Table of content:

Guidelines on the details of the various categories of variations

Annex

E. ADMINISTRATIVE CHANGES

e1

E.1 Change in the (invented) name of the finished product

e2

E.2 Change in name of the active substance, excipient, medical device (part), or packaging component

e3

E.3 Change in ATC Code

e4

E.4 Change in the name and/or address of the marketing authorisation holder, ASMF holder, storage site of the master and/or working cell bank, manufacturing site for an active substance, intermediate or finished product, primary and/or secondary packaging site, manufacturer responsible for batch release, site where quality control takes place, and/or supplier of a packaging component, medical device (part), starting material, reagent and/or excipient (when mentioned in the dossier)

e5

E.5 Deletion of manufacturing sites for an active substance, intermediate or finished product, storage of master and/or working cell bank, primary and/or secondary packaging site, manufacturer responsible for batch release, site where quality control takes place, and/or supplier of a packaging component, medical device (part), starting material, reagent and/or excipient (when mentioned in the dossier)

q

Q. QUALITY CHANGES

qi

Q.I ACTIVE SUBSTANCE

qia

Q.I.a) Manufacture

qia1

Q.I.a.1 Change in the manufacturing site of a starting material/intermediate used in the manufacturing process of the active substance or change in the manufacturing site (including where relevant quality control testing sites) of the active substance

qia2

Q.I.a.2 Change in the manufacturing process of the active substance, intermediate of an active substance or starting materials for biological active substance

qia3

Q.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

qia4

Q.I.a.4 Change to in-process controls applied during the manufacture of the active substance, intermediate of an active substance or starting materials for biological active substance

qia5

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

qia6

Q.I.a.6 Changes to the active substance of a vaccine against human coronavirus or other vaccine that has the potential to address a public health emergency in the Union

qib

Q.I.b) Control of active substance

qib1

Q.I.b.1 Change in the specification attribute and/or acceptance criteria of an active substance, starting material/reagent/intermediate used in the manufacturing process of the active substance

qib2

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

qib3

Q.I.b.3 Change to an in-house reference standard/preparation for a biological active substance

qiс

Q.I.c) Container closure system

qiс1

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

qiс2

Q.I.c.2 Change in the specification attribute and/or acceptance criteria of the immediate packaging of the active substance

qiс3

Q.I.c.3 Change in analytical procedure for the immediate packaging of the active substance

qiс4

Q.I.c.4 Change of a secondary packaging component of the active substance (including replacement, addition or deletion), when mentioned in the dossier

qid

Q.I.d) Stability

qid1

Q.I.d.1 Change in the re-test period/storage period or storage conditions of the active substance or intermediates used in the manufacturing process of the biological active substance

qie

Q.I.e) Additional regulatory tools

qie1

Q.I.e.1 Introduction of a new design space (method operable design range (MODR)) or extension of an approved design space for the active substance

qie2

Q.I.e.2 Introduction of a post-approval change management protocol (PACMP) related to the active substance

qie3

Q.I.e.3 Deletion of a post-approval change management protocol (PACMP) related to the active substance

qie4

Q.I.e.4 Changes to a post-approval change management protocol (PACMP)

qie5

Q.I.e.5 Implementation of changes foreseen in a post-approval change management protocol (PACMP)

qie6

Q.I.e.6 Introduction of a product lifecycle management document (PLCM) related to the active substance

qie7

Q.I.e.7 Changes related to the active substance in line with an approved product lifecycle management document (PLCM)

qie8

Q.I.e.8 Changes to an approved product lifecycle management document (PLCM) related to the active substance

qii

Q.II. FINISHED PRODUCT

qiia

Q.II.a) Description and composition

qiia1

Q.II.a.1 Change or addition of imprints, bossing (embossing/debossing) or other markings including replacement, or addition of inks used for product marking

qiia2

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

qiia3

Q.II.a.3 Change in the composition (excipients) of the finished product

qiia4

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

qiia5

Q.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

qiia6

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

qiib

Q.II.b) Manufacture

qiib1

Q.II.b.1 Change in the manufacturing site for part or all of the manufacturing process of the finished product (except for batch release and batch control testing sites)

qiib2

Q.II.b.2 Change to batch release arrangements and batch control testing of the finished product

qiib3

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

qiib4

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

qiib5

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

qiic

Q.II.c) Control of excipients

qiic1

Q.II.c.1 Change in the specification attribute and/or acceptance criteria of an excipient

qiic2

Q.II.c.2 Change in analytical procedure for an excipient

qiic3

Q.II.c.3 Change in source of an excipient or reagent with TSE risk, which is used in the manufacture of an active substance or in a finished product

qiic4

Q.II.c.4 Change in synthesis, manufacturing or recovery of an excipient (when described in the dossier)

qiid

Q.II.d) Control of finished product

qiid1

Q.II.d.1 Change in the specification attribute and/or acceptance criteria of the finished product

qiid2

Q.II.d.2 Change to analytical procedure for the finished product

qiid3

Q.II.d.3 Variations related to real-time release testing in the manufacture of the finished product

qiie

Q.II.e) Container closure system

qiie1

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

qiie2

Q.II.e.2 Change in shape or dimensions of the container or closure (immediate packaging) of the finished product

qiie3

Q.II.e.3 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)

