Good ANDA 
Submission Practices 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
January 2022 
Generic Drugs 
    
Good ANDA 
Submission Practices 
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  
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 2022 
Generic Drugs 
 
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
III.   PATENT AND EXCLUSIVITY DEFICIENCIES ........................................................ 3 
A.  Documentation and Notification of a Legal Action Filing .......................................................... 5 
B.  Resolution or Appeal of a Legal Action ....................................................................................... 6 
C.  Notice of a Paragraph IV Certification ........................................................................................ 7 
D.  New or Revised Information in the Orange Book ....................................................................... 8 
E.  Amendments to an Unapproved ANDA....................................................................................... 9 
F.  Notification of Commercial Marketing ........................................................................................ 9 
IV.  LABELING DEFICIENCIES ....................................................................................... 10 
A.  Draft Container Labels and Carton Labeling ........................................................................... 10 
B.  Adequate Differentiation for Container Labels and Carton Labeling ................................... 10 
C.  Labeling Format .......................................................................................................................... 11 
D.  Parenteral Drug Products ........................................................................................................... 11 
1.  1. Package Type ................................................................................................................................. 11 
2.  2. Product Strength ............................................................................................................................ 11 
3.  3. Ferrules and Cap Overseals .......................................................................................................... 12 
V.  PRODUCT QUALITY DEFICIENCIES ..................................................................... 13 
A.  Drug Substance ............................................................................................................................ 13 
4.  1. Active Pharmaceutical Ingredient Starting Material ..................................................................... 13 
5.  2. API Manufacturing Process ........................................................................................................... 14 
6.  3. Impurities ....................................................................................................................................... 15 
7.  4. Specifications for Isolated Intermediates ....................................................................................... 16 
8.  5. Justification of the API Specification ............................................................................................. 16 
B.  Drug Product ................................................................................................................................ 17 
9.  1. Establishing Critical Quality Attributes ........................................................................................ 17 
10. 2. Impurities:  Identification, Control, and Qualification .................................................................. 17 
11. 3. Inactive Ingredients ....................................................................................................................... 19 
12. 4. Validating Analytical Methods ...................................................................................................... 20 
C.  In Vitro Dissolution (Biopharmaceutics) ................................................................................... 20 
13. 1. Development and Validation of an In-House Dissolution Testing Method When Dissolution 
Testing Cannot Be Standardized ........................................................................................................ 21 
14. 2. Dissolution Acceptance Criteria .................................................................................................... 21 
D.  Facilities ........................................................................................................................................ 23 
15. 1. Identification of Manufacturing Facilities ..................................................................................... 23 
16. 2. Readiness for Inspection ................................................................................................................ 24 
i  Contains Nonbinding Recommendations 
 
17. 3. Selection of Contract Manufacturing Facilities and CGMPs ........................................................ 24 
E.  Commercial Manufacturing Process .......................................................................................... 25 
F.  Microbiology Considerations ...................................................................................................... 26 
18. 1. In-Process Bioburden Testing and Acceptance Criteria ............................................................... 26 
19. 2. Description and Validation of Bacterial Endotoxins Test Method ................................................ 26 
20. 3. Microbiological Data to Support Extended Storage Times ........................................................... 27 
VI.  BIOEQUIVALENCE DEFICIENCIES........................................................................ 28 
A.  Bioanalytical Study Data ............................................................................................................. 28 
B.  Clinical Summary ........................................................................................................................ 28 
C.  Differences from Product-Specific Guidances .......................................................................... 29 
D.  BE and Safety Information Related to In Vivo BE Studies ..................................................... 29 
E.  Differences in Formulations and Inactive Ingredients ............................................................. 30 
F.  Waiver Requests Under 21 CFR 314.99(b) ................................................................................ 30 
ii  Contains Nonbinding Recommendations 
 
Good ANDA Submission Practices 
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 preparing to submit to FDA abbreviated new drug 
applications (ANDAs).  This guidance highlights common, recurring deficiencies that may lead 
to a delay in the approval of an ANDA.  It also makes recommendations to applicants on how to 
avoid these deficiencies with the goal of minimizing the number of review cycles necessary for 
approval.    
   
The contents of this document do not have the force and effect of law and are not meant to bind 
the public in any way, unless specifically incorporated into a contract. This document is intended 
only to provide clarity to the public regarding existing requirements under the law. FDA 
guidance documents, including this guidance, should be viewed only as recommendations, unless 
specific regulatory or statutory requirements are cited. The use of the word should in FDA 
guidance means that something is suggested or recommended, but not required. 
 
II.  BACKGROUND 
 
The Generic Drug User Fee Amendments of 2012 (GDUFA I)2 was signed into law on July 9, 
2012.  Based on an agreement negotiated by FDA and industry,3 GDUFA I was designed to 
increase the likelihood that American consumers have timely access to low-cost, safe, effective, 
and high-quality generic drugs and to improve the predictability of the ANDA review process.  
Under GDUFA I, FDA constructed a modern generic drug program that resulted in a significant 
and sustained increase in communications between FDA and industry, ANDA regulatory actions, 
and ANDA approvals.   
 
 
1 This guidance has been prepared by the Office of Generic Drugs and the Office of Pharmaceutical Quality in the 
Center for Drug Evaluation and Research at the Food and Drug Administration.  
2 The Food and Drug Administration Safety and Innovation Act (Public Law 112-144).  
3 This agreement is reflected in the Generic Drug User Fee Act Program Performance Goals and Procedures letter 
available at https://www.fda.gov/media/82022/download. 
  1  Contains Nonbinding Recommendations 
 
Despite the advances made under GDUFA I, approximately half of all ANDAs with GDUFA 
review goals required three or more review cycles to reach approval or tentative approval.4  
Multiple review cycles are highly inefficient, require significant resources from applicants and 
FDA, and delay timely patient access to more affordable generic drugs. 
 
Accordingly, after receiving public input, FDA and industry negotiated a revised agreement, 
reflected in GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal 
Years 2018-2022 (GDUFA II Commitment Letter),5 and GDUFA was reauthorized (GDUFA 
II)6 on August 18, 2017.  GDUFA II includes important program enhancements that are designed 
to improve the predictability and transparency of ANDA assessments7 and to minimize the 
number of review cycles necessary for approval.  These program enhancements are intended to 
foster the development of high-quality submissions, ensure the timely resolution of filing 
reconsideration requests, promote the correction of deficiencies in the current review cycle, and 
support the development of high-quality resubmissions.  
 
This guidance has been developed as part of FDAs Drug Competition Action Plan,8 which, in 
coordination with the GDUFA9 program and other FDA activities, is expected to increase 
competition in the market for drugs, facilitate entry of high-quality and affordable generic drugs, 
and improve public health.  In 2018, FDA issued the Good ANDA Assessment Practices Manual 
of Policies and Procedures (MAPP 5241.3),10 which establishes good ANDA assessment 
practices for the Office of Generic Drugs and the Office of Pharmaceutical Quality to increase 
their operational efficiency and effectiveness.  This guidance and MAPP 5241.3 are intended to 
build upon the success of the GDUFA program and to help reduce the number of review cycles 
for an ANDA to attain approval. 
 
This guidance describes common, recurring deficiencies identified during FDAs substantive 
assessment of ANDAs with respect to (1) patents and exclusivities, (2) labeling, (3) product 
 
4 A tentative approval is a notification from FDA that an ANDA otherwise meets the requirements for approval 
under the Federal Food, Drug, and Cosmetic Act but cannot be approved until the expiration of a period of patent 
and/or exclusivity protection; until the expiration of a 30-month stay of approval; or, because of a court order in 
patent litigation, before a specific date.  See 21 CFR 314.3(b) and 314.105(d). 
5 https://www.fda.gov/media/101052/download. 
6 Pub. Law 115-52. 
7 Currently, the Office of Generic Drugs and the Office of Pharmaceutical Quality generally uses the term 
assessment in place of review.  Assessment means 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.  
8 More information on FDAs Drug Competition Action Plan is available at https://www.fda.gov/drugs/guidance-
compliance-regulatory-information/fda-drug-competition-action-plan. 
9 In this guidance, GDUFA refers to the generic drug user fee program codified in the Generic Drug User Fee 
Amendments of 2012 and the Generic Drug User Fee Amendments of 2017. 
10 Applicants may review the Center for Drug Evaluation and Researchs Manuals of Policies and Procedures, which 
are Federal directives and documentation of internal policies and procedures that are made available to the public at 
https://www.fda.gov/about-fda/center-drug-evaluation-and-research-cder/cder-manual-policies-procedures-mapp.  
  2  Contains Nonbinding Recommendations 
 
quality, and (4) bioequivalence (BE).11  This guidance also provides recommendations to 
applicants on how to avoid these deficiencies.  FDA comprehensively communicates deficiencies 
identified during a substantive review12 of an ANDA in complete response letters.13  Applicants 
may address the deficiencies identified by FDA by submitting an amendment to their 
application.14    
 
This guidance does not include a comprehensive list of all of the deficiencies identified during 
ANDA assessment.  In addition, it is each applicants responsibility to submit a high-quality, 
complete application that FDA can approve in the first review cycle.  FDA strongly encourages 
applicants to review FDA regulations and all applicable guidances for industry to understand 
FDAs current thinking on each topic. 
 
