M4 Organization of the 
Common Technical Document 
for the Registration of 
Pharmaceuticals for Human Use 
 
 
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 
ICH 
 
  M4 Organization of the 
Common Technical Document 
for the Registration of 
Pharmaceuticals for Human Use 
 
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) 
  
October 2017 
ICH  
  Contains Nonbinding Recommendations 
 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  SCOPE OF THE GUIDANCE ........................................................................................ 2 
III.  GENERAL PRINCIPLES................................................................................................ 3 
IV.  ORGANIZATION OF THE COMMON TECHNICAL DOCUMENT ...................... 3 
V.  ANNEX: GRANULARITY DOCUMENT ..................................................................... 7 
APPENDICES FOR ECTD V4 SUBMISSIONS ............................................................................... 22 
 
 
 
 
  Contains Nonbinding Recommendations 
 
M4 Organization of the Common Technical Document for the 
Registration of Pharmaceuticals for Human Use 
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 create 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 staff responsible for this guidance as listed on the title 
page.   
 
 
 
 
I.  INTRODUCTION  
 
This is one in a series of guidances that provide recommendations for applicants preparing the 
Common Technical Document for the Registration of Pharmaceuticals for Human Use (CTD) for 
submission to the U.S. Food and Drug Administration (FDA).  This guidance presents the agreed 
upon common format for the preparation of a well-structured Common Technical Document for 
applications that will be submitted to regulatory authorities.  A common format for the technical 
documentation will significantly reduce the time and resources needed to compile applications 
for registration of human pharmaceuticals and will ease the preparation of electronic 
submissions.  Regulatory reviews and communication with the applicant will be facilitated by a 
standard document of common elements.  In addition, exchange of regulatory information 
between regulatory authorities will be simplified. 
 
This guidance replaces two FDA guidance documents, the 2001 guidance for industry M4 
Organization of the CTD and the 2005 Granularity Document Annex to M4 Organization of the 
CTD.  This merger reflects the 2002 addition of the Annex: Granularity Document into the 
Organization of the Common Technical Document for the Registration of Pharmaceuticals for 
Human Use. 
 
The guidance provides recommendations on the organization of the CTD and the electronic 
common technical document (eCTD) for Modules 2 through 5 providing direction on the 
location and hierarchy of headings within modules, document pagination and segregation, 
section numbering within documents, and the formatting of the table of contents.  The guidance 
provides separate tables describing the recommended granularity for paper and eCTD v3.2.2 
                                                 
1 This guidance was developed within the M4Q CTD and M8 eCTD Implementation Working Groups of the 
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and 
has been subject to consultation by the regulatory parties, in accordance with the ICH process. This document has 
been endorsed by the ICH Assembly at Step 4 of the ICH process in June 2016.  At Step 4 of the process, the final 
draft is recommended for adoption to the regulatory bodies of the European Union (EU), Japan, the United States, 
Canada, and Switzerland. 
    1    Contains Nonbinding Recommendations 
 
submissions, and for paper and eCTD v4 submissions, and includes Appendices for eCTD v4 
Submissions to facilitate the implementation of the next major version of the eCTD. 
  
In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidances means that something is suggested or recommended, but 
not required.  
 
II.  SCOPE OF THE GUIDANCE 
 
This guidance primarily addresses the organization of the information to be presented in 
registration applications for new pharmaceuticals (including biotechnology-derived and 
biological products). 
 
This guidance is not intended to indicate what studies are required.  It merely indicates an 
appropriate format for the data that have been acquired.  Applicants should not modify the 
overall organization of the CTD as outlined in the guidance.  However, in the Nonclinical and 
Clinical Summaries, applicants can modify individual formats if needed to provide the best 
possible presentation of the technical information, in order to facilitate the understanding and 
evaluation of the results. 
    2    Contains Nonbinding Recommendations 
 
III.  GENERAL PRINCIPLES 
 
Throughout the CTD, the display of information should be unambiguous and transparent, in 
order to facilitate the review of the basic data and to help a reviewer become quickly oriented to 
the application contents.  Text and tables should be prepared using margins that allow the 
document to be printed on both A4 paper (EU and Japan) and 8.5" x 11" paper (U.S.).  The left-
hand margin should be sufficiently large that information is not obscured by the method of 
binding.  Font sizes for text and tables should be of a style and size that are large enough to be 
easily legible, even after photocopying.  Times New Roman, 12-point font is recommended for 
narrative text.  Every page should be numbered, according to the granularity document.  
Acronyms and abbreviations should be defined the first time they are used in each module.  
References should be cited in accordance with the current edition of the Uniform Requirements 
for Manuscripts Submitted to Biomedical Journals, International Committee of Medical Journal 
Editors (ICMJE).2    
 
IV.  ORGANIZATION OF THE COMMON TECHNICAL DOCUMENT 
 
The CTD is organized into five modules.  Module 1 is region specific.  Modules 2, 3, 4, and 5 
are intended to be common for all regions.  Conformance with this guidance should ensure that 
Modules 2 through 5 are provided in a format acceptable to the regulatory authorities. 
 
Module 1.  Administrative Information and Prescribing Information 
This module should contain documents specific to each region; for example, application 
forms or the proposed label for use in the region.  The content and format of this module 
can be specified by the relevant regulatory authorities. 
 
Module 2.  Common Technical Document Summaries 
    Module 2 should begin with a general introduction to the pharmaceutical, including its 
pharmacologic class, mode of action, and proposed clinical use.  In general, the 
introduction should not exceed one page. 
 
    Module 2 should contain 7 sections in the following order: 
 CTD Table of Contents 
 CTD Introduction 
 Quality Overall Summary (QOS) 
 Nonclinical Overview 
 Clinical Overview 
                                                 
2 The first edition of the Uniform Requirements for Manuscripts Submitted to Biomedical Journals was conceived 
by the Vancouver Group and was published in 1979. 
    3    Contains Nonbinding Recommendations 
 
 Nonclinical Written and Tabulated Summaries 
 Clinical Summary 
 
    The organization of these summaries is described in the ICH guidances for industry M4Q 
The CTD  Quality, M4S The CTD  Safety, and M4E The CTD  Efficacy.   
 
