# L_2021007EN.01002201.xml

| 11.1.2021 | EN | Official Journal of the European Union | L 7/22 |
| --- | --- | --- | --- |

11.1.2021

EN

Official Journal of the European Union

L 7/22

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COMMISSION IMPLEMENTING REGULATION (EU) 2021/17

of 8 January 2021

establishing a list of variations not requiring assessment in accordance with Regulation (EU) 2019/6 of the European Parliament and of the Council

(Text with EEA relevance)

THE EUROPEAN COMMISSION,

Having regard to the Treaty on the Functioning of the European Union,

Having regard to Regulation (EU) 2019/6 of the European Parliament and of the Council of 11 December 2018 on veterinary medicinal products and repealing Directive 2001/82/EC (1), and in particular Article 60(1) thereof,

Whereas:

| (1) | The Commission is required under Regulation (EU) 2019/6 to establish a list of changes to the terms of the marketing authorisation, so called variations, that do not require assessment in order to be implemented. When doing so, the Commission is to take account of the criteria listed in Article 60(2) thereof. |
| --- | --- |

(1)

The Commission is required under Regulation (EU) 2019/6 to establish a list of changes to the terms of the marketing authorisation, so called variations, that do not require assessment in order to be implemented. When doing so, the Commission is to take account of the criteria listed in Article 60(2) thereof.

| (2) | The European Medicines Agency, established by Regulation (EC) No 726/2004, provided advice on a list of variations not requiring assessment to the Commission on 30 August 2019, based on the current framework and classifying most minor variations as having no impact on the quality, safety or efficacy of the veterinary medicinal product. The Commission took into account the advice, the criteria listed in Article 60(2), as well as all necessary conditions and most current documentation requirements to ensure that the variations not requiring assessment do not present a risk to public health, animal health or the environment. |
| --- | --- |

(2)

The European Medicines Agency, established by Regulation (EC) No 726/2004, provided advice on a list of variations not requiring assessment to the Commission on 30 August 2019, based on the current framework and classifying most minor variations as having no impact on the quality, safety or efficacy of the veterinary medicinal product. The Commission took into account the advice, the criteria listed in Article 60(2), as well as all necessary conditions and most current documentation requirements to ensure that the variations not requiring assessment do not present a risk to public health, animal health or the environment.

| (3) | In order for certain variations to be classified as not requiring assessment, different requirements need to be fulfilled. It is therefore necessary to list these requirements, including conditions and documentation to be provided by the marketing authorisation holder, to keep the product dossier updated. Fulfilment of the requirements will form a basis for rejection or approval of the variation. |
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(3)

In order for certain variations to be classified as not requiring assessment, different requirements need to be fulfilled. It is therefore necessary to list these requirements, including conditions and documentation to be provided by the marketing authorisation holder, to keep the product dossier updated. Fulfilment of the requirements will form a basis for rejection or approval of the variation.

| (4) | As regards variations recorded in the Union product database by the marketing authorisation holder, the competent authority of the Member State or the Commission, as applicable, should record the information whether this is tacitly approved or rejected within the applicable administrative deadline. |
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(4)

As regards variations recorded in the Union product database by the marketing authorisation holder, the competent authority of the Member State or the Commission, as applicable, should record the information whether this is tacitly approved or rejected within the applicable administrative deadline.

| (5) | The measures provided for in this Regulation are in accordance with the opinion of the Standing Committee on Veterinary Medicinal Products, |
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(5)

The measures provided for in this Regulation are in accordance with the opinion of the Standing Committee on Veterinary Medicinal Products,

HAS ADOPTED THIS REGULATION:

Article 1

Variations listed in the Annex, which satisfy the requirements applicable to them as set out therein, shall not require assessment.

Article 2

This Regulation shall enter into force on the twentieth day following that of its publication in the Official Journal of the European Union.

It shall apply from 28 January 2022.

This Regulation shall be binding in its entirety and directly applicable in all Member States.

Done at Brussels, 8 January 2021.

For the Commission

The President

Ursula VON DER LEYEN

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(1)  
  OJ L 4, 7.1.2019, p. 43.

1

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ANNEX

Variations not requiring assessment

| | Variation | Requirements

  The requirements indicated in the line for the main section are valid for each sub-section of the given section. Any additional requirement specified in the sub-section should be read together with the requirements indicated in the main section. |
| --- | --- | --- |
| Number | | Conditions | Documents to be provided |
| A | Administrative changes | | |
| 1 | Change in the name or address or contact details of: | | |
| a) | — | the marketing authorisation holder |

Variation

Requirements

The requirements indicated in the line for the main section are valid for each sub-section of the given section. Any additional requirement specified in the sub-section should be read together with the requirements indicated in the main section.

Number

Conditions

Documents to be provided

A

Administrative changes

1

Change in the name or address or contact details of:

a)

—

the marketing authorisation holder

The marketing authorisation holder shall remain the same legal entity.

b)

| — | a manufacturer or supplier of the active substance, starting material, reagent or intermediate used in the manufacture of the active substance or a quality control testing site (where specified in the dossier) where no European Pharmacopoeia (Ph. Eur.) Certificate of Suitability (CEP) is part of the approved dossier. |
| --- | --- |

—

a manufacturer or supplier of the active substance, starting material, reagent or intermediate used in the manufacture of the active substance or a quality control testing site (where specified in the dossier) where no European Pharmacopoeia (Ph. Eur.) Certificate of Suitability (CEP) is part of the approved dossier.

The manufacturing or quality control site and all manufacturing operations shall remain the same.

The manufacturer or supplier shall already be incorporated in the Union IT systems storing and providing organisational data.

c)

| — | an active substance master file (ASMF) holder |
| --- | --- |

—

an active substance master file (ASMF) holder

The manufacturing site and all manufacturing operations shall remain the same.

The ASMF holder shall already be incorporated in the Union IT systems storing and providing organisational data.

Updated ‘letter of access’ to the Active Substance Master File.

d)

| — | a manufacturer of an excipient (where specified in the dossier) |
| --- | --- |

—

a manufacturer of an excipient (where specified in the dossier)

The manufacturing site and all manufacturing operations shall remain the same.

The manufacturer shall already be incorporated in the Union IT systems storing and providing organisational data.

e)

| — | a manufacturer or importer of the finished product (including batch release or quality control testing sites) |
| --- | --- |

—

a manufacturer or importer of the finished product (including batch release or quality control testing sites)

The manufacturing site and all manufacturing operations shall remain the same.

The manufacturer or importer shall already be incorporated in the Union IT systems storing and providing organisational data.

2

Change in the (invented) name of the veterinary medicinal product

The acceptability review of the new name by the Agency or the national competent authority, as applicable, shall be finalised and is positive.

3

Change in name of the active substance or of an excipient

The substance shall remain the same.

For veterinary medicinal products for food-producing species, the entry in Regulation (EC) No°470/2009 for this substance shall be amended before implementation of this change.

