ANDA Submissions   
Content and Format 
 
Guidance for Industry 
 
 
    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
 
June 2019 
Generics 
 
Revision 1   
ANDA Submissions   
Content and Format 
Guidance for Industry 
 
 
 
 
 
 
Additional copies are available from: 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD 20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353 
Email: druginfo@fda.hhs.gov  
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm 
 
and/or 
 
Office of Communication, Outreach and Development  
Center for Biologics Evaluation and Research 
 Food and Drug Administration 
10903 New Hampshire Ave., Bldg. 71, Room 3128 
Silver Spring, MD 20993-0002 
Phone: 800-835-4709 or 240-402-8010 
Email: ocod@fda.hhs.gov 
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm  
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
Center for Biologics Evaluation and Research (CBER) 
 
September 2018 
Generics   
TABLE OF CONTENTS 
 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
III.  CTD FORMAT ................................................................................................................. 3 
A.  Module 1  Administrative Information ...................................................................................... 4 
1.  Forms and Cover Letter ............................................................................................................ 4 
2.  Administrative Information ....................................................................................................... 5 
3.  References ................................................................................................................................. 7 
4.  Other Correspondence .............................................................................................................. 8 
5.  Labeling ................................................................................................................................... 10 
B.  Module 2  CTD Summaries ....................................................................................................... 12 
1.  Quality Overall Summary ........................................................................................................ 12 
2.  Clinical Summary .................................................................................................................... 14 
C.  Module 3  Quality....................................................................................................................... 15 
1.  Drug Substance ....................................................................................................................... 15 
2.  Drug Product ........................................................................................................................... 18 
3.  Appendices .............................................................................................................................. 27 
4.  Regional Information .............................................................................................................. 27 
5.  Literature References .............................................................................................................. 28 
D.  Module 4  Nonclinical Study Reports ....................................................................................... 28 
E.  Module 5  Clinical Study Reports ............................................................................................. 29 
1.   Complete Study Data ............................................................................................................... 29 
2.  Literature References .............................................................................................................. 32 
APPENDIX:  SUGGESTED COVER LETTER TEMPLATE ............................................ A-1 
   
ANDA Submissions  Content and Format 
Guidance for Industry1 
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic.  It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.   
 
 
 
 
I.  INTRODUCTION  
 
This guidance is intended to assist applicants in preparing abbreviated new drug applications 
(ANDAs) for submission to FDA under section 505(j) of the Federal Food, Drug, and Cosmetic 
Act (FD&C Act) (21 U.S.C. 355(j)).  This guidance details the information that should be 
provided in each section of the common technical document (CTD) format for human 
pharmaceutical product applications2 and identifies supporting guidance documents and 
recommendations issued by FDA to assist applicants in preparing their ANDA submission.  This 
guidance identifies the information that an applicant should include to ensure that a complete, 
high-quality application is submitted to FDA.  FDA has previously published guidance 
documents on the filing process, including the guidance for industry about refuse-to-receive 
standards, 3 and common, recurring deficiencies4 which should be reviewed thoroughly prior to 
submission of an ANDA.      
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required.  
 
 
                                                 
1 This guidance has been prepared by the Office of Generic Drugs in the Center for Drug Evaluation and Research 
(CDER) in cooperation with the Center for Biologics Evaluation and Research (CBER), both at the Food and Drug 
Administration.  
2 As discussed in section III of this guidance, the CTD format streamlines the ANDA submission requirements for 
Japan, the European Union, and the United States. 
3 See the guidance for industry ANDA Submissions  Refuse-to-Receive Standards (Rev. 2).  We update guidances 
periodically.  To make sure you have the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/def ault.htm. 
4 See the draft guidance for industry Good ANDA Submission Practices.  When final, this guidance will represent 
the FDAs current thinking on this topic.    
1   
II.  BACKGROUND 
 
The Drug Price Competition and Patent Term Restoration Act of 1984 (Public Law 98-417) 
(Hatch-Waxman Amendments) created an abbreviated approval pathway for duplicates of a 
previously approved drug product in section 505(j) of the FD&C Act.  An ANDA relies on the 
Agencys previous finding of safety and effectiveness for a reference listed drug (RLD)5 and, as 
a result, may be approved without submission of the same type and extent of information that is 
requested for a stand-alone new drug application to establish the safety and effectiveness of the 
proposed product.6  Section 505(j) of the FD&C Act, together with its implementing regulations, 
generally requires that an ANDA must contain information to demonstrate that the proposed 
drug product and the applicable RLD are the same with respect to active ingredient(s), dosage 
form, route of administration, strength, previously approved conditions of use, and, with certain 
exceptions, labeling.7  An ANDA must also include sufficient information (1) to demonstrate 
that the proposed product is bioequivalent to the RLD8 and (2) to ensure the products identity, 
strength, quality, and purity.  Consistent with any statutory provisions related to the exclusivity of 
and patents listed for the RLD, FDA must approve an ANDA unless there is insufficient evidence 
that these criteria are met or there is inadequate information to ensure the identity, strength, 
quality, and purity of the drug product.9    
 
GDUFA10 was signed into law to speed the delivery of safe and effective generic drugs to the 
public and reduce costs to industry.  As part of the commitments under the first iteration of 
GDUFA, FDA agreed to meet certain obligations, including performance review goals for the 
review of new ANDAs.  To meet these and any future performance goals as provided for in 
subsequent reauthorizations of GDUFA, FDA is issuing this guidance to assist ANDA applicants 
in improving the quality of their submissions, to increase the number of original ANDAs 
acknowledged for receipt upon initial submission, and to decrease the number of ANDA review 
cycles.  FDA is committed to providing comprehensive assistance in the early stages of the 
application process so that an ANDA will contain all information necessary for FDA to complete 
its review in one review cycle.   
 
 
                                                 
5 An RLD is the listed drug identified by FDA as the drug product upon which an applicant relies in seeking 
approval of its ANDA.  21 CFR 314.3(b).  A listed drug is a new drug product that has been approved under 
section 505(c) or 505(j) of the FD&C Act, which has not been withdrawn or suspended under section 505(e)(1) 
through (e)(5) or section 505(j)(6) of the FD&C Act, and which has not been withdrawn from sale for what FDA has 
determined are reasons of safety and effectiveness.  Id.  Listed drug status is evidenced by the drug products 
identification in the current edition of FDAs Approved Drug Products With Therapeutic Equivalence Evaluations 
[(the Orange Book)] as an approved drug.  Id.      
6 See section 505(j)(2)(A) of the FD&C Act.  (Generally, clinical studies to demonstrate safety and effectiveness are 
outside the scope of information that can be required for ANDAs.) 
7 See section 505(j)(2)(A) and 505(j)(4) of the FD&C Act, 21 CFR 314.94, and 21 CFR 314.127.   
8 See section 505(j)(2)(A)(iv) and 505(j)(4)(F) of the FD&C Act and 21 CFR 320.21(b).   
9 Section 314.127. 
10 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. 
2   
III.  CTD FORMAT    
 
The CTD format was developed by the International Council for Harmonisation of Technical 
Requirements for Pharmaceuticals for Human Use (ICH) in an attempt to streamline the 
submission requirements for Japan, the European Union, and the United States.  The CTD 
collects quality, safety, and efficacy information into a common format that has been adopted by 
ICH regulatory authorities.  The electronic CTD (eCTD) is the standard format for electronic 
regulatory submissions for ANDAs.  As of May 5, 2017, ANDAs and submissions to ANDAs 
(which includes amendments, supplements, and reports) must be submitted to FDA 
electronically in eCTD format.11, 12  
 
FDA has issued several guidance documents specific to the CTD and eCTD submissions.13  The 
information contained in these guidances focuses on the technical aspects of filing a CTD 
application and should be reviewed thoroughly prior to submitting an ANDA.  This guidance, 
however, specifically addresses the content of the CTD for an ANDA. 
 
The CTD is comprised of the following modules:  
 
  Module 1:14  Administrative Information and Prescribing Information  
  Module 2:  Summaries  
  Module 3:  Quality  
  Module 4:  Nonclinical  
  Module 5:  Clinical   
 
The sections that follow in this guidance provide additional detail about the information that 
should be submitted in the applicable modules, sections, and subsections.   
 
                                                 
11 Guidance for industry Providing Regulatory Submissions in Electronic Format  Certain Human Pharmaceutical 
Product Applications and Related Submissions Using the eCTD Specifications (Rev. 4).  See also section 745A(a) of 
the FD&C Act (21 U.S.C. 379k-1(a)) and guidance for industry Providing Regulatory Submissions in Electronic 
Format  Submissions Under Section 745A(a) of the Federal Food, Drug, and Cosmetic Act.     
12 Any record in electronic form submitted to FDA under requirements of the FD&C Act is subject to the provisions 
of part 11 (21 CFR part 11) unless exempted.  Part 11 regulations were issued in 1997 to provide criteria to FDA for 
accepting electronic records, electronic signatures, and handwritten signatures executed to electronic records as 
equivalent to paper records and handwritten signatures on paper.  See the guidance for industry Part 11, Electronic 
Records; Electronic Signatures  Scope and Application. 
13 See the FDA guidance web page at 
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm and electronic 
submissions web page at 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/de
fault.htm.  See also the biologics web page at 
http://www.fda.gov/BiologicsBloodVaccines/DevelopmentApprovalProcess/ucm163685.htm.  
14 Module 1 contains administrative information and is not considered part of the common application.  Each 
regulatory authority that accepts the CTD uses its own Module 1.  The information described for Module 1 in this 
guidance applies only to ANDAs submitted to the U.S. FDA.  Modules 2 through 5 of the CTD are common for all 
regions. 
3   
A.  Module 1  Administrative Information 
 
1.  Forms and Cover Letter 
 
Section 1.1 contains the following forms:15  
 
  Form FDA 356h (Form 356h)  Application to Market a New or Abbreviated New 
Drug or Biologic for Human Use, which ANDA applicants must fully complete and 
sign for their submissions16  
  
