Completeness 

Assessments for Type II 

API DMFs Under 

GDUFA 

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) 
 
 
October 2017 

Pharmaceutical Quality/CMC/Generics 
 
 
Revision 1
   
Completeness 

Assessments for Type II 

API DMFs Under 

GDUFA 

Guidance for Industry 

 
Additional copies are available from: 

Office of Communications,  Division of  Drug Information 
  
Center for Drug Evaluation  and Research 

Food and  Drug Administration 
 
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or 
 
 
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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)  
October 2017 

Pharmaceutical Quality/CMC/Generics 
 
 
Revision 1  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS  
 
 
 
I.   INTRODUCTION............................................................................................................. 1
  
II.   BACKGROUND ............................................................................................................... 2
  
III.   COMPLETENESS ASSESSMENT ................................................................................ 2 
 
A.   Information Confirmed During the Completeness Assessment ................................................. 3
  
B.   Check of Completeness Assessment Elements ............................................................................. 4 
 
IV.   COMPLETENESS ASSESSMENT OUTCOMES ........................................................ 5 
 
V.   API INFORMATION INCLUDED IN A GENERIC DRUG SUBMISSION ............. 6 
 
VI.   SUMMARY ....................................................................................................................... 6 
 
DEFINITIONS .............................................................................................................................. 7 
 
APPENDIX 1 ................................................................................................................................. 8 
 
i  Contains Nonbinding Recommendations 
 
Completeness Assessments for Type II API DMFs Under GDUFA 

1
 
Guidance for Industry  
 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA or Agency) on 
this topic. It does not establish any rights for any person and is not binding on FDA or the public.  You 
can use an alternative approach if it satisfies the requirements of the applicable statutes and regulations.  
To discuss an alternative approach, contact the FDA office responsible for this guidance as listed on the 
title page.  
 
 
 
 
I.  INTRODUCTION  
 
This guidance is intended for holders of Type II active pharmaceutical ingredient (API) drug 
master files (DMFs) that are or will be referenced in an abbreviated new drug application 
(ANDA), an amendment to an ANDA, a prior approval supplement (PAS) to an ANDA, or an 
amendment to a PAS (generic drug submissions).  The guidance explains that, as of October 1, 
2012, under the Generic Drug User Fee Amendments of 2012, commonly referred to as 
GDUFA:2  
 
   DMF holders are required to pay a DMF fee when first authorizing the reference of their 
DMF in a generic application3  
   Type II API DMFs must undergo an FDA completeness assessment (CA)  
 
The guidance makes recommendations about the information that should be included in the DMF 
to facilitate a GDUFA CA. The guidance does not apply to Type II API DMFs used to support 
new drug applications (NDAs), biologics license applications (BLAs),4 other submissions that 
are not generic drug submissions, or any other types of DMFs.5  
 
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 Center for Drug Evaluation and Research and the Center for Biologics 

Evaluation and Research at the Food and Drug Administration. 
 
2 Public Law 112-144, Title III. 

3 For these purposes, such  authorization is deemed to have  occurred when the DMF is referenced  on or after 

October 1, 2012, in a generic drug submission  by an initial letter of authorization, Section  744B(a)(2)(A) of the 

Federal Food, Drug, and Cosmetic Act (FD&C Act) (21  U.S.C. 379j-42(a)(2)(A). 

4  Type II API, API intermediate, and drug product DMFs are not used to support BLAs submitted pursuant to 
 
sections 351(a) and 351(k) of the Public Health  Service Act (42 U.S.C. 262).  

5 See section  744A(7)  of the FD&C Act (21  U.S.C. 379j-41(7)). 

 
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  Contains Nonbinding Recommendations 
 
 
 
II.  BACKGROUND  

 
Under GDUFA, beginning October 1, 2012, the holder of a Type II API DMF must pay a one-
time DMF fee when the DMF is first referenced in a generic drug submission submitted to FDA 
on the basis of a letter of authorization (LOA) from the DMF holder.6  Also under GDUFA, 
holders of Type II API DMFs that were evaluated before October 1, 2012, must pay a one-time  
fee for the DMF when their DMF is first referenced in a new ANDA, an ANDA or PAS 
amendment, or an ANDA PAS on or after October 1, 2012.7  Only Type II API DMFs for use in 
generic drug submissions incur this one-time fee.  
 
