Commission Regulation (EC) No 1146/98 of 2 June 1998 amending Regulation (EC) No 541/95 concerning the examination of variations in the terms of a marketing authorisation granted by a competent authority of a Member State
3. 6. 98 ‹ EN ‹ Official Journal of the European Communities L 159/31 COMMISSION REGULATION (EC) No 1146/98 of 2 June 1998 amending Regulation (EC) No 541/95 concerning the examination of variations in the terms of a marketing authorisation granted by a competent authority of a Member State THE COMMISSION OF THE EUROPEAN COMMUNITIES, Having regard to the Treaty establishing the European Community, Having regard to Council Directive 75/319/EEC of 20 May 1975, on the approximation of provisions laid down by law, regulations or administrative action relating to medicinal products (1), as last amended by Directive 93/39/EEC (2), and in particular Article 15 thereof, Having regard to Council Directive 81/851/EEC of 28 September 1981, on the approximation of legislation of relating to veterinary medicinal the Member States products (3), as last amended by Directive 93/40/EEC (4), and in particular Article 23 thereof, Whereas, following practical experience in the application of Commission Regulation (EC) No 541/95 (5) appropriate provisions should be made to the terms of this Regula- tion; Whereas it is appropriate to provide for a procedure to be followed in the case where national competent authority imposes urgent safety restrictions; the marketing authorisation authorisation holder, holder shall be obliged to submit an application for a variation taking account of the safety restrictions imposed by the national authorities. This application shall be submitted without delay to the national competent authorities concerned for the application of the procedures set out in Articles 6 and 7 of this Regu- lation. This paragraph is without prejudice to Article 15a of Directive 75/319/EEC and Article 23a of Direc- tive 81/851/EEC’. 2. In Article 4, paragraph 2 is replaced by the following text: The reference Member State shall ‘2. forthwith inform all other concerned Member States about the the procedure. The reference date of Member State shall also inform the marketing author- isation holder(s) about the date of the start of the pro- cedure’. the start of 3. After Article 7, Article 7a and Article 7b are added: Whereas, moreover, it is necessary to simplify the notifi- cation procedure for minor variations and to introduce some changes to the annexes to this Regulation; ‘Article 7a the provisions of Whereas, this Regulation are in ac- cordance with the opinion of the Standing Committee on Medicinal Products for Human Use and the Standing Committee on Veterinary Medicinal Products, HAS ADOPTED THIS REGULATION: Article 1 Regulation (EC) No 541/95 is amended as follows: 1. In Article 1 the following paragraph 3 is added: ‘3. Where national competent authorities impose urgent provisional safety restrictions on the marketing (1) OJ L 147, 9. 6. 1975, p. 13. (2) OJ L 214, 24. 8. 1993, p. 22. (3) OJ L 317, 6. 11. 1981, p. 1. (4) OJ L 214, 24. 8. 1993, p. 31. (5) OJ L 55, 11. 3. 1995, p. 7. Because of the specificities inherent in the manufac- turing of human influenza vaccines, the following dispositions are applicable: 1. Within 30 days following the date of the start of the procedure, the national competent authorities of the reference Member State shall prepare an assessment report on a pharmaceutical dossier and a draft de- cision which shall be addressed to the other national competent authorities concerned. 2. Within that period, the competent authority of the reference Member State may send the marketing authorisation holder a single request for information in addition to that already supplied pursuant to inform the other competent Article 6. It shall authorities concerned. 3. Within 12 days of receipt of the draft decision and the assessment report, the other competent national authorities concerned shall accept this draft decision and inform the competent national authority of the reference Member State to this effect. L 159/32 ‹ EN ‹ Official Journal of the European Communities 3. 6. 