WHO GENERAL GUIDANCE ON VARIATIONS TO MULTISOURCE PHARMACEUTICAL PRODUCTS. (February 2014)

Transcription

1 February 2014 Draft for comment World Health Organization 2014 All rights reserved. WHO GENERAL GUIDANCE ON VARIATIONS TO MULTISOURCE PHARMACEUTICAL PRODUCTS (February 2014) DRAFT FOR COMMENT Should you have any comments on the attached revision, please send these to Dr S. Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms (kopps@who.int) with a copy to Ms Marie Gaspard (gaspardm@who.int) by 7 April Our working documents will be sent out electronically only and will also be placed on the Medicines website for comment under Current projects. If you do not already receive our draft working documents please let us have your address (to bonnyw@who.int) and we will add it to our electronic mailing list. This draft is intended for a restricted audience only, i.e. the individuals and organizations having received this draft. The draft may not be reviewed, abstracted, quoted, reproduced, transmitted, distributed, translated or adapted, in part or in whole, in any form or by any means outside these individuals and organizations (including the organizations' concerned staff and member organizations) without the permission of the World Health Organization. The draft should not be displayed on any website. Please send any request for permission to: Dr Sabine Kopp, Group Lead, Medicines Quality Assurance, Technologies, Standards and Norms, Department of Essential Medicines and Health Products, World Health Organization, CH-1211 Geneva 27, Switzerland. Fax: (41-22) ; kopps@who.int. The designations employed and the presentation of the material in this draft do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this draft. However, the printed material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. This draft does not necessarily represent the decisions or the stated policy of the World Health Organization.

2 page SCHEDULE FOR THE PROPOSED ADOPTION PROCESS OF DOCUMENT QAS/14.575: WHO GENERAL GUIDANCE ON VARIATIONS TO MULTISOURCE PHARMACEUTICAL PRODUCTS Development of draft based on WHO Expert Committee on Specifications for Pharmaceutical Preparations prepared by Ms G.N. Mahlangu, Director-General, Medicines Control Authority of Zimbabwe, Harare, Zimbabwe October 2013 February 2014 Circulation for comments March April 2014 Compilation of feedback May 2014 Review of feedback and comments with assessors and experts June 2014 Recirculation for feedback July 2014 Compilation of feedback September 2014 Discussion at forty-ninth meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations Any further action, as necessary October

3 page Contents page 1. Introduction Objectives. 1.2 Scope and application of the guideline. 2. Glossary. 3. General considerations Reporting types Notification Minor variation Major variation New applications and extension applications 3.3 Labelling information 3.4 Conditions to be fulfilled Documentation required 4. General stability considerations 5. Comparative studies Comparative in vivo studies Comparative in vitro studies Variations (changes) to pharmaceutical aspects of registered products which may be made without prior approval Annual notification Immediate notification Do and tell Variations (changes) to pharmaceutical aspects of registered products which require prior approval before implementation Minor variation Major variation 82 83

4 page INTRODUCTION This guidance document is intended to provide supportive information on how to present an application to implement a change to a registered multisource medicinal product. A marketing authorization holder or applicant is responsible for the safety, efficacy and quality of a medicinal product that is placed on the market throughout its life-cycle. As such, changes are required or necessary for an approved or registered product to account for technical and scientific progress, to improve the quality of the medicinal product, to meet market requirements such as scale-up or additional manufacturing sites, or updates to product information (e.g. updates to information on adverse reactions). The common areas for change are pharmaceutical aspects (quality control, source of raw materials, manufacturing, shelf-life etc.) and product information. Such changes, regardless of the nature of the change, are referred to as variations and may require the approval of national medicines regulatory authority (NMRA) prior to implementation. Technical requirements for the different types of variations are set out in these guidelines in order to facilitate the submission of appropriate documentation by applicants and their assessment by NMRAs. 1.1 Objectives This guidance document is intended to assist applicants with the classification of changes made to a registered or approved finished pharmaceutical product (FPP) and provide guidance on the technical and other general data requirements to support changes to the quality attributes of the active pharmaceutical ingredient (API) or FPP. Variation applications are categorized into major variation, minor variation (prior approval) and minor variation (notification). 1.2 Scope and application of the guideline These guidelines can be used by both NMRAs and applicants with respect to changes to the quality sections of product dossiers for an API or an FPP. This guidance should be read in conjunction with the Guidelines on submission of documentation for a multisource finished product

