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ICH CTD Format for Marketing Authorization Application

CTD The common technical document (CTD) is an international standard for the structure of applications for marketing authorization of a medical product The CTD is the outcome of the ICH process The CTD is mandatory since 01/July/2003 The CTD does not define the scientific content of the dossier

CTD OBJECTIVES CTD presents the agreed common format for preparation of a well-structured dossier 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 and will ease the preparation of electronic submissions.

ICH/CTD The Common Technical Document (CTD) is organized into 5 modules.

Documents in each Module Information 1 Administrative and prescribing information (region specific) 2 Summaries and overview 3 quality 4 Non-clinical study reports 5 Clinical study reports

Relationship between CTD and old EU Format Module 1 < --------> Part IA/B Module 2 < --------> Part IC Module 3 < --------> Part II Module 4 < --------> Part III Module 5 < --------> Part IV

ICH/CTD Module 1 Administrative Information and Prescribing Information

1. Module 1: ADMINISTRATIVE AND PRESCRIBING INFORMATION 1.1 Table of contents. 1.2. Administrative information 1.2.1. Drug submission application 1.2.2. Drug submission fee application 1.2.3. Submission certification 1.2.4. IRC Number 1.2.5. Establishment licensing information 1.2.6. GMP certification 1.2.7. International registration status 1.2.8. Other application information 1.3. product labeling 1.3.1. Summary of product characteristics. 1.3.2. product monograph 1.3.3. Instruction for medical use

1. Module 1: ADMINISTRATIVE AND PRESCRIBING INFORMATION 1.3.4. Draft for all inner and outer labels 1.3.5. Specimen 1.4. Bioequivalence studies summaries 1.5. Information about the expert 1.5.1 Information about the independent experts: 1.5.2. Information about the quality expert. 1.5.3. Information about the non clinical expert. 1.5.4. Information about clinical expert. 1.6. Environmental risk assessment Annex

Summary of product characteristic SPC Summary of product characteristic

SPC Generic name/Trade name Qualitative and quantitative composition Pharmaceutical form and strengths Clinical particulars

SPC 4.1. Therapeutic indications 4.2. Route of administration 4.3. Contra indications 4.4. Special warnings and precautions for use 4.5. interaction with other medicinal products and other forms of interaction 4.6. Pregnancy and lactation 4.7. Effects on ability to drive and use machines 4.8. Undesirable effects 4.9. Overdose

SPC 5. Pharmacological properties 5.1. Pharmacodynamic properties 5.2. Pharmacokinetic properties 5.3. Pre clinical safety data

SPC 6. Pharmaceutical particulars 6.1. List of excipients 6.2. Incompatibility 6.3. Shelf life 6.4. Special precautions for storage 6.5. Nature and contents of container 6.6. Special precautions for disposal and other handling

SPC Administrative data 7. MARKETING AUTHORIZATION HOLDER 8. MARKETING AUTHORIZATION NUMBER(S) 9. DATE OF FIRST AUTHORIZATION/RENEWAL OF THE AUTHORIZATION 10. DATE OF REVISION OF THE TEST

Quality Expert Name Experience Education Position held

Module 2: Overviews and Summaries 2.1 CTD TOC Modules 2-5 2.2 Introduction 2.3 Quality Overall Summary 2.4 Nonclinical Overview 2.5 Clinical Overview 2.6 Nonclinical Summary 2.7 Clinical Summary

2.2 Introduction • One page dealing with – Pharmacological class – Mode of action – Proposed clinical use

2-3. QOS Quality Overall Summary 2.3. Introduction 2.3.S (active substances) 2.3.P (finished product) 2.3.A Appendixes 2.3.R Regional information

2.3. QOS Marketing Authorization holder Manufacturer (S) Formula Introduction Dosage Form Packaging Salt Reproducibility of product’s quality

2.3.S QOS: Drug Substance 1. General information 2. Manufacture – Flow diagram 3. Characterisation - Tabulated summary of data, including graphical representation 4. Control of drug substance – Tabulated summary of batch analysis data, with graphical representation

2.3.S QOS: Drug Substance 5. Reference standards or materials 6. Container closure system (CCS) 7. Stability – Tabulated summary of study results, graphical representation