  Form FDA 3794  Generic Drug User Fee Cover Sheet17 
 
  Form 3674  Certification of Compliance Under 42 U.S.C.  282(j)(5)(B), with 
Requirements of ClinicalTrials.gov Data Bank (42 U.S.C.  282(j)) 
 
1.2 Contains a cover letter.  A suggested cover letter template is included in this guidance in the 
appendix.18  In addition, FDA recommends that a cover letter clearly state in its header whether 
it proposes any of the following:  
 
  A new strength of a solid oral dosage-form drug product 
 
  A change in concentration for a parenteral dosage-form drug product 
 
  A change in vial size, fill volume, and/or package size to a parenteral dosage-form drug 
product (i.e., total drug content) 
 
  A change in concentration of an oral liquid, ophthalmic, otic, transdermal, or topical 
drug product 
 
  A change in the formulation for any dosage form19  
                                                 
15 FDA forms listed in this section and in other parts of this guidance are available at 
http://www.fda.gov/AboutFDA/ReportsManualsForms/Forms/default.htm.  
16 Section 314.94(a)(1).  
17 All applicants submitting original ANDAs, except for original ANDAs for positron emission tomography drugs 
(see section 744B(l) of the FD&C Act (21 U.S.C. 379j-42(l)), are required to pay the generic drug user fee.  See 
Generic Drug User Fee Cover Sheet and Payment Information, available at 
http://www.fda.gov/forindustry/userfees/genericdruguserfees/ucm322629.htm.  
18 Applicants are not required to use this template.  However, if applicants utilize the template, they should use 
judgment in adapting the template to their specific needs. 
19 Applicants who are requesting a change in the formulation for any dosage form should identify the level of the 
change in the header.  Applicants should consult scale-up and post-approval changes (SUPAC) guidances for 
industry to determine the appropriate level of change.  FDA has developed SUPAC guidances for immediate-release 
solid oral dosage forms, modified-release solid oral dosage forms, and nonsterile semisolid dosage forms, which are 
available CDER guidance web page for Pharmaceutical Quality/CMC guidances.  The SUPAC guidances focus on 
4   
 
  A switch from a prescription drug product to an over-the-counter product (Rx-to-OTC 
switch) 
 
  The reactivation of a product listed in the discontinued section of FDAs Approved 
Drug Products With Therapeutic Equivalence Evaluations (the Orange Book) 
 
1.2 Contains (1) copies of any controlled correspondence from FDA related to meetings FDA 
holds with applicants to discuss their development of a generic drug product that is the subject of 
an ANDA and (2) any copies of the minutes from those meetings.   
 
2.  Administrative Information  
 
1.3.1.2 Contains a U.S. agent letter of appointment, if applicable.  The U.S. agent letter of 
appointment is a separate document submitted in addition to the U.S. agents signature on Form 
356h, if applicable.  If the applicant does not reside or have a place of business in the United 
States, an agent that resides or maintains a place of business in the United States must 
countersign the application.20 
 
1.3.2 Contains the field copy certification.21  Applicants should notify the applicable Office of 
Regulatory Affairs district office by letter that their eCTD submission will be submitted to FDA.  
Because the district offices have access to the complete submission on the FDA network, an 
individual field copy is no longer required for the district office.  The letter should include the 
drug name, application number, FDA center, and FDA division reviewing the application.22      
 
1.3.3 Contains the signed debarment certification required under the Generic Drug Enforcement 
Act of 1992.23  The applicant must certify that it did not and will not use the services of any 
debarred persons in connection with the application.24  The applicant must also list all 
convictions described in section 306(k) and 306(a) and (b) of the FD&C Act (21 U.S.C. 335a(k), 
335a(a), and 335a(b), respectively).  Under section 306(k)(1) of the FD&C Act, the applicant 
may use the following language:  
 
                                                 
post-approval changes; however, FDA recommends that applicants consult these guidances to determine the level of 
change for both amendments to original ANDAs and prior approval supplements.  
20 21 CFR 314.50(a)(5). 
21 Section 314.94(d)(5). 
22 See the eCTD Technical Conformance Guide, available at 
http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSub
missions/UCM465411.pdf.  
23 Section 306(k) and 306(a) and (b) of the FD&C Act (21 U.S.C. 335a(k), 335a(a), and 335a(b), respectively). 
24 See the draft guidance for industry Submitting Debarment Certification Statements for more information on 
debarment certifications, including a discussion on persons covered by those certifications.  When final, this 
guidance will represent FDAs current thinking on this topic. 
5   
(Name of Applicant) hereby certifies that it did not and will not use in any capacity the 
services of any person debarred under section 306 of the Federal Food, Drug, and 
Cosmetic Act in connection with this application.  
 
Qualifying phrases, such as to the best of our knowledge, should be avoided.  
Similarly, applicants with no convictions to list should submit a statement to that effect.25   
 
1.3.4 Contains a financial certification (FDA Form 3454) for any clinical investigator who has no 
disclosable financial interests in, or arrangements with, any applicant of the covered clinical 
study and a disclosure statement (FDA Form 3455) for each clinical investigator who, or whose 
spouse or dependent child, has or had disclosable financial interests in and/or arrangements with 
any sponsor of the covered clinical study.26    
 
1.3.5 Contains the patent and exclusivity information.   
 
1.3.5.1 Contains the patent information.  Applicants are required to provide an 
appropriate patent certification or statement for each patent issued by the U.S. Patent and 
Trademark Office and subsequently listed in the Orange Book that claims (1) the drug 
substance, (2) the drug product, and/or (3) a use of the RLD that is cited by the ANDA.27  
FDA recommends that when providing patent information, applicants include the 
expiration date for each patent, whether the RLD is protected by any pediatric 
exclusivity, and when any such pediatric exclusivity will expire.   
 
1.3.5.2 Contains the patent certification(s).  If the Orange Book does not list a patent for 
the RLD, the ANDA applicant must certify that such patent information has not been 
submitted by the NDA holder for listing in the Orange Book (Paragraph I Certification).28 
 
For each patent issued by the U.S. Patent and Trademark Office and subsequently listed 
in the Orange Book, the applicant must certify to one of the following paragraphs:29 
 
  That the patent information has expired (Paragraph II Certification) 
 
  The date on which the patent will expire (Paragraph III Certification) 
 
                                                 
25 See the letter from Roger L. Williams to all ANDA and abbreviated antibiotic application applicants (January 15, 
1993), available at 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM072885.pdf.   
26 21 CFR part 54. 
27 Section 314.94(a)(12). 
28  Section 314.94(a)(12)(i)(A)(1).  If in the opinion of the ANDA applicant and to the best of its knowledge there 
are no patents claiming the drug product, drug substance, or method of use of the drug product, the applicant must 
submit to its ANDA a certification stating that opinion.  Section 314.94(a)(12)(ii). 
29 Section 505(j)(2)(A)(vii) of the FD&C Act and  314.94(a)(12)(i)(A)(2) through (4). 
6   
  That the patent is invalid, unenforceable, or will not be infringed by the 
manufacture, use, or sale of the drug product for which the ANDA is submitted 
(Paragraph IV Certification) 
 
If the RLD is covered by a patent claiming a method of using the listed drug and the labeling for 
the drug product for which the applicant is seeking approval does not include any indication or 
other condition of use that is covered by the method-of-use patent, the applicant must also submit 
a statement explaining that the method-of-use patent does not claim any of the proposed 
indications or other condition of use.30   
 
Applicants submitting a Paragraph IV Certification must provide the following language:31  
 
I, (name of applicant), certify that Patent No.                 (is invalid, unenforceable, or 
will not be infringed by the manufacture, use, or sale of) (name of proposed drug 
product) for which this application is submitted. 
 
Applicants submitting a Paragraph IV Certification must also certify that they will provide notice 
to the owner of the patent(s) and to the holder of the approved application that lists the patent(s) 
that is/are being challenged.32, 33   
 
Applicants should also submit an exclusivity statement regarding their marketing intentions 
when the applicant intends to remove or carve out any protected indication or other condition of 
use from the labeling to gain market entry for other uses prior to expiry of exclusivity for that 
protected indication or other condition of use.  
 
3.  References 
 
1.4.2 Contains the statement of a right of reference for each and every drug master file (DMF) 
referenced in the application and identified on Form 356h.  Applicants should submit the letter of 
authorization provided to the applicant by the DMF holder which gives authorization to rely on 
the information in the DMF.34  
 
                                                 
30 Section 314.94(a)(12)(iii). 
31 Section 314.94(a)(12)(i)(A)(4). 
32 Section 314.94(a)(12)(i)(A)(4). 
33 The process for this notice is provided in section 505(j)(2)(B) of the FD&C Act and in 21 CFR 314.95.  An 
ANDA applicant must send notice of a paragraph IV certification on or after the date on which it receives a 
paragraph IV acknowledgment letter from FDA but not later than 20 days after the date of the postmark on the 
paragraph IV acknowledgment letter stating that the application is sufficiently complete to permit a substantive 
review.  See  314.95(a) and (b).   
34 21 CFR 314.420(d).  More information on DMFs, as well as the list of DMFs that FDA has received, is available 
at 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/DrugMasterFilesDMFs/d
efault.htm. 
7   
4.  Other Correspondence 
 
1.12.4 Contains a statement, if applicable, that a request for a proprietary name has been made.  
An ANDA applicant requesting a proprietary name should submit that request when the ANDA 
is submitted to help ensure that an acceptable name is available at the time of approval.  When 
requesting a proprietary name, a separate electronic submission should be made and identified as 
a REQUEST FOR PROPRIETARY NAME REVIEW.35          
 
1.12.11 Contains the basis for submission.36, 37  The applicant should provide:  (1) the name of 
the RLD, (2) the application number of the RLD, and (3) the holder of the application for the 
RLD. 
 