5 page (1) and Guidance on variations (2) as well as other related WHO guidelines or applicable national guidelines. The NMRAs reserve the rights to request for additional information where necessary, in line with national requirements. This guidance document is applicable only to APIs and excipients manufactured by chemical synthesis or semisynthetic processes and FPPs containing such APIs and excipients. APIs produced by fermentation and APIs of biological, biotechnological or herbal origin are treated as special cases. It is recommended that the principles established in this guidance document be applied to similar quality changes that occur during the development of the product and that the recommended supporting data be included with the initial application for registration of a medicinal product. When a variation leads to a revision of the package insert, the patient information leaflet (PIL) and labelling, 1 the updated product information should be submitted as part of the application. For variations that require generation of stability data on the API or FPP, the stability studies required, including commitment batches, should always be continued to cover the currently accepted retest or shelf-life period. The NMRAs should be informed immediately if any problems with the stability of APIs or FPPs occur during storage, e.g. if found to be outside specifications or potentially outside specifications. Applicants should be aware that some variations might require the submission of additional consequential variations. Therefore for any given change the applicant should consider whether one or more variations might be required to be submitted. If changes to the dossier only concern editorial changes, such changes need not be submitted as a separate variation but can be included as a notification together with a subsequent 1 Different regions/countries use different terminology for product information. In this document package insert, PIL and label are used to refer to product information.

6 page variation concerning that part of the dossier. In such a case a declaration should be provided that the contents of the associated sections of the dossier have not been changed by the editorial changes beyond the substance of the variation submitted. 2. GLOSSARY The definitions provided below apply to the terms used in this guidance. They may have different meanings in other contexts and documents. active pharmaceutical ingredient (API) A substance used in the FPP, intended to furnish pharmacological activity or to otherwise have direct effect in the diagnosis, cure, mitigation, treatment or prevention of disease, or to have direct effect in restoring, correcting or modifying physiological functions in human beings. active pharmaceutical ingredient (API) starting material A raw material, intermediate, or an API that is used in the production of an API and that is incorporated as a significant structural fragment into the structure of the API. An API starting material can be an article of commerce, a material purchased from one or more suppliers under contract or commercial agreement, or produced in-house. applicant For the purposes of this document, the term applicant refers to any person or entity that holds the legal responsibility for the product on the market by submission of the required documentation on a product that has been listed after evaluation as registered or approved. biobatch The batch used to establish bioequivalence or similarity to the comparator product as determined in bioequivalence or biowaiver studies, respectively. final intermediate Product formed in the last reaction in the synthetic pathway that undergoes synthetic transformation to the API or the crude API. Purification is not considered to be a synthetic transformation.

7 page finished pharmaceutical product (FPP) A finished dosage form of a pharmaceutical product, which has undergone all stages of manufacture including packaging in its final container and labelling. in-process control Check performed during manufacture to monitor or to adjust the process in order to ensure that the final product conforms to its specifications. manufacturer A company that carries out operations such as production, packaging, repackaging, labelling and relabelling of pharmaceuticals. multisource (generic) pharmaceutical product Pharmaceutically equivalent products that may or may not be therapeutically equivalent. officially recognized pharmacopoeia (or compendium) Those pharmacopoeias recognized by the national regulatory agencies (e.g. national pharmacopoeia (if applicable), The International Pharmacopoeia (Ph.Int.), the European Pharmacopoeia (PhEur.), the British Pharmacopoeia (BP), the Japanese Pharmacopoeia (JP) and the United States Pharmacopeia (USP)). pilot-scale batch A batch of an API or FPP manufactured by a procedure fully representative of and simulating that to be applied to a full production-scale batch. For example, for solid oral dosage forms, a pilot scale is generally, at a minimum, one-tenth that of a full production scale or tablets or capsules, whichever is the larger, unless otherwise adequately justified. production batch A batch of an API or FPP manufactured at production scale by using production equipment in a production facility as specified in the application. register A list of all the pharmaceutical products authorized for marketing in a particular country. The

