European Medicines Agency practical guidance on the application form for centralised type IA and IB variations

Transcription

1 16 December 2014 EMA/233564/2014 Procedure Management and Business Support Division European Medicines Agency practical guidance on the application form for centralised type IA and IB variations This document is intended as guidance to faciliate the completion of the application form for type IA and IB varaitions to be submitted in the Centralised Procedure and should be read in conjuction with the EMA/CMDh Explanatory Notes on Variation Application Form (CMDh/EMA/133/2010). This document in not exhaustive, therefore in the situation that certain aspects are not be covered, aplicants may wish to contact the releveant query service or 30 Churchill Place Canary Wharf London E14 5EU United Kingdom Telephone +44 (0) Facsimile +44 (0) Send a question via our website An agency of the European Union European Medicines Agency, Reproduction is authorised provided the source is acknowledged.

2 APPLICATION FOR VARIATION TO A MARKETING AUTHORISATION HUMAN VETERINARY NATIONAL AUTHORISATION IN MRP Variation procedure number(s) 1 : Please leave blank. The procedure number will be assigned by the Agency upon receipt of the application EU AUTHORISATION Please leave blank. NATIONAL AUTHORISATION Not applicable in the centralised procedure for IA/IB variations Reference Member State / Reference Authority for worksharing AT BE BG CY CZ DE DK EE EL ES FI FR HR HU Concerned Member State(s) AT BE BG CY CZ DE DK EE EL ES FI FR HR HU Type of Application (tick all applicable options) All applicable options should be indicated by ticking the appropriate boxes Type IA IN Single variation Type IA Grouping of variations Type IB unforeseen 2 Including a line extension 3 Type IB Worksharing Type Type Art Change(s) concern(s) (for Type IB and Type variations only, tick all changes applicable): Indication Paediatric requirements Safety Following Urgent Safety Restriction Quality Annual variation for human influenza vaccines Non-food producing target species Other Please leave blank for type IA variations 1 Human Medicinal Products: Number to be completed by the Marketing Authorisation Holder, reflecting the correct sequential Mutual Recognition Procedure Number according to Chapter 1 of the Best Practice Guides for the submission and processing of variations in the Mutual Recognition Procedure ( Veterinary Medicinal Products: Variation number to be issued by the Reference Member State before submission of the application according to the corresponding VMRFG Best Practice Guide ( Centralised procedure: The sequential EMA procedure number (not the MAH s internal number) should be provided here, when known to the Marketing Authorisation Holder. For worksharing procedures with EMA as reference authority, the high-level EMA worksharing procedure number needs to be provided. 2 A variation is considered unforeseen when the proposed variation is not considered a minor variation of Type IB following the Commission Guideline, or has not been classified as a Type IB variation in an Article 5 recommendation. When one or more of the conditions established in the guideline for a Type IA variation are not met, the concerned change may be submitted as a Type IB variation unless the change is specifically classified as a major variation of Type. 3 If the variations are part of a grouped submission including a line-extension, this application form should be considered an annex to the application form for the extension application. 4 Type variation submitted under Article 29 of Regulation (EC) No 1901/

3 Name and address of the Applicant/MA holder 5 : ABC Ltd. Sole street, no.1 DA1 5BY London United Kingdom Name and address of contact person 6 : ABC Ltd John Smith Camden Road, AB11 2HA London, United Kingdom Telephone number: Fax number (optional): john.smith@abc.com Contact details of the authorised contact person should be up-to-date. If they need to be modified, the change in contact person form should be ed to PA-BUS@ema.europa.eu 5 For worksharing or grouped variations affecting more than one MA, indicate the MA holder to be used as reference MA holder for the handling of the procedure. 6 As specified in section in Part IA/Module 1 Application Form. If different, attach letter of authorisation. For worksharing or grouped variations affecting more than one MA, a single contact should be designated for the application (see also Signatory box below). 3

