Table of content:

Guidelines on the details of the various categories of variations (obsolete)

Annex

A. Administrative changes

A.1 Change in the name and/or address of the marketing authorisation holder

A.2 Change in the (invented) name of the medicinal product

A.3 Change in name of the active substance or of an excipient

A.4 Change in the name and/or address of: a manufacturer (including where relevant quality control testing sites); or an ASMF holder; or a supplier of the active substance, starting material, reagent or intermediate used in the manufacture of the active substance (where specified in the technical dossier) where no Ph. Eur. Certificate of Suitability is part of the approved dossier; or a manufacturer of a novel excipient (where specified in the technical dossier)

A.5 Change in the name and/or address of a manufacturer/importer of the finished product (including batch release or quality control testing sites)

A.6 Change in ATC Code / ATC Vet Code

A.7 Deletion of manufacturing sites for an active substance, intermediate or finished product, packaging site, manufacturer responsible for batch release, site where batch control takes place, or supplier of a starting material, reagent or excipient (when mentioned in the dossier)

A.8 Changes to date of the audit to verify GMP compliance of the manufacturer of the active substance

B. Quality changes

B.I Active substance

B.I.a) Manufacture

B.I.a.1 Change in the manufacturer of a starting material/reagent/intermediate used in the manufacturing process of the active substance or change in the manufacturer (including where relevant quality control testing sites) of the active substance, where no Ph. Eur. Certificate of Suitability is part of the approved dossier

B.I.a.2 Changes in the manufacturing process of the active substance

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

B.I.a.4 Change to in-process tests or limits applied during the manufacture of the active substance

B.I.a.5 Changes to the active substance of a seasonal, pre- pandemic or pandemic vaccine against human influenza

B.I.a.6 Changes to the active substance of a vaccine against human coronavirus (This section is introduced with Addendum to the Variations Guidelines (2021/C 215 I/01))

B.I.b) Control of active substance

B.I.b.1 Change in the specification parameters and/or limits of an active substance, starting material / intermediate / reagent used in the manufacturing process of the active substance

B.I.b.2 Change in test procedure for active substance or starting material/reagent/intermediate used in the manufacturing process of the active substance

B.I.c) Container closure system

B.I.c.1 Change in immediate packaging of the active substance

B.I.c.2 Change in the specification parameters and/or limits of the immediate packaging of the active substance

B.I.c.3 Change in test procedure for the immediate packaging of the active substance

B.I.d) Stability

B.I.d.1 Change in the re-test period/storage period or storage conditions of the active substance where no Ph. Eur. Certificate of Suitability covering the retest period is part of the approved dossier

B.I.e) Design Space and post-approval change management protocols

B.I.e.1 Introduction of a new design space or extension of an approved design space for the active substance, concerning:

B.I.e.2 Introduction of a post approval change management protocol related to the active substance

B.I.e.3 Deletion of an approved change management protocol related to the active substance

B.I.e.4 Changes to an approved change management protocol

B.I.e.5 Implementation of changes foreseen in an approved change management protocol

B.II FINISHED PRODUCT

B.II.a) Description and composition

B.II.a.1 Change or addition of imprints, bossing or other markings including replacement, or addition of inks used for product marking.

B.II.a.2 Change in the shape or dimensions of the pharmaceutical form

B.II.a.3 Changes in the composition (excipients) of the finished product

B.II.a.4 Change in coating weight of oral dosage forms or change in weight of capsule shells

B.II.a.5 Change in concentration of a single-dose, total use parenteral product, where the amount of active substance per unit dose (i.e. the strength) remains the same

B.II.a.6 Deletion of the solvent / diluent container from the pack

B.II.b) Manufacture

B.II.b.1 Replacement or addition of a manufacturing site for part or all of the manufacturing process of the finished product

B.II.b.2 Change to importer, batch release arrangements and quality control testing of the finished product

B.II.b.3 Change in the manufacturing process of the finished product, including an intermediate used in the manufacture of the finished product