qiie4

Q.II.e.4 Change in the specification attribute and/or acceptance criteria of the immediate packaging of the finished product

qiie5

Q.II.e.5 Change in analytical procedure for the immediate packaging of the finished product

qiie6

Q.II.e.6 Change in pack size of the finished product

qiie7

Q.II.e.7 Change in manufacturer, sterilisation process or supplier of packaging components (when mentioned in the dossier)

qiie8

Q.II.e.8 Change of a secondary packaging component of the finished product (including replacement or addition or deletion), when mentioned in the dossier

qiif

Q.II.f) Stability

qiif1

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

qiig

Q.II.g) Additional regulatory tools

qiig1

Q.II.g.1 Introduction of a new design space or extension of an approved design space for the finished product

qiig2

Q.II.g.2 Introduction of a post-approval change management protocol related to the finished product (PACMP)

qiig3

Q.II.g.3 Deletion of a post-approval change management protocol (PACMP) related to the finished product

qiig4

Q.II.g.4 Changes to a post-approval change management protocol (PACMP)

qiig5

Q.II.g.5 Implementation of changes foreseen in a post-approval change management protocol (PACMP)

qiig6

Q.II.g.6 Introduction of a product lifecycle management document (PLCM) related to the finished product

qiig7

Q.II.g.7 Changes related to the finished product in line with an approved product lifecycle management document (PCLM)

qiig8

Q.II.g.8 Changes to an approved an approved product lifecycle management document (PLCM) related to the finished product

qiih

Q.II.h) Adventitious Agents Safety

qiih1

Q.II.h.1 Update to the ‘Adventitious Agents Safety Evaluation’ information (Section 3.2.A.2)

qiii

Q.III CEP/TSE/MONOGRAPHS

qiii1

Q.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

qiii2

Q.III.2 Change to comply with Ph. Eur. or with a national pharmacopoeia of a Member State for active substances, reagents, intermediates, excipients, immediate packaging materials and active substance starting materials

qiv

Q.IV MEDICAL DEVICES

qiv1

Q.IV.1 Changes to a device co-packaged with the medicinal product or referenced in the product information

qiv2

Q.IV.2 Changes to an integral medical device (part)

qiv3

Q.IV.3 Changes to the dimensions, specification attributes and/or acceptance criteria or analytical procedures for an integral medical device (part)

qv

Q.V CHANGES TO A MARKETING AUTHORISATION RESULTING FROM OTHER REGULATORY PROCEDURES

qva

Q.V.a) PMF/VAMF

qva1

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

qva2

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

qvb

Q.V.b) Referral

qvb1

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

C. SAFETY, EFFICACY, PHARMACOVIGILANCE CHANGES

c1

C.1 Change(s) in the summary of product characteristics, labelling or package leaflet intended to implement the outcome of a Union referral procedure

c2

C.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

c3

C.3 Change(s) in the summary of product characteristics, labelling or package leaflet intended to implement the outcome of a procedure concerning PSUR or PASS, or the outcome of the assessment done by the competent authority under Article 45 or 46 of Regulation (EC) No 1901/2006, or the outcome of a PRAC signal recommendation, or to adapt to a joint recommendation of EU competent authorities (e.g. a Core SmPC, or following the assessment of an Urgent Safety Restriction etc.)

c4

C.4 Change(s) in the summary of product characteristics, labelling or package leaflet due to new quality, preclinical, clinical or pharmacovigilance data.

c5

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

c6

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

c7

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

c8

C.8 Introduction of a summary of pharmacovigilance system for medicinal products

c9

C.9 Introduction of, or change(s) to, the obligations and conditions of a marketing authorisation, including the risk management plan

c10

C.10 Inclusion or deletion of black symbol and explanatory statements for medicinal products in the list of medicinal products that are subject to additional monitoring

c11

C.11 Submission of results of assessments carried out on target patient groups in order to comply with Article 59(3) of Directive 2001/83/EC and any resulting change(s) to the package leaflet.

c12

C.12 Other variations not specifically covered elsewhere in this Annex which involve the submission of studies, including bioequivalence studies, to the competent authority

M. PMF/VAMF

m1

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

m2

M.2 Change or transfer of the current PMF certificate holder to a new PMF certificate holder, i.e. different legal entity

m3

M.3 Change in the name and/or address of a blood establishment and/or blood/plasma collection centres

m4

M.4 Addition or relocation of a blood/plasma collection centre within a blood establishment already included in the PMF

m5

M.5 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

m6

M.6 Addition of a new blood establishment for the collection of blood/plasma not included in the PMF

m7

M.7 Addition or relocation of a centre/laboratory for testing of donations and/or plasma pools within an establishment already included in the PMF

m8

M.8 Addition of a new laboratory for testing of donations and/or plasma pool not included in the PMF

m9

M.9 Changes of an establishment or centre(s) in which storage of plasma is carried out or organisation(s) involved in the transport of plasma

m10

M.10 Addition or replacement of blood and plasma tests

m11

M.11 Change of inventory hold procedure

m12

M.12 Addition or replacement of blood containers (e.g. bags, bottles)

m13

M.13 Change in storage/transport

m14

M.14 Introduction of test for a new viral marker when this will have significant impact on the viral risk assessment

m15

M.15 Change in the plasma pool preparation (e.g. manufacturing method, pool size, storage of plasma pool samples)

m16

M.16 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)