Module 3.  Quality 
Information on Quality should be presented in the structured format described in the 
M4Q guidance. 
 
Module 4.  Nonclinical Study Reports 
The nonclinical study reports should be presented in the order described in the M4S 
guidance. 
 
Module 5.  Clinical Study Reports 
The human study reports and related information should be presented in the order 
described in the M4E guidance. 
 
The overall organization of the CTD is presented on the following pages.  
    4    Contains Nonbinding Recommendations 
 
Diagrammatic Representation of the Organization of the ICH CTD 
Common Technical Document 
 
 
Module 1 
Regional 
Not part of the CTD 
Administrative 
 
Information 
1 
1.1 Submission  
Table of 
Contents (T of C) 
 
CTD T of C 
2.1 
CTD Introduction 
Module 2 
2.2 
 
Nonclinical  Clinical 
  Overview  Overview 
Quality   2.4  2.5  CTD 
Overall 
 
Summary  Nonclinical Written  Clinical 
2.3  and Tabulated  Summary 
Summaries  2.7 
2.6 
Module 3  Module 4  Module 5 
Quality  Nonclinical  Clinical 
3  Study Reports  Study Reports 
3.1 T of C  4  5 
4.1 T of C  5.1 T of C 
   
 
    5    Contains Nonbinding Recommendations 
 
Organization of the Common Technical Document for the 
Registration of Pharmaceuticals for Human Use 
Module 1:  Administrative Information and Prescribing Information 
1.1 Table of Contents of the Submission Including Module 1 
1.2 Documents Specific to Each Region (for example, application forms, prescribing 
information) 
 
Module 2:  Common Technical Document Summaries 
2.1 Table of Contents of Modules 2-5  
2.2 CTD Introduction 
2.3 Quality Overall Summary 
2.4 Nonclinical Overview 
2.5 Clinical Overview 
2.6 Nonclinical Written and Tabulated Summaries 
Pharmacology  
Pharmacokinetics 
Toxicology 
2.7 Clinical Summary 
Biopharmaceutic Studies and Associated Analytical Methods 
Clinical Pharmacology Studies 
Clinical Efficacy 
Clinical Safety 
Literature References 
Synopses of Individual Studies 
 
Module 3:  Quality 
3.1 Table of Contents of Module 3 
3.2 Body of Data 
3.3 Literature References 
 
Module 4:  Nonclinical Study Reports 
4.1 Table of Contents of Module 4 
4.2 Study Reports 
4.3 Literature References 
 
Module 5:  Clinical Study Reports 
5.1 Table of Contents of Module 5 
5.2 Tabular Listing of All Clinical Studies  
5.3 Clinical Study Reports  
5.4 Literature References  
    6    Contains Nonbinding Recommendations 
 
V.  ANNEX: GRANULARITY DOCUMENT 
 
The CTD specifies many section headings and numbers.  Could guidance be provided for 
all modules on headings in relation to document location and the section headings within 
those documents?  Could guidance also be provided on where in the CTD and eCTD 
multiple documents can be located in the hierarchy? 
As a consequence of this definition, could guidance be given on how documents should be 
paginated and on what the modules table of contents should therefore, include? 
Definition of a Document 
 
A document is defined for a paper submission as a set of pages, numbered sequentially and 
divided from other documents by a tab (see Document Pagination and Segregation section of this 
Annex).  A document can be equated to a file for an electronic submission.  The granularity of 
the paper and electronic submissions should be equivalent, although if a paper submission is 
updated to be an electronic submission, some changes in granularity could be introduced to 
facilitate ongoing lifecycle management.  In an electronic submission, a new file starts at the 
same point as it should in a paper submission, a tab divides the documents. 
 
In deciding whether one or more documents or files are appropriate, it should be considered that 
once a particular approach is adopted, the same approach is used throughout the life of the 
dossier since it is the intention that replacement documents/files be provided when information 
is changed.   
 
The following tables describe the levels in the CTD/eCTD hierarchy at which documents/files 
should be placed and whether single or multiple documents are appropriate at each point.  This 
describes all sections of a CTD/eCTD, but for individual submissions, all sections might not be 
applicable.   
 
For Modules 2.3 and 3, the recommended granularity depends on the version of the eCTD 
standard that is used to prepare the submission, whereas the same Modules 4 and 5 granularity 
apply to all eCTD standards.  
  
For submissions filed using eCTD v3.2.2: Refer to Tables 1, 2, 5, and 6, as well as the additional 
guidance provided in separate ICH eCTD Q&As. 
 
For submissions filed using eCTD v4: Refer to Tables 3, 4, 5, and 6, as well as the additional 
guidance provided in Appendices A through F. 
 
    7    Contains Nonbinding Recommendations 
 
For paper CTD submissions: Refer to Tables 1, 2, 5, and 6 or Tables 3, 4, 5, and 6. (Additionally, 
see regional guidance.) 
   
    8    Contains Nonbinding Recommendations 
 
TABLE 1: Module 2 (paper and eCTD v3.2.2 submissions) 
Module 2  2.1  The TOC is only called for in  Key 
the paper version of the CTD;  Documents rolled up to this level are not 
there is no entry needed for the  considered appropriate. 
eCTD.  One document may be submitted at this level. 
2.2     
One or multiple documents can be submitted at 
2.3  Introduction    this level. 
Note 1  2.3.S  2.3.S.1  Documents may not be submitted at this level 
Note 2  2.3.S.2  for eCTD submissions (documents may be 
written at this level but must be submitted at the 
2.3.S.3 
higher level). 
2.3.S.4 
2.3.S.5  Note 1: Optionality of granularity for the QOS is 
provided in order to accommodate different levels 
2.3.S.6 
of complexity of products. The applicant can 
2.3.S.7 
choose the level at which the QOS is managed. 
2.3.P  2.3.P.1 
Note 3  2.3.P.2  Note 2: One document should be submitted for 
each drug substance. 
2.3.P.3 
2.3.P.4  Note 3: For a drug product supplied with 
reconstitution diluent(s), the information on the 
2.3.P.5 
diluent(s) should be provided in a separate part 
2.3.P.6 
P document. 
2.3.P.7 
Note 4: One document for each indication should 
2.3.P.8 
be submitted, although closely related indications 
2.3.A  2.3.A.1 
can be within a single document. 
2.3.A.2 
2.3.A.3   
2.3.R     
2.4     
 
