ANDA Submissions
Amendments and 
Requests for Final 
Approval to Tentatively 
Approved ANDAs 
Guidance for Industry 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
  
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
January 2024 
Generic Drugs 
 
Revision 1 
  ANDA Submissions
Amendments and Requests 
for Final Approval to 
Tentatively Approved 
ANDAs 
 
 
 
 
 
 
 
 
 
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 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
 
January 2024 
Generic Drugs 
 
Revision 1 
   
 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
A.  ANDA Approval Pathway ............................................................................................................. 2 
B.  Patent Certifications and ExclusivitiesEffect on Timing of ANDA  Approval ..................... 3 
C.  Tentative Approval and Amendments to Tentatively Approved ANDAs ................................ 4 
III.  AMENDMENTS TO TENTATIVELY APPROVED ANDAS .................................... 5 
A.  Review Goals for Amendments Other Than Requests for Final Approval .............................. 5 
B.  Status of a Tentatively Approved ANDA Upon Submission of an Amendment ...................... 6 
IV.  SUBMISSION OF AND REVIEW GOALS FOR REQUESTS FOR FINAL 
APPROVAL .................................................................................................................................. 6 
A.  Requests for Final Approval ......................................................................................................... 6 
B.  Applications With Granted TA Status Less Than 3 Years Before Earliest Lawful     
Approval Date ......................................................................................................................................... 7 
C.  Applications Granted TA Status 3 or More Years Before Earliest Lawful Approval Date.... 8 
D.  Complete Responses and Reissued Tentative Approvals in Response to Requests for Final 
Approval .................................................................................................................................................. 8 
V.  POST-TA CHANGES THAT MAY IMPACT FINAL APPROVAL .......................... 9 
VI.  CONTENT OF REQUESTS FOR FINAL APPROVAL ............................................ 12 
 
 
  Contains Nonbinding Recommendations 
ANDA SubmissionsAmendments and Requests for Final 
Approval to Tentatively Approved ANDAs 
Guidance for Industry1 
 
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 in preparing and submitting amendments to 
tentatively approved abbreviated new drug applications (ANDAs), including requests for final 
approval.  This guidance provides recommendations on the timing and content of amendments to 
tentatively approved ANDAs to facilitate submission in a timely fashion to enable final approval 
on the earliest date on which the ANDA may lawfully be approved based on patent and/or 
exclusivity protections (earliest lawful ANDA approval date). 
 
This guidance replaces the final guidance of the same title issued in September 2020.  This 
guidance is being issued to incorporate the performance goals currently outlined in the GDUFA2  
Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023-2027 
(GDUFA III commitment letter)3, and it describes how FDA will handle requests for final 
approval and amendments to  tentatively approved ANDAs subject to the performance goals in 
the GDUFA III commitment letter.  It also contains clarifying revisions to section II.B 
concerning patent certifications and exclusivities and their effect on timing of ANDA approval. 
 
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. 
 
 
 
1 This guidance has been prepared by the Office of Generic Drugs in the Center for Drug Evaluation and Research 
(CDER) at the Food and Drug Administration (FDA).  You may submit comments on this guidance at any time.  
Submit comments to Docket No. FDA-2017-D-6821 (available at https://www.regulations.gov/docket?D=FDA-
2017-D-6821).  See the instructions in that docket for submitting comments on this and other Level 2 guidances. 
 
2 GDUFA refers to the generic drug user fee program codified in the Generic Drug User Fee Amendments of 2012, 
the Generic Drug User Fee Amendments of 2017, and the Generic Drug User Fee Amendments of 2022.  
3 The GDUFA III commitment letter is available at https://www.fda.gov/media/153631/download.   
  1  Contains Nonbinding Recommendations 
 
II.  BACKGROUND 
 
The Generic Drug User Fee Amendments of 2012 (GDUFA I)4 amended the Federal Food, 
Drug, and Cosmetic Act (FD&C Act) to authorize FDA to assess and collect user fees to provide 
the Agency with resources5 to help ensure patients have access to quality, safe, and effective 
generic drugs.  GDUFA fee resources bring greater predictability and timeliness to the review of 
generic drug applications.  GDUFA has been reauthorized every 5 years to continue FDAs 
ability to assess and collect GDUFA fees, and this user fee program has been reauthorized two 
times since GDUFA I, most recently in the Generic Drug User Fee Amendments of 2022.6  As 
described in the GDUFA III commitment letter applicable to this latest reauthorization, FDA has 
agreed to performance goals and program enhancements regarding aspects of the generic drug 
assessment program that build on previous authorizations of GDUFA.  New enhancements to the 
program are designed to maximize the efficiency and utility of each assessment cycle, with the 
intent of reducing the number of assessment cycles for ANDAs and facilitating timely access to 
generic medicines for American patients.  
 
