CTD Guideline — Notice to Applicants

Söğütözü Mahallesi, 2176. Street No:5 06520 Çankaya/ANKARA Telephone No: (0 312) 218 30 00 Fax No: (0 312) 218 34 60 E-mail: [email protected] Internet Address: https://www.titck.gov.tr Kep Address: [email protected]

CTD GUIDELINE IRD-KLVZ-02

  First Version Effective Date 	01.01.2006

1st Revision Effective Date 18.01.2022 2nd Revision Effective Date 15.11.2022

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Volume 2B

Notice to Applicants

Medicinal products for human use

Common Technical Document (CTD) Presentation and format of the dossier

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Foreword

This Notice to Applicants (NtA) for medicinal products for human use has been prepared in order to fulfil the obligations of Annex I of the Regulation on Licensing of Medicinal Products for Human Use.

The NtA is currently published as the following volumes:

Volume 2A dealing with licensing procedures

Volume 2B dealing with the presentation and format of the dossier

Volume 2C dealing with licensing guidelines

All updates of the volumes mentioned above can be found on the pharmaceutical unit website of the European Commission at the following address:

https://ec.europa.eu/health/documents/eudralex/vol-2_en

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Introduction

Volume 2B, which relates to the presentation of the dossier, provides guidance on how the files prepared for licensing applications should be compiled. In preparing this guideline, the relevant guidelines have been taken into account (for example, on the ICH website: http://www.ich.org and the documents published on the European Commission website).

Volume 2B CTD, which is the update of the Notice to Applicants, contains the revised ICH CTD guideline with respect to Quality, Safety and Efficacy aspects (see http://ich.org).

A list of CPMP/ICH guidelines related to each module has been attached and must be taken into consideration in the preparation of the licensing dossier. These will be updated at regular intervals.

The CTD is an internationally agreed format for the planned presentation of applications to be submitted to the licensing authorities in the three ICH regions: Europe, the USA and Japan. The objective of the CTD is to save time and resources and to facilitate licensing reviews and communication.

The CTD provides an appropriate format for the data obtained. Applicants should not alter the general structure of the Common Technical Document, as set out in the guideline. However, in the non-clinical and clinical overviews, applicants may modify individual formats where necessary in order to provide the best possible tabular presentation of technical information to facilitate the understanding and evaluation of the results.

The CTD format will be applicable to all application types (new chemical active substances, radiopharmaceuticals, vaccines, herbal products, etc.). Applicants need to consult the Agency in order to determine the applicability of this format to a specific product type.

Terminology

Since the Common Technical Document is an international document, European legal terms such as "active substance", "medicinal product" and "marketing authorisation" have not been used in developing the document. Applicants are reminded that the term "medicinal product for human use" covers both pharmaceutical and biological medicinal products. Unless otherwise specified, this term should be used synonymously with "product". Similarly, the term "active substance" should be used synonymously with the term "drug substance".

Terms used in ICH documents may be used in the CTD part of the application.

Submission of Licensing Applications:

The current requirements relating to the content of the dossier must be presented in accordance with Article 8 and Annex I of the Regulation on Licensing of Medicinal Products for Human Use.

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Applicants are advised to consult the official internet addresses given below in order to verify the latest updated information:

For the most recently updated information, applicants should consult:

http://www.titck.gov.tr http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev2.htm