2.5     
2.6  2.6.1       
2.6.2   
2.6.3   
2.6.4   
2.6.5   
2.6.6   
2.6.7   
2.7  2.7.1   
2.7.2   
2.7.3   
Note 4 
2.7.4   
2.7.5   
2.7.6   
    9    Contains Nonbinding Recommendations 
 
TABLE 2: Module 3 (paper and eCTD v3.2.2 submissions) 
Once a granularity option is chosen, continue with that option during the applications 
lifecycle. 
Module 3  3.1  The TOC is only called for in the paper 
Key 
Note 1  version of the CTD; there is no entry needed 
Documents rolled up to this level are not 
for the eCTD. 
considered appropriate. 
3.2  3.2.S  3.2.S.1  3.2.S.1.1 
One or multiple documents can be 
Note 2  3.2.S.1.2 
submitted at this level. 
3.2.S.1.3 
Documents may not be submitted at this 
3.2.S.2  3.2.S.2.1  level for eCTD submissions (documents 
3.2.S.2.2  may be written at this level but must be 
3.2.S.2.3  submitted at the higher level). 
3.2.S.2.4  Note 1: In choosing the level of 
3.2.S.2.5  granularity for this Module, the applicant 
3.2.S.2.6  should consider that, when relevant 
information is changed at any point in the 
3.2.S.3  3.2.S.3.1 
products lifecycle, replacements of 
3.2.S.3.2 
complete documents/files should be 
3.2.S.4  3.2.S.4.1 
provided in the CTD and eCTD. 
Note 3 
3.2.S.4.2 
Note 2: For a drug product containing 
3.2.S.4.3 
more than one drug substance, the 
3.2.S.4.4 
information requested for part S should 
3.2.S.4.5  be provided in its entirety for each drug 
3.2.S.5    substance. 
3.2.S.6   
Note 3: One or more control strategy 
3.2.S.7  3.2.S.7.1  summary documents may optionally be 
3.2.S.7.2  placed here. 
3.2.S.7.3 
Note 4: For a drug product supplied with 
3.2.P  3.2.P.1    reconstitution diluent(s), the information 
Note 4  3.2.P.2  3.2.P.2.1  on the diluent(s) should be provided in a 
Note 5  separate part P, as appropriate. 
3.2.P.2.2 
Note 5: The lower level of each heading 
Note 5 
included in the common technical 
3.2.P.2.3 
document quality (CTD-Q) section at this 
3.2.P.2.4  point is unlikely to contain individual 
3.2.P.2.5  documents or files. 
3.2.P.2.6 
 
3.2.P.3  3.2.P.3.1 
 
3.2.P.3.2 
3.2.P.3.3   
3.2.P.3.4   
3.2.P.3.5 
 
3.2.P.4  3.2.P.4.1 
3.2.P.4.2   
3.2.P.4.3   
3.2.P.4.4 
 
3.2.P.4.5 
3.2.P.4.6 
    10    Contains Nonbinding Recommendations 
 
3.2.P.5  3.2.P.5.1   
Note 3 
3.2.P.5.2 
 
3.2.P.5.3 
 
3.2.P.5.4 
3.2.P.5.5   
3.2.P.5.6  Note 6: Refer to regional guidances. 
3.2.P.6   
Note 7: Literature References should be 
3.2.P.7   
listed in the tables of contents. 
3.2.P.8  3.2.P.8.1 
3.2.P.8.2 
3.2.P.8.3 
3.2.A  3.2.A.1   
3.2.A.2   
3.2.A.3   
3.2.R  Note 6   
3.3  One file per     
reference 
Note 7 
   
    11    Contains Nonbinding Recommendations 
 
TABLE 3: Module 2 (paper and eCTD v4 submissions) 
Module 2  2.1  A TOC is not applicable for the  Key 
eCTD.  Documents rolled up to this level are not 
2.2  considered appropriate.  
   
2.3  Introduction  One document may be submitted at this 
 
Note 1, Note 2  2.3.S  level. 
Note 1, Note 3    One or multiple documents can be submitted 
  at this level. 
 
Note 1: Granularity options for the QOS are 
 
available to accommodate varying 
  complexities of products.  An applicant can 
  submit a single 2.3 document or write 
  document(s) as 2.3 Introduction, 2.3.S (or 
2.3.P  2.3.S.x), 2.3.P (or 2.3.P.x), 2.3.A.x, and 2.3.R, 
 
Note 1, Note 4  and submit at the 2.3.x or 2.3.x.n levels as 
 
shown in the table.  Refer to Appendix A for 
 
keyword guidance for drug substance and drug 
  product. 
 
Note 2: A document may be split for technical 
 
reasons (e.g., if it exceeds the maximum PDF 
  size limit). 
2.3.A  2.3.A.1 
Note 1, Note 5  Note 3: For a drug product containing >1 drug 
2.3.A.2  substance, separate document(s) may be 
Note 1, Note 6  provided for each drug substance (by using the 
2.3.A.3  substance keyword).  Typically, separate 
Note 1  documents are not provided for each 
2.3.R  manufacturer.  Refer to Appendix A for 
Note 1    keyword guidance. 
2.4 
    Note 4: For a drug product supplied with 
2.5  reconstitution diluent(s), separate document(s) 
   
2.6  2.6.1  may be provided for the diluent(s) (by using 
 
2.6.2  the product keyword).  If there is >1 dosage 
 
form, then separate document(s) may be 
2.6.3 
  provided for each (by using the dosage form 
2.6.4 
  keyword).  Refer to Appendix A for keyword 
2.6.5    guidance. 
2.6.6 
   