A.  ANDA Approval Pathway 
 
The process for obtaining approval to market a drug product approved under a new drug 
application (NDA) differs from that for obtaining approval to market a generic drug under an 
ANDA.  A sponsor7 of an innovator drug must submit an NDA, which must contain, among 
other things, a demonstration of the safety and effectiveness of the drug for the conditions of use 
for which approval is sought.8   
 
To obtain approval of a generic drug, an ANDA applicant is not required to provide independent 
evidence of the safety and effectiveness of that generic drug.  Instead, the applicant relies on 
FDAs finding that the reference listed drug (RLD)9 relied upon by the ANDA applicant is safe 
and effective.  The ANDA applicant must identify the RLD on which it seeks to rely and, among 
other things, demonstrate that the proposed generic drug product and the applicable RLD are the 
same with respect to their active ingredient(s), dosage form, route of administration, strength, 
conditions of use, and labeling (with certain permissible exceptions).10  An ANDA must also 
include sufficient information (1) to demonstrate that the proposed product is bioequivalent to 
the RLD11 and (2) to ensure the products identity, strength, quality, and purity.12 
 
 
4 Title III of the Food and Drug Administration Safety and Innovation Act, Public Law 112-144. 
5 User fees are available for obligation in accordance with appropriations acts.  
6 Enacted as Title III of Division F (the FDA User Fee Reauthorization Act of 2022) of the Continuing 
Appropriations and Ukraine Supplemental Appropriations Act, 2023 (Public Law 117-180). 
7 The term sponsor and the term applicant are used interchangeably in this guidance to refer to any person who 
submits an NDA or ANDA or an amendment or supplement to an NDA or ANDA and any person who owns an 
approved NDA or ANDA. 
8 Section 505(b)(1) of the FD&C Act (21 U.S.C. 355(b)(1)). 
9 An RLD is the listed drug identified by FDA as the drug product on which an ANDA applicant relies in seeking 
approval of its ANDA.  21 CFR 314.3(b).   
10 See section 505(j)(2)(A) and 505(j)(4) of the FD&C Act and 21 CFR 314.94 and 21 CFR 314.127. 
11 See section 505(j)(2)(A)(iv) and 505(j)(4)(F) of the FD&C Act and 21 CFR 320.21(b).  
12 Section 505(j)(2)(A)(vi) and 505(j)(4)(A) of the FD&C Act.   
  2  Contains Nonbinding Recommendations 
B.  Patent Certifications and ExclusivitiesEffect on Timing of ANDA 
  Approval  
 
The timing of ANDA approval depends on, among other things, the patent and/or exclusivity 
protections for the RLD.  Not later than 30 days after the date of approval of an NDA, the NDA 
applicant must submit certain information to FDA for each patent that claims the drug for which 
the applicant submitted the application and is a drug substance (active ingredient) patent or a 
drug product (formulation or composition) patent, or that claims a method of using such drug for 
which approval has been granted in the NDA, and for which a claim of patent infringement could 
reasonably be asserted if a person not licensed by the owner of the patent engaged in the 
manufacture, use, or sale of the drug.13  FDA publishes (or lists) certain patent information 
submitted by the NDA holder under section 505(c) of the FD&C Act in its publication Approved 
Drug Products With Therapeutic Equivalence Evaluations, known as the Orange Book.14  An 
ANDA must contain an appropriate patent certification for each patent that claims the RLD or a 
method of using the RLD for which the ANDA applicant seeks approval in its ANDA and for 
which the NDA applicant is required to submit information.15  In particular, the ANDA applicant 
generally must submit to FDA one of four specified certifications regarding such patents, under 
section 505(j)(2)(A)(vii) of the FD&C Act (21 U.S.C. 355(j)(2)(A)(vii)): 
 