Reformatting of dossiers of medicinal products previously authorised

There is no obligation to reformat the dossiers of medicinal products previously licensed in the new CTD format. If the marketing authorisation holder wishes to reformat its dossier, this will be permitted; however, it is not recommended that this be done in the non-clinical and clinical parts of the dossier. Nevertheless, particularly after 1 July 2007, in order to facilitate the handling of variations and new forms of a product, it is recommended that companies voluntarily reformat the Quality-related part of the documentation in accordance with the CTD format. This reformatting should include the entire Quality-related sections, including and integrating any Active Substance Master File (if available) as well as all approved variations. A written statement provided by the Marketing Authorisation Holder should also be submitted, indicating that the content/data of the Quality Module is exactly the same as the approved Quality section and that no change has occurred in the dossier as a result of the reformatting. The reformatted Quality documentation presented in CTD format must include a new Module 3 in CTD format; however, it is not mandatory for it to include the Quality Overall Summary, together with a signed template for the Quality Expert. The submission of Module 1 is not required. If the original Section II contains data related to bioequivalence, these data must be taken from Section II, reformatted according to the new CTD structure and submitted annexed in a separate file. The reformatted documentation should preferably be submitted simultaneously with, but separately from, a variation, the presentation of the product in different dosages and forms (variation), or a renewal. Where necessary, a clear distinction must be made between the reformatted (unchanged) information and the documentation supporting the variation/variation or renewal submitted at the same time. Since the reformatting of a dossier does not involve any change in the content of the dossier, it does not fall under the definition of a variation from a legal perspective.

The Agency decides whether a fee will be charged. Submission of the application

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The Common Technical Document is organized into five modules.

Administrative, national information is given in Module 1. This module contains the national requirements in terms of administrative data (Application Form, Summary of Product Characteristics, Package Leaflet and Labelling, etc.).

Module 2 contains high-level summaries that must be prepared by persons (experts) with appropriate qualifications and experience (Quality Overall Summary, Nonclinical Overview/Summaries and Clinical Overview/Summaries). For legal reasons, although the term "Expert Report" must be used, the content is expected to be provided in the Quality Overall Summary, Nonclinical Overview/Summary and Clinical Overview/Summary documents. Module 2 now takes the place of the former Expert Reports. Experts must provide brief information in the section on information about the experts in Module 1.4 regarding their training and specific expertise, and must sign it.

Module 3 presents chemical, pharmaceutical and biological documentation. This information must be structured as specified in Guideline M4Q.

Documentation on Toxicological and Pharmacological Tests performed on the drug/active substance and a drug/medicinal product must be provided in the Nonclinical Summaries (from Module 2) and by the Nonclinical Study Reports (Module 4). These reports must be presented in the manner specified in Guideline M4S.

Documentation on Clinical Trials conducted in relation to the drug/medicinal product can be obtained from the Clinical Summaries (from Module 2) and the Clinical Trial Reports (Module 5). These reports must be presented in the manner specified in Guideline M4E.

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Schematic Representation of the Organization of the CTD

Module 2

Module 1 Not part of the CTD

    Regional

  Administrative

  Information

 1.0

          CTD Table of Contents

       2.1

        CTD Introduction

     2.2

Nonclinical Clinical
Overview Overview
2.4 2.5

Quality Nonclinical Clinical CTD Overall Summaries Summaries 2.3 2.6 2.7

Module 3 Module 4 Module 5 Nonclinical Clinical Quality Study Reports Study Reports 3.0 4.0 5.0

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Preparation and Organization of the CTD

In all stages of the CTD, the presentation of the information must be clear and transparent in order to facilitate the review of the core data and to enable the reviewer to quickly navigate to the application contents. Texts and tables must be prepared using margins such that the document can be printed on A4 paper. The left margin must be sufficiently wide so as to prevent the information from becoming invisible when the document is filed. Font sizes for text and tables must be of a type and size that can be easily read even after photocopying. Times New Roman 12 point font is recommended for text. Abbreviations and short names must be defined on first use in each module.

Page Numbering and Grouping

Each document must be prepared in line with the CHMP/ICH/2887/99 Revision 1 CTD Organisation recommendation.

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Specific Guidance for Different Application Types

Although this format requires certain adaptations for specific application/medicinal product types, it is intended for applications for all categories of preparations/medicinal products (new chemical substances, radiopharmaceuticals, vaccines, herbals, etc.) and all application types (stand-alone, generics, biosimilars, etc.).

