Guidelines on Submission of Documentation for Registration of Veterinary Biological Products

Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 GUIDELINES ON SUBMISSION OF DOCUMENTATION FOR REGISTRATION OF VETERINARY BIOLOGICAL PRODUCTS DECEMBER, 2021 Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 2 of 65 GUIDELINES DEVELOPMENT HISTORY DRAFT ZERO 05/10/2021 ADOPTION BY RWANDA FDA 22/10/2021 STAKEHOLDERS CONSULTATION 08/12/2021 ADOPTION OF STAKEHOLDERS COMMENTS 10/12/2021 DATE OF APPROVAL 24/12/2021 DATE FOR COMING INTO EFFECT 27/12/2021 Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 3 of 65 Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 4 of 65 TABLE OF CONTENT GUIDELINES DEVELOPMENT HISTORY ................................................................................ 2 TABLE OF CONTENT .................................................................................................................. 4 ABBREVIATIONS AND ACRONYMS ....................................................................................... 8 DEFINITIONS ................................................................................................................................ 9 0. INTRODUCTION .................................................................................................................... 12 0.0. Background ............................................................................................................................ 12 0.1. Scope ...................................................................................................................................... 12 0.2. Preparation and Presentation of Information in CTD format ................................................ 13 0.3. Submission of application ...................................................................................................... 13 0.4. Types of Product Registration Applications .......................................................................... 14 0.5. Application requirements ....................................................................................................... 15 0.6. Receiving of new applications for product registration ......................................................... 15 0.7. Officially Recognized References ......................................................................................... 15 0.8. Harmonization with other international regulators ................................................................ 15 0.9. Rwanda FDA Dossier Assessment Procedures ...................................................................... 16 0.9.1. Dossier Assessment for product quality, efficacy, and safety ............................................ 16 0.9.2. Compliance with the current Good Manufacturing Practices (cGMP) ............................... 16 0.9.3. Rwanda FDA Peer Review Committee for Product Registration ....................................... 17 0.10. Timelines for product registration ........................................................................................ 17 MODULE 1: ADMINISTRATIVE AND PRODUCT INFORMATION .................................... 18 1.1 Comprehensive table of Content for all modules .................................................................... 18 1.2 Cover Letter ............................................................................................................................ 18 1.3 Application form ..................................................................................................................... 18 1.4 Manufacturing and Marketing Authorization ......................................................................... 18 1.5 Mock-Ups ................................................................................................................................ 18 1.6 Summary of product characteristics (SmPC) .......................................................................... 19 1.7 Container Labeling .................................................................................................................. 19 1.8 Product Information Leaflet (PIL) .......................................................................................... 19 1.9 Product Samples ...................................................................................................................... 19 1.10 List of Countries where the Product has been Licensed and Summary of Approval Conditions ..................................................................................................................................... 19 1.11 Good Manufacturing Practice (GMP) ................................................................................... 19 1.12 Authorization of the Local Technical Representative ........................................................... 20 1.13 Certificates of Suitability of monographs of the European Pharmacopoeia (CEP) or APIMF 20 MODULE 2: OVERVIEWS AND SUMMARIES ...................................................................... 21 2.1 A table of contents. ................................................................................................................. 21 2.2 Introduction. ............................................................................................................................ 21 2.3 Overall quality summary. ........................................................................................................ 21 2.4 Overview and summary of the nonclinical studies ................................................................. 21 2.5 Overview and summary of the clinical studies ....................................................................... 21 MODULE 3: QUALITY (CHEMISTRY, MANUFACTURING, AND CONTROLS) .............. 23 3.1 Table of contents of module three ........................................................................................... 23 3.2.S Active substance .................................................................................................................. 23 3.2.S.1 General information .......................................................................................................... 23 Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 5 of 65 3.2.S.1.1 Nomenclature ................................................................................................................. 23 3.2.S.1.2 Structure ......................................................................................................................... 23 3.2.S.1.3 General properties .......................................................................................................... 23 3.2.S.2 Manufacture ...................................................................................................................... 23 3.2.S.2.1 Manufacturer(s) ............................................................................................................. 23 3.2.S.2.2 Description of the manufacturing process and process control ..................................... 24 3.2.S.2.3 Control of materials ....................................................................................................... 25 3.2.S.2.4 Control of Critical Steps and Intermediates................................................................... 26 3.2.S.2.5 Process Validation and/or evaluation ............................................................................ 26 3.2. S.2.6 Manufacturing Process Development ........................................................................... 26 3.2.S.3 Characterization of Veterinary Biological active substance ............................................. 28 3.2.S.3.1 Elucidation of Structure and other characteristics ......................................................... 28 3.2.S.3.2 Impurities ....................................................................................................................... 28 3.2. S.4. Control of Active Substance ........................................................................................... 28 3.2.S.4.1 Specification .................................................................................................................. 28 3.2.S.4.2 Analytical Procedures .................................................................................................... 28 3.2.S.4.3 Validation of Analytical Procedures .............................................................................. 29 3.2.S.4.4 Batch Analysis ............................................................................................................... 29 3.2.S.4.5 Justification of Specification ......................................................................................... 29 3.2.S.5 Reference Standard ........................................................................................................... 29 3.2.S.6 Container Closure system ................................................................................................. 29 3.2.S.7 Stability ............................................................................................................................. 30 3.2.S.7.1 Stability Summary and Conclusions .............................................................................. 30 3.2.S.7.2 Post-approval Stability Protocol and Stability Commitment......................................... 30 3.2.S.7.3 Stability Data ................................................................................................................. 30 3.2. P FINISHED BIOLOGICAL PRODUCT ............................................................................. 30 3.2. P.1. Description and composition of the biological Product ................................................. 30 3.2. P.2. Pharmaceutical development .......................................................................................... 31 3.2.P.2.1 Active Substance ........................................................................................................... 31 3.2.P.2.2 Drug Product .................................................................................................................. 31 3.2.P.2.3 Development of the manufacturing process .................................................................. 31 3.2.P.2.4 Container closure system selected ................................................................................. 32 3.2.P.2.5 Microbiological Attributes............................................................................................. 32 3.2.P.2.6 Compatibility ................................................................................................................. 32 3.2.P.3 Manufacture processes of the biological product ............................................................. 32 3.2.P.3.1 Manufacturer.................................................................................................................. 32 3.2.P.3.2 Batch formula ................................................................................................................ 32 3.2.P.3.3 Description of the manufacturing process ..................................................................... 32 3.2.P.3.4 Control of critical and intermediate steps ...................................................................... 33 3.2.P.3.5 Validation and/or evaluation of the processes ............................................................... 33 3.2.P.3.6 Description of the batch identification system .............................................................. 34 3.2.P.4 Control of excipients......................................................................................................... 34 Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 6 of 65 3.2.P.4.1 Specifications ................................................................................................................. 34 3.2.P.4.2 Analytical procedures .................................................................................................... 34 3.2.P.4.3 Validation of the analytical procedures ......................................................................... 34 3.2.P.4.4 Justification of specifications ........................................................................................ 34 3.2.P.4.5 Substances of Human or Animal Origin ........................................................................ 34 3.2.P.4.6 Novel excipients ............................................................................................................ 35 3.2.P.5 Control of the finished biological product ........................................................................ 35 3.2.P.5.1 Specifications of the biological product ........................................................................ 35 3.2. P.5.2. Analytical procedures of the biological product .......................................................... 35 3.2. P.5.3. Validation of the analytical procedures ....................................................................... 35 3.2. P.5.4. Batch analysis .............................................................................................................. 35 3.2.P.5.5 Characterization and/or determination of impurities ..................................................... 36 3.2.P.5.6 Justification of specifications ........................................................................................ 36 3.2.P.6 Reference standards and materials .................................................................................... 36 3.2.P.7 Container Closure System ................................................................................................ 36 3.2.P.8 Stability of the Biological Product ................................................................................... 37 3.2.P.8.1 Protocols and results of the stability study that justify the proposed validity period .... 37 3.2.P.8.2 Post-approval stability program ..................................................................................... 