8 page medicines regulatory authority of the country in question maintains the register. registered medicines products Pharmaceutical products that have a marketing authorization. stringent regulatory authority (SRA) A stringent regulatory authority is: the medicines regulatory authority in a country which is: (a) a member of the International Conference on Harmonisation (ICH) (European Union (EU), Japan and the United States of America); or (b) an ICH Observer, being the European Free Trade Association (EFTA) as represented by Swiss Medic and Health Canada (as may be updated from time to time); or (c) a regulatory authority associated with an ICH member through a legally-binding, mutual recognition agreement including Australia, Iceland, Liechtenstein and Norway (as may be updated from time to time); only in relation to good manufacturing practices (GMP) inspections: a medicines regulatory authority that is a member of the Pharmaceutical Inspection Co-operation Scheme (PIC/S) as specified at validation The demonstration, with documentary evidence, that any procedure, process, equipment, material, activity or system actually leads to the expected results. variation A change to any aspect of a pharmaceutical product, including but not limited to a change to formulation, method and site of manufacture, specifications for the finished product and ingredients, container and container labelling and product information. 3. GENERAL CONSIDERATIONS 3.1 Reporting types The definitions outlined in the following reporting types are intended to provide guidance with respect to the classification of quality-related changes. Specific examples of changes are provided in these guidelines. However, it should be noted that a change not covered by these

9 page guidelines, should be considered as a major change by default. Whenever the applicant is unclear about the classification of a particular change, the respective NMRA should be contacted. It remains the responsibility of the applicant to submit relevant documentation to justify that the change will not have a negative impact on the quality of the product. Individual changes normally require the submission of separate variations. Grouping of variations is acceptable only under the following circumstances: when variations are consequential to each other, e.g. introduction of a new impurity specification that requires a new analytical procedure; when the same change affects multiple FPPs, e.g. addition of a new API manufacturing site for multiple FPPs; when all the changes fall under annual notification. Applicants are also advised to exercise caution whenever several changes to the same FPP are envisaged. Although each of the individual changes may be classified as a particular reporting type, classification within a higher-risk category may be warranted as a result of the composite effect of these changes. In all such cases, applicants are advised to contact the NMRA prior to submission of the variation application to obtain guidance on classifying such changes Notifications Notifications are changes that could have minimal or no adverse effects on the overall safety, efficacy and quality of the FPP. Such notifications may not require prior acceptance, but must be notified to the NMRA immediately after implementation, i.e. immediate notification (IN), or within 12 months following implementation, i.e. annual notification (AN) Minor variation Minor variations are changes that may have minor effects on the overall safety, efficacy and quality of the FPP. Applicants must satisfy themselves that they meet all of the prescribed conditions for the change and submit all required documentation with the variation application.

10 page Prior approval by the NMRA may be required, before the changes can be implemented. The timeline and implementation of the variation are subject to the NMRA s specific proposals and should be made publicly available Major variation Major variations are changes that could have major effects on the overall safety, efficacy and quality of the FPP. In general, a change that is supported by extensive documentation and/or requires extensive assessment of the supporting documentation would be considered as major variation, e.g. a change supported by in vivo studies. Prior approval by the NMRA is required before the changes can be implemented. The timeline and implementation of the variation are subject to the NMRA s specific proposals. The NMRA reserves the right to recategorize the application type, where deemed appropriate. Subject to country specific procedure, recategorization may require the applicant to resubmit a new application or additional data according to the correct category. 3.2 New applications and extension applications Certain changes are so fundamental that they alter the terms of the accepted dossier and consequently cannot be considered as changes. In these cases a new dossier must be submitted in line with applicable national requirements for applications for registration of medicines. Examples of such changes are listed below: 1. Change of the API to a different API. 2. Inclusion of an additional API in a multicomponent product. 3. Removal of one API from a multicomponent product. 4. Change in the dose and/or strength of one or more APIs. 5. Change from an immediate-release product to an extended or delayed-release dosage form or vice versa. 6. Change from a liquid to a powder for reconstitution or vice versa. 7. Changes in the route of administration.