If the generic drug differs from the RLD in strength, route of administration, dosage form, or in 
that one active ingredient is substituted for one of the active ingredients in a listed combination 
drug product, applicants must first submit a suitability petition to FDAs Division of Dockets 
Management to obtain permission to file their ANDA.38  FDA will review the suitability petition 
to determine whether the requested change from the listed drug will impact the safety and 
effectiveness of the generic product and if any applicable requirements of the Pediatric Research 
Equity Act may be waived.  The suitability petition must be approved by FDA before the ANDA 
is submitted.39  For an ANDA based on an approved petition under 21 CFR 10.30 or 314.93, the 
name of the RLD in section 1.12.11 must be the same as the listed drug in the petition, and 
section 1.12.11 must contain the FDA docket number for the petition and a copy of FDAs 
correspondence approving the suitability petition.40  When an applicant submits a petitioned 
ANDA, the basis for submission is the RLD and the approved suitability petition.  Section 
1.12.11 should contain (1) the name of the RLD, which must be the same as the listed drug 
identified in the approved suitability petition, (2) a reference to the suitability petitions FDA-
assigned document number, and (3) a copy of FDAs correspondence approving the suitability 
petition.41, 42  When an ANDA applicant seeks approval of a generic drug that is a duplicate of a 
                                                 
35 See the guidance for industry Contents of a Complete Submission for the Evaluation of Proprietary Names 
(Rev.1). 
36 Section 314.94(a)(3).  See also the draft guidance for industry Referencing Approved Drug Products in ANDA 
Submissions.  When final, this guidance will represent the FDAs current thinking on this topic. 
37 Applicants should review the guidance for industry Variations in Drug Products That May Be Included in a 
Single ANDA to determine whether one or more ANDAs should be submitted for variations of a specific drug 
product dosage form.   
38 21 CFR 314.93(b).  To request such a change from the RLD, the suitability petition must be submitted in 
accordance with 21 CFR 10.20 and in the format specified in 21 CFR 10.30. 
39 Section 314.93(b). 
40 Section 314.94(a)(3)(i) and (iii). 
41 Section 314.94(a)(3)(i) and (iii).  See also the draft guidance for industry Referencing Approved Drug Products in 
ANDA Submissions. 
42 If after approval of a suitability petition and before approval of an ANDA submitted pursuant to the approved 
petition, a drug product is approved in an NDA for the change described in the petition, the suitability petition and 
the listed drug identified in the petition can no longer be the basis for submission.  The applicant must submit a new 
8   
drug product in an approved petitioned ANDA (and for which the same drug has not been 
approved under section 505(c) of the FD&C Act), the basis for submission is the RLD and the 
approved suitability petition.  Section 1.12.11 should contain:  (1) the RLD, which must be the 
same as the listed drug identified in the approved suitability petition, and RLD application 
number; (2) a reference to the suitability petitions FDA-assigned docket number; and (3) a copy 
of FDAs correspondence approving the suitability petition.  The first petitioned ANDA 
approved should be used for and identified in the appropriate sections of a subsequent ANDA as 
the reference standard.  However, the RLD for that subsequent ANDA remains the listed drug 
referenced in the approved suitability petition.43  
 
1.12.12 Contains information demonstrating that the generic product is the same as the RLD.44   
Same as means that the generic product is identical to the RLD in active ingredient(s), dosage 
form, strength, route of administration, and conditions of use, except that conditions of use for 
which approval cannot be granted because of exclusivity or an existing patent may be omitted.45  
To demonstrate that the proposed generic drug product meets this standard, applicants should 
provide:  
 
(1)  A statement that the conditions of use for the generic product have been previously 
approved for the RLD46   
 
(2)  Information to show that the active ingredient(s) in the generic drug product is/are the 
same as the active ingredient(s) in the RLD47  
 
(3)  Information to show that the route of administration, dosage form, and strength of the 
generic drug product are the same as those of the RLD48  
 
(4)  As applicable, information to indicate the strength of the generic drug product used in 
the in vivo bioequivalence (BE) studies (fasting and fed) to demonstrate BE of the 
generic drug product to the RLD     
 
FDA recommends that applicants submit, within their original application, all strengths that they 
intend to market.  Applicants generally should not submit a new pharmacy bulk package strength 
or fill volume in an amendment.49    
 
                                                 
ANDA that identifies the drug product with the same active ingredient, dosage form, route of administration, and 
strength that has been approved under an NDA as the RLD and as its basis for submission.  See 314.93(f)(2).  
43 See the draft guidance for industry Referencing Approved Drug Products in ANDA Submissions.  
44 See section 505(j)(2)(A) of the FD&C Act and  314.94. 
45 21 CFR 314.92(a)(1). 
46 Section 314.94(a)(4). 
47 Section 314.94(a)(5). 
48 Section 314.94(a)(6). 
49 See the guidance for industry Variations in Drug Products That May Be Included in a Single ANDA for 
exceptions. 
9   
1.12.14 Contains the environmental assessment,50 the environmental impact statement,51 or the 
claim of categorical exclusion52 and the justification for the exclusion.  A claim of categorical 
exclusion must (1) include a statement of compliance with the categorical exclusion criteria 
and (2) state that to the applicant's knowledge, no extraordinary circumstances exist.53   
 
1.12.15 Contains a request, if applicable, to waive the requirement that applicants submit 
evidence either measuring in vivo bioavailability (BA) or demonstrating in vivo BE of the 
generic product (known as a biowaiver).54  The data necessary to support a waiver request can 
vary by product.  For this reason, applicants should submit a controlled correspondence to 
GenericDrugs@fda.hhs.gov, consult both the Product-Specific Guidances for Generic Drug 
Development website55 for current product-specific guidances and the Biopharmaceutics 
guidances website,56 or contact the appropriate Center for Biologics Evaluation and Research 
review division prior to submission of the application, as appropriate.  
 
5.  Labeling 
 
1.14.1 Contains labeling for the generic drug product.57  If the application is for a sterile 
pharmacy bulk package product, applicants should complete and submit a Pharmacy Bulk 
Package Sterility Assurance table58 to address sterility assurance aspects of the drug product 
associated with the labeling and the microbiological study data that may be submitted in the 
application.   
 
                                                 
50 See 21 CFR 25.20. 
51 21 CFR 25.22. 
52 21 CFR 25.30 or 21 CFR 25.31. 
53 21 CFR 25.15(a). 
54 21 CFR 320.22. 
55 The Product-Specific Guidances for Generic Drug Development website is available at 
https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm075207.htm.   
56 The Biopharmaceutics guidances website is available at 
https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm064964.htm. 
57 See section 314.94(a)(8)(ii).  See also the draft guidance for industry Safety Considerations for Container Labels 
and Carton Labeling Design To Minimize Medication Errors.  When final, this guidance will represent the FDAs 
current thinking on this topic. 
58 This table is available on the Abbreviated New Drug Application (ANDA) Forms and Submission Requirements 
web page at 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplicati
ons/AbbreviatedNewDrugApplicationANDAGenerics/ucm120955.htm. 
10   
1.14.1.1 Contains the draft label and labeling59 for each strength and container including 
the package size in a text-based PDF file.60  Applicants should ensure that the label and 
labeling design61 do not contribute to medication error62 and confirm whether the container 
closure is child resistant. 
 
1.14.1.2 Contains the annotated draft labeling text, including side-by-side labeling 
comparison of the generic drug products container(s) and carton(s) to the RLDs 
container(s) and carton(s) for each strength (or total drug content and concentration for 
injections) and for each container closure system.  All differences should be highlighted 
and annotated.  Applicants should indicate the RLD version (e.g., strength, package size, of 
carton) used for the side-by-side comparison.63   
 
1.14.1.3 Contains the prescribing and patient information in text-based PDF, Microsoft 
Word, and structured product labeling files.   
 
1.14.1.4 Contains the Pharmacy Bulk Package Sterility Assurance table,64 if applicable.   
 
1.14.1.5 Contains the labeling history. 
 
Applicants are encouraged to review and use the Labeling Question-Based Review (QbR) model 
when developing labels and labeling.65  Responses to the QbR should be provided in section 
1.14.1.5, as applicable. 
 
1.14.3 Contains the RLD labeling and a comparison of that labeling to the draft labeling for the 
generic product.  Applicants must submit side-by-side labeling comparison(s) with all 
differences annotated and explained.66  Applicants should also submit the RLD package insert, 
                                                 
59 FDA has determined that, in general, an ANDA may be approved based on a draft labeling provided that the only 
deficiencies in the draft labeling are of an editorial or similarly minor nature.  See the guidance for industry 
Acceptability of Draft Labeling To Support ANDA Approval.   
60 For all PDF submissions, FDA recommends that applicants submit text-based PDF files, not image-based PDF 
files. 
61 For FDA to assess whether there are any significant deficiencies in the draft carton and container labeling, the 
design should not only reflect the content of the carton and/or container but also provide an accurate representation 
of the layout, text size, style, color, and other formatting factors that will be used for the final printed labeling.   
62 See the draft guidance for industry Safety Considerations for Container Labels and Carton Labeling Design To 
Minimize Medication Errors. 
63 For example, if the proposed product is to be packaged in a bottle as 30-, 60-, and 100-count along with a 10-
count blister packaging, side-by-side comparisons should be provided for the bottle count and the blister packaging 
for each strength.  Also for example, if the proposed product comes in a 5 milligram (mg)/milliliter (mL), 5 mL, and 
10 mL vial, and a 10 mg/mL, 5 mL, and 10 mL vial, a side-by-side comparison should be provided for all four size 
and concentration combinations.   
64 This table is available on the Abbreviated New Drug Application (ANDA) Forms and Submission Requirements 
web page, note 58.  
65 See the Abbreviated New Drug Application (ANDA) Forms and Submission Requirements web page, note 58.  
66 Section 314.94(a)(8)(iv).   
11   
Medication Guide, one container label, and one outer carton, if applicable, for each strength and 
package size listed in the application.67  Applicants are reminded to use the most recent RLD 
labeling available at the Drugs@FDA website. 
 