37 3.2.P.8.3 Stability data .................................................................................................................. 37 3.2.P.8.4 Shipping ......................................................................................................................... 38 3.2.A APPENDICES .................................................................................................................... 38 3.2.A.1 Literatures References ...................................................................................................... 38 3.2.A.2 Adventitious Agents Safety Evaluation ........................................................................... 38 3.2.A.3 Excipients ......................................................................................................................... 39 3.2.R Executed and Master batch manufacturing record .............................................................. 39 MODULE 4: NON-CLINICAL TRIALS .................................................................................... 40 4.1Table of contents of module 4 ................................................................................................. 40 4.2 Reports on studies ................................................................................................................... 40 1.3 Literature References .............................................................................................................. 40 MODULE 5: CLINICAL STUDIES ............................................................................................ 41 5.1 Table of contents of the Module ............................................................................................. 41 5.2 Reports on Field trial .............................................................................................................. 41 5.4 Special Consideration ............................................................................................................. 41 5.5 Bibliographic references ......................................................................................................... 41 ENDORSEMENT OF THE GUIDELINES ............................................................................. 41 Appendix 1. Application Form ..................................................................................................... 43 (Application form Adopted from the Regional Regulatory Harmonization for Livestock Products in Sub-Saharan Africa) ................................................................................................................. 43 Appendix 2. Registration Certificate of Veterinary Biological Products ..................................... 50 DAR/FMT/157 .............................................................................................................................. 50 Appendix 3. Summary of Product Characteristics ........................................................................ 52 Appendix 4. Container labeling .................................................................................................... 55 Appendix 5. Product Information leaflet (PIL)............................................................................. 57 Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 7 of 65 Appendix 6. Quality Overall Summary for Veterinary Biological Products ................................ 58 2.3.S.2.3 Control of materials ....................................................................................................... 59 2.3.S.2.4 Control of Critical Steps and Intermediates................................................................... 60 2.3.S.2.5 Process Validation and/or evaluation ............................................................................ 60 2.3.S.2.6 Manufacturing Process Development ............................................................................ 60 2.3.S.3 Characterization of Veterinary Biological active substance ....................................... 60 3.2.S.3.1 Elucidation of Structure and other characteristics ......................................................... 60 3.2.S.3.2 Impurities ....................................................................................................................... 60 2.3.S.4.4 Batch Analysis ............................................................................................................... 60 2.3.S.4.5 Justification of Specification ......................................................................................... 60 2.3.S.5 Reference Standard ........................................................................................................ 60 2.3.S.6 Container Closure system .............................................................................................. 60 2.3.S.7 Stability ............................................................................................................................ 60 2.3.S.7.1 Stability Summary and Conclusions .............................................................................. 60 2.3.S.7.2 Post-approval Stability Protocol and Stability Commitment......................................... 60 2.3.S.7.3 Stability Data ................................................................................................................. 60 2.3.P.3 Manufacture processes of the biological product ........................................................ 61 2.3.P.3.2 Batch formula ................................................................................................................ 62 2.3.P.3.3 Description of the manufacturing process ..................................................................... 62 2.3.P.3.4 Control of critical and intermediate steps ...................................................................... 62 2.3.P.3.5 Validation and/or evaluation of the processes ............................................................... 62 2.3.P.3.6 Description of the batch identification system .............................................................. 62 2.3.P.5 Control of the finished biological product.................................................................... 63 2.3.P.5.5 Characterization and/or determination of impurities ..................................................... 64 2.3.P.5.6 Justification of specifications ........................................................................................ 64 2.3.P.6 Reference standards and materials ............................................................................... 64 2.3.P.7 Container Closure System ............................................................................................. 64 2.3.P.8 Stability of the Drug Product ........................................................................................ 64 3.2.P.8.1 Protocols and results of the stability study that justify the proposed validity period .... 64 2.3.P.8.2 Post-approval stability program ..................................................................................... 64 2.3.P.8.3 Stability data .................................................................................................................. 65 2.3.P.8.4 Shipping ......................................................................................................................... 65 Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 8 of 65 ABBREVIATIONS AND ACRONYMS ATC vet code Anatomical Therapeutic Chemical code. This is a classification system for veterinary medicinal products. ATC vet, is based on the same main principles as the ATC classification system for drug substances used in human medicine. BMRs Batch Manufacturing Records CVMP Committee for Veterinary Medicinal Products CTD Common Technical Document DNA Deoxyribonucleic Acid EAC East African Community EMA European Medicines Agency, formally known as EMEA, European Medicines Evaluation Agency INN International Non-proprietary Names MCB Master Cell Bank MCS Master Cell Seed OIE Office International des Épizooties (International Office of Epizootics) PhEur European Pharmacopoeia rDNA ribosomal DNA (Deoxyribonucleic acid) Rwanda FDA Rwanda Food and Drugs Authority; SmPC Summary of Product Characteristics; TSE Transmissible Spongiform Encephalopathy VICH GL Guideline of VICH VICH International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products. WCB Working Cell Bank WCS Working Cell Seed Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 9 of 65 DEFINITIONS For these guidelines, the following definitions shall apply: Anti-drug antibody: An antibody that binds to the active substance of a biotherapeutic product. Anti-product antibody: An antibody that binds to the active substance, impurities or excipients of a biotherapeutic product. Applicant: The Person or company that submit an application for a Marketing Authorization (registration) or license to sell a medicinal product, an update or amendment to existing marketing authorization. Once the marketing authorization is granted, the applicant becomes the Marketing Authorization Holder for that particular medicinal product. Authority: means the Rwanda Food and Drugs or its acronym “Rwanda FDA”, established under Article 2 of the Law. Batch: A defined quantity of starting material, packaging material, or product processed in one process or series of processes so that it can be expected to be homogenous. To complete certain stages of manufacture, it may be necessary to divide a batch into a number of sub batches, which are further processed in one process or a series of processes, so that each sub batch can be expected to be homogenous. Biomarkers: A laboratory measurement that reflects the activity of a disease process, correlates (either directly or inversely) with disease progression, and may also be an indicator of therapeutic response. A genomic biomarker is a measurable DNA and/or RNA marker that measures the expression, function, or regulation of a gene. Biotherapeutic: A biological medicinal product with the indication of treating diseases. Comparability exercise: The activities – including study design, the conduct of studies, and evaluation of data that are designed to investigate whether a pre-change product and a post change product are highly similar. Critical quality attribute: A physical, chemical, biological or microbiological property or characteristic that is selected for its ability to help indicate the consistent quality of the product within an appropriate limit, range, or distribution to ensure the desired product quality. Drug product: A pharmaceutical product type in a defined container closure system that contains a drug substance, generally in association with excipients. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 10 of 65 Drug substance: Means any component that provides a pharmacological activity or other direct effects in the diagnosis, cure, mitigation, treatment of disease, or to affect the structure or any function of the body of animals. Excipient: Any pharmacologically inert substance used for combining with an active substance to achieve the desired bulk, consistency, etc. Impurity: Any component present in the drug substance or drug product that is not the desired product, a product-related substance, or excipient including buffer components. An impurity may be either process- or product-related. In-process control: Checks performed during production to monitor and, if necessary, to adjust the process to ensure that the intermediate or product conforms to its specifications. The control of the environment or equipment may also be regarded as a part of in-process control. In-silicomodeling: A computer-simulated model. Local Technical Representative: A person or company with sufficient pharmaceutical expertise that is incorporated within the country and who will be responsible for facilitating communication with the Applicant and when the product is registered shall assume all legal responsibilities. Master cell bank (MCB): An aliquot of a single pool of cells that generally has been prepared from the selected cell clone under defined conditions, dispensed into multiple containers, and stored under defined conditions. Primary Cell Cultures: Cultures of cells, essentially unchanged from those in the animal tissues from which they have been prepared and being no more than 5 in vitro passages to production level from the initial preparation from the animal tissue. rDNA-derived biological: Biological product prepared by recombinant DNA technology. Recombinant DNA technology: Technology that joins together (i.e., recombines) DNA segments from two or more different DNA molecules that are inserted into a host organism to produce new genetic combinations. It is also referred to as gene manipulation or genetic engineering because the original gene is artificially altered and changed. These new genes, when inserted into the expression system, form the basis for the production of rDNA-derived protein(s). Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 11 of 65 Specification The working cell bank is prepared from aliquots of a homogeneous suspension of cell obtained from culturing the master cell bank under defined culture conditions. Veterinary Biologicals: Products of biological origin other than immunological products intended to be used in animals to promote their health and wellbeing. They include a wide range of products such as hormones, pheromones, blood and blood components, allergenic, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. They can be composed of sugars, proteins, or nucleic acids, or complex combinations of these substances, or maybe living entities such as cells and tissues or a substance of synthetic origin that is manufactured, sold, or represented for use in restoring, correcting, or modifying organic functions in animals. Biologicals are isolated from a variety of natural sources: human, animal, or microorganism and may be produced by biotechnology methods and other cutting edge technologies. Withdrawal period: The minimum time that must elapse between the cessation of treatment of a food-producing animal and either the slaughter of the animal for human consumption or the resumption of the supply for human consumption of products, such as eggs, milk derived from the animal. Working cell bank (WCB): The working cell bank is prepared from aliquots of a homogeneous suspension of cells obtained from culturing the master cell bank under defined culture conditions. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 12 of 65 0. INTRODUCTION 0.0. Background These guidelines were elaborated to guide applicants who intend to register biological products for veterinary use in Rwanda. They were developed in reference to relevant international guidelines. Additionally, appropriate documents were consulted for consolidation. The present guidelines have been prepared by taking into consideration the need for a regional and worldwide harmonization, which will assist in the preparation and assessment of a well structured dossier to be submitted for the registration of veterinary biological products on the Rwandan market. This document provides details about the type of Quality information concerning the manufacture and control of a veterinary biological product that the applicant should include in the registration application dossier. It also describes the data required to support the Safety and the Efficacy of the product. In addition, these guidelines describe administrative information to be included in the application dossier. The Guidelines set out procedures and requirements for the application for registration of veterinary biological products using the Common Technical Document (CTD). The CTD has five Modules: Module 1: Administrative Requirements Module 2: Overviews and Summaries Module 3: Quality Module 4: Non Clinical Study reports Module 5: Clinical study reports Information in these modules should be presented in relevant sections. Any additional data including experts‟ comments should be included as an addendum to the relevant part, and may be provided as a supplement to, and/or incorporated into the relevant summary. 0.1. Scope These guidelines apply only to veterinary biological products other than immunological products intended for marketing in Rwanda. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 13 of 65 Veterinary biologicals include a range of products such as hormones, pheromones, enzymes, vitamins, blood and blood components, allergenic, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. They describe data required to demonstrate that a veterinary biological product intended for marketing in Rwanda complies with the established requirements. They should be read in conjunction with other international guidelines on quality, safety, and efficacy as cited in this guideline namely The World Organization for Animal Health (OIE), the European Medicines Agency (EMA), and Veterinary International Conference of Harmonization (VICH). Adherence to these guidelines by applicants will facilitate timely review and processing of product registration. 0.2. Preparation and Presentation of Information in CTD format The applicant shall prepare and present the product’s information dossier in the CTD format according to the requirements as stipulated in these guidelines: a) The application should be typed in English. Any document which is in any language other than English must be accompanied by a certified or notarized English translation. b) The application must contain a complete index of the various appendices. c) The summaries (Quality Overall Summary) should be formatted as a word document Downloadable on Authority’s website (Appendix 5 of these guidelines) and the body data in PDF. d) All pages of the application should be numbered in the style: page x of y. e) The application should be submitted in a virus-free CD-ROM or External Driver Addressed to Rwanda FDA. f) The PDF documents should be in Optical Character Recognition (OCR), selectable and searchable. g) A separate application is required for each product. 0.3. Submission of application An application for registration of veterinary biologicals for either locally manufactured or imported shall be made in writing via a cover letter and application form dated and signed by the applicant. If the applicant is a foreign company, the applicant shall appoint a local technical representative through whom an application shall be submitted. The local agent shall be a registered wholesale Veterinary pharmacy company or an accredited manufacturer's representative. The appointment of a Local Technical representative is certified by an appointment letter that is supported by a power of attorney notarized in the country of origin. The application should be submitted to Rwanda FDA at the following address: Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 14 of 65 Director General Rwanda Food and Drugs Authority info@rwandafda.gov.rw Nyarutarama Plaza, KG 9 Avenue, Kigali, Rwanda 0.4. Types of Product Registration Applications For the purposes of submission of Product Dossier to Rwanda FDA, applications are classified into three categories as follows: 1. New applications for registration: An application for registration of product that is intended to be placed on the Rwandan market for the first time or product which was on the market without a registration certificate. A new application may only be made by the applicant and he/she shall be the person who signs the declaration portion of Rwanda FDA application form. A separate application is required for each product that differs in active ingredient(s), strength, dosage form, proprietary names though containing the same ingredients or is considered to be different products. However, products containing the same active ingredients and the same strength made by the same manufacturer at the same manufacturing site, to the same specifications and dosage form, but differing only in packing or pack sizes require only one application. 2. Renewal of product registration: Applications for renewal of a registered product. The application shall be made at least 3 months before the expiry of existing registration according to requirements stipulated in the Rwanda FDA application guideline for renewal of the market authorization. 3. Variation of a registered product: An application for any change in the registered products. All applications for variation to a registered product shall be made according to requirements stipulated in the Rwanda FDA application Guideline for Variation of Registered veterinary products. 4. Annual retention Application for retention of registered veterinary biological products on the register should be submitted. Applications are submitted at least 2 months before the end of each year, from the date of issuing the market authorization (MA). mailto:info@rwandafda.gov.rw Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 15 of 65 Application requirements for a registered veterinary biological product retention include: Application cover letter Proof of payment of prescribed fees (Refer to regulations related to regulatory service tariff/fees and fines: https://www.rwandafda.gov.rw/web/fileadmin/Regulation Related to%20Regulatory servic e tariff fees and fines.pdf. 0.5. Application requirements An application dossier for registration of veterinary biological products in Rwanda shall include the following: 1. Signed and dated original hard copy of a cover letter 2. Signed and dated application form for product registration (Appendix 1) 3. Proof of payment of registration fee at the time of submission 4. Two CD-ROMs containing CTD document Format in (PDF), QOS in MS-Word 5. Two commercial samples of each pack size (The submission of samples should comply with the storage conditions as prescribed by the manufacturer to avoid any alteration of the product during transportation). 6. Proof of payment of Rwanda FDA GMP inspection for the finished product manufacturing site or GMP certificate by Rwanda FDA (if applicable) 0.6. Receiving of new applications for product registration An application consists of electronic copies, online submission, or specified hard copies where applicable. The application of product registration is only received by the Authority when the payment of prescribed registration fees is made. After receiving a product registration application, a reference number is assigned to the application dossier submitted and it will be used in all subsequent correspondences relating to the application. An acknowledged receipt will be issued. 0.7. Officially Recognized References The official recognized pharmacopeias by the Authority are British Pharmacopoeia (BP), European Pharmacopoeia (Ph. Eur.), The International Pharmacopoeia (Ph.Int), Japanese Pharmacopoeia (JP) and United States Pharmacopeia (USP). References should be cited in accordance with the current edition of compendia. 0.8. Harmonization with other international regulators Rwanda FDA harmonizes its registration processes as much as possible with other competent, Stringent Regulatory Authorities (SRAs) and international organizations such as The World Organization for Animal Health (OIE) and the Veterinary International Conference on https://www.rwandafda.gov.rw/web/fileadmin/Regulation Related to%20Regulatory service tariff fees and fines.pdf https://www.rwandafda.gov.rw/web/fileadmin/Regulation Related to%20Regulatory service tariff fees and fines.pdf Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 16 of 65 Harmonization (VICH). Where specific guidelines are unavailable, Rwanda FDA adopts Committee for Medicinal Products Veterinary Use (CMPV) Guidelines, which are available at the following websites EMA: https://www.ema.europa.eu/en/ and Veterinary International Conference on Harmonization (VICH) Guidelines: https://www.vichsec.org/en/. 0.9. Rwanda FDA Dossier Assessment Procedures 0.9.1. Dossier Assessment for product quality, efficacy, and safety After Rwanda FDA receives a complete product application dossier, the application will be scheduled for assessment according to the First in First out (FIFO) rules. Priority assessment may be granted where the product is intended for the control of rare disease conditions through an expression of interest (EOI DHT/FMT/032) or in the case of an emergency situation. A product dossier is reviewed by two assessors to provide scientific and regulatory oversight regarding the quality, safety, and efficacy of the product under assessment. Rwanda FDA reserves the right to request any additional information to establish the quality, safety, and efficacy of a veterinary biological product. During the assessment, additional data and/or samples may be requested through an official communication letter. Once a query has been issued to the applicant, the assessment process stops until Rwanda FDA receives a written response to the raised queries. Further processing of the application may only be undertaken if responses to queries issued in the official communication letter contain all outstanding information requested in one submission. Failure to comply with this condition or if the queries have been reissued for the fourth time and the applicant provides unsatisfactory responses, the application will be rejected. If the responses to the queries are not submitted within ninety (90) calendar days from the date they were issued, it will be considered that the applicant has withdrawn the application unless the applicant has requested for extension of the deadline to Rwanda FDA. Thereafter, registration of the product may only be considered upon submission of a new application. 0.9.2. Compliance with the current Good Manufacturing Practices (cGMP) The GMP inspection is part of the product registration process. Rwanda FDA should inspect the facility or use other means to verify whether the manufacturing site complies with cGMP regulations and/or guidelines before a product is registered. No product shall be registered unless the facility complies with cGMP. During the assessment, assessors may highlight GMPs issues and communicate to the department that has the mandate of inspection and compliance. https://www.ema.europa.eu/en/ https://www.vichsec.org/en/ Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 17 of 65 More information on GMP requirements and application for GMP inspection is detailed in the Rwanda FDA Guidelines on Good Manufacturing Practices and its annexes (Refer to the GMP guidelines document No DIS/GDL/002 and its annexes No DIS/GDL/003) downloadable from Rwanda FDA website. 0.9.3. Rwanda FDA Peer Review Committee for Product Registration After Dossier Assessment Workshop, a final dossier assessment report shall be presented to Rwanda FDA Peer Review Committee (PRC) before making final decisions for granting or rejecting registration of the product. In the event, that there are safety, quality, or efficacy issues to be resolved as per the decision of the PRC, the application shall remain pending until the resolution of the raised issues. If the applicant fails to provide the required data within ninety calendar days (90), the application shall be considered withdrawn. Rwanda FDA will register the product data on safety, quality, and efficacy are considered satisfactory and a registration certificate of veterinary biological products (Appendix 2) will be granted. The registration shall be valid for a period of five (5) years with annual retention. If the Rwanda FDA suspends or cancels the registration validity, a written official communication shall be made to the applicant. 0.10. Timelines for product registration Product dossiers shall be scheduled for assessment according to the First in First out (FIFO) basis upon compliance with the requirements. A new application shall be processed within nine (9) months of receipt of the application. The applicant will be required to provide any requested additional data within ninety (90) calendar days. Additional data or query responses shall be processed within sixty (60) calendar days. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 18 of 65 MODULE 1: ADMINISTRATIVE AND PRODUCT INFORMATION Module 1 should contain all administrative documents (for example, application forms and certifications), labeling, general correspondence. and annexes. Documents should be organized in the order listed below. Generally, all of the documents in Module 1, other than the annexes, should be provided in a single volume. The annexes to the module should be submitted in separate volumes. The official language is English as a mandatory language. 