GUIDELINES FOR SUBMITTING APPLICATION FOR …

1 1 GUIDELINES FOR SUBMITTING APPLICATION FOR REGISTRATION OF A MEDICINE 2007 2 TABLE OF CONTENTS i. ABBREVIATIONS ii. FOREWORD iii. INTRODUCTION iv. GLOSSARY 1. APPLICATION FORM FOR REGISTRATION AND MARKETING OF A MEDICINE IN THE SADC REGION 1 2. GUIDELINES FOR SUBMITTING applications GENERAL INFORMATION 1. Applicants 14 2. APPLICATION forms 14 3. APPLICATION fees 14 4. Confidentiality 15 5. Same / Separate applications 15 PART I PART IA: ADMINISTRATIVE INFORMATION 1. Details of applicant 17 2. Details of responsible person 17 3. Details of manufacturer 17 4. Source (manufacturer) of Active Pharmaceutical Ingredient(s) 17 5. Product information 17 6. Registration Status 18 7. Proposed Indications 19 8.

2 Unit formula 19 9. Declaration by applicant 21 PART IB PRODUCT PROFILE 10. Summary of Product Characteristics 21 Proposed packaging, package insert, patient information 23 leaflet definitions & requirements for labelling 11. Package Insert 23 12. Patient Information Leaflet 23 13A. Immediate Container Label 26 13B. Outer Packaging Label 27 EXPERT REPORTS FOR PARTS II, III, IV AND IV 27 PART II CHEMICAL AND PHARMACEUTICAL INFORMATION 3 PART IIA COMPOSITION 28 PART IIB DEVELOPMENT PHARMACEUTICS 28 PART IIC CONTROL OF STARTING MATERIALS 28 PART IID CONTAINER CLOSURE SYSTEM (IMMEDIATE CONTAINER) 31 PART IIE CONTROL TESTS ON INTERMEDIATE PRODUCTS 31 PART IIF CONTROL TESTS ON FINISHED PRODUCTS 31 PART IIG METHOD OF PREPARATION FOR THE FINISHED PRODUCT 32 PART IIH STABILITY TESTS ON THE FINISHED PRODUCTS 32 PART III BIOAVAILABILITY/BIOEQUIVALENCE DATA 33 PART IV SUMMARY OF TOXICO-PHARMACOLOGY OF THE MEDICINE PART IVA SINGLE DOSE TOXICITY 33 PART IVB REPEAT DOSE TOXICITY 33 PART IVC REPRODUCTION STUDIES 33 PART IVD GENOTOXICITY 33 PART IVE CARCINOGENICITY 34 PART IVF PHARMACODYNAMICS 34 PART IVG PHARMACOKINETICS 34 PART IVH LOCAL TOLERANCE 34 PART IVI OTHER TOXICITY STUDIES 34 DISCUSSION AND CONCLUSION 34 PART V SUMMARY OF CLINICAL STUDIES PART VA HUMAN

3 PHARMACOLOGY 1. PRODUCT DEVELOPMENT RATIONALE 35 2. SUMMARY OF BIOPHARMACEUTICAL STUDIES AND ASSOCIATED METHODS 35 3. SUMMARY OF CLINICAL PHARMACOLOGY STUDIES 36 PART VB CLINICAL DOCUMENTATION 1. SUMMARY OF CLINICAL EFFICACY 38 2. SUMMARY OF CLINICAL SAFETY 41 ANNEXURE I RECOMMENDED WORDING OF WARNINGS ON PACKAGES 50 ANNEXURE II MEDICINES REGULATORY AUTHORITIES IN THE SADC MEMBER STATES 55 ANNEXURE III FEES APPLICABLE TO EACH SADC MEMBER STATE 57 4 ABBREVIATIONS: API Active pharmaceutical ingredient(s) ATC Anatomical therapeutic classification BA Bioavailability BE Bioequivalence BP British pharmacopeoia CEP European certificate of suitability CoA Certificate of analysis EP European pharmacopoeia GLP Good Laboratory Practices GMP Good Manufacturing Practices GSM General sales medicines IM Intra-muscular INN International non-proprietary name IR Infra red N Narcotic NCE New chemical entity NMR Nuclear magnetic resonance P Pharmacy only PD Pharmacodynamic PIL Patient information leaflet PK Pharmacokinetic PP Prescription preparation SADC Southern African Development Community USP United States pharmacopeoia WHO World Health Organisation FOREWORD 5 By Executive Secretary I am happy that, efforts of harmonizing regulation of medicines in the Southern African Development community (SADC)

4 Countries which began more than 5 years ago following the SADC Health Ministers declaration in 1999 are beginning to bear fruit. Though the full set of envisaged GUIDELINES for regulation of medicines is not yet accomplished, the completion of these set of GUIDELINES is an important milestone towards the harmonization of registration of medicines. Registration of medicine is the first step towards achieving the SADC countries noble goal of improving access to essential medicines of good quality, safe and efficacious. Of course registration GUIDELINES are important tools, but may be rendered useless if all member states do not internalize and implement them I therefore urge every SADC member state to take steps to internalize them into national laws and enforce their implementation. I also urge SADC medicine Regulatory Authorities to double their efforts to complete the remaining GUIDELINES , forms and other documents because without them it will be impossible to attain the cherished goals.