2.3 P QOS: Drug Product 1. Description and composition 2. Pharmaceutical development – Tabulated summary of composition of formulations, dissolution profiles 3. Manufacture - Flow diagram 4. Control of excipients 5. Control of drug product – Tabulated summary of batch analysis data, graphical representation

2.3 Drug Product 6. Reference standards or materials 7. Container closure system (CCS) 8. Stability – Tabulated summary of stability data, graphical representation

2.3.A Appendices 1. Facilities and equipment – Biotech: with summary 2. Adventitious agents safety evaluation – Measures to control adventitious agents in production – Summary of reduction factors • Novel excipients 2.3.R Regional information

ICH/CTD Module 2 (Summaries) Quality (Module 3) Overall Summary, Non-clinical (Module 4) Overview/Summaries, and Clinical (Module 5) Overview/Summaries.

ICH/CTD Module 3 (Quality) Documentation of Chemical and Pharmaceutical on active substance and/or medicinal product is provided in Quality Report, Module 3.

ICH/CTD Module 3 (Quality) 3.1 Table of Contents 3.2 Body of Data 3.3 Literature References

Module 3 (Quality) Module 3: Quality 3.1 Table of Contents 3.2 Body of Data 3.2.S Drug Substance 3.2.P Drug Product 3.2.R Regional Information 3.2.A Appendices 3.3 Literature References

Module 3 (Quality) 3.1. Table of contents The first document in this module should be a TOC listing all of the documents provided for module 3.

Module 3 (Quality) 3.2. Body of data Each individual sub-section related to the drug substance and drug product should be provided as: an individual document either bound separately, or divided by tab identifiers,

Module 3 (Quality) 3. 2. Body of data 3. 2. S. Drug Substance 3. 2. S Module 3 (Quality) 3.2. Body of data 3.2.S. Drug Substance 3.2.S.1 General Information 3.2.S.1.1 Nomenclature INN Compendial name if relevant Chemical name(s) 3.2.S.1.2 Structure 3.2.S.1.3 General Properties – International Non-Proprietary Name (INN), – National Approved Names, – US Adopted Name (USAN), – British Approved Names (BAN) – Laboratory Code(s), – Systematic Chemical Name(s), IUPAC – Other Names (e.g. Proprietary). – CAS registry number;

3.2.S.1.3 General Properties Appearance, physiochemical characteristics Category Absorption, toxicity, protein binding Half life, organism affected

Module 3 (Quality) 3. 2. Body of data 3. 2. S. Drug Substance 3. 2. S Module 3 (Quality) 3.2. Body of data 3.2.S. Drug Substance 3.2.S.2 Manufacture 3.2.S.2.1 Manufacturers [name, manufacturer] 3.2.S.2.2 Manufacturing Process and Process Controls 3.2.S.2.3 Control of Materials 3.2.S.2.4 Controls of Critical Steps and Intermediates 3.2.S.2.5 Process Validation and/or Evaluation 3.2.S.2.6 Manufacturing Process development

Module 3 (Quality) 3. 2. Body of data 3. 2. S. Drug Substance 3. 2. S Module 3 (Quality) 3.2. Body of data 3.2.S. Drug Substance 3.2.S.3 Characterization 3.2.S.3.1 Elucidation of Structure and other Characteristics 3.2.S.3.2 Impurities

3.2.S.3.1 S.3.1.1 UV S.3.1.2 IR S.3.1.3 NMR S.3.1.4 HPLC S.3.1.5 Mass spectrometry

S.3.2 Impurity starting material S.3.2.1 process intermediate during the process degradation S.3.2.2 Residual solvent 2.3 control of impurity 2.4 impurity structure

Module 3 (Quality) 3. 2. Body of data 3. 2. S. Drug Substance 3. 2. S Module 3 (Quality) 3.2. Body of data 3.2.S. Drug Substance 3.2.S.4 Control of Drug Substance 3.2.S.4.1 Specification 3.2.S.4.2 Analytical Procedures 3.2.S.4.3 Validation of Analytical Procedures 3.2.S.4.4 Batch Analyses 3.2.S.4.5 Justification of Specification