4

Change in ATCvet Code

The change shall only be introduced following alteration to the index of the ATCvet Code.

B

Changes to the quality part of the dossier

1

Change in the name or address or contact details of a supplier of a packaging component or of a device of the finished product (where mentioned in the dossier)

The supplier shall already be incorporated in the Union IT systems storing and providing organisational data.

The manufacturing site shall remain the same.

2

Change in the nomenclature (1) of the material for immediate packaging of the finished product

The change shall only be introduced following amendment to the name of the container in the standard terms database on the European Directorate for the Quality of Medicines and HealthCare (EDQM) website.

3

Deletion of:

Amendment of the relevant section(s) of the dossier.

a)

| — | a manufacturing site 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 for an active substance, reagent or excipient (when mentioned in the dossier) |
| --- | --- |

—

a manufacturing site 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 for an active substance, reagent or excipient (when mentioned in the dossier)

The deletion shall not be due to critical deficiencies concerning manufacturing.

There shall at least remain one site or manufacturer, as previously authorised, performing the same function as the one(s) concerned by the deletion.

There shall at least remain one site or manufacturer responsible for batch release within the European Union or the European Economic Area.

b)

| — | a manufacturing process for the active substance or the finished product, including an intermediate used in the manufacture of the finished product when an alternative is already approved |
| --- | --- |

—

a manufacturing process for the active substance or the finished product, including an intermediate used in the manufacture of the finished product when an alternative is already approved

The finished product, active substance, intermediates or in-process materials used in the manufacture of the finished product shall still conform to the approved specifications.

The deletion shall not be due to critical deficiencies concerning manufacturing.

c)

| — | a non-significant in-process test during the manufacture of the active substance (e.g. deletion of an obsolete in-process test) |
| --- | --- |

—

a non-significant in-process test during the manufacture of the active substance (e.g. deletion of an obsolete in-process test)

The change shall not relate to a commitment or to an unexpected event during manufacture.

The change shall not concern a critical in-process test and shall not have the potential to affect the identity, quality, purity, potency or physical characteristics of the active substance, starting material, intermediate or reagent used in the manufacturing process of the active substance.

Comparative table of former and new in-process test.

d)

| — | a non-significant specification parameter (e.g. deletion of an obsolete parameter) of






  — | an active substance; |
| --- | --- | --- |

—

a non-significant specification parameter (e.g. deletion of an obsolete parameter) of

—

an active substance;

| — | a starting material; |
| --- | --- |

—

a starting material;

| — | an intermediate or reagent used in the manufacturing process of the active substance |
| --- | --- |

—

an intermediate or reagent used in the manufacturing process of the active substance

The change shall not relate to a commitment or to an unexpected event during manufacture.

The change shall not concern a critical specification parameter or have the potential to affect the identity, quality, purity, potency or physical characteristics of the active substance, starting material, intermediate or reagent used in the manufacturing process of the active substance.

Comparative table of former and new specifications.

e)

| — | a test procedure






  — | for the active substance or a starting material, reagent or intermediate of the active substance; |
| --- | --- | --- |

—

a test procedure

—

for the active substance or a starting material, reagent or intermediate of the active substance;

| — | for the immediate packaging of the active substance; |
| --- | --- |

—

for the immediate packaging of the active substance;

| — | for an excipient or the finished product; |
| --- | --- |

—

for an excipient or the finished product;

| — | for the immediate packaging of the finished product |
| --- | --- |

—

for the immediate packaging of the finished product

An alternative test procedure shall already be authorised by the national competent authority or the Agency and this test procedure has not been added through a variation procedure according to Article 61 of Regulation (EU) 2019/6.

f)

| — | one of the authorised bulk or final containers (including packaging of an active substance) or immediate packaging of the finished product that does not lead to the complete deletion of a strength or pharmaceutical form |
| --- | --- |

—

one of the authorised bulk or final containers (including packaging of an active substance) or immediate packaging of the finished product that does not lead to the complete deletion of a strength or pharmaceutical form

Where applicable, the remaining product presentations shall be adequate for the dosing instructions and treatment duration as defined in the summary of product characteristics.

g)

| — | a non-significant specification parameter (e.g. deletion of an obsolete parameter) in the specification parameters or limits of the immediate packaging of the active substance or the finished product |
| --- | --- |

—

a non-significant specification parameter (e.g. deletion of an obsolete parameter) in the specification parameters or limits of the immediate packaging of the active substance or the finished product

The change shall not relate to a commitment or to an unexpected event during manufacture of the immediate packaging material and storage of the active substance or the finished product.

The change shall not concern a critical parameter or have the potential to affect the identity or quality of the immediate packaging.

Comparative table of former and new specifications.

h)

| — | an approved change management protocol related to the active substance or the finished product |
| --- | --- |

—

an approved change management protocol related to the active substance or the finished product

The change shall not be the result of an unexpected event or an out of specification result during the implementation of the change(s) described in the protocol.

i)

| — | a component or components of the flavouring or colouring system |
| --- | --- |

—

a component or components of the flavouring or colouring system

The change shall not be applicable to a biological or immunological medicinal product.

The change shall not have the potential to affect the identity, strength, quality, purity, potency, safety or effectiveness of the finished product.

j)

| — | a solvent or diluent container from the pack |
| --- | --- |

—

a solvent or diluent container from the pack

The pharmaceutical form shall remain unchanged. There shall be appropriate alternative means to obtain the solvent or diluent as required for the safe and effective use.

k)

| — | a non-significant in-process test (e.g. deletion of an obsolete test) during the manufacture of the finished product |
| --- | --- |

—

a non-significant in-process test (e.g. deletion of an obsolete test) during the manufacture of the finished product

The change shall not relate to a commitment or to an unexpected event during manufacture.

The change shall not concern a critical parameter or have the potential to affect the identity, quality, purity, potency or physical characteristics of the finished product or starting material, intermediate or reagent used in the manufacturing process of the finished product.

Comparative table of former and new in-process tests and limits.

l)

| — | details on testing frequency by the finished product manufacturer of an excipient or an active substance or of packaging material for the immediate packaging of an active substance or the finished product, when mentioned in the dossier |
| --- | --- |

—

details on testing frequency by the finished product manufacturer of an excipient or an active substance or of packaging material for the immediate packaging of an active substance or the finished product, when mentioned in the dossier

m)

| — | a non-significant specification parameter (e.g. deletion of an obsolete parameter) in the specification parameters or limits of an excipient |
| --- | --- |

—

a non-significant specification parameter (e.g. deletion of an obsolete parameter) in the specification parameters or limits of an excipient

The change shall not relate to a commitment or to an unexpected event during manufacture.

The change shall not concern a critical parameter or have the potential to affect the identity, quality, purity, potency or physical characteristics of the excipient.