1.1 Comprehensive table of Content for all modules 1.2 Cover Letter Applicant should include a Cover Letter with all applications. A copy of the letter should be placed at the beginning of Module 1. The cover letter shall be signed by the proposed Market Authorization Holder. 1.3 Application form An application to register a veterinary biological product must be accompanied by a completed Application Form (Appendix 1). The application form should be duly filled with relevant information and attachments, dated signed, and stamped appropriately. 1.4 Manufacturing and Marketing Authorization A valid manufacturing license/authorization or a valid Certificate of Pharmaceutical Product (CoPP), or an equivalent certificate issued by a competent authority of the country of origin to the manufacturer of the finished biological product should be submitted. If applicable a valid manufacturing authorization for the production of the diluent should also be provided. In addition, valid manufacturing authorization(s) for the active ingredient (s) manufacturer (s) should be provided. 1.5 Mock-Ups Mock-ups of the sample(s) presentation of the veterinary biological product available at the time of initial application should be submitted. The purpose of this is to provide an example of the product, including accessories, if any, to verify that they correspond to what is described for the characteristics of the product under evaluation. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 19 of 65 1.6 Summary of product characteristics (SmPC) A summary of characteristics of the veterinary biological product under evaluation should be submitted. The SmPCs should be prepared following the content and the format as provided in Appendix 3. After the assessment and the approval of the submitted SmPC, the latter will be published online following the consent of the applicant. 1.7 Container Labeling Containers should be labeled as recommended in Appendix 4 of this guideline. This should be provided as mock-ups 1.8 Product Information Leaflet (PIL) Every container of Veterinary Biological Products should be accompanied by an information leaflet. One copy of the information leaflet prepared based on the provisions of Appendix 5 should be provided. 1.9 Product Samples Two Samples of the finished product with their certificates of analysis, labels, and cartons of the primary and secondary packaging of the product, including the package insert and accessories should be provided. The number of samples can increase depending on the nature and type of the product applied for registration, ideally, samples should be provided to allow full monograph analysis. The submission of samples should comply with the storage conditions as prescribed by the manufacturer to avoid any alteration of the product during transportation. 1.10 List of Countries where the Product has been Licensed and Summary of Approval Conditions If applicable, the applicant should provide the list of countries where the product is registered at the time of the application for registration. In the event the product has been registered in other countries, copies of registration certificates should be attached. 1.11 Good Manufacturing Practice (GMP) A valid certificate of GMP compliance should be provided. This should include manufacturers that are involved in any stage of the production process, for example, the manufacturer(s) of the finished biological product, active ingredient (s), the diluents, and those responsible for labeling and packaging of the finished biological product. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 20 of 65 In addition, a copy of a GMP certificate issued by Rwanda FDA or proof of application (such as a proof of payment), to GMP inspection of the finished biological product manufacturing site by Rwanda FDA should be submitted. 1.12 Authorization of the Local Technical Representative Any applicant who is not resident in Rwanda shall appoint a local technical representative (LTR) who must be a company authorized by Rwanda FDA to deal in veterinary products. The appointment shall be notified to the Authority by submitting a letter of appointment from the applicant supported by an original copy of power of attorney duly notarized in the country of origin authorizing the company to represent the manufacturer and market the product in Rwanda. 1.13 Certificates of Suitability of monographs of the European Pharmacopoeia (CEP) or APIMF If CEP is available, applicants should present a copy of CEP. Where reference is made to an Active Pharmaceutical Master File (APIMF), the applicant should provide the APIMF file number and a Letter of Access to the APIMF as appropriate. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 21 of 65 MODULE 2: OVERVIEWS AND SUMMARIES The purpose of this module is to summarize the quality (chemical, pharmaceutical, and biological), nonclinical and clinical information presented in modules 3, 4, and 5 in the market authorization application. The experts who draft these summaries should take an objective approach to the decisive points related to the quality of the product, clinical and nonclinical studies performed, report all pertinent data for the evaluation, and refer to the corresponding tables included in modules 3, 4, and 5. The information in module 2 should be presented in the following order: 2.1 A table of contents. A table of content of module 2 should be provided. 2.2 Introduction. A summary of the type of veterinary biological product, composition, mechanism of action, and proposed indications for the product should be provided. 2.3 Overall quality summary. A general summary of the quality of the product should be presented, related to the chemical, pharmaceutical, and biological aspects. This summary should refer exclusively to the information, data, and justifications included in module 3 or other modules of the registration document. This section should follow the format as specified in the Quality Overall Summary template (Appendix 6). 2.4 Overview and summary of the nonclinical studies A comprehensive and critical assessment of the results of the evaluation of the biological product in a controlled environment to support the safety and efficacy of the product should be presented. An overview and summary of the results of the pharmacological, pharmacokinetic, and toxicological tests should be presented. 2.5 Overview and summary of the clinical studies This section should include a critical analysis of the clinical study results included in the clinical in module 5. Information should include a summary of the clinical development of the product, the design of the pivotal studies, and the decisions related to the clinical studies and their performance and it should include an overview of the clinical conclusions and an evaluation of the risks/benefits in relation to the results of the clinical studies and justification of the proposed Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 22 of 65 dosages. All the data related to efficacy/effectiveness and safety assessed through the development of the product should be summarized in this section be presented, as well as any study limitations. Summaries should include all the clinical studies performed and a synopsis of each study. The data should be presented in a written and tabulated summary in the following order: 1. Introduction 2. Detailed discussion of the product development 3. Overview and summary of the mechanism of action 4. Overview and summary of the efficacy 5. Overview and summary of the safety 6. Conclusions on risk/benefit analysis 7. Literature References Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 23 of 65 MODULE 3: QUALITY (CHEMISTRY, MANUFACTURING, AND CONTROLS) 3.1 Table of contents of module three 3.2.S Active substance The information requested under this section should be supplied individually for each active substance used in the final veterinary biological product. 3.2.S.1 General information 3.2.S.1.1 Nomenclature Information concerning the nomenclature of the active substance (e.g. proposed INN name, Pharmacopeial name, proprietary name, company/laboratory code (could include trade mark name), other names or codes, if any), and identification number of production strain should be provided. 3.2.S.1.2 Structure The structural formula, molecular formula, and molecular weight should be provided as well as the schematic amino acid sequence indicating glycosylation sites or other post-translational modifications and relative molecular mass, as appropriate. 3.2.S.1.3 General properties A list of physicochemical and other relevant properties of the active substance, including biological activity, should be provided. The description of a biological product should indicate the biological system in which it is produced (e.g. bacterial, fungal, or mammalian cells) as well as the presentation of the finished product. 3.2.S.2 Manufacture 3.2.S.2.1 Manufacturer(s) The name, physical address, and responsibility of each manufacturer, including contractors, and each production site or facility involved in the manufacturing and testing should be provided. The physical address should include units and blocks for each production site. The sites or facilities involved in the creation, testing, and storing of the cell banks should be listed. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 24 of 65 3.2.S.2.2 Description of the manufacturing process and process control Information on the manufacturing process should be presented in the form of a flow diagram that indicates each step of the process including identification of the critical steps and points at which process controls are conducted. A narrative description of the manufacturing process including information on cell bank and cell culture, harvest(s), purification, and modification reaction including filling storage and shipping conditions should be provided. The in-process controls for each step or stage of the process should be indicated. The explanation should be provided on batch numbering system and any pooling of harvest or intermediates as well as the scale of culture and batch. a. Cell culture The following information should be provided: i. Flow diagram from working cell bank (WCB) through harvest; ii. Information for each stage should be provided (population doublings, cell concentrations, volumes, pH, cultivation time, temperature) and transfers between steps. iii. Description of each step including any media, materials, or additives used for both cell growth and induction. iv. Information with respect to operating parameters for each stage with links to in-process controls or specifications. b. Purification The following information should be provided: i. Flow diagram from crude harvest, extraction, and purification to final step to obtaining final active substance. ii. Information for each stage should be provided (pH, conductivity, processing times, hold times, elution profiles, fraction (selection) including viral inactivation step(s) if applicable. iii. In-process controls, including acceptance criteria, should be described in detail and should be validated. Special attention should be given to the removal of viruses, nucleic acid, host cell proteins, and impurities considered to pose a risk of action. iv. Particular attention should be given to demonstrating the removal and/or inactivation of possible contaminating viruses and residual DNA from products manufactured using continuous cell lines; v. Description of each step including scale (columns, membranes), lifetime usage for resins/membranes, regeneration, buffers used, and transfer between steps. vi. Reprocessing steps should be described with criteria. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 25 of 65 c. Drug substance filling, storage, and transport The following information should be provided: i. Procedure used to fill active substance into container with associated process controls and acceptance criteria. ii. Container closure system, storage, and shipping conditions. iii. Free/thaw or re-filtration procedures. iv. Hold times should be specified. 3.2.S.2.3 Control of materials Information on raw materials used in cell culture and purification should be described with respect to raw material grade or specification, product contact filter, media composition, resins, and contact membranes. Control of source and starting materials of biological origin should be summarized and detailed information should be provided. a. Source, history, and generation of cell-substrate A description of the host cell, its source and history, and of the expression vector used in production, including source and history, should be provided in detail. The description should include details of the origin and identity of the gene being cloned as well as the construction, genetic elements contained, and structure of the expression vector. An explanation of the source and function of the component parts of the vector, such as the origins of replication, promoters, or antibiotic markers, should be provided in addition to a restriction-enzyme map indicating at least those sites used in construction. b. Cell Banking system, characterization, and testing Information on the cell banking system; quality control activities and cell line stability during production and storage (including procedures used to generate the Master and Working Cell Bank(s) should be provided in detail. Information should include MCB and WCB, future WCB and End of Production Cell Bank, and establishment of the limit of in vitro cell age (LIVCA). The type of cell bank system used, the size of the cell bank(s), the container (vials, ampoules, or other appropriate vessels) and closure system used, the methods for the preparation of the cell bank(s) including the cryoprotectants and media used, and the conditions employed for cryopreservation or long-term storage should all be documented and described in detail. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 26 of 65 3.2.S.2.4 Control of Critical Steps and Intermediates Testing and acceptance criteria for the control of critical steps in the manufacturing processes should be provided. 3.2.S.2.5 Process Validation and/or evaluation a. Validation summaries of each unit operation, hold times, sanitary processing, and virus validation Sufficient information on validation and evaluation studies to demonstrate that the manufacturing process (including reprocessing steps) is suitable for its intended purpose and to substantiated selection of critical process controls (operational parameters and in-process tests) and their limits for critical manufacturing steps (e.g. cell culture, harvesting, purification, and modification) should be provided. b. Outline Validation strategy and scale used to complete studies Information should include a description of the plan for conducting the study and the results, analysis, and conclusions from the executed study (ies). c. Reference analytical procedures used for analysis The validation of corresponding assay and analytical methods should be cross-referenced or provided as part of justifying the selection of critical process controls and limits. For manufacturing steps, intended to remove or inactive viral contaminants, the information from evaluation studies should be provided. Validation process should include for example: Facilities, cleaning and microbiological control, Cell growth and harvesting e.g. Cell growth kinetics and antibody productivity profiles demonstrated for each bioreactor for appropriate timeframe, Removal of media components/additives during purification and Capacity of purification process to remove contaminating virus. Refer to EMA/CHMP/BWP/187338/2014. 3.2. S.2.6 Manufacturing Process Development a. Development program outline, scale(s) and tools used (design of experiment, FMEA, statistical evaluations) The developmental history of the manufacturing process should be provided. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 27 of 65 b. Process description and batch information from development scale(s) i. Outline any changes through development scale up to commercial (clinical batches) The description of change(s) made to the manufacture of drug substance batches used in support of the marketing application (e.g. non-clinical or clinical studies) including for example, changes to the process or critical equipment. The reason for the change should be explained. Relevant information on drug substance batches manufactured during development, such as the batch number, manufacturing scale and use (e.g. stability, non-clinical reference material) in relation to the change should also be provided. ii. Major changes need to be assessed for potential impact on product quality The significance of change should be assessed by evaluating its potential to impact the quality of the drug substance (and/or intermediate, if appropriate). For manufacturing changes that are considered significant, data from comparative analytical testing on relevant drug substance should be provided along with a discussion of the data including a justification for selection of the test and assessment of results. Selection of tests and results used to assess manufacturing changes during development Testing used to assess the impact of manufacturing changes on the drug substance(s) and the corresponding finished drug product(s) may also include non-clinical and clinical studies in other modules of the submission should be included. iii. Process Characterization shall include  Establishment of operating parameters and in processcontrols for commercial scale manufacture.  Elimination of operating parameters/in process controls based on development work that deemed them non-critical.  Freeze/thaw development data used to set number of cycles for drug substance.  Post approval – Comparability assessment of current to proposed change including side by-side batch release data, Co-mixture analysis with reference standard and subset of initial characterization testing to evaluation primary, secondary and tertiary structure. It is recommended that information on study design and product knowledge should be presented in this section. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 28 of 65 3.2.S.3 Characterization of Veterinary Biological active substance 3.2.S.3.1 Elucidation of Structure and other characteristics Information on the physical-chemical and/or biological characterization should be provided. For the intended product and product-related substances, details should be provided, if applicable, on primary, secondary, and higher-order structure, post-translational forms (e.g., glycoforms), biological activity, and purity. 3.2.S.3.2 Impurities Information on impurities should be provided. All potential impurities, including process-related impurities and degradation products for purification arising from manufacturing, storage or found in stability study batches, should be described regardless of whether they have been detected in any batches. The actual impurity levels detected (including quantities found in clinical, toxicological, bioavailability, and proposed commercial batches) should be reported, for example, using a summary table. The information should also include a discussion of results that are close to or outside limits. A rationale should be provided for the choice of tests used, the proposed limits, and their qualification. A rationale for excluding any impurity test(s) from routine release testing due to trace levels should also be provided, where applicable 3.2. S.4. Control of Active Substance 3.2.S.4.1 Specification At minimum release specifications for drug substance shall include appearance, and description, identity, purity, and potency. Information on the source, including as appropriate species of animal, type of microorganism should be included in the specifications, etc. (Refer to VICH GL40). 3.2.S.4.2 Analytical Procedures The analytical procedure used for testing the active substance should be provided in sufficient detail to enable reproducible testing by another laboratory. Analytical procedure summaries should be provided that minimally includes the following subsections: Principle, Procedure, and Data Analysis. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 29 of 65 3.2.S.4.3 Validation of Analytical Procedures Analytical validation information, including experimental data for the analytical procedure used for testing the drug substance, should be provided. Typical validation characteristics to be considered are selectivity, precision (repeatability, intermediate precision, and reproducibility), accuracy, linearity, range, limit of quantitation, limit of detection, robustness, and system suitability. Analytical method validation data should be performed to provide assurance of the method transferability to an additional testing site post initial approval. 3.2.S.4.4 Batch Analysis Description of batches and results of three batch analyses should be provided. Results should be presented for three commercial batches against acceptance criteria. Consideration to include graphs and/or gels for those tests that are qualitative or where the specification is “Comparable to Reference Material‟. 3.2.S.4.5 Justification of Specification Justification for the active substance specification should be provided. Rationale for use of tests for specific quality attributes taking into account the specifications and linking to the manufacturing process, stability of active substance, pre-clinical/clinical studies, and analytical procedures should be provided. 3.2.S.5 Reference Standard Quality information of Reference standard or material used for testing of active substance should be provided. The information should include a description of the manufacturing process of reference standard, and where appropriate Characterization, stability, and storage of the reference standard should also be detailed. 3.2.S.6 Container Closure system A description of the container closure systems for the drug substance should be provided, including specifications for their component materials. The specifications should include description and identification (and critical dimensions with drawings where appropriate). Suitability and compatibility of the materials of construct with active substance should also be demonstrated, literature reference may suffice when applicable. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 30 of 65 3.2.S.7 Stability Stability studies should include: Storage conditions i.e. Temperature and relative humidity for accelerated and stress Conditions. (Refer to VICH GL17). 3.2.S.7.1 Stability Summary and Conclusions The types of studies conducted, protocols used, and the results of the studies should be summarized. Should include the study conditions, including all of the storage conditions (temperature, humidity, light) in which the drug substance is evaluated, analytical methods, specifications, summary of results, and conclusions. 3.2.S.7.2 Post-approval Stability Protocol and Stability Commitment The post-approval stability protocol and stability commitment should be provided. 3.2.S.7.3 Stability Data Results of the stability studies (e.g., forced degradation studies and stress conditions) should be presented in an appropriate format such as tabular, graphical, or narrative. 3.2. P FINISHED BIOLOGICAL PRODUCT This section should contain information on the final product including all drug substances and excipients. If any proprietary preparation or mixtures are used as components, a complete statement of composition and other information that will properly describe and identify these materials should be provided. For all ingredients of human or animal origin, testing results or certificates of analysis demonstrating freedom from adventitious agents should be provided. 3.2. P.1. Description and composition of the biological Product A description of the finished biological product and its composition should be provided. The information provided should include: a. Description of the dosage form b. Composition, i.e., list of all components of the dosage form, and their amount on a per unit basis (including overages, if any, the function of the components, and a reference to their quality standards (e.g., compendial monographs or manufacturer’s specifications). c. Description of accompanying reconstitution diluents (s) if any. d. Type of container and closure used for the dosage form and accompanying reconstitution diluent, if applicable Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 31 of 65 Overages need to be justified – not intended to compensate for inadequate stability or manufacturing process. A table can be used to summarize the information for this part. 3.2. P.2. Pharmaceutical development Information and data on the development studies conducted to establish the dosage form, the formulation manufacturing process, container closure system, microbiological attributes, and usage instructions as appropriate for the purpose specified in the application, should be presented. Additionally, this section should identify and describe the formulation and process attributes (clinical parameters) that may influence batch reproducibility, product performance, and drug product quality. Manufacturing process changes made during clinical study program should be explained and justified. A link between formulation development and clinical batches should also be provided. Supportive data and results from specific studies or published literature may be included within or attached to the Pharmaceutical Development Section. Additional supportive data may be referenced to the relevant non-clinical sections of the application. The report should include the following: 3.2.P.2.1 Active Substance The description and properties of the active substance should be provided. Compatibility with the rest of the components in the finished biological product including preservatives and other additives should be demonstrated, where applicable. 3.2.P.2.2 Drug Product Information on the development of the formulation, considering the proposed route of administration should be provided. Details on the physicochemical and biological properties of the product, indicating the relevant parameters for developing the drug product should be included. In addition, justification of the final qualitative/quantitative formula of the biological product should be provided. 3.2.P.2.3 Development of the manufacturing process Description of the selection and optimization of the manufacturing process, particularly for critical aspects should be provided. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 32 of 65 3.2.P.2.4 Container closure system selected Information on the materials selected, protection against humidity and light, compatibility of the materials should be provided. Information on the suitability of the container closure system used for the storage, transportation (shipping), and use of the drug product should be discussed. Results of the extractable study should be presented and depending on the results, also a leachable study with e.g. placebo in final container should be presented. 3.2.P.2.5 Microbiological Attributes Information on the integrity of the container closure system to prevent microbial contamination should be presented. 3.2.P.2.6 Compatibility Information on the compatibility of the drug product with the manufacturing process contacts (e.g; online filters, bags), container closure system including dosage devices where applicable, and diluents should be provided. 3.2.P.3 Manufacture processes of the biological product 3.2.P.3.1 Manufacturer Name(s), physical address(es) including unit(s) and/or block(s), and functions of each manufacturing site involved in all stages of the processes should be listed. Valid manufacturing license and/or certificates of GMP compliance of the sites and other pertinent organizational information for each manufacturer responsible for any portion of the manufacture or testing operations for the drug products should be provided. 