B.II.b.4 Change in the batch size (including batch size ranges) of the finished product

B.II.b.5 Change to in-process tests or limits applied during the manufacture of the finished product

B.II.c) Control of excipients

B.II.c.1 Change in the specification parameters and/or limits of an excipient

B.II.c.2 Change in test procedure for an excipient

B.II.c.3 Change in source of an excipient or reagent with TSE risk

B.II.c.4 Change in synthesis or recovery of a non- pharmacopoeial excipient (when described in the dossier) or a novel excipient

B.II.d) Control of finished product

B.II.d.1 Change in the specification parameters and/or limits of the finished product

B.II.d.2 Change in test procedure for the finished product

B.II.d.3 Variations related to the introduction of real-time release or parametric release in the manufacture of the finished product

B.II.e) Container closure system

B.II.e.1 Change in immediate packaging of the finished product

B.II.e.2 Change in the specification parameters and/or limits of the immediate packaging of the finished product

B.II.e.3 Change in test procedure for the immediate packaging of the finished product

B.II.e.4 Change in shape or dimensions of the container or closure (immediate packaging)

B.II.e.5 Change in pack size of the finished product

B.II.e.6 Change in any part of the (primary) packaging material not in contact with the finished product formulation (such as colour of flip-off caps, colour code rings on ampoules, change of needle shield (different plastic used))

B.II.e.7 Change in supplier of packaging components or devices (when mentioned in the dossier)

B.II.f) Stability

B.II.f.1 Change in the shelf-life or storage conditions of the finished product

B.II.g) Design Space and post approval change management protocol

B.II.g.1 Introduction of a new design space or extension of an approved design space for the finished product, concerning:

B.II.g.2 Introduction of a post approval change management protocol related to the finished product

B.II.g.3 Deletion of an approved change management protocol related to the finished product

B.II.g.4 Changes to an approved change management protocol

B.II.g.5 Implementation of changes foreseen in an approved change management protocol

B.II.h) Adventitious Agents Safety

B.II.h.1 Update to the “Adventitious Agents Safety Evaluation” information (section 3.2.A.2)

B.III CEP/TSE/MONOGRAPHS

B.III.1 Submission of a new or updated Ph. Eur. certificate of suitability or deletion of Ph. Eur. certificate of suitability: For an active substance; For a starting material/reagent/intermediate used in the manufacturing process of the active substance; For an excipient

B.III.2 Change to comply with Ph. Eur. or with a national pharmacopoeia of a Member State

B.IV Medical Devices

B.IV.1 Change of a measuring or administration device

B.IV.2 Change in specification parameters and/or limits of a measuring or administration device for veterinary medicinal products

B.IV.3 Change in test procedure of a measuring or administration device for veterinary medicinal products

B.V. Changes to a marketing authorisation resulting from other regulatory procedures

B.V.a) PMF/VAMF

B.V.a.1 Inclusion of a new, updated or amended Plasma Master File in the marketing authorisation dossier of a medicinal product. (PMF 2^nd step procedure)

B.V.a.2 Inclusion of a new, updated or amended Vaccine Antigen Master File in the marketing authorisation dossier of a medicinal product. (VAMF 2^nd step procedure)

B.V.b) Referral

B.V.b.1 Update of the quality dossier intended to implement the outcome of a Union referral procedure

C. SAFETY, EFFICACY, PHARMACOVIGILANCE CHANGES

C.I HUMAN AND VETERINARY MEDICINAL PRODUCTS

C.I.1 Change(s) in the Summary of Product Characteristics, Labelling or Package Leaflet intended to implement the outcome of a Union referral procedure

C.I.2 Change(s) in the Summary of Product Characteristics, Labelling or Package Leaflet of a generic / hybrid / biosimilar medicinal products following assessment of the same change for the reference product

C.I.3 Change(s) in the Summary of Product Characteristics, Labelling or Package Leaflet of human medicinal products intended to implement the outcome of a procedure concerning PSUR or PASS, or the outcome of the assessment done by the competent authority under Articles 45 or 46 of Regulation 1901/2006

C.I.4 Change(s) in the Summary of Product Characteristics, Labelling or Package Leaflet due to new quality, preclinical, clinical or pharmacovigilance data.