Comparative table of former and new specification parameters or limits.

n)

| — | a non-significant specification parameter (e.g. deletion of an obsolete parameter such as odour and taste or identification test for a colouring or flavouring material) in the specification parameters or limits of the finished product |
| --- | --- |

—

a non-significant specification parameter (e.g. deletion of an obsolete parameter such as odour and taste or identification test for a colouring or flavouring material) in the specification parameters or limits of the finished product

The change shall not relate to a commitment or to an unexpected event during manufacture.

The change shall not concern a critical parameter or have the potential to affect the identity, strength, quality, purity, potency or physical characteristics of the finished product.

Comparative table of former and new specification parameters or limits.

o)

| — | a measuring or administration device |
| --- | --- |

—

a measuring or administration device

The change shall not affect the delivery, use or safety of the finished product.

p)

| — | a non-significant specification parameter (e.g. deletion of an obsolete parameter) of a measuring or administration device |
| --- | --- |

—

a non-significant specification parameter (e.g. deletion of an obsolete parameter) of a measuring or administration device

The change shall not relate to a commitment or to an unexpected event during manufacture. The change shall not concern a critical parameter or have the potential to affect the identity or quality of the measuring or administration device.

Comparative table of former and new specifications.

q)

| — | a test procedure of a measuring or administration device |
| --- | --- |

—

a test procedure of a measuring or administration device

An alternative test procedure shall already be authorised by the national competent authority or the Agency.

r)

| — | pack size(s) of the finished product |
| --- | --- |

—

pack size(s) of the finished product

The remaining pack-sizes shall be consistent with the posology and treatment duration as approved in the summary of product characteristics.

s)

| — | a supplier of packaging components or devices (when mentioned in the dossier) |
| --- | --- |

—

a supplier of packaging components or devices (when mentioned in the dossier)

The change shall not include the deletion of a packaging component(s) or a device(s).

t)

| — | a Ph. Eur. CEP






  — | for an active substance; |
| --- | --- | --- |

—

a Ph. Eur. CEP

—

for an active substance;

| — | for a starting material, reagent or intermediate used in the manufacturing process of the active substance; |
| --- | --- |

—

for a starting material, reagent or intermediate used in the manufacturing process of the active substance;

| — | for an excipient |
| --- | --- |

—

for an excipient

At least one manufacturer for the same substance shall remain in the dossier.

u)

| — | a Ph. Eur. Transmissible Spongiform Encephalopathy (TSE) CEP






  — | for an active substance; |
| --- | --- | --- |

—

a Ph. Eur. Transmissible Spongiform Encephalopathy (TSE) CEP

—

for an active substance;

| — | for a starting material, reagent or intermediate of an active substance; |
| --- | --- |

—

for a starting material, reagent or intermediate of an active substance;

| — | for an excipient |
| --- | --- |

—

for an excipient

At least one manufacturer for the same substance shall remain in the dossier.

v)

| — | a pharmaceutical form or strength (2) |
| --- | --- |

—

a pharmaceutical form or strength (2)

Remaining form(s) or strength(s) shall be suitable to allow accurate dosing of the product and treatment duration without the use of multiple presentations (e.g. several pipettes or tablets) or the use of unapproved divided doses (e.g. half tablets that are not already authorised).

4

Changes to the production process or the storage of active substance where no Ph. Eur. CEP is part of the approved dossier of an active substance (including starting material, reagent or intermediate)

For starting materials and reagents the specifications (including in-process controls, methods of analysis of all materials), shall be identical to those already approved. For intermediates and active substance(s) the specifications (including in process controls, methods of analysis of all materials), method of preparation (including batch size) and detailed route of synthesis shall be identical to those already approved.

a)

| — | change in the manufacturer of the active substance (including relevant quality control testing sites) |
| --- | --- |

—

change in the manufacturer of the active substance (including relevant quality control testing sites)

The change shall not be applicable to a sterile active substance or a biological or immunological substance.

The change shall not be applicable to a herbal substance or a herbal preparation in a herbal medicinal product.

The new manufacturer shall be part of the same pharmaceutical group as the currently approved manufacturer and already be incorporated in the Union IT-systems storing and providing organisational data.

The change shall not have the potential to affect the identity, quality, purity, potency or physical characteristics of the active substance, starting material, intermediate or reagent used in the manufacturing process of the active substance.

The Amendment of the relevant section(s) of the dossier shall be provided, as appropriate, for:

| — | TSE data, |
| --- | --- |

—

TSE data,

| — | batch data, |
| --- | --- |

—

batch data,

| — | qualified person (QP) declaration and |
| --- | --- |

—

qualified person (QP) declaration and

| — | confirmation of GMP compliance. |
| --- | --- |

—

confirmation of GMP compliance.

b)

| — | changes to quality control testing arrangements for the active substance: replacement or addition of a site where batch control or testing of the active substance takes place |
| --- | --- |

—

changes to quality control testing arrangements for the active substance: replacement or addition of a site where batch control or testing of the active substance takes place

The change shall not be applicable to a sterile active substance or a biological or immunological substance.

The new manufacturer or site shall already be incorporated in the Union IT-system storing and providing organisational data.

Method transfer from the former to the new site shall have been successfully completed.

c)

| — | introduction of a new site of micronisation for the manufacturer of the active substance (including relevant quality control testing sites) |
| --- | --- |

—

introduction of a new site of micronisation for the manufacturer of the active substance (including relevant quality control testing sites)

The change shall not be applicable to a sterile active substance or a biological or immunological substance.

The new manufacturer or site shall already be incorporated in the Union IT-systems storing and providing organisational data.

The change shall not provoke an adverse change in physico-chemical properties.

The particle size specification for the active substance and the corresponding analytical method shall remain the same.

Amendment of the relevant section(s) of the dossier for QP declaration and comparative batch data from the former and new site, as appropriate.

d)

| — | new storage site of Master Cell Bank or Working Cell Banks for the manufacturer of a starting material, reagent or intermediate used in the manufacturing process of the active substance or the active substance itself |
| --- | --- |

—

new storage site of Master Cell Bank or Working Cell Banks for the manufacturer of a starting material, reagent or intermediate used in the manufacturing process of the active substance or the active substance itself

No change shall be made to the storage conditions, the shelf-life and the specifications.

The new manufacturer or site shall already be incorporated in the Union IT-systems storing and providing organisational data.

5

Reduction of re-test period or storage period where no Ph. Eur. CEP covering the retest period is part of the approved dossier

The change shall not be the result of unexpected events arising during manufacture or because of stability concerns.

Amendment of the relevant section(s) of the dossier including specifications and stability confirmation, as appropriate.

6

Change to more restrictive storage conditions:

The change shall not be the result of unexpected events arising during manufacture or because of stability concerns.

Amendment of the relevant section(s) of the dossier including specifications and stability confirmation, as appropriate.

a)

| — | of the reference standard (when mentioned in the dossier) |
| --- | --- |

—

of the reference standard (when mentioned in the dossier)

b)

| — | of the active substance |
| --- | --- |

—

of the active substance

7

Change to an approved stability protocol of an active substance (including starting material, reagent or intermediate)

The change shall not be the result of unexpected events arising during manufacture or because of stability concerns.