4 PRODUCTS CONCERNED BY THIS APPLICATION 7 This section should be left blank for centrally authorised products. (Invented)Name(s): Active substance(s) Pharmaceutical form Strength MA holder name(s): MA number(s): 8 MRP Variation Number 8 WonderPil Acetylsalicylic acid Film-coated tablet 500 mg ABC Ltd. EU/1/08/123/001 - EU/1/08/123/003 Only the presentation(s) (EU number(s)) affected by the change(s) should be listed. Please do not include by default the latest Annex A with the list of all approved presentations. For applications relating solely to the addition of new presentation(s), only the new presentation(s) should be indicated (EU number(s) confirmed with the Agency prior to submission). If different changes apply to different presentations, all affected presentations should be listed in the table and a detailed description of the changes, together with an explanation of which change(s) applies to which presentation(s), should be included in the Precise scope section of the Application Form. 7 If this list is very extensive (more than one page) it may be added as annex to the application form. For products authorised via the Centralised Procedure, the Annex A of the product(s) concerned should be provided as an Annex to the application form. For worksharing procedures submitted to the EMA, which include nationally authorised products, relevant product and Member State details should be provided as an Annex B to the application form (Using the template on the EMA website). 8 Indicate the MA numbers affected (a range may be appropriate). For the MRP variation number, which is a product specific number, see the Best Practice Guide on Variations, Chapter 1, example: NL/H/0123/ /IB/033/G 4

5 TYPE(S) of CHANGE(S) By ticking this box the applicant confirms that the extract from the Variations Guidelines is included and that the applicable conditions are met and required documentation provided. Where needed, the applicant can add clarification as to why it considers conditions to be fulfilled or where the required documentation or justification can be found, as per the example in the attached guideline extract. Copy of the relevant page(s) from the Guideline for this/these change(s) is attached and the relevant boxes for conditions and documentation (both for Type IA and Type IB) are ticked VARIATIONS INCLUDED IN THIS APPLICATION: Identical scopes should be repeated as many times as needed B..a.3 Changes in the composition (excipients) of the finished product Procedure type a) Changes in components of the flavouring or colouring system Implement. Date: 1. Addition, deletion or replacement IA IN IB Increase or reduction IA IB Implement. Date: Biological veterinary medicinal products for oral use for 3. which the colouring or flavouring agent is important for the uptake by target animal species b) Other excipients Any minor adjustment of the quantitative composition of 1. the finished product with respect to excipients Qualitative or quantitative changes in one or more 2. excipients that may have a significant impact on the safety, quality or efficacy of the medicinal product Change that relates to a biological/immunological 3. product Any new excipient that includes the use of materials of 4. human or animal origin for which assessment is required of viral safety data or TSE risk 5. Change that is supported by a bioequivalence study 6. Replacement of a single excipient with a comparable excipient with the same functional characteristics and at a similar level IB Implement. Date: IA IB Implementation dates for type-ia variations should be included here. B.I.a.3 Change in batch size (including batch size ranges) of active substance or intermediate used in the manufacturing process of the active substance Up to 10-fold increase compared to the originally approved a) batch size Procedure type b) Downscaling down to 10-fold IA IB c) d) e) The change requires assessment of the comparability of a biological/immunological active substance More than 10-fold increase compared to the originally approved batch size The scale for a biological/immunological active substance is ncreased / decreased without process change (e.g. duplication of line) z) Other variation IA IB IB IB Implement. Date: IA IB Implement. Date: Art 5 Implement. Date: This box should be ticked when the classification is subject to an Article-5 recommendation procedure: (Clarification -not for publication): Art5 can be done either by the EMA or the CMDh). 5

6 (Select and include in this section the applicable variation(s) from the list presented at the end of this application form template (see detailed instructions provided with the list). The above example and the list of variations at the end of the form should subsequently be deleted from the completed form to be submitted). PRECISE SCOPE AND BACKGROUND FOR CHANGE, AND JUSTIFICATION FOR GROUPING, WORKSHARING AND CLASSIFICATION OF UNFORESEEN CHANGES (if applicable) (Include a description and background of all the proposed changes. In case of grouping and worksharing a justification should be provided in a separate paragraph. If a variation concerns an unforeseen change, include a justification for its proposed classification). This is a grouped variation application to introduce changes relating to the active substance (acetylsalicylic acid) and to the finished product (WonderPil 500 mg film-coated tablets). B..a.3.a.1 To remove carnauba wax (component of the colouring system used in the film-coat) from the composition of the finished product (include background of change) B.I.a.3.a To increase the batch size of the active susbtance from 150 kg to 360 kg. Describe details (background) of the change(s) applied for. The precise scope should be clear and detailed. When there is a grouped procedure, the changes should be made clear in the precise scope section and should correspond to the Present and proposed table. For Type IB grouped applications a justification for grouping should be provided. For type IA grouped applications, there is no need to provide a justification for grouping. In case of IG variations, the same scope (change) must be applied to all products concerned by the application. There is no need to repeat for each product the scope(s) applied for as this will incur into unnecessary fees being invoiced. 6