3.2.S.5 Reference Standards or Materials [name, manufacturer] Module 3 (Quality) 3.2. Body of data 3.2.S. Drug Substance 3.2.S.5 Reference Standards or Materials 3.2.S.5 Reference Standards or Materials [name, manufacturer]

Module 3 (Quality) 3. 2. Body of data 3. 2. S. Drug Substance 3. 2. S Module 3 (Quality) 3.2. Body of data 3.2.S. Drug Substance 3.2.S.6 Container Closure System 3.2.S.6 Container Closure System [name, manufacturer]

s.6 container closure system S.6.1 summary of primary and secondary packaging 6.2 suitability of container closure system 6.3 specification of C.C & COA 6.4 shematic drawing (if necessary)

Module 3 (Quality) 3. 2. Body of data 3. 2. S. Drug Substance 3. 2. S Module 3 (Quality) 3.2. Body of data 3.2.S. Drug Substance 3.2.S.7 Stability 3.2.S.7.1 Stability Summary and Conclusions 3.2.S.7.2 Post-approval (on going) Stability Protocol and Stability Commitment 3.2.S.7.3 Stability Data

Module 3 (Quality) 3.2. Body of data 3.2.P Drug Product

Module 3 (Quality) 3. 2. Body of data 3. 2. P Drug Product 3. 2. P Module 3 (Quality) 3.2. Body of data 3.2.P Drug Product 3.2.P.1 Description and Composition of the Drug Product Description of the dosage form Composition (i.e., list of all components, amount on a per unit basis (including overages, if any) their function, and a reference (e.g., compendial monographs or manufacturer’s specifications) Description of accompanying reconstitution diluents Type of container and closure used for the dosage form

Composition of Lamivudine Tablets 150 mg Strength 150 mg Ingredients Quality standard Unit composition Function in the Formulation mg % Lamivudine (as API) USP 34-NF29 150 50 Active Ingredient Microcrystalline Cellulose 108 36 Diluent & Disintegrant Pregelatinized Starch 25.5 8.5 Binder/Disintegrant Sodium Starch Glycolate 12 4 Disintegrant Magnesium Stearate 1.5 0.5 Lubricant Sodium Lauryl Sulfate EP 2010 3 1 Total ----------- 300 100 ---------------

Composition of Lamivudine Tablets 150 mg Strength 150 mg Composition of tablet coating Quality standard Unit composition Function in the Formulation mg % HPMC (6cp) USP 34-NF29 9.43 66.77 Film-forming Agent Polyethylene Glycol 4000 2.35 16.63 Titanium Dioxide White Pigment & Opacifier Isopropyl Alcohol 0.038 mL ----- Solvent Purified Water 0.1 mL Solvent & Vehicle Total ----------- 14.13 100 ---------------

Tips on Composition Constituents including those removed during processing, e.g. granulation solvents: should be clearly identified by means of a pharmacopoeia monograph name if one exists,

Tips on Composition Colouring materials should be identified by the EC code number if appropriate. It is recognised that for multi-national companies wish to use coloring materials approved elsewhere than the EU to allow use of the same dosage form in all centers.

Dosage Form Composition to be expressed as: Solid Dosage Forms: Tablets, Capsules and Boluses: Quantity per unit dose Oral liquids, Syrups and Suspensions: Quantity per unit dose (usually 5mL) Aerosols Quantity per unit dose, puff

Dosage Form Composition to be expressed as: Injectable Preparations: mg per in the unit container or usable volume of the product, w/v), or I.U. of active constituents in the unit container (taking into account usable volume of the product).

Dosage Form Composition to be expressed as: Topical preparations Percentage: Ointments, Creams and Gels %w/w Toothpaste %w/w, Lotions %w/v Eye & Nasal Drops: % w/v Oral Drops: mg in ml

Tips on Composition Exact quantities are not required for constituents used in: Tablet coating, or Capsule shells although the qualitative formulation of these must be declared.

Tips on Composition For excipients where a slight variation in quantities may be required from batch to batch: These may be expressed in the formula as a range (and justified in the Development Pharmaceutics section).

Overage The inclusion of an overage normally applies only to active constituents, preservatives, etc. Where an overage is included it must be stated whether this is intended to cover: losses during manufacture, loss of potency on storage or both.

Overage Justification for an overage should be provided in the Development Pharmaceutics section.