The format in question is intended to show how the information included in the application should be appropriately organized, not to indicate which trials are required for a successful approval. If no information is available under a specific heading or it is not required, that part of the application must be marked as "not applicable" or "not relevant", while the section heading and, where necessary, a justification for the absence of the trial must be provided in the Quality Overall Summary, Nonclinical Overview and Clinical Overview.

For applications for well-established medicinal use (bibliographic), generic, biosimilar, hybrid and variations (presentation of the product in different dosages and forms), the Nonclinical/clinical overviews/summaries must focus on application-specific topics. Applicants must also take into account Volume 2A Licensing Procedures of the Rules Governing Medicinal Products in the European Union.

For generic, biosimilar and hybrid applications and for variations (presentations of the product in different dosages and forms), cross-references to previous applications submitted in the "old" format will be accepted. Re-formatting into the CTD format of "old" documentation that has already been evaluated and authorized is not required.

1. Well-established medicinal use (bibliographic) applications

In applications made pursuant to subparagraph 2 of paragraph (a) of the first paragraph of Article 9 of the Regulation on Licensing of Medicinal Products for Human Use, the Nonclinical/clinical overviews/summaries must demonstrate that the component(s) of the medicinal product has/have a well-established medicinal use with an acceptable level of safety or efficacy as given in Annex I of the said Regulation.

Tabulated clinical or nonclinical summaries must be provided in Module 2. Tables may not be necessary for substances with a long-standing and well-known period of use, but an appropriate justification will be required for this. The Overviews must always be included.

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2. Informed consent, generic, hybrid or biosimilar applications

2a) Consent of the reference marketing authorisation holder;

Applications made pursuant to subparagraph 1 of paragraph (a) of Article 9 of the Regulation on Licensing of Medicinal Products for Human Use may refer to the expert reports contained in the reference medicinal product dossier or to documentation containing quality/non-clinical/clinical overviews/summaries, provided that the marketing authorisation holder of the reference medicinal product gives its consent.

2b) Applications concerning generic, hybrid medicinal products and biosimilar medicinal products;

Applications made pursuant to subparagraph 4 of paragraph (a) of Article 9 of the Regulation on Licensing of Medicinal Products for Human Use, and to paragraphs (b) and (c) of the first paragraph of Article 9 of the same Regulation, shall include Module 2 Quality Overall Summary, Non-Clinical Overview and Clinical Overview. Non-clinical and Clinical Summaries may be provided, but they are mandatory only if additional new studies are included in the documentation.

3. Variation Applications Made Under the Regulation on Variations to Marketing Authorisations of Licensed Medicinal Products for Human Use

After 1 January 2007, all variation applications must be submitted using the CTD format. However, cross-references to "old" format documentation will be acceptable, because the content is the same. Explicit references to any "old" format are required.

Examples:

• Any new (additional or revised) data supporting the variation must be presented using the CTD format.

• Where any unchanged data needs to be submitted, for example, in cases where a copy of the approved particulars may need to be submitted in accordance with the Guideline on Variations to Marketing Authorisations of Licensed Medicinal Products for Human Use, the marketing authorisation holder should subsequently update these particulars to the new CTD format. The marketing authorisation holder should provide a declaration that any reformatted document is unchanged, so that it will be able to use these "updated" (CTD) particulars for any future variation application.

If a cross-reference is made only to an approved datum, a cross-reference may be made (by Section and part) even if the file containing the datum is in the "old" format. If the marketing authorisation holder wishes to present the (unchanged) datum in the new CTD format, such an application will also be acceptable, as this will facilitate the handling of future variations. However, the marketing authorisation holder must provide a declaration that the reformatted document is unchanged.

Type IA/IB and Type II Variation Applications and their supporting documentation – where applicable – should be presented in accordance with the Guideline on Variations to Marketing Authorisations of Licensed Medicinal Products for Human Use.