3.2.P.3.2 Batch formula Batch lot formula should be provided that includes a list of all components of the dosage form to be used in the manufacturing process, their amounts on a per batch basis, including overages, and a reference to their quality standards should be provided. 3.2.P.3.3 Description of the manufacturing process  A flow diagram should be presented giving the steps of the process, indicating the points where materials enter the process. The critical steps and points at which process controls, intermediate tests, or final product controls are conducted should be identified. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 33 of 65  A narrative of the manufacturing process, equipment and materials used, the room or area where the operation is performed (may reference the simple floor diagram), in-process controls, and the critical points identified should be provided. 3.2.P.3.4 Control of critical and intermediate steps Tests and acceptance criteria developed to identify the critical steps in the manufacturing process should be provided with justification. A listing of the in-process controls and tests performed on the product at each step should be submitted. Specifications for intermediate products should be provided and they should be followed during routine production. 3.2.P.3.5 Validation and/or evaluation of the processes Description, documentation, and results of the studies on validation and/or evaluation of the manufacturing process, should be provided for the critical steps or critical tests employed in the manufacturing process. A product quality review may be submitted in place of the information below: The following information should be provided: a. A copy of the process validation protocol, specific to the biological product, that identifies the critical equipment and process parameters that can affect the quality of the product and defines testing parameters, sampling plans, analytical procedures, and acceptance criteria; b. A commitment that three consecutive, production-scale batches of the biological product will be subjected to prospective validation in accordance with the above protocol. The applicant should submit a written commitment that information from these studies will be available for verification. c. Validation information relating to the adequacy and efficacy of any sterilization process (e.g. medicinal product, packaging component should be submitted. The process validation report should include inter alia the following: a. A reference to the current master production document. b. A discussion of the critical equipment. c. The process parameters that can affect the quality of the biological (critical process parameters (CPPs)) including challenge experiments and failure mode operation d. Details of the sampling: sampling points, stages of sampling, methods of sampling, and the sampling plans (including schematics of blender/ storage bins for uniformity testing of the final blend). e. The testing parameters/ acceptance criteria including in-process and release specifications and including comparative dissolution profiles of validation batches against the batch(es) used in the bioavailability or biowaiver studies. f. The analytical procedures or a reference to appropriate section(s) of the dossier. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 34 of 65 g. The results/data obtained. Refer to EMA/CHMP/CVMP/QWP/BWP/70278/2012 3.2.P.3.6 Description of the batch identification system Information on how the lots are defined in the stage of filling, lyophilization (if it applies) and packaging should be provided. 3.2.P.4 Control of excipients 3.2.P.4.1 Specifications Information on the specifications for all the excipients employed in the formulation should be provided. List of raw materials meeting in-house specifications including the tests performed and specifications of Biological starting materials with information on the requirements to avoid the risk of transmissible spongiform encephalopathies (TSEs) in the final product including Certificate of Suitability (CEP) should be included. 3.2.P.4.2 Analytical procedures Description or bibliographic reference of the analytical methods used to control all the excipients employed in the formulation should be submitted. 3.2.P.4.3 Validation of the analytical procedures All analytical methods used to control the excipients in the final formulation should be validated and validation reports provided if applicable. 3.2.P.4.4 Justification of specifications Justification for the proposed specifications of the excipients should be provided. 3.2.P.4.5 Substances of Human or Animal Origin For excipients of human or animal origin, information should be provided regarding the source/origin, description of the quality tests performed, specifications, determination of adventitious agents, and viral safety. Additionally, testing results or certificates of analysis demonstrating their freedom from adventitious agents should be provided. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 35 of 65 3.2.P.4.6 Novel excipients When used for the first time in veterinary biological product or for a new route of administration, detailed information should be provided on the manufacture, characterization, and control, and data supporting safety established in nonclinical and clinical studies in relation to the drug substance used. 3.2.P.5 Control of the finished biological product 3.2.P.5.1 Specifications of the biological product Specifications for the biological product should be provided. At minimum, specification should contain test and acceptance criteria for description and appearance, identity, quantity, potency, purity, and impurities. For Intermediate Products (as appropriate): Highlight the list of the routine tests performed and specifications for intermediates. 3.2. P.5.2. Analytical procedures of the biological product Detailed information on the analytical procedures used for quality control of the biological product should be provided. This section should not be presented as summaries or references. 3.2. P.5.3. Validation of the analytical procedures Information on the validation of the analytical procedures for the biological product, including experimental data should be provided. This information should include a complete description of the protocol used for each bioassay, the control standards, the validation of inherent variability of test, and the establishment of acceptance limits for each assay. 3.2. P.5.4. Batch analysis A description of all batches selected to assure the identity, purity, strength and/or potency, as well as the lot-to-lot consistency of the drug product and the specifications used for the drug product should be submitted. Description should include (size, origin, and use) and test result of all relevant batches e.g pre clinical, clinical pilot, scale-up, and if available production-scale batches) used to establish specifications and evaluate consistency in manufacturing. Provide certificates of analysis and analytical results for at least three consecutive batches signed by authorized personnel. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 36 of 65 3.2.P.5.5 Characterization and/or determination of impurities Details on the characterization and/or determination of impurities, as applicable, depending on the nature of active substance and method used to manufacture the biological product should be provided. 3.2.P.5.6 Justification of specifications Justification of the proposed biological product specifications should be provided. 3.2.P.6 Reference standards and materials Information on the reference standards and/or materials used for testing the finished biological product should be provided. 3.2.P.7 Container Closure System Detailed description of the container closure system used for the biological product plus any accessories accompanied with it should be provided. The description should include the type and form of the container closure system, including the materials of which they are made and quality specifications. Detailed information concerning the supplier(s), address(es), and the results of compatibility, toxicity, and biological tests should be included. When a delivery device is presented as part of the drug product (e.g. prefilled syringe, single-use autoinjector), it is important to demonstrate the functionality of such a combination, such as the reproducibility and accuracy of the dispensed dose under testing conditions which should simulate the use of the drug product as closely as possible. For multi-use containers such as vials or cartridges for a pen injector, proper in-use stability studies should be performed to evaluate the impact of the in-use period of the vial or the assembled device on the formulation and the functionality of the pen injector. Dose accuracy should be demonstrated for the first and last dose delivered. In addition, the effect of multiple injections/withdrawals on the closure system should be demonstrated. Description should also be used on the specialized devices used to monitor the consistency of delivery if they are intended to become an important part of the product’s container closure system. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 37 of 65 3.2.P.8 Stability of the Biological Product 3.2.P.8.1 Protocols and results of the stability study that justify the proposed validity period Stability study report including the study protocol, specifications, analytical methods, detailed description of the container closure system for the product evaluated, storage conditions (temperature and relative humidity), and results for at least three lots of biological product prepared from different lots of active substances should be provided and the reports should contain conclusions as well as the proposed validity period. A minimum of twelve months’ data at the time of submission should be provided in cases where storage periods greater than six months are requested unless otherwise justified. For storage periods of less than six months, the stability data should cover the whole proposed shelf life. The stability studies should be submitted in controlled documentation. Stability studies under accelerated and stress conditions, including the impact of the container closure system, should also be provided. Refer to VICH GL 17. For drug products that require reconstitution, in-use stability studies should be provided. 3.2.P.8.2 Post-approval stability program Include the stability program or stability commitment to be carried out once the drug product is in the market, including the number of batches to be included in the study each year and the tests to be performed. These results should be submitted periodically to update the information on the stability of the drug product. 3.2.P.8.3 Stability data Evidence should be provided to demonstrate that the product is stable for the proposed validity period under the indicated storage conditions. The stability of each dosage form should be separately documented. The summary results, which support the proposed expiration-dating period, under recommended conditions, in the final container and closure system, should be provided. Stability data submitted should be for at least three consecutive batches and include the following: a. Information on stability of drug product, quality control methods and rationale for the choice of tests for determining stability. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 38 of 65 b. Information on the dates of manufacture of the lots, the lot numbers, the vial and dose size, and the scale of production. For lyophilized products, the data supporting the shelf-life of the product following reconstitution should be included. If the biological product is frozen, data supporting the stability of the product through a stated number of freeze-thaw cycles should be provided. A plan for an on-going stability program should be provided. This should include the protocol to be used, number of final lots to be entered into the stability protocol each year and how such lots will be selected. A stability study protocol should be provided. The policy for assigning the date of manufacture of each component as well as the final product (e.g. combination formulation) and diluents, as appropriate should be described. 3.2.P.8.4 Shipping Details should be provided on the measures used to guarantee the adequacy of temperature and humidity conditions for shipping the biological product from the place of production to the place of final sale, including all the storage and distribution stages and indicating the controls performed in each of the stages. The declaration should be signed by quality control personnel. 3.2.A APPENDICES 3.2.A.1 Literatures References Appendices Provide key literatures reference used, if applicable. 3.2.A.2 Adventitious Agents Safety Evaluation Information on control or avoidance of non-viral adventitious agents (TSE, bacteria, mycoplasma) should be supported by TSE certificates of suitability and ensure Raw material and/or production process controls in place. 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, 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. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 39 of 65 Viral Adventitious Agents Viral safety evaluation studies to demonstrate that materials are safe, and approaches use to test, evaluate and/or eliminate are suitable. This shall include: a) Materials of biological origin – cell bank testing. b) Production testing. c) Viral testing of unprocessed bulk. d) Viral clearance studies – small-scale demonstration of viral inactivation and removal steps used in manufacturing. 3.2.A.3 Excipients This appendix is required where applicable. Novel Excipients - For any novel excipient, including adjuvants, preservatives and stabilizers, used for the first time in a biological product for veterinary use or for a new route of administration, information to support the quality, safety, and suitability for use should be provided in this appendix. This section should be submitted according to the active substance and/or drug product CTD format described in this document along with cross references to nonclinical studies (Module 4) and clinical studies (Module 5) supporting the safety of a novel excipient. Other Excipients - Any extensive active substance and/or biological product information, which is necessary to support the quality, safety, suitability for use, and “approvability‟ of any (non novel) non-compendial excipient, and/or any excipient of human or animal origin, should also be provided in this section. 