Under GDUFA, Type II API DMFs intended for reference in a generic drug submission for 
which the fee is paid will undergo a CA. Section 744B(a)(2)(D)(iii) of the FD&C Act requires 
FDA to make publicly available on its Web site a list of DMF numbers that correspond to DMFs 
that, having successfully undergone a CA in accordance with criteria to be published by FDA, 
are available for reference. 
 
Although the requirement for a CA for Type II API DMFs is new, FDA has previously evaluated 
DMFs in accordance with the criteria set out in the GDUFA Completeness Assessment Checklist 
for Type II API DMFs (CA Checklist), attached to this guidance as Appendix 1.  In order to 
ensure adequate time for the CA, FDA strongly encourages the DMF holder to submit a 
complete DMF and pay the DMF fee at least 6 months prior to the submission of an ANDA or 
PAS that will rely on the DMF. When submitting a DMF, the DMF holder should also submit 
Form FDA 3794, the Generic Drug User Fee Cover Sheet, which includes the minimum  
information necessary for FDA to determine whether a DMF holder has satisfied all relevant user 
fee obligations.8   
 
DMF holders are encouraged to submit their DMFs using the Electronic Common Technical 
Document (eCTD) format.9  More information is available on the eCTD format on FDAs Web 
site.10   
 
 
III.   COMPLETENESS ASSESSMENT 
                                                 
6  Section 744B(a)(2)  of  the  FD&C  Act (21 U.S.C. 379j-42(a)(2)).  For discussion of  LOAs, see 21  CFR 314.420(b) 

and 314.50(g)(1).  

7 The fee amount will be announced in the Federal Register not later than  60 days before the start of the fiscal year 

(generally on  or about August 1  of the previous  fiscal year).  
 
8 See http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM322676.pdf. 

9 Note that 24  months after the guidance for industry Providing Regulatory Submissions  in Electronic Format   

Certain  Human Pharmaceutical Product Applications and  Related  Submissions Using the eCTD Specification is 

finalized (i.e., May 5, 2017), DMFs will be required to  be submitted using the eCTD format pursuant to the 

implementation timeline identified in the final guidance. 

10 See information about electronic submissions at 
 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/uc 
m153574.htm. 
 
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  Contains Nonbinding Recommendations 
 
FDA will perform a CA once a DMF holder files a Type II API DMF11 with the Form FDA 3794 
and there is an initial verification of the fee payment.  The CA does not replace the full scientific 
review, which determines whether the information contained in the DMF is adequate to support 
an ANDA regulatory action. 
 
In brief, FDA will undertake a CA to determine the following: 
  
   Is the DMF active?   
   Has the fee been paid?  
   Has the DMF been previously reviewed?  
   Does the DMF pertain to a single API?   
   Does the DMF contain certain administrative information?   
   Does the DMF contain all the information necessary to enable a scientific review?12  
   Is the DMF written in English?13  
 
FDA will conduct the CA by determining the answers to a series of questions listed in the CA 
Checklist, which is included in Appendix 1. DMFs for which the fee has been paid and which 
have been found complete in accordance with the criteria for a CA set out in the CA Checklist 
will be identified on FDAs public Web site as available for reference in support of a generic 
drug submission. 
 
For complex APIs, in addition to the recommendations in the CA Checklist, DMF holders should 
ensure the DMF provides the data necessary for the Agency to review the DMF with respect to 
active ingredient sameness. Information on active ingredient sameness is discussed in the 
products specific bioequivalence (BE) guidance when it becomes available on FDAs Web 
site.14   
 
In accordance with the Generic Drug User Fee Amendments Reauthorization Performance Goals 
and Program Enhancements (GDUFA II Commitment Letter),15 FDA committed to complete the 
initial CA review for 90% of Type II API DMFs within 60 days of the later of the date of DMF 
submission or DMF fee payment. 
 
A.   Information Confirmed During the Completeness Assessment  
 
                                                 
11 See FDAs Web site on Drug Master Files at 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/DrugMasterFilesDMFs/d 

efault.htm. 

12 Id.  

13 If any part of the application  is in a foreign language, an accurate and complete English translation shall be  

appended to  such  part.  See 21 CFR 314.101(d)(5). 