III.   PATENT AND EXCLUSIVITY DEFICIENCIES     
 
The timing of ANDA approval depends on, among other things, the patent and exclusivity 
protections for the reference listed drug (RLD) on which the applicant relies in seeking approval.  
An applicant must provide, in its ANDA, information related to any patents listed for the RLD in 
FDAs Approved Drug Products With Therapeutic Equivalence Evaluations (the Orange Book) 
prior to the submission of the ANDA.15  In particular, an ANDA applicant generally must submit 
to FDA one of four specified certifications regarding the patents for the RLD under section 
505(j)(2)(A)(vii) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 
355(j)(2)(A)(vii)).  If a method-of-use patent listed for the RLD does not claim a use for which 
the applicant is seeking approval, a statement that the method-of-use patent does not claim such a 
 
11 The deficiencies and accompanying recommendations in this guidance are organized by FDAs review disciplines 
and generally follow the same order as the electronic common technical document.  Information on the electronic 
common technical document format is available at https://www.fda.gov/drugs/electronic-regulatory-submission-and-
review/electronic-common-technical-document-ectd. 
12 Prior to a substantive review, FDA conducts a filing review to determine whether an ANDA is substantially 
complete and will be received.  See 21 CFR 314.101(b), (d), and (e).  FDA communicates with ANDA applicants 
that deficiencies were identified during the filing review of their submitted application either through a notification 
to the applicants or in a refuse-to-receive decision.   
13 It should be noted that the Agency also issues discipline review letters, which are defined in the GDUFA II 
Commitment Letter as a letter used to convey preliminary thoughts on possible deficiencies found by a discipline 
reviewer and/or review team for its portion of the pending application at the conclusion of the discipline review.  In 
addition, information requests are communications sent to an applicant during a review to request further 
information or clarification that is needed or would be helpful to allow completion of the discipline review. 
GDUFA II Commitment Letter. 
14 For information on amendment classifications and categories, please see FDAs guidance for industry ANDA 
Submissions  Amendments to Abbreviated New Drug Applications Under GDUFA (July 2018).  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/. 
15 The Orange Book is available at https://www.accessdata.fda.gov/scripts/cder/ob/.  See section III.D of this 
guidance for more information on patent certification submission requirements for new patents listed for the RLD 
after an applicant submits an ANDA, or the revision of information related to a patent listed for the RLD after an 
applicant submits an ANDA.   
  3  Contains Nonbinding Recommendations 
 
use must be submitted.16    
 
If the Orange Book does not list a patent for the RLD that, in the opinion of the ANDA applicant 
and to the best of its knowledge, claims the RLD or that claims a use of such listed drug for 
which the applicant is seeking approval,17 the ANDA applicant must certify that such patent 
information has not been submitted by the new drug application (NDA) holder for listing in the 
Orange Book (a paragraph I certification).18 
 
With respect to each patent listed in the Orange Book for the RLD, the applicants patent 
certification must state one of the following: 
 
  That such patent has expired (a paragraph II certification)19 
 
  The date on which such patent will expire (a paragraph III certification)20 
 
  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)21 
 
On or after the date on which FDA has received an ANDA for review,22 an applicant that has 
submitted a paragraph IV certification to a listed patent must provide the NDA holder and each 
patent owner notice of its paragraph IV certification, including a description of the legal and 
factual basis for the ANDA applicants assertion that the patent is invalid, unenforceable, or will 
not be infringed.23  If a patent is listed at the time an original ANDA is submitted and, in 
response to a notice of a paragraph IV certification, the NDA holder or patent owner 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 latter of the date 
 
16 Section 505(j)(2)(A)(viii) of the FD&C Act; see also 21 CFR 314.94(a)(12)(iii). 
17 If, in the opinion of the applicant and to the best of its knowledge, there are no patents claiming the RLD that are, 
or should have been, listed in the Orange Book, the applicant must include in the ANDA a certification in the 
following form: 
In the opinion and to the best knowledge of (name of applicant), there are no patents that claim the listed 
drug referred to in this ANDA or that claim a use of the listed drug. 
21 CFR 314.94(a)(12)(ii). 
18 Section 505(j)(2)(A)(vii)(I) of the FD&C Act; see also 21 CFR 314.94(a)(12)(i)(A)(1). 
19 Section 505(j)(2)(A)(vii)(II) of the FD&C Act; see also 21 CFR 314.94(a)(12)(i)(A)(2). 
20 Section 505(j)(2)(A)(vii)(III) of the FD&C Act; see also 21 CFR 314.94(a)(12)(i)(A)(3). 
21 Section 505(j)(2)(A)(vii)(IV) of the FD&C Act; see also 21 CFR 314.94(a)(12)(i)(A)(4)(i).   
22 21 CFR 314.101(b). 
23 Section 505(j)(2)(B) of the FD&C Act; see also 21 CFR 314.95.  See section III.C of this guidance for more 
information on notice of a paragraph IV certification. 
  4  Contains Nonbinding Recommendations 
 
of receipt of the notice by any patent owner or the NDA holder, or such shorter or longer time as 
the court might order.24   
 
The statute provides an incentive and a reward to certain ANDA applicants that expose 
themselves to the risk of patent litigation; the statute does so by granting a 180-day period of 
exclusivity vis-a-vis certain other ANDA applicants to the applicant that is first to file a 
substantially complete ANDA that contains, and for which the applicant lawfully maintains, a 
paragraph IV certification to a listed patent for the RLD (First Applicant).25 
 
A.  Documentation and Notification of a Legal Action Filing 
 
Applicants that file a paragraph IV patent certification26 must subsequently amend their ANDA 
to provide documentation to FDA regarding (1) their notice of certification that was sent to the 
patent owner(s) and NDA holder and (2) any legal action that has been taken against the 
applicant under that paragraph IV notice.27  Specifically, applicants must amend their ANDA to 
provide documentation: 
 
  That their notice of a paragraph IV certification was sent on a date that complies with the 
time frame provided in the regulations for sending this notice 
 
  Of the date that this notice was received by the patent owner(s) and NDA holder28   
 
This documentation must be submitted to the ANDA within 30 days after the last date on which 
the notice was received by the patent owner(s) and NDA holder.29   
 
Applicants also must notify FDA in writing within 14 days of the filing of any legal action filed 
within 45 days of receipt of the notice of paragraph IV certification by any recipient.30  Such 
notification must include a statement that an action for patent infringement has been filed, 
specifying the court, the date the action was filed, the case number, and the patent number(s) of 
the patent(s) at issue in the action,31 and should also include a complete copy of the complaint.  
If a legal action was not filed by the patent owner(s), its representative(s), or the exclusive patent 
licensee within 45 days of its or their receipt of the notice of the paragraph IV certification, the 
 
24 Section 505(j)(5)(B)(iii) of the FD&C Act; see also 21 CFR 314.107(b)(3)(i).  Note that, in some circumstances, 
the period of the stay may be 712 years after the date of approval of the RLD rather than 30 months from the date of 
the notice.  See 21 CFR 314.107(b)(3)(i)(B).  
25 Section 505(j)(5)(B)(iv) of the FD&C Act; see also 21 CFR 314.107(c). 
26 Paragraph IV patent certifications are described in section 505(j)(2)(A)(vii) of the FD&C Act and 21 CFR 
314.94(a)(12)(i)(A)(4). 
27 21 CFR 314.95(e) and 21 CFR 314.107(f)(2). 
28 21 CFR 314.95(e). 
29 Id. 
30 21 CFR 314.107(f)(2)(i). 
31 See 21 CFR 314.107(f)(2)(i).  For a complete list of the information that must be included in a notification of legal 
action, see 21 CFR 314.107(f)(2)(i). 
  5  Contains Nonbinding Recommendations 
 
applicant should submit an amendment to its ANDA promptly after the 45-day period elapses 
stating that no legal action was taken by the patent owner(s), its representative(s), or the 
exclusive patent licensee.   
 
However, applicants have often not submitted to FDA written documentation in a timely fashion:  
 
  Of their timely sending notice of a paragraph IV certification and of the dates that the 
patent owner(s) and NDA holder received notice of a paragraph IV certification 
 
  That the patent owner(s), its representative(s), and/or the exclusive patent licensee have 
filed a legal action 
 
  That includes a statement that the patent owner(s), its representative(s), and/or the 
exclusive patent licensee did not file a legal action within 45 days of receipt of the notice 
of the paragraph IV certification 
 
Applications that lack all required patent/legal documentation or those that do not respond in a 
timely manner to a request for information may receive a complete response letter.32 
 
B.  Resolution or Appeal of a Legal Action 
 
If an applicant submitted a paragraph IV certification, litigation is brought against that applicant, 
and the court enters a decision in favor of the patent owner(s) and/or NDA holder finding the 
patent valid and infringed, that applicant must notify FDA of the courts decision within 14 days 
of the date of entry by the court.33    
 
If the applicant appeals the court decision within the time permitted to appeal, the applicant 
similarly must notify the Agency within 14 days of the date of appeal.34  If the applicant does not 
appeal the courts decision, the applicant must submit an amendment to change its paragraph IV 
certification to a paragraph III certification; this amendment must certify that the patent will 
expire on a specific date.35  Alternatively, if applicable, the applicant can amend its ANDA to no 
longer seek approval for a method of use claimed by the patent and submit a statement under 
section 505(j)(2)(A)(viii) of the FD&C Act.36   
 
 
32 A complete response letter is a written communication to an applicant from FDA usually describing all of the 
deficiencies that the Agency has identified in an NDA or ANDA that must be satisfactorily addressed before it can 
be approved. 21 CFR 314.3; see also 21 CFR 314.110. 
33 21 CFR 314.107(e)(2). 
34 Id. 
35 21 CFR 314.94(a)(12)(viii)(A). Note that a paragraph IV certification remains appropriate if the basis for non-
infringement (of an otherwise valid and infringed patent) is that the ANDA applicant has obtained a license from the 
patent owner with respect to the patent.  See 21 CFR 314.94(a)(12)(v). 
36 21 CFR 314.94(a)(12)(viii)(A).  
  6  Contains Nonbinding Recommendations 
 
Similarly, if the litigation results in a district court decision, a court of appeals mandate, or a 
settlement order or consent decree signed and entered by the . . . district court or court of 
appeals37 that specifies that the patent in question is invalid, unenforceable, or not infringed, or 
finding the patent valid and infringed, the ANDA applicant must submit to the ANDA:  a copy of 
the court judgment, settlement order, or consent decree signed and entered by the court; written 
notification of whether or not there is an appeal within the time permitted for an appeal; a copy 
of any order by the court terminating the 30-month or 712-year stay of approval; a copy of any 
preliminary injunction and/or subsequent court order lifting the injunction; and a copy of any 
court order pursuant to 35 U.S.C. 271(e)(4)(A) that the ANDA may not be approved earlier than 
the date specified.38  If the litigation is resolved with written consent to approval of the ANDA 
from the patent owner or the exclusive patent licensee, a copy of that written consent must be 
submitted.39 
 