4. Variation Applications Made Under the Regulation on Variations to Marketing Authorisations of Licensed Medicinal Products for Human Use

Non-clinical/clinical overviews/summaries should focus in particular on the following elements:

• An evaluation of the results of studies conducted in addition to the studies on the licensed medicinal product for human use. The results should be discussed in the perspective of what is known from the published literature and previous submissions. Additional studies should be presented in the table formats given in this Notification to Applicants.

• Currently published literature relevant to the substance concerned and to the variation application should be submitted. The documentation may include annotated articles published in peer-reviewed journals acceptable for use for this purpose.

• Any claim in the Summary of Product Characteristics (SmPC) that is known or derived from particulars of the medicinal product for human use or the therapeutic class concerned should be discussed in the non-clinical/clinical overviews/summaries and substantiated by published literature or additional studies.

As of 1 July 2007, variation applications for the product must be presented using the CTD format. However, reference may be made to the "old" sections of the dossier that have previously been evaluated and licensed; such references may be made only where no additional data are submitted for those sections. In such cases, it is not mandatory to reformat the previously evaluated and licensed "old" documentation.

Module 1 and 2 must always be submitted. Where no new clinical or non-clinical data are submitted, expert reports may replace the relevant overviews/summaries. However, it is mandatory to submit a summary and overview section in the new CTD format covering the new information or data submitted to support the application. All headings (numbers and titles) must be included in this summary/overall summary in CTD format; however, where a cross-reference can be made, since the data are unchanged, a statement such as "Not applicable — unchanged" (or similar) must be included.

In addition to presenting the quality data concerning variation applications for new presentation forms of the product in CTD format, marketing authorisation holders are recommended to completely reformat "old format" Section II, which has been evaluated and licensed, in order to obtain a comprehensive CTD Module 3 covering all strengths/pharmaceutical forms. By way of exception, in the case of multiple strengths and/or pharmaceutical forms, the Quality module of the variation of the medicinal product for human use may include only the data related to the new strength/pharmaceutical form and may cross-refer to the relevant "old" quality data. Where a subsequent variation affects the "old" section, marketing authorisation holders are required to (at least) reformat the relevant section in CTD format.

4. Renewal Applications:

As of 1 January 2007, all applications made for renewal must be submitted using the CTD format. The guidance set out in the relevant guidelines/recommendations on the handling of renewals should be taken into account. See Volume 2C, http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev2.htm

Specific guidance on herbal medicinal products

Within the framework of this document, the terms "herbal substances and preparations" should be considered equivalent to the terms "herbal drugs and herbal drug preparations" as defined in the European Pharmacopoeia.

For ease of reference, the section headings in Modules 2 and 3 have been copied. The texts under the section headings are only explanations and descriptions relating to herbal medicinal products. The content of these sections should include the relevant information described in the Guideline published by the Agency.

See here for specific information on herbal medicinal products:

• Module 2

• Module 3

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Active Substance Master File (ASMF)

The existing guideline on the ASMF procedure (CHMP QWP/227/02) 3 applies in principle; that is, the responsibility of the applicant applying for a marketing authorisation for a medicinal product for human use is to ensure that the entire ASMF — in other words, both the applicant's "open" part and the "closed" part of the active substance manufacturer — is submitted directly to the competent authorities by the active substance manufacturer in CTD format and arrives at the same time as the marketing authorisation application. A copy of the "Letter of Access" must be included in Module 1, in the Application Form as Annex 6.10, and must be addressed to the competent authority to which the application is submitted.

The part of the ASMF that is "open" to the applicant must be included in section 3.2.S of the quality documentation presented in CTD format.

In the ASMF, the "closed" part of the active substance manufacturer must follow the structure of Module 3.2.S of the CTD. For the information included in the "closed" part of the active substance manufacturer, the Overall Quality Summary must also be presented as part of the ASMF.

When a new ASMF application is made in CTD format as part of the quality data, the entire ASMF (the open and closed parts of the ASMF and the Overall Quality Summary) must be presented in CTD format.