Module 3 (Quality) 3. 2. Body of data 3. 2. P Drug Product 3. 2. P Module 3 (Quality) 3.2. Body of data 3.2.P Drug Product 3.2.P.2 Pharmaceutical Development information on the development studies conducted to establish that the dosage form, the formulation, manufacturing process, container closure system, microbiological attributes.

Module 3 (Quality) 3. 2. Body of data 3. 2. P Drug Product 3. 2. P Module 3 (Quality) 3.2. Body of data 3.2.P Drug Product 3.2.P.2 Pharmaceutical Development Process attributes (critical parameters) that can influence batch reproducibility, product performance, and drug product quality.

Module 3 (Quality) 3. 2. Body of data 3. 2. P Drug Product 3. 2. P Module 3 (Quality) 3.2. Body of data 3.2.P Drug Product 3.2.P.2 Pharmaceutical Development The compatibility of the drug substance with the excipients. Additionally, key physicochemical characteristics (e.g., water content, solubility, particle size distribution, polymorphic or solid state form) of the drug substance that can influence the performance of the drug product should be discussed.

Module 3 (Quality) 3. 2. Body of data 3. 2. P Drug Product 3. 2. P Module 3 (Quality) 3.2. Body of data 3.2.P Drug Product 3.2.P.2 Pharmaceutical Development 3.2.P.2.1 Components of the Drug Product 3.2.P.2.1.1 Drug Substance For a drug product supplied with reconstitution diluents, information on the diluents should be provided in a separate part P. For combination products, the compatibility of drug substances with each other should be discussed.

Module 3 (Quality) 3. 2. Body of data 3. 2. P Drug Product 3. 2. P Module 3 (Quality) 3.2. Body of data 3.2.P Drug Product 3.2.P.2 Pharmaceutical Development 3.2.P.2.1.2 Excipients The choice of excipients listed in 3.2.P.1, their concentration, and the characteristics that can influence the drug product performance should be discussed relative to their respective functions.

Module 3 (Quality) 3. 2. Body of data 3. 2. P Drug Product 3. 2. P Module 3 (Quality) 3.2. Body of data 3.2.P Drug Product 3.2.P.2 Pharmaceutical Development 3.2.P.2.2 Drug Product 3.2.P.2.2.1 Formulation Development 3.2.P.2.2.2 Overages [name, dosage form] 3.2.P.2.2.3 Physicochemical and Biological Properties 3.2.P.2.3 Manufacturing Process Development 3.2.P.2.4 Container Closure System 3.2.P.2.5 Microbiological Attributes

Module 3 (Quality) 3. 2. Body of data 3. 2. P Drug Product 3. 2. P Module 3 (Quality) 3.2. Body of data 3.2.P Drug Product 3.2.P.3 Manufacture 3.2.P.3.1 Manufacturers 3.2.P.3.2 Batch Formula 3.2.P.3.3 Description of Manufacturing Process and Process Controls 3.2.P.3.4 Controls of Critical Steps 3.2.P.3.5 Process Validation and/or Evaluation

Batch Formula (core) Strength 150 mg Batch Size 450000 tablets Ingredients Quality standard Unit composition Batch quantities mg % kg Lamivudine (as API) USP 34-NF29 150 50 67.5 Microcrystalline Cellulose 108 36 48.6 Pregelatinized Strach 25.5 8.5 11.475 Sodium Strach Glycolate 12 4 5.4 Magnesium Stearate 1.5 0.5 0.675 Sodium Lauryl Sulfate EP 2010 3 1 1.35 Total ----------- 300 100 135

Batch Formula (coat) Strength 150 mg Composition of tablet coating Quality standard Unit composition Batch quantities mg % kg HPMC (6cp) USP 34-NF29 9.43 66.77 4.2435 Polyethylene Glycol 4000 2.35 16.63 1.0575 Titanium Dioxide Isopropyl Alcohol 0.038 mL ----- 17.1 L Purified Water 0.1 mL 45 L Total ----------- 14.13 100 6.3575