98 4. The clinical data and, where appropriate, those concerning the stability of the medicinal product shall be addressed by the applicant to the com- petent authorities of the reference Member State and to those of the other Member States concerned at the latest 12 days following the end of the time limit laid down in paragraph 3. The reference Member State shall evaluate these data and draft a final decision within seven days of the reception of the data mentioned in the first subparagraph. Each of the other national competent authorities shall accept this draft decision and adopt a decision in conformity with this project within the seven following days. 5. If, in the course of the procedure foreseen in the present Article, a competent authority raises a ques- tion of public health which they consider poses an obstacle to the mutual recognition of the decision to be taken, reference shall be made without delay to the provisions of Article 15, last paragraph, of Directive 75/319/EEC. Article 7b Notwithstanding Article 7a, in case of a pandemic situ- ation duly recognised by the World Health Organisa- tion, competent national authorities may exceptionally and temporarily consider the variation to be accepted after a complete application has been lodged and before the end of the procedure foreseen in Article 7a’. 4. In Annex I: — The text of point A is replaced by the following text: ‘A. By derogation, the procedure set out in Articles 6 and 7 of the present Regulation shall apply: — to the minor variations Nos 11, 12, 13, 15 and 16 as referred to below and to minor variations 24 and 25 if the test procedure used is not a physicochemical method for medicinal products falling within the scope of Council Directives 89/342/EEC (1), or 89/381/EEC (2), or 90/677/EEC (3), or for medicinal products which had been con- sidered as arising under List A of Directive 87/22/EEC, — to any minor variation when a specific inspection of a manufacturing site needs to be carried out’. General condition: the modified manufacturing authorisation must be submitted to the com- petent authority. — Change in the name of a manufacturer of the medicinal product Condition to be fulfilled: the manufacturing site shall remain the same. — Change of the manufacturing site(s) for part or all of the manufacturing process of the medicinal product Condition to be fulfilled: no change either in the manufacturing process or in the specifica- tions, including test methods. — withdrawal of the manufacturing authoriza- tion for a site of manufacture’. — The text of variation No 5 is replaced by the fol- lowing text: ‘5. Change in the colouring system of the product (addi- tion, deletion or replacement of colourant(s)) Condition to be fulfilled: 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 formula- tion’. — The text of variation No 6 is replaced by the fol- lowing text: ‘6. Change in the flavouring system of the product (addition, deletion or replacement of flavour(s)) Condition to be fulfilled: proposed flavour must be in accordance with 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’. — After variation No 10 the following text is added: ‘10a. Addition or replacement of measuring device for oral liquid dosage forms and other dosage forms Condition to be fulfilled: the size and, where applicable, the proposed measuring device must be compatible with the approved posology’. the accuracy of — After variation No 11 the following text is added: — The text of variation No 1 is replaced by the fol- lowing text: ‘11a. Change in the name of a manufacturer of the active substance ‘1. Change following modification(s) to the manufac- turing authorisation(s) Condition to be fulfilled: the manufacturer of the active substance shall remain the same. 3. 6. 98 ‹ EN ‹ Official Journal of the European Communities L 159/33 11b. Change in supplier of an intermediate compound used in the manufacture of the active substance change is introduced within six months of adop- tion of the revised monograph’. Condition to be fulfilled: the specifications, synthetic route and quality control procedures are the same as those already approved’. — The heading of variation No 30 is replaced by the following text: — After variation No 12 the following text is added: ‘Alternative condition: “. or a certificate of suit- ability is provided”. from the European Pharmacopoeia ‘30. Change in pack size for a medicinal product’ A supplementary condition is added: aging material remains the same’. ‘The pack- — A new condition is added to variation No 31: 12a. Change in specification of starting material or intermediate used in the manufacture of the active substance ‘The change does not concern a fundamental component of the packaging material which affects the delivery or use of the product’. Condition to be fulfilled: specification must be tightened or addition of new test and limits. ’ — After variation No 15 the following text is added: ‘15a. Change in in-process controls applied during the manufacture of the product — The heading of variation No 32 is replaced by the following text: ‘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’. — After variation No 33 variation No 34 is added: Condition to be fulfilled: specification must be tightened or addition of new test and limits’. ‘34. Change in the manufacturing process of a non component due to the subsequent proteinaceous introduction of a