2.6.7 
 
2.7  2.7.1   
 
2.7.2   
 
2.7.3 
 
Note 7   
2.7.4   
 
2.7.5 
   
2.7.6 
   
Note 5: If multiple facilities are presented, one document may be provided for each facility by using the facility 
keyword.  Refer to Appendix F for keyword guidance. 
Note 6: For multiple components (e.g., combination vaccines) or for combination products, one document may be 
provided for each component by using the component keyword.  Refer to Appendix F for keyword guidance.  
    12    Contains Nonbinding Recommendations 
 
Note 7: One document for each indication should be submitted, although closely related indications can be within a 
single document. 
    13    Contains Nonbinding Recommendations 
 
TABLE 4: Module 3 (paper and eCTD v4 submissions) 
Once a granularity option is chosen, continue with that option during the applications 
lifecycle. 
Module 3  3.1  A TOC is not applicable for the eCTD.  Key 
Note 1  3.2  3.2.S  3.2.S.1   Documents rolled up to this level are 
Note 2, Note 3  Note 4  not considered appropriate and no 
 
  document is to be present at this level. 
3.2.S.2  3.2.S.2.1  One or multiple documents can be 
Note 2  3.2.S.2.2  submitted at this level. 
One or multiple documents can be 
3.2.S.2.3 
submitted at this level, but its content 
3.2.S.2.4 
is not rolled up from lower levels. 
3.2.S.2.5 
Note 1: In choosing the level of 
3.2.S.2.6 
granularity for Module 3, the applicant 
3.2.S.3  3.2.S.3.1 
Note 2  3.2.S.3.2  should consider that when relevant 
information is changed at any point in 
3.2.S.4  3.2.S.4.1  the products lifecycle, replacements of 
Note 2  3.2.S.4.2  complete documents/files should be 
3.2.S.4.3  provided.  
3.2.S.4.4  Note 2: Document(s) may be present at 
3.2.S.4.5  this level in addition to having 
3.2.S.5  document(s) at lower level(s); refer to 
 
Appendix B. 
3.2.S.6 
 
3.2.S.7  3.2.S.7.1  Note 3: For a drug product containing 
Note 2  3.2.S.7.2  more than one drug substance, the S 
information should be provided in its 
3.2.S.7.3 
Note 5  entirety for each drug substance.  Refer 
to Appendix A. Refer to health authority 
3.2.P  3.2.P.1 
Note 2, Note 6  3.2.P.2  3.2.P .2.1  for guidance if a drug substance is 
already approved. 
Note 7  Note 4 
3.2.P.2.2  Note 4: The lower level of each heading 
Note 4  included in CTD-Q at this point is 
3.2.P.2.3  unlikely to contain individual documents 
or files. 
3.2.P.2.4 
3.2.P.2.5  Note 5: For stability, the information 
3.2.P.2.6  may be provided in its entirety or per 
manufacturer, stability study protocol, 
3.2.P.3  3.2.P.3.1 
Note 2  3.2.P.3.2  and/or any other distinguishing 
information.  Refer to Appendix C. 
3.2.P.3.3 
Note 6: For a drug product supplied with 
3.2.P.3.4 
reconstitution diluent(s), the P 
3.2.P.3.5 
information on the diluent(s) should be 
3.2.P.4  3.2.P.4.1 
provided in its entirety as separate drug 
Note 8  3.2.P.4.2  product(s), as appropriate.  Refer to 
3.2.P.4.3  Appendix A. 
3.2.P.4.4 
Note 7: For the P.2 content, use the 
3.2.P.4.5  3.2.P.2 (i.e., roll up of P.2.1 to P.2.6) or 
3.2.P.4.6  3.2.P.2.x level.  Additionally, a Control 
3.2.P.5  3.2.P.5.1  Strategy Summary may be placed at 
Note 2  3.2.P.5.2  3.2.P.2.  A single 3.2.P.2 document is 
    14    Contains Nonbinding Recommendations 
 
3.2.P.5.3  not recommended for Quality by Design 
3.2.P.5.4  or large molecule applications. 
3.2.P.5.5   
3.2.P.5.6 
3.2.P.6 
 
3.2.P.7 
Note 9   
   
3.2.P.8  3.2.P.8.1 
Note 2  3.2.P.8.2 
3.2.P.8.3 
Note 10 
3.2.A  3.2.A.1 
Note 2  Note 11   
3.2.A.2 
Note 12   
3.2.A.3 
Note 13   
3.2.R 
Note 14     
3.3  One file 
per 
   
reference 
           
Note 8: For excipient guidance on when to use the 3.2.P.4 and/or 3.2.P.4.x level, refer to Appendix D. 
Note 9: For a drug product containing >1 container closure system, the information may be provided in its 
entirety or per system or per other distinguishing information.  Refer to Appendix E. 
Note 10: For stability, the information may be provided in its entirety or per container closure system, 
manufacturer, strength, stability study protocol, and/or any other distinguishing information.  Refer to 
Appendix C. 
Note 11: If >1 facility is provided, document(s) may be provided per facility.  Refer to Appendix F. 
Note 12: Typically only one 3.2.A.2 document is provided, but if there is >1 component (e.g., multiple 
component vaccines or combination products), then document(s) may be provided per component. Refer to 
Appendix F. 
Note 13: If >1 excipient is provided, document(s) may be provided per excipient. 
Note 14: Use 3.2.R or its subsections, if applicable.  Refer to regional guidance. 
 
