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.II. FINISHED PRODUCT – Q.II.e) Container closure system

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

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

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)

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

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

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

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

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

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Q.II.e.1 Change in immediate packaging of the finished productConditions to be fulfilledDocumentation to be suppliedProcedure type
(a) Change in qualitative and quantitative composition of an approved container   
1. Solid pharmaceutical forms1, 2, 3, 5, 61, 2, 3, 5IA
2. Semi-solid and non-sterile liquid pharmaceutical forms 1, 2, 4, 5IB
3. Sterile liquid finished products  II
4. The change relates to a less protective pack where there are associated changes in storage conditions and/or reduction in shelf life  II
(b) Change in type of container or addition of a new container   
1. Solid, semi-solid and non-sterile liquid pharmaceutical forms 1, 2, 4, 5IB
2. Sterile finished products  II
(c) Deletion of a container   
Deletion of an immediate packaging container that does not lead to the complete deletion of a strength or pharmaceutical form41, 6IA
Conditions
1. The change only concerns the same packaging/container type (e.g. blister to blister).
2. The proposed packaging material must be at least equivalent to the approved material in respect of its relevant properties.
3. Relevant stability studies have been started under ICH conditions and relevant stability parameters have been assessed in at least two pilot scale or industrial scale batches and at least three months satisfactory stability data are at the disposal of the applicant at time of implementation. However, if the proposed packaging is more resistant than the existing packaging e.g. thicker blister packaging, the three months’ stability data do not yet have to be available. These studies must be finalised and the data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
4. The remaining product presentation(s) must be adequate for the dosing instructions and treatment duration as mentioned in the summary of product characteristics.
5. The finished product is not a biological finished product.
6. The finished product is not sterile.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format), including revised product information, as appropriate.
2. Appropriate data on the new packaging (comparative data on permeability, e.g. for O2, CO2 moisture). Where appropriate, proof must be provided that no adverse interaction between the content and the packaging material occurs (e.g. data on migration of components of the proposed material into the content and loss of components of the product into the pack), including confirmation that the material complies with relevant pharmacopoeial requirements or legislation of the Union on plastic material and objects in contact with foodstuffs.
3. A declaration that the required stability studies have been started under ICH conditions (with indication of the batch numbers concerned) and that, as relevant, the required minimum satisfactory stability data were at the disposal of the applicant at time of implementation and that the available data did not indicate a problem. Assurance should also be given that the studies will be finalised and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
4. The results of stability studies that have been carried out under ICH conditions, on the relevant stability parameters, on at least two pilot or industrial scale batches, covering a minimum period of 3 months, and an assurance is given that these studies will be finalised, and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
5. Comparative table of the current and proposed immediate packaging specifications, if applicable.
6. Declaration that the remaining pack-size(s) is/are consistent with the dosage regimen and duration of treatment and adequate for the dosing instructions as approved in the summary of product characteristics.
Note: For Q.II.e.1.b) applicants are reminded that any change which results in a ‘new pharmaceutical form’ requires the submission of an Extension application.

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Q.II.e.2 Change in shape or dimensions of the container or closure (immediate packaging) of the finished productConditions to be fulfilledDocumentation to be suppliedProcedure type
(a) Non-sterile finished products1, 2, 31, 3IA
(b) Sterile finished products 1, 2, 3IB
Conditions
1. No change in the qualitative or quantitative composition of the container.
2. The change does not concern a fundamental part of the packaging material, which affects the delivery, use, safety or stability of the finished product.
3. In case of a change in the headspace or a change in the surface/volume ratio, stability studies in accordance with the relevant guidelines have been started and relevant stability parameters have been assessed in at least one pilot scale or industrial scale batches and at least three months stability data are at the disposal of the applicant. Assurance is given that these studies will be finalised and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format), including description, detailed drawing and composition of the container or closure material, and including revised product information as appropriate.
2. Re-validation studies have been performed in case of sterile products. The batch numbers of the batches used in the re-validation studies should be indicated, where applicable.
3. In case of a change in the headspace or a change in the surface/volume ratio, a declaration that the required stability studies have been started under ICH conditions (with indication of the batch numbers concerned) and that, as relevant, the required minimum satisfactory stability data (at least three months stability data for at least one pilot scale or industrial scale batches) were at the disposal of the applicant at time of implementation for a Type IA notification and time of submission of a Type IB notification, and that the available data did not indicate a problem. Assurance should also be given that the studies will be finalised and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).

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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)Conditions to be fulfilledDocumentation to be suppliedProcedure type
(a) Change that affects the product information11IAIN
(b) Change that does not affect the product information11IA
Conditions
1. The change does not concern a part of the packaging material, which affects the delivery, use, safety or stability of the finished product.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format), including revised product information as appropriate.