14 For example, for enoxaparin  sodium:  listed sameness equivalence criteria in the draft  guidance include mode of
  
depolymerization, source material, physicochemical properties, disaccharide building blocks, fragment mapping, 

sequence of oligosaccharide species, and biological and biochemical assays.  If the appropriate product-specific data 

is not in the DMF, the DMF will be  deemed incomplete.  

15 Available at 

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM370352.pdf. 

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  Contains Nonbinding Recommendations 
 
FDA will use the CA Checklist to perform the CA.  At the top of the cover page of the CA 
Checklist, FDA will fill in basic information about the DMF, including its name, number, receipt  
date, and whether the DMF was submitted in electronic or paper format.   
 
The FDA will also note whether the primary DMF the ANDA references refers to any other 
DMFs (subject DMFs). A primary DMF can reference subject DMFs, which provide additional 
information needed to completely describe the manufacture of an API.16  Before submitting its 
DMF, the primary DMF holder should check with the holders of any referenced subject DMFs to 
make sure the subject DMFs are filed with FDA and FDA still considers them active.   
 
1.   Is the DMF Active?  
 
Before assigning a DMF to a reviewer for a CA, FDA will confirm that the DMF is active.17  If 
the primary DMF or any referenced subject DMFs on file at FDA are inactive, FDA will 
consider the primary DMF incomplete and send a letter notifying the DMF holder.   
 
2. Has the DMF fee been paid? 
 
Before assigning a DMF to a reviewer for a CA, FDA will confirm that the DMF fee has been 
paid. If it has not, FDA will not assign the DMF for CA.  ANDA applicants that reference a 
DMF for which a fee is due will be notified that the DMF holder has not paid the fee.  If the 
DMF fee is not paid within 20 days after notification, FDA will refuse to receive the ANDA 
referencing the DMF. 
 
3. Has the DMF been previously reviewed for chemistry, manufacturing, and 
controls (CMC) by FDA in the context of a review of a prior application?    
 
If FDA has reviewed the DMF for CMC after November 30, 2007, the DMF will be considered 
to have passed the CA without further analysis.  If the DMF was reviewed for CMC prior to 
November 30, 2007, a CA assessment will need to be performed. For all DMFs that have not 
previously received a full CMC review, a CA assessment will need to be performed.  If the DMF 
has not previously received this full review, it will be assigned to a reviewer for a CA.   
 
B.   Check of Completeness Assessment Elements   
 
FDA will complete the administrative part of  the CA Checklist (i.e., General Information) 
during the CA. If the DMF is incomplete, FDA will send the DMF holder a GDUFA DMF 
Incomplete Letter.  With certain exceptions specified in this guidance document, this letter will 
provide comments about each element that resulted in an incomplete designation for the CA. 
   
If an item is marked n/a and does not apply to the DMF, the element is treated the same as if it 
were marked yes.  
 
                                                 
16 For example, a subject DMF may describe the manufacture of a material used in producing the active ingredient.  

If a subject DMF does not meet the definition of a Type  II API DMF, it will not incur a DMF fee.  

17 Active is defined in the Definitions section of this  guidance. 
 
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  Contains Nonbinding Recommendations 
 
1. Is the subject of the DMF a single API produced by one manufacturing 
process? 
 
The subject of a DMF should be limited to one API and one manufacturing process.  If a DMF 
includes information on more than one API or more than one manufacturing process for an API, 
the DMF will be deemed incomplete.  If the DMF describes multiple APIs, the DMF holder 
should file separate DMFs for each API.  Similarly, if there are multiple manufacturing processes  
for an API, the DMF holder should file separate DMFs for each manufacturing process. 
 
2. 	Does the DMF holder need to submit a complete update?   
 
If the DMF is in paper format and it has been five years or more since the DMF received a 
complete update,18 or if there have been more than five amendments to the DMF, the DMF 
holder should provide a complete and comprehensive update to it.  If such a DMF has not 
received an update, FDA will consider the DMF incomplete.  The DMF holder must submit a 
complete update for FDA to determine whether it passes the CA.19  
 
FDA believes that the remainder of the CA Checklist is self-explanatory.  
 
 
IV.  COMPLETENESS ASSESSMENT OUTCOMES 
 
Following the CA, FDA will find the DMF either complete or incomplete.   
 