 
   
    15    Contains Nonbinding Recommendations 
 
TABLE 5: Module 4 (paper and eCTD submissions) 
 
Module 4  4.1  The TOC is only called for in the paper version of the CTD;  Key 
there is no entry needed for the eCTD.  Documents rolled up to this level 
4.2  4.2.1  4.2.1.1  Studies Note 1    are not considered appropriate. 
4.2.1.2  Studies Note 1    One or multiple documents can 
4.2.1.3  Studies Note 1    be submitted at this level. 
4.2.1.4  Studies Note 1    Note 1: Typically, a single 
4.2.2  4.2.2.1  Studies Note 1    document should be provided for 
4.2.2.2  Studies Note 1    each study report included in 
4.2.2.3  Studies Note 1    Module 4.  However, where the 
study report is large, (e.g., a 
4.2.2.4  Studies Note 1   
carcinogenicity study), the 
4.2.2.5  Studies Note 1   
applicant can choose to submit 
4.2.2.6  Studies Note 1    the report as more than one 
4.2.2.7  Studies Note 1    document.  In this case, the text 
4.2.3  4.2.3.1  Studies Note 1    portion of the report should be 
4.2.3.2  Studies Note 1    one document and the appendices 
can be one or more documents. In 
4.2.3.3  4.2.3.3.1  Studies Note 1 
choosing the level of granularity 
4.2.3.3.2  Studies Note 1 
for these reports, the applicant 
4.2.3.4  4.2.3.4.1  Studies Note 1  should consider that when 
4.2.3.4.2  Studies Note 1  relevant information is changed 
4.2.3.4.3  Studies Note 1  at any point in the products 
4.2.3.5  4.2.3.5.1  Studies Note 1  lifecycle, replacements of 
complete documents/files should 
4.2.3.5.2  Studies Note 1 
be provided. 
4.2.3.5.3  Studies Note 1 
4.2.3.5.4  Studies Note 1  Note 2: Literature References 
should be listed in the tables of 
4.2.3.6  Studies Note 1   
contents. 
4.2.3.7  4.2.3.7.1  Studies Note 1 
 
4.2.3.7.2  Studies Note 1 
4.2.3.7.3  Studies Note 1 
4.2.3.7.4  Studies Note 1 
4.2.3.7.5  Studies Note 1 
4.2.3.7.6  Studies Note 1 
4.2.3.7.7  Studies Note 1 
4.3  One file per       
reference Note 2 
 
 
    16    Contains Nonbinding Recommendations 
 
TABLE 6: Module 5 (paper and eCTD submissions) 
 
Module 5  5.1  The TOC is only called for in the paper version  Key 
of the CTD; there is no entry needed for the 
Documents rolled up to this level are not 
eCTD. 
considered appropriate. 
5.2       
One document can be submitted at this 
5.3  5.3.1  5.3.1.1  Studies Note 1 
level.  
5.3.1.2  Studies Note 1 
One or multiple documents can be 
5.3.1.3  Studies Note 1  submitted at this level. 
5.3.1.4  Studies Note 1 
Note 1: The applicants should ordinarily 
5.3.2  5.3.2.1  Studies Note 1 
provide the study reports as multiple 
5.3.2.2  Studies Note 1  documents (a synopsis, a main body of the 
5.3.2.3  Studies Note 1  study report, and appropriate appendices).  
5.3.3  5.3.3.1  Studies Note 1  Appendices should be organized in 
5.3.3.2  Studies Note 1  accordance with the ICH E3 guidance, 
which describes the content and format of 
5.3.3.3  Studies Note 1 
the clinical study report.  In choosing the 
5.3.3.4  Studies Note 1 
level of granularity for reports, the 
5.3.3.5  Studies Note 1  applicant should consider that when 
5.3.4  5.3.4.1  Studies Note 1  relevant information is changed at any 
5.3.4.2  Studies Note 1  point in the products lifecycle, 
5.3.5  5.3.5.1  Studies Note 1  replacements of complete documents/files 
Note 2  5.3.5.2  Studies Note 1  should be provided. 
5.3.5.3  Studies Note 1  Note 2: For applications in support of more 
5.3.5.4  Studies Note 1  than one indication, this section should be 
repeated for each indication. 
5.3.6     
5.3.7  Studies Note 1    Note 3:  Literature References should be 
listed in the tables of content. 
5.4  One file     
per   
reference 
Note 3     
    17    Contains Nonbinding Recommendations 
 
Document Pagination and Segregation 
 
Every document should be numbered starting at page one, except for individual literature 
references, where the existing journal page numbering is considered sufficient. Applicants need 
not display the number as 1 of n where n is the total number of pages in the document. 
Additionally, all pages of a document should include a unique header or footer that briefly 
identifies its subject matter.  In a paper-based drug submission, a similar identifier should be 
used on a tab that precedes the document, to facilitate finding that document within the dossier. 
An abbreviation of the full section number and title can be used. 
 
If a section contains more than one document, a specific table of contents for that section can be 
included to identify the chronology and titles of the documents contained therein, e.g.,  
 Tab with 3.2.S.4.2 Analytical Procedures 
  Table of Contents, listing the title of Procedure A, Procedure B, Procedure 
o
C  
 Tab with 3.2.S.4.2 Procedure A; 
  Procedure A (i.e., document, page 1-n)  
o
 Tab with 3.2.S.4.2 Procedure B; 
  Procedure B (i.e., document, page 1-n)  
o
 Tab with 3.2.S.4.2 Procedure C; 
  Procedure C (i.e., document, page 1-n)  
o
If a section contains only a single document (e.g., 3.2.S.1.1 Nomenclature), only a tab identified 
by 3.2.S.1.1 Nomenclature should precede the document.  
 
Section Numbering within Documents 
 
In order to avoid 5th, 6th, etc. level subheading numbering (e.g., 2.6.6.3.2.1) within a document, 
the applicant can use a shortened numbering string.  In this case, the document number and the 
name (e.g., 2.6.6 Toxicology Written Summary) should appear in page headers or footers and 
then section numbering within the document can be used, for example, 1, 1.1, 2, 3, 3.1, 3.2, etc.  
Use of the full numbering string (e.g., 2.6.6.3.2.1) is also considered acceptable. 
 
Table of Contents Formatting 
 
Module 2 
 
The 2.1 CTD Table of Contents should go down to the third (e.g., 2.3.S) or fourth (e.g., 2.3.S.1) 
level, depending on how a document is defined for the QOS.  (See Definition of a document for 
Module 2.)   
    18    Contains Nonbinding Recommendations 
 
Module 3 
 
The table of contents provided under 3.1 should cover the high-level section numbering, the 
associated section heading, and the Volume number in the order that they appear in the drug 
submission.  This table of contents would be used to identify the contents of Module 3 as defined 
in the M4Q guidance.  It should go down to the fifth level only (e.g., 3.2.P.2.1).  Note that 
additional subsections and subheadings are defined in the M4Q guidance beyond this level (e.g., 
under 3.2.P.2) and this formatting should be used within the dossier, despite not being included 
in the 3.1 Table of Contents. The lower level table of contents described under Document 
Pagination and Segregation should be excluded from the 3.1 Table of Contents. 
 