1.14.3.1 Contains a side-by-side labeling comparison, with any differences annotated and 
explained, and the Medication Guide, if applicable.  In addition, applicants should do the 
following:  
 
(1)   State that a sufficient number of Medication Guides will be included in each 
package size (i.e., an amount to ensure that the authorized dispenser is able to 
provide a Medication Guide to each patient receiving a prescription for the drug 
product)68 
 
(2)   Confirm that the Medication Guides will be distributed in accordance with 21 
CFR 208.24 
 
1.14.3.3 Contains the RLD labeling, the Medication Guide, one RLD container label, and 
one RLD outer carton label for each strength and package size, if applicable.  
 
1.16.1 Contains a risk management plan (non-REMS)69 for products that require tools to 
minimize risks while preserving benefits.   
  
1.16.2 Contains, for applicants relying on an RLD with a risk evaluation and mitigation strategy 
(REMS), a REMS for the generic drug product and any REMS supporting documents.70  A 
REMS for an ANDA must have the same Medication Guide and patient package insert as the 
RLD.71  In addition, if applicable, a REMS for an ANDA must use a single, shared system of 
elements to assure safe use unless FDA waives the requirement under section 505-1(i)(1)(B) of 
the FD&C Act (21 U.S.C. 355-1(i)(1)(B)).  However, an ANDA REMS does not include a 
timetable for submission of assessments of the REMS and does not include a communication 
plan.72  
 
B.  Module 2  CTD Summaries 
 
1.  Quality Overall Summary 
 
                                                 
67 See section 314.94(a)(8)(i). 
68 21 CFR 208.24(b)(1). 
69 See section 505-1 of the FD&C Act (21 U.S.C. 355-1). 
70 See the draft guidance for industry Format and Content of a REMS Document.  When final, this guidance will 
represent the FDAs current thinking on this topic. 
71 Section 505-1(i)(1)(A) of the FD&C Act. 
72 Id.  
12   
2.3 Contains the Quality Overall Summary (QOS), which provides an overview of the chemistry, 
manufacturing, and controls (CMC) section of the application.73  The QOS summarizes 
information from both section 2.3.S about the drug substance (i.e., the active pharmaceutical 
ingredient (API)) and section 2.3.P about the drug product.  In section 2.3.S, applicants should 
provide separate information on each drug substance contained in the product.  All information 
provided in the QOS should be accurate and supported by information, data, or a justification 
that should also be included in Module 3 or other parts of the application.74   
 
Applicants should use the QbR model when writing their QOSs.  FDA introduced the QbR 
initiative in 2005 as a tool for the review of the CMC (i.e., the drug substance and drug product 
quality sections of the ANDA)75 and updated the QbR model in 2011 to include additional CMC 
questions from microbiology.  The QbR model assists applicants in developing their QOS by 
providing specific questions that, when answered, ensure that applicants submit adequate 
information for FDA review.  FDA has posted the QbR-QOS outlines designed for simple 
dosage form products (solution or immediate-release solid oral dosage forms)76 and for sterility 
assurance of products terminally sterilized by moist heat.77, 78  FDA has also developed example 
QOS summaries for controlled-release capsules79 and immediate-release tablets.80  Additionally, 
FDA recommends that applicants refer to the QbR Frequently Asked Questions and the QbR for 
Sterility Assurance of Terminally Sterilized Products:  Frequently Asked Questions for further 
guidance on completing the QOS, including page limits.81   
 
Failure to submit the QOS in text-based PDF and Microsoft Word files will result in a deficiency 
during the filing review conducted by FDA upon submission of the ANDA.  FDA recommends 
against submitting a scanned PDF copy of the QOS. 
 
                                                 
73 Section 314.50(c)(2)(iv). 
74 See the ICH guidance for industry M4Q:  The CTD  Quality.  ICH guidances for industry can be found on the 
FDA guidance web page at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/def 
ault.htm. 
75 See the Abbreviated New Drug Application (ANDA) Forms and Submission Requirements web page, note 58. 
76 See the Question-Based Review for CMC Evaluations of ANDAs web page, available at 
https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplicat
ions/AbbreviatedNewDrugApplicationANDAGenerics/ucm120971.htm.  
77 Id.  
78 Portions of the QbR for terminally sterilized products may also directly apply to sterile drug products that are 
aseptically filled.  Specifically, the P.1, P.2, P.5, P.8, Appendices A.2, and Regional Information components of 
section 2.3.P would also apply to sterile products that are aseptically filled.  
79 See the Question-Based Review for CMC Evaluations of ANDAs web page, note 76.  
80 Id.  
81 Id.  
13   
2.  Clinical Summary 
 
2.7 Contains summary data critical to the determination of BE.82  FDA has developed model 
summary tables to assist applicants in summarizing the BE data.83, 84  The 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.  
These model tables are available on the FDA Abbreviated New Drug Application (ANDA) 
Forms and Submission Requirements web page.85  In addition, applicants should submit 
summary tables for all studies conducted, regardless of whether they are passing or failed 
studies,86 in text-based PDF and Microsoft Word files. 
 
2.7.1 Contains a summary of biopharmaceutic studies and associated analytical methods, as well 
as summary tables87 in a standardized format for data to be submitted, including, but not 
necessarily limited to:  BE summary tables for in vitro feeding tube testing, clinical endpoint 
summary tables, topical dermatologic corticosteroid in vivo BE study summary tables, in vitro 
binding BE study summary tables, and BE summary tables for aqueous nasal spray solutions.  
This section also contains the identity and complete addresses of all sites used to generate data 
submitted in support of the determination of BE (e.g., data submitted either under 21 CFR 
320.21(b) or 320.24(b) or in support of a Biopharmaceutics Classification System waiver 
request).88  Additionally, certificates of analysis (COAs) of all RLDs used in the 
biopharmaceutic studies should be provided in this section. 
 
Section 2.7 also contains dissolution data testing for the whole tablet and the half tablet (if 
applicable), comparing the test product to the RLD.  Additionally, comparative individual unit 
data should be provided along with COAs for all RLDs used in the testing.  Dissolution should 
be conducted in all medias recommended by the Agency or the United States Pharmacopeia 
(USP).89   
 
                                                 
82 21 CFR 320.21(b) and 21 CFR 320.24(b). 
83 See the Abbreviated New Drug Application (ANDA) Forms and Submission Requirements web page, note 58, for 
the Model Bioequivalence Data Summary Tables.  
84 FDA has developed various BE summary tables to assist applicants including, for example, clinical endpoint BE 
study tables, BE summary tables for in vitro feeding tubes, and summary tables for the listing and characterization 
of impurities and a justification for the limits in drug substance and drug products.  See the Abbreviated New Drug 
Application (ANDA) Forms and Submission Requirements web page, note 65.   
85 Applicants should periodically refer to the Abbreviated New Drug Application (ANDA) Forms and Submission 
Requirements web page, note 58, because the Agency may update existing tables or expand the number of tables to 
address additional study types as well as waiver requests. 
86 See the guidance for industry Submission of Summary Bioequivalence Data for ANDAs. 
87 See the Abbreviated New Drug Application (ANDA) Forms and Submission Requirements web page, note 58. 
88 See the guidance for industry Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release 
Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System.  
89 See, for example, FDAs Dissolution Methods Database, available at 
https://www.fda.gov/Drugs/InformationOnDrugs/ucm135742.htm.  
14   
C.  Module 3  Quality 
 
Module 3 contains all of the CMC information necessary to support the application,90 including 
the information supporting and verifying what was summarized in section 2.3.  The specific 
placement of product quality microbiology information in Module 3 is listed in CDERs Manual 
of Policies and Procedures (MAPP) 5040.1 Product Quality Microbiology Information in the 
Common Technical Document  Quality (CTD-Q).91, 92  Any analytical procedure submitted in 
the summaries of Module 2 should be described in sufficient detail to allow an analyst to 
reproduce the conditions and obtain results comparable to what is stated in the application.93  It 
is recommended that applicants review the following three guidances for industry to assist in the 
preparation of Module 3:  (1) ANDAs:  Impurities in Drug Products, (2) ANDAs:  Impurities in 
Drug Substances, and (3) ANDAs:  Stability Testing of Drug Substances and Products.94 
 
1.  Drug Substance 
 
3.2.S contains the CMC information specific to the drug substance(s).95  For a drug product 
containing more than one drug substance, the information requested for part S should be 
provided in its entirety for each drug substance as a separate Module 3.2.S.   
 
3.2.S.1 Contains general information about the drug substance, including:  (1) the nomenclature, 
(2) the structure, and (3) general properties.  Section 3.2.S.1 should not include any references to 
the DMF.   
 
3.2.S.2 Contains information related to the manufacture of the drug substance.  This section 
should include all intermediate and final drug substance manufacturing facilities listed on the 
Form 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).  All 
testing labs that perform functions integral to the control strategy  including, but not limited to, 
                                                 
90 Section 314.94(a)(9)(i). 
91 For this and other MAPPs, see the Manual of Policies and Procedures (CDER) web page at 
http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cder/manualofpoliciesprocedures/d
efault.htm.   
92 See also the guidances for industry Submission Documentation for Sterilization Process Validation in 
Applications for Human and Veterinary Drug Products and Sterile Drug Products Produced by Aseptic Processing 
 Current Good Manufacturing Practice. 
93 See the guidance for industry Analytical Procedures and Methods Validation for Drugs and Biologics.   
94 FDA further recommends that applicants review, as applicable, the ICH guidance for industry M7(R1) Assessment 
and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals To Limit Potential Carcinogenic Risk and 
the draft guidances for industry Elemental Impurities in Drug Products and Quality Attribute Considerations for 
Chewable Tablets.  When final, these guidances will represent the FDAs current thinking on these topics.  In 
addition, FDA recommends that applicants review, as applicable, the following guidances for industry:  Tablet 
Scoring:  Nomenclature, Labeling, and Data for Evaluation; Size of Beads in Drug Products Labeled for Sprinkle 
(Rev. 1); Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules; ANDAs:  Stability Testing of 
Drug Substances and Products:  Questions and Answers; and ANDA Submissions  Refuse-to-Receive Standards 
(Rev. 2). 
95 Section 314.50(d)(1)(i). 
15   
a characterization and comparison of molecules and comparability testing  should be listed.  
This section should include any testing sites that generate stability testing, and release data to 
support the application as well as the testing sites for planned commercial testing.   
 