 	  If the DMF is found complete, FDA will post the DMF number on a publicly available 
list on FDAs Web site to indicate the DMF is available for reference by generic drug 
submission applicants.20   
 
 	  If the DMF is found incomplete, the CA findings and comments will be compiled in a 
GDUFA DMF Incomplete Letter to the DMF holder that explains why the DMF was 
deemed incomplete.  Information about the CA status of a DMF, other than the lack of a 
public listing on the FDAs Web site, will not be provided to anyone except the DMF 
holder and, as necessary, any generic drug submission applicant that the DMF holder has 
authorized to rely on the DMF. 
 
	   To remedy a GDUFA DMF Incomplete Letter and pass the CA, the DMF holder should 
submit an amendment to its DMF to correct the deficiencies identified in the Incomplete 
Letter, or, if FDA has determined that the DMF should undergo a complete update, the 
DMF holder should resubmit the DMF with that update.  FDA will then assess the 
                                                 
18 All changes must be reported as amendments.  Annual reports are  NOT to be used to report changes in the DMF. 
 
19 The requirement for a complete update does not apply to the DMF if the entire DMF is in eCTD format, which 

always presents the DMF in its current state.  The Agency highly encourages DMF holders to convert the entire 
 
DMF into an eCTD submission, which does not require reference to any  previous paper submission. 

20 For the public list of  DMFs available for reference, see http://www.fda.gov/gdufa. 

 
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  Contains Nonbinding Recommendations 
 
revised DMFs completeness.  If there are no deficiencies at this time, FDA will declare 
the DMF to be complete and to have passed the CA.   
 
	   Although a DMF may be deemed incomplete upon its first CA, FDA will work with 
DMF holders to provide guidance on how to revise the DMF so it may be found complete 
after resubmission. Once the DMF passes the CA, FDA will make the DMF number 
publicly available on its Web site.21  
 
 
V.  API INFORMATION INCLUDED IN A GENERIC DRUG SUBMISSION  
 
If a generic drug submission contains all the necessary API information and does not rely on 
information contained in a DMF, no CA will be performed.  Instead, this information will be 
evaluated during the ANDA filing review.22  However, because GDUFA requires collection of a 
one-time fee for API information included in a generic drug submission (i.e., an (a)(3)(F) fee),23  
the applicant submitting the generic drug submission containing the API information must pay 
this fee.  
 
 
VI.  SUMMARY  
 
Once the DMF fee is received, FDA will evaluate the DMF to make sure it meets the CA criteria.  
 
   If the DMF passes the CA, it will be found complete and the DMF number will be made 
publicly available on FDAs Web site.  
   If the DMF fails the CA, FDA will send a GDUFA DMF Incomplete Letter describing to 
the DMF holder the missing elements in its DMF. 
	   If the DMF holder addresses all the deficiencies and amends the DMF or completely 
updates the DMF per the CA request, the FDA will complete its CA.  If the DMF is then 
found complete, the DMF number will be made publicly available on FDAs Web site.  
	   If a generic drug submission contains all the necessary API information and does not 
reference a DMF, the generic drug submission applicant will be required to pay the 
(a)(3)(F) fee.  No CA will be conducted.  
 
                                                 
21 Under GDUFA, a condition for a Type II API DMF to  be considered available for reference is that it has not 
failed an initial completeness assessment (Section  744B(a)(2)(D)(ii)(II) of the FD&C Act).  FDA does not  interpret 
that provision  as disqualifying a DMF if it has ever failed a CA.  Instead,  FDA considers this condition to be  
satisfied when, after submission of an amendment or resubmission of the DMF to address deficiencies identified by 
FDA, FDA finds that the DMF has passed the CA. 
22 See guidance for industry  ANDA Submissions  Refuse-to-Receive Standards. 
23 Section 744B(a)(3)(F) of the FD&C Act.  
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DEFINITIONS 
 
Active pharmaceutical ingredient24 (as defined by GDUFA): 
  
(A) A substance, or a mixture when the substance is unstable or cannot be transported on 
its own, intended 
(i) to be used as a component of a drug; and 
(ii) to furnish pharmacological activity or other direct effect in the diagnosis, cure, 
mitigation, treatment, or prevention of disease, or to affect the structure or any 
function of the human body; or 
(B) a substance intended for final crystallization, purification, or salt formation, or any 
combination of those activities, to become a substance or mixture described in 
subparagraph (A). 
 