  That such patent information has not been filed (a paragraph I certification) 
  That such patent has expired (a paragraph II certification) 
  The date on which such patent will expire (a paragraph III certification) 
  That such patent is invalid, unenforceable, or will not be infringed by the manufacture, 
use, or sale of the new drug for which the application is submitted (a paragraph IV 
certification).16 
 
If an applicant submits a paragraph I or II certification, the patent in question will not delay 
ANDA approval.  If an applicant submits a paragraph III certification, the applicant agrees to 
wait until the relevant patent has expired before seeking final approval of its ANDA.  If, 
however, an applicant wishes to seek final approval of its ANDA before a listed patent has 
expired by challenging the validity of that patent, by claiming that the patent would not be 
infringed by the generic drug product proposed in the ANDA, or by claiming that the patent is 
unenforceable, the applicant must submit a paragraph IV certification to FDA.17 
 
An applicant submitting a paragraph IV certification to a listed patent must provide the NDA 
holder and each patent owner with notice of its paragraph IV certification, including a 
description of the legal and factual basis for the ANDA applicants assertion that the patent is 
 
13 Section 505(c)(2) of the FD&C Act. 
14 Section 505(j)(7)(A)(iii) of the FD&C Act. The Orange Book is available at 
http://www.accessdata.fda.gov/scripts/cder/ob/default.cfm. 
15 Section 505(j)(2)(A)(vii) of the FD&C Act and 21 CFR 314.94(a)(12)(i)(A). 
16 Section 505(j)(2)(A)(vii) of the FD&C Act; see also 21 CFR 314.94(a)(12)(i)(A).   
17 See 21 CFR 314.94(a)(12)(i)(A)(4).  When a patent is listed only for a method of use, an ANDA applicant not 
seeking approval for that method of use can submit a section viii statement that acknowledges that patent 
information has been submitted to FDA for a patent claiming a given method of use, but states that the patent at 
issue does not claim a use for which the applicant seeks approval.  Section 505(j)(2)(A)(viii) of the FD&C Act.  See 
also 21 CFR 314.94(a)(12)(iii)(A). 
  3  Contains Nonbinding Recommendations 
invalid, unenforceable, or will not be infringed.18  If a patent is listed at the time an ANDA is 
submitted and, in response to notice of a paragraph IV certification, the patent owner or its 
representative or the exclusive patent licensee initiates a patent infringement action against the 
ANDA applicant within 45 days of receiving the required notice, approval of the ANDA 
generally will be stayed for 30 months from the later of the date of receipt of the notice by any 
owner of the patent or the NDA holder or such shorter or longer time as the court might order.19  
If a patent is listed in the Orange Book after an ANDA is submitted but before the ANDA is 
approved, the applicant for the pending ANDA generally must amend its application and provide 
an appropriate patent certification or statement to the newly listed patent.  However, a 30-month 
stay would not result from an ANDA applicant submitting a paragraph IV certification to a 
patent for which the relevant patent information was submitted after the ANDA applicant 
submitted its application.20 
 
The statute provides an incentive and a reward to generic drug applicants that expose themselves 
to the risk of patent litigation.  It does so by making first applicants eligible for 180-day 
exclusivity vis-a-vis certain other ANDA applicants, known as subsequent applicants..21  In 
addition, the FD&C Act provides for a number of exclusivities for RLDs that can affect the 
timing of final approval of an ANDA.22  
 
C.  Tentative Approval and Amendments to Tentatively Approved ANDAs 
 
If an ANDA meets the substantive requirements for approval but cannot receive final approval 
from FDA due to patent or exclusivity reasons, FDA will tentatively approve the ANDA.  
Tentative approval (TA)  
 
 . . . is notification that an NDA or ANDA otherwise meets the requirements for approval 
under the Federal Food, Drug, and Cosmetic Act, but cannot be approved because there is 
a 7-year period of orphan exclusivity for a listed drug under section 527 of the [FD&C 
Act] and [21 CFR]  316.31 . . . or that a 505(b)(2) application or ANDA otherwise 
meets the requirements for approval under the [FD&C Act], but cannot be approved until 
the conditions in  314.107(b)(1)(iii), (b)(3), or (c) are met; because there is a period of 
exclusivity for the listed drug under  314.108; because there is a period of pediatric 
exclusivity for the listed drug under section 505A of the [FD&C Act]; because there is a 
period of exclusivity for the listed drug under section 505E of the [FD&C Act]; or 
because a court order pursuant to 35 U.S.C. 271(e)(4)(A) orders that the NDA or ANDA 
may be approved no earlier than the date specified.  A drug product that is granted 
tentative approval is not an approved drug and will not be approved until FDA issues an 
approval letter after any necessary additional review of the NDA or ANDA.23 
 
