Structure of Dossier of Medicinal Product- Q part Gabriel K. Kaddu Head, Drug Assessment and Registration National Drug Authority Training workshop: Training workshop on regulatory requirements for registration of Artemisinin based combined medicines and assessment of data submitted to regulatory authorities, February 23-27, 2009, Kampala, Uganda.

Structure of Dossier of Medicinal product Q part World Health Organization Structure of Dossier of Medicinal product Q part 19 April, 2017 Outline of presentation Objective of the presentation The Common Technical Document (CTD) for the Registration of Pharmaceuticals for Human Use: Quality – M4Q MODULE 3: QUALITY Guideline on Submission of documentation for Prequalification of Multi- source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDs, Malaria and Tuberculosis

Overview of Dossier Requirements and Guidelines Objective of the presentation: To provide an overview of the dossier requirements and Guidelines used or referenced under the WHO Prequalification Program To demonstrate how the requirements and guidelines can be applied or used as reference.

Overview of Dossier Requirements and Guidelines (1) World Health Organization Overview of Dossier Requirements and Guidelines (1) 19 April, 2017 Common Technical Document (CTD) An initiative under the ICH: Europe, Japan and USA. http://www.ich.org

Structure of dossier of medicinal products, information on the CTD format (1) A common format for the technical documentation: significantly reduces the time and resources needed to compile applications for registration of human pharmaceuticals eases the preparation of electronic submissions Facilitates regulatory reviews and communication with the applicant by a standard document of common elements Simplifies exchange of regulatory information between Regulatory Authorities This guideline is not intended to indicate what studies are required. It merely indicates an appropriate format for the data that have been acquired.

World Health Organization CTD format (2) 19 April, 2017 GENERAL PRINCIPLES Text and tables should be prepared using margins that allow the document to be printed on A4 paper. 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 easily legible, even after photocopying. Times New Roman, 12-point font, is recommended for narrative text. Every page should be numbered. 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)1.

CTD format (3) 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. Module 1. Administrative Information and Prescribing Information Should contain documents specific to each region; e.g. 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 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)

CTD format (4) Module 2. Common Technical Document Summaries Should begin with a general introduction to the pharmaceutical, including its pharmacological class, mode of action, and proposed clinical use. In general, the Introduction should not exceed one page. Should contain 7 sections in the following order : 2.1 Common Technical Document Table of Contents (Modules 2-5) 2.2 CTD Introduction 2.3 Quality Overall Summary 2.4 Non-clinical Overview 2.5 Clinical Overview 2.6 Non-clinical Written and Tabulated Summaries Pharmacology Pharmacokinetics Toxicology 2.7 Clinical Summary Biopharmaceutical Studies and Associated Analytical Methods Clinical Pharmacology Studies Clinical Efficacy Clinical Safety Literature References Synopses of Individual Studies

CTD format (5) Module 3. Quality Module 3: Quality Information on Quality should be presented in the structured format described in Guideline M4Q. Module 3: Quality 3.1 Table of Contents of Module 3 3.2 Body of Data 3.3 Literature References

CTD format: Numbering System: Module 3

Overview of Dossier Requirements and Guidelines (2) Guideline on Submission of documentation for Prequalification of Multi-source (Generic) Finished Pharmaceutical Products (FPPs) Used in the Treatment of HIV/AIDs, Malaria and Tuberculosis http://mednet3.who.int/prequal

Generic Guide: Documentation on Quality Part to be submitted to the WHO PQ team Covering letter Product dossier on Quality part PQIF (annex 8 to the main generic guide): properly filled out in WinWord format, www.who.int/prequal/

Generic Guide: Quality dossier / Section 1 Information on the Finished Pharmaceutical Product (FPP) 1.1. Details of the Product - Name, dosage form and strength of the product - Approved generic name (INN) - Visual description of the FPP - Visual description of the packaging 1.2. Samples (visual examination and comparison with the SPC and PIL 1.3. Regulatory situation in Member States / list countries - Countries where a MA has been issued - Countries where a MA has been withdrawn - Countries where a Marketing Application has been rejected, deferred

