EN Official Journal of the European Union C 17/1

Communication from the Commission — Guideline on the details of the various categories of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products

(2010/C 17/01)

1. INTRODUCTION

Commission Regulation (EC) No 1234/2008 of 24 November 2008, concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products (1), hereinafter ‘the variations Regulation’, was published in the Official Journal on 12 December 2008. The variations Regulation aims to establish a simple, clearer and more flexible legal framework for the handling of variations to marketing authorisation of medicinal products, while ensuring a high level of protection of public and animal health.

The variations Regulation lays down general rules on the types and classification of variations in Articles 2 and 3 and in Annex II. In addition, Article 4(1)(a) charges the Commission with the task of drawing up guidelines on the details of the various categories of variations.

Consequently, this guideline provides details of the classification of variations into the following categories as defined in Article 2 of the variations Regulation: minor variations of Type IA, minor variations of Type IB and major variations of Type II and provides further details, where appropriate, on the scientific data to be submitted for specific variations and how this data should be documented. It should be noted that the general documentation accompanying every application for variations to the term of a marketing authorisation is laid down in Annex IV to the variations Regulation and in the Commission guideline on the operation of the procedures laid down in Chapters II, III and IV of Commission Regulation (EC) No 1234/2008 of 24 November 2008 concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products.

Definitions relevant to this guideline are provided in Directive 2001/82/EC, Directive 2001/83/EC, Regulation (EC) No 726/2004 as well as in the variations Regulation. In addition, for the purpose of this guideline ‘test procedure’ has the same meaning as ‘analytical procedure’ and ‘limits’ have the same meaning as ‘acceptance criteria’. ‘Specification parameter’ means the quality attribute for which a test procedure and limits are set, e.g. assay, identity and water content. The addition or deletion of a specification parameter therefore includes its corresponding test method and limits.

Where reference has to be made to specific variations in this Guideline, the variation in question should be quoted using the following structure: X.N.x.n

— X refers to the capital letter of the chapter in the Annex to this Guideline where the variation is included (e.g. A, B, C or D),

— N refers to the roman number of the section inside a chapter where the variation is included (e.g. I, II, III …),

— x refers to the letter of the subsection inside a chapter where the variation is included (e.g. a, b, c …),

— n refers to the number given in the Annex to this Guideline to a specific variation (e.g. 1, 2, 3 …).

This guideline will be regularly updated, taking into account the recommendations delivered in accordance with Article 5 of the Regulation as well as scientific and technical progress.

2. CLASSIFICATION GUIDANCE ON MINOR VARIATIONS OF TYPE IA, MINOR VARIATIONS OF TYPE IB AND MAJOR VARIATIONS OF TYPE II

The Annex to this Guideline consists of four chapters classifying variations related to: A) Administrative changes; B) Quality changes; C) Safety, Efficacy and Pharmacovigilance changes and D) Specific changes to Plasma Master Files and Vaccine Antigen Master Files.

For each chapter the Annex contains:

— a list of variations which should be classified as minor variations of Type IA or major variations of Type II in accordance with the definitions of Article 2 of the variations Regulation and the classifications provided in Annex II to the variations Regulation. It is also indicated which minor variations of Type IA require immediate notification as established in Article 8(1) of the variations Regulation,

— a list of examples that should be considered as minor variations of Type IB, in the understanding that this category applies by default as established in Article 3 of the variations Regulation and that the Annex to this Guideline does not therefore attempt to establish an exhaustive list for this category of variations.

The Annex does not deal with the classification of extensions as they are exhaustively listed in Annex I to the variations Regulation. All changes specified in Annex I to the variations Regulation must be considered extensions of the marketing authorisations; any other change can not be classified as such.

When one or more of the conditions established in the Annex to this Guideline for a minor variation of Type IA 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 II.

Specific supporting data for Type IB and Type II variations will depend on the specific nature of the change. In some cases, reference is made to specific scientific guidelines.

Furthermore, if a variation leads to a revision of the summary of product characteristics, labelling or package leaflet (in this guideline jointly referred to as ‘the product information’), this change is considered part of that variation. In such cases updated product information has to be submitted as part of the application. Mock-ups or specimens should be provided according to ‘The rules governing medicinal products in the European Community’, Volume 2A, Procedures for marketing authorisations; Chapter 7, General information of the Notice to applicants (hereinafter Chapter 7 of Notice to applicants), or as discussed with the reference Member State or the Agency on a case-by-case basis.

There is no need to notify the competent authorities of an updated monograph of the European pharmacopoeia or a national pharmacopoeia of a Member State in the case that compliance with the updated monograph is implemented within six months of its publication and reference is made to the ‘current edition’ in the dossier of an authorised medicinal product.

Any change to the content of the dossier that supports a European Pharmacopoeia Certificate of Suitability, should be submitted to the European Directorate for the Quality of Medicines (EDQM). However, if the certificate is revised following EDQM evaluation of this change, any marketing authorisation concerned must be updated accordingly.

With reference to Part III point 1 of Annex I to Directive 2001/83/EC, changes to Plasma Master Files (hereinafter PMFs) and Vaccine Antigen Master Files (VAMFs) follow the evaluation procedures for variations set-out in the variations Regulation. Therefore, Chapter D in this guideline provides a list of variations which are specific to such PMFs or VAMFs. Following review of these variations, any marketing authorisation concerned must be updated in accordance with Chapter B.V of this guideline. In case the documentation of the human plasma used as starting material for a plasma derived medicinal product is not submitted as a PMF, variations to this starting material as described in the marketing authorisation dossier should also be handled in accordance with this Annex.

References in this guideline to changes to the marketing authorisation dossier mean addition, replacement or deletion, unless specifically indicated. If amendments to the dossier only concern editorial changes, such changes should generally not be submitted as a separate variation, but they can be included in a variation concerning that part of the dossier. In such cases a declaration that the content of the concerned part of the dossier has not been changed by the editorial changes beyond the substance of the variation submitted should be provided.

(1) OJ L 334, 12.12.2008, p. 7.