 
18 Section 505(j)(2)(B) of the FD&C Act and 21 CFR 314.95(c). 
19 Section 505(j)(5)(B)(iii) of the FD&C Act and 21 CFR 314.107(b)(3)(i). 
20 Id.  See also 21 CFR 314.94(a)(12)(vi).   
21 See section 505(j)(5)(B)(iv)(I), 505(j)(5)(B)(iv)(II)(aa)-(cc), and 505(j)(5)(D)(iii) of the FD&C Act.  
22 See section II.C of this draft guidance for the definition of tentative approval, which includes a listing of the 
exclusivities that affect the timing of final approval of an ANDA.  
23 21 CFR 314.3(b).  See also section 505(j)(5)(B)(iv)(II)(dd)(AA) of the FD&C Act and 21 CFR 314.105(d).   
  4  Contains Nonbinding Recommendations 
Under section 505 of the FD&C Act, a drug product that is the subject of a tentatively approved 
ANDA is not an approved drug and does not have an effective approval until FDA issues an 
approval after any necessary additional review of the application.24   
 
An ANDA applicant may submit amendments to a tentatively approved application that propose 
changes to the application, request final approval, or propose changes and request final approval.  
As explained in this draft guidance, an amendment may delay FDAs final approval of the 
ANDA until after the earliest lawful ANDA approval date, depending on the timing of 
submission of the amendment and the nature of the changes proposed in the amendment and any 
related deficiencies identified upon review.  This guidance is intended to assist applicants in 
preparing an amendment for submission in a timely fashion to obtain final approval on the 
earliest lawful approval date.  In particular, applicants that wish to request final approval should 
determine whether changes are necessary before requesting this final approval, review any 
changes that have been made to their application since the TA was granted (see section V of this 
draft guidance), and consider the possible review goal dates that may be assigned to the request 
for final approval to request final approval in a timely fashion.   
 
 
III.  AMENDMENTS TO TENTATIVELY APPROVED ANDAs 
 
A.  Review Goals for Amendments Other Than Requests for Final Approval 
 
There are several types of amendments that can be submitted after an ANDA receives TA.  The 
GDUFA III commitment letter describes review goal dates for the different amendment types, 
and FDA has provided additional information and recommendations related to these different 
types of amendments in its guidance for industry ANDA SubmissionsAmendments to 
Abbreviated New Drug Applications Under GDUFA (Amendments Guidance).25  Relevant to 
this discussion, if an applicant submits an amendment to its ANDA (1) after the ANDA has 
received TA but (2) before the applicant submits a request for final approval, the amendment 
will, in general, receive a review goal date consistent with the review goal dates outlined in the 
GDUFA III commitment letter and described in the Amendments Guidance.  For example, if an 
applicant submits a standard amendment adding a new facility requiring preapproval inspection, 
FDA will classify that amendment as a major amendment requiring preapproval inspection and 
set a 10-month review goal for that amendment.   
 
As described in the Amendments Guidance, FDA also may, in limited situations, defer 
assessment of an amendment other than a request for final approval if the earliest lawful 
approval date for that ANDA is not for several years.  For example, FDA may defer 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 several years.26   
 
24 See section 505(j)(5)(B)(iv)(II)(dd)(BB); see also 21 CFR 314.105(d).   
25 We update guidances periodically.  For the most recent version of a guidance, check the FDA guidance web page 
at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
26 For further discussion on FDAs practice of deferring assessment of certain amemdments and when the Agency 
may defer assessment of an amendment to a tentatively approved ANDA, see Amendments Guidance at 13 and 14-
15. 
  5  Contains Nonbinding Recommendations 
 
To note, FDA will not defer assessment of amendments to ANDAs that have been tentatively 
approved and are included in the Presidents Emergency Plan for AIDS Relief (PEPFAR).27  
Under PEPFAR, certain antiretroviral products that have been granted a TA may be distributed 
for use outside of the United States, even when there is still patent and/or exclusivity protection 
in the United States.  For such products, FDA will set a goal date for assessing amendments to 
PEPFAR ANDAs that reflects their distribution under that program and is consistent with the 
description in the Amendments Guidance.  
 