Module 3 (Quality) 3. 2. Body of data 3. 2. P Drug Product 3. 2. P Module 3 (Quality) 3.2. Body of data 3.2.P Drug Product 3.2.P.4 Control of Excipients 3.2.P.4.1 Specifications 3.2.P.4.2 Analytical Procedures 3.2.P.4.3 Validation of Analytical Procedures 3.2.P.4.4 Justification of Specifications 3.2.P.4.5 Excipients of Human or Animal Origin 3.2.P.4.6 Novel Excipients

Module 3 (Quality) 3. 2. Body of data 3. 2. P Drug Product 3. 2. P Module 3 (Quality) 3.2. Body of data 3.2.P Drug Product 3.2.P.5 Control of Drug Product 3.2.P.5.1 Specifications 3.2.P.5.2 Analytical Procedures 3.2.P.5.3 Validation of Analytical Procedures 3.2.P.5.4 Batch Analyses 3.2.P.5.5 Characterization of Impurities 3.2.P.5.6 Justification of Specifications

Module 3 (Quality) 3. 2. Body of data 3. 2. P Drug Product 3. 2. P Module 3 (Quality) 3.2. Body of data 3.2.P Drug Product 3.2.P.6 Reference Standards 3.2.P.6 Reference Standards or Materials

3.2.P.7 Container Closure System Module 3 (Quality) 3.2. Body of data 3.2.P Drug Product 3.2.P.7 Containers 3.2.P.7 Container Closure System Containers <661> Permeation <671> Biological reactivity test, in vitro <87> Biological reactivity test, in vivo <88>

Module 3 (Quality) 3. 2. Body of data 3. 2. P Drug Product 3. 2. P Module 3 (Quality) 3.2. Body of data 3.2.P Drug Product 3.2.P.7 Containers A brief description of the containers to be used should be given. It is also helpful if any outer packages to be used are also mentioned in appropriate cases e.g. cardboard cartons to provide light protection for photosensitive material packed in clear glass ampoules.

Module 3 (Quality) 3. 2. Body of data 3. 2. P Drug Product 3. 2. P Module 3 (Quality) 3.2. Body of data 3.2.P Drug Product 3.2.P.8 Stability 3.2.P.8.1 Stability Summary and Conclusion 3.2.P.8.2 Post-approval Stability Protocol and Stability Commitment 3.2.P.8.3 Stability Data

Module 3 (Quality) 3.3. Literatures 3.2.R. REGIONAL INFORMATION 3.2.A. APPENDICES A1 Facilities and Equipment A2 Adventitous Agents Safety Evaluation A3 Novel Excipients 3.3 LITERATURE REFERENCES

For non-viral adventitious agents: Detailed information should be provided on the avoidance and control of non-viral adventitious agents (e.g., transmissible spongiform encephalopathy agents, bacteria, mycoplasma, and fungi). This information can include, for example, certification and/or testing of raw materials and excipients, and control of the production process, as appropriate for the material, process and agent

For viral adventitious agents: Detailed information from viral safety evaluation studies should be provided in this section. Viral evaluation studies should demonstrate that the materials used in production are considered safe, and that the approaches used to test, evaluate, and eliminate the potential risks during manufacturing are suitable.

A3 Novel Excipients For excipient(s) used for the first time in a drug product or by a new route of administration, full details of manufacture, characterisation, and controls, with cross references to supporting safety data (nonclinical and/or clinical) should be provided according to the drug substance format

3.2.R Regional information: EU • Process validation scheme for the drug product • Medical device • Certificate(s) of suitability (CEP) Medicinal products containing or using in the manufacturing process materials of animal and/ or human origin

Module 4 Module 4: Nonclinical Study Reports 4.2 Study Reports 4.1 Table of Contents 4.2 Study Reports 4.2.1 Pharmacology 4.2.2 Pharmacokinetics 4.2.3 Toxicology 4.3 Literature References

Module 5 Module 5: Clinical Study Reports 5.1 Table of Contents 5.2 Tabular Listing of All Clinical Studies 5.3 Clinical Study Reports 5.4 Literature References

Module 5 Invitro Invivo PSUR Bioequivalency Irritation test (Human) Irritation test (Animal) ------> Module 4 Module 5

ICH/CTD Guidance M4: Organization of the CTD M4Q: The CTD — Quality M4S: The CTD — Safety M4E: The CTD — Efficacy.

Thanks for your kind attention