3.2.R Executed and Master batch manufacturing record Submit Batch Manufacturing Record (BMR) of a real batch manufactured within at most six months before the submission of the application. In addition, submit master production document(s) for the proposed production batch size(s). Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 40 of 65 MODULE 4: NON-CLINICAL TRIALS The submission in this section should be organized as summarized below: 4.1Table of contents of module 4 4.2 Reports on studies 4.2.1 Pharmacology 4.2.1.1 Pharmacodynamic studies 4.2.2 Pharmacokinetics (when applicable) 4.2.3 Toxicology 4.2.3.1 General toxicology information 4.2.3.2 Special toxicology 4.2.3.3 Toxicity of new substances used in formulation (new adjuvant, stabilizers, additives). 4.2.4 Special Considerations 1.3 Literature References Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 41 of 65 MODULE 5: CLINICAL STUDIES The submission in this section should be organized as summarized below: 5.1 Table of contents of the Module 5.2 Reports on Field trial 5.2.1 Efficacy Study 5.2.2 Safety Study 5.3 Animal Ethics Committee Approval 5.4 Special Consideration 5.5 Bibliographic references ENDORSEMENT OF THE GUIDELINES Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 42 of 65 ANNEXES Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 43 of 65 Appendix 1. Application Form Rwanda Food and Drugs Authority Nyarutarama Plaza, Rwanda KG 9 Avenue, Kigali P.O. Box 1948, Kigali, Rwanda E-mail: info@rwandafda.gov.rw Website: www.rwandafda.gov.rw (Application form Adopted from the Regional Regulatory Harmonization for Livestock Products in Sub-Saharan Africa) A separate application form is required for each strength and/or pharmaceutical dosage form. Different pack sizes of the same product can be included on the same form. SECTION 1 - PRODUCT NAME(s) 1.1. Proposed trade name of the product 1.2. International Non-Proprietary Name (Generic Name) SECTION 2 – APPLICATION DETAILS 2.1 Product Type Please select either pharmaceutical OR Biological/Immunological ☐ Pharmaceutical ☐ Biological A VMP sourced from a biological source that is not a vaccine ☐ Immunological - vaccine. QMS No: DAR /FOM/154 Rev. No: 0 Effective date: 27/12/2021 Revision due date: 27/12/2024 mailto:info@rwandafda.gov.rw Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 44 of 65 2.2 Type of Drug Substance Please select only one ☐ Newly marketed Product with New Drug Substance ☐ Newly marketed Product with New Combination of Drugs Substances ☐ Newly marketed Product with Existing Drug Substance ☐ Re-evaluation of an Existing Product SECTION 3 – PRODUCT DETAILS 3.1 Formulation (provide the full formulation details) Please add extra rows, if required. 3.2 Therapeutic Subgroup Classification (example, inactivated viral vaccine, diuretic drug) and ATC Code (if applicable) 3.3 Dosage Form and Strength (example, solution for injection) 3.4 Visual appearance including colour (example, clear, light yellow oily solution) 3.5 Target Species and Route(s) of Administration Target Species Route of Administration Food-producing? (tick as appropriate) 1 Yes ☐ No ☐ Name of the substance Concentration in the final product Description of Function (example, active substance, attenuated virus, adjuvant, excipient) 1 2 Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 45 of 65 2 Yes ☐ No ☐ Please add extra rows, if required. 3.6 Do all active substances have the appropriate Maximum Residue Limits (MRLs) set in the species and for the route of administration(s) for which they are indicated? For example, from Codex, EU or other. YES ☐ NO ☐ If yes, states the MRLS Target Species Tissue MRLs Reference (Codex, EU,…) If no, please tell us what you are doing to obtain the appropriate MRL(s): 3.7 Pack type details Please provide information of all pack types including their container and closures. Pack Size (example, 100 ml) Container (example HDPE bottle) Closure (example, polyethylene screw-cap) 1 2 Please add extra rows, if required. 3.8 Proposed shelf-life (if applicable also include the proposed shelf life after reconstitution or dilution or after first opening container) Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 46 of 65 SECTION 4 – CONTACT INFORMATION 4.1 Details of the proposed Marketing Authorization Holder (MAH) or Applicant contact: Company Name: Company Address: Telephone No. Email 4.2 Name, address and contact details of the proposed Manufacturers 4.2.1. Name, address and contact details of the proposed finished product manufacturer(s): If the proposed named manufacturer is the same as the proposed MAH, simply enter ‘same as MAH’ in the field below. Name, address and telephone number, Email Brief description of functions performed (e.g. bulk manufacturing, batch release, primary or secondary packaging) 1 2 Please add extra rows, if required. 4.2.2. Name, address and contact details of the proposed manufacturer (s) of Active pharmaceutical ingredient (s) or active Immunogenic Substance(s): Name, address and telephone number, Email Brief description of functions performed (e.g. bulk manufacturing, batch release, primary or secondary packaging) 1 2 Please add extra rows, if required. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 47 of 65 SECTION 5 – REGULATORY STATUS 5.1 Regulatory Status in Country of Origin. Provide the regulatory status in the country of manufacture and the authorisation number/reference. 5.2 Regulatory Status in Other Territories. Regulatory status of the proposed product in other countries globally, including successful or pending, rejected, withdrawn, suspended or revoked applications. Country/Region with successful authorisations Please add extra rows, if required. Country/Region where applications are pending Please add extra rows, if required. Country/Region where applications/authorisations have been rejected, withdrawn, suspended or revoked Please add extra rows, if required. SECTION 6 – DECLARATION Contact details of the person responsible for the application: A legal representative of the applying company to take full responsibility for the application on behalf of the MAH and is answerable to the authority. Name: Company Name: Address (including country): Telephone No. Email Address: Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 48 of 65 Position and Affiliation: I confirm that the information provided in support of this application is correct at the time of submission. I understand that if any information provided in this application is later found to be false or incorrect, the authorization may be suspended or revoked. SIGNATURE: DATE: *Note: - not signing this box will lead to your application being rejected at validation. If fees have been paid, attach proof of payment ANNEX 1: Rwanda Specific Information If applications are being made to a number of countries, please provide the following details for each country (please replicate this annex for each country) A.1 Contact details of in-country Local Technical Representative: An in-country legal representative of the company holding the original authorization to take full responsibility for the product on behalf of the MAH and is answerable to the authority. Name: Address (including country): Telephone No. Email Address: A.2 Name and contact details of person responsible for pharmacovigilance: Name: Telephone No. Email Address: Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 49 of 65 A.3 Proposed Distribution Category in country (example, controlled drug, drug requiring prescription by veterinarian etc.) A.4 Proposed Storage Conditions (if applicable, also include the proposed storage condition after first opening and after reconstitution) A.5 Intended Use Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 50 of 65 Appendix 2. Registration Certificate of Veterinary Biological Products DAR/FMT/157 REGISTRATION CERTIFICATE OF VETERINARY BIOLOGICAL PRODUCT Made under Law No. 003/2018 of 09/02/2018 establishing the Rwanda FDA and determining its mission, organization and functioning in his article 3 and article 8 and regulation No. CBD/TRG/010. The Authority here issues Registration number: Rwanda FDA-VBP-MA-000 ****** This is to certify that the Veterinary Biological Product described below has been registered in Rwanda subject to conditions indicated at the back of this certificate. Brand Name: ****** Name of the Active ingredient(s) and Strength: ****** Indication: ****** Dosage Form and appearance: ****** Pack size and Packaging type: ****** Shelf life in months and Storage statement: ****** Distribution category: ****** Name of Marketing Authorization Holder: ****** Name and address of manufacturer: ****** Name of Local Technical Representative: ****** Issued on: ****** Expires on: ****** Dr. Emile BIENVENU Director General Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 51 of 65 Conditions for Veterinary Biological Product Registration 1. This certificate must be returned to the Authority if canceled, invalidated or if the registered veterinary biological product is withdrawn. 2. Any change in the information submitted for the purpose of registration must be notified to the Rwanda FDA within 30 days of the change. 3. This certificate shall be invalid immediately after the expiry date and the Marketing Authorization Holder shall ensure that application for renewal of registration is made 90 days before expiry of registration. 4. Registered veterinary biological product cannot be advertised without prior approval of the Authority. 5. The veterinary biological product shall comply with all relevant provisions of Rwanda FDA regulations at all times. 6. The Marketing Authorization Holder shall ensure that registered veterinary biological product complies with Rwandan labelling and packaging requirements at all times. 7. The Marketing Authorization Holder shall ensure that the manufacturing facilities where a registered veterinary biological product is produced comply at all times with Rwanda FDA Good Manufacturing Practice requirements. 8. The Marketing Authorization Holder shall notify Rwanda FDA of the change of a Local Technical Representative at all times. 9. The registration of the veterinary biological product shall continue to be valid for five (5) years provided that annual retention fee is paid. 10. The Authority reserves the right to withdrawal this certificate when conditions 1 to 7 are contravened and when the risks of using this veterinary biological product outweighs the benefits or it is in public interest to do so. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 52 of 65 Appendix 3. Summary of Product Characteristics Template for the Summary of Product Characteristics (SmPCs) for a Veterinary Biological Product 1. Name of the veterinary biological product State the name under which the product will be marketed. 2. Qualitative and quantitative composition Provide the qualitative and quantitative composition per unit dosage form in terms of the active substance(s) and excipients in a format as indicated below: Each dose of (product name) contains: Active substance(s): Adjuvant(s) (if any): Excipient(s): 3. Dosage form State clearly the dosage form of the product. Any descriptive terms to give an indication of the exact type of dosage form should also be included. The visual and physical characteristics of the product also should be stated. 4. Clinical particulars 4.1. Target species State target species, including any sub-category where appropriate. 4.2. Indications for use Provide information on indications of the product in the target species. 4.3. Contraindications State the contraindications for this veterinary biological product e.g. not for use in pregnant animals, very young and old animals. 4.4. Special warnings State any specific warnings associated with this product. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 53 of 65 4.5. Special precautions for use State precautions to be taken by the person administering the veterinary biological product (if any). State the precautions that should be taken for use in animals. 4.6. Adverse effects following the administration (frequency and seriousness). State the side effects and adverse reactions of the product. Within each frequency grouping, undesirable effects should be presented in order of decreasing seriousness. 4.7. Use during pregnancy, lactation or lay Provide information on the use of the product in pregnant, lactating animals or laying birds and the reasons for any relevant recommendation. Information about the use of the product during pregnancy or lactation may have been provided in the sections dealing with contra-indications or special precautions for use. In such cases, a cross-reference to the relevant section will be sufficient. 4.8. Interaction with pharmaceutical or other biologicals and other forms of interaction State briefly the interactions of the product with other types of medicinal products, or state whether compatible with other biological products likely to be used at the same time. 4.9. Amount to be administered and administration route State the dose, dosage schedule and route of administration. 4.10. Overdose (symptoms, emergency procedures, if necessary) Describe symptoms observed at higher dose levels. Give the recommended management and emergency procedures. 4.11. Withdrawal period State the withdrawal periods (if applicable). 5. Pharmaceutical properties State the pharmaceutical properties of the product. 6. Biological veterinary product particulars Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 54 of 65 6.1. Incompatibilities Provide information on incompatibilities of the product with medicinal and other biological products. 6.2. Shelf life Shelf life (in months) of the veterinary biological product. State the biological shelf life after reconstitution (where applicable). For multi-dose packages state the in use shelf life after first opening (where applicable). 