B.  Status of a Tentatively Approved ANDA Upon Submission of an Amendment  
 
When an applicant submits an amendment to a tentatively approved ANDA, FDA will determine 
whether to assess that amendment or defer it, as described above.  If the Agency decides to 
assess the amendment, for tracking purposes, FDA will convert the status of the ANDA in its 
internal systems from TA to under review; that internal designation will remain until FDA takes 
an action on the amendment.  If FDA defers the amendment, the ANDA will remain in TA status 
in FDAs internal systems until FDA assesses that amendment.  If after assessment of the 
amendment, FDA determines that the ANDA meets all the requirements for TA or final 
approval, FDA will reissue the TA or grant a final approval, as appropriate.  If FDA identifies 
deficiencies that have not been resolved during assessment of the amendment that are 
communicated in a complete response letter (CRL), the ANDAs status will be converted to 
complete response status until (1) the applicant adequately addresses the deficiencies identified 
in the CRL in a subsequent amendment and (2) FDA reissues a TA or grants final approval, as 
appropriate.   
 
 
IV.  SUBMISSION OF AND REVIEW GOALS FOR REQUESTS FOR FINAL 
APPROVAL 
 
A.  Requests for Final Approval 
 
FDA does not automatically grant final approval upon the expiration of any periods of 
exclusivity or patent protection that served as the basis of the TA.28  As described in FDAs 
regulations:  
 
A drug product that is granted tentative approval is not an approved drug and will not be 
approved until FDA issues an approval after any necessary additional review of the 
ANDA.  FDAs tentative approval of a drug product is based on information available to 
FDA at the time of the tentative approval letter (i.e., information in the ANDA and the 
status of current good manufacturing practices of the facilities used in the manufacturing 
and testing of the drug product) and is therefore subject to change on the basis of new 
 
27 See FDAs PEPFAR web page, available at https://www.fda.gov/international-programs/presidents-emergency-
plan-aids-relief-pepfar.  
28 FDA may act upon an amendment by granting final approval absent a formal request from the applicant if:  (1) an 
ANDA applicant submits an amendment to a tentatively approved application, as described in section III of this 
draft guidance; and (2) upon conclusion of FDAs assessment of that amendment, that ANDA is determined to be 
eligible for final approval. 
  6  Contains Nonbinding Recommendations 
information that may come to FDAs attention.  A new drug product may not be 
marketed until the date of approval.29 
 
Accordingly, an applicant with an ANDA in TA status generally submits an amendment to its 
ANDA explicitly requesting final approval to market its drug product.30  All requests for final 
approval are considered amendments to the application.  In general, these amendments will be 
classified as major or minor and assessed by FDA consistent with the review goal dates outlined 
in the GDUFA III commitment letter and described in the Amendments Guidance.  It is, 
therefore, incumbent on the applicant to accurately plan the timing of its request for final 
approval. 
 
The two following subsections provide recommendations to ANDA applicants for submitting a 
request for final approval based on when TA was granted.  As noted in this section, all requests 
for final approval, including those subject to changes in the relevant patent and exclusivity 
barriers to approval, are assigned goal dates consistent with the GDUFA performance goals.   
 
B.  Applications With Granted TA Status Less Than 3 Years Before Earliest 
Lawful Approval Date 
 
If an ANDA received a TA less than 3 years before the earliest lawful approval date, FDA 
recommends that the ANDA applicant submit an amendment with enough time to permit FDA to 
assess that amendment before the date on which the applicant seeks final approval (e.g., the 
earliest lawful ANDA approval date).  An applicant also should clearly identify, in its cover 
letter, that the amendment is a request for final approval.  A request for final approval that 
contains no new data, information, or other changes to the ANDA is considered a minor 
amendment.  FDA generally assesses these minor amendments within 3 months.  Accordingly, 
ANDA applicants should submit such a request for final approval as a minor amendment no later 
than 3 months before the date on which the applicant is seeking final approval.   
 