Active DMF:  A drug master file (DMF) for which the FDA has made a determination that the 
DMF was acceptable for filing administratively and is up to date.  
 
DMF holder:25  Designated owner of the DMF, which may be different from the U.S. agent 
listed as the contact. 
 
Generic drug submission:26  An abbreviated new drug application (ANDA), an amendment to 
an ANDA, a prior approval supplement (PAS) to an ANDA, or an amendment to a PAS.  
 
Letter of authorization (LOA):27  A written statement by the holder or designated U.S. agent or 
representative permitting FDA to refer to information in the DMF in support of another 
persons28 generic drug submission.  
 
Type II Active Pharmaceutical Ingredient Drug Master Files:29  The submission of API 
information to the FDA by the DMF holder who intends to authorize generic drug applicants to 
rely on the information to support submissions to the FDA without the holder having to disclose 
the information to the generic drug applicants.   
                                                 
24 Section 744A(2) of the FD&C Act. 

25 See 21 CFR 314.420(a).  

26 Section 744A(7) of the FD&C Act. 

27 See FDAs Web site on Drug Master Files at: 

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/DrugMasterFilesDMFs/d 

efault.htm. 

28 The word person includes individual, partnership, corporation, and association (section 201(e) of the FD&C 
 
Act.  

29 Section 744A(12)  of the FD&C Act; also see 21 CFR 314.420(a)(2).  

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APPENDIX 1 
 
GDUFA COMPLETENESS ASSESSMENT CHECKLIST FOR 
TYPE II API DMFs 
 
 
DMF NUMBER: 

DMF HOLDER:
    
DRUG NAME (subject): 

 
SUBMIT DATE:
     
RECEIVED DATE:   

Electronic or paper submission:   

 
DMF(s) referenced by the primary DMF being assessed, if applicable:    

 
 
 EXPEDITED ASSESSMENT per REQUEST from FDA by: (requestor name here) 
   
 
Primary reviewer:    Review recommendation for completeness  
               assessment:       
Date:         COMPLETE  INCOMPLETE   
 
1.  Has the GDUFA fee been paid?  Enter date paid:   
 
Yes     No   
 
2.   Is the DMF active?  
 
 Yes     No
  
 
  If no, DMF is INCOMPLETE per policy.  Issue Incomplete Letter to DMF holder. 

 
3.  Has the DMF been  reviewed, after November 30, 2007, for chemistry, manufacturing, and controls  (CMC) by  
FDA in the context of a review of  a prior application?   
       
 Yes     No   
 
If yes, the DMF is COMPLETE per policy. 
If no, review DMF with checklist. 
 
ADDITIONAL COMMENTS REGARDING THE DMF:   
 
 
 
 
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Checklist Review   
 
GENERAL INFORMATION  
      NOTE(S) 
  1.  Subject  of the DMF is a single  Yes     No   For #1:  The DMF is limited to: (i) 
API produced  by one    one API, although multiple 
 
manufacturing process.     manufacturing  sites for a single API 
        are permitted when the same process 
2.   For previously submitted   is used in each of those sites; (ii) one 
Yes      No  
  DMFs, the DMF holder  has  manufacturing process,  although  
 
submitted a complete update.  certain process alternatives/changes 
   
  may be permissible with sufficient 
 
3.  Provides current Good   supportive  information provided.  
 
Yes      No  
Manufacturing Practice (cGMP)  Examples include: validated 
 
  Statement of Commitment.  reprocess/rework procedures; 
 
  micronization leading to different  
  4.  Provides complete name,    particle  sizes (excluding nano  
  address, and contact information  Yes      No   particles); addition of a stabilizing 
for holder.     agent for stability purposes; and 
 
    minor process variation that leaves 
 
5. Designates U.S. Agent for    the chemical transformation the 
 
non-U.S. DMF holders, with   Yes    No   n/a  same, with little risk to the impurity 
 
appropriate designation letter.     profile.  
 