At the applicants discretion, a table of contents can also be included for a particular section that 
contains multiple documents, in order to identify the chronology and the document subject 
matter.  If there is a desire to introduce additional headers or subsection numbering beyond those 
which are defined in the M4Q guidance, these should only be included within a document and 
should be created neither as a separate document nor as a new subsection.  In this case, a specific 
table of contents for that document can be included to identify the chronology and titles of the 
subsections contained therein.  These documents and subsections should not appear in the 3.1 
Table of Contents.   
 
Furthermore, additional attachments or appendices should not be incorporated into this 
formatting, except as a document under a section where multiple documents might be provided.  
In this case, a cross-reference should be made within the relevant section to the attached or 
appended document.  If there is a desire to append or attach additional information to a section 
that is comprised of only one document, this information should be incorporated within that 
document.    
 
All table of contents title entries should either correspond to heading names and section 
numbering as defined in the M4Q guidance or to identifiers appearing on tabs (for a paper-based 
drug submission only), preferably by their full title, which should easily identify any abbreviated 
title that might be used on the corresponding tab.  The table of contents should not specify any 
page numbers.   
 
Literature References should be listed in a table of contents specific for this section. 
 
Module 4 
 
The table of contents for Module 4 should include all of the numerical items listed in the CTD 
guidance in order to identify all of the important components of the application (for example, 
4.2.3.5.1 Fertility and Early Embryonic Development) and should continue down to at least the 
level of the study report.  Thus, each study report should be identified in the table of contents.  
    19    Contains Nonbinding Recommendations 
 
The sections of a study report could be identified in the Module 4 Table of Contents of the 
dossier or only in the table of contents of the individual study report. 
 
Illustration of part of the Module 4 Table of Contents 
4.2.3.2  Repeat-Dose Toxicity 
Study aa-aaa:     30-day repeat dose toxicity study with Drug C in rat 
Study bb-bbb:     6-month repeat dose toxicity study with Drug C in rat 
Study cc-ccc:     30-day repeat dose toxicity study with Drug C in dog 
Study dd-ddd:     6-month repeat dose toxicity study with Drug C in dog 
 
4.2.3.3  Genotoxicity 
4.2.3.3.1    In vitro 
Study ee-eee:     Ames test with Drug C, etc. 
 
Module 5 
 
The table of contents for Module 5 should include all of the numerical items listed in the CTD 
guidance in order to identify all of the important components of the application (for example, 
5.3.5.1.1 Placebo Controlled Trials) and should continue down to at least the level of the clinical 
study report.  Thus each clinical study report should be identified in the table of contents.  The 
sections of a clinical study report (E3) could be identified in the Module 5 Table of Contents of 
the dossier or only in the table of contents of the individual clinical study report. 
 
Illustration of part of the Module 5 Table of Contents 
5.3.5  Indication Z - Reports of Efficacy and Safety Studies 
5.3.5.1  Indication Z - Study Reports of Controlled Clinical Trials Pertinent to the 
Claimed Indication 
5.3.5.1.1  Indication Z - Placebo Controlled Trials 
Study xx-xxx:   A double blind, placebo-controlled trial of Drug A in Indication Z 
Study yy-yyy:   A double blind.... 
 
5.3.5.1.2    Indication Z - Active Controlled Trials 
Study zz-zzz:   A double blind, active controlled trial of Drug A versus Drug C in 
Indication Z 
 
    20    Contains Nonbinding Recommendations 
 
5.3.5  Indication Q - Reports of Efficacy and Safety Studies  
  5.3.5.1  Indication Q - Study Reports of Controlled Clinical Trials Pertinent to the Claimed 
Indication, etc. 
   
    21    Contains Nonbinding Recommendations 
 
APPENDICES FOR ECTD V4 SUBMISSIONS 
Appendix A: Guidance on Using the Substance, Manufacturer, Product, and Dosage Form 
Keywords 
 
These keywords (called attributes in v3.2.2) are optional and should only be used when 
needed; to add value to the review, one or more keywords could be used to repeat a section and 
uniquely identify it.  The applicant decides when and how to use these keywords. 
In all cases, a short informative value is adequate per keyword, since the keyword is intended to 
be an aid to a viewer of the application (e.g., to differentiate different drug substance or drug 
product sections), and not for computerized data management.  Alternatively, documents could 
be differentiated by using unique titles, or by explaining differences within one document (e.g., 
with a comparative table of the manufacturing processes). 
The keywords used in Module 2.3 need not match those used in Module 3. 
For Module 2.3, the least granular option is a document that covers all topics, in which case there 
are no keywords.  If the applicant uses a finer level of granularity (e.g., 2.3.S), a document (or 
documents with unique titles) could be provided using separate values for substance and/or 
manufacturer.  In this case, 2.3.S and 3.2.S keyword values (if used) can be different.  
The substance keyword was designed primarily to distinguish different drug substances found 
in drug products containing multiple drug substances or for different drug products that are co-
packaged.  An international non-proprietary name (INN) is recommended for this keyword.  
Long  INN names may  be shortened.  Consider the inclusion of  any  moiety to distinguish 
between different salt-forms that can be used in different dosage forms.  If an INN is not 
available, a company code will suffice. 
The manufacturer keyword was designed to facilitate lifecycle management where there might 
be different manufacturers (e.g., using a different drug substance route of synthesis (chemical 
entity) or manufacturing process (biologic)).  If the applicant determines that there is no need to 
have multiple 3.2.S or 3.2.P sections (e.g., where few 3.2.S.x topics have 
manufacturer/site/process-specific documents (either now or likely in the future)) then the use of 
this keyword is not recommended; there is no benefit of a general umbrella term such as all or 
applicant or not specified.  The value for the manufacturer keyword might be a firms 
name, the first word or abbreviation of a long company name, a site name, or simply words that 
differentiate different routes or processes.  Use a term that is less likely to change during the life 
of the application. 
The value for the product keyword could be used to distinguish, for example, between an 
active, device, placebo, and/or a diluent drug product section, if applicable.  The value 
for the product keyword could also be utilized to distinguish between an A-type versus a B-
type drug product preparation and/or it could include strength information (if a separate 3.2.P 
section for another strength(s) can be justified).  Proprietary names such as trademarks are not 
recommended, since proposed trademarks are not always accepted by authorities (trademark 
acceptability may not be known until after the eCTD application has been submitted).  
    22    Contains Nonbinding Recommendations 
 