A request for final approval that contains substantive changes to an ANDA or references changes 
submitted in a prior amendment that was deferred by FDA will be classified as a major or minor 
amendment based on the content in the request for final approval and will be assigned a review 
goal date that corresponds with that classification, as articulated in the GDUFA III commitment 
letter and described in the Amendments Guidance.  For example, a request for final approval that 
includes changes to include a new facility or a notification that there was a change in the status 
of the current manufacturing and testing facilities compliance with current good manufacturing 
practices, both of which may require an inspection, could receive a goal date consistent with a 
standard major amendment in which an inspection is required (i.e., 10 months from the date of 
submission).   
 
 
 
 
29 21 CFR 314.105(d). 
30 See 21 CFR 314.107(b)(4). 
  7  Contains Nonbinding Recommendations 
C.  Applications Granted TA Status 3 or More Years Before Earliest Lawful 
Approval Date 
 
As noted above, FDA recommends that the ANDA applicant submit an amendment with enough 
time to permit FDA to assess that amendment before the date on which the applicant seeks final 
approval (e.g., the earliest lawful ANDA approval date).  If an ANDA has been in TA status for 
3 or more years before the earliest lawful approval date, the lengthy passage of time since the TA 
may necessitate a more extensive assessment of the ANDA before final approval may be 
granted.  For example, bioequivalence standards may have changed; product quality standards 
may have changed; or significant RLD labeling changes may have been approved (see section V 
of this draft guidance).  Therefore, FDA recommends that the ANDA applicant consider the 
changes and updates made to the application since the TA was granted and submit the request for 
final approval as a minor or major amendment, as appropriate.31  Submission of the request as a 
major amendment allows FDA to:  (1) assess any changes that have been made since the 
application was granted TA; (2) complete any necessary inspection(s) of the ANDAs referenced 
facilities; and (3) grant final approval on the earliest lawful approval date.  Considering the 
possible review goal dates that may be assigned to the request for final approval, this amendment 
should be submitted no later than 10 months before the date on which the applicant seeks 
approval (e.g., the earliest lawful ANDA approval date), as described further in the Amendments 
Guidance.32      
 
D.  Complete Responses and Reissued Tentative Approvals in Response to 
Requests for Final Approval 
 
As described in section III.B of this draft guidance, if FDA identifies deficiencies in the request 
for final approval that are not addressed by an ANDA applicant during assessment and 
communicates those deficiencies in a CRL, the ANDA will be placed in complete response 
status until the deficiencies are adequately addressed by the applicant in a subsequent 
amendment.33  An applicant that receives a CRL must adequately address the deficiencies before 
FDA may reissue the TA or grant final approval, as applicable.34   
 
FDA may reissue a TA in response to a request for final approval of a tentatively approved 
ANDA if a review goal date is set for before the earliest lawful approval date.  For example, 
FDA may reissue the TA if (1) an applicant submits the request in advance of the time it will 
take FDA to assess the amendment under the applicable GDUFA review goals and (2) FDA does 
not identify any deficiencies in the request.  Alternatively, if appropriate, FDA may choose to 
work through the goal date and grant final approval on the earliest lawful approval date if that 
 
31 Note that the Agency will evaluate the amendment upon submission to determine whether the amendment is 
major or minor and assign a goal date accordingly (see section VI of this draft guidance). 
32 In certain cases, a major amendment requiring preapproval inspection may be designated as priority and subject to 
an 8-month review goal where certain facility information is pre-submitted.  See the GDUFA III commitment letter 
at Sections I.A.5.b. and XI.U.  See also Amendments Guidance at 6-7 and the draft guidance for industry ANDAs: 
Pre-Submission Facility Correspondence Related to Prioritized Generic Drug Submissions (Pre-Submission Facility 
Correspondence) (2022).  When final, the guidance will represent the FDAs current thinking on this topic. 
33 We note that FDA may communicate with the applicant, as appropriate, during assessment of the applicants 
application.   
34 21 CFR 314.110(b). 
  8  Contains Nonbinding Recommendations 
date is imminent rather than reissuing the TA on the goal date.35  If FDA reissues the TA, the 
applicant should submit a new request for final approval per the recommendations outlined in 
this draft guidance.    
 
