MINISTRY OF HEALTH AND SOCIAL SERVICES

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1 MINISTRY OF HEALTH AND SOCIAL SERVICES NAMIBIA MEDICINES REGULATORY COUNCIL POST REGISTRATION AMENDMENT GUIDELINES These guidelines are meant to provide assistance to industry and health care professionals on how to comply with the governing statutes and regulations. They also provide assistance to the secretariat of the Namibia Medicines Regulatory Council (NMRC) on how NMRC s mandates and objectives should be implemented in a manner that is fair, consistent and effective. NMRC reserves the right to request information or material or define conditions not specifically described in these guidelines, in order to allow the NMRC to adequately assess the safety, efficacy or quality of a medicinal product. NMRC is committed to ensuring that such requests are justifiable and that decisions are evidence based. Page 1 of 9

2 INTRODUCTION Marketing authorization or registration of medicinal products is a dynamic process. It involves pre-marketing assessment of medicine dossiers to verify quality, safety and efficacy based on the existing evidence. Thereafter it involves changes depending on emerging issues that arise during the lifetime of the product. The Holder of the Certificate of Registration (HCR) is therefore required to take into account technical and scientific progress of a registered product throughout its lifetime. The holder is also required to make any amendment that may be required to enable the registered product be manufactured and checked by means of generally accepted scientific methods. For purposes of these guidelines post-registration is defined as a variation to the contents of the dossier such as they existed at the time the decision to grant registration was adopted by the NMRC or after approval of any previous amendment. Amendments to the registration dossier are necessary to maintain the safety, quality and efficacy of a medicine and to ensure compliance with current technical requirements, adhere to administrative aspects, keep abreast of scientific progress or to reflect new therapeutic indications / warnings or other safety matters. It is therefore the objective of the NMRC to process, as quickly as possible, amendment applications made by the: Holder of the certificate of registration (HCR) to registered medicines Applicant of old medicines Prospective holder of the certificate of registration (PHCR) / Applicant in response to committee recommendations. This document has been prepared as a tool to address matters concerning amendments to both facilities including change in HCR as well as changes in pharmaceutical and analytical aspects of the medicine. This guideline applies only to conventional medicinal products for human use. Comprehensive documentation to support the amendment application including all documents amended as a result of the application should be supplied and any other conditions determined by the NMRC must be complied with. A notification or application for approval of a post registration amendment shall concern only one type of amendment. Where several amendments are to be made to a single marketing authorization, a separate notification and/or application for approval shall be submitted in respect of each type of amendment sought. Each such notification or application shall also contain a reference to the other notifications and/or applications. Post registration amendment applicants are advised to consult the Medicines and Related Substances Control Act (Act 13 of 2003) and it regulations in order to comply fully with the regulatory requirements in respect of the applicable fees. These should be paid whether amendment application is approved or not. For purposes of clarity this guideline has classified post-registration amendments into two categories: Page 2 of 9

3 A. Amendments that require notification only These amendments include administrative changes and other changes that unlikely to have a significant impact on the quality and performance of a dosage form. These amendments should not be made with amendments that require prior approval. These changes should be recorded in the product review and be available for inspection. At any point when an amendment application is submitted for a product, all these amendments pertaining to the product should also be included in the NMRF PART 1Ac) Amendment history and also be clearly addressed in the Amendment Schedule, and the latest amendments to any particular aspect should be submitted. Written notification of the amendment should be forwarded to The Registrar of Medicines 30 days prior to intended implementation. The covering letter for this amendment becomes the notification. The appropriately amended Annexures / PARTs affected by the change should be submitted together with the relevant data/documentation. NOTIFICATIONS: 1. Change in the name and/or address of a manufacturer of the API whether or not a European Pharmacopoeia certificate of suitability is available 2. Change of contact person, product name, product owner or batch numbering system 3. Renaming (e.g. street name, postal) of manufacturing site of drug substance or drug product 4. Withdrawal/deletion of manufacturer (drug substance, drug product, packer or batch releaser) 5. Deletion of pack size of drug product 6. Change or inclusion of pack size for drug product 7. Deletion of colour/flavour/fragrance (including capsules shells) and removal of printing ink on the dosage form 8. Replacement or addition of colourant/ flavourant/ fragrance (final product specifications excluding description remains the same) 9. Granulating solution < 20 % of the original stated granulating solution 10. Change in the quantity of sugar or film coating material only: no change in final product specification except mass 11. Change in composition of the sugar coating material: no change in final product specifications except mass (either qualitative, or qualitative and quantitative, excluding change in sealant) 12. Quantity of pharmaceutical ingredient change (overages): a) Overage of API change: < 10 % of active b) Overage of water soluble vitamins < 50 % of vitamin content c) Preservative* (semi-solid dosage form)< 10 % of preservative Page 3 of 9