The change shall not have the potential to affect the identity, strength, quality, purity, potency or physical characteristics of the active substance.

Amendment of the relevant section(s) of the dossier including results of appropriate real time stability studies.

8

Implementation of changes foreseen in an approved change management protocol (CMP) for the active substance

The change shall be in accordance with the approved CMP and the results of studies performed indicate that the predefined acceptance criteria specified in the protocol are met.

The implementation of the change shall require no further supportive data to the CMP.

Amendment of the relevant section(s) of the dossier.

9

Change in batch size (including batch size ranges) of active substance or intermediate used in the manufacturing process of the active substance

The change shall not be applicable to a sterile active substance or a biological or immunological substance.

The change shall not adversely affect the reproducibility of the process.

The change shall not be the result of unexpected events arising during manufacture or because of stability concerns.

Changes to the manufacturing methods shall only be those necessitated by scale-up or downscaling, e.g. use of different-sized equipment. The batches tested shall have the proposed batch size.

Amendment of the relevant section(s) of the dossier including batch data, as appropriate.

a)

| — | up to 10-fold increase compared to the originally approved batch size |
| --- | --- |

—

up to 10-fold increase compared to the originally approved batch size

The active substance and all intermediates, reagents, catalysts or solvents shall still conform to the approved specifications.

b)

| — | downscaling down to 10-fold |
| --- | --- |

—

downscaling down to 10-fold

c)

| — | more than 10-fold increase compared to the originally approved batch size |
| --- | --- |

—

more than 10-fold increase compared to the originally approved batch size

The intermediates, reagents, catalysts or solvents used in the process shall remain the same.

The active substance and all intermediates, reagents, catalysts or solvents shall still conform to the approved specifications.

The change shall not provoke an adverse change in qualitative and quantitative impurity profile, potency or in physico-chemical properties of the active substance.

The change shall not refer to the restricted part of an ASMF.

10

Change to in-process tests or limits applied during the manufacture of the active substance

The change shall not be a consequence of any commitment from previous assessments to review specification limits.

The change shall not result from unexpected events arising during manufacture e.g. new unqualified impurity; change in total impurity limits.

Amendment of the relevant section(s) of the dossier for the new test method, validation and batch data, as appropriate.

Comparative table of former and new in-process tests and limits.

a)

| — | tightening of in-process limits |
| --- | --- |

—

tightening of in-process limits

The change shall be within the range of currently approved limits. The test procedure shall remain the same, or changes in the test procedure shall be minor.

b)

| — | addition of a new in-process test and limits |
| --- | --- |

—

addition of a new in-process test and limits

Any new test method shall not concern a novel non-standard technique or a standard technique used in a novel way.

The new test method shall not be a biological, immunological or immunochemical method, or a method using a biological reagent for a biological active substance, except if this method is a standard pharmacopoeial microbiological method.

11

Change in the specification parameters or limits of an active substance, starting material, intermediate or reagent used in the manufacturing process of the active substance or of the immediate packaging of the active substance

The change shall not result from unexpected events arising during manufacture (e.g. new unqualified impurity or change in total impurity limits).

The change shall not be a consequence of any commitment from previous assessments to review specification limits (e.g. made during the procedure for the marketing authorisation application or a variation procedure according to Article 62 of Regulation (EU) 2019/6) unless it has been previously assessed and agreed as part of a follow-up measure in a previous procedure under Regulation (EU) 2019/6.

Amendment of the relevant section(s) of the dossier.

Comparative table of former and new specification parameters and limits.

a)

| — | tightening of specification limits for veterinary medicinal products subject to Official Control Authority Batch Release (OCABR) |
| --- | --- |

—

tightening of specification limits for veterinary medicinal products subject to Official Control Authority Batch Release (OCABR)

The test procedure shall remain the same, or changes in the test procedure shall be minor.

The change shall be within the range of currently approved limits.

b)

| — | tightening of specification limits of an active substance, starting material, intermediate or reagent used in the manufacturing process of the active substance |
| --- | --- |

—

tightening of specification limits of an active substance, starting material, intermediate or reagent used in the manufacturing process of the active substance

The test procedure shall remain the same, or changes in the test procedure shall be minor.

The change shall be within the range of currently approved limits.

c)

| — | tightening of specification limits of the immediate packaging of the active substance |
| --- | --- |

—

tightening of specification limits of the immediate packaging of the active substance

The test procedure shall remain the same, or changes in the test procedure shall be minor.

d)

| — | addition of a new specification parameter to the specification with its corresponding test method |
| --- | --- |

—

addition of a new specification parameter to the specification with its corresponding test method

The new test method shall not concern a novel non-standard technique or a standard technique used in a novel way.

The new test method shall not be a biological, immunological or immunochemical method, or a method using a biological reagent for a biological active substance, except if this method is a standard pharmacopoeial microbiological method.

The change shall not concern a genotoxic impurity.

Amendment of the relevant section(s) of the dossier for the new method and validation, and batch data, as appropriate.

12

Minor changes:

a)

| — | to an approved test procedure






  — | for active substance; |
| --- | --- | --- |

—

to an approved test procedure

—

for active substance;

| — | for the finished product; |
| --- | --- |

—

for the finished product;

| — | for the immediate packaging of the active substance or the finished product; |
| --- | --- |

—

for the immediate packaging of the active substance or the finished product;

| — | of a measuring or administration device |
| --- | --- |

—

of a measuring or administration device

The test method shall not be a biological, immunological or immunochemical method, or a method using a biological reagent for a biological active substance.

Appropriate validation studies shall have been performed in accordance with the relevant guidelines and show that the updated test procedure is at least equivalent to the former test procedure.

There shall be no changes of the total impurity limits; no new unqualified impurities shall be detected.

The method of analysis shall remain the same (e.g. a change in column length or temperature, but not a different type of column or method).

Amendment of the relevant section(s) of the dossier and comparative validation data, as appropriate.

b)

| — | to an approved test procedure |
| --- | --- |

—

to an approved test procedure

| — | for a starting material, reagent or intermediate used in the manufacturing process of the active substance; |
| --- | --- |

—

for a starting material, reagent or intermediate used in the manufacturing process of the active substance;

| — | for an excipient |
| --- | --- |

—

for an excipient

The test method shall not be a biological, immunological or immunochemical method, or a method using a biological reagent for a biological active substance.

Appropriate validation studies shall have been performed in accordance with the relevant guidelines and show that the updated test procedure is at least equivalent to the former test procedure.

There shall be no changes of the total impurity limits; no new unqualified impurities shall be detected.

The method of analysis shall remain the same (e.g. a change in column length or temperature, but not a different type of column or method).