7 In the present/proposed table, the applicant should: - indicate the dossier section numbers at the lowest possible level according to CTD, - followed by the scope number - followed by the actual current and proposed wording as per footnote 9 (i.e. a general statement that the section has been updated is not acceptable); - list all the changes declared in the precise scope section. If the description of changes is extensive it is possible to include an Annex to the application form. - highlight all changes (underline additions and strikethrough deletions). Module 3.2.P.1 (B..a.3.a.1) PRESENT 9,10 PROPOSED 9,10 Module 3.2.P.1 (B..a.3.a.1) Excipients: carnauba wax corn starch hypromellose powdered cellulose triacetin Excipients: carnauba wax corn starch hypromellose powdered cellulose triacetin Module 3.2.S.2.2 (B.I.a.3.a) The validated manufacturing process is the same as described in Part 3.2.P.3 of the registration dossier. Three consecutive batches were validated: abc 1, abc 2 and abc 3. The manufacturing site of the mentioned batches s XYZ Ltd and the batch size is 150kg. SmPC 6.1 List of excipients carnauba wax corn starch hypromellose powdered cellulose triacetin Labelling 3. List of excipients Excipients: carnauba wax, corn starch, hypromellose, powdered cellulose, triacetin Module 3.2.S.2.2 (B.I.a.3.a) The validated manufacturing process is the same as described in Part 3.2.P.3 of the registration dossier. Three consecutive batches were validated: abc 1, abc 2 and abc 3. The manufacturing site of the mentioned batches is XYZ Ltd and the batch size is 360kg. SmPC 6.1 List of excipients carnauba wax corn starch hypromellose powdered cellulose triacetin Labelling 3. List of excipients Excipients: carnauba wax, corn starch, hypromellose, powdered cellulose, triacetin D-U-N-S number: 11 D-U-N-S number: 11 9 Specify the precise present and proposed wording or specification, including dossier section number(s) at the lowest possible level. 10 For SPC, labelling and package leaflet changes, underline or highlight the changed words presented in the table above or provide as a separate Annex 11 If applicable, include D-U-N-S number. The Data Universal Numbering System (D-U-N-S) is a system developed by Dun & Bradstreet (D&B) which assigns a unique digit numeric identifier to a single business entity. It is used in this case to facilitate the identification of manufacturing sites outside of EEA 7

8 Insert EU/EMEA ASMF number here if the ASMF is affected. EU or National ASMF number: 12 EU or National ASMF number: 12 OTHER APPLICATIONS 13 IB/23G extension of shelf life IA/21 change in the post code of the manufacturer /24 substantial change to the manufacturing process Product Information (PI) - related tick boxes should indicate which sections are modified by the change(s). If the PI is not affected, this section should not be removed. The following amended product information proposals are provided in the relevant sections of the EU- CTD format or NTA volume 6B format, where applicable: Summary of Product Characteristics Manufacturing Authorisation Holder responsible for batch release and conditions of the Marketing Authorisation 14 Labelling Package leaflet Mock-ups 15 Specimens 15 Tickboxes should be ticked as applicable. Declaration of the Applicant: I hereby submit a notification/application for the above Marketing Authorisation(s) to be varied in accordance with the proposals given above. I declare that (Please tick the appropriate declarations): There are no other changes than those identified in this application (except for those addressed in other variations submitted in parallel); Where applicable, all conditions as set for the variation(s) concerned are fulfilled; For type IA notifications: the required documents as specified for the changes concerned have been submitted; Where applicable, national fees have been paid; This notification/application has been submitted simultaneously in RMS and all CMSs (for products within the Mutual Recognition Procedure and worksharing) or both to EMA and (Co-) Rapporteur (for products within the Centralised Procedure) or, in case of worksharing involving the EMA, to the relevant National Competent Authorities and/or RMS/CMS (as applicable) and the EMA; For worksharing or grouped variations affecting more than one MA: the MAs concerned belong to the same MAH. Change(s) will be implemented from 16 : Next production run/next printing Date: 12 If applicable, include EU or National ASMF reference number (only if EU ASMF reference number is not available) 13 Due to complexity it is not necessary to complete this section for worksharing or grouped variations The affecting implementation more than one MA. date for type- 14 only for centrally authorised products (Annex of the EU MA) IA variations should not be 15 see Chapter 7 of Volume 6A of the Notice to Applicants or Transfer of information contained in Notice to Applicants, Volume 2A, Chapter 7 included here ( ) or Dossier requirements for Centrally Authorised Products ( 16 Only to be completed for Type IB This and Type box should variations. always be ticked for variation applications which include one or more Type IA/IAIN variations affecting several medicinal products from the same MAH (IG submissions). 8