     
  6. Contains Letters of     A separate DMF should be filed  for:  
  Authorization for any DMFs  Yes   No   n/a  different salt form; different synthetic 
  referenced to support this DMF.    route; and significant process 
      variation resulting in a different  
  7.   All DMFs referenced in this    impurity profile and  requiring a 
  DMF have been filed with  the   Yes   No   n/a  different control strategy.  
Agency and are active.     
 
    For the definition of API and the 
 
8.  Contains label with storage    Agencys interpretation,  refer to  
 
conditions and expiry/retest date.  Yes   No    GDUFA Q&A  guidance.  
 
     
9. Contains bovine spongiform     For #2:  Five  years or  five amendments  
encephalopathy (BSE)/    are a good guide to determine the 
transmissible spongiform   Yes   No   n/a  necessity  for submission of  a complete  
encephalopathy (TSE)    update, because a large number of 
certification, if animal-sourced.    amendments with significant changes 
    make it difficult to determine the current  
10.  Contains information on     state of the information in the DMF.  
adventitious agents, if animal- Yes   No   n/a  The complete update should reflect the  
sourced.    current state of the process and not 
    require reference to any previous  
11.  Contains information on     submission for  information.  
presence of pesticides, if plant- Yes   No   n/a    
sourced.    The requirement for a complete 
  update  does not apply to the  DMF if  
the entire DMF is in electronic 
common technical document (eCTD) 
format, which always presents the 
DMF in its current state.  We highly 
encourage DMF holders to convert  
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  Contains Nonbinding Recommendations 
 
the entire DMF into an eCTD 
submission,  which does not  require 
reference to any previous paper 
submission.   
 
 
 
MODULE 2:  SUMMARIES30                  
eCTD No.      NOTE(S)  
2.3   12.  Contains a Quality Overall  Yes    No     n/a  For #12:   If a QoS is provided, the 
Summary (QoS).     Question-based Review (QbR) 
 
format is highly encouraged. 
 
 
MODULE 3:   QUALITY 
3.2 Body of Data 
3.2.S API [name, manufacturer]                                                                                   
eCTD No.      NOTE(S) 
3.2.S.1   General Information     
   
Contains complete General   
Information on the following: 
 
 
 
13.  Nomenclature.  
 Yes     No  
 
 
 
 
14.  Structure.  
Yes      No  
 
 
 
15.  General  Properties:  basic   
information regarding the general   Yes      No   
properties of the API.   
                                                 
30 DMF holders are highly encouraged to submit files in eCTD format.  See information about electronic  
submissions at  
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/ElectronicSubmissions/uc 
m153574.htm and ICH M4Q:  
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/CTD/M4_R1_Quality/M4Q__R1_.pdf.  Note that 24  
months after the guidance for industry Providing Regulatory Submissions  in Electronic Format   Certain Human  
Pharmaceutical Product Applications and Related  Submissions Using the eCTD Specification is finalized (i.e., May 
5,  2017), DMFs will be submitted using the eCTD format pursuant to the implementation timeline identified in the 
final guidance.  
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eCTD No.      NOTE(S) 
  Manufacture      
     
 
3.2.S.2.1 Contains complete     
Manufacturer Information on   
3.2.S.2    
the following for each site:   
 
   
 
16.  Name and full address(es) of   For #16:   Separate facilities used  for 
Yes     No  
the manufacturing facility(ies),   release testing of the API and for 
 
contact name  of on-site   additional processing  (e.g., 
 
individual,  phone and fax  micronization) should also be  listed.  
numbers, and e-mail address.      
    Central File Number (CFN), Facility 
    Establishment Identifier (FEI), and  
    Data Universal Numbering System  
    (DUNS) numbers should  be  provided  
if available. 
3.2.S.2.2 Contains Description 
 
 
of Manufacturing Process and 
   
Process Controls addressing the  
following:     
    For #17: For a fermentation 
17.  If the API is synthetic/semi- Yes    No   n/a  process, information pertaining to  
synthetic, provides complete    the quality and control of the 
synthetic scheme from     microorganism, cell bank systems, 
appropriately supported starting     and media components should be  
materials. Scheme includes    provided.  
structural representation with 
 
 
reagents, reaction conditions, 
 
molar ratio, etc.   
 
 
Yes    No     
18.   Flow chart for every stage.  
 