Timely notification that the court has issued a decision or that the courts decision has been 
appealed and, when applicable, submission of a timely amendment of the patent certification(s) 
are necessary for FDA to determine the timing of an ANDAs approval.40 
 
C.  Notice of a Paragraph IV Certification 
 
An applicant may not provide notice of a paragraph IV certification that was submitted in an 
original ANDA to the patent owner(s) and NDA holder until that applicant receives a paragraph 
IV acknowledgment letter from FDA.41  Similarly, if an applicant submits an amendment to its 
ANDA that includes a paragraph IV certification and FDA has not yet informed the applicant 
that the ANDA was received for review, that applicant must wait to provide notice of its 
paragraph IV certification to the patent owner(s) and NDA holder until after the applicant has 
received a paragraph IV acknowledgment letter from FDA that the ANDA was received for 
review.42  The applicant must send notice of the paragraph IV certification contained in the 
amendment on or after the date it receives acknowledgment from FDA that the ANDA was 
received for review; this notice must be sent no later than 20 days after the date of the postmark 
on the paragraph IV acknowledgment letter from FDA.43  If FDA has notified the applicant that 
it has received the ANDA and the ANDA applicant submits a subsequent amendment that 
 
37 21 CFR 314.107(e)(1). 
38 Id.  Please note that an applicant should also submit to the ANDA a copy of any court order that extends a stay of 
approval. 
39 Id. 
40 See 21 CFR 314.107(b)(3). 
41 21 CFR 314.95(b)(2).  A paragraph IV acknowledgment letter is a written, postmarked communication from FDA 
to an applicant stating that the Agency has determined that an ANDA containing a paragraph IV certification is 
sufficiently complete to permit a substantive review and indicates that the ANDA is regarded as received.  21 CFR 
314.3(b). 
42 21 CFR 314.95(b)(1) and 21 CFR 314.95(d)(2). 
43 Id. 
  7  Contains Nonbinding Recommendations 
 
includes a paragraph IV certification (see section III.E of this guidance), the notice must be sent 
at the same time that the amendment is submitted.44 
 
Notice of a paragraph IV certification is invalid if (1) it was submitted in an original ANDA or in 
an amendment before the applicants receipt of the paragraph IV acknowledgment letter or (2) it 
was sent before the first working day after the day the patent is published in the Orange Book.45   
 
D.  New or Revised Information in the Orange Book 
 
If a new patent is listed for the RLD after an applicant submits an ANDA or information related 
to a patent listed for the RLD is revised46 after an applicant submits an ANDA, that applicant 
must address these changes to the patent listing for the RLD by submitting an appropriate patent 
certification or statement for each patent, unless the new patent information was not timely 
submitted to FDA by the NDA holder for the RLD.47  However, some applicants have either:  
 
  Provided serial submissions of amendments with paragraph IV certifications and sent 
multiple notices of paragraph IV certifications in anticipation of a newly issued patent 
being listed in the Orange Book,48 which is not permissible under FDAs regulations49 or 
 
  Failed to submit an appropriate patent certification or statement for each newly listed 
patent or revised patent information   
 
An applicant must not submit a paragraph IV certification to the ANDA for a newly listed patent 
earlier than the first working day after the day the patent is published in [the Orange Book].50  
FDA recommends that applicants monitor the Orange Book and address newly listed patents and 
revised patent information in a timely manner to avoid unnecessary delays to ANDA approval.   
 
In addition, ANDA applicants have failed to address new exclusivities for the RLD, which may 
result in a delay in FDAs approval of an application.  FDA recommends that applicants monitor 
the Orange Book and address exclusivities in a timely manner to avoid unnecessary delays to 
ANDA approval.   
 
 
44 21 CFR 314.95(d)(1).  Similarly, if the ANDA applicant submits a supplement to an approved ANDA and that 
supplement requires a patent certification, if the applicant submits a paragraph IV certification its notice must be 
sent at the same time that the supplement is submitted to FDA.  Id.   
45 21 CFR 314.95(b)(2) and 21 CFR 314.95(d)(2). 
46 For example, if a new use code is added to the Orange Book for a currently listed patent for the RLD, the 
applicant must provide an updated paragraph IV certification or statement to FDA to address the newly listed use 
code.   
47 21 CFR 314.107(b)(2); see also 21 CFR 314.94(a)(12)(i), 21 CFR 314.94(a)(12)(iii), and 21 CFR 
314.94(a)(12)(vi).   
48 See 81 FR 69580 at 69610 (Oct. 6, 2016). 
49 21 CFR 314.94(a)(12)(viii)(C)(1)(ii). 
50 Id. 
  8  Contains Nonbinding Recommendations 
 
E.  Amendments to an Unapproved ANDA 
 
An amendment to an unapproved ANDA must contain either: 
 
  an appropriate patent certification or statement or a recertification for a previously 
submitted paragraph IV certification if approval is sought (1) to add a new indication or 
other condition of use, (2) to add a new strength, (3) to make other than minor changes in 
product formulation, or (4) to change the physical form or crystalline structure of the 
active ingredient or 
 
  A statement verifying that the amendment does not contain one of those four types of 
changes51  
 
Applicants, however, at times have failed to provide either: 
 
  An appropriate patent certification or statement (or recertification) or 
 
  The required statement in their amendment to an unapproved ANDA verifying that the 
amendment did not contain one of the four types of changes described above 
 
To address this requirement, FDA recommends that applicants provide an appropriate patent 
certification or statement (or recertification) or, if applicable, include a verification statement 
(stating, e.g., This amendment does not contain one of the proposed changes under 21 CFR 
314.96(d)(1)) in the cover letter of their amendment to an unapproved ANDA. 
 
F.  Notification of Commercial Marketing 
 
The 180-day exclusivity period commences upon any First Applicants commercial marketing of 
its drug product (including the commercial marketing by the First Applicant of the RLD or an 
authorized generic).52  Under either scenario, a First Applicant must submit correspondence to its 
ANDA notifying FDA within 30 days of the date of its first commercial marketing of its drug 
product or the reference listed drug.53  If a First Applicant commences marketing of its 
approved drug product (or the RLD or an authorized generic) and does not notify FDA within 
this time frame, the date of first commercial marketing will be deemed [by FDA] to be the date 
of the drug products approval.54   
 
To address this requirement and avoid losing the benefit of part of the 180-day exclusivity 
period, applicants must submit the required notification of commercial marketing to FDA within 
the 30-day time frame. 
 
 
51 21 CFR 314.96(d). 
52 Section 505(j)(5)(B)(iv) of the FD&C Act and 21 CFR 314.3. 
53 21 CFR 314.107(c)(2). 
54 Id. 
  9  Contains Nonbinding Recommendations 
 
IV.  LABELING DEFICIENCIES 
 
A.  Draft Container Labels and Carton Labeling  
 
Generally, an ANDAs labeling must be the same as its RLDs labeling.55  There are, however, 
limited exceptions, including an exception for differences caused by the ANDA and RLD being 
produced or distributed by different manufacturers.56  These differences between the ANDAs 
labeling and the RLDs labeling may include differences (e.g., in the expiration date or in the 
formulation) that were made to comply with current FDA labeling guidelines or other FDA 
guidance.57  As discussed in the FDA guidance for industry Acceptability of Draft Labeling to 
Support ANDA Approval, FDA reviews ANDA container labels and carton labeling to make 
certain that differences from the RLDs labeling do not raise safety concerns.58  During this 
assessment, FDA considers formatting factors such as the font size, style, and color of the 
required text; the labelings identification of different product strengths; and other methods used 
to ensure that the required information is presented with appropriate prominence.59  Applicants 
sometimes submit draft container labels and carton labeling that do not accurately represent the 
formatting factors that will be used with the final printed labels and labeling, which makes it 
challenging for FDA to confirm that the final printed labels and labeling will be adequate. 
 
To ensure that container labels and carton labeling are adequately evaluated for potential 
deficiencies, FDA recommends that the draft version of container labels and carton labeling 
reflect the content as well as an accurate representation of the layout, text size and style, color, 
and other formatting factors that will be used with the [final printed labeling].60  In addition, 
applicants that receive approval based on draft labeling are responsible for ensuring the content 
of the [final printed labeling] is identical to the approved labeling.61  Failure to do so may 
render the product misbranded and an unapproved new drug.62   
 
B.  Adequate Differentiation for Container Labels and Carton Labeling 
 
Factors such as the color and format of container labels and carton labeling can help differentiate 
multiple strengths within the same product line as well as multiple products within a companys 
product line, thereby reducing the likelihood of medication errors.  Applicants, however, have 
submitted container labels and carton labeling for products that lack an adequate differentiation 
between various strengths and from other drug products.   
 
 
55 Section 505(j)(2)(A)(v) of the FD&C Act and 21 CFR 314.94(a)(8)(iv). 
56 Id. 
57 21 CFR 314.94(a)(8)(iv). 
58 FDA guidance for industry Acceptability of Draft Labeling to Support ANDA Approval (October 2015), at 3.   
59 Id. 
60 Id. 
61 Id. 
62 Id. 
  10  Contains Nonbinding Recommendations 
 
FDA recommends that applicants ensure that the color and/or format of container labels and 
carton labeling is adequately differentiated from other pending and approved products in their 
product line.  As noted in FDAs draft guidance for industry Safety Considerations for Container 
Labels and Carton Labeling Design to Minimize Medication Errors, when applying color, 
applicants should ensure that the text highlighted by the color has adequate color contrast 
against the background color.63  In addition, [c]olor differentiation is most effective when the 
color used has no association with a particular feature and there is no pattern in the application of 
the color scheme.64   
 
C.  Labeling Format 
 
FDA requests that labeling be submitted in Microsoft Word, Structured Product Labeling (SPL), 
and text-based portable document format (PDF) files.65  Labeling submitted in PDF format 
should be text based, not scanned, to enable the use of search and compare functions.  Applicants 
should also ensure consistency in the content between their different formats (i.e., in their 
Microsoft Word, SPL, and text-based PDF files).  If the text of the labeling differs in any of the 
three requested formats, applicants may be asked to resubmit their labeling for assessment.   
 