biotechnology step — After variation No 20 the following text is added: General remarks: ‘20a. Extension of the shelf life or retest period of the active substance Condition to be fulfilled: stability studies have been done to the protocol which was approved at the the time of the issue of the studies must marketing authorisation; show that the agreed end of shelf life specifi- cations are still met’. — After variation No 24 the following text is added: ‘24a. Change in test procedure for a starting material or intermediate used in the manufacture of the active substance Condition to be fulfilled: results of method validation show new test procedure to be at least equivalent to the former procedure. Specification not adversely affected’. — The footnote of variation No 26 is changed as follows: ‘In cases where the marketing authorisation holder refers to the current edition of the pharmacopoeia, no variation application is required provided the This specific variation is without prejudice to other variations in this Annex which can be applied in this particular context. Community legislation applicable to specific groups of products (*) has to be complied with. The medicinal products containing a proteina- ceous component obtained through a biotech- nology process fall within the scope of part A of Council Regulation (EEC) No 2309/93 (**). — Change in the manufacturing process for components compliant with a European Phar- macopoeia monograph and verified by means of a certificate of suitability from the European Pharmacopoeia the specifica- Conditions to be fulfilled: tions and physicochemical properties and all component of characteristics remain the same. the — Change in the manufacturing process for components requesting a new impurities test procedure L 159/34 ‹ EN ‹ Official Journal of the European Communities 3. 6. 98 the characteristics Conditions to be fulfilled: the specifica- tions and physicochemical properties and all component of remain the same. The manufacturing method is liable to leave impurities not controlled in the pharmacopoeia mono- graph, 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. (*) Food and food ingredients compliant with Regulation (EC) No 258/97 of the European (OJ L 43, Parliament and of the Council 14. 2. 1997, p. 1), colours for use in foodstuffs within the scope of Council Directive 94/36/EEC (OJ L 237, 10. 9. 1994, p. 13), food additives within the scope of Council Direc- tive 88/388/EEC (OJ L 184, 15. 7. 1988, p. 61), extraction solvents within the meaning of Council Directive 88/344/EEC (OJ L 157, 24. 6. 1988, p. 28) as last amended by Direc- tive 92/115/EEC (OJ L 409, 31. 12. 1992, p. 31) and foods or food ingredients derived from a biotechnology step which has been introduced in the manufacture/production are not required to be notified as a variation to the terms of the marketing authorisation. (**) OJ L 214, 24. 8. 1993, p. 1. ’ 5. In Annex II: — After the heading, the text of the first paragraph and the following subheading are replaced as follows: ‘Certain changes to a marketing authorisation have to be considered to fundamentally alter the terms of this authorisation and therefore cannot be con- sidered as a variation in the meaning of Article 15 of Directive 75/319/EEC or in the meaning of this Regulation. For Article 23 of Directive 81/851/EEC and cannot be granted following variation procedures foreseen in Articles 4 to 7 of these changes, listed below, any application has to be considered within a complete scientific evaluation procedure (as for the granting of a marketing authorisation). As the case may be, an authorisation or a modification to the existing marketing authori- sation will have to be issued by the competent national authorities. This Annex is without prejudice to the provisions of Article 4 of Directive 65/65/EEC and Article 5 of Directive 81/851/EEC’. — The text of variation No 1, paragraph (i) is replaced by the following text: ‘(i) addition of one or more active substance(s) including antigenic components for vaccines, without prejudice and 7b concerning human influenza’, to Articles 7a — The text of variation No 4, paragraph (ii) is replaced by the following text: ‘(ii) shortening of the withdrawal period of a veter- inary medicinal product if the change is not linked to the establishment or a modification in accordance to a maximum residue limit with Regulation (EEC) No 2377/90 (*). (*) OJ L 224, 18. 8. 1990, p. 1. ’ Article 2 This Regulation shall enter into force on the third day following its publication in the Official Journal of the European Communities. This Regulation shall be binding in its entirety and directly applicable in all Member States. Done at Brussels, 2 June 1998. For the Commission Martin BANGEMANN Member of the Commission