6.3. Special precautions for storage State the recommended storage conditions (e.g. temperature, light) as established by stability studies. The storage temperature must be stated in figures. 6.4. Nature and composition of packaging State briefly the type(s) of packing and pack size(s) being applied for registration. The pack sizes declared here should correspond with the samples submitted. 6.5. Special precautions for the disposal of unused products or waste State Material derived from the use of such products. Provide practical instructions for the safe disposal of the biological product and waste materials derived from the used/unused products (if applicable). 7. Marketing Authorization holder/License holder State the name and physical address of the registrant including telephone, fax number and e-mail. In addition, provide the name and physical address of the manufacturer including telephone, fax number and e-mail if different from the Marketing Authorization Holder. 8. Date of revision of the text To be stated at the time of approval of changes to the SmPC. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 55 of 65 Appendix 4. Container labeling Every immediate and outer container of any veterinary biological product shall be labeled in clearly legible indelible letters in English. Particulars to appear on the primary package 1. Name of the veterinary biological product 2. Name and quantity of active substance(s) 3. Target species 4. Indication(s) 5. Dosage and administration 6. Contraindications (see the package leaflet) 7. Content by volume or number of doses 8. Storage conditions 9. Date of manufacture, expiry, and batch number in an uncoded form 10. Name and physical address of the finished product manufacturer 11. For Veterinary Use only For containers of less than or equal to 10 ml capacity that are marketed in an outer pack such as a carton, the outer packaging will bear all the required information while the immediate container will only contain items (1), (2), (3), (5), (7), (8), (9). Alternatively, a logo that unambiguously identifies the company or the name of the dosage form, or the route of administration can be used. Particulars to appear on the secondary package 1. Name of the veterinary biological product 2. Name and quantity of active substance(s) and excipients 3. Target species 4. Indication(s) 5. Dosage and administration 6. Contraindications 7. Warnings and precautions, “for animal treatment only” “keep out of reach of children” are Mandatory 8. Withdrawal Period (if applicable) 9. Content by volume or number of doses 10. Storage conditions 11. Date of manufacture, expiry, and batch number in an Uncoded form 12. Name and physical address of the manufacturer Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 56 of 65 Small packs container As a minimum, the following information is printed directly on blister or/and strip: 1. Name, strength, and pharmaceutical form of the veterinary biological product. 2. Name of the manufacturer. 3. The batch number assigned by the manufacturer. 4. The manufacturing and expiry dates. Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 57 of 65 Appendix 5. Product Information leaflet (PIL) Particulars to appear on the package leaflet 1. Name of the veterinary biological product 2. Name and quantity of active substance(s) and excipients 3. Indication(s) 4. Contraindications, warnings and precautions 5. Adverse effects following the admnistration (frequency and Seriousness) 6. Target species 7. Amount to be administered and administration route for each Species 8. Withdrawal period (where applicable) 9. Special storage precautions  do not use after the expiry date stated on the <label><carton><bottle>  <shelf-life after first opening the container.>  <shelf-life after dilution or reconstitution according to directions.>  <do not use the product if you notice {description of the visible signs of Deterioration}.> 10. Special warning(s) 11. Content of pack(s) by volume or number of doses 12. Special precautions for the disposal of unused product or waste materials, if any (dispose according to local regulations) 13. Name and physical address of the manufacturer and Marketing authorization holder, if different from the Manufacturer. For any information about this veterinary biological product, please contact the local representative of the marketing authorization holder. 14. Date on which the package leaflet was last revised Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 58 of 65 Appendix 6. Quality Overall Summary for Veterinary Biological Products Rwanda Food and Drugs Authority Nyarutarama Plaza, Rwanda KG 9 Avenue, Kigali P.O. Box 1948, Kigali, Rwanda E-mail: info@rwandafda.gov.rw Website: www.rwandafda.gov.rw Quality Overall Summary (QOS) for Veterinary Biological Products GENERAL INSTRUCTIONS Quality overall summary (QOS) template should be completed for veterinary biological product (VBP) containing active substances. All sections and fields in the QOS template that would be applicable should be completed. It is understood that certain sections and fields may not apply and should be indicated as such by reporting “not applicable” in the appropriate area with an accompanying explanatory note. The use of tables to summarize the information is encouraged, where possible. The tables included in the template may need to be expanded or duplicated (e.g. for multiple strengths), as necessary. These tables are included as illustrative examples of how to summarize information. Other approaches to summarize the information can be used if they fulfill the same purpose. Please state the exact location (Annex number) of any appended documents in the relevant sections of the form. See the “Guideline on submission of documentation for registration of veterinary biological for general and detailed instructions on the completion of this template. Should you have any questions regarding this form, please contact the Rwanda Food and Drugs Authority (Rwanda FDA). 2.3 S ACTIVE SUBSTANCE (NAME, MANUFACTURER) 2.3. S.1. General information 2.3.S.1.1 Nomenclature  Biological name (including strain and/ or clone designation)  Chemical name. QMS No: DAR /FOM/157 Rev. No: 0 Effective date: 27/12/2021 Revision due date: 27/12/2024 mailto:info@rwandafda.gov.rw Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 59 of 65  The name(s) or designation of the strain of organism used to produce the active immunogenic substance 2.3.S.1.2 Structure  Structural formula  Schematic amino acids sequence/molecular formula  Relative molecular mass 2.3.S.1.3 General properties  Physicochemical Characterization  Biological Activity 2.3.S.2 Manufacture 2.3.S.2.1 Manufacturer(s) a. Name, address and responsibility (e.g. fabrication, packaging, labelling, testing, and storage) of each manufacturer, including contractors and each proposed production site or facility involved in these activities: Name and address (including block(s)/unit(s)) Responsibility b. Manufacturing authorization for the production of API(s) and, where available, certificate of GMP compliance (GMP information should be provided in Module 1). 2.3. S.2.2. Description of the manufacturing process and process controls 1. Flow diagram of manufacturing process 2. Narrative description of the manufacturing process (es) 2.3.S.2.3 Control of materials a. Source, history and generation of cell substrate b. Cell Banking system, characterization and testing Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 60 of 65 2.3.S.2.4 Control of Critical Steps and Intermediates 2.3.S.2.5 Process Validation and/or evaluation a. Validation summaries of each unit operation, hold times, sanitary processing, and virus validation b. Outline Validation strategy and scale used to complete studies c. Reference analytical procedures used for analysis 2.3.S.2.6 Manufacturing Process Development a. Development program outline, scale(s) and tools used (design of experiment, FMEA, statistical evaluations) b. Process description and batch information from development scale(s) 2.3.S.3 Characterization of Veterinary Biological active substance 3.2.S.3.1 Elucidation of Structure and other characteristics 3.2.S.3.2 Impurities 2.3. S.4. Control of Active Substance 2.3.S.4.1 Specification 2.3.S.4.2 Analytical Procedures 2.3.S.4.3 Validation of Analytical Procedures 2.3.S.4.4 Batch Analysis 2.3.S.4.5 Justification of Specification 2.3.S.5 Reference Standard 2.3.S.6 Container Closure system 2.3.S.7 Stability 2.3.S.7.1 Stability Summary and Conclusions 2.3.S.7.2 Post-approval Stability Protocol and Stability Commitment 2.3.S.7.3 Stability Data 2.3.P FINISHED VETERINARY BIOLOGICAL PRODUCT (NAME, MANUFACTURER) Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 61 of 65 2.3.P.1 Description and Composition a. Description of the finished veterinary biological product. b. Composition of the finished veterinary biological product. Component and quality standard (and grade, if applicable) Fu nction Strength (label claim) Quant. per unit or per mL % Quant. per unit or per mL % Quantity per unit or per mL % Complete with appropriate titles Subtotal 1 complete with the appropriate title Subtotal 2 Total c. Description of accompanying reconstitution diluents (s) if any. d. Type of container and closure used for the dosage form and accompanying reconstitution diluent, if applicable 2.3. P.2. Pharmaceutical development 3.2.P.2.1 Active Substance 3.2.P.2.2 Drug Product 3.2P.2.3 Development of the manufacturing process 3.2.P.2.4 Container closure system 3.2.P.2.5 Microbiological Attributes 3.2.P.2.6 Compatibility 2.3.P.3 Manufacture processes of the biological product 2.3.P.3.1 Manufacturer(s) Name, address and responsibility (e.g. fabrication, packaging, labelling, and testing) of each Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 62 of 65 manufacturer, including contractors and each proposed production site or facility involved in manufacturing and testing: Manufacturing authorization, marketing authorization and, where available, certificate of GMP (GMP information should be provided in Module 1). 2.3.P.3.2 Batch formula List of all components of the finished drug product to be used in the manufacturing process and their amounts on a per batch basis. 2.3.P.3.3 Description of the manufacturing process a. Flow diagram of the manufacturing process b. Narrative description of the manufacturing process 2.3.P.3.4 Control of critical and intermediate steps Summary of controls performed at the critical steps of the manufacturing process and on isolated intermediates: Step Controls (parameters/limits/frequency of testing) 2.3.P.3.5 Validation and/or evaluation of the processes 2.3.P.3.6 Description of the batch identification system 2.3.P.4 Control of excipients 2.3.P.4.1 Specifications Summary of the specifications Name and address (include block(s)/unit(s)) Responsibility Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 63 of 65 2.3.P.4.2 Analytical Procedures Summary of the analytical procedures for supplementary tests 2.3.P.4.3 Validation of Analytical Procedures Summary of the validation information for the analytical procedures for supplementary tests (where applicable) 2.3.P.4.4 Justification of Specifications Justification of the specifications (e.g., evolution of tests, analytical procedures and acceptance criteria, exclusion of certain tests, differences from officially recognized compendia standard(s)). 2.3.P.4.5 Excipients of Human or Animal Origin For Finished biological products using excipients without risk of transmitting agents of animal spongiform encephalopathies, a letter of attestation confirming this can be found in: CEP(s) demonstrating TSE-compliance can be found in: 2.3.P.4.6 Novel Excipients 2.3.P.5 Control of the finished biological product 2.3.P.5.1 Specifications of the biological product 2.3.P.5.2 Analytical Procedures of the biological product (a) Summary or references to analytical procedures 2.3.P.5.3 Validation of Analytical Procedures (a) Summary or references to the validation information 2.3.P.5.4 Batch analysis (a) Description of the lots: Strength and Batch Number Bact Size Date and site of production Use (e.g clinica, compatibility studies) Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 64 of 65 2.3.P.5.5 Characterization and/or determination of impurities 2.3.P.5.6 Justification of specifications 2.3.P.6 Reference standards and materials Information on the reference standards and/or materials used for testing the finished biological product should be provided. 2.3.P.7 Container Closure System Description of the container closure systems, including unit count or fill size, container size or volume: Description (including materials of construction) Strength/concentration Unit count or fill size Container size (e.g. 1mL, 2 mL, 5 mL. etc. ) 2.3.P.8 Stability of the Drug Product 3.2.P.8.1 Protocols and results of the stability study that justify the proposed validity period a. Summary of accelerated and long-term testing parameters (e.g. studies conducted): Storage conditions (◦C, % RH) Strength and batch number Batch Size Container Closure System Completed (and proposed) test intervals b. Proposed storage statement and shelf-life (and in-use storage conditions and in-use period, if applicable): Container Closure System Storage statement Shelf - Life 2.3.P.8.2 Post-approval stability program Stability protocol for Primary stability batches, Commitment batches and Ongoing batches Guidelines on Submission of Documentation for Registration of Veterinary Biological Products Doc. No.: DAR/GDL/067 Revision Date: 13/12/2021 Effective Date: 27/12/2021 Revision No.: 0 Approval Date: 24/12/2021 Review Due Date: 27/12/2024 Page 65 of 65 2.3.P.8.3 Stability data a. The actual stability results should be provided in Module 3. b. Summary of analytical procedures and validation information for those procedures not previously summarized in 3.2.P.5 (e.g. analytical procedures used only for stability studies): c. Data to support freeze thaw cycles recommended 2.3.P.8.4 Shipping The procedures used to guarantee the cold chain.