4 d) Preservative* (other dosage forms) < 20 % of preservative * specifically refers to antimicrobial preservatives 13. Change in inactive pharmaceutical ingredient (IPI) range: -Immediate release solid oral dosage form. -Modified release solid oral dosage form (only non-release controlling IPIs) IPI (m/m) per total target dosage form mass % IPI Filler 5 % Disintegrant: Starch 3 % Other 1 % Binder 0,5 % Lubricant Ca/Mg stearate 0,25 % Other 1 % Glidant: Talc 1 % Other 0,1 % Filmcoat 1 % The total effect of all IPI changes should not be more than 5 % m/m relative to the total dosage mass. Calculation example API 500 mg Total IPIs 100 mg Total dosage mass 600 mg Lactose: change from 30 to 45 mg (+15/600) = +2,5 % Cellulose: change from 50 to 35 mg (- 15/600) = - 2,5 % Absolute total change = 5 % 14. Change in mass of empty capsule shell (size) 15. Change to container dimensions, same content size Change of container presentation size (addition or removal), same container and closure system 16. Change to appearance/description (excluding scoring for dosage claim and shape of tablets) restricted to shape, imprinting/embossing and printing 17. Change to dimensions of tablet or capsule, without any other change to the final product specifications 18. Pharmaceutical ingredient specifications and/or analytical methods which are more stringent, additional, upgrade to latest pharmacopoeia and minor change of method (same principle of analysis) Page 4 of 9

5 19. Final product specifications and/or analytical methods which are more stringent, additional, upgrade to latest pharmacopoeia (e.g latest editions of BP, USP, Ph.Eur) and minor change of method (same principle of analysis) 20. Change of name of active or other ingredient to an INN or approved name 21. Change in: process timing and/or operating speeds (if validated), but same final product specifications and content uniformity process temperature and/or humidity (within validation range), but same final product specifications and content uniformity order of addition of pharmaceutical ingredients with same processing principles and same final product specifications 22. Change/additional source to a different site of the same parent company of API (route of synthesis including purification step and specifications the same) 23. Change in batch size of active substance or intermediate of up to 10-fold compared to the original batch size approved at the time of registration of the product or in a case of downscaling provided that any changes to the manufacturing methods are only those necessitated by scale-up, e.g. use of different-sized equipment. The change must not affect the reproducibility of the process. In addition the downscaling should not be the result of unexpected events arising during manufacture or because of stability concerns. 24. Film coating change from organic solution to aqueous solution (Qualitative composition of components, excluding change in sealant if used e.g. modified release) 25. Packaging material: Changes in composition of the immediate container (at least equivalent in protection of light and moisture permeability to that of the existing container) * Composition not equivalent, but provides better protection to the product (stability not affected) * Changes to colour, at least equivalent in protection (light sensitive products) * Changes to closures in contact with product in compliance with the USP permeation test *To prove equivalence use USP criteria for containers 26. Change in : Equipment or process machinery but with same processing principles e.g. low energy/low energy Process timing and/or operating speed, but same final product specifications and content uniformity Process temperature and/or environmental humidity, but same final product specifications Page 5 of 9

6 27. Change to shape of tablet if the surface area is different 28. Scale-up and down to and including ten times the batch used to support stability and efficacy or the approved or validated batch using the same: Formulation Equipment design and operating principles Controls and SOPs 29. Replacement an IPI with a comparable* IPI with the same functional characteristics, resulting in no change in the dissolution profile for solid oral dosage forms. The final product specifications should remain unchanged. *in terms of chemical structure, physical form and/or pharmaceutical effect. 30. Automation of one or more process steps without change in process methodology 31. Addition or replacement of measuring device for oral liquid or other dosage forms 32. Change of product labeling due to safety updates 33. Change of product labeling of language(s) other than English 34. Computer process control for steps to replace manual control B. Amendments that require prior approval These amendments are likely to have a significant impact on the quality and performance of a dosage form. The appropriately amended PARTs / Annexures affected by the change should be submitted together with the relevant data/documentation. Written approval from the NMRC should be obtained before the change may be implemented. The applicant should also submit documentary evidence of other national regulatory authority approvals or other decisions pertaining to the application and specifically approvals or other decisions from the country of origin, RSA (MCC), USA (FDA), European Union (EMEA), UK (MHRA), Sweden (MPA), Canada (Health Canada), Australia (TGA), and Japan (MWH). AMENDMENTS: 1. Inactive Pharmaceutical Ingredient (IPI) a) Addition of one or more IPIs b) Ranges more than allowed for notification changes for immediate release solid oral dosage forms and for modified release solid oral dosage forms (non-release controlling ingredient) c) Addition or removal or increasing or decreasing any release controlling ingredient d) Changes in technical grade i.e. Avicel PH102 to Avicel PH200 Page 6 of 9