The value for the dosage form keyword might consist of a short descriptive text such as 
powder for suspension.  Including details such as strength, concentration, or fill volume in the 
dosage form keyword is not recommended.  
Appendix B: Further Explanation of Blue Granularity and Control Strategy Summaries 
 
Blue granularity: As of ICH eCTD v4.0, a new blue granularity option was introduced to 
Module 3.  Inclusion of documents at this level is not a new expectation, but documents can be 
useful in certain circumstances. Examples are:  
  A cross-reference to a Drug Master File could be placed at the 3.2.S or 3.2.P level.  
  A cross-reference to a Certificate of Suitability could be placed at the 3.2.S.4 or 3.2.P.5 
level. 
 
  A Note to the Reviewer could be placed at any blue (or green) level. 
  An Overall Control Strategy Summary could be placed at several possible locations (see 
below).  
 
These optional documents should have clear and informative titles. 
 
Control strategy summaries:  Currently there are no specific locations defined for control 
strategy summaries in Module 3, so the placement of overall control strategy summaries is at the 
applicants discretion.  For example, overall control strategy summaries may be placed at the 
level of 3.2.S.4 and 3.2.P.5, 3.2.S.2.6 and 3.2.P.2 (or 3.2.P.2.3), or 3.2.S.4.5 and 3.2.P.5.6.  The 
applicant should state in Module 2.3 (e.g., 2.3 Introduction) where all the Module 3 control 
strategy summaries are located. 
Appendix C: Stability Data Guidance 
Applicants may choose a granularity that best suits their business needs and as appropriate for 
the application.  The use of the descriptor keyword is optional and the applicant decides when 
and how to use it.  Each descriptor keyword value generates a separate 3.2.S.7.3 and/or 
3.2.P.8.3 section.  All stability data can be organized using one or multiple documents and within 
one or multiple Stability Data sections.  
If there are several documents within a section, some differentiation can be achieved by 
informative naming of the documents titles.  Examples of titles for documents assigned to 
3.2.P.8.3 could be: 
  Blister  10 mg  long-term storage 
  Blister  10 mg  accelerated 
  Accelerated  bottles  10 mg, 25 mg 
  Accelerated  blisters  10 mg, 25 mg 
  36 months  bottles  10 mg, 25 mg 
 
    23    Contains Nonbinding Recommendations 
 
When there are multiple documents under a section, the priority number assigned to each 
document determines the order in which the documents appear within the section. 
 
Additional or other information may be provided either in the value for the descriptor keyword 
or in the documents title (e.g., storage condition, orientation of the container, and/or information 
such as primary versus supportive).  It is not recommended to use general umbrella terms 
such as all strengths. 
Appendix D: Excipient Guidance 
Applicants may choose a granularity that best suits their business needs and as appropriate for 
the application.  All excipient data can be organized using one or multiple documents and within 
one or multiple excipient sections.  The use of the excipient keyword is optional and the 
applicant decides when and how to use it.  Each excipient keyword value generates a separate 
3.2.P.4 and/or 3.2.A.3 section.  The excipient keyword does not have to be used (i.e., only one 
excipient section can be provided even if there is more than one excipient in the drug product).  
However, if repeating 3.2.P.4 sections are used, then the excipient keyword should be used as 
it identifies and distinguishes the content of the section.  General terms (e.g., compendial, 
coating agent, non-compendial) and/or specifically-named excipient keyword values are 
acceptable. 
 
One or multiple documents can be submitted covering each excipient, all excipients, each 
excipient topic (i.e., 3.2.P.4.1 through 3.2.P.4.6), or all excipient topics: 
  Option 1 (using a single 3.2.P.4 section without any lower level granularity):  This 
option is appropriate if the overall volume of information is small, such as when only 
compendial excipients are used.  In this case, only a single document would typically be 
submitted at the 3.2.P.4 level, with or without an excipient keyword, and the document 
would cover all excipients used and all excipient topics (i.e., 3.2.P.4.x). 
 
  Option 2 (using multiple 3.2.P.4 sections without lower level granularity for 
3.2.P.4.x):  One or multiple documents can be submitted at the 3.2.P.4 level (and not at a 
3.2.P.4.x level) per excipient or grouping of excipients, covering relevant excipient 
topics.  The excipient keyword is used to identify the name of a single or group of 
excipient(s) (e.g., compendial).  A single document might be used to cover either all 
topics (3.2.P.4.x) or each topic separately. 
 
  Option 3 (using multiple 3.2.P.4 sections with 3.2.P.4.x granularity):  One or multiple 
documents can be submitted at the appropriate 3.2.P.4.x level per excipient CTD topic.  
Multiple documents at the same 3.2.P.4.x level (e.g., separate documents for each 
excipient or grouping of excipients covering each of the 3.2.P.4.x topics) can be 
distinguished using informative document titles and/or in combination with the use of the 
excipient keyword, if desired. 
    24    Contains Nonbinding Recommendations 
 
 
Options 2 and 3 might be combined in a sequence.  For example, a single document covering all 
compendial excipients (i.e., a grouping with an excipient keyword of compendial, for example, 
can be provided at a 3.2.P.4 level in one section (Option 2), but more granular documents can be 
provided in named or grouped (e.g., coating agent) non-compendial excipient sections at the 
relevant 3.2.P.4.x levels (Option 3). 
 
For all options, there is no ICH consensus on granularity if no human, animal, and/or novel 
excipients are used.  Refer to regional guidance recognizing that an excipient keyword such as 
Human-Animal-Novel might be a possibility for a separate section used to discuss 3.2.P.4.5 
and 3.2.P.4.6. 
 