D.  Parenteral Drug Products 
 
1.  Package Type    
 
Generally, labeling indicating the package type (i.e., single-dose, multiple-dose, or single-
patient-use) for ANDAs of parenteral drug products must be the same as the labeling indicating 
the RLDs package type.66  For example, if the RLD is appropriately labeled and packaged in a 
single-dose, the ANDA should also be labeled and packaged in a single-dose. 
 
Applicants have proposed package types for parenteral drug products that differ from those 
approved for the RLD (e.g., an applicant proposed a single-dose vial when the RLD is packaged 
in a multi-dose vial), which resulted in a deficiency. 
 
2.  Product Strength 
 
A parenteral drug products strength is critically important information that should be clearly 
displayed and correctly expressed on the container label to avoid dosing errors, among other 
reasons.  Overdoses have occurred with small-volume parenterals because of end-user failure to 
determine the total amount of the drug product in the container.  As described in FDAs draft 
 
63 FDA draft guidance for industry Safety Considerations for Container Labels and Carton Labeling Design to 
Minimize Medication Errors (April 2013), at 8.  When final, this guidance will represent FDAs current thinking on 
this topic. 
64 Id.  
65 FDA guidance for industry ANDA Submissions  Content and Format of Abbreviated New Drug Applications 
(June 2019). 
66 Section 505(j)(2)(A)(v) of the FD&C Act and 21 CFR 314.94(a)(8)(iv). 
  11  Contains Nonbinding Recommendations 
 
guidance for industry Safety Considerations for Container Labels and Carton Labeling Design to 
Minimize Medication Errors,  
 
[i]n most cases, the user noticed the concentration (e.g., 10 [milligrams] (mg)/[milliliter] 
(mL)) but failed to see the net quantity (e.g., 10 mL), which often appears in a different 
location on the container label.  This confusion has led to administration of the entire 
contents of the container, when only a portion of the total volume was needed.67 
 
To avoid confusion, the strength per total volume should be the primary and prominent 
expression on the principal display panel of the label, followed in close proximity by strength per 
milliliter enclosed by parentheses. 68  The following format has been found acceptable:69   
 
500 mg/10 mL  
(50 mg/mL) 
 
3.  Ferrules and Cap Overseals  
 
The ferrules and cap overseals of injectable drug products should clearly and concisely convey 
cautionary statements that will help prevent imminent, life-threatening situations.70  In particular, 
FDA recommends that the text on ferrules and cap overseals either be limited to important 
safety messages critical for the prevention of imminent, life-threatening situations or remain 
blank.71  An example of such a statement is Warning-Paralyzing Agent.  Applicants should 
refer to the FDA draft guidance for industry Safety Considerations for Container Labels and 
Carton Labeling Design to Minimize Medication Errors (April 2013) for further 
recommendations.72  
 
In some instances, applicants have submitted proposed labeling for ANDAs covering drug 
products with integrated ferrules and cap overseals that does not convey safety information 
critical for the prevention of imminent, life-threatening situations.  In other instances, applicants 
have proposed labeling containing information on ferrules and cap overseals that is not 
recommended for certain drug products (e.g., some proposed ferrules and cap overseals of 
injectable drug products have displayed lot numbers, logos, or product names).  Applicants 
should consider the appropriateness of including or excluding such information for drug products 
with integrated ferrules or cap overseals because this inclusion or exclusion may impact the 
approvability of a particular application.  
 
 
67 FDA draft guidance for industry Safety Considerations for Container Labels and Carton Labeling Design to 
Minimize Medication Errors (April 2013), at 11. 
68 Id. 
69 Id. 
70 Id. at 17; see also U.S. Pharmacopeia General Chapter <7>. 
71 FDA draft guidance for industry Safety Considerations for Container Labels and Carton Labeling Design to 
Minimize Medication Errors (April 2013), at 17. 
72 See also U.S. Pharmacopeia General Chapter <7>. 
  12  Contains Nonbinding Recommendations 
 
In addition, FDA recommends that applicants state in Module 3.2.P.7 of their ANDA submission 
whether text appears on the ferrule and cap overseal and, if so, what the text is.73  Applicants 
should also indicate the color of the ferrule and cap overseal and ensure that the color black, 
which is to be used only with potassium chloride injectable products,74 is not used for other drug 
products. 
 
V.  PRODUCT QUALITY DEFICIENCIES 
 
A.  Drug Substance 
 
Applicants are required to submit data and information in their ANDAs about the drug 
substance(s) in their proposed drug products.75  To satisfy this requirement, FDA regulations 
permit applicants either to provide this information directly in their ANDA or to reference a drug 
master file (DMF) in their ANDA.76  Specifically, in their ANDA, applicants may choose to 
either (1) include all sections of Module 3.2.S.2 or (2) reference a DMF, which should contain 
the same information that would have been provided by the applicant in Module 3.2.S.2.   
 
Changes made to a DMF referenced in an ANDA that may impact the safety, efficacy, quality, or 
substitutability of the drug product may be considered unsolicited amendments to the ANDA and 
therefore may extend existing GDUFA review goals or create new review goals.77  It is 
important for applicants to be aware of when amendments will be submitted to the DMF because 
these amendments may affect the adequacy of the DMF to support approval of the ANDA. 
 
The recommendations in this section apply both to DMF holders and applicants that submit all of 
the drug substance information directly to their application in Module 3.2.S.2 instead of 
referencing the information in a DMF. In such cases, the term DMF holder should be 
interpreted as applicant. 
      
1.  Active Pharmaceutical Ingredient Starting Material 
 
In Module 3.2.S.2, DMF holders78 should include information on the control of materials used in 
the manufacture of the drug substance and provide a justification for the starting material 
 
73 See FDA guidance for industry ANDA Submissions  Content and Format of Abbreviated New Drug 
Applications (June 2019), at 25.   
74 See U.S. Pharmacopeia General Chapter <7>. 
75 21 CFR 314.94(a)(5). 
76 Id.; 21 CFR 314.420(b). 
77 FDA guidance for industry ANDA Submissions  Amendments to Abbreviated New Drug Applications Under 
GDUFA (July 2018).   
78 As noted above, the recommendations in section V.A of this guidance also apply to applicants that submit all of 
the drug substance information directly to their application in Module 3.2.S.2 instead of referencing the information 
in a DMF. 
  13  Contains Nonbinding Recommendations 
 
selection for the process.  Often, the designated starting material is a late-stage intermediate, and 
DMF holders fail to include: 
  The route of synthesis to the proposed starting material to support the starting material 
specification (i.e., the impurity control) 
 
  A discussion on the fate and purge of the potential impurities arising from the starting 
material manufacturing process (this information can also be in Module 3.2.S.3.2) 
 
  The carry-over studies of reagents/solvents into the final active pharmaceutical ingredient 
(API) (this information can also be in Module 3.2.S.3.2)79 
 
  A demonstration of the suitability of analytical methods used to detect impurities in the 
starting material80 
  
Without this information, FDA cannot assess the starting material selection and its impact on 
both the manufacturing process and the final drug substance quality. 
FDA recommends that DMF holders provide sufficient information, in Module 3.2.S.2, on their 
API starting material, including the information described above.  For recommendations on the 
justification and selection of starting materials, DMF holders should review the International 
Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human 
Use (ICH) guidances for industry Q11 and ICH Q11 Development and Manufacture of Drug 
Substances Questions and Answers (February 2018) (ICH Q11 Q&A).     
 
2.  API Manufacturing Process 
 
DMF holders should fully describe their API manufacturing process, but they have commonly 
failed to include the following information as part of a complete description of the API 
manufacturing process:    
 
  A detailed synthetic scheme 
  The molar ratios of starting materials/reagents 
  The reaction conditions (e.g., time and temperatures) 
  A flow chart of the manufacturing process 
  The batch size for each step (i.e., input/output of materials) 
  The batch blending or mixing operations 
  The recovered solvents, reprocessing, and reworking (when applicable) 
 
79 International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for 
Human Use guidance for industry Q11 Development and Manufacture of Drug Substances (November 2012), at 6.1 
(ICH Q11).  ICH guidances for industry can be found on the FDA Drugs guidance web page 
at https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs. 
80 Id. at 5.2.1. 
  14  Contains Nonbinding Recommendations 
 
  Data demonstrating the consistent manufacture of the claimed polymorphic form (e.g., x-
ray powder diffraction (XRD), Fourier-transform infrared spectroscopy (FT-IR), 
differential scanning calorimetry (DSC), melting point)81  
 
FDA recommends that DMF holders provide complete information in Module 3.2.S.2.2 on their 
API manufacturing process, including, as applicable, the information discussed above.  DMF 
holders should include a flow chart for every stage, and if the API is synthetic or semisynthetic, 
they should provide a complete synthetic scheme from the appropriately supported starting 
materials.82   
 
3.  Impurities 
 
a.  API characterization information 
 
DMF holders should include characterization information for the API, including information on 
all potential impurities.  In some cases, however, DMF holders have failed to provide 
information on the identification and purge of impurities (i.e., process impurities and 
degradants), including those with mutagenic potential.83  
 
DMF holders should include a discussion of impurities in Modules 3.2.S.2 and 3.2.S.3.  For 
information on the limits for potentially genotoxic impurities, FDA recommends that DMF 
holders refer to ICH M7 and carefully assess and consider all of the control options outlined in 
ICH M7. 
  
b.  Safety assessment of mutagenic potential for actual and potential 
impurities  
 
The impurity profile of a proposed generic drug should not pose a greater mutagenic risk than the 
RLD.  DMF holders should provide an assessment of the actual and potential mutagenic 
impurities resulting from synthesis or degradation of the drug substance and discuss the 
corresponding control strategy as outlined in ICH M7.  The bulleted list below describes (1) 
information DMF holders have commonly failed to include about their evaluation of actual and 
potential genotoxic impurities, and, when appropriate, (2) FDAs recommendations on 
conducting these evaluations: 
 