3.2.S.2.1 Contains information about each drug substance manufacturer, including the:  
 
(1)  Name and full address of the facility(ies) of each manufacturer, including the 
contractors, and each proposed production site or facility involved in the 
manufacturing and testing 
 
(2)  Contact information for an agent at the facility (including phone and fax 
numbers and email addresses)  
 
(3)  U.S. agents name, if applicable  
 
(4)  Function or responsibility of the manufacturer  
 
(5)  Type II DMF number for the API or any critical or final intermediates, if 
applicable  
 
(6)  Central File Number, Facility Establishment Identifier, and Data Universal 
Numbering System numbers, if known  
 
Subsections 3.2.S.2.2 through 3.2.S.2.6 may refer to the DMF.  If there is no DMF 
referenced in the application, detailed information should be provided in these 
subsections.   
 
3.2.S.2.2 Contains a complete description of the manufacturing process and process 
controls, including the manufacturing and sterilization processes for the sterile 
substance(s) used in the sterile drug product.96 
 
  3.2.S.2.3 Contains the control of materials used in the manufacture of the drug substance. 
 
  3.2.S.2.4 Contains controls of critical steps and intermediates. 
 
3.2.S.2.5 Contains process validation and/or evaluation, including the manufacturing and 
sterilization processes for the sterile drug substance(s) used in the sterile drug product. 
 
                                                 
96 See MAPP 5040.1 Product Quality Microbiology Information in the Common Technical Document  Quality 
(CTD-Q) and the Guideline for Submitting Supporting Documentation in Drug Applications for the Manufacture of 
Drug Substances web page, available at 
https://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/guidances/ucm149499.htm.  See also QbR for 
Sterility Assurance of Terminally Sterilized Products:  Quality Overall Summary Outline; QbR for Sterility 
Assurance of Terminally Sterilized Products:  Frequently Asked Questions; and QbR for Sterility Assurance of 
Aseptically Processed Products, which are all available on the Question-Based Review for CMC Evaluations of 
ANDAs web page, note 76. 
16   
  3.2.S.2.6 Contains the manufacturing process development.  
 
3.2.S.3 Contains characterization information for the API.   
 
  3.2.S.3.1 Contains an elucidation of the API structure and other characteristics. 
 
3.2.S.3.2 Contains all potential impurities.97  FDA recommends that applicants complete 
the Summary Tables for the Listing and Characterization of Impurities and Justification 
of Limits in Drug Substance and Drug Products.98   
 
3.2.S.4 Contains information about the control of the drug substance, including the validation 
procedures and the results of the microbiological analytical tests, as applicable.   
 
3.2.S.4.1 Contains the drug substance specification.  The specification includes the tests, 
acceptance criteria, and references to methods in tabular form, including any 
microbiological attributes for the drug substance (e.g., sterility for a sterile product or 
microbial limits for a non-sterile product), as appropriate. 
 
3.2.S.4.2 Contains the analytical procedures (compendial and/or in-house), including, if 
appropriate, the analytical procedures used to perform microbiological tests of the drug 
substance.   
 
3.2.S.4.3 Contains a validation of the analytical procedures, including:  
 
(1)  The full validation reports for the in-house methods and their equivalence to 
USP procedures, if available for the drug substance  
 
(2)  A verification of USP General Chapter <1226> or DMF procedures, if 
referenced  
 
(3)  Legible spectra and chromatograms for reference standards and test samples  
 
(4)  The Sample Statement(s) of Availability and identification of the drug 
substance99  
 
3.2.S.4.4 Contains the batch analysis, including the COAs from both the drug substance 
manufacturer(s) and the drug product manufacturer(s) for the batches used to produce the 
                                                 
97 FDA may refuse to receive an ANDA for:  (1) failing to provide justification for proposed limits in drug 
substances and drug products for specified identified impurities that are above qualification thresholds, (2) failing to 
provide justification for proposed limits for specified unidentified impurities that are above identification thresholds, 
and (3) proposing limits for unspecified impurities (e.g., any unknown impurity) that are above identification 
thresholds.  See the guidance for industry ANDA Submissions  Refuse to Receive for Lack of Justification of 
Impurity Limits.   
98 See the Abbreviated New Drug Application (ANDA) Forms and Submission Requirements web page, note 58.  
99 See section 314.50(e)(1). 
17   
exhibit batch(es) of the drug product.  Applicants should clearly identify the drug 
substance lot(s) used in any BE studies. 
 
3.2.S.4.5 Contains a justification of the specification, including, but not limited to, 
references to compendia (e.g., the USP, the European Pharmacopeia, and the Japanese 
Pharmacopeia), the ICH, and/or the RLD analysis.  FDA recommends that applicants 
complete the Summary Tables for the Listing and Characterization of Impurities and 
Justification of Limits in Drug Substance and Drug Products.100   
 
3.2.S.5 Contains information about the reference standards or materials.  Appropriate 
certification, characterization, and qualification information should be provided for the reference 
standards of the drug substance and impurities.      
 
3.2.S.6 Contains information about the container closure systems.101  If the application contains a 
sterile substance for use in a sterile drug product, this section will also contain both a description 
of the container closure system used for the drug substance and a validation of the container 
closure integrity.  The applicant may refer to the DMF. 
 
3.2.S.7 Contains stability information.   
 
3.2.S.7.1 Contains stability summary and conclusions.  The applicant may refer to the 
DMF for complete stability data.  However, the retest date or expiration date of the API 
should, at a minimum, be provided at both the drug product manufacturing site and the 
drug substance manufacturing site.102  
 
3.2.S.7.2 Contains the postapproval stability protocol.  The applicant may refer to the 
DMF. 
 
3.2.S.7.3 Contains stability data.  The applicant may refer to the DMF. 
 
2.  Drug Product 
 
3.2.P contains detailed information known about the drug product.103  During the development of 
the application, applicants should review the ICH guidance for industry Q8(R2) Pharmaceutical 
Development (Rev. 2), the guidance for industry Submission Documentation for Sterilization 
Process Validation in Applications for Human and Veterinary Drug Products, and the product-
specific CMC guidances for industry (e.g., metered dose inhalers and nasal sprays), as 
applicable.  A drug product supplied with a reconstitution diluent should include a separate 
section 3.2.P with the diluent information.  Additionally, a drug product supplied with multiple 
                                                 
100 See the Abbreviated New Drug Application (ANDA) Forms and Submission Requirements web page, note 58. 
101 See the guidance for industry Container Closure Systems for Packaging Human Drugs and Biologics. 
102 See the guidances for industry ANDAs:  Stability Testing of Drug Substances and Products and ANDAs:  Stability 
Testing of Drug Substances and Products:  Questions and Answers. 
103 Section 314.50(d)(1)(ii). 
18   
active tablets and inert tablets should include a separate section 3.2.P for each strength of active 
tablets along with a separate section 3.2.P for the inert tablets. 
 
3.2.P.1 Contains the description and composition of the drug product.  For each drug strength,104 
applicants should provide:  
 
(1)  The quantitative composition and function of each component in their generic drug 
product, include any solvents and processing aids that are used during the manufacture 
of the drug product 
 
(2)  Information related to the physical description of the product (tablet size, scoring) and 
comparison to the RLD105  
 
(3)  The quality standards (e.g., the USP or the National Formulary) of components; the 
composition of colors, flavors,106 and imprinting ink, if applicable  
 
(4)  The amounts of their inactive ingredients that are appropriate per the Inactive 
Ingredient Database107 (per dose or unit dose) and a justification, preferably in a tabular 
format, for those amounts  
 
(5)  A conversion from percentage to milligram (mg)/dose values for all components, as 
applicable 
 
(6)  A conversion from percentage to mg/milliliter (mL) and/or mg/vial for injectable and 
injection products, indicating the unit of percentage (weight/weight or weight/volume) 
for liquid dosage forms 
 
(7)  A conversion from percentage to mg/mL for oral solution products 
 
(8)  A conversion from percentage to mg/dose for dry powder to oral solution or oral 
suspension 
 
(9)  An identification and justification of any formulation overages or overfills that appear 
in the final product   
 
                                                 
104 ICH guidance documents indicate that the information for all strengths should be combined and presented 
together in one drug product section.  If the quality information is the same between all strengths, the data should 
appear only once.  See, e.g., the guidances for industry M4:  The CTD  Quality Questions and Answers/Location 
Issues and M2 eCTD:  Electronic Common Technical Document Specification 
105 See the guidances for industry Tablet Scoring:  Nomenclature, Labeling, and Data for Evaluation and Size, 
Shape, and Other Physical Attributes of Generic Tablets and Capsules.  
106 Flavor manufacturers can provide the composition information directly to the reviewer if the information is not 
available to ANDA applicants because of proprietary reasons. 
107 The Inactive Ingredient Database is available at https://www.accessdata.fda.gov/scripts/cder/iig/index.cfm.  
19   
(10)  A daily elemental iron calculation or statement of adherence to 21 CFR 73.1200108   
 
(11)  If the proposed product is packaged with a specific diluent, a demonstration that the 
diluent is qualitatively and quantitatively the same as the diluent packaged with the 
RLD  
 
(12)  For products that contain aspartame, a calculation of the amount of phenylalanine (mg 
per dosage unit)109   
 
(13)  For nonprescription products that contain potassium, calcium, magnesium, and/or 
sodium, a calculation for the potassium, calcium, magnesium, and/or sodium content of 
a single maximum recommended dose110  
 
(14)  For products that contain alcohol, a calculation of the absolute alcohol in terms of 
percent volume (volume/volume)111  
 
(15)  For antibiotics that contain sodium, a calculation for the sodium content (per 
tablet/capsule or per unit dose)   
 
For sterile products, applicants should include a brief description of the primary container 
closure system, as well as any secondary packaging, for each configuration in section 3.2.P.1, 
and detailed information on the primary container closure system and secondary packaging 
should be included in section 3.2.P.7.  
 
