A GUIDELINE ON DOSSIER REQUIREMENTS FOR TYPE I VARIATIONS November 1999

Transcription

1 EUROPEAN COMMISSION ENTERPRISE DIRECTORATE-GENERAL Pharmaceuticals and cosmetics Final Revision 0 NOTICE TO APPLICANTS A GUIDELINE ON DOSSIER REQUIREMENTS FOR TYPE I VARIATIONS November 1999 This guideline will be included in The rules governing medicinal products in the European Community Volume 2C Regulatory Guidelines and Volume 6A (chapter 5 - Variations) The Notice to Applicants Rue de la Loi 200, B-1049 Bruxelles/Wetstraat 200, B-1049 Brussel - Belgium - Office: AN88, 1/55. Telephone: direct line (+32-2) , switchboard Fax: Telex: COMEU B Telegraphic address: COMEUR Brussels.

2 GUIDELINE ON DOSSIER REQUIREMENTS FOR TYPE I VARIATIONS In accordance with Regulation (EEC) No. 2309/93 and Directives 75/319/EEC and 81/851/EEC, a common approach to the procedures for variations to the terms of a marketing authorization have been identified. These procedures facilitate the task of both industry and authorities and also guarantee that changes to the medicinal product do not give rise to public health concerns. Regulations (EC) No. 541/95 and 542/95 - as amended by Regulations (EC) No. 1146/98 and No. 1069/98 respectively - set out the provisions relating to variations and categorised them into Type I and Type II. For acceptance of a Type I variation documentation to demonstrate compliance with the conditions to be fulfilled must be submitted. In order to clarify what documentation should be submitted with these Type I variations, this guideline has been prepared. It elaborates the documentation required for both Regulation (EC) No. 541/95 and Regulation (EC) No. 542/95. Sometimes reference is made to specific guidelines. However, the applicant should always check whether other guidelines are also applicable for the variation concerned. In the first two columns of the following table each Type I variation is defined using the terminology of Annex I to the Regulations. The first column has the heading Change in or of. Please note that for variations 1, 11, 11b, 13, 15a, 16, 24, 24a, 25, 27, 28, 29 and 30 Change can also mean Addition besides Replacement. For variations 1, 11, 11b, 13, 16, 30 and 32 Change can also mean Deletion. For each variation the relevant part of the dossier to be (re-)submitted or updated is identified in the third column, and any other documentation required also given. The appropriate fee must also be paid, in accordance with the prevailing rules at the time of submission. For applications including a certificate of suitability from the European Pharmacopoeia and when the variation concerns the dossier submitted for the certificate, the documentation required for this change is to be submitted to the Secretariat of the European Pharmacopoeia as described in Resolution AP-CSP (98) 2 Certification of Suitability of monographs of the European Pharmacopoeia (appendix VIII). If the certificate is revised following evaluation of this change, any marketing authorisation concerned must be updated by a copy of the revised certificate, with additional information if necessary (such as batch analysis, stability data when the re-test period may be affected and is not covered by the certificate). In general, each time a certificate is revised, the competent authorities concerned shall be notified and the marketing authorisations concerned updated by a copy of the revision. The Type I variation procedure sets out to provide for rapid and efficient processing of variations. Applicants should be aware that submitting redundant or irrelevant information does not facilitate rapid procedures. On the other hand deficient documentation can lead to a rejection of the variation application. Applications for Type I variations will be rejected if the applicant has not supplemented the documentation within 30 days of receipt of a notification of the competent authority that the original documentation is not adequate. Rejections do not prejudice the applicant's right to resubmission.

3 1. Change following modification(s) to the manufacturing authorisation(s) - Change in the name of a manufacturer of medicinal product General condition: the modified manufacturing authorisation must be submitted to the competent authority. - The manufacturing site shall remain the same. - Updated part IA for products in the Centralised Procedure; - Signed declaration that the change does not involve a change of site of manufacture; - Revised drafts of the package leaflet /insert 1 and labelling where applicable (specimens and mock-ups where requested by competent authorities) incorporating the variation applied for; - Statement as to when the change will be implemented for future production batches. 1