11 page Labelling information For any change to labelling information (package insert, PIL, labels), the NMRA must be notified and submission of the revised labelling information is expected as per country specific proposal or requirements. 3.4 Conditions to be fulfilled For each variation, attempts have been made to identify particular circumstances where lower reporting requirements, e.g. notifications, are possible. A change that does not meet all of the conditions stipulated under general and specific circumstances for the notifications are automatically considered at the next higher level of change, i.e. require prior approval before implementation. 3.5 Documentation required All data recommended to support a change should be provided with the submission. When recommended supporting data cannot be submitted, a detailed rationale should be provided. Regardless of the documents specified, applicants should ensure that they have provided all relevant information to support the variation. Additional documentation may be required. For all changes it remains the responsibility of the applicant to provide all necessary documents to demonstrate that the change does not have a negative impact on the safety, efficacy or quality of the FPP. Where applicable, the following should be included in the application for variations requiring prior approval: a covering letter (including a list of changes describing each in sufficient detail to allow for a quick assessment as to whether the appropriate reporting category has been used); section of the original dossier affected by the change(s); current and proposed condition(s); reason for the change(s);

12 page where relevant, a side-by-side comparison of the previously approved and the proposed information; replacement of the relevant sections of the dossier as per acceptable dossier format for the respective NMRAs with the proposed changes clearly annotated; copies of package insert, PIL and labels, if relevant; registration status and date of the proposed change(s) in other countries/agencies that had approved the variation(s), especially the country of origin and the reference agencies. It should be noted that the NMRA reserves the right to request further information not explicitly described in these guidelines. Alternative approaches to the principles and practices described in this document may be acceptable provided they are supported by adequate scientific justification. It is also important to note that the NMRA may request information or material, or defines conditions not specifically described in this guidance, in order to adequately assess the safety, efficacy and quality of an FPP. 4. GENERAL STABILITY CONSIDERATIONS The effect of the changes on an approved medicinal product on the stability of the medicinal product should be evaluated. For general guidance on conducting stability studies, applicants are referred to the WHO Guideline on Stability Studies [3]. For variation submissions, the following points also should be considered: In most cases (except those involving scale up), stability data from pilot scale batches will be acceptable to support the proposed change. Where stability data show a trend toward potency loss or degradant increase under accelerated conditions, it is recommended that historical accelerated stability data from a representative pre-change batch be submitted for comparison. It is also recommended that under these circumstances, all available long-term data on test batches from ongoing studies be provided in the supplement. Submission of historical accelerated and available long-term data would facilitate review and approval of the supplement. A commitment should be included to conduct long-term stability studies through the expiration-dating period, according to the approved protocol, on the first or first three production batches and to report the results in the annual reports.

13 page COMPARATIVE STUDIES 5.1 Comparative in vivo studies A number of changes outlined include recommendations for supporting comparative in vivo studies (e.g. comparative bioavailability studies). Applicants should consult the ICH Q5E guideline and applicable WHO guidance documents when conducting comparative in vivo studies. 5.2 Comparative in vitro studies A number of changes outlined include recommendations for supporting comparative in vitro studies (e.g. comparative dissolution studies). Where an in vitro comparison is recommended to support a variation, the comparison should be made to the product manufactured according to the same formulation and manufacturing process used in the pivotal clinical and/or comparative bioavailability studies approved for the original drug submission (e.g. including batch formula, manufacturing process). This is referred to as the "approved product" in the appendices. Alternative approaches to this recommendation may be acceptable if scientifically justified. For example, a comparison to an applicant's marketed product (rather than the product used in the pivotal clinical and/or comparative bioavailability studies) could be justified if a significant body of information has been established for the marketed drug product. For the purposes of this document, a significant body of information for the marketed drug product is likely to exist after a reasonable number of batches of the drug product will be marketed during the specified period of time (e.g. a minimum of 10 batches). Applicants should refer to the General Chapters available in the current Schedule B pharmacopoeia for general dissolution and drug release specifications (e.g. United States Pharmacopeia (USP) <711>, USP <724>, European Pharmacopoeia (Ph.Eur.) 2.9.3). 5.3 Variations (changes) to pharmaceutical aspects of registered products which may be made without prior approval