  An assessment of potential and actual impurities with a risk assessment and a follow-up 
evaluation of mutagenicity at the time of the ANDA submission.  For impurities that 
require an evaluation of the mutagenic potential, a hazard assessment should initially 
include conducting either (1) literature and database searches on the carcinogenicity and 
 
81 In addition to Module 3.2.S.2.2, this information can also appear in Modules 3.2.S.4.4, 3.2.S.3.1, and/or the 
stability sections. 
82 See FDA guidance for industry Completeness Assessments for Type II API DMFs Under GDUFA (October 2017), 
at 11; see also ICH Q11 and ICH Q11 Q&A. 
83 See ICH guidance for industry M7 Assessment and Control of DNA Reactive (Mutagenic) Impurities in 
Pharmaceuticals to Limit Potential Carcinogenic Risk (March 2018) (ICH M7). 
  15  Contains Nonbinding Recommendations 
 
bacterial mutagenicity potential or (2) Quantitative Structure-Activity Relationship 
((Q)SAR) and Structure Activity Relationship studies.  Failure to include a full 
evaluation of potential mutagenic risk at the time of the ANDA submission can disrupt 
the review process and prevent the timely assessment of the ANDA.   
  Appropriate spike/purge or purging factor studies performed in a manner representative 
of the commercial process, with a corresponding fit-for-purpose analytical method to 
support Options 3-4 described in ICH M7.84 
  A (Q)SAR evaluation that includes both an expert-based and a statistical-based model for 
bacterial mutagenicity prediction.  (DMF holders have supplied a single model or used 
models without submitting sufficient information on their validation.)  DMF holders 
should submit full study reports for in silico predictions.85   
  An appropriately conducted in vitro bacterial reverse mutation assay to address a positive 
prediction by a (Q)SAR analysis.  For these assays, DMF holders should (1) test neat 
impurities; (2) test concentrations up to 5,000 micrograms/plate, unless limited by 
precipitation or cytotoxicity; and (3) if a top dose in an in vitro bacterial reverse 
mutagenicity assay is limited because an impurity is unstable or difficult to synthesize, 
DMF holders should provide a well-documented scientific justification demonstrating 
due diligence to synthesize the impurity.86   
4.  Specifications for Isolated Intermediates 
 
DMF holders should justify their specification for isolated intermediates so that FDA assessors 
can understand why the DMF holder set that specification.  The justification should focus on 
how the impurity specifications for the intermediates were chosen, particularly if that was the 
only point in the process where a particular impurity was controlled.  If the DMF holder did not 
isolate an intermediate, it should explain why that was a reasonable choice.  FDA also 
recommends that DMF holders review the FDA guidance for industry Completeness Assessments 
for Type II API DMFs Under GDUFA (October 2017), which makes recommendations about the 
information on intermediates that should be included in a DMF.  
 
5.  Justification of the API Specification  
 
 
84 As described in ICH M7: (1) under Option 3, the DMF holder controls potentially genotoxic impurities upstream 
at higher than the threshold of toxicological concern with spike/purge data to less than 30% of that threshold and (2) 
under Option 4, the DMF holder does not use a control based on high chemical reactivity, solubility, and proven 
process-purging capability. 
85 For additional information, see Amberg, A, L Beilke, and J Bercu, et al., 2016, Principles and Procedures for 
Implementation of ICH M7 Recommended (Q)SAR Analyses, Regul Toxicol Pharmacol, 77:1324; Barber, C, A 
Amberg, and L Custer, et al., 2015, Establishing Best Practise in the Application of Expert Review of Mutagenicity 
Under ICH M7, Regul Toxicol Pharmacol, 73:367377. 
86 ICH M7; ICH guidance for industry S2(R1) Genotoxicity Testing and Data Interpretation for Pharmaceuticals 
Intended for Human Use (June 2012); and OECD Guidelines for Testing of Chemicals, Section 4:  Health Effects, 
available at http://www.oecd-ilibrary.org/environment/test-no-471-bacterial-reverse-mutation-test_9789264071247-
en.   
  16  Contains Nonbinding Recommendations 
 
Tests for Critical Quality Attributes (CQAs) should be included in the drug substance 
specifications, but DMF holders have failed to demonstrate a clear rationale that includes CQAs 
when establishing drug substance specifications.  DMF holders should follow the ICH limits or 
justify their proposed limits for the existing tests (i.e., the limits for impurities, including the 
residual solvents). 
 
FDA recommends that DMF holders set appropriate limits based on ICH guidances for 
industry87 and include a complete justification and the necessary information for qualification of 
the limits when they exceed ICH recommendations, as explained in the FDA guidance for 
industry ANDAs:  Impurities in Drug Substances (July 2009).  
 
B.  Drug Product 
 
1.  Establishing Critical Quality Attributes 
  
CQAs describe product characteristics that are chosen to demonstrate that any given drug 
product is of sufficient quality to ensure that drug products safety and effectiveness.  Failure to 
establish appropriate CQAs of the proposed generic drug product (including meaningful ranges 
or limits) may lead to a determination that the ANDA cannot be approved.88 
 
FDA recommends that applicants evaluate their drug products using (1) the general and dosage 
form-specific recommendations for the relevant characteristics and testing described in the ICH 
guidance for industry Q6A Specifications:  Test Procedures and Acceptance Criteria for New 
Drug Substances and New Drug Products:  Chemical Substances (December 2000) (ICH Q6A) 
and (2) the recommendations on quality target product profiles and CQAs in the ICH guidance 
for industry Q8(R2) Pharmaceutical Development (November 2009).  In their ANDA, applicants 
should include information developed from their use of these two ICH guidances for industry to 
support their selection of and rationale for CQAs. 
 
2.  Impurities:  Identification, Control, and Qualification 
 
a.  Identifying and controlling impurities  
Applicants identification and control of impurities are important aspects in ensuring the safety 
of the drug product.  When applicants have used inadequate approaches for generating and 
identifying impurities and have failed to provide an appropriate rationale for their acceptance 
criteria for impurities, FDA has refused to approve their ANDA.89 
 
To develop acceptance criteria for impurities in generic drug products, FDA recommends that 
applicants refer to the FDA guidance for industry ANDAs:  Impurities in Drug Products 
 
87 ICH guidances for industry Q3A Impurities in New Drug Substances (June 2008) (Q3A), Q3C Impurities:  
Residual Solvents (December 1997) (ICH Q3C), Q3D Elemental Impurities (September 2015) (ICH Q3D), and ICH 
M7. 
88 See, e.g., section 505(j)(4)(A) of the FD&C Act. 
89 Id. 
  17  Contains Nonbinding Recommendations 
 
(November 2010); the FDA guidance for industry Elemental Impurities in Drug Products 
(August 2018); the ICH guidance for industry Q3B(R2) Impurities in New Drug Products (July 
2006) (ICH Q3B(R2)), ICH Q3C, ICH Q3D, and ICH M7. 
 
b.  Safety qualification of impurities in drug substances or drug products that 
exceed relevant qualification thresholds  
Generic drug formulations are expected to have the same safety profile as the RLD.90  Applicants 
may qualify drug substance degradants or drug product impurities either by using a comparative 
impurity analysis with the RLD91 or by submitting a safety justification for these impurities if 
they exceed the relevant qualification thresholds.92  A safety justification for impurities that 
exceed the relevant qualification thresholds should include an assessment of both genetic 
toxicology and general toxicity (14- to 90-day) in a single species.  Below is information that 
applicants should include in their application but have commonly failed to include:   
 
  Applicants should provide general toxicity information to qualify their impurity.  
Applicants have submitted (Q)SAR evaluations to predict general toxicity, but their in 
silico predictions have not been validated for the endpoints of a general toxicity study.  
To address this, applicants should submit either safety information such as a repeat-dose 
general toxicology study or published literature to characterize the safety of the impurity 
for the intended route of administration.   
  When providing a justification that an impurity is a metabolite, applicants should provide 
qualitative and quantitative information to support this justification.  Applicants have 
submitted qualitative information that an impurity is a metabolite but failed to provide 
quantitative data to demonstrate the relevant systemic exposure to the proposed impurity 
level.  Applicants should provide quantitative information (e.g., plasma levels of the 
metabolite in animals and humans at the maximum daily dose or the exposure levels in 
animals that equals or exceeds the proposed clinical exposure levels) to demonstrate that 
the systemic exposure is at such a level to qualify the proposed level of the impurity.   
  Applicants should provide full articles of the publications that are cited in their 
justification to facilitate a complete assessment of their ANDA. 
Applicants should submit nonclinical information to Module 4 of their submission.  Applicants 
that submit a justification for the safety of their impurities should also include references and 
hyperlinks between related topics in the quality module (Module 3) and the nonclinical safety 
module (Module 4). 
 
90 See, e.g., 21 CFR 314.3(b) (defining therapeutic equivalents as approved drugs products that are 
pharmaceutical equivalents for which bioequivalence has been demonstrated, and that can be expected to have the 
same clinical effect and safety profile when administered to patients under the conditions specified in the labeling).  
An approved ANDA and its RLD are therapeutic equivalents, unless the ANDA was approved pursuant to an 
approved suitability petition (see section 505(j)(2)(C) of the FD&C Act and 21 CFR 314.93). 
91 FDA guidances for industry ANDAs:  Impurities in Drug Substances (July 2009) and ANDAs:  Impurities in Drug 
Products (November 2010). 
92 ICH Q3A; ICH Q3B(R2). 
  18  Contains Nonbinding Recommendations 
 
 
3.  Inactive Ingredients  
 
a.  Justification by reference to the Inactive Ingredient Database 
Unless otherwise specified in 21 CFR 314.94(a)(9)(iii) through (v), applicants must identify and 
characterize the inactive ingredients in their proposed drug product and provide information 
demonstrating that these inactive ingredients do not affect the safety or efficacy of that product.93  
The quantity of an inactive ingredient in a given formulation may be acceptable based on prior 
determinations by FDA of the safety of that inactive ingredient in FDA-approved products.  
However, applicants have sought approval for formulations that contain amounts of inactive 
ingredients at levels higher than the previously approved maximums listed in the Agencys 
Inactive Ingredient Database (IID)94 without providing a justification for exceeding those 
previously approved maximum levels. 
 