Amendment of the relevant section(s) of the dossier and comparative data, as appropriate.

c)

| — | to an approved test procedure for an in-process test |
| --- | --- |

—

to an approved test procedure for an in-process test

| — | for active substance; |
| --- | --- |

—

for active substance;

| — | for the finished product |
| --- | --- |

—

for the finished product

The test method shall not be a biological, immunological or immunochemical method, or a method using a biological reagent for a biological active substance.

Appropriate validation studies shall have been performed in accordance with the relevant guidelines and show that the updated test procedure is at least equivalent to the former test procedure.

There shall be no changes of the total impurity limits; no new unqualified impurities shall be detected.

The method of analysis shall remain the same (e.g. a change in column length or temperature, but not a different type of column or method).

Amendment of the relevant section(s) of the dossier.

d)

| — | in the manufacturing process of an active substance |
| --- | --- |

—

in the manufacturing process of an active substance

The change shall not be applicable to a biological or immunological active substance.

The change shall not be a change in the geographical source, manufacturing route or production for a herbal medicinal substance.

The change shall relate only to an immediate release solid oral dosage form or oral solution and shall not provoke an adverse change in qualitative and quantitative impurity profile or in physico-chemical properties.

The active substance and all intermediates, reagents, catalysts or solvents shall still conform to the approved specifications. The change shall not refer to the restricted part of an ASMF. The manufacturing steps shall remain the same.

Amendment of the relevant section(s) of the dossier.

e)

| — | in synthesis or recovery of a non-pharmacopoeial excipient (when described in the dossier) or a novel excipient |
| --- | --- |

—

in synthesis or recovery of a non-pharmacopoeial excipient (when described in the dossier) or a novel excipient

The excipients and all intermediates, reagents, catalysts, solvents or in-process controls shall still conform to the approved specifications (e.g. qualitative and quantitative impurity profile). Adjuvants and preservatives shall be excluded from the scope of this entry.

Synthetic routes and specifications shall be identical, and there shall be no change in physico-chemical properties.

Amendment of the relevant section(s) of the dossier for batch data, comparative data, and specification, as appropriate.

f)

| — | to an in-process limit range for the finished product |
| --- | --- |

—

to an in-process limit range for the finished product

The change shall not be the result of unexpected events arising during manufacture or because of stability concerns.

The change shall concern an in-process test, which is also part of the finished product specification at release, and the new in-process limit range shall be within the approved release limit.

Amendment of the relevant section(s) of the dossier.

Comparative table of former and new in-process limits.

g)

| — | to an approved change management protocol of the active substance that does not change the strategy defined in the protocol |
| --- | --- |

—

to an approved change management protocol of the active substance that does not change the strategy defined in the protocol

The intermediates, reagents, catalysts or solvents used in the process shall remain the same. The active substance and all intermediates, reagents, catalysts or solvents shall still conform to the approved specifications. There shall be no adverse change in qualitative and quantitative impurity profile or in physico-chemical properties. The change shall not refer to the restricted part of an ASMF.

The changes shall be within the range of currently approved limits.

In case of biological products, this change shall be only possible if comparability is not required.

Changes in the geographical source, manufacturing route or production of a herbal substance or herbal preparation of a herbal medicinal product shall be excluded.

Amendment of the relevant section(s) of the dossier.

13

Changes to a test procedure (including replacement or addition) for a reagent used in the manufacturing process of the active substance or immediate packaging of the active substance:

The new test method shall not concern a novel non-standard technique or a standard technique used in a novel way.

Amendment of the relevant section(s) of the dossier for comparative validation data, as appropriate.

a)

| — | for a reagent, which does not have a significant effect on the overall quality of the active substance |
| --- | --- |

—

for a reagent, which does not have a significant effect on the overall quality of the active substance

The active substance shall not be a biological or immunological substance. There shall be no changes to the total impurity limits; no new unqualified impurities shall be detected.

The method of analysis shall remain the same (e.g. a change in column length or temperature, but not a different type of column or method). Appropriate validation studies, performed in accordance with the relevant guidelines, shall show that the updated test procedure is at least equivalent to the former test procedure.

b)

| — | for the immediate packaging of the active substance |
| --- | --- |

—

for the immediate packaging of the active substance

The active substance shall not be a biological or immunological substance.

When the change concerns replacement of a method, the change shall not be a consequence of any commitment from previous assessments to review specification limits (e.g. made during the procedure for the marketing authorisation application or a variation procedure according to Article 62 of Regulation (EU) 2019/6) unless it has been previously assessed and agreed as part of a follow-up measure in a previous procedure under Regulation (EU) 2019/6.

A document listing the comparative validation results or, if justified, the comparative analysis results, showing that the former test and the new one are equivalent.

14

Change in qualitative or quantitative composition of the immediate packaging for the active substance

Sterile or liquid formulations or biological or immunological active substances shall be excluded.

The new packaging material shall be at least equivalent to the approved material in respect of its relevant properties and no interaction shall occur between the content and the packaging material. Stability studies shall have been started according to the current approved stability protocol and under International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (VICH) conditions; relevant stability parameters shall have been assessed in at least two pilot scale or industrial scale batches, and at least three months satisfactory stability data shall be at the disposal of the applicant. The stability profile shall be similar to the currently registered situation. However, if the new packaging is more resistant than the existing packaging, the three months’ stability data do not yet have to be available.

Amendment of the relevant section(s) of the dossier including stability confirmation.

If the new packaging is more resistant than the former packaging, studies which have only started shall be finalised and the data shall be provided immediately afterwards to the competent authorities.

15

Addition of or change to a calendar package for a pack size already registered in the dossier

The primary packaging material shall remain the same.

16

Change or addition of imprints, bossing or other markings including replacement, or addition of inks used for product marking of the finished product

The change shall not affect the delivery, use or safety of the finished product.

The finished product release and shelf life specifications shall not have been changed except for appearance.

The ink shall comply with the relevant pharmaceutical legislation.

The change shall not relate to a scored tablet that is intended to be divided into equal doses.

Amendment of the relevant section(s) of the dossier.

17

Change in the shape or dimensions of the pharmaceutical form for immediate release tablets, capsules, suppositories and pessaries

The dissolution profile of the product shall remain unchanged. For herbal medicinal products, where dissolution testing may not be feasible the new disintegration time of the product shall be comparable to the former one.

The release and end of shelf-life specifications of the product shall not have been changed.

The qualitative or quantitative composition and mean mass shall remain unchanged.

The change shall not relate to a scored tablet that is intended to be divided into equal doses.

Amendment of the relevant section(s) of the dossier.

18

Change(s) in the composition (excipients) of a non-sterile finished product

The change shall not be applicable to a biological or immunological medicinal product.

The change shall not have the potential to affect the identity, strength, quality, purity, potency, physical characteristics, safety or effectiveness of the finished product.

Stability studies shall have been started according to the current approved stability protocol and under International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (VICH) conditions; relevant stability parameters shall have been assessed in at least two pilot scale or industrial scale batches, and at least three months satisfactory stability data shall be at the disposal of the applicant. The stability profile shall be similar to the currently registered situation.