For generic drug products containing inactive ingredient changes permitted in accordance with 
 314.94(a)(9)(iii)-(v), applicants must also identify and characterize the changes and provide 
information that demonstrates that these changes do not affect the safety or efficacy of the drug 
product.112  (In other words, applicants must identify and demonstrate that any differences in the 
identity or amount of an inactive ingredient between the proposed product and the RLD product 
will have no effect on the safety or efficacy of the proposed product.)  Given that the nature of 
the data and information necessary to demonstrate safety and efficacy can vary by product, 
applicants should submit a controlled correspondence to GenericDrugs@fda.hhs.gov or consult 
the Product-Specific Guidances for Generic Drug Development website113 for current product-
specific data recommendations prior to their submission of the application. 
 
3.2.P.2 Contains the pharmaceutical development report (for the product and the manufacturing 
process) and the microbial attributes (container closure integrity testing report for sterile product 
                                                 
108 FDA recommends that applicants provide a calculation of elemental iron intake based on the maximum daily 
dose of the drug product. 
109 21 CFR 201.21. 
110 21 CFR 201.72, 201.70, 201.71 and 201.64, respectively. 
111 21 CFR 201.10(d)(2). 
112 Section 314.94(a)(9)(iii)-(v). 
113 Product-Specific Guidances for Generic Drug Development web page, note 55. 
20   
and the antimicrobial effectiveness testing for multi-dose sterile products, and if the sterile drug 
product is packaged, single-use/dose/multi-dose and/or pharmacy bulk.)    
 
If the applicant has moved toward a Quality by Design approach,114 applicants may demonstrate 
this approach in section 3.2.P.2.  Applicants are encouraged to review FDAs Quality by Design 
for ANDAs:  An Example for Modified Release Dosage Forms and An Example for Immediate-
Release Dosage Forms.115  For sterile products that are reconstituted (or further diluted) and 
stored prior to administration, the applicant should provide microbiological studies to support the 
worst-case postconstitution or postdilution storage times, diluents, and conditions that are stated 
in the product package insert labeling.  The study should be a risk assessment that shows that 
adventitious microbial contamination does not grow (generally accepted as no more than 
0.5log  growth) under the specified storage conditions.116  
10
 
The applicant should include:  
 
(1)  A table comparing the equipment, process parameters, and in-process controls for all 
exhibit and commercial batches 
 
(2)  The procedures for reprocessing/reworking, if applicable  
 
(3)   The batch reconciliation data 
 
The applicant should clearly indicate which manufacturing process: 
 
(1)  Was used in the preparation of the BE batch(es) 
 
(2)  Is proposed for commercial production 
 
3.2.P.3 Contains information about the manufacture of the generic drug product.  
 
3.2.P.3.1 Contains information about the drug product manufacturer(s), including the:  
 
(1)  Name and full address of the facility(ies) of each manufacturer, including the 
contractors, and each proposed production site or facility involved in the 
manufacturing and testing 
 
(2)  Contact information for an agent at the facility (including phone and fax 
numbers and email addresses) 
 
(3)  U.S. agents name, if applicable 
                                                 
114 Quality by Design is defined as systematic approach to development that beings with predefined objectives and 
emphasizes product and process understanding and process control, based on sounds science and quality risk 
management.  See the ICH guidance for industry Q8(R2) Pharmaceutical Development.  
115 See the Question-Based Review for CMC Evaluations of ANDAs web page, note 76.  
116 See MAPP 5016.1 Applying ICH Q8(R2), Q9, and Q10 Principles to CMC Review. 
21   
 
(4)  Function or responsibility of the manufacturer117  
 
(5)  Current good manufacturing practice certifications for both the applicant and 
the drug product manufacturer (if they are different entities) 
  
(6)  Central File Number, Facility Establishment Identifier, and Data Universal 
Numbering System numbers, if known  
 
This section should also contain all facilities listed on Form 356h as well as all research and 
development manufacturing and testing sites that generated data to support the application in 
accordance with  314.50(d)(1)(ii)(b).  All testing labs that perform functions integral to the 
control strategy, including but not limited to characterization and comparison of molecules, 
comparative analytical testing, and comparability testing labs, should be listed.  For testing sites, 
applicants should include any testing sites that (1) generate stability testing/release data and BE 
data to support the application and (2) are used for commercial testing.   
 
3.2.P.3.2 Contains the batch formula for the generic drug product, including:  (1) the 
amounts of the components including processing aids, if any, that come into contact with 
the drug substance or product during any stage of the manufacture (quantitative 
comparison, including the total numbers of dosage units, between the pilot scale and 
commercial scale in a tabular form recommended) and (2) an indication and justification 
of any overage(s) or weight adjustment(s) used.  The applicant should clearly identify the 
formulation used in any BE studies, including the study identification number.   
 
3.2.P.3.3 Contains a complete description of the manufacturing process and controls, 
including:  
 
(1)  A description of the manufacturing process and facility.  (For a sterile drug 
product, this section should contain a description of the manufacturing and 
sterilization processes (e.g., the sterilization and/or depyrogenation of the 
primary packaging, the product contact manufacturing equipment, and the bulk 
drug product) and the associated manufacturing in-process controls.) 
  
(2)  A manufacturing process flowchart showing the process flow, applicable 
process parameters, and in-process controls.  If process analytical technology 
methods are used, applicants should indicate those methods in the 
manufacturing flowchart. 
  
(3)  The master production batch record(s) for the largest intended production runs 
(i.e., commercial batch records) that is/are no more than 10 times the exhibit 
batch(es). 
  
                                                 
117 Applicants are encouraged to provide the complete testing description if the facility performs testing on the drug 
substance, the drug product, or both.   
22   
(4)  The master packaging record(s) for the intended marketing container(s).  (If 
commercial scale batch records are not written in English, applicants must 
submit an English translation for them.118) 
 
(5)  An indication whether the drug product is a sterile product. 
  
(6)  A reprocessing statement in accordance with 21 CFR 211.115.  
 
3.2.P.3.4 Contains 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. 
 
3.2.P.3.5 Contains information to demonstrate that the manufacturing process produces a 
dosage form that meets the product specifications, including an evaluation of the data 
generated for the critical material attributes and the critical process parameters that were 
found to meet the established scale-up guideline and/or acceptance criteria.  (For a sterile 
product, this section should contain a validation of the sterilization processes (such as 
validation (bacterial retention studies) of the sterilizing grade filters) and/or the 
depyrogenation processes (such as the processes for the sterilization and/or 
depyrogenation of the primary packaging, the product contact manufacturing equipment, 
and the bulk drug product) and the manufacturing processes that impact the sterility 
assurance of the drug product.)119 
 
3.2.P.4 Contains information on the control of the excipients, including the identity of the source 
of inactive ingredients (including the supplier and the suppliers address) and the grades (e.g., 
compendial or noncompendial).   
 
3.2.P.4.1 Contains the testing specifications, including the retest schedule and the 
excipient manufacturers or suppliers COA(s). 
 
3.2.P.4.2 Contains the analytical procedures for the noncompendial methods used for 
testing the excipients.  For compendial excipients, applicants should reference the USP or 
the National Formulary but need not mention the analytical procedure.  
 
3.2.P.4.3 Contains the validation data of the noncompendial or in-house analytical 
procedures.   
 
3.2.P.4.4 Contains a justification of the specifications and includes:  (1) the applicants or 
the drug product manufacturers COA(s), (2) the residual solvents statement(s) from the 
                                                 
118 Section 314.50(g)(2). 
119 See the guidance for industry Submission Documentation for Sterilization Process Validation in Applications for 
Human and Veterinary Drug Products and MAPP 5040.1 Product Quality Microbiology Information in the 
Common Technical Document  Quality (CTD).  
23   
manufacturer(s), and (3) the bovine spongiform encephalopathy, transmissible 
spongiform encephalopathy, and melamine certifications, as applicable.120 
 
3.2.P.5 Contains information on the control of the drug product.   
 
3.2.P.5.1 Contains the specifications for the drug product, including the microbiological 
specifications (e.g., the microbial limits, sterility, and bacterial endotoxins), as applicable.  
These specifications should include the tests, acceptance criteria, and references to 
methods in a tabular format.121     
 
3.2.P.5.2 Contains a description of the analytical procedures (compendial and/or in-
house) used for testing the drug product, including any microbiological tests, as 
applicable.  For sterile drug products, this section should contain the methods for the 
product release tests (e.g., sterility tests or bacterial endotoxins tests (if applicable)).  
 
3.2.P.5.3 Contains the validation of the analytical procedure, including:  
 
(1)  The full validation reports for the in-house methods and their equivalence to 
USP procedures, if available for the drug product 
  
(2)  A verification of USP General Chapter <1226> procedures, if referenced 
  
(3)  The legible spectra and chromatograms for reference standards and test samples 
  
(4)  The Sample Statement(s) of Availability and identification of the finished 
dosage form of the drug products122, 123  
 
For sterile drug products, this section should contain the validation procedures and results 
for the microbiological analytical tests (e.g., sterility tests or bacterial endotoxins tests (if 
applicable)). 
 
3.2.P.5.4 Contains the batch analysis, including the executed COAs for all presentations 
and/or strengths of the finished dosage form.  The applicant should clearly identify the 
drug product batch(es) used in any BE studies, including the study identification number.  
 