3 Guideline on the Active Substance Master File procedure for the previous European Drug Master File (EDMF), CPMP/QWP/227/02

http://www.emea.eu.int/htms/human/qwp/qwpdraft.htm

Variations to the ASMF:

If a change has been made to any part of the ASMF, the documentation relating to that change must be presented in CTD format. In this process, it is recommended that the ASMF holder reformat the entire ASMF. This will facilitate the handling of changes/variations affecting the data in the relevant ASMF.

The ASMF holder must make a clear distinction between the following:

• The reformatting of ASMF data previously assessed by the Agency,
• New documentation supporting the change in the ASMF data.

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If an ASMF has been reformatted into CTD format without any change in the data, a signed statement must be submitted by the ASMF holder guaranteeing that the content of that ASMF is identical to the current version of the ASMF.

After the ASMF has been reformatted, the new "open" part of the ASMF in CTD format must be sent by the ASMF holder to the relevant marketing authorisation holder, so as to enable the marketing authorisation holder to update all marketing authorisations for which the relevant ASMF has been used. The presentation of the ASMF in CTD format will be accepted without any need to reformat the relevant quality data in the dossier of the medicinal product for human use.

In the event of a change in the ASMF data, the relevant variation must be submitted to the authorities by the marketing authorisation holder. For marketing authorisations in which an ASMF is used, in variation applications made for the authorised product, the ASMF holder must reformat the entire ASMF into CTD format and thereby ensure that the "new" ASMF format is included in the variation application for the product, rather than cross-referencing the "old" ASMF format.

Monographs relating to the Certificate of Suitability of the European Pharmacopoeia (CEP)

Applicants may use the CEP scheme in place of some of the information required in Module 3 for active substances described in the European Pharmacopoeia.

The Active Substance section must refer to the Certificate of Suitability in the relevant sections of Module 3.2.S. As Certificates of Suitability are assessed to replace the relevant sections, no additional information will be needed except for technical product characteristics not covered by the Certificate of Suitability (e.g. the Certificate of Suitability does not describe a specific technical grade).

A comprehensive copy of the Certificates of Suitability (including annexes) must be presented in Module 1 and Module 3 R, and in Annex 6.10 of the Application Form.

Compliance with BSE/TSE can also be demonstrated by means of a Certificate of Suitability.

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European Community Guideline on Quality, Safety and Efficacy

When preparing the dossier for a marketing authorisation application, applicants must take into account the Community guideline on the quality, safety and efficacy of medicinal products published by the Commission in "The Rules Governing Medicinal Products in the European Community", Volumes 3A, 3B, 3C: Guidelines on the quality, safety and efficacy of medicinal products for human use, and subsequent updates adopted by the Committee for Proprietary Medicinal Products. Guidelines adopted in the ICH process are considered Community guidelines after being adopted and published by the CPMP. References to the relevant Community or ICH guidelines have been included in the relevant sections or in each section of the dossier. For the latest updates of the Community/ICH guidelines, applicants are advised to consult the EMEA website at http://www.emea.eu.int.index/indexh1.htm (Notice to Applicants — Guidelines and Guidance Documents).

In the quality-related part of the dossier, the monographs and general chapters of the European Pharmacopoeia are also applicable. All materials of ruminant origin must also comply with the requirements of the Certificate of Suitability.