14 page Annual notification Changes that may be applied without prior approval but included in annual notifications (AN) are listed below: 1. Changes in batch size of the API or intermediate involving up to 10-fold compared to the currently accepted batch size on condition that (a) the product continues to meet specifications, (b) the dissolution profile is not significantly altered, (c) a stability study has been commenced on at least one full-scale production batch and (d) the change does not concern a sterile API. 2. Additional tests and limits for starting materials or finished products on condition that these do not reflect a change in processing, e.g. from a fine to microfine particle size. 3. A change in the content of an excipient of up to ±5%. 4. Alteration of the quantitative composition of a tablet or capsule coating amounting to less than 2% of the total weight of the tablet or capsule. On condition that (a) the coating has no modifiedrelease properties, (b) there is no API in the coating, (c) any new colours are permitted by the European Commission s List of Permitted Food Colours (4), or the United States Food and Drug Agency s (US-FDA) Summary of Color Additives for Use in the United States in Foods, Drugs, Cosmetics, and Medical Devices (5) and (d) the change is notified. 5. Changes to the volume of granulating fluid of up to ±15%, provided that (a) the product continues to meet specifications and (b) the dissolution profile is not significantly altered. 6. Changes to the quantitative content of agents whose only function is to make the product viscous. On condition that (a) it has been demonstrated that any solid material present is at least equally well suspended and (b) a stability study has been commenced on at least two batches of the altered product. 7. Change in weight of tablet coatings or capsule shells involving immediate-release oral FPPs. On condition that (a) multipoint in vitro dissolution profiles of the proposed version of the product (determined in the routine release medium on at least two batches of pilot- or production-scale) are similar to the dissolution profiles of the biobatch, (b) coating is not a critical factor for the release mechanism and (c) specifications for the FPP are updated only with respect to weight and dimensions,

15 page if applicable. 8. Alteration of methods of manufacture and manufacturing equipment on condition that (a) the product is not a slow- or otherwise modified-release product, (b) a new stability study has been commenced on at least two batches of the altered product, (c) no change in the specifications of the intermediates or the FPP, (d) the dissolution profiles are similar to those of the biobatch and (e) the manufacturing processes for the currently accepted and proposed products use the same principles (e.g. a change from wet to dry granulation, from direct compression to wet or dry granulation, or vice versa, would be considered a change in manufacturing principle), the same processing intermediates and there are no changes to any manufacturing solvent used in the process. 9. Change in the batch size of the FPP involving downscaling. On condition that (a) the change does not affect the reproducibility and/or consistency of the product, (b) the change pertains only to immediate-release oral pharmaceutical forms and to non-sterile liquid forms and (c) changes to the manufacturing method and/or to the in-process controls are only those necessitated by the change in batch size, e.g. use of different-sized equipment. 10. Change to in-process tests or limits applied during the manufacture of the FPP or intermediate involving (a) tightening of in-process limits, (b) deletion of a test and (c) addition of new tests and limits. 11. Additional tests and limits for starting materials or finished products on condition that these do not reflect a change in processing, e.g. from a fine to microfine particle size. 12. Change in specifications of an excipient to comply with an officially-recognized pharmacopoeia provided that there is no change to the specifications other than those required to comply with the pharmacopoeia (e.g. no change in particle size distribution). 13. Update to the specifications to comply with an officially-recognized pharmacopoeial monograph as a result of an update to this monograph to which the FPP is controlled 14. Change in the analytical procedures for the FPP involving updating the analytical procedure with an officially-recognized pharmacopoeial monograph as a result of an update to that monograph Immediate notification do and tell

16 Working document QAS/ page 16 Applicants must satisfy themselves that they meet all of the prescribed conditions for the change and submit all required documentation with the notification application. Such changes can be implemented immediately at the time of submission and they can be considered accepted if an objection is not issued by the NMRA within a reasonable period subject to country specific proposal after the date of acknowledgement of receipt of the application. Examples of such changes are listed below: Change to the marketing authorization holder (name, address and/or legal entity). On condition that there is no change to the product, including sites of manufacture Change in the name and/or corporate address of the supplier of the FPP on condition that the supplier of the product remains the same legal entity Deletion of a manufacturing site or manufacturer involving production or testing of the API/FPP intermediate or API/FPP provided that at least one other site continues to perform the same function(s) as the site(s) intended to be deleted and that the deletion of the site is not a result of critical deficiencies in manufacturing Change in the manufacturing process of the API. On condition (a) that there is no change in the physical state (e.g. crystalline, amorphous) of the API, (b) for low solubility APIs, there is no change in the polymorphic form and whenever particle size is critical (including low solubility APIs) there is no significant change in the particle size distribution compared to that of the API lot used in the preparation of the biobatch, (c) where materials of human or animal origin are used in the process, the manufacturer does not use any new process for which assessment of viral safety data or transmissible spongiform encephalopathy (TSE) risk assessment is required, (d) no change in qualitative and quantitative impurity profile or in physicochemical properties of the API, (e) the change does not affect the sterilization procedures of a sterile API, (f) the change involves only steps before the final intermediate and (g) the change does not require revision of the starting material, intermediate or API specifications.