   
 
19.  Description of  the 
Yes     No    
manufacturing process.  
 
   
 
 
  For #20:   Justification for 
3.2.S.2.3 Contains information  designation of each starting material 
 
on the Control of Materials, as  should  be in agreement with the 
 
follows:  general principle outlined in  
  
  International Conference on  
 
Starting Material:   Harmonisation (ICH) Q11.  This can 
 
  include information, if applicable, 
20. Starting material, clearly  Yes   No    on:   
 
designated, with appropriate 
     Name, address, and contact 
justification.  
information of the manufacturer(s) 
 
 
of each proposed starting material. 
Yes     No  
21. Name of each manufacturer. 
     A flow diagram and description 
  outlining the synthetic route and 
Yes      No  
22.  Specification.   conditions of  each proposed  
 
  starting material. 
Yes      No  
23. Analytical method.     Discussion  of the impurities 
 
  (including residual solvents  and  
Yes      No   
inorganic impurities) arising  from  
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eCTD No.      NOTE(S) 
24. Certificate of Analysis (CoA)    the manufacturing process of each 
from manufacturer.   proposed starting material. 
 
  Yes     No      The ability of analytical 
25. CoAs from  the DMF holder.     procedures to  detect impurities in  
    the starting material. 
Reagents/Solvents:   Yes     No      The fate and purge of those 
26. Specifications.     impurities and their derivatives in  
    Yes     No   subsequent processing steps.  
27.  Representative CoAs.        How the proposed specification 
    for each starting material will 
  contribute to the control strategy.  
3.2.S.2.4 Contains information 
   
for Controls of Critical Steps 
  For #26: Specifications should 
and Intermediates, as follows: 
  clearly identify the test methods. For 
 
Yes     No   non-compendial methods, the  
28.   In-process controls and tests,  
  method description should be 
described for each critical step. 
  provided.  
 
   
Intermediates:     
    Yes      No    
29. Specifications for each   
 
identified intermediate.   
  Yes     No    
30. Analytical methods for each     
intermediate.      
     
3.2.S.2.5 Process Validation      
and/or Evaluation     For #31: If the  validation has been  
    performed, the DMF holder  should 
  Yes    No    n/a   provide a validation summary, 
31.  Contains a summary of 
  including  batch descriptions with  
Process Validation and/or  
  traceability among steps/stages, and 
Evaluation information.  
   Yes    No    n/a   analytical test results for the starting 
 
  materials, intermediates, in-process 
32.  Provides sterility assurance 
  controls, and final API,  preferably in  
data for sterile API. 
a tabular format.  
 
 
 
 
3.2.S.2.6 Manufacturing  For #32: The full sterilization 
 
Process Development  process validation and the method  
Yes     No   
  validation of sterility tests for the 
 
33.  Contains a summary of  sterilized API should be provided, 
Manufacturing Process  including but not limited to: 
Development.  description of the specific 
sterilization processes for the bulk 
drug substance and all associated 
manufacturing equipment,  
components, and containers/closures,  
description of  sterile processing  
areas, list of all filling  
lines/rooms/suites, legible floor plans 
for sterile API manufacturers,  
description of  environmental  
monitoring program for sterile 
  12
  Contains Nonbinding Recommendations 
 
eCTD No.      NOTE(S) 
products, validation data for 
sterilization  of bulk API, filter 
validation  data if applicable, 
validation  data for the sterilization  
and depyrogenation of the final  
container/closure system, validation 
data for the sterilization of all  
manufacturing equipment  and  
components, description of  process 
simulation/media fill program and  
associated  data from  media fill runs  
and container/closure integrity 
testing results.  
3.2.S.3   Characterization      
     
3.2.S.3.1 Provides information     
to support the Elucidation of      
Structure and other   
 
Characteristics of the API as   
 
follows:   
 
  For #34: Data interpretation should 
 
34. Characterization information  be provided; spectroscopic 
appropriate for the material (e.g.,  Yes     No   comparison with authenticated  
nuclear magnetic resonance    material (e.g., United States 
(NMR),  infrared (IR), ultraviolet    Pharmacopeia (USP) Convention 
(UV), mass spectrometry (MS),    reference standard), if available, is 
elemental analysis, etc.).    encouraged to  confirm the structure.   
     