Amendment of the relevant section(s) of the dossier including stability confirmation.

a)

| — | increase or reduction of a component or components of the flavouring or colouring system |
| --- | --- |

—

increase or reduction of a component or components of the flavouring or colouring system

Quantitative change(s) shall not exceed +/- 10 % of the existing concentration of the component.

There shall be no change in functional characteristics of the pharmaceutical form (e.g. disintegration time, dissolution profile).

The finished product specification shall only have been updated in respect of appearance, odour or taste and, if relevant, deletion of an identification test.

For veterinary medicinal products for oral use, the change shall not negatively affect the uptake by target animal species.

b)

| — | any minor adjustment of the quantitative composition of the finished product with respect to excipients |
| --- | --- |

—

any minor adjustment of the quantitative composition of the finished product with respect to excipients

Quantitative change(s) shall not exceed +/- 10 % of the existing concentration of the component.

The change shall not affect the functional characteristics of the pharmaceutical form (e.g. disintegration time, dissolution profile).

For solid oral dosage forms, the dissolution profile of the changed product shall be determined on a minimum of two pilot scale batches and shall be comparable to the former one. No significant differences regarding comparability shall occur. For herbal medicinal products, where dissolution testing may not be feasible, the disintegration time of the changed product shall be comparable to the former one.

The change shall not be the result of stability issues and shall not result in potential safety concerns, e.g. differentiation between strengths.

Amendment of the relevant section(s) of the dossier.

Either a Ph. Eur. Certificate of Suitability for any new component of animal susceptible to TSE risk or where applicable, documentary evidence that the specific source of the TSE risk material has been previously assessed by the competent authority and shown to comply with the scope of the current Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathies via Human and Veterinary Medicinal Products. The following information shall be included for each such material: name of manufacturer, species and tissues from which the material is a derivative, country of origin of the source animals and its use.

c)

| — | addition or replacement of a component or components of the flavouring or colouring system |
| --- | --- |

—

addition or replacement of a component or components of the flavouring or colouring system

The change shall not affect the functional characteristics of the pharmaceutical form (e.g. disintegration time, dissolution profile).

For veterinary medicinal products for food-producing species, the entry in Regulation (EC) No° 470/2009 for this substance shall be amended before implementation of this change.

For solid oral dosage forms, the dissolution profile of the changed product shall be determined on a minimum of two pilot scale batches and shall be comparable to the former one. No significant differences regarding comparability shall occur. For herbal medicinal products, where dissolution testing may not be feasible, the disintegration time of the changed product shall be comparable to the former one.

The change shall not be the result of stability issues and shall not result in potential safety concerns (e.g. differentiation between strengths).

Amendment of the relevant section(s) of the dossier.

Either a Ph. Eur. Certificate of Suitability for any new component of animal susceptible to TSE risk or where applicable, documentary evidence that the specific source of the TSE risk material has been previously assessed by the competent authority and shown to comply with the scope of the current Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathies via Human and Veterinary Medicinal Products. The following information shall be included for each such material: name of manufacturer, species and tissues from which the material is a derivative, country of origin of the source animals and its use.

19

Change in coating weight of oral dosage forms or change in weight of capsule shells for a solid oral pharmaceutical form

The change shall not be the result of stability issues and shall not result in potential safety concerns (e.g. differentiation between strengths).

For veterinary medicinal products for oral use, the coating shall not be a critical factor for the release mechanism and the change shall not affect the uptake by target animal species.

The finished product specification shall only be updated in respect of weight and dimensions, if applicable.

The dissolution profile of the changed product shall be determined on a minimum of two pilot scale batches and shall be comparable to the former one. For herbal medicinal products, where dissolution testing may not be feasible, the disintegration time of the changed product shall be comparable to the former one.

Relevant stability studies shall have been started under VICH conditions and relevant stability parameters shall have been assessed in at least two pilot scale or industrial scale batches and at least three months satisfactory stability data shall be at the disposal of the applicant at time of implementation.

Amendment of the relevant section(s) of the dossier including stability confirmation.

20

Replacement or addition of a primary packaging site of a non-sterile finished product

The change shall not be applicable to a biological or immunological medicinal product.

The primary packaging site shall already be introduced in the Union IT systems storing and providing organisational data.

The site shall be appropriately authorised to manufacture the pharmaceutical form or product concerned and satisfactorily inspected.

The validation scheme shall be available or validation of the manufacture at the new site has been successfully carried out according to the current protocol with at least three production scale batches, as appropriate.

If the manufacturing site and the primary packaging site are different, conditions of transport and bulk storage shall be specified and validated.

Amendment of the relevant section(s) of the dossier.

21

Replacement or addition of a secondary packaging site of a finished product

The secondary packaging site shall already be introduced in the Union IT systems storing and providing organisational data.

The site shall be appropriately authorised to manufacture the pharmaceutical form or product concerned and satisfactorily inspected.

Amendment of the relevant section(s) of the dossier.

22

Change to importer, batch control arrangements and quality testing (replacement or addition of a site) for a finished product

The site shall be already introduced in the Union IT systems storing and providing organisational data.

The site shall be appropriately authorised and satisfactorily inspected.

The change shall not be applicable to a biological or immunological medicinal product.

Method transfer from the former to the new site shall have been successfully completed.

23

Replacement or addition of a manufacturer of a finished product responsible for importation

The site shall already be introduced in the Union IT systems storing and providing organisational data.

The site shall be appropriately authorised and satisfactorily inspected

24

Replacement or addition of a manufacturer responsible for batch release including batch control or testing of a non-sterile finished product

The manufacturer or the site shall already be introduced in the Union IT systems storing and providing organisational data.

The site shall be appropriately authorised and satisfactorily inspected.

The change shall not be applicable to a biological or immunological medicinal product.

Method transfer from the former to the new site shall have been successfully completed.

25

Change in the packaging material of bulk product (intermediate product) not in contact with the bulk product formulation (including replacement or addition)

The manufacturing steps shall remain the same. The finished product, intermediates or in-process controls used in the manufacture of the finished product shall still conform to the approved specifications.

The secondary packaging shall not play a functional role on the stability of the bulk product, or if it does, it shall not be less protective than the approved one.

Amendment of the relevant section(s) of the dossier.

26

Change in the batch size (including batch size ranges) of the finished product:

The change shall not be applicable to a biological or immunological medicinal product.

The change shall not be the result of unexpected events arising during manufacture or because of stability concerns. The change shall not affect reproducibility or consistency of the product.

The changes to the manufacturing method or to the in-process controls shall be only those necessitated by the change in batch-size, e.g. use of different sized equipment. A validation scheme shall be available or a validation of the manufacture shall have been successfully carried out according to the current protocol with at least three batches of the new batch size in accordance with the relevant guidelines.

Amendment of the relevant section(s) of the dossier.