4 - 2,3 Change of the manufacturing site(s) for part or all of the manufacturing process of the medicinal product - Withdrawal of the manufacturing authorization for a site of manufacture - No change either in the manufacturing process or in the specifications, including test methods. - Updated part IA for products in the Centralised Procedure; - In case of an additional site for batch release, a full justification must be provided based on technical and/or public (or animal) health grounds (e.g. to ensure free availability of the product throughout the Community); - Proof that the proposed site is appropriately authorized for the pharmaceutical form concerned: a new or modified manufacturing licence for a manufacturing site within the EEA, or a GMP certificate issued by an EU competent authority for a manufacturing site outside the EEA; - Declaration in writing that the manufacturing process and release and end-of-shelf-life specifications are the same as already approved; - Copy of approved release and end-of-shelf-life specifications; - Batch analysis data on one production batch and two pilot batches simulating the production process (or two production batches) and comparative data on the last 3 batches from the previous site; batch data on the next 2 full production batches should be available on request or reported if outside specifications (with proposed action); Where the change relates to a new manufacturer responsible for batch release or a new site where only batch release takes place or where the change relates to a new packager (secondary packaging or labelling), the submission of batch data are not necessary; - Validation data of the manufacturing process at the new site for products consisting of vaccines, toxins, serums and allergens, medicinal products derived from human blood or plasma, immunological veterinary medicinal products and products derived from biotechnology; - Revised drafts of the package leaflet /insert 1 and labelling where applicable (specimens and mock-ups where requested by competent authorities) incorporating the variation applied for; - Statement as to when the change will be effective. - Updated part IA for products in the Centralised Procedure; - Revised drafts of the package leaflet /insert 1 and labelling where applicable (specimens and mock-ups where requested by competent authorities) incorporating the variation applied for; - Statement as to when the change will be effective. 2

5 2. Name of the medicinal product (either invented name or common name) 3. Name and/or address of the marketing authorization holder (see Art 4a of Directive 65/65/EEC or Art. 5a of Directive 81/851/EEC) Confusion with names of other existing medicinal products or INN (international nonproprietary name) names must be avoided. When the name is a common name, the change has to be made in the following order: from common name to pharmacopoeial name or to INN. The marketing authorization holder shall remain the same person. - Revised drafts of the SPC, package leaflet/insert 1 and labelling (specimens and mock-ups where requested by competent authorities) incorporating the variation applied for; - Statement as to when the product will be marketed under the new name; - For products in the mutual recognition procedure, the variation application has to be submitted in all original CMSs, even if the proposed name is only applicable for a single Member State - For products in the centralised procedure, the new name must apply for all Member States; it is suggested that the check by the EMEA on the acceptability of the new trade name by the Member States should be finalised before the variation application is submitted. Note: if the MA holder wishes to amend the presentation of the full name of the product in the product information as (Trade)name<strength><pharmaceutical form> then this can be processed as a Type I variation. - Updated part IA for products in the Centralised Procedure; - Signed declaration that the MA holder remains the same legal entity; - Revised drafts of the SPC, package leaflet/insert 1 and labelling (specimens and mock-ups where requested by competent authorities) incorporating the variation applied for; - Statement as to when the change will be effective. 3

6 4. Replacement of an excipient with a comparable excipient (excluding adjuvants for vaccines and biologically derived excipients) No change in dissolution profile for solid dosage forms. Same functional characteristics. - Amendment to relevant sections of Parts II A, II B, II C and II E; - Justification for the change/choice of excipients etc. must be given by appropriate development pharmaceutics (including stability aspect, and antimicrobial preservation where appropriate); 4 - Comparative dissolution profile data of at least one representative pilot/production batch of the finished product in the new and old composition for solid dosage forms; - Justification for not submitting a new bioequivalence study according to the current NfG on The Investigation of Bioavailability and Bioequivalence; - Declaration that the relevant stability studies in accordance with the relevant guidelines have been started and that at least 3 months stability data are at the disposal of the applicant (at least two pilot scale or industrial scale batches with indication of batch numbers) and that the relevant stability studies will be finalised; data should be provided only if outside specifications (with proposed action); Note: For vaccines, toxins, serums and allergens, medicinal products derived from human blood or plasma, immunological veterinary medicinal products and products derived from biotechnology, for which the manufacturing process is an intrinsic part of the quality of the product, 6 months stability data have to be submitted. - Revised drafts of the SPC, package leaflet/insert 1 and labelling where applicable (specimens and mock-ups where requested by competent authorities) incorporating the variation applied for; - Declaration that the release and end-of-shelf life specifications of the finished product have not been changed; - Copy of approved release and end of shelf-life specifications; - For veterinary medicines: for food producing species, proof that the excipient is included in annex II of Council Regulation (EEC) No. 2377/90 or, if not, justification that the excipient does not have pharmacological activity at the dose which it is administered to the target animal; - Data to demonstrate that the new excipient does not interfere with the finished product specification test method (if appropriate). 4

7 5. Change in the colouring system of the product (addition, deletion or replacement of colourant(s)) Same functional characteristics, no change in dissolution profile for solid dosage forms. Any minor adjustment to the formulation to maintain the total weight should be made by an excipient which currently makes up a major part of the formulation. - Amendment to relevant sections of Parts II A, II B, II C (Proposed colourant must be in accordance with Directive 78/25/EEC) and II E and should include identification method for the new colourant; - Revised drafts of the SPC, package leaflet/insert 1 and labelling where applicable (specimens and mock-ups where requested by competent authorities) incorporating the variation applied for; - Sample of new product, where applicable (see NtA, Requirements for samples in the Member States); - Declaration that the relevant stability studies in accordance with the relevant guidelines have been started and that at least 3 months stability data are at the disposal of the applicant (at least two pilot scale or industrial scale batches with indication of batch numbers) and that the relevant stability studies will be finalised; data should be provided only if outside specifications (with proposed action); - Declaration that the release and end-of-shelf-life specifications have not been changed (except for appearance). - Data to demonstrate that the new excipient does not interfere with the finished product specification test method (if appropriate). 5

