Variations Guidelines

Guidelines on the details of the various categories of variations

ANNEX

E. ADMINISTRATIVE CHANGES

Q. QUALITY CHANGES

Q.I ACTIVE SUBSTANCE

Q.I.a) Manufacture

Q.I.b) Control of active substance

Q.I.c) Container closure system

Q.I.d) Stability

Q.I.e) Additional regulatory tools

Q.II. FINISHED PRODUCT

Q.II.a) Description and composition

Q.II.b) Manufacture

Q.II.c) Control of excipients

Q.II.d) Control of finished product

Q.II.e) Container closure system

Q.II.f) Stability

Q.II.g) Additional regulatory tools

Q.II.h) Adventitious Agents Safety

Q.III CEP/TSE/Monographs

Q.IV Medical devices

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

Q.V.a) PMF/VAMF

Q.V.b) Referral

C. SAFETY, EFFICACY, PHARMACOVIGILANCE CHANGES

M. PMF/VAMF

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Note: For quick navigation, use the browser search function (e.g. Ctrl+F) and enter the variation category without the full stop (e.g. Q.II.b.3 -> qiib3).

Valid Version — C/2025/5045 (effective 16.01.2026)

Previous version is available here: Variations Guidelines 2013/C 223/01

Q. QUALITY CHANGES – Q.I ACTIVE SUBSTANCE – Q.I.e) Additional regulatory tools

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

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

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

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

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

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

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

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

#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 substanceCondition to be fulfilledDocumentation to be suppliedProcedure type
(a) New design space for one or more unit operations in the manufacturing process of the active substance including the resulting in-process controls and/or analytical procedures 1, 2, 3II
(b) New design space for an analytical procedure for a starting material/reagent/intermediate and/or the active substance 1, 2, 3IB
(c) Changes to, or extension of, an approved design space for the active substance and/or an analytical procedure for a starting material/reagent/intermediate 1, 2, 3IB
Documentation
1. The design space has been developed in accordance with the relevant European and international scientific guidelines. Results from product, process and analytical development studies including risk assessment and multivariate studies or process modelling, as appropriate, demonstrating where relevant that a systematic understanding of how material attributes and process parameters impact the critical quality attributes of the active substance has been achieved.
2. Description of the design space in tabular format, and/or in the form of mathematical equation, as relevant, including the variables (material attributes and process parameters, as appropriate) with their proposed ranges and limits.
3. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).

#qie2

Q.I.e.2 Introduction of a post-approval change management protocol (PACMP) related to the active substanceCondition to be fulfilledDocumentation to be suppliedProcedure type
  1, 2, 3II
Documentation
1. Detailed description for the proposed change.
2. Post-approval change management protocol related to the active substance.
3. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).

#qie3

Q.I.e.3 Deletion of a post-approval change management protocol (PACMP) related to the active substanceCondition to be fulfilledDocumentation to be suppliedProcedure type
 11, 2IA
Conditions
1. The deletion of the post-approval change management protocol related to the active substance is not a result of unexpected events or out of specification results during the implementation of the change(s) described in the protocol and does not have any effect on the already approved information in the dossier.
Documentation
1. Justification for the proposed deletion.
2. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).

#qie4

Q.I.e.4 Changes to a post-approval change management protocol (PACMP)Condition to be fulfilledDocumentation to be suppliedProcedure type
(a) Major changes to a post-approval change management protocol  II
(b) Minor changes to a post-approval change management protocol that do not change the strategy defined in the protocol 1IB
Documentation
1. Declaration that the changes do not change the overall strategy defined in the protocol and are not broader than the currently approved protocol.

#qie5

Q.I.e.5 Implementation of changes foreseen in a post-approval change management protocol (PACMP)Condition to be fulfilledDocumentation to be suppliedProcedure type
(a) Implementation of changes foreseen in a PACMP via Type IA notification11, 2, 3IA
(b) Implementation of changes foreseen in a PACMP via Type IAIN notification21, 2, 3, 4IAIN
(c) Implementation of changes foreseen in a PACMP via Type IB notification 1, 2, 3, 4IB
Conditions
1. The proposed change has been performed fully in line with the post-approval change management protocol which requires its notification within 12 months following implementation.
2. The proposed change has been performed fully in line with the post-approval change management protocol, which requires its immediate notification following implementation.
Documentation
1. Reference to the post-approval change management protocol.
2. Declaration that the change is in accordance with the post-approval change management protocol and that the study results meet the acceptance criteria specified in the protocol (1)
3. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).
4. Results of the studies performed in accordance with the post-approval change management protocol.
(1) Note: Other changes to or with respect to an in-house reference standards/preparations, not covered by an approved protocol, should be classified in analogy to respective changes affecting the biological active substance/finished product.

#qie6

Q.I.e.6 Introduction of a product lifecycle management document (PLCM) related to the active substanceCondition to be fulfilledDocumentation to be suppliedProcedure type
  1, 2, 3II
Documentation
1. The content of the product lifecycle management document has been developed in accordance with the relevant European and international scientific guidelines. Results from product, process and analytical development studies (e.g. interaction of the different parameters, including risk assessment and multivariate studies, as appropriate) demonstrating where relevant that a systematic understanding of how material attributes and process parameters impact the critical quality attributes of the active substance has been achieved.
2. The product lifecycle management document includes a description of the material attributes, quality attributes and process parameters (or analytical procedure parameters), their proposed limits and ranges, and future variation reporting categories, in a tabular format.
3. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).

#qie7

Q.I.e.7 Changes related to the active substance in line with an approved product lifecycle management document (PLCM)Condition to be fulfilledDocumentation to be suppliedProcedure type
(a) Major change to the active substance in line with an approved PLCM 1, 2, 3II
(b) Minor change to the active substance in line with an approved PLCM11, 2, 3IA
(c) Minor change to the active substance in line with an approved PLCM21, 2, 3IAIN
(d) Minor change to the active substance in line with an approved PLCM 1, 2, 3IB
Conditions
1. The change has been foreseen in the product lifecycle management document as a Type IA variation requiring notification within 12 months following implementation.
2. The change has been foreseen in the product lifecycle management document as a Type IA variation requiring immediate notification following implementation.
Documentation
1. A summary and justification of the proposed change(s), clearly describing the present and proposed situation and supporting documentation.
2. An updated product lifecycle management document (PLCM) with relevant sections modified.
3. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).

#qie8

Q.I.e.8 Changes to an approved product lifecycle management document (PLCM) related to the active substanceCondition to be fulfilledDocumentation to be suppliedProcedure type
(a) Major changes to an approved PLCM  II
(b) Minor changes to an approved PLCM 1, 2, 3IB
Documentation
1. A summary and justification of the proposed change(s), clearly describing the present and proposed situation and supporting documentation.
2. An updated product lifecycle management document (PLCM) with relevant sections modified.
3. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).

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