17 529 Working document QAS/ page Change in batch size of the API or intermediate involving downscaling on condition that (a) no changes to the manufacturing process other than those necessitated by changes in scale (e.g. use of a different size of equipment) and (b) the change does not affect the reproducibility of the process Changes to the test parameters, acceptance criteria or analytical procedures of the API manufacturer that do not require a change to the FPP manufacturer s API specifications Change to the test parameters or acceptance criteria of the API specifications of the FPP manufacturer involving (a) replacement of a test parameter, (b) relaxation of an acceptance criterion and (c) addition of test parameter. On condition that (a) for insoluble APIs there is no change in the polymorphic form and whenever particle size is critical (including low-solubility APIs), there is no change in particle size distribution acceptance criteria, (b) no additional impurity found over the International Conference on Harmonisation of Technical Requirements for Registration of Human Medicines (ICH) identification threshold and (c) the change does not concern sterility testing Change to the analytical procedures used to control the API by the FPP manufacturer involving change from a currently accepted in-house analytical procedure to an analytical procedure in an officially-recognized pharmacopoeia or from the analytical procedure in one officially-recognized pharmacopoeia to an analytical procedure in another officially- recognized pharmacopoeia Changes to the container-closure system in immediate contact with the product or additional types of container-closure on condition that (a) the product is not a sterile product, (b) the new system offers equal or better protection to the product, (c) stability data are available on two batches of the product in the new container for at least three months under accelerated conditions (as defined in relevant guidelines) or one year under non-accelerated conditions, (d) a stability study has been commenced on at least two batches of the altered product for the full duration of the shelf-life and (e) the change is notified. Changes may not be made to labelling without prior approval Reduction in the retest period or shelf-life of the API provided the change is not

18 Working document QAS/ page 18 necessitated by unexpected events arising during manufacture or because of stability concerns Change in the composition of a solution dosage form. On condition that (a) the affected excipient(s) does/do not function to affect the solubility and/or the absorption of the API, (b) the affected excipient(s) does/do not function as a preservative or preservative enhancer, (c) no change in the specifications of the affected excipient(s) or the FPP, (d) no change in the physical characteristics of the FPP (e.g. viscosity, osmolality, ph), (e) the change does not concern a sterile FPP and (f) the excipients are qualitatively the same. The change in the amount (or concentration) of each excipient is within ±10% of the amount (or concentration) of each excipient in the originally approved product Changes to flavours, perfumes or colours on condition that (a) any new colours are permitted by the European Commission s List of Permitted Food Colours (4), or the United States Food and Drug Agency s (US-FDA) Summary of Color Additives for Use in the United States in Foods, Drugs, Cosmetics, and Medical Devices (5), (b) the change is notified, (c) stability data are available on two batches of the altered product for at least three months under accelerated conditions (as defined in relevant guidelines) or one year under non-accelerated conditions and (d) a new stability study has been commenced on at least two batches of the altered product for the full duration of the shelf-life A change or addition of imprints, embossing or other markings on solid dosage forms, including replacement or addition of inks used for product markings and change in scoring configuration. On condition that (a) these do not imply an unapproved indication or patient population, (b) no unapproved colour (as defined above) is introduced, (c) any changes to scoring are consistent with the dose schedules in the approved product information and (d) the change is notified Change in dimensions without change in qualitative or quantitative composition and mean mass of tablets, capsules, suppositories and pessaries. On condition that (a) specifications for the FPP are updated only with respect to dimensions of the FPP and (b) multipoint in vitro dissolution profiles of the current and proposed versions of the product (determined in the routine release medium, on at least one batch of pilot- or production-scale) are comparable.