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Correlation Table

Comparison of the CTD (NtG, Volume 2B, May 2006 edition) and NtG, Volume 2B (1998 edition)

                                        MODULE 1 – ADMINISTRATIVE INFORMATION AND prescribing information

CTD CTD (NtG, Volume 2B, May 2006 edition) NtG, Volume 2B (1998 edition) NtG 1.0 Cover letter 1.1 Comprehensive table of contents --- 1.2 Application Form Administrative Information I A 1.3 Product Information Summary of Product Characteristics, labelling and package leaflet I B 1.3.1 Summary of Product Characteristics, Labelling and Package Leaflet Summary of Product Characteristics I B 1 Summary of Product Characteristics, and package leaflet proposals 1.3.2 Mock-ups I B 2 1.3.3 Specimens 1.3.4 Readability Testing 1.3.5 Currently approved SmPCs in Member States SmPCs previously approved by Member States I B 3

1.3.6 Braille 1.4 Information on the Experts Expert Reports: Signatures of the Experts I C 1.4.1 Quality 1.4.2 Non-clinical 1.4.3 Clinical 1.5 Specific requirements for different types of applications --- 1.5.1 Information on Bibliographical Applications --- 1.5.2 Information on Generic, Hybrid or Biosimilar Applications

1.5.3 Information on Applications for Allergen Products 1.5.4 Exceptional Circumstances 1.5.5 Conditional Approval 1.6 Environmental Risk Assessment Environmental risk assessment 1.6.1 Non-GMO Environmental risk assessment / ecotoxicity (for non-GMO) III R 1.6.2 GMO Data on the environmental risk assessments of products containing or consisting of genetically modified organisms (GMOs) II H 1.8 Pharmacovigilance Information 1.8.1 Pharmacovigilance System 1.8.2 Risk Management System 1.9 Information on Clinical Trials

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MODULE 2 – COMMON TECHNICAL DOCUMENT SUMMARIES CTD CTD (NRF, Volume 2B, 2001 edition) NRF, Volume 2B (1998 edition) NRF 2.6 Nonclinical Overview Appendices to the toxicopharmacological expert report I C 2 2.6.1 Pharmacology Written Summary Written Summary I C 2 2.6.2 Pharmacology Tabulated Summary Tabulated formats I C 2 2.6.3 Pharmacokinetics Written Summary Written Summary I C 2 2.6.4 Pharmacokinetics Tabulated Summary Tabulated formats I C 2 2.6.5 Toxicology Written Summary --- --- 2.6.6 Toxicology Tabulated Summary Tabulated formats I C 2 2.7 Clinical Overview Appendices to the clinical expert report I C 3 2.7.1 Summary of Biopharmaceutic and Associated Analytical Methods Written Summary I C 3 2.7.2 Summary of Clinical Pharmacology Studies Written Summary I C 3 2.7.3 Summary of Clinical Efficacy Written Summary I C 3 2.7.4 Summary of Clinical Safety Written Summary I C 3 2.7.5 Summaries of Individual Studies Tabulated formats I C 3

MODULE 3 – QUALITY CTD CTD (NRF, Volume 2B, 2001 edition) NRF, Volume 2B (1998 edition) NRF 3.1 TABLE OF CONTENTS OF MODULE 3 --- --- 3.2 DATA Chemical, Pharmaceutical and Biological Documentation II 3.2.S ACTIVE SUBSTANCE 3.2.S.1 General Information Scientific Data II C 1.2 3.2.S.1.1 Nomenclature Nomenclature II C 1.2.1 3.2.S.1.2 Structure Description: Structural formula II C 1.2.2 3.2.S.1.3 General Properties Physicochemical characterization II C 1.2.5 3.2.S.2 Manufacture Manufacture II C 1.2.3 3.2.S.2.1 Manufacturer(s) Name(s) and address(es) of the manufacturing source(s) II C 1.2.3 3.2.S.2.2 Description of Manufacturing Process and Process Controls Synthetic route or manufacturing route II C 1.2.3 3.2.S.2.3 Control of Materials Quality control during manufacture II C 1.2.4 3.2.S.2.4 Control of Critical Steps and Intermediates Quality control during manufacture II C 1.2.4 3.2.S.2.5 Process Validation and/or Evaluation --- --- 3.2.S.2.6 Manufacturing Process Development --- 3.2.S.3 Characterisation 3.2.S.3.1 Elucidation of Structure and Other Characteristics Chemical development II C 1.2.5 3.2.S.3.2 Impurities Impurities II C 1.2.6 3.2.S.4 Control of the Active Substance Specifications and routine tests II C 1.1 3.2.S.4.1 Specifications Specifications and routine tests II C 1.1 3.2.S.4.2 Analytical Procedures Specifications and routine tests II C 1.1 3.2.S.4.3 Validation of Analytical Procedures Chemical development: Analytical Validation II C 1.2.5 3.2.S.4.4 Batch Analyses Batch analysis II C 1.2.7 3.2.S.4.5 Justification of Specifications Chemical development: Opinions on the selection of routine tests and standards II C 1.2.5 3.2.S.5 Reference Standards or Materials Chemical development: Complete characterization of primary reference materials Batch Analysis: Reference materials II C 1.2.5