8 6 Change in the flavouring system of the product (addition, deletion or replacement of flavour(s)) Proposed flavour must be in accordance with Council Directive 88/388/EEC. Any minor adjustment to the formulation to maintain the total weight should be made by an excipient which currently makes up a major part of the formulation. - Amendment to relevant sections of Part II A, II B, II C and II E; - Amended sections of Part II C must contain details of qualitative composition of the flavour, demonstration of consistency of composition (e.g. by GLC data of three batches) and any new specifications for the flavour. In case data on the flavour are submitted directly by the supplier of the flavour this data must be in the possession of the competent authority before the procedure can be started; name of supplier and the date of the submission of the data of the flavour must be stated in annex to the application; - Revised drafts of the SPC, package leaflet/insert 1 and labelling where applicable (specimens and mock-ups where requested by competent authorities) incorporating the variation applied for; - Declaration that the release and end-of-shelf life specifications of the product have not been changed (except for flavour); - Declaration that the relevant stability studies in accordance with the relevant guidelines have been started and that at least 3 months stability data are at the disposal of the applicant (at least two pilot scale or industrial scale batches with indication of batch numbers) and that the relevant stability studies will be finalised; data should be provided only if outside specifications (with proposed action); - Data to demonstrate that the new excipient does not interfere with the finished product specification test method (if appropriate). 6

9 7. Change in coating weight of tablets or change in weight of capsule shells 8. Qualitative composition of immediate packaging material No change in dissolution profile. The proposed packaging material must be at least equivalent to the approved material in respect of its relevant properties. The change does not relate to sterile products. - Amendment to relevant sections of Parts II A, II B and II E; 4 - Comparative dissolution profile data of at least one pilot/production batch of the finished product in the new and old composition (for modified release products using in vitro data which have been correlated with in vivo data). - Justification for not submitting a new bioequivalence study according to the current NfG on The Investigation of Bioavailability and Bioequivalence; - Declaration that the release and end-of-shelf-life specifications of the medicinal product have not been changed (except for average weight). - Amendment to relevant section of Part II A and II C; - Justification for the change in packaging material and appropriate scientific studies on the new packaging (comparative data on permeability e.g. for O2, CO2, moisture) - For semisolid and liquid dosage forms, proof must be provided that no interaction between the content and the packaging material occurs (e.g. no migration of components of the proposed material into the content and no loss of components of the product into the pack); - Validation data must be given for all new analytical methods of the packaging material; - Declaration that the relevant stability studies in accordance with the relevant guidelines have been started and that at least 3 months stability data are at the disposal of the applicant (at least two pilot scale or industrial scale batches with indication of batch numbers) and that the relevant stability studies will be finalised; data should be provided only if outside specifications (with proposed action); - Declaration that the product will still meet the release and end-of-shelf-life specifications of the product; - Revised drafts of the SPC, package leaflet/insert 1 and labelling where applicable (specimens and mock-ups where requested by competent authorities) incorporating the variation applied for. 7

10 9. Deletion of an indication The continued safety in use of the medicinal product has not been the subject of concern from pharmacovigilance, preclinical safety or quality data. - Reason for deletion of indication and declaration that no safety concerns exist for the product; - Revised draft of the SPC, package leaflet/insert 1 and labelling where applicable (specimens and mock-ups where requested by competent authorities) incorporating the variation applied for; - Statement as to when the change will be effective. 10. Deletion of a route of administration Justification must be given. The continued safety in use of the medicinal product has not been the subject of concern from pharmacovigilance, preclinical safety or quality data. - Reason for deletion of route of administration and declaration that no safety concerns exist for the product; - Revised draft of the SPC, package leaflet/insert 1 and labelling where applicable (specimens and mock-ups where requested by competent authorities) incorporating the variation applied for; - Statement as to when the change will be effective. Justification must be given. 8

11 10a. 5 Addition or replacement of measuring device for oral liquid dosage forms and other dosage forms The size and, where applicable, the accuracy of the proposed measuring device must be compatible with the approved posology. - Amendments to relevant sections of Part II A and II C; - Description of the device (including a detailed drawing) and name of supplier where appropriate; - Samples of the new measuring device where applicable (see NtA, Requirements for samples in the Member States); - Justification that size and accuracy of the device are adequate for the posology as is approved in the SPC; - Revised draft of the SPC, package leaflet/insert 1 and labelling where applicable (specimens and mock-ups where requested by competent authorities) incorporating the variation applied for; - The composition of the device material. Where applicable the materials should comply with the Ph. Eur.; - Data on stability/compatibility between device material and medicinal product if appropriate; - Reference to CE marking for device where relevant. 9