19 597 Working document QAS/ page Addition or replacement of a manufacturing site for part or all of the manufacturing process for an FPP involving (a) secondary packaging of all types of FPPs, (b) primary packaging site of solid FPPs (e.g. tablets, capsules), semi-solid FPPs (e.g. ointments, creams) and solution liquid FPPs and (c) primary packaging site of other liquid FPPs (suspensions, emulsions). On condition that (a) satisfactory good manufacturing practices (GMP) inspection in the last three years and (b) site appropriately authorized by an NMRA (to manufacture the pharmaceutical form and the product concerned) Change in the batch size of the FPP involving up to and including a factor of compared to the biobatch. On condition that (a) the change does not affect the reproducibility and/or consistency of the product, (b) the change pertains only to immediate-release oral pharmaceutical forms and to non-sterile liquid forms, (c) changes to the manufacturing method and/or to the in-process controls are only those necessitated by the change in batch size, e.g. use of different-sized equipment, (d) a validation protocol is available or validation of the manufacture of three production-scale batches has been successfully undertaken in accordance with the current validation protocol and (f) the biobatch size was at least units in the case of solid oral dosage forms Change to in-process tests or limits applied during the manufacture of the FPP or intermediate involving revision or replacement of a test Change in the specifications of the FPP involving test parameters and acceptance criteria: (a) relaxation of an acceptance criterion; or (b) replacement of a test parameter provided that the change to the specifications does not affect the stability and the performance of the product and the change does not concern sterility testing Analytical methodology for the finished product on condition that (a) validation shows that the new method is equivalent to or better than the existing method and (b) major changes (e.g. ultra violet assay to high-pressure liquid chromatography (HPLC)) are notified Change in the package size involving: (a) change in the number of units (e.g. tablets, ampoules, etc.) in a package; and (b) change in the fill weight or fill volume of non-parenteral multidose products. On condition that (a) the change is consistent with the posology and

20 Working document QAS/ page 20 treatment duration accepted in the package insert and (b) no change in the primary packaging material Changes to the container-closure system in immediate contact with the product or additional types of container-closure. On condition that (a) the product is not a sterile product, (b) the new system offers equal or better protection to the product, (c) stability data are available on two batches of the product in the new container for at least three months under accelerated conditions (as defined in relevant guidelines) or one year under non-accelerated conditions, (d) a stability study has been commenced on at least two batches of the altered product for the full duration of the shelf-life and (e) the change is notified. Changes may not be made to labelling without prior approval Change in any part of the (primary) packaging material not in contact with the FPP formulation (e.g. colour of flip-off caps, colour code rings on ampoules or change of needle shield), provided the change does not concern a fundamental part of the packaging material, which affects the delivery, use, safety or stability of the FPP Reduction in the shelf-life of the FPP (as packaged for sale) or in the in-use period of the FPP (after first opening or after reconstitution or dilution). New sites of manufacture require prior approval because the NMRA should see evidence of compliance with GMP, e.g. a WHO-type certificate of pharmaceutical product (6). Changes or additions to pack size also require prior approval because the new size must be consistent with the approved uses of the product. Changes may not be made to labelling without prior approval, except for changes to layout without alteration of text or meaning. Pictures or diagrams may not be added without prior approval because they may imply an unapproved indication. Notifications of variations, and applications to vary, must be accompanied by this statement: No variations have been made other than (1) those notified herewith and (2) changes which are permitted without notification or prior approval according to the guidelines of the medicines regulatory authority of...

21 page Variations (changes) to pharmaceutical aspects of registered products which require prior approval before implementation Minor variation Below is a list of variations considered minor. In addition to the general documents stated in section 3.5. Documentation required, specific documentation in support of each type of variation should be provided. 1. Replacement or addition of a new manufacturing site or manufacturer of an API involving API testing only provided the transfer of analytical methods has been successfully undertaken and no change in the FPP manufacturer s API specifications. 2. Change of drug product name. 3. Change of the specification of drug substance a) specification limits are tightened and b) addition of new test parameter and limits. 4. Change in product labelling should be in accordance to country specific labelling requirement and this includes: a) change of the layout/artwork without altering meaning; b) addition/deletion/replacement of pictures, diagrams, bar code, logos and/or texts that do not imply an unapproved indication; c) addition/strengthening of warnings, precautions, contraindications and/or adverse events/effects to the approved product labelling; d) tightening of product s target population; e) deletion of indication. 5. Change in batch size of the API or intermediate involving more than 10-fold increase compared to the currently accepted batch size. 6. Change to the specifications or analytical procedures applied to materials used in the manufacture of the API (e.g. raw materials, starting materials, reaction intermediates, solvents, reagents, catalysts) involving addition or replacement of a specification parameter as a result of a