3.2.S.3.2 Provides information     
on Impurities, as  follows:   
 
   
 
35.  A table including the  Yes      No   For #35:  Potential genotoxic 
name(s), structure(s), origin     impurities can be included in  this 
(degradant, process impurity) of   table or summarized in a separate 
 
observed/potential organic  table.  
 
impurities.   
 
 
 
36.  Information on  potential 
inorganic impurities (inorganic)  Yes      No  
(e.g., metal catalysts, reagents).   
   
37.  Potential residual solvents.  Yes      No   
   
3.2.S.4   Provides information to     For 3.2.S.4:  A summary of the 
support the Control of the    control strategy, as illustrated in  ICH 
API, as follows:    Q11, is highly encouraged.  
   
 
38.  Full test specification.    
 Yes     No  
     
39.  Description of the analytical      
methods. 
Yes      No     
 
  For #40: Method verification reports  
  13
  Contains Nonbinding Recommendations 
 
eCTD No.      NOTE(S) 
40.  Method  validation and/or     should be provided for compendial  
method verification reports.    Yes     No   methods, such as assay or related 
    substance by high-performance 
41.  CoAs for representative    liquid chromatography  (HPLC); the 
batches (batch analysis).    method equivalency study should be 
  Yes     No   provided  when an in-house method  
42.  Justification  for each     is used in lieu of a compendial  
specification.  method.   
 
 
Yes     No   
 
 
3.2.S.5   Provides information to      
support the Reference     
Standards or  Materials, as     
follows: 
   
 
  For #44: Qualification data on  in-
API: 
  house primary RSs includes 
 
  spectroscopic characterization and 
43. The source, lot #, CoA (for  
quantification  by mass balance.  
 Yes     No  
primary reference standard (RS) 
When a compendial RS is used as  
 
and working standard (WS)). 
the primary RS, the lot number and 
   
certificate are sufficient.  WSs  
44.  Qualification data on the     Yes    No  
should  be adequately qualified  
drug substance (DS) RS.    
against the primary RS.  
   
Spectroscopic comparison with 
Impurities:   
compendial reference standards, 
    
when available, is highly 
45.   The source, lot #, and CoA    Yes     No  
encouraged.  Data can be cross-
for RS and WS for each   
referenced to  3.2.S.3.2, if  
identified impurity.   
appropriate. 
   
 
46.  Qualification data on the     Yes    No    
For #46: See note for #44 above. 
impurity RS.   
   
3.2.S.6   Provides information to      
support the Container/Closure     
System, as  follows:     
     
47.  Description of  container/    
Yes     No  
closure system (including contact    
 
material and secondary material).   
 
   
 
48.  Certification statements for  For #48: The certification statement 
 
contact materials for use in  food   from the supplier should state that 
and drugs.   Yes     No   each primary packaging material for 
    the DS is safe to  use in contact with  
49. Manufacturer, specifications,    food, with an appropriate reference  
and representative CoA for    to the indirect food additive 
primary contact material and   Yes     No    regulations (21 CFR 174-186). 
functional secondary  packaging     
component.  
3.2.S.7   Provides information to      
support the Stability of the   
API, as follows:   
  14
  Contains Nonbinding Recommendations 
 
eCTD No.      NOTE(S) 
    
3.2.S.7.1 Stability Summary    
and Conclusions   
 
 
50. Indicates clearly the retest  
 Yes     No  
date or expiration date of API. 
 
 
 
 
 
 
 
3.2.S.7.2 Postapproval Stability  
Protocol and Stability    
Commitment   
   
51.  Provides stability protocol.  Yes      No  
   
52.  Provides stability  Yes      No  
commitment.   
 
 
3.2.S.7.3 Stability Data  
 
 
 
53.  Provides Stability Data. 
Yes      No  
 
MODULE 3: 3.2.R REGIONAL INFORMATION (API) 
 
eCTD No.       NOTE(S) 
3.2.R   Provides regional information,  For #54:  Yields, results of in-
  as follows:    process controls, and intermediate 
    analysis should be  provided  where 
3.2.R.1.S Executed Batch  appropriate. 
 
Records for API   
 
 
54.  Provides representative   
 
executed  batch records, with 
 Yes     No   
translation, where appropriate. 
 
 
 
 
  15