                                                 
120 See the guidance for industry Pharmaceutical Components at Risk for Melamine Contamination.  
121 For products requiring a bacterial endotoxin specification (i.e., when a USP monograph reports an endotoxins 
specification for a parenteral or intrathecal drug product), the applicant should alternatively propose a bacterial 
endotoxins specification based on the maximum patient dosage prescribed in the package insert labeling, not based 
on the USP monograph.  The acceptance criteria for the maximum endotoxins dose to a patient are established in 
USP General Chapter <85>. 
122 Section 314.50(e)(1). 
123 Applicants are to provide method validation or verification reports for all analytical methods in section 3.2.P.5.3. 
24   
3.2.P.5.5 Contains the characterization of impurities.124  FDA recommends that 
applicants control all degradation products and process solvents if they are used during 
the manufacture of the finished dosage form.  FDA also recommends that applicants 
complete the Summary Tables for the Listing and Characterization of Impurities and 
Justification of Limits in Drug Substance and Drug Products.125 
 
3.2.P.5.6 Contains the justification of the specifications, including but not limited to 
references to compendia (e.g., the USP or the Japanese Pharmacopeia), the ICH, and/or 
the RLD analysis.  FDA recommends that applicants complete the Summary Tables for 
the Listing and Characterization of Impurities and Justification of Limits in Drug 
Substance and Drug Products.126 
 
3.2.P.6 Contains information about the reference standards or reference materials used for testing 
the drug product. 
 
3.2.P.7 Contains information on the container closure system, including:  
 
(1)  A summary of the primary and/or secondary container closure system (including data 
for any resin used and technical diagrams/drawings of the container closure 
components, a statement whether the closure for each proposed packaging 
configuration is child resistant or non-child resistant, and a description of markings on 
the cap/ferrule overseals127)  
 
(2)  The component specifications, including dimensional (drawing) and test data for each 
packaging component received by the applicant128  
 
(3)  The packaging configuration(s) and size(s)  
 
(4)  The container closure testing data in accordance with USP General Chapters <660>, 
<661>, and <671> (for solid oral, dosage forms, test for water permeation and light 
transmission; for liquids, test for leachable, extractables, and light transmission) 
  
(5)  The source of the container closure system supply and the suppliers address129    
 
                                                 
124 See the guidance for industry ANDA Submissions  Refuse to Receive for Lack of Justification of Impurity 
Limits. 
125 See the Abbreviated New Drug Application (ANDA) Forms and Submission Requirements web page, note 58.  
126 Id.  
127 See USP General Chapter <7>. 
128 See the guidance for industry Container Closure Systems for Packaging Human Drugs and Biologics. 
129 See the guidance for industry Container Closure Systems for Packaging Human Drugs and Biologics.  See also 
the draft guidance for industry Selection of the Appropriate Package Type Terms and Recommendations for 
Labeling Injectable Medical Products Packaged in Multiple-Dose, Single-Dose, and Single-Patient-Use Containers 
for Human Use.  When final, this guidance will represent the FDAs current thinking on this topic. 
25   
For controlled substances, the applicant should provide a description of the tamper-evident 
properties of the container closure system as described in 21 CFR 1302.06.  For OTC products, 
the applicant should confirm that the container closure system meets the requirements of 21 CFR 
211.132. 
 
3.2.P.8 Contains the stability data130, 131   
 
3.2.P.8.1 Contains the stability summary and conclusions for the finished dosage form, 
including:  
 
(1)  The preapproval stability protocol  
(2)  The proposed expiration dating period for marketing packaging  
(3)  The proposed expiration dating period for bulk packaging, if applicable  
(4)  A storage temperature statement   
 
3.2.P.8.2 Contains the post-approval stability protocol.  If the applicant and drug product 
manufacturer are different  entities, stability protocols should be provided by the 
applicant.  This section should also contain analytical procedures and testing schedules 
for maintenance of the microbial product quality (e.g., the container closure 
integrity/sterility, bacterial endotoxins, and microbial limits), as appropriate.132  
 
3.2.P.8.3 Contains stability data, including:  
 
(1)  Accelerated and long-term data 
 
(2)  Intermediate stability data, if applicable133  
 
(3)  The batch numbers on the stability records that are the same as the test batch  
 
(4)  The date the stability studies were initiated  
 
                                                 
130 See the guidances for industry ANDAs:  Stability Testing of Drug Substances and Products and ANDAs:  Stability 
Testing of Drug Substances and Products:  Questions and Answers.  
131 FDA recommends that applicants use either three pilot-scale batches or two pilot-scale batches plus one small-
scale batch with both accelerated and long-term data provided for each batch covering a period of no less than 6 
months (180 days).   
132 See the guidance for industry Container and Closure System Integrity Testing in Lieu of Sterility Testing as a 
Component of the Stability Protocol for Sterile Products.  
133 The applicant should provide either three pilot-scale batches or two pilot-scale batches and one small-scale batch 
with both accelerated and long-term data provided for each batch covering a period of no less than 6 months (180 
days) and with data from three time points (e.g., 0, 3, and 6 months).  However, if 6 months of accelerated data show 
a significant change or failure of any attribute in one or more batches, the applicant should also include 6 months of 
intermediate stability studies at the time of submission.  See the guidance for industry ANDA Submissions  Refuse-
to-Receive Standards (Rev. 2).  
26   
(5)  The date that each stability sample was removed from the stability chamber for 
each testing time point134  
 
(6)  Data on all presentations of the container-closure system 
 
For primary batches of liquids, solutions, semi-solids, and suspensions, the product 
should be placed into worst-case and non-worst-case scenarios.  For post-approval 
stability studies, the applicant should pick the worst-case orientation for the study.   
 
The following information and data can also be included in this section:  
 
(1)  One-time special stability studies conducted to confirm the quality of the 
constituted drug products (for example, parenterals and/or powders 
reconstituted with diluents and/or drug admixtures) per the labelings 
instructions 
  
(2)  One-time thermal cycling studies (freeze-thaw/heat-cool), as applicable 
  
(3)  One-time in-use stability studies for oral liquids and other dosage forms (e.g., a 
solution to be used within a certain period of opening the container per labeling 
instructions, compatibility with a dropper when provided as part of the container 
closure system), as applicable 
  
3.  Appendices  
 
3.2.A.2 Contains an appendix for the Adventitious Agents Safety Evaluation for sterile products.  
This section will contain a description of the processes used to control for potential 
contamination with adventitious agents (e.g., transmissible spongiform encephalopathy and 
viruses).  These processes may include assays to detect adventitious agents and actions taken to 
avoid them, as well as procedures to eliminate or inactivate them.   
 
4.  Regional Information 
 
3.2.R Contains regional information for the drug substance and the drug product.135     
 
3.2.R.1.S Contains the executed batch records for the drug substance.  Applicants may refer to 
the DMF(s) for this information.  If no DMF is referenced in the application, applicants should 
provide the executed and blank master batch records.  The executed records should clearly 
identify the drug substance lot(s) used in any BE studies. 
 
3.2.R.2.S Contains any comparability protocols proposed for the drug substance.136   
                                                 
134 See the guidance for industry ANDAs:  Stability Testing of Drug Substances and Products.  
135 Section 314.50(d)(1)(ii)(b). 
136 See the draft guidance for industry Comparability Protocols  Chemistry, Manufacturing, and Controls 
Information.  When final, this guidance will represent the FDAs current thinking on this topic. 
27   
 
3.2.R.3.S Contains the methods validation package for non-USP drugs.  This information may 
also be placed in section 3.2.S.4.3. 
 
3.2.R.1.P.1 Contains the executed batch records137 that include:  (1) a copy of the executed batch 
record(s) with equipment specified and the packaging records (the packaging and labeling 
procedures); (2) the batch reconciliation and label reconciliation for the theoretical yield, the 
actual yield, and the packaged yield, all in a tabular format; and (3) the bulk package 
reconciliation for any bulk packaging that is considered a commercial container.  The bulk 
package reconciliation is recommended if the bulk packaging is used to achieve the minimum 
package requirement.  As part of the bulk package reconciliation recommendation, the applicant 
should submit bulk package stability data in section 3.2.P.8.3.138     
 
3.2.R.1.P.2 Contains information on components including but not limited to the 
applicants and suppliers COAs for the drug substance lots, inactive ingredients lots, and 
packaging components lots that are contained in the exhibit batches of the drug product, 
as well as the suppliers address.  
 
3.2.R.2.P Contains the comparability protocols for the drug product, if applicable.139   
 
3.2.R.3.P Contains the methods validation package.  This package may also be contained in 
section 3.2.P.5.3. 
 
5.  Literature References  
 
3.3 Contains copies of any documents referred to in the application.  The documents may include 
published articles, official meeting minutes, or other regulatory guidance or advice provided to 
the applicant.  FDA recommends that these documents be provided in text-based PDF files.    
 
D.   Module 4  Nonclinical Study Reports 
 
ANDAs generally do not contain data that are typically included in Module 4.  If nonclinical 
study reports or safety assessments are submitted in support of a proposed specification (i.e., 
toxicology studies to qualify (1) impurities per the ICH guidances for industry Q3A140 and 
                                                 
137 If the batch records are not written in English, applicants must submit an English translation for them.  Section 
314.50(g)(2). 
138 If the bulk package is to be shipped, the applicant should submit accelerated stability data at 0, 3, and 6 months; 
if the bulk package is warehoused only for repackaging, the applicant may provide real-time stability data at 0, 3, 
and 6 months.  The applicant should provide bulk package labeling in section 1.14.1 and bulk package container and 
closure information in section 3.2.P.7. 
139 See the draft guidance for industry Comparability Protocols  Chemistry, Manufacturing, and Controls 
Information. 
140 See the ICH guidance for industry Q3A Impurities in New Drug Substances (Rev. 2). 
28   
Q3B(R2),141 (2) residual solvents, (3) leachables, or (4) excipients), these reports or assessments 
should be included in Module 4. 
 