FDA recommends that applicants (1) refer to the IID to determine the maximum level of an 
inactive ingredient in previously approved drug products with the same route of administration 
and not exceed that level or (2) submit controlled correspondence to the Agency requesting 
information on whether the use of a particular inactive ingredient is acceptable in an ANDA if it 
is higher than the maximum shown as previously approved in the IID.95  Applicants should 
provide an adequate justification to the Agency regarding the safety of that inactive ingredient if 
the amount exceeds the maximum level previously approved as indicated in the IID for the 
proposed route of administration (see subsection (b) immediately below).   
 
    b.  Justification of the safety of inactive ingredients in generic drug products  
      that exceed the maximum level in the IID 
 
A generic drug formulation should include inactive ingredients that have a well-defined safety 
profile for the proposed context of use (i.e., dose, route of administration, duration of use, and 
patient population) and maintain the same safety profile as the RLD.  Thus, applicants should 
provide a safety justification for inactive ingredients that exceed FDA-approved levels for the 
route of administration as reflected in the IID.  Below is information that applicants should 
include in a safety justification for inactive ingredients that exceed FDA-approved levels: 
 
  Applicants should provide a justification to demonstrate that an inactive ingredient is safe 
for the proposed context of use (i.e., dose, route of administration, duration of use, and 
patient population).  Applicants have submitted justifications that fail to address context-
specific information that is necessary to evaluate the safety of a proposed dose, route of 
administration, or duration of use for an inactive ingredient in a specific patient 
 
93 21 CFR 314.94(a)(9)(ii). 
94 FDAs IID is available at https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm.  See also FDAs draft 
guidance for industry Using the Inactive Ingredient Database (July 2019). When final, this guidance will represent 
the FDAs current thinking on this topic. 
95 See FDA guidance for industry Controlled Correspondence Related to Generic Drug Development (December 
2020) at 11.     
  19  Contains Nonbinding Recommendations 
 
population.  Additionally, applicants have proposed inactive ingredients without a well-
established safety profile, which has led to FDAs refusal to approve the ANDA.96  
Generic drug formulations do not undergo clinical safety studies during ANDA 
development, so inactive ingredients without an established safety profile should not be 
included in a generic drug formulation.   
  Applicants should provide a complete account of the composition of complex mixtures of 
inactive ingredients (e.g., flavors and fragrances)  including the mixtures individual 
components and quantities  in either the ANDA or by referencing a DMF.  Applicants 
should identify each component of a complex mixture, including its synonyms, the 
Chemical Abstracts Service Number, and any applicable citations to the Code of Federal 
Regulations that are relevant to its proposed use.  In addition, applicants should include 
safety information for each component, including a history of the components prior use 
and safety profile (i.e., the components general safety and genetic toxicity).  
  Applicants should provide a justification supporting the safety of a proposed inactive 
ingredient grade when relying on the established safety information from a similar grade 
of inactive ingredient.97  The grades of an inactive ingredient may have different 
manufacturing processes, impurity profiles, and chemical or physical characteristics.  
Because these factors may result in different safety profiles for each grade of inactive 
ingredient, sufficient details should be provided so that FDA can identify the proposed 
inactive ingredient grade and determine whether similarities or differences between 
grades may affect safety.   
4.  Validating Analytical Methods  
 
Analytical methods that applicants use for the analysis of drug products should be validated by 
the applicant to determine if these methods are suitable for such use.  However, applicants have 
failed to appropriately validate their analytical methods, which has led to incorrect results and 
incorrect conclusions about the drug product quality because the analytical methods were not 
specific, accurate, or precise.  This failure has contributed to FDAs refusal to approve the 
ANDAs.98   
 
FDA recommends that applicants (1) refer to the ICH guidance for industry Q2(R1) Validation of 
Analytical Procedures:  Text and Methodology (March 1995) to identify the appropriate 
validation of the analytical methods used in their drug product analysis and (2) provide method 
validation reports in their application.    
 
C.  In Vitro Dissolution (Biopharmaceutics) 
 
 
96 See, e.g., section 505(j)(4)(H) of the FD&C Act. 
97 See FDA guidance for industry Nonclinical Studies for the Safety Evaluation of Pharmaceutical Excipients (May 
2005). 
98 See, e.g., section 505(j)(4)(A) of the FD&C Act. 
  20  Contains Nonbinding Recommendations 
 
1.  Development and Validation of an In-House Dissolution Testing Method 
When Dissolution Testing Cannot Be Standardized  
 
It is critical that applicants submit a complete method development and validation report when 
an in-house dissolution testing method is used.99  Below is information that should be included in 
the dissolution method development and validation report but applicants have commonly 
omitted: 
 
  Solubility data for the drug substance over the physiologic pH range 
 
  A detailed description of both the dissolution test being proposed for the evaluation of the 
product and the developmental parameters used to select the proposed dissolution method  
 
  Data (with appropriate statistics, e.g., sample size, defined variable(s), and testing of 
meaningful changes within the design space) to support the discriminating ability of the 
selected dissolution method related to the critical material attributes and critical process 
parameters   
 
  Complete dissolution data (i.e., individual (n=12), mean, range, and percent relative 
standard deviation at each time point and mean profiles) and detailed information for all 
strengths of the generic drug product and the reference product (e.g., the batch/lot 
number, manufacturing date, manufacturing site, testing date, and batch size) in Module 
2.7.1   
 
  Supportive validation data for the dissolution method (e.g., method robustness and 
method transfer) and analytical method (e.g., specificity, precision, accuracy, linearity, 
and stability) 
 
FDA recommends that applicants include a summary of the in vitro dissolution development in 
Module 3.2.P.2.2.3 with a cross-reference to studies in Module 5, as appropriate.  A justification 
for the dissolution specification should be included in Module 3.2.P.5.6.  FDA also recommends 
that applicants refer to the U.S. Pharmacopeia (USP) General Chapter <1092> and certain FDA 
guidances for industry100 that provide general guidelines on the development and validation of 
dissolution procedures.   
 
2.  Dissolution Acceptance Criteria 
 
The specification for solid oral dosage forms normally includes a test to measure the in vitro 
release of a drug substance from the drug product.  Applicants should provide a justification for 
the in vitro release specification (i.e., the dissolution method and acceptance criteria) that is 
reflective of the dissolution data from the representative batch that underwent in vivo BE testing 
 
99 Id. 
100 See FDA guidances for industry Dissolution Testing of Immediate Release Solid Oral Dosage Forms (August 
1997) and Dissolution Testing and Acceptance Criteria for Immediate-Release Solid Oral Dosage Form Drug 
Products Containing High Solubility Drug Substances (August 2018).   
  21  Contains Nonbinding Recommendations 
 
(bio-batch) and supported by exhibit and registration batches that were included for stability.101  
Below is information that should be included in the selection of dissolution acceptance criteria: 
 
Immediate-release solid oral dosage forms: 
 
  A single-point acceptance criterion where Q=80%102 dissolution occurs103  
 
  The setting of the dissolution acceptance criterion, which is drug product specific and 
based on USP Level 2 testing (n=12) (understanding that Level 2 testing and Level 
3104 testing may be needed) 
 
  Support for a wider (i.e., more permissive) dissolution specification with an approved 
in vitro/in vivo correlation model, a physiologically based absorption and 
pharmacokinetic model, or a clinically relevant justification 
 
Modified-release solid oral dosage forms: 
 
  Acceptance criteria time points that cover the early, middle, and late stages of the 
release profile for extended-release products 
 
  Dissolution acceptance criteria range recommendations that are based on (1) a mean 
target value 10% at any given time point and (2) >80% for the last specification time 
point  
 
  Support for a wider (i.e., more permissive) dissolution specification with an approved 
in vitro/in vivo correlation model, a physiologically based absorption and 
pharmacokinetic model, or a clinically relevant justification 
 
  A two-stage testing approach for delayed-release dosage forms 
 
Applicants should provide a justification for the in vitro release specification in Module 
3.2.P.5.6.  Applicants should also refer to certain FDA guidances for industry105 and ICH 
guidance for industry106 that provide general guidelines for dissolution specification settings.  In 
addition, the applicants dissolution specification should not only confirm adequate formulation 
 
101 FDA guidance for industry ANDAs:  Stability Testing of Drug Substances and Products (June 2013). 
102 USP General Chapter <711> defines the quantity, Q, as the amount of dissolved active ingredient specified in 
the individual monograph, expressed as a percentage of the labeled content of the dosage unit.    
103 Other criteria may be acceptable with adequate justification. 
104 USP General Chapter <711>.  
105 See FDA guidances for industry Extended Release Oral Dosage Forms:  Development, Evaluation, and 
Application of In Vitro/In Vivo Correlations (September 1997) and Dissolution Testing of Immediate Release Solid 
Oral Dosage Forms (August 1997). 
106 ICH guidance for industry Q6A.   
  22  Contains Nonbinding Recommendations 
 
and process controls but also, when appropriate, ensure consistent in vivo performance to the 
bio-batch. 
 