12 11 6,7 Manufacturer(s) of active substance 11a. Change in the name of a manufacturer of the active substance The specifications, synthetic route and quality control procedures are the same as those already approved or a European Pharmacopoeia certificate of suitability covering the active substance is submitted. The manufacturer of the active substance shall remain the same. - Updated part IA for products in the Centralised Procedure; - Amendment to relevant sections of Part II C; - Batch analysis data of at least two batches (minimum pilot scale); - For vaccines, toxins, serums and allergens, medicinal products derived from human blood or plasma, immunological veterinary medicinal products and products derived from biotechnology, for which the manufacturing process is an intrinsic part of the quality of the product, 6 months stability data in accordance with the relevant guidelines for the active substance and for the product manufactured with this substance have to be submitted. Further, a declaration that the real time stability studies will be finalised; data should be provided only if outside specifications (with proposed action); - A Ph. Eur. certificate of suitability or a revision of the certificate submitted in Part II C, if appropriate, or A declaration from the marketing authorisation holder that the synthetic route (or where appropriate the method of preparation 8 e.g. for herbal medicinal products), quality control procedures and specifications are the same as those already approved including a statement that the MA-holder does have access to the appropriate information (this can include a new Drug Master File (DMF) 9, 10 with the necessary requirements, if the conditions are met). - Updated part IA for products in the Centralised Procedure; - Amendment to relevant sections of Part II C; - Signed declaration that the manufacturing site remains the same; - A revision of the Ph. Eur. certificate of suitability submitted in Part II C, if appropriate; - Statement as to when the change will be effective. 10

13 11b. 11,12 Change in supplier of an intermediate compound used in the manufacture of the active substance The specifications, synthetic route and quality control procedures are the same as those already approved. - Amendment to relevant sections of Part II C; - Batch analysis data of at least two batches (minimum pilot scale) of the intermediate compound and of the active substance - A Ph. Eur. certificate of suitability or a revision of the certificate submitted in Part II C, if appropriate, or A declaration from the marketing authorisation holder that the synthetic route (or where appropriate the method of preparation 8 e.g. for herbal medicinal products), quality control procedures and specifications for the intermediate compound and for the active substance are the same as those already approved including a statement that the MA-holder does have access to the appropriate information (this can include an update of an existing approved Drug Master File (DMF) 9, 10, if appropriate and if the conditions are met). 11

14 12. 6 Minor change of manufacturing process of the active substance Specifications not adversely affected. No change in the physical properties. No new impurities or change in level of impurities which would require further qualifications in safety studies. Alternative condition: or a certificate of suitability from the European Pharmacopoeia is provided. - Amendment to relevant section of Part II C including a direct comparison of the present process and the new process; - Batch analysis data of at least two batches (minimum pilot scale); - For vaccines, toxins, serums and allergens, medicinal products derived from human blood or plasma, immunological veterinary medicinal products and products derived from biotechnology, for which the manufacturing process is an intrinsic part of the quality of the product, 6 months stability data in accordance with the relevant guidelines for the active substance and for the product manufactured with this substance have to be submitted. Further, a declaration that the real time stability studies will be finalised; data should be provided only if outside specifications (with proposed action); - A certificate of suitability from the European Pharmacopoeia, or a revision of the certificate submitted in Part II C, if appropriate, or The following data package which can also include an update to an approved Drug Master File (DMF) 9,if appropriate:. evidence must be provided that any potential new impurities are detectable at an acceptable limit of detection; declaration that no new impurities have been introduced at or above the accepted threshold for qualification of impurities or that there is no increase in the level of impurities, which require further safety studies;. validation data must be provided for all new analytical methods (where applicable) (see also variation 24);. declaration that the specifications of the active substance have not been changed (see also variation 14) or if there is any change to the specifications (i.e. tightening), the texts of the current and proposed specifications should be provided (side by side comparison where possible);. copy of approved specifications of the active substance. 12

15 12a. Change in specification of starting material or intermediate used in the manufacture of the active substance Specification must be tightened or addition of new test and limits. - Amendment to relevant section of Part II C; - A certificate of suitability from the European Pharmacopoeia, or a revision of the certificate submitted in Part II C, if appropriate. or A description of the analytical methodology and summary of validation data must be provided for all new analytical methods (where applicable). (see also variation 24a) 13

