (DEC. 2001)51 
 
The following is the excerpt of text from the 2001 amendments guidance describing major and 
minor amendments. 
 
B.  When is an amendment classified as major? 
 
Responses to the following examples of deficiencies would result in a major amendment. 
This should not be considered an all-inclusive listing. 
 
1.  Manufacture of a new batch of drug product (with supporting information) for any 
reason; for example: 
 
 
Composition change or reformulation 
 
Change in the source of a drug substance 
 
Change in manufacturing site  
 
Need for a new bioequivalence study (21 CFR 320.21) 
 
New in vitro study for a specific product (e.g., metered dose inhalers) 
 
Change in major manufacturing process  
 
New strength of the product 
 
Unacceptable impurities or impurity levels (21 CFR 314.94(a)(9)) 
 
Unacceptable excipients found during the review (21 CFR 314.94(a)(9)) 
 
Failed stability data  
 
Change in the container-closure system (other than solid oral dosage 
forms) 
 
2.  New bioequivalence study (21 CFR 320.21) that is not related to manufacture of a 
new batch of the drug product 
 
3.  New analytical methods and full validation data (21 CFR 314.94(a)(9)) 
 
                                                 
51 The GDUFA II Commitment Letter specifically references the December 2001 guidance for industry Major, 
Minor and Telephone Amendments to Abbreviated New Drug Applications as a source for what constitutes major 
and minor amendments.  See GDUFA II Commitment Letter at 26.  To assure continued agreement with respect to 
the GDUFA II Commitment Letter, FDA is making excerpted portions of the 2001 amendments guidance an 
appendix to this one.  We have maintained only these excerpted portions as certain statements in the 2001 guidance 
no longer apply (e.g., the reference to the 180-day queue), and this appendix should be consulted only with respect 
to the examples of major and minor amendment. 
  25  Contains Nonbinding Recommendations 
Any other circumstances that might be considered to be a major amendment should get 
division level concurrence, including an assessment that the application is of such overall 
poor quality that substantive review is not possible. 
   
Many of the deficiencies that would be categorized as a major amendment for chemistry 
would also pertain to the sterility assurance and/or microbiology review (i.e., change in 
facility or container-closure system).  Generally, the microbiology review would not 
affect the designation determined through the CMC review.  However, in rare instances, 
the sterility assurance and/or microbiology reviews, rather than chemistry, may determine 
the major amendment designation.  This could occur, for example, when extensive 
validation work is necessary (21 CFR 314.94(a)(9)). 
 
When is an amendment classified as minor? 
 
Except for those amendments that are classified as major or telephone, amendments will 
be designated as minor.  Minor amendments often consist of deficiencies that are outside 
the control of the applicant or deficiencies that are more easily addressed than those in a 
major amendment.  Though most amendments will likely be minor, some examples 
include, but are not limited to: 
 
1.  Deficiencies in the drug master file (DMF) 
 
2.  Problems regarding good manufacturing practices (GMPs) 
 
3.  Incomplete dissolution data  
 
4.  Labeling deficiencies that have not been adequately addressed 
 
Sterility assurance and/or microbiology issues that would likely take less than a full day 
to review would generally fall into the minor amendment category.  However, as stated 
previously, the microbiology designation is determined by the chemistry review.  
  
  26