Quality dossier / Section 2 Active Pharmaceutical Ingredient (API) Generic Guide: Quality dossier / Section 2 Active Pharmaceutical Ingredient (API)

Generic Guide: Quality/Section 2: API Scientific data on the API can be submitted in the following order of preference A valid Certificate of Suitability (CoS) or CEP, latest version, with all its annexes issued by EDQM An APIMF (Active Pharmaceutical Ingredient Master File) submitted by the API manufacturer, containing the whole information requested in section 2 Complete submission of data requested in Section 2

Generic Guide: Quality/Section 2: API Complete submission option 2.1. Nomenclature (INN, chemical name, CAS No.) 2.2. Properties of the API** 2.3. Site(s) of manufacture 2.4. Route(s) of synthesis** 2.5. Specifications** 2.6. Container- closure system 2.7. Stability testing ** The requirements may differ depending on if the API is pharmacopoeial or non-pharmacopoeial

World Health Organization 19 April, 2017 Generic Guide: Quality/Section 2: API, Certification of Suitability (CoS) / CEP Option Issued by EDQM for substances described in the Ph. Eur. www.edqm.eu 2 types of CEPs: quality CEP and TSE CEP Information which can be found on a quality CEP CEP reference, CEP holder, site of manufacture of the substance, monograph according to which the dossier is evaluated, additional impurities and residual solvents not mentioned in the monograph, additional methods to those of the monograph are appended, re-test period with packaging system and storage condition (if applicable), date of validity of the CEP A quality CEP certifies that the quality of the substance can be checked according to the Ph. Eur. by applying the analytical methods described in the Ph. Eur. monograph supplemented by those appended to the CEP.

Generic Guide: Quality/Section 2: API, APIMF Option World Health Organization 19 April, 2017 Generic Guide: Quality/Section 2: API, APIMF Option Procedure implemented since January 2007, www.who.int/prequal To protect the "know-how" of the manufacturer of the API While giving the whole information on manufacture of the API to the WHO PQ team of assessors While giving a part of the information to the applicant to Prequalification/ manufacturer of the finished product An APIMF is composed of: Applicant's /Open part + Restricted / Closed part Manufacturer of the API should make available to the applicant to Prequalification the Applicant's part + Letter of access

Generic Guide: Quality/Section 2: API. APIMF Option World Health Organization Generic Guide: Quality/Section 2: API. APIMF Option 19 April, 2017 Manufacturer of the API should submit on the other hand the Applicant's part + Restricted + Letter of access to WHO team An APIMF is to be submitted only in support of a FPP dossier An APIMF is not an independent dossier of API Scope open to pharmacopoeial and non-pharmacopoeial APIs Scope of APIMF only open to APIs See annex 1 of the APIMF guide for the content of an APIMF Content of APIMF corresponds to data required in section 2 of the prequalification quality dossier without difference between pharmacopoeial and non-pharmacopoeial APIs

World Health Organization Generic Guide: 19 April, 2017 Quality dossier / Section 3 Finished Pharmaceutical Product (FPP)

Generic Guide: Quality/Section 3: FPP World Health Organization Generic Guide: Quality/Section 3: FPP 19 April, 2017 3.1. Manufacturing and marketing authorization 3.2. Pharmaceutical development 3.3. Formulation 3.4. Sites of manufacture 3.5. Manufacturing process 3.6. Manufacturing process controls of Critical steps and intermediates 3.7. Process validation and Evaluation 3.8. Specifications for excipients 3.9. Control of the FPP 3.10. Container/closure system (s) and other packaging 3.11. Stability testing

Generic Guide: Quality/Section 3: FPP World Health Organization Generic Guide: Quality/Section 3: FPP 19 April, 2017 3.12. Container labelling 3.13. Product information for health professionals 3.14. Patient information and package leaflet 3.15. Justification for any differences to the product in the country or countries issuing the submitted WHO-type certificate(s)

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