16 13. 6 Batch size of active substance Batch data must show that the change does not affect consistency of production, or physical properties. - Amendment to relevant section of Part II C; - Batch analysis data (in a comparative tabulated format) on a minimum of one production batch manufactured to both the currently approved and the proposed sizes. Batch data on the next 2 full production batches should be made available upon request and reported by the MA holder if outside specification (with proposed action) as a post-approval commitment; - For vaccines, toxins, serums and allergens, medicinal products derived from human blood or plasma, immunological veterinary medicinal products and products derived from biotechnology, for which the manufacturing process is an intrinsic part of the quality of the product, 6 months stability data in accordance with the relevant guidelines for the active substance and for the product manufactured with this substance have to be submitted. Further, a declaration that the real time stability studies will be finalised; data should be provided only if outside specifications (with proposed action); - A certificate of suitability from the European Pharmacopoeia, or a revision of the certificate submitted in Part II C, if appropriate, or The following data package which can also include an update to an approved Drug Master File (DMF) 9 if appropriate:. declaration that the specifications of the active substance have not been changed;. copy of approved specifications of the active substance;. evidence must be provided that any potential impurities are detectable at an acceptable limit of detection. 14

17 14. Change in specifications of active substance Specifications must be tightened or addition of new test and limits. - Amendment to relevant section of Part II C; - Comparative batch analysis data covering all tests in the specifications for at least 2 pilot/production batches; - A certificate of suitability from the European Pharmacopoeia, or a revision of the certificate submitted in Part II C, if appropriate, or The following data package:. validation data must be provided for all new analytical methods (where applicable) (see also variation 24);. 4 comparative dissolution profile data for the finished product (if appropriate) on at least one pilot production batch containing the active substance complying with the current and proposed specifications;. comparative list of current and proposed specifications of active substance. 15

18 15. 6 Minor change in the manufacture of the medicinal product 15a. Change in inprocess controls applied during the manufacture of the product. Medicinal product specifications are not adversely affected. New process must lead to an identical product regarding all aspects of quality, safety and efficacy. Specification must be tightened or addition of new test and limits. - Amendment to relevant sections of Part II B which contains: for semisolid and liquid products in which the active substance is present in non dissolved form: appropriate validation of the change including microscopic imaging of particles to check for visible changes in morphology; comparative size distribution data by an appropriate method; for solid dosage forms: 4 dissolution profile data of 1 representative production batch and comparative data of the last 3 batches from the previous process; data on the next 2 full production batches should be available on request or reported if outside specification (with proposed action); - Declaration that the release and end-of-shelf-life specifications of the product have not been changed or if there is any change of the specifications (i.e. tightening), the texts of the current and proposed specifications should be provided (side by side comparison where possible); - Justification for not submitting a new bioequivalence study according to the current NfG on The Investigation of Bioavailability and Bioequivalence; - Copy of approved release and end-of-shelf-life specifications. - In case of change to a sterilisation process, justification and validation should be provided. - Amendment to relevant sections of Part II B and II D; - A description of the analytical methodology and summary of validation data must be provided for all new analytical methods (where applicable). 16

19 16. 6 Batch size of finished product 17. Change in specification of the medicinal product The change does not affect consistency of production. Specifications must be tightened or addition of new tests and limits. - Amendment to relevant sections of Part II B; - Batch analysis data (in a comparative tabulated format) on a minimum of one production batch manufactured to both the currently approved and the proposed batch sizes. Batch data on the next 2 full production batches should be available on request or reported if outside specifications (with proposed action); - Products for which a content uniformity test is mandatory: also data on homogeneous distribution of the active substance within a batch should be provided; - Declaration that the release and end-of-shelf-life specifications of the product have not been changed; - Copy of approved release and end-of-shelf-life specifications. - Amendment to relevant section of Part II E and II F; - A description of the analytical methodology and summary of validation data must be provided for all new analytical methods (where applicable); 4 - Comparative dissolution profile where appropriate; - Comparative batch analysis data covering all tests in the specification for at least 2 production scale batches; - Comparative listing of current and proposed release and end-of-shelf-life specifications of the product. 17

20 18. Synthesis/ recovery of nonpharmacopoeial excipients which had been described in the original dossier Specifications are not adversely affected. No new impurities or change in level of impurities which would require further qualification in safety studies. - Amendment to relevant sections of Part II C which contain appropriate validation data; - Comparative batch analysis data of at least two batches; - Declaration that the specifications of excipients have not been changed or if there is any change to the excipient specifications (i.e. tightening), the texts of the current and proposed specifications should be provided (side by side comparison where possible); - Declaration that no new impurities have been introduced or that there is no increase in the level of impurities, which require further safety studies. No change in physicochemical properties. 18

21 19. Change in specification of excipients in the medicinal product (excluding adjuvants for vaccines) Specifications must be tightened or addition of new tests and limits. - Amendment to relevant section of Part II C; - A description of the analytical methodology and summary of validation data must be provided for all new analytical methods (where applicable). (see also variation 27); 4 - Comparative dissolution profile data of at least one pilot/production batch of the finished product, if appropriate; - Justification for not submitting a new bioequivalence study according to the current NfG on The Investigation of Bioavailability and Bioequivalence; - Comparative batch analysis data covering all tests in the specification for at least 2 pilot/production batches of the finished product; - Comparative list of current and proposed specifications of the excipients. 19