D.  Facilities  
 
1.  Identification of Manufacturing Facilities 
 
Applicants should provide information on their manufacturing facilities both in their Form FDA 
356h and in the appropriate module within the application.  However, applicants have not 
consistently provided (1) complete manufacturing facility information in their Form FDA 356h 
and (2) manufacturing facility information in the correct modules within their application, both 
of which have made this information not readily accessible to Agency reviewers and led to 
FDAs refusal to approve the ANDAs.107   
 
For original (initial) applications . . . CMC supplements, and resubmissions to these submission 
types, applicants should include complete information on the locations of all manufacturing, 
packaging, and control sites for both [the] drug substance and [the] drug product in Form FDA 
356h (i.e., the facility information that is listed in Modules 3.2.S.2 and 3.2.P.3.1).108  Form FDA 
356h should include information on:109  
 
  All drug product (in-process material and final) manufacturing and testing sites  
including the stability testing, primary packaging, and labeling sites  that are proposed 
to be involved in the commercial manufacture of the drug product110   
 
  All intermediate (i.e., performing operations governed by the ICH guidance for industry 
Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients 
(September 2016)) and final drug substance manufacturing and testing sites, including the 
sterilization and micronization sites, that are proposed to be involved in the commercial 
manufacture of the drug substance 
 
  For combination products,111 all manufacturing sites112 for the non-lead constituent part 
of the combination product, including any separate sites responsible for design activities, 
that are proposed to be involved in the commercial manufacture of the finished product  
 
 
107 See, e.g., section 505(j)(4)(A) of the FD&C Act. 
108 Instructions for Filling out Form 356h  Application to Market a New or Abbreviated New Drug or Biologic for 
Human Use, available at https://www.fda.gov/about-fda/reports-manuals-forms/forms. 
109 See 21 CFR 314.50. 
110 FDA does not recommend listing facilities (1) that have not performed any functions or (2) for which a 
technology transfer of data has not occurred. 
111 See 21 CFR 3.2(e). 
112 See 21 CFR 4. 
  23  Contains Nonbinding Recommendations 
 
  All current good manufacturing practice (CGMP) storage and warehousing facilities 
under the control of the drug manufacturers Quality Management System involved in the 
manufacture of the drug product  
 
Applicants do not need to list bioequivalence testing sites, excipient testing sites, and 
container/closure manufacturing and testing establishments on their Form FDA 356h.113 
 
Module 3.2.S.2 should include all manufacturing facilities that are listed on Form FDA 356h as 
well as all research and development manufacturing and testing sites that generated data to 
support the application in accordance with 21 CFR 314.50(d)(1)(ii)(b).  This module should also 
include any testing sites that generate stability testing or release data to support the application as 
well as the testing sites for the planned commercial testing.   
 
2.  Readiness for Inspection 
 
All manufacturing facilities should be ready for inspection at the time of the ANDA submission, 
and applicants should indicate whether each site is ready for inspection on their Form FDA 356h.  
In the past, applicants have specified on Form FDA 356h that a manufacturing facility was ready 
for inspection, but once FDA was ready to commence inspection, the manufacturing facility 
indicated it was not ready for this inspection, which has led to FDAs refusal to approve the 
ANDAs.114 
 
If there are extenuating circumstances that prevent a facility from being ready for inspection, 
applicants should indicate this on Form FDA 356h.  FDA considers it a good business practice 
for applicants to regularly communicate with manufacturing facilities, including contract 
manufacturing facilities, about changes in their inspection status to prevent any problems that 
may delay approval of their application. 
 
3.  Selection of Contract Manufacturing Facilities and CGMPs 
 
Applicants should consider several factors in selecting suitable contract manufacturing facilities, 
including their manufacturing capability for the product and compliance with CGMPs.  In the 
application, applicants should certify that contract manufacturing facilities are compliant with 
CGMPs.115  FDA has observed that applicants have certified that contract manufacturing 
facilities are CGMP compliant, but upon assessment or inspection, FDA determined that they 
were not compliant at the time of the ANDA submission, which caused the ANDA to not be 
approved.  
 
FDA recommends that applicants and contract manufacturing facilities clearly define the CGMP-
related roles and manufacturing operations and activities of each of the parties in a quality 
 
113 Instructions for Filling out Form FDA 356h  Application to Market a New or Abbreviated New Drug or 
Biologic for Human Use (08/18 edition), at Field 28: Establishment Information. 
114 See, e.g., section 505(j)(4)(A) of the FD&C Act; 21 CFR 314.127. 
115 Section 505(j)(4)(A) of the FD&C Act; see also FDA guidance for industry ANDA Submissions  Content and 
Format of Abbreviated New Drug Applications (June 2019).   
  24  Contains Nonbinding Recommendations 
 
agreement.116  A quality agreement should clearly describe the materials or services to be 
provided, quality specifications, and communication mechanisms between the applicant and the 
contract manufacturing facility.   
 
E.  Commercial Manufacturing Process  
 
Applicants should provide  in Modules 3.2.P.2, 3.2.P.3, and 3.2.R  both details of the 
commercial manufacturing process and information to support the use of that particular process.  
These details and information help FDA determine whether applicants are ready to commercially 
manufacture a drug product.  However, applicants often provide inconsistent, inaccurate, or 
incomplete information in these modules, which has led to FDAs refusal to approve the 
ANDA.117  Below is information that should be included in these modules: 
 
  Applicants should provide, in Module 3.2.P.2, a justification for their process selection 
that relies on established scientific principles to identify potential risks to their 
manufacturing process.  This justification should include batch data (from the exhibit 
and/or development batches) that demonstrate that any risks to the manufacturing process 
are adequately mitigated.  Applicants should also include a discussion of their risk 
mitigation approaches and explain any differences between the exhibit and commercial 
batches regarding their manufacturing processes and in-process controls. 
 
  Applicants should demonstrate that their proposed control strategy will ensure that the 
quality of the intermediate critical material attributes will remain unchanged across the 
exhibit and commercial batches.  Applicants should clearly identify and justify, in 
Module 3.2.P.3.4, the in-process controls utilized in the exhibit and commercial batch 
manufacturing processes. 
 
  The commercial batch formula identified in Module 3.2.P.3.2 should (1) reflect the unit 
dose composition identified in Module 3.2.P.1 and (2) clearly identify and justify any 
overage and overfill used.  Applicants should provide a table comparing the quantity and 
the quality standard of each ingredient, including any solvents removed during the 
process, used in the exhibit and commercial batches.118 
 
  Applicants should demonstrate a readiness for the commercial scale manufacture of the 
drug product by providing the set points and ranges of the commercial scale process 
parameters in the commercial equipment.  Applicants should also clearly identify and 
justify, in Module 3.2.P.3, any differences in the equipment used for the exhibit and 
commercial batches, as well as provide process parameters that are (1) scaled-up using 
established principles, (2) supported by process development data, and (3) specified (i.e., 
 
116 FDA guidance for industry Contract Manufacturing Arrangements for Drugs:  Quality Agreements (November 
2016).  
117 See, e.g., section 505(j)(4)(A) of the FD&C Act. 
118 Please note that FDA may request the manufacture of a new batch if there are inappropriate overages, overfills, 
or composition differences in the exhibit and commercial batches. 
  25  Contains Nonbinding Recommendations 
 
To Be Determined should not be used) and not open-ended (e.g., no more than 200 
revolutions per minute). 
 
  Applicants should use a table, in Module 3.2.P.3.3, to submit the hold times and hold 
conditions of the intermediates and bulk drug products used in the commercial process.119 
 
  For each executed batch record provided in Module 3.2.R, applicants should clearly 
specify the batch usage (e.g., development and stability).  In particular, the batch used for 
BE testing should be noted along with the BE study identifier.     
 
F.  Microbiology Considerations  
 
1.  In-Process Bioburden Testing and Acceptance Criteria 
 
An ANDA for an aseptically processed generic drug product should contain in-process 
acceptance criteria for the total number of microorganisms associated with the unfiltered bulk 
drug solution prior to its sterilization (bioburden) because the bioburden can contribute 
impurities (e.g., endotoxin) to, and lead to degradation of, the drug product.120  Applicants have 
commonly submitted ANDAs for drug products without providing bioburden testing and in-
process bioburden acceptance criteria for the bulk drug solution prior to any filtration, which has 
led to FDAs refusal to approve the ANDAs.121 
 
As described in the guidances for industry For the Submission of Documentation for Sterilization 
Process Validation in Applications for Human and Veterinary Drug Products (November 1994) 
and Sterile Drug Products Produced by Aseptic Processing  Current Good Manufacturing 
Practice (September 2004), FDA recommends that applicants both establish a prefiltration 
bioburden acceptance criteria and design manufacturing process controls to minimize the 
bioburden in the bulk drug solution prior to sterilization.  
 
2.  Description and Validation of Bacterial Endotoxins Test Method 
 
An application for a parenteral generic drug product requiring a product endotoxin specification 
should contain both a description and validation of the bacterial endotoxins test method used.  
However, applicants have submitted ANDAs for parenteral generic drug products with a product 
endotoxin specification that have not described the bacterial endotoxins test method used, 
including the sample preparation and routine test dilution.  Without this test method description, 
 
119 Please note that Module 3.2.P.3.4 should contain the controls of the critical steps and intermediates, including: 
(1) the acceptance criteria and test results for the exhibit batch(es), (2) a comparison of the controls and equipment 
between the exhibit and commercial batch manufacture, and (3) information about the holding periods. See FDA 
guidance for industry ANDA Submissions  Content and Format (June 2019), at 23. 
 
120 FDA guidance for industry Sterile Drug Products Produced by Aseptic Processing  Current Good 
Manufacturing Practice (September 2004), at 36.  For information regarding recommended microbiological controls 
during manufacture of PET drug products, refer to the FDA guidance for industry PET Drugs  Current Good 
Manufacturing Practice (CGMP) (December 2009). 
121 See, e.g., section 505(j)(4)(A) of the FD&C Act. 
  26  Contains Nonbinding Recommendations 
 
the Agency has been unable to determine whether the bacterial endotoxins method was 
adequately validated, which has led to FDAs refusal to approve the ANDAs.122  For the 
bacterial endotoxins method validation, applicants have not always accounted for the additional 
dilution that resulted from sample pooling in maximum valid dilution (MVD) calculations, 
which has again led to FDAs refusal to approve the ANDAs.123   
 
Applications for parenteral generic drug products requiring a product endotoxin specification 
should contain a description and validation of the endotoxins test method used,124 including any 
test sample pooling and dilution performed routinely for method validation.  In validating the 
chosen test method, applicants should understand that FDA generally accepts sample pooling for 
  
small-volume parenterals (those with volumes of 100 mL or less) as long as the 
MVD is adjusted to a proportional, lower value because of the potential for 
diluting a unit containing harmful levels of endotoxins with other units containing 
lower, less harmful, levels of endotoxins.  This adjusted MVD is obtained by 
dividing the MVD computed for an individual sample by the total number of 
samples to be pooled . . . .  If this reduction in MVD results in an inability to 
overcome product-related assay interference because of an insufficient dilution, 
then the samples should be tested individually.125 
 
3.  Microbiological Data to Support Extended Storage Times 
 
If the proposed generic drug product is sterile and the draft labeling contains instructions for 
extended post-constitution and/or post-dilution storage times for the drug product, then these 
storage times should be supported by microbiological data.  This data should demonstrate that 
the drug product does not support microbial growth from inadvertent contamination over the 
storage periods/conditions described in the labeling. 
 