9 Proof of payment (when relevant) Have all relevant fees been prepaid to competent authorities? Yes (for fees paid, attach proof of payment in Annex) Please specify fee category under National rules: No For Member State(s): Please specify the reasons according to National requirements (exemption or later payment). Billing address (when relevant) Company name: ABC Ltd. VAT number: Address: Sole street, no.1, London Postcode: DA1 5BY Country: United Kingdom Telephone: Telefax (optional): Purchase order (PO) number: If the application form is signed on behalf of the authorised contact person, an authorisation letter should be provided to confirm the delegation of signature. Main Signatory 17 Print name John Smith For worksharing/grouping for more than one MA: the main signatory confirms authorisation to sign on behalf of the designated contacts as specified in section in Part IA/Module 1 Application Form for each of the MAs concerned. Status (Job title) Regulatory affairs specialist Date Second Signatory Print name Status (Job title) Date 17 The main signatory is mandatory 9

10 The following documents are to be annexed to the Application form in order to facilitate the review of the application: Variations guidelines extract should be attached to every submission; Letter of Authorization or Power of Attorney, should be attached when the application form is signed on behalf of the authorised contact person; Any other document which doesn t fit within the ectd structure, but facilitates validation. (e.g. justification for deleting a finished product specification parameter). General points to consider when completing the application form: The application form should be consistent with the cover letter. Providing confusing or contradictory information can delay the procedure; All changes listed under the precise scope section and in the present/proposed table should be reflected under the Types of changes section, by their corresponding scope indent, as per the Variations Guidelines; Please also consult the EMA/CMDh explanatory notes on Variation Application Form for further assistance. 10

11 Classification guideline extract: B..a.3 Changes in the composition (excipients) of the finished product Cond. to be fulfilled Docum. to be supplied Proced. type a) Changes in components of the flavouring or colouring system 1. Addition, deletion or replacement 1, 2, 3, 4, 5, 6, 7, 9, 11 1, 2, 4, 5, 6 IA IN 2. Increase or reduction 1, 2, 3, 4, 11 1, 2, 4 IA Biological veterinary medicinal products for oral use for which the 3. colouring or flavouring agent is important for the uptake by target animal species b) Other excipients Any minor adjustment of the quantitative composition of the 1, 2, 4, 8, 1. finished product with respect to excipients 9, 10 1, 2, 7 IA Qualitative or quantitative changes in one or more excipients that 2. may have a significant impact on the safety, quality or efficacy of the medicinal product 3. Change that relates to a biological/immunological product Any new excipient that includes the use of materials of human or 4. animal origin for which assessment is required of viral safety data or TSE risk 5. Change that is supported by a bioequivalence study Replacement of a single excipient with a comparable excipient with 1, 3, 4, 5, 6. the same functional characteristics and at a similar level 6, 7, 8, 9, 10 IB Conditions No change in functional characteristics of the pharmaceutical form e.g. disintegration time, dissolution 1. profile. Any minor adjustment to the formulation to maintain the total weight should be made by an excipient 2. which currently makes up a major part of the finished product formulation. The finished product specification has only been updated in respect of appearance/odour/taste and if 3. relevant, deletion of an identification test. Stability studies have been started under ICH/VICH conditions (with indication of batch numbers) and relevant stability parameters have been assessed in at least two pilot scale* or industrial scale batches and at least three months satisfactory stability data are at the disposal of the applicant (at time of implementation for Type IAs and at time of notification for Type IBs) and that the stability profile is similar to the currently 4. registered situation. Assurance is given that these studies will be finalised and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specification at the end of the approved shelf life (with proposed action). In addition, where relevant, photo-stability testing should be performed. Any new proposed components must comply with the relevant Directives (e.g. Directive 94/36/EC and /128/EC for colours for use in foodstuffs and Directive 88/388/EEC for flavours). 11