22 20. Extension of shelf-life as foreseen at time of authorisation Stability studies have been done to the protocol which was approved at the time of the issue of the marketing authorisation. The studies must show that the agreed end-of-shelflife specifications are still met. - Amendment to relevant sections of Part II F must contain results of appropriate real time stability studies (tabulated format; at least two pilot or production scale batches) of the product in the authorised packaging material covering the duration of the requested shelflife in accordance with the relevant stability guidelines; - Declaration that the continued stability studies have been done to the protocol which was approved at the time of issue of the marketing authorisation and that the agreed end-ofshelf-life specifications are still met; - Revised drafts of the SPC, package leaflet/insert 1 and labelling where applicable (specimens and mock-ups where requested by competent authorities) incorporating the variation applied for; - Copy of approved end-of-shelf-life specifications. The shelf-life does not exceed five years. 20

23 20a. Extension of the shelf life or retest period of the active substance Stability studies have been done to the protocol which was approved at the time of the issue of the marketing authorisation; the studies must show that the agreed end-of-shelflife specifications are still met. - Amendment to relevant sections of Part II F; - A certificate of suitability from the European Pharmacopoeia, or a revision of the certificate submitted in Part II C, if appropriate (only acceptable if the retest period is mentioned in the Ph.Eur. certificate) or The following data package:. declaration that the additional stability studies have been done to the protocol which was approved at the time of issue of the marketing authorisation and that the agreed end-ofshelf-life specifications are still met;. stability data should be presented on at least two pilot or production scale batches in the approved packaging material covering the duration of the requested shelf-life (real time data);. copy of approved end-of-shelf-life specifications. 21

24 21. Change in shelf-life after first opening Studies must show that the agreed end-of-shelflife specifications are still met. - Amendment to relevant sections of Part II F must contain results of appropriate real time stability studies on at least two production scale batches of the product in the authorised packaging material after first opening in accordance with the relevant stability guidelines; where applicable, results of appropriate microbiological testing should be included. - Declaration that the additional real time stability studies show that the agreed end-of-shelflife specifications after first opening are still met; - Revised drafts of the SPC, package leaflet/insert 1 and labelling where applicable (specimens and mock-ups where requested by competent authorities) incorporating the variation applied for; - Copy of approved end-of-shelf-life specifications. 22

25 22. Change in shelf-life after reconstitution 23. Storage conditions Studies must show that the agreed end-of-shelflife specifications are still met for the reconstituted product. Stability studies have been done to the protocol which was approved at the time of issue of the marketing authorisation. The studies must show that the agreed end-ofshelf-life specifications are still met. - Amendment to relevant sections of Part II F must contain results of appropriate real time stability studies on at least two production scale batches of the reconstituted product in accordance with the relevant stability guidelines; where applicable, results of appropriate microbiological testing should be included; - Declaration that the additional real time stability studies show that the agreed end-of-shelflife specifications after reconstitution are still met for the reconstituted product; - Revised drafts of the SPC, package leaflet/insert 1 and labelling where applicable (specimens and mock-ups where requested by competent authorities) incorporating the variation applied for; - Copy of approved end-of-shelf-life specifications. - Amendments to relevant sections of Part II F must contain results of appropriate real time stability studies on at least two pilot or production scale batches of the product in the authorised packaging material in accordance with the relevant guidelines; - Declaration that the real time stability studies have been done to the protocol which was approved at the time of issue of the marketing authorisation and that the agreed end-ofshelf-life specifications are still met; - Revised drafts of the SPC 13, package leaflet/insert 1 and labelling where applicable (specimens and mock-ups where requested by competent authorities) incorporating the variation applied for; - Copy of approved end-of-shelf-life specifications; 23

26 Change in test procedure of active substance 24a. 15 Change in test procedure for a starting material or intermediate used in the manufacture of the active substance Results of method validation show new test procedure to be at least equivalent to the former procedure. Results of method validation show new test procedure to be at least equivalent to the former procedure. Specification not adversely affected. - Amendment to relevant sections of Part II C which includes a description of the analytical methodology, a summary of validation data, and comparative analytical results between the current test and the proposed one, if appropriate; Amendment to relevant sections of Part II F, if appropriate; - A certificate of suitability from the European Pharmacopoeia, or a revision of the certificate submitted in Part II C, if appropriate, or The following data package:. declaration that the specifications of the active substance have not been changed (see also variation 14);. copy of approved specifications;. if a new impurity is detected with the new test procedure, justification that the newlydetected impurity is toxicologically acceptable. - Amendment to relevant sections of Part II C which includes a description of the analytical methodology, a summary of validation data, and comparative analytical results between the current test and the proposed one, if appropriate; Amendment to relevant sections of Part II F, if appropriate; - A certificate of suitability from the European Pharmacopoeia, or a revision of the certificate submitted in Part II C, if appropriate, or The following data package:. declaration that the specifications of the starting material or intermediate have not been changed (see also variation 12a);. if a new impurity is detected with the new test procedure, justification that the newlydetected impurity is toxicologically acceptable. 24