 
V.  POST-TA CHANGES THAT MAY IMPACT FINAL APPROVAL 
 
FDA has identified common developments that may result in an applicant making changes that 
should be submitted in an amendment to its tentatively approved ANDA before final approval is 
granted.  FDA is providing the following non-exhaustive list of these common developments to 
assist ANDA applicants, as applicable, in ensuring that their tentatively approved ANDAs are 
complete and up-to-date before they request final approval.  For these and other changes, FDA 
reminds applicants that they should consider whether the changes would be classified as major or 
minor, and then plan accordingly in determining when to submit such a request to ensure 
approval by the earliest lawful approval date. 
 
Product Quality Updates 
 
  New active pharmaceutical ingredient (API) source in a Type II API drug master file 
 
  Scientific and technical changes to the product, process, analytical methods, and/or 
specifications 
 
  New and/or updated United States Pharmacopeia (USP) chapters and/or monographs36 
 
  Updated stability data 
 
  New facilities 
 
  Changes in the status of referenced facilities  
 
  Changes to the size, shape, or color of a solid oral dosage form 
 
  New test methods 
 
  New submission batch data 
 
  New packaging information (particularly for injectable products) 
 
 
35 See the GDUFA III commitment letter at Section II.B.3 (FDA will continue assessment of an ANDA past the 
goal date if, in FDAs judgment, it may be possible to approve . . . an ANDA within 60 days after the goal date . . . 
[w]hen the application meets the requirements for tentative approval by the goal date, but the legally permissible 
ANDA approval date is within 60 days after the goal date, and FDA may be able to approve the ANDA when it 
becomes legally permissible to do so.). 
36 The United States Pharmacopeia-National Formulary (USP-NF) is available at http://www.uspnf.com/. 
  9  Contains Nonbinding Recommendations 
  New equipment or methods for sterilization and/or depyrogenation (for sterile drug 
products) 
 
  Updates to drug master files 
 
Bioequivalence Updates 
 
  New in vivo or in vitro bioequivalence studies or other analyses, e.g., conducted 
consistent with recommendations in a newly issued, revised, or finalized product-specific 
guidance (PSG), if they are relevant to the ANDA and new data or analyses should be 
generated37 
 
Labeling Updates 
 
  Changes to labeling to reflect approved changes to the labeling for the RLD, including 
changes to the labeling to reflect subsequently approved indications 
 
  Changes to labeling to reflect changes in new and/or updated USP chapters and/or 
monographs 
 
  Changes to labeling to reflect new product quality information or information related to 
bioequivalence studies 
 
  Changes to labeling to reflect an omission of an indication or other aspect of labeling 
protected by patent or exclusivity under the FD&C Act,38 including labeling to reflect the 
split approval of an application (i.e., labeling to reflect final approval of only certain 
strengths of a drug that were previously tentatively approved in the ANDA) 
 
 
 
37 To facilitate generic drug product availability and to assist the generic pharmaceutical industry with: (1) 
identifying the most appropriate methodology for developing drugs (see 21 CFR 320.24); and (2) generating 
evidence needed to support ANDA approval (see 21 CFR 314.94(a)(7) and  320.21(b)), FDA publishes PSGs 
describing the Agencys current thinking and recommendations on how to develop generic drug products that are 
therapeutically equivalent to specific RLDs.  PSGs are available at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm075207.htm.  We note that 
applicants can use an alternate approach if it satisfies the requirements of the applicable statutes and regulations, and 
that these alternate approaches, or questions about the PSG, may be submitted to an applicants ANDA.  Note that, 
under the GDUFA III commitment letter, when a new or revised PSG is published and an applicant or prospective 
applicant has already commenced an in vivo bioequivalence study (i.e., the study protocol has been signed by the 
study sponsor and/or the contract research organization) the applicant or prospective applicant may request a PSG 
Teleconference to obtain Agency feedback on the potential impact of the new or revised PSG on its development 
program.  See the GDUFA III commitment letter at Section III.C.5.   
38 See footnote 18.  If an applicant submits a change in patent certification that may result in or otherwise requests a 
carve-out of any protected indications or other conditions of use from the labeling to obtain final approval before the 
protection for that indication or other condition of use expires, FDAs assessment of those carve-outs may require 
consultations to offices outside of the Office of Generic Drugs.  If a consult is needed, FDA may need additional 
assessment time.  Therefore, applicants should be aware that carve-out assessments may require more assessment 
time than the assessment time allotted for a minor amendment.  
  10  Contains Nonbinding Recommendations 
  Changes to labeling to reflect statements previously carved out that are no longer 
protected by patent or exclusivity under the FD&C Act39 
 