FDA recommends that applications contain a summary of the microbiological study, including 
the challenge organisms and challenge titers, the product sample concentrations and storage 
conditions, the diluents tested, and a summary of the study results.  In addition, applicants should 
refer to FDAs Question-based Review (QbR) for Sterility Assurance of Terminally Sterilized 
Products: Quality Overall Summary Outline,126 Question-based Review (QbR) for Sterility 
Assurance of Terminally Sterilized Products:  Frequently Asked Questions,127 and Question-
 
122 See, e.g., section 505(j)(4)(A) of the FD&C Act. 
123 Id. 
124 FDA guidances for industry Pyrogen and Endotoxins Testing:  Questions and Answers (June 2012), at 4, and 
Submission Documentation for Sterilization Process Validation in Applications for Human and Veterinary Drug 
Products (November 1994), at 8. 
125 FDA guidance for industry Pyrogen and Endotoxins Testing:  Questions and Answers (June 2012), at 4. 
126 This document is available at https://www.fda.gov/media/81729/download. 
127 This document is available at https://www.fda.gov/media/81734/download.  
  27  Contains Nonbinding Recommendations 
 
based Review (QbR) for Sterility Assurance of Aseptically Processed Products:  Quality Overall 
Summary Outline.128 
 
VI.  BIOEQUIVALENCE DEFICIENCIES     
 
A.  Bioanalytical Study Data 
 
For FDA to determine whether a bioanalytical method is acceptable, it is critical for applicants to 
submit complete bioanalytical study reports and to validate bioanalytical methods used in their 
BE studies.  Below is information that should be included in an applications bioanalytical study 
report: 
 
  Complete dilution integrity data, stock stability data, and recovery data 
  Analytical raw data from the study runs (accepted and rejected) of all subjects  
  Serially selected chromatograms for 20% of the study subjects  
  Bioanalytical standard operating procedures used in the application  
 
FDA recommends that applicants submit complete bioanalytical reports and review the FDA 
guidance for industry Bioanalytical Method Validation (May 2018) to help ensure that applicants 
provide appropriate bioanalytical method validation data.  Providing complete bioanalytical 
study reports and bioanalytical methodology validation data will help ensure that FDA has the 
appropriate information to determine whether the method used was suitable and reliable.    
 
B.  Clinical Summary  
 
Applicants should submit clinical summary data from in vivo BE studies, which are critical to 
FDAs determination of BE.  To help applicants summarize this data,  
 
FDA has developed model summary tables . . . .  The[se] tables provide a format 
for applicants to summarize various aspects of the BE submission such as the 
design and outcome of in vivo and in vitro BE studies as well as the results of in 
vitro dissolution testing.129   
 
Applicants can find these model tables on the FDA ANDA Forms and Submission Requirements 
website.130  
 
Applicants, however, have submitted summary tables that are neither filled out completely nor 
prepared properly.  For example, applicants have failed to list, in formulation tables, all of the 
 
128 This document is available at https://www.fda.gov/media/88696/download. 
129 FDA guidance for industry ANDA Submissions  Content and Format of Abbreviated New Drug Applications 
(June 2019), at 14.   
130 These tables are available at https://www.fda.gov/drugs/abbreviated-new-drug-application-anda/abbreviated-
new-drug-application-anda-forms-and-submission-requirements.  Applicants should periodically refer to that 
website because the Agency may update the existing tables or add new tables to address both additional study types 
and waiver requests. 
  28  Contains Nonbinding Recommendations 
 
strengths of the products for which they are seeking approval.  Applicants have also submitted 
summary tables to FDA in a scanned document rather than in a text-based PDF file and 
Microsoft Word document.       
 
FDA recommends that applicants provide accurate and complete information in their model 
summary tables.  Applicants should submit summary tables for all studies conducted, whether 
they were passing or failing studies,131 in a text-based PDF file and Microsoft Word 
document.132   
 
C.  Differences from Product-Specific Guidances 
  
ANDAs that use bioequivalence methods that differ from recommendations in a relevant 
product-specific guidance133 should provide a detailed justification for the alternative approach, 
as well as data to support the alternative approach, in the original ANDA submission.  Below is 
information that should be included, as applicable: 
 
  A detailed justification for and data (such as their inclusion/exclusion criteria or 
demographic information) to support why their use of a particular study population does 
not affect their BE determination 
 
  A detailed explanation of how any difference in their primary endpoint from that 
recommended in the product-specific guidance is as sensitive as the product-specific 
guidances recommended endpoint for detecting differences between the RLD and the 
generic drug product  
 
  A detailed justification, in their protocol and Statistical Analysis Plan, for why their 
proposed prespecified statistical method is different from the product-specific guidances 
recommendation 
D.  BE and Safety Information Related to In Vivo BE Studies 
 
In original ANDA submissions, applicants should include all of the BE and safety information 
related to the conduct of in vivo BE studies that is listed in the FDA guidance for industry ANDA 
Submissions  Content and Format of Abbreviated New Drug Applications (June 2019).  
However, applicants have not always included in their original ANDAs the information that is 
necessary for FDA to fully evaluate the BE of the generic drug product in a timely manner, 
resulting in FDAs refusal to approve the ANDAs.134  Below is information that applicants 
should provide: 
 
 
131 FDA guidance for industry Submission of Summary Bioequivalence Data for ANDAs (May 2011). 
132 FDA guidance for industry ANDA Submissions  Content and Format of Abbreviated New Drug Applications 
(June 2019), at 14.   
133 FDA regularly publishes product-specific guidances that describe the Agencys current thinking and expectations 
on how to develop generic drug products that are therapeutically equivalent to the RLD.   
134 See, e.g., section 505(j)(4)(F) of the FD&C Act. 
  29  Contains Nonbinding Recommendations 
 
  To ensure the welfare of human subjects involved in comparative clinical BE studies, 
applicants should provide, with dates, their protocol, Institutional Review Board approval 
forms, and consent forms.  If their protocol was amended after the study was initiated, 
applicants should highlight the changes, compare the original protocol with the amended 
protocol, and provide an explanation for why the change did not affect the safety or 
efficacy of the study product. 
 
  For subjects with serious adverse events (including death)135 or who became pregnant, 
applicants should provide a written narrative that provides complete follow-up details on 
the condition of the subjects so that the Agency can complete a comprehensive review of 
safety reports for the generic drug product.  In particular, if a pregnancy follow-up is not 
complete at the time of the original ANDA submission, applicants should provide 
updates (such as whether the pregnancy resulted in a live birth) as soon as the 
information becomes available.     
E.  Differences in Formulations and Inactive Ingredients  
 
For drug products for parenteral use, applicants should provide a clear justification and 
documentation for any differences permissible under FDA regulations between the formulation 
of the proposed generic drug product and the formulation of the RLD.136  In addition, if 
applicants used inactive ingredients or amounts of inactive ingredients in their placebo test 
formulation used for BE testing that were different than the inactive ingredients or amounts of 
inactive ingredients in the proposed generic drug product formulation, they should provide a 
rationale and documentation in their original ANDA submission that explains why these 
differences did not affect their demonstration of BE of the proposed generic drug product to the 
RLD.  Applicants, however, have commonly failed to provide necessary justifications and 
documentation for these differences, which has led to FDAs refusal to approve the ANDAs.137 
 
F.  Waiver Requests Under 21 CFR 314.99(b) 
 
Applicants have submitted ANDAs for formulations for products that are not qualitatively and 
quantitatively (Q1/Q2) the same as the approved RLDs formulation but for which Q1/Q2 
sameness is generally required under FDAs regulations.138  When an applicant has sought 
approval for a formulation that is Q1/Q2 the same as an RLD formulation that was previously 
marketed, FDA has determined that, in appropriate circumstances, under 21 CFR 314.99(b), it 
may waive the requirement in the regulation that the inactive ingredients in the proposed generic 
 
135 21 CFR 312.32(a). 
136 See, e.g., 21 CFR 314.94(a)(9)(iii). 
137 See, e.g., section 505(j)(4)(F) of the FD&C Act. 
138 21 CFR 314.94(a)(9)(iii) to (v).  Generally, a generic drug product is considered qualitatively and quantitatively 
the same as the RLD if the concentration or amount of each inactive ingredient in the generic drug product differs by 
no more than +/- 5% of the concentration or amount for the same ingredient in the RLD. 
  30  Contains Nonbinding Recommendations 
 
drug product be the same as those in the currently marketed RLD formulation if the statutory 
requirement regarding safety of inactive ingredients139 has been met.   
 
FDA recommends that ANDA applicants: 
 
  Determine whether they are seeking approval of a drug product where Q1/Q2 sameness 
to the RLD is required but the proposed generic drug product duplicates a previously 
approved (and not current) RLD formulation140 
 
  Consider submitting a request for waiver of the above-identified regulatory requirements 
under 21 CFR 314.99(b)141   
 
FDA will determine whether to grant a waiver under 21 CFR 314.99(b) during its substantive 
review of the ANDA. 
 
 
 
139 See, e.g., section 505(j)(4)(H) of the FD&C Act; see also 21 CFR 314.94(a)(9)(ii). 
140 21 CFR 314.127(a)(8). 
141 In general, a citizen petition under 21 CFR 10.25(a) and 10.30 seeking a determination that the previously 
approved (and not current) RLD formulation was not withdrawn for safety or effectiveness reasons is also 
submitted, unless the FDA has already made such a determination; see FDA guidance for industry Determining 
Whether to Submit an ANDA or a 505(b)(2) Application (May 2019), at 9 n.42. 
  31