E.  Module 5  Clinical Study Reports 
 
Module 5 contains all of the clinical study report data needed to support the application and to 
demonstrate that the generic drug product is bioequivalent to the RLD.142  To facilitate the 
submission of complete data, FDA develops product-specific guidances,143 summary data tables 
(as referenced in section III.B.2 of this guidance),144 and multiple guidances on 
biopharmaceutics.145  Applicants should use an eCTD Study Tagging File for each study 
submitted.146  
 
1.    Complete Study Data 
 
5.2 Contains the tabular listing of all clinical studies (e.g., pivotal, pilot, and failed studies) 
conducted.  
  
5.3 Contains the clinical study reports and related information. 
 
5.3.1 Contains the complete study data for the biopharmaceutic studies147 and the lot 
numbers and strength of the products used in the BE study(ies).  Applicants should 
document the study type.   
 
5.3.1.2 Contains reports of the comparative BA and BE studies (e.g., fasting or fed studies).  This 
section should also contain information of in vivo BE studies including, but not limited to:148 
 
  A synopsis of the study  
  A study report  
  The studys protocol and amendments  
                                                 
141 See the ICH guidance for industry Q3B(R2) Impurities in New Drug Products (Rev. 2). 
142 Section 314.94(a)(7). 
143 See the Product-Specific Guidances for Generic Drug Development web page, note 55.  
144 See the Abbreviated New Drug Application (ANDA) Forms and Submission Requirements web page, note 58.  
145 See the Biopharmaceutics guidances website, note 56. 
146 See ICH M2 EWG:  The eCTD Backbone File Specification for Study Tagging Files, available at 
http://estri.ich.org/STF/STFV2-6-1.pdf. 
147 See the ICH guidance for industry M4E(R2):  The CTD  Efficacy (Rev. 1).  
148 See the FDA Study Data Standards Resources web page at 
https://www.fda.gov/ForIndustry/DataStandards/StudyDataStandards/default.htm to access the current FDA Data 
Standards Catalog. 
29   
  All case report forms  
  A list of the independent ethics committees or institutional review boards and consent 
and/or assent forms 
  The institutional review boards approval letters for the protocol, amendments, and 
consent/assent forms  
  A list and description of the investigators  
  The number of subjects enrolled in each study site 
  The signatures of the principal or coordinating investigator(s) or the sponsors 
responsible medical officer  
  A listing of the subjects receiving the test drug(s) from a specified batch  
  The randomizations scheme  
  The audit certificates and reports  
  A statistical analysis plan and amendments 
  Documentation of interlaboratory standardization methods of quality assurance 
procedures, if used149  
  The publications based on the study150  
  The important publications referenced in the report151 
  A list of the discontinued patients, including the specific reason for each 
discontinuation152 
  A list of subjects included in the per protocol (PP), modified/intent-to treat ((M)ITT), 
and safety populations153 
  A list of subjects excluded from the PP, (M)ITT, and safety populations154 
                                                 
149 See the Abbreviated New Drug Application (ANDA) Forms and Submission Requirements web page, note 58. 
150 Id.  
151 Id. 
152 Id. 
153 Id. 
154 Id. 
30   
  A reason for excluding the PP, (M)ITT, and safety populations for each subject155 
  Any protocol deviations, including the specific reason for each deviation  
  Demographic data  
  Drug concentration data  
  Treatment compliance rate data 
  The individual subjects response scores/data per visit  
  The adverse event listings  
  The concomitant medication listings  
  A listing of the individual laboratory measurements by subject  
  The site (identifier)  
  The individual subject data listings  
  The in vivo and/or in vitro BE study datasets 
  A summary dataset containing a separate line listing for each subject156 
  An analysis dataset containing a separate line listing for each visit per subject157 
  The individual analysis datasets (e.g., adverse events or concomitant medications)158 
  The analysis programs  
  The annotated case report form  
  The annotated electrocardiogram waveform datasets  
  The image files  
  The narrative safety reports for serious adverse events 
  Source data  
                                                 
155 Id. 
156 Id. 
157 Id. 
158 Id. 
31   
  In vitro BE study information159 
5.3.1.3 Contains in vitro-in vivo correlation study reports.   
 
5.3.1.4 Contains reports of bioanalytical and analytical methods.  If a method is used in multiple 
studies, the method and its validation should be included only once in section 5.3.1.4 and then 
referenced again in the individual study reports.  Additionally, 100% raw numerical data and 
20% chromatograms should be provided for each study.160 
 
Case report forms should be placed under the study to which they pertain and appropriately 
tagged.161   
 
The data provided in all of these sections should support the summary tables submitted in section 
2.7.  All comparative dissolution data from the in vitro-in vivo correlation study reports should 
be placed in section 2.7 with the dissolution summary tables.   
 
2.  Literature References 
 
5.4 Contains copies of any documents referred to in the application.  The documents may include 
published articles, official meeting minutes, or other regulatory guidance or advice provided to 
the applicant.  Applicants should submit one copy of all important references cited in the QOS or 
the individual technical reports contained in section 5.3.162  FDA recommends that these 
documents be provided in text-based PDF files. 
   
 
                                                 
159 This information may also be included in section 5.3.1. 
160 See the draft guidance for industry Bioanalytical Method Validation (Rev. 1).  When final, this guidance will 
represent the FDAs current thinking on this topic. 
161 See the ICH guidance for industry M4E(R2):  The CTD  Efficacy (Rev. 1). 
162 Id. 
32   
APPENDIX:  SUGGESTED COVER LETTER TEMPLATE1 
 
Date 
 
Heading:  Provide the pre-assigned abbreviated new drug application (ANDA) number, if  
    applicable  
Indicate, if applicable, that the submission is an original application  
Indicate that expedited review is being requested by providing the statement, 
Expedited Review Request 
 
Reference:   Provide the name of generic product name and strengths  
 
Dear Sir or Madam: 
 
Paragraph 1:   Provide the name of the applicant   
  Provide the name of the generic drug product and strengths 
  Provide the drug product packaging description as single patient-use or single 
dose, multiple dose, and/or pharmacy bulk 
 
Paragraph 2:  Provide the reference listed drug (RLD) application number 
  Provide the proprietary name, nonproprietary name, and drug product strengths as 
it appears on the RLD labeling  
  Provide the name of the RLD holder 
 
Paragraph 3:  Indicate whether the GDUFA2 fee has been paid 
  Provide the amount of any GDUFA fees that were paid 
  Provide the User Fee Payment ID Number 
  Indicate that a copy of the Generic Drug User Fee Cover Sheet is contained in 
section 1.1   
 
Paragraph 4:   Indicate whether a Pre-Submission Facility Correspondence (PFC) was submitted   
  Provide the date of any PFC submission 
 
Paragraph 5:  Indicate whether the application is for a combination product or a complex 
product (as defined in the GDUFA Reauthorization Performance Goals and 
Program Enhancements Fiscal Years 2018-2022 (GDUFA II Commitment 
Letter)) 
  Indicate whether Controlled Correspondence was used to develop the application 
  Provide the numbers of any Controlled Correspondence that were used to develop 
the application 
  Indicate that copies of any Controlled Correspondence are contained in section 
1.2 
                                                 
1 Applicants are not required to use this template.  However, if applicants utilize the template, they should use 
judgment in adapting the template to their specific needs. 
2 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. 
A-1 
   
  Indicate whether meeting minutes are contained in the application  
  Indicate that copies of any meeting minutes are contained in section 1.2 
  Indicate whether the Food and Drug Administration (FDA) reviewed any 
protocols or conducted telephone conferences with the applicant during 
development of the application 
  Indicate whether a suitability petition was approved in relation to this application  
  Indicate that the docket number of the suitability petition and a copy of FDAs 
approval letter are contained in section 1.12.11 
  Indicate whether a citizen petition was filed that relates to this application 
  Indicate that the docket number of the citizen petition, a copy of the petition, and 
FDAs response (if applicable) are contained in section 1.12.11  
 
Paragraph 6:  Indicate that Letters of Authorization for DMFs are contained in section 1.4.1 
  List all drug master files (DMFs) referenced in the application  
 
Product name  DMF number  DMF holder  FEI/DUNS  Fee status 
and address 
         
 
  Indicate whether any approved ANDAs are referenced in the application 
List all ANDAs referenced in the application  
   
Product name  ANDA  ANDA  FEI/DUNS  Fee status 
number  holder and 
address 
         
 
Paragraph 7:  Indicate whether any information or data in the application should be highlighted 
for a specific disciplines review 
  Indicate whether any method of sterilization (e.g., aseptic processing or terminal 
sterilization) was used for the drug product  
  Indicate that any pharmacological/toxicological data for review is contained in 
section 3.2.P.1  
 
Paragraph 8:  Identify the sites where the ANDA batches were manufactured (including each 
sites FEI or DUNS number) 
  Identify the sites where the marketed product will be manufactured for marketing 
(including each sites FEI or DUNS number) 
 
Paragraph 9:  Indicate the proposed drug product expiration date and the basis for the request is 
contained in section 3.2.P.8.1 
 
Paragraph 10: Provide the basis for the expedited review request (if applicable) 
 
Paragraph 11: Indicate whether a letter of Non-Repudiation Agreement for digital signatures was 
submitted to FDA 
A-2 
   
  Provide the date of any letter of Non-Repudiation Agreement for digital 
signatures 
 
Paragraph 12: Indicate the file structure (e.g., Microsoft Word, structured product labeling, or 
PDF) of the labeling 
 
Paragraph 13:  Indicate whether the RLD has a risk evaluation and mitigation strategy 
  Indicate that information on any proposed risk evaluation and mitigation strategy 
is contained in section 1.16 
 
Paragraph 14: Indicate that information related to the physical description of the product (e.g., 
the tablet size or scoring) and a comparison of the physical properties of the 
generic product to the physical properties of the RLD are contained in section 
3.2.P.1 
  Provide information about the tamper-resistant properties of the drug product 
   
Paragraph 15: Provide a summary table of subsections applicable to the ANDA 
 
Paragraph 16:  Provide a summary of any comparability protocol that is contained in the 
application 
 
Paragraph 17:  Provide the name and contact information for a technical point of contact 
 
Paragraph 18: Provide the signatorys contact information  
 
Signature 
   
 
A-3