  Changes to containers, blisters, cartons, and other finished dosage form packaging  
 
  New proprietary name requests or requests to reassess a proprietary name that had been 
conditionally granted  
 
Orange Book Listing, Patent, and Exclusivity Updates 
 
  Updated patent certification or statement (or a recertification for a previously submitted 
paragraph IV certification) with the types of amendments described in 21 CFR 
314.96(d)(1) or a verification that the proposed change described in the amendment is not 
one of the types of amendments described in 21 CFR 314.96(d)(1)40 
 
  An appropriate patent certification or statement to a timely filed, newly listed patent for 
the RLD 
 
  An appropriate exclusivity statement to address a new exclusivity for the RLD 
 
  Changes in a patent certification (e.g., a change from a paragraph IV to a paragraph III 
certification) 
 
  Litigation updates (e.g., notification of court actions or written consent to approval41) 
 
  Confirmation that the RLD is identified in the Active section of the Orange Book42 
 
   
 
39 If an ANDA applicant submits an amendment seeking approval for a subsequently approved indication or other 
condition of use that is protected by patent, the applicant must submit an appropriate patent certification in the 
amendment and provide documentation of timely sending and receipt of notice, as appropriate.  See 314.96(d)(1) 
and 314.95(e). 
40 See 21 CFR 314.96(d).  
41 See 21 CFR 314.107(e).  
42 When an RLD is moved to the Discontinued section of the Orange Book, that RLD remains a listed drug (see 21 
CFR 314.3(b)) and is available for reference by an ANDA applicant unless FDA makes a determination that the 
RLD was withdrawn from sale for reasons of safety or effectiveness.  Under 21 CFR 314.161(a), such a 
determination can be made by FDA at any time after the drug has been voluntarily withdrawn from sale, but FDA 
must make this determination before approving an ANDA that refers to the listed drug.   
  11  Contains Nonbinding Recommendations 
VI.  CONTENT OF REQUESTS FOR FINAL APPROVAL 
 
A request for final approval should clearly identify, in its cover letter, all changes to the ANDA 
that have been made since the TA was granted.43  It is incumbent on the ANDA applicant (1) to 
monitor for updates related to the applicants drug product (e.g., changes in bioequivalence 
recommendations or requirements; RLD labeling changes or updates; or USP changes or 
updates) and (2) to ensure that amendments addressing these updates are timely submitted to and 
are clearly identified for FDA either before a request for final approval (i.e., in a post-TA 
amendment) or in the request for final approval amendment itself, permitting FDA sufficient 
assessment time to meet the ANDAs earliest lawful approval date (see sections III and IV of this 
draft guidance).   
 
Applicants should submit a complete and accurate Form FDA 356h44 with their request for final 
approval.  Additionally, FDA recommends that requests for final approval indicate all of the 
following: 
 
  If there has been no change to the ANDA between FDAs issuance of the TA and the 
applicants request for final approval, the applicant should clearly state that there has 
been no change to the ANDA. 
 
  If editorial or other nonsubstantive changes have been made to the ANDA between 
FDAs issuance of the TA and the applicants request for final approval, the request for 
final approval should clearly state what those changes were and identify where, in the 
ANDA, those changes were made. 
 
  If the ANDA contains substantive new information since FDAs issuance of the TA, the 
request for final approval should clearly identify the new information, the changes that 
have been made, and the location of information supporting these changes in the ANDA, 
including any changes submitted in an amendment that was deferred by FDA.  The 
request for final approval should also contain, for FDAs assessment of that request, 
supporting information commensurate with that change.   
 
  If the labeling for the proposed drug product has changed, as compared to the labeling 
submitted with the original ANDA, applicants should include a side-by-side labeling 
comparison of their proposed labeling with their last submission and/or the current RLD 
labeling.  This comparison should annotate any differences and explain any changes that 
have been made, including those made because of updates in product quality or 
bioequivalence information.  
 
  The amendment classification (major or minor) proposed by the applicant consistent with 
the criteria outlined in the Amendments Guidance. 
 
43 FDA also recommends that applicants requesting final approval list all amendments submitted to FDA for 
assessment after the TA.   
44 Form FDA 356h is available at http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm. 
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