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Q.II.e.4 Change in the specification attribute and/or acceptance criteria of the immediate packaging of the finished productConditions to be fulfilledDocumentation to be suppliedProcedure type
(a) Change of specification acceptance criteria1, 2, 3, 41, 2IA
(b) Addition of a specification attribute to the specification with its corresponding analytical procedure1, 2, 51, 2, 3, 5IA
(c) Deletion of a non-significant or obsolete specification attribute1, 2, 61, 2, 4IA
(d) Replacement of a specification attribute with its corresponding analytical procedure 1, 2, 3IB
Conditions
1. The change is not a consequence of any commitment from previous documentation checks to review specification acceptance criteria (e.g. made during the procedure for the marketing authorisation application or a Type II variation procedure).
2. The change does not result from unexpected events arising during manufacture or because of stability concerns and is not as a result of a safety or quality issue.
3. Any change should be within the range of currently approved acceptance criteria.
4. The analytical procedure remains the same, or changes in the procedure are minor.
5. Any new analytical procedure does not concern a novel non-standard technique or a standard technique used in a novel way.
6. The change is not related to a revision of the control strategy with an intention to minimise testing of parameters and attributes (critical or non-critical).
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).
2. Comparative table of current and proposed specifications.
3. Details of any new analytical procedure and validation data, where relevant.
4. Justification/risk assessment showing that the parameter is non-significant or that it is obsolete.
5. Justification of the new specification attribute and the acceptance criteria.

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Q.II.e.5 Change in analytical procedure for the immediate packaging of the finished productConditions to be fulfilledDocumentation to be suppliedProcedure type
(a) Minor change to an approved analytical procedure1, 2, 31, 2IA
(b) Other changes to an analytical procedure (including replacement or addition)1, 31, 2IA
(c) Deletion of an analytical procedure if an alternative analytical procedure is already authorised41IA
Conditions
1. Appropriate validation studies have been performed in accordance with the relevant guidelines and show that the updated analytical procedure is at least equivalent to the former analytical procedure.
2. The method of analysis should remain the same (e.g. a change in column length or temperature, but not a different type of column or method).
3. Any new analytical procedure does not concern a novel non-standard technique or a standard technique used in a novel way.
4. An alternative analytical procedure is already authorised for the specification attribute.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format), including a description of the analytical methodology, a summary of validation data.
2. Comparative validation results or if justified comparative analysis results showing that the current analytical procedure and the proposed one are equivalent. This requirement is not applicable in case of an addition of a new analytical procedure.

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Q.II.e.6 Change in pack size of the finished productConditions to be fulfilledDocumentation to be suppliedProcedure type
(a) Introduction of a new pack size or change in the number of units (e.g. tablets, ampoules, etc.) in a pack   
1. Change within the range of the currently approved pack sizes1, 21, 3IAIN
2. Change outside the range of the currently approved pack sizes 1, 2, 3IB
(b) Deletion of pack size(s)31, 2IA
(c) Change in the fill weight/fill volume of sterile multidose (or single-dose, partial use) parenteral finished products  II
(d) Change in the fill weight/fill volume of non-parenteral multi-dose (or single-dose, partial use) products 1, 2, 3IB
(e) Addition of or change to a calendar package for a pack size already registered in the dossier21IAIN
Conditions
1. New pack size should be consistent with the posology and treatment duration as approved in the summary of product characteristics.
2. The immediate packaging material remains the same.
3. The remaining product presentation(s) must be adequate for the dosing instructions and treatment duration as mentioned in the summary of product characteristics.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format) including revised product information as appropriate.
2. Justification for the new/remaining pack-size, showing that the new/remaining size is/are consistent with the dosage regimen and duration of treatment as approved in the summary of product characteristics.
3. Declaration that stability studies will be conducted in accordance with the relevant guidelines for products where stability parameters could be affected. Data to be reported only if outside specifications (with proposed action).
Note: For Q.II.e.6.c) and d), applicants are reminded that any changes to the ‘strength’ of the finished product require the submission of an Extension application.

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Q.II.e.7 Change in manufacturer, sterilisation process or supplier of packaging components (when mentioned in the dossier)Conditions to be fulfilledDocumentation to be suppliedProcedure type
(a) Addition or replacement of a manufacturer or supplier1, 2, 3, 41, 2IA
(b) Addition or replacement of a site responsible for sterilisation of a packaging component, and/or a change to the sterilisation process 3, 4IB
Conditions
1. No deletion of packaging component.
2. The qualitative and quantitative composition of the packaging components and design specifications remain the same.
3. The specifications and quality control analytical procedure are at least equivalent.
4. The sterilisation method and conditions remain the same, if applicable.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).
2. Comparative table of current and proposed specifications, if applicable.
3. Description of the sterilisation method and sterilisation cycle. Validation of the sterilisation cycle should be provided if the sterilisation cycle does not use the reference conditions stated in the Ph. Eur.
4. Evidence that the sterilisation has been conducted and validated in accordance with GMP and/or relevant ISO standards, as per guideline on the sterilisation of the medicinal product, active substance, excipient and primary container.

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Q.II.e.8 Change of a secondary packaging component of the finished product (including replacement or addition or deletion), when mentioned in the dossierConditions to be fulfilledDocumentation to be suppliedProcedure type
 1, 2, 3, 41IA
Conditions
1. The secondary packaging does not play a functional role on the stability of the finished product, or if it does, it is not less protective than the approved one.
2. The changed packaging component must be adequate for the storage of the finished product at the authorised conditions.
3. The change should not be due to critical deficiencies of the former packaging component.
4. The change is not a result of any unexpected events arising during manufacture or storage of the finished product.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).

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