12 Any new component does not include the use of materials of human or animal origin for which assessment is required of viral safety data or compliance with the current Note For Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products. Where applicable, the change does not affect the differentiation between strengths and does not have a negative impact on taste acceptability for paediatric formulations. The dissolution profile of the new product determined on a minimum of two pilot scale* batches is comparable to the old one (no significant differences regarding comparability, see the relevant (Human or Veterinary) guidance on Bioavailability). For herbal medicinal products where dissolution testing may not be feasible, the disintegration time of the new product is comparable to the old one. The change is not the result of stability issues and/or should not result in potential safety concerns i.e. differentiation between strengths. 10. The product concerned is not a biological/immunological medicinal product. For veterinary medicinal products for oral use, the change does not affect the uptake by target animal 11. species. Documentation Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate), including identification method for The any applicant new colorant, is advised where to 1. relevant, and including revised product information as appropriate. add clarifications as these can speed up the Module 3.2.P.1 validation of the A declaration that the required stability studies have been started under ICH/VICH procedure. conditions (with indication of the batch numbers concerned) and that, as relevant, the required minimum satisfactory stability data were at the disposal of the applicant at time of implementation and that the available data did not indicate 2. a problem. Assurance should also be given that the studies will be finalised and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action). N A The results of stability studies that have been carried out under ICH/VICH conditions, on the relevant stability parameters, on at least two pilot* or industrial scale batches, covering a minimum period of 3 months, and an assurance is given that these studies will be finalised, and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action). Sample of the new product, where applicable (see Notice to Applicants Requirements for samples in the Member States). Either a Ph. Eur. Certificate of Suitability for any new component of animal susceptible to TSE risk or where applicable, documentary evidence that the specific source of the TSE risk material has been previously assessed by the competent authority and shown to comply with the scope of the current Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathies via Human and Veterinary Medicinal Products. The following information should be included for each such material: Name of manufacturer, species and tissues from which the material is a derivative, country of origin of the source animals and its use. For the Centralised Procedure, this information should be included in an updated TSE table A (and B, if relevant). Data to demonstrate that the new excipient does not interfere with the finished product specification test methods, if appropriate. Module 3.2.P.5.3 Justification for the change/choice of excipients etc. must be given by appropriate development pharmaceutics (including stability aspects and antimicrobial preservation where appropriate). For solid dosage forms, comparative dissolution profiledata 16 of at least two pilot scale* batches of the 8. finished product in the new and old composition. For herbal medicinal products, comparative disintegration data may be acceptable. 12

13 B.I.a.3 Change in batch size (including batch size ranges) of active substance or intermediate used in the manufacturing process of the active substance a) Up to 10-fold increase compared to the originally approved batch size Cond. to be fulfilled 1, 2, 3, 4, 6, 7, 8 Docum. to be supplied Proced. type 1, 2, 5 IA b) Downscaling down to 10-fold 1, 2, 3, 4, 5 1, 2, 5 IA c) d) e) The change requires assessment of the comparability of a biological/immunological active substance More than 10-fold increase compared to the originally approved batch size The scale for a biological/immunological active substance is increased / decreased without process change (e.g. duplication of line) Conditions , 2, 3, 4 IB 1, 2, 3, 4 IB Any changes to the manufacturing methods are only those necessitated by scale-up or downscaling, e.g. use of different-sized equipment. Test results of at least two batches according to the specifications should be available for the proposed batch size. The product concerned is not a biological/immunological medicinal product. The change does not adversely affect the reproducibility of the process. The change should not be the result of unexpected events arising during manufacture or because of stability concerns. The specifications of the active substance/intermediates remain the same. The active substance is not sterile. The batch size is within the 10-fold range of the batch size foreseen when the marketing authorisation was granted or following a subsequent change not agreed as a Type IA variation. Documentation 3. 5 Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate). Module 3.2.S.4.4 The batch numbers of the tested batches having the proposed batch size. Module 3.2.S.4.4 Batch analysis data (in a comparative tabulated format) on a minimum of one production batch of the active substance or intermediate as appropriate, manufactured to both the currently approved and the proposed sizes. Batch data on the next two full production batches should be made available upon request and reported by the marketing authorisation holder if outside specification (with proposed action). 4. Copy of approved specifications of the active substance (and of the intermediate, if applicable). A declaration from the marketing authorisation holder or the ASMF holder as appropriate that the changes to the manufacturing methods are only those necessitated by scale-up or downscaling, e.g. use of differentsized equipment, that the change does not adversely affect the reproducibility of the process, that it is not the result of unexpected events arising during manufacture or because of stability concerns and that the specifications of the active substance/intermediates remain the same. Justification attached to the Application form 13