C.I.5 Change in the legal status of a medicinal product for centrally authorised products

C.I.6 Change(s) to therapeutic indication(s)

C.I.7 Deletion of: a) a pharmaceutical form b) a strength

C.I.8 Introduction of, or changes to, a summary of pharmacovigilance system for medicinal products for human use

C.I.9 Change(s) to an existing pharmacovigilance system as described in the detailed description of the pharmacovigilance system (DDPS).

C.I.10 Change in the frequency and/or date of submission of periodic safety update reports (PSUR) for human medicinal products

C.I.11 Introduction of, or change(s) to, the obligations and conditions of a marketing authorisation, including the risk management plan

C.I.12 Inclusion or deletion of black symbol and explanatory statements for medicinal products in the list of medicinal products that are subject to additional monitoring

C.I.13 Other variations not specifically covered elsewhere in this Annex which involve the submission of studies to the competent authority

C.II VETERINARY MEDICINAL PRODUCT – SPECIFIC CHANGES

C.II.1 Variations concerning a change to or addition of a non-food producing target species.

C.II.2 Deletion of a food producing or non-food producing target species.

C.II.3 Changes to the withdrawal period for a veterinary medicinal product

C.II.4 Variations concerning the replacement or addition of a serotype, strain, antigen or combination of serotypes, strains or antigens for a veterinary vaccine against avian influenza, foot-and-mouth disease or bluetongue.

C.II.5 Variations concerning the replacement of a strain for a veterinary vaccine against equine influenza.

C.II.6 Changes to the labelling or the package leaflet which are not connected with the summary of product characteristics.

C.II.7 Introduction of a new Pharmacovigilance system

C.II.8 Change in the frequency and/or date of submission of periodic safety update reports (PSUR)

D. PMF / VAMF

D.1 Change in the name and/or address of the VAMF certificate holder

D.2 Change in the name and/or address of the PMF certificate holder

D.3 Change or transfer of the current PMF certificate holder to a new PMF certificate holder, i.e. different legal entity

D.4 Change in the name and/or address of a blood establishment including blood/plasma collection centres

D.5 Replacement or addition of a blood/plasma collection centre within a blood establishment already included in the PMF

D.6 Deletion or change of status (operational/non- operational) of establishment(s)/centre(s) used for blood/plasma collection or in the testing of donations and plasma pools

D.7 Addition of a new blood establishment for the collection of blood/plasma not included in the PMF

D.8 Replacement or addition of a blood centre for testing of donations and/or plasma pools within an establishment already included in the PMF

D.9 Addition of a new blood establishment for testing of donations and/or plasma pool not included in the PMF

D.10 Replacement or addition of a new blood establishment or centre(s) in which storage of plasma is carried out

D.11 Deletion of a blood establishment or centre(s) in which storage of plasma is carried out

D.12 Replacement or addition of an organisation involved in the transport of plasma.

D.13 Deletion of an organisation involved in the transport of plasma

D.14 Addition of a CE-marked test kit to test individual donations as a new test kit or as a replacement of an existing test kit

D.15 Addition of a non-CE marked test kit to test individual donations as a new test kit or as a replacement of an existing test kit

D.16 Change of kit/method used to test pools (antibody or antigen or NAT test).

D.17 Introduction or extension of inventory hold procedure.

D.18 Removal of inventory hold period or reduction in its length.

D.19 Replacement or addition of blood containers (e.g. bags, bottles)

D.20 Change in storage / transport

D.21 Introduction of test for viral markers when this introduction will have significant impact on the viral risk assessment.

D.22 Change in the plasma pool preparation (e.g. manufacturing method, pool size, storage of plasma pool samples)

D.23 Change in the steps that would be taken if it is found retrospectively that donation(s) should have been excluded from processing (“look-back” procedure).