27 Change in test procedures of the medicinal product Medicinal product specifications are not adversely affected. Results of method validation show new test procedure to be at least equivalent to the former procedure. - Amendment to relevant sections of Part II E and/or Part II F which includes a description of the analytical methodology, appropriate validation data and comparative analytical results between the current test and the proposed one, if appropriate; - Declaration that the release and end-of-shelf life specifications of the product have not been changed or if there is any change to the specifications, the texts of current and proposed specifications should be provided (side by side comparison where possible) (see 17); - Copy of the approved release and end-of-shelf-life specifications. 25

28 26. Changes to comply with supplements to pharmacopoeias (In cases where the marketing authorisation refers to the current edition of the pharmacopoeia no variation application is required provided the change is introduced within six months of adoption of the revised monograph) 27. Test procedures of nonpharmacopoeial excipients Change is made exclusively to implement the new provisions of the supplement. Results of method validation show new test procedure to be at least equivalent to the former test procedure. - Amendments to appropriate parts of Part II C1 and C2 and Part II E; - Active substances: when changing from a non-eu pharmacopoeia or from company specifications documentation should be provided to demonstrate the suitability of the new monograph in the European Pharmacopoeia or national pharmacopoeia of the Member State to control the substance from that particular manufacturer. For substances described in the Ph.Eur. this may be done for example by:. comparing a list of potential impurities in the substance with the transparency note of the monograph, or. a certificate of suitability from the European Pharmacopoeia, or a revision of the certificate submitted in Part II C, if appropriate; - Excipients/active substances: In case the new Ph. Eur. specification or national pharmacopoeia of the Member State of active substances or excipients may affect the quality of the finished product, comparative batch analysis data covering all tests in the finished product specification for at least 2 production scale batches should be provided together with comparative dissolution profile where appropriate. Note (Finished products) : In case of a new general monograph (on dosage form) or a new general requirement a single application may be submitted for a list of products covered by the new monograph/requirement, unless the new requirement calls for product specific validation. - Amendment to relevant sections of Part II C which includes a description of the analytical methodology, a summary of validation data, and comparative analytical results between the current test and the proposed one; - Declaration that the specifications of the excipients have not been changed (see also variation 19). 26

29 28. Test procedure of immediate packaging 29. Test procedure of administration device 30. Change in pack size for a medicinal product Results of method validation show new test procedure to be at least equivalent to the former test procedure. Results of method validation show new test procedure to be at least equivalent to the former test procedure. Specifications of the medicinal product are not affected, the new size is consistent with the dosage regimen and duration of use as approved in the SPC. The change does not relate to parenteral preparations. The packaging material remains the same. - Amendment to relevant sections of Part II C which includes a description of the analytical methodology, appropriate validation data and comparative analytical results between the current test method and the proposed one, if appropriate; - Declaration that the specifications of the immediate packaging have not been changed. - Amendment to relevant sections of Part II C which includes a description of the analytical methodology, appropriate validation data and comparative analytical results between the current test method and the proposed one, if appropriate; - Reference to CE marking for device where applicable; - Declaration that the specifications of the administration device have not been changed. - Amendment to relevant sections of Part II A, II C and II E where appropriate; - Declaration that the specifications of the medicinal product are not affected. - Justification that the new size is consistent with the dosage regimen and duration of use as is approved in the SPC; - Revised drafts of the SPC, package leaflet/insert 1 and labelling (specimens and mock-ups where requested by competent authorities) incorporating the variation applied for; - Declaration that the container and closure composition is unchanged and in the case of plastics, an assurance that the polymer wall thickness is at least as thick as the current packs; - Declaration that stability studies will be conducted for products where stability parameters could be affected. Data to be reported only if outside specifications (with proposed action). Note: If the product is a parenteral and the change only concerns the number of containers in the outer packaging, then the change can be processed as a Type I variation. 27

30 31. Change in container shape. No change in the quality and in the stability of the product in the container. No change in the container-product interactions. - Amendment to relevant sections of Part II A and II C3 (including a detailed drawing of the current and proposed forms) if applicable; - Samples of old and new containers where applicable (see NtA, Requirements for samples in the Member States); - Declaration that the specifications of the container (except for shape) have not been changed; - Declaration that the release and end-of-shelf-life specifications of the product have not been changed. The change does not concern a fundamental component of the packaging material which affects the delivery or use of the product. 28