7 e) Replacement of more than one IPI. 2. Sugarcoat: Changes in composition (qualitative and/or quantitative), which result in a change in final product specification. 3. Overage greater than the overages allowed for in Notification changes under A above. a) Wide therapeutic effect b) No increase in the severity of known side effects c) No additional side effects 4. Pharmaceutical ingredient specifications and/or analytical methods: a) Less stringent requirement b) Deletion of specification c) Not in accordance with latest pharmacopoeia (full motivation) 5. Final product specification and/or analytical methods a) Less stringent b) Deletion (excluding particle size0 c) Not in accordance with latest pharmacopoeia (full motivation) 6. API (suspension dosage form): Change in crystalline or polymorphic form 7. Change to scoring of tablet (change in dosage regimen) 8. Packaging material: a) Changes in composition of the immediate container affecting stability b) Changes to less protective colour (light sensitive products) c) Changes to closures in contact with product not in compliance with the USP permeation test 9. Change/additional source of API to a different company (route of synthesis stated to be the same, specifications the same) 10. Additional source/change in API source (route of synthesis not the same), or Minor change in route of synthesis, resulting in no change of API specifications or more stringent API specifications, and no change in qualitative and quantitative impurity profile or in physico-chemical properties. 11. Additional source/change in API source where the route of synthesis is not the same or where the route of synthesis change results in change of API specifications 12. Change in batch size of API more than 10-fold compared to the original batch size approved at the time of registration provided that any changes to the manufacturing methods are only those necessitated by scale-up, e.g. use of different-sized equipment and that the change does not affect the reproducibility of the process. Page 7 of 9

8 13. Change in the re-test period of the active substance and/or change in the storage conditions for the active substance provided that the change is not the result of unexpected events arising during manufacture or because of stability concerns 14. Change in the re-test period of the active substance and/or change in the storage conditions for the active substance due to change that is the result of unexpected events arising during manufacture or because of stability concerns 15. Change in type of process used in the manufacturing of the product outside validation (i.e. completely different method of processing) such as change from dry to wet granulation 16. Shelf-life extension (final product) 17. Extension of the shelf-life of an intermediate of an active raw material, providing shelf-life and storage conditions of final active materials does not change 18. Different equipment/process machinery with different processing principles. If change occurs current manufacturer, if retained, should follow same manufacturing procedures unless product integrity can be maintained by both processes 19. Change in process of combining phases in the production of semi-solid topical dosage form 20. Change in sterilization process and method (e.g. from filtration sterilization to autoclaving) 21. Scale-up to more than ten times the size of the batch used to support stability and efficacy, using the same: formulation, equipment design and operating principles, controls and standard operating procedures (SOPs) 22. Scale-up to more than ten times the batch size of the approved and validated batch 23. Change from a glass ampoule to a glass vial with an elastomeric closure; a change to a pre-filled dosage form from another container system; a change that adds or deletes silicone treatment to container closure system; changes in the size and /or shape of a container for a sterile drug product if the head space changes and a change to a flexible container system bag from another container system 24. Change of Holder of Certificate of Registration (HCR) of the product 25. Proprietary name application for name change and up date following approval of name change Page 8 of 9

9 Amendments that are considered new applications 1. Change in the API to a different API 2. Inclusion or removal of an API(s) from a multi-component product unless specifically required by Council 3. Change in the quantity of one or more of the API(s), per dosage unit excluding overages and/or potency adjustments 4. Change in the dosage form including, change from an immediate release product to modified-release dosage form or vice versa and change from liquid to powder for reconstitution, or vice versa 5. A change in the route of administration. For amendments not covered by this guideline and/or if the specified conditions are not complied with, the normal data requirements apply and prior approval should be obtained. References European Agency for the Evaluation of Medicinal Products (2003): Marketing Authorization Variations for Medicinal Products for Human Use Health Sciences Authority (2009): Guidance on Medicinal Product Registration in Singapore Medicines Control Council South Africa (2008): Post Registration Amendments Tanzania Food and Drug Authority (TFDA) (2008): Application Guidelines for Variation of Registered human medicinal products WHO (2007): Guidance on variation to a prequalified product dossier Page 9 of 9