22 page safety or quality issue. 7. Change of the specification of drug substance a) specification limits are tightened and b) addition of new test parameter and limits. 8. Change to the test parameters or acceptance criteria of the API specifications of the FPP manufacturer a) addition of a test parameter, b) replacement of test parameter and c) relaxation of an acceptance criterion. 9. Change to the analytical procedures used to control the API by the FPP manufacturer involving modification or replacement of an analytical procedure. 10. Change in the immediate packaging (primary and functional secondary components) for the storage and shipment of the API provided the change is not due to instability issues. 11. Change in the retest period or shelf-life of the API involving extension provided (a) no change to the primary packaging in direct contact with the API or to the recommended condition of storage and (b) stability data were generated in accordance with the currently accepted stability protocol. 12. Any change in the labelled storage conditions of the API provided (a) the stability studies must show compliance with specification and (b) no change in shelf-life/retest period. 13. Change or addition of imprints, embossing or other markings, including replacement or addition of inks used for product markings and change in scoring configuration involving addition of a score line. On condition that (a) the change does not affect the stability or performance characteristics (e.g. release rate) of the FPP, (b) changes to the FPP specifications are those necessitated only by the change to the appearance or to the scoring and (c) addition or deletion of a score line from a generic product is consistent with a similar change in the comparator product or was requested by NMRA. 14. Change in dimensions without change in qualitative or quantitative composition and mean mass of gastroresistant, modified or prolonged-release FPPs and scored tablets. On condition that specifications for the FPP are updated only with respect to dimensions of the FPP and multipoint in vitro dissolution profiles of the current and proposed versions of the product (determined in the routine release medium, on at least one batch of pilot- or production-scale) are comparable.

23 page Addition or replacement of a manufacturing site for part or all of the manufacturing process for an FPP involving all other manufacturing operations except batch control and/or release testing. On condition that (a) no change in the batch formula, description of manufacturing process and process controls, equipment class and process controls, controls of critical steps and intermediates or FPP specifications, (b) satisfactory inspection in the last three years, (c) site appropriately authorized by an NMRA (to manufacture the pharmaceutical form and the product concerned) and (d) validation protocol is available or validation of the manufacturing process at the new site has been successfully carried out on at least three production-scale batches in accordance with the current protocol. 16. Change in the manufacturing process of the FPP. 17. Change in the specifications or analytical procedures for an excipient involving change or replacement of an analytical procedure. 18. Replacement or addition of a primary packaging type provided the change does not concern a sterile FPP. 19. Change in qualitative and/or quantitative composition of the immediate packaging material for semisolid and liquid FPPs. On condition that (a) the change does not concern a sterile FPP, (b) no change in the packaging type and material (an example of an allowable change is blister to blister) and (c) the relevant properties of the proposed packaging are at least equivalent to those of the currently accepted material. 20. Extension in the shelf-life of the FPP (as packaged for sale) provided there is no change to the primary packaging type in direct contact with the FPP and to the recommended conditions of storage and stability data were generated in accordance with the currently accepted stability protocol. 21. Extension in the in-use period of the FPP (after first opening or after reconstitution or dilution). 22. Change in the labelled storage conditions of the FPP (as packaged for sale), the product during the in-use period or the product after reconstitution or dilution Major variation

24 page Variations, which fail to fulfil the conditions for notifications or minor variations automatically, become major variations. In addition, variations, which are not covered by these guidelines, should be considered as a major change by default. References 1. Guidelines on submission of documentation for a multisource (generic) finished pharmaceutical product for the WHO Prequalification of Medicines Programme: quality part. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-sixth report. Geneva, World Health Organization. Technical Report Series, No. 970, 2012, Annex Guidance on variations to a prequalified dossier. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-first report. Geneva, World Health Organization. Technical Report Series, No. 943, 2007, Annex Guidelines for stability testing of active pharmaceutical ingredients and finished pharmaceutical products. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Forty-third report. Geneva, World Health Organization. Technical Report Series, No. 953, 2009, Annex European Commission. List of permitted food colours: EC Directive 94/36/EC. Official Journal of the European Communities 1994; L FDA. Summary of Color Additives for Use in the United States in Foods, Drugs, Cosmetics, and Medical Devices Guidelines for implementation of the WHO Certification Scheme on the Quality of Pharmaceutical Products Moving in International. In: WHO Expert Committee on Specifications for Pharmaceutical Preparations. Thirty-fourth report. Geneva, World Health Organization. Technical Report Series, No. 863, 1996, Annex 10. ***