Where relevant, the batch numbers, corresponding batch size, the manufacturing date of batches (3) used in the validation study and the validation data or the validation protocol (scheme) shall be provided.

a)

| — | up to 10-fold increase compared to the originally approved batch size of an immediate release oral pharmaceutical forms or of a non-sterile liquid based pharmaceutical form |
| --- | --- |

—

up to 10-fold increase compared to the originally approved batch size of an immediate release oral pharmaceutical forms or of a non-sterile liquid based pharmaceutical form

The batch size shall be within the 10-fold range of the batch size foreseen when the marketing authorisation was granted.

b)

| — | up to 10-fold increase compared to the originally approved batch size for the pharmaceutical form medicinal gas |
| --- | --- |

—

up to 10-fold increase compared to the originally approved batch size for the pharmaceutical form medicinal gas

The batch size shall be within the 10-fold range of the batch size foreseen when the marketing authorisation was granted.

c)

| — | downscaling down to 10-fold compared to the originally approved batch size of an immediate release oral pharmaceutical forms or to non-sterile liquid based pharmaceutical form |
| --- | --- |

—

downscaling down to 10-fold compared to the originally approved batch size of an immediate release oral pharmaceutical forms or to non-sterile liquid based pharmaceutical form

The batch size shall be within the 10-fold range of the batch size foreseen when the marketing authorisation was granted.

d)

| — | downscaling down to 10-fold (for the pharmaceutical form medicinal gas |
| --- | --- |

—

downscaling down to 10-fold (for the pharmaceutical form medicinal gas

The batch size shall be within the 10-fold range of the batch size foreseen when the marketing authorisation was granted.

e)

| — | more than 10-fold increase compared to the originally approved batch size for an immediate release, solid oral pharmaceutical form |
| --- | --- |

—

more than 10-fold increase compared to the originally approved batch size for an immediate release, solid oral pharmaceutical form

3 months stability data for at least one pilot batch under VICH condition.

27

Change to in-process tests or limits applied during the manufacture of the finished product:

The change shall not relate to a commitment or to an unexpected event during manufacture.

The change shall not have the potential to affect the identity, strength, quality, purity, potency or physical characteristics of the finished product, intermediates or in-process materials.

Comparative table of former and new in-process tests or limits.

a)

| — | tightening of in-process limits |
| --- | --- |

—

tightening of in-process limits

The change shall be within the range of currently approved limits.

The test procedure shall remain the same, or changes in the test procedure shall be minor.

Amendment of the relevant section(s) of the dossier.

b)

| — | addition of a new in-process test and limits |
| --- | --- |

—

addition of a new in-process test and limits

Any new test method shall not concern a novel non-standard technique or a standard technique used in a novel way.

The new test method shall not be a biological, immunological or immunochemical method, or a method using a biological reagent for a biological active substance, except if this method is a standard pharmacopoeial microbiological method.

Amendment of the relevant section(s) of the dossier for method and validation, batch data and relevant comparative data.

28

Change in the specification parameters or limits of an excipient

The change shall not be a consequence of any commitment from previous assessments to review specification limits (e.g. made during the procedure for the marketing authorisation application or a variation procedure according to Article 62 of Regulation (EU) 2019/6).

The change shall not be a result of unexpected events arising during manufacture, e.g. new unqualified impurity or change in total impurity limits.

a)

| — | tightening of specification limits |
| --- | --- |

—

tightening of specification limits

The change shall be within the range of currently approved limits. The test procedure shall remain the same, or changes in the test procedure shall be minor.

b)

| — | addition of a new specification parameter to the specification with its corresponding test method |
| --- | --- |

—

addition of a new specification parameter to the specification with its corresponding test method

Any new test method shall not concern a novel non-standard technique or a standard technique used in a novel way.

The new test method shall not be a biological, immunological or immunochemical method, or a method using a biological reagent for a biological active substance, except if this method is a standard pharmacopoeial microbiological method.

The change shall not concern a genotoxic impurity.

Amendment of the relevant section(s) of the dossier for method and validation, batch data and relevant comparative data.

29

Change in source of an excipient or reagent with TSE risk from material with TSE risk to vegetable or synthetic origin

The excipient, finished product release and end of shelf life specifications shall remain the same.

The change shall not concern an excipient or reagent used in the manufacture of a biological or immunological active substance or in a biological or immunological medicinal product.

Amendment of the relevant section(s) of the dossier.

Declaration from the manufacturer or the marketing authorisation holder of the material that it is purely of vegetable or synthetic origin.

30

Change in the specification parameters or limits of the finished product:

The change shall not be a consequence of any commitment from previous assessments to review specification limits (e.g. made during the procedure for the marketing authorisation application or a variation procedure according to Article 62 of Regulation (EU) 2019/6), unless the supporting documentation has already been assessed and approved within the context of another procedure under Regulation (EU) 2019/6.

The change shall not result from unexpected events arising during manufacture, e.g. new unqualified impurity or change in total impurity limits.

Amendment of the relevant section(s) of the dossier.

Comparative table of former and new specification parameters and limits.

a)

| — | tightening of specification limits |
| --- | --- |

—

tightening of specification limits

The change shall be within the range of currently approved limits.

The test procedure shall remain the same, or changes in the test procedure shall be minor.

b)

| — | tightening of specification limits for finished products subject to Official Control Authority Batch Release |
| --- | --- |

—

tightening of specification limits for finished products subject to Official Control Authority Batch Release

The change shall be within the range of currently approved limits.

The test procedure shall remain the same, or changes in the test procedure shall be minor.

c)

| — | addition of a new specification parameter to the specification with its corresponding test method |
| --- | --- |

—

addition of a new specification parameter to the specification with its corresponding test method

Any new test method shall not concern a novel non-standard technique or a standard technique used in a novel way.

The test method shall not be a biological, immunological or immunochemical method, or a method using a biological reagent for a biological active substance except if this method is a standard pharmacopoeial microbiological method.

The change shall not concern any impurities (including genotoxic) or dissolution.

Amendment of the relevant section(s) of the dossier for method and validation, batch data and relevant comparative data.

d)

| — | update of the dossier to comply with the provisions of an updated general monograph of the Ph. Eur. for the finished product |
| --- | --- |

—

update of the dossier to comply with the provisions of an updated general monograph of the Ph. Eur. for the finished product

The change shall be within the range of currently approved limits.

The test procedure shall remain the same, or changes in the test procedure shall be minor.

The change shall not concern any impurities (including genotoxic) or dissolution.

31

Uniformity of dosage units is introduced to replace the currently registered method

The change shall follow changes to the Ph. Eur. Standard 2.9.5. Uniformity of mass or Ph. Eur. Standard 2.9.6 Uniformity of content.

Amendment of the relevant section(s) of the dossier.

Comparative table of former and new specification parameters and limits.

32

Change in the specification parameters or limits of the finished product to describe more accurately the appearance of the product

The change shall not be a result of any unexpected events arising during manufacture or testing of the finished product.

Amendment of the relevant section(s) of the dossier.