31 32. Change of imprints, bossing or other markings (except scoring) on tablets or printing on capsules including addition or change of inks used for product marking 33. Change of dimensions of tablets, capsules, suppositories or pessaries without change of quantitative composition and mean mass New markings do not cause confusion with other tablets or capsules. No change in dissolution profile. - Amendment to relevant sections of Part II A, II B, II C (for proposed new inks, the colourants must be in accordance with Directive 78/25/EEC) and II E (including a detailed drawing or written description of the current and proposed situation); - Samples of the finished product where applicable (see NtA, Requirements for samples in the Member States); - Declaration that the release and end-of-shelf-life specifications of the product have not been changed (except for appearance); - Revised drafts of the SPC (where applicable), package leaflet/insert 1 and labelling (specimens and mock-ups where requested by competent authorities) incorporating the variation applied for. - Amendment to relevant sections of Part II B and II E (including a detailed drawing of the current and proposed situation); - Comparative dissolution data on at least one pilot/production batch of the current and proposed dimensions; - Declaration that the release and end-of-shelf-life specifications of the product have not been changed (except for dimensions); - Revised drafts of the SPC (where applicable), package leaflet/insert 1 and labelling (specimens and mock-ups where requested by competent authorities) incorporating the variation applied for; - Samples of the finished product where applicable (see NtA, Requirements for samples in the Member States); - Data of breakability test of tablets at release must be given and commitment to submit data of breakability at the end of shelf-life. 29

32 34. Change in the manufacturing process of a non proteinaceous component due to the subsequent introduction of a biotechnology step For general remarks, see Article 1, paragraph 17 of Commission Regulation No 1069/98 and Article 1, paragraph 4, last dash of Commission Regulation No 1146/98. - Change in the manufacturing process for components compliant with a European Pharmacopoeia monograph and verified by means of a certificate of suitability from the European Pharmacopoeia The specifications and physicochemical properties and all characteristics of the component remain the same. - Batch analysis data of at least two batches (minimum pilot scale); - Certificate of suitability from the European Pharmacopoeia, or a revision of the certificate submitted in Part II C, if appropriate. 30

33 - Change in the manufacturing process for components requesting a new impurities test procedure The specifications and physicochemical properties and all characteristics of the component remain the same. The manufacturing method is liable to leave impurities not controlled in the pharmacopoeia monograph, these impurities must be declared and a suitable test procedure must be described. This supplementary test must be specified in a certificate of suitability from the European Pharmacopoeia. - Batch analysis data of at least two batches (minimum pilot scale); - Certificate of suitability from the European Pharmacopoeia, or a revision of the certificate submitted in Part II C, if appropriate. 31

34 NOTES 1 The Directives use the term "package leaflet" for human medicinal products, where for veterinary products "package insert" is used. 2 The addition or replacement of a manufacturing site also falls within the scope of this variation. In case of a change in or a new manufacturing site in a country outside the EEA without an operational GMP mutual recognition agreement with the EU, marketing authorisation holders are advised to consult the relevant competent authorities first before making the submission of the application for the variation and to provide information about any previous EU/EEA inspection in the last 2-3 years and/or any planned EU/EEA inspection(s) including inspection dates, product category inspected, Supervisory Authority and other relevant information. This will facilitate the arrangement for a GMP inspection by an inspection service of one of the Member States if needed. The same advice is given if the new site is outside the company. It is recommended that inspection issues are resolved before submission of the variation. 3 For vaccines, toxins, serums and allergens, medicinal products derived from human blood or plasma, immunological veterinary medicinal products and products derived from biotechnology, for which the manufacturing process is an intrinsic part of the quality of the product, a change to the manufacturing authorisation can entail further changes, such as change in batch size of the active substance (variation 13) or minor changes in the manufacture of the medicinal product (variation 15). Such further changes would be covered by the same application (i.e. a single fee). In the event that such a further change fell within the scope of variations 11, 12, 13, 15, 16, or variations 24 and 25 if the test procedure used is not a physicochemical method, the procedures set out in Articles 6 and 7 of Regulation (EC) No. 541/95 (Mutual Recognition Procedure) or in Articles 6, 7 and 8 of Regulation (EC) No. 542/95 (Centralised Procedure) apply. For chemically synthesised medicinal products, the specifications set out the quality of the product and therefore further variations would not always be necessary. 4 Comparative disintegration time data may be acceptable for herbal medicinal products. 5 Variation 10a is not intended to cover measuring devices which form a single integral product with the medicinal product. Therefore, for example changes to any component of metering valves/pumps of inhalation products are not considered to fall within the scope of this variation. 6 For products consisting of vaccines, toxins, serums and allergens or derived form human blood or human plasma and for biotech products which have been considered as arising under List A of Directive 87/22/EEC or under Part A of the Annex to Regulation (EEC) 2309/93 the procedure for a Type II variation is applicable. 7 A change to a new site of the same manufacturer also falls within the scope of this variation. 32