II C 1.2.7 3.2.S.6 Container Closure System 3.2.S.7 Stability Stability test(s) on the active substance(s) II F1

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3.2.P MEDICINAL PRODUCT 3.2.P.1 Description and Composition of the Medicinal Product Composition and container (brief description) II A1 II A2

MODULE 3 – QUALITY CTD CTD (NRF, Volume 2B, 2001 edition) NRF, Volume 2B (1998 edition) NRF 3.2.P.2 Pharmaceutical Development Pharmaceutical development and clinical trial formulations II A 4 II A3 3.2.P.2.4 Controls and critical steps and intermediates Manufacturing Process (including in-process controls and drug amalgamation operations) Control tests on intermediates II B3

II D 3.2.P.3 Manufacture Method of Preparation II B 3.2.P.3.1 Manufacturer(s) Administrative Information I A 3.2.P.3.2 Batch Formula Manufacturing Formulas II B 1 3.2.P.3.3 Description of Manufacturing Process and Process Controls Manufacturing Process (including in-process controls and drug amalgamation operations) II B 2 3.2.P.3.4 Controls of Critical Steps and Intermediates Manufacturing process (including in-process controls and drug amalgamation operations) II B 2 3.2.P.3.5 Process Validation and/or Evaluation Validation of processes II B 3 3.2.P.4 Control of Excipients Excipient(s) II C 2 3.2.P.4.1 Specifications Specifications and routine tests II C 2.1 3.2.P.4.2 Analytical procedures Specifications and routine tests II C 2.1 3.2.P.4.3 Validation of analytical procedures Scientific data II C 2.2 3.2.P.4.4 Justification of specifications Scientific data II C 2.2 3.2.P.4.5 Excipients of human or animal origin --- 3.2.P.4.6 Novel Excipients (reference to A 3) Excipient(s) not described in the pharmacopoeia Scientific data II C 2.2.1

II C 2.2 3.2.P.5 Control of the medicinal product Control Tests on the Finished Products II E 3.2.P.5.1 Specification(s) Product Specifications Quality specifications for the proposed shelf life II E 1.1 II F 2 3.2.P.5.2 Analytical procedures Control Methods II E 1.2 3.2.P.5.3 Validation of analytical procedures Analytical validation of methods II E 2.1 3.2.P.5.4 Batch analyses Batch analysis II E 2.2 3.2.P.5.5 Characterisation of impurities --- 3.2.P.5.6 Justification of specifications Opinions on the selection of routine tests and standards II E 2.1 3.2.P.6 Reference Standards or Materials Batch analysis: Reference materials II E 2.2 3.2.P.7 Container Closure System Packaging Materials (Immediate Packaging) II C 3 3.2.P.8 Stability Stability Tests on the Finished Products II F 2 3.2.A APPENDICES 3.2.A.1 Facilities and Equipment --- 3.2.A.2 Adventitious Agents Safety Evaluation --- 3.2.A.3 Excipients --- 3.2.R REGIONAL INFORMATION Validation of the process --II B3-- 3.3 LITERATURE REFERENCES OTHER INFORMATION II Q