5 It is my expectation that at the time of celebrating the 10th anniversary of the birth of SADC in 200- all GUIDELINES forms and other relevant documents will be in place and in use. Finally I would like to thank all those who in one way or another contributed to the development and completion of these GUIDELINES . My special thanks are due to the European Union for financial support, member states and medicine Regulatory Authorities Leaders and Experts for their tireless efforts in developing the GUIDELINES and the World Health Organization for financial and technical support. z Augusto Salom o 6 INTRODUCTION These GUIDELINES are intended to assist applicants to generate and compile data for APPLICATION to register medicines in the Southern African Development Community (SADC). The GUIDELINES will apply in all SADC member states.

6 The GUIDELINES cover both generic and New medicines. The GUIDELINES are divided into three main sections as follows. The first section deals with glossary- the definition of terms as applied to these GUIDELINES . The second section is the APPLICATION form and the third section is the GUIDELINES for registration of medicine with the following main parts; general GUIDELINES for SUBMITTING applications , Part IA deals with administrative data while Part IB deals with product profile. Part II prescribes requirements for submission of data on chemical and Pharmaceutical Information to substantiate quality of the product. Part III deals with Bioavailability/bioequivalence data for generic medicines to demonstrate therapeutic interchangability with innovator product. Part IV prescribes the requirements for submission of toxico-pharmacological data to justify the pharmacological and safety profile of the product while Part V prescribes requirements for submission of data for clinical studies to demonstrate clinical safety and efficacy of the product.

7 Annexed to the GUIDELINES are the recommended wordings of warnings on packages. 7 GLOSSARY Absorption Process whereby an active pharmaceutical ingredient is transported unchanged from the site of administration across a bio membrane to the general circulation. Active Pharmaceutical Ingredient (API)/Active substance/Drug Substance/Medicinal Substance A substance or compound that is intended to be used in the manufacture of a pharmaceutical product as a pharmacologically active compound. Adverse drug reaction (serious) An adverse drug reaction which is fatal, life-threatening, permanently or significantly disabling, require or prolongs hospitalisation, causes congenital anomaly or requires intervention to prevent permanent impairment or damage. Analytical method A detailed description of the procedures to be followed in performing tests for conformity with specification/specifications.

8 Analytical procedure It is detailed description of steps necessary to perform each analytical test including but not limited to sample, reference standard and reagent preparations, use of the apparatus, generation of the calibration curve, use of the formulae for the calculation. Analytical validation This is a demonstration with documentary evidence that an analytical procedure leads to the expected results. Anatomic-Therapeutic Chemical Classification This is a classification of drugs according to site of action (anatomical), therapeutic indication and chemical group. Synonymous with pharmacotherapeutic classification 8 Applicant The person or company that applies for registration, licensing or marketing authorisation of a new pharmaceutical product or an update or variation to an existing marketing authorisation Approved name A non proprietary name of a medicinal product containing specified API approved by Medicine Regulatory Authorities (MRA) in SADC member states.

9 Assay method Quantitative method for determination of percentage purity of a drug substance or content of active ingredients in a preparation or crude drug. Authorisation holder A person or company in whose name the marketing authorisation has been granted. Authorised person Is an appointed person with qualification, knowledge and sufficient experience in the area of APPLICATION . Batch (or lot) A defined quantity of starting material, packaging material or bulk, intermediate or finished product that is intended or purported to be homogeneous in character and quality, and which has been produced during a defined cycle of manufacture. Batch certificate A document which provides information on quality of a particular batch. Batch manufacturing record A document stating the materials used and the operations carried out during the processing of a given batch, including details of in-process controls and packaging information.

10 Batch number (lot number) A distinctive combination of numbers and/or letters which specifically identifies a batch or lot and permits its history to be traced. 9 Bioavailability The extent and rate at which an active ingredient or active moiety is delivered to the general circulation from a particular dosage form or for medicines not intended to be absorbed into the bloodstream, bioavailability reflects the rate and extent to which the active ingredient or active moiety becomes available at the site of action. Bioequivalence Bioequivalence is defined as the lack of a significant difference in the rate and extent to which the active ingredient or active moiety in pharmaceutically equivalent or pharmaceutical alternative medicines become available in the general circulation or at the site of drug action, when administered at the same molar dose, under similar conditions and in an appropriately designed study, such that their effects can be expected to be essentially the same.