Considerations when choosing excipient granularity include the amount of information to be 
provided and future lifecycle potential, business processes for the generation and sources of 
global documentation, and the re-usability of information for worldwide markets. 
 
Since the current use of the excipient keyword is intended to be an aid to the viewer of the 
application, and not for computerized data management, avoid multiple documents per 
compendial excipient where content is just a reference(s) to a compendial monograph(s). 
 
Per the M4Q guidance, all components of the dosage form should be listed in 3.2.P.1 
(Description and Composition of the Drug Product), each with its function and reference to a 
quality standard (e.g., compendial monographs, manufacturers specifications).  Within section 
3.2.P.4 (Control of Excipients), it is an ICH expectation to provide excipient specifications in 
3.2.P.4.1 (Specifications).  An optional re-listing of the excipients within 3.2.P.4 or a link back to 
the list in 3.2.P.1 might be helpful in some cases, but it is not an ICH expectation to repeat a list 
of excipients in 3.2.P.4. 
If a non-compendial excipient becomes compendial   
If the application has only one 3.2.P.4 section where either the excipient keyword is not used or 
the excipient keyword is used without compendial or non-compendial as its keyword value, 
then affected document (s) can be replaced or removed. 
 
If the application contains more than one 3.2.P.4 section:  
  If the excipient name was used as the keyword value and there is no other section for 
grouped compendial excipient(s) (e.g., compendial as its keyword value) then the 
affected document content needs to be updated (or a new document created).  An option 
for the next sequence is to apply a status code value of suspended in the original 
section; then create a new 3.2.P.4 section with a new identifier and a new keyword value 
(e.g., compendial) and apply the updated or new document to the new 3.2.P.4 section.   
 
    25    Contains Nonbinding Recommendations 
 
  If groupings of excipients were used with keyword values of compendial and non-
compendial, for example, then in the compendial section any affected document or 
documents is or are replaced with the updated content.  In the non-compendial section, 
the document or documents that now correspond to pharmacopoeial content have the 
status code value of suspended applied to them. 
 
If extensive information was provided in 3.2.A.3 on the originally non-compendial excipient, 
apply the status code value of suspended if there is a desire to no longer maintain or lifecycle 
this information under 3.2.A.3. 
If an excipient is renamed 
As of ICH eCTD v4.0, it is possible to change the keyword value or display name. 
For a novel excipient that is no longer regarded as being novel 
If there is a desire to no longer maintain or lifecycle this information under 3.2.P.4.6 and/or 
3.2.A.3, as applicable, then apply the status code value of suspended to the original section. 
Update 3.2.P.4 to acknowledge that the excipient is no longer regarded as novel.   
Appendix E: Container Closure System Guidance 
Applicants may choose granularity that best suits their business needs.  All container closure 
information could be in one document or multiple documents and within one or multiple 
container sections.  The use of the container keyword is optional and the applicant decides 
when and how to use it.  Each container keyword value generates a separate 3.2.P.7 section 
(e.g., for products supplied in more than one type of container closure system).   
If there are several documents within a section, some differentiation can be achieved by 
informative naming of the documents titles.  Examples of titles of documents assigned to 3.2.P.7 
could be: 
 Description  Blister 
 Description  HDPE Bottle  50 mL 
 HDPE Bottle  50 mL  Description 
 HDPE Bottle  50 mL  Manufacturers 
 HDPE Bottle  50 mL  Specification 
 
When there are multiple documents under a section, the priority number assigned to each 
document determines the order in which the documents appear within the section. 
 
Additional or other information may be provided in the document title (e.g., packaging 
component information (Al lidding, PVC laminate)) to differentiate documents. 
 
Alternatively, individual documents for each container closure system (e.g., bottles versus 
blisters) could be provided. 
    26    Contains Nonbinding Recommendations 
 
Appendix F: Guidance on Using the Facility and Component Keywords 
Applicants may choose granularity that best suits their business needs.   
 
Facility: The use of the facility keyword is optional and the applicant decides when and how 
to use it.  Each facility keyword value generates a separate 2.3.A.1 and/or 3.2.A.1 section.  All 
facility information could be in one document or multiple documents and within one or multiple 
Facility sections.  
 
The value for the facility keyword might be a town or a sites location (e.g., East Park) or it 
might be more specific (e.g., East Park Building 2).  Additional details may be used in the 
naming of the document titles appearing under the 2.3.A.1 and/or 3.2.A.1 section to further 
supplement the keyword value. 
 
Although documents containing information that is applicable to more than one 3.2.A.1 section 
(e.g., room classifications) can be placed under each section, reviewer preference is to minimize 
the number of documents with identical content. If only a limited number of documents can be 
shared across sections, use less specific keyword values (resulting in fewer sections) instead of 
detailed values (that result in many sections).  If a sufficient number of documents are common 
across facilities, only one 3.2.A.1 section can be provided (i.e., without a keyword) and 
combined with the use of distinctive document titles or comparative tables within the documents. 
 
Component: The use of the component keyword is optional and the applicant decides when 
and how to use it.  Each component keyword value generates a separate 2.3.A.2 and/or 3.2.A.2 
section. All adventitious agent safety evaluation information could be in one document or 
multiple documents and within one or multiple adventitious agent safety evaluation sections (i.e., 
each section covering a different drug substance and/or drug product component).  For 
products containing a single drug substance and requiring an adventitious agents safety 
evaluation, one 3.2.A.2 document covering both the 3.2.S and 3.2.P sections may be sufficient.  
The use of a component keyword is not necessary in this case.  
 
For drug products containing multiple drug substances (e.g., multiple component vaccines or 
combination products), it may be appropriate to provide a separate adventitious agents safety 
evaluation for each drug substance component, in which case a unique component keyword 
may be used to identify and distinguish the information in repeated sections, with the combined 
use of one or multiple documents. 
 
For some combination products, where an adventitious agents safety evaluation may need to be 
provided for each drug substance component as well as the combined product, the use of the 
component keyword may also be practical in combination with one or multiple documents. 
 
    27