MODULE 4 – NONCLINICAL STUDY REPORTS CTD CTD (NRF, Volume 2B, 2001 edition) NRF, Volume 2B (1998 edition) NRF 4.1 TABLE OF CONTENTS OF MODULE 4 --- --- 4.2 STUDY REPORTS TOXICOPHARMACOLOGICAL DOCUMENTATION III 4.2.1 PHARMACOLOGY PHARMACODYNAMICS III F 4.2.1.1 Primary pharmacodynamics Pharmacodynamic effects related to the proposed indications III F 1

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4.2.1.2 Secondary pharmacodynamics General pharmacodynamics III F 2 4.2.1.3 Safety pharmacology General pharmacodynamics III F 2 4.2.1.4 Pharmacodynamic drug interactions Drug interactions III F 3 4.2.2 PHARMACOKINETICS PHARMACOKINETICS III G 4.2.2.1 Analytical Methods and Validation Reports Other Information III Q 4.2.2.2 Absorption Pharmacokinetics after single dose Pharmacokinetics after repeated administration III G 1 III G 2

MODULE 4 – NONCLINICAL STUDY REPORTS CTD CTD (EWP, Volume 2B, 2001 edition) EWP, Volume 2B (1998 edition) EWP 4.2.2.3 Distribution Distribution in normal and pregnant animals III G 3 4.2.2.4 Metabolism Biotransformation III G4 4.2.2.5 Excretion Pharmacokinetics III G 1, 2 4.2.2.6 Pharmacokinetic Drug Interactions (nonclinical) --- 4.2.2.7 Other pharmacokinetic studies --- 4.2.3.1 Single dose toxicity Single dose toxicity studies III A 1 4.2.3.2 Repeat dose toxicity Repeat dose toxicity studies III A 2 4.2.3.3 Genotoxicity Mutagenic Potential III D 4.2.3.4 Carcinogenicity Carcinogenic Potential III E 4.2.3.5 Reproductive and developmental toxicity Reproductive Function Embryofetal and Perinatal Toxicity III B III C 4.2.3.6 Local tolerance Local Tolerance III H 4.2.3.7 Other toxicity studies Other Information III Q 4.3 LITERATURE REFERENCES OTHER INFORMATION III Q

MODULE 5 – CLINICAL STUDY REPORTS CTD CTD (EWP, Volume 2B, 2001 edition) EWP, Volume 2B (1998 edition) EWP 5.1 TABLE OF CONTENTS FOR MODULE 5 --- --- 5.2 TABULATED LISTS OF ALL CLINICAL STUDIES EXPERT REPORT ON CLINICAL DOCUMENTATION, ANNEX 2: WRITTEN SUMMARY – TABULATED GENERAL SUMMARY I C 3 5.3 CLINICAL STUDY REPORTS CLINICAL DOCUMENTATION IV 5.3.1 Biopharmaceutical study reports Pharmacokinetics IV A 2 5.3.2 Reports on pharmacokinetic studies conducted using human biomaterials Pharmacokinetics IV A 2 5.3.3 Reports on human pharmacokinetic (PK) studies Pharmacokinetics IV A 2 5.3.4 Reports on human pharmacodynamic (PD) studies Pharmacodynamics IV A 1 5.3.5 Reports on efficacy and safety studies Clinical Trials IV B 1 5.3.6 Reports on post-marketing experiences Post-marketing experience (if any) IV B 2 5.3.7 Case report forms and individual patient listings, when submitted Appendices section of each clinical trial report, when submitted (Appendix 16.3) IV B 1 5.4 LITERATURE REFERENCES PUBLISHED AND UNPUBLISHED EXPERIENCE (EXCEPT 1) OTHER INFORMATION IV B 3

IV Q

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REVISION HISTORY Revision No Revision Date Justification and Explanations 01 18.01.2022 02 18.11.2022 Update in guideline format has been carried out.