Comparative table of former and new specification parameters and limits.

33

Change in test procedure for the finished product to comply with Ph. Eur.:

The change shall not concern changes of the total impurity limits; no new unqualified impurities shall be detected.

The method of analysis shall remain the same (e.g. a change in column length or temperature, but not a different type of column or method).

The test method shall not be a biological, immunological or immunochemical method, or a method using a biological reagent for a biological active substance, except if this method is a standard pharmacopoeial microbiological method.

Amendment of the relevant section(s) of the dossier.

a)

| — | update of the test procedure to comply with the updated general monograph in the Ph. Eur. |
| --- | --- |

—

update of the test procedure to comply with the updated general monograph in the Ph. Eur.

b)

| — | update of the test procedure to reflect compliance with the Ph. Eur. and remove reference to the outdated internal test method and test method number |
| --- | --- |

—

update of the test procedure to reflect compliance with the Ph. Eur. and remove reference to the outdated internal test method and test method number

34

Change in qualitative and quantitative composition of the immediate packaging for a solid pharmaceutical form for a finished product

For solid pharmaceutical forms, the change shall only concern the same packaging or container type (e.g. blister to blister).

The finished product shall not be sterile.

The change shall not affect the delivery, use, safety or stability of the finished product.

Relevant stability studies shall have been started under VICH conditions and relevant stability parameters shall have been assessed in at least two pilot scale or industrial scale batches and at least three months satisfactory stability data shall be at the disposal of the applicant at time of implementation. However, if the new packaging is more resistant than the existing packaging, the three months’ stability data do not yet have to be available.

The new packaging material shall be at least equivalent to the approved material in respect of its relevant properties.

Amendment of the relevant section(s) of the dossier.

Comparative table of former and new immediate packaging specifications, permeability data and interaction data, as appropriate.

35

Change in the specification parameters or limits of the immediate packaging of the finished product:

The changes shall not be a consequence of any commitment from previous assessments to review specification limits (e.g. made during the procedure for the marketing authorisation application or a variation procedure according to Article 62 of Regulation (EU) 2019/6) unless the supporting documentation has already been assessed and approved within the context of another procedure under Regulation (EU) 2019/6.

The change shall not result from unexpected events arising during manufacture.

Comparative table of former and new specifications or limits.

a)

| — | tightening of specification limits |
| --- | --- |

—

tightening of specification limits

The change shall be within the range of currently approved limits.

The test procedure shall remain the same, or changes in the test procedure shall be minor.

b)

| — | addition of a new specification parameter to the specification with its corresponding test method |
| --- | --- |

—

addition of a new specification parameter to the specification with its corresponding test method

Any new test method shall not concern a novel non-standard technique or a standard technique used in a novel way.

Amendment of the relevant section(s) of the dossier for method and validation and batch data, as appropriate.

36

Change in test procedure for the immediate packaging of the finished product (including replacement or addition)

The change shall not be applicable to a biological or immunological medicinal product.

Appropriate validation studies shall have been performed in accordance with the relevant guidelines and show that the updated test procedure is at least equivalent to the former test procedure.

Any new test method shall not concern a novel non-standard technique or a standard technique used in a novel way.

Amendment of the relevant section(s) of the dossier for method and validation and batch data, as appropriate.

37

Change in shape or dimensions of the container or closure (immediate packaging) of a non-sterile finished product

The change shall not concern a part of the packaging material, which affects the delivery, use, safety or stability of the finished product.

The change shall not concern the qualitative or quantitative composition of the container.

In case of a change in the headspace or a change in the surface/volume ratio, stability studies in accordance with the relevant guidelines shall have been started, relevant stability parameters shall have been assessed in at least two pilot scale or industrial scale batches, and at least three months stability data shall be at the disposal of the applicant.

Amendment of the relevant section(s) of the dossier.

38

Change in pack size (number of units e.g. tablets, ampoules, etc. in a pack) within the range of the currently approved pack size (3)

The new pack size shall be consistent with the posology and treatment duration as approved in the Summary of Product Characteristics.

The primary packaging material shall remain the same.

39

Change in any part of the primary packaging material not in contact with the finished product formulation (such as change of colour due to different plastic used for flip-off caps, colour code rings on ampoules or change of needle shield)

The change shall not concern a part of the packaging material that affects the delivery, use, safety or stability of the finished product.

Amendment of the relevant section(s) of the dossier.

40

Replacement or addition of a supplier of packaging components or devices (when mentioned in the dossier)

The qualitative and quantitative composition of the packaging components or device and design specifications shall remain the same. The change shall not have the potential to affect the identity, quality or purity of the packaging component or devices.

Amendment of the relevant section(s) of the dossier.

41

Change in the shelf-life or to an approved stability protocol of the finished product:

The change shall not be the result of unexpected events arising during manufacture or because of stability concerns.

Amendment of the relevant section(s) of the dossier.

a)

| — | reduction of the shelf life of the finished product as packaged for sale, after first opening or after dilution or reconstitution |
| --- | --- |

—

reduction of the shelf life of the finished product as packaged for sale, after first opening or after dilution or reconstitution

b)

| — | change to an approved stability protocol |
| --- | --- |

—

change to an approved stability protocol

The change shall not have the potential to affect the identity, strength, quality, purity, potency or physical characteristics of the finished product.

The change shall not concern a widening of the acceptance criteria in the parameters tested, a removal of stability indicating parameters or a reduction in the frequency of testing.

42

Implementation in practice of changes already foreseen in an approved change management protocol (CMP) for the finished product

The change shall be in accordance with the approved CMP and the results of studies performed indicate that the predefined acceptance criteria specified in the protocol are meet.

The implementation of the change shall require no further supportive data to the CMP.

43

Editorial changes to part 2 of the dossier if inclusion in an upcoming procedure concerning part 2 is not possible

Comparative table of the changes to the dossier.

44

Submission of a new or updated Ph. Eur. CEP from an already approved manufacturer for a non-sterile:

| — | active substance; |
| --- | --- |

—

active substance;

| — | starting material, reagent or intermediate used in the manufacturing process of the active substance; |
| --- | --- |

—

starting material, reagent or intermediate used in the manufacturing process of the active substance;

| — | excipient |
| --- | --- |

—

excipient

The finished product release and end of shelf life specifications shall remain the same.

The change shall not have the potential to affect the identity, quality, purity, potency or physical characteristics of the active substance, starting material, reagent or intermediate used in the manufacturing process of the active substance, or of the excipient.

No additional data shall be required.

The manufacturing process of the active substance, starting material, reagent, intermediate or excipient shall not include the use of material from human or animal origin.

For a herbal substance or a herbal preparation the manufacturing route, physical form, extraction solvent and drug extract ratio (DER) shall remain the same.

The manufacturer shall already be approved and incorporated in the Union IT systems storing and providing organisational data.

Amendment of the relevant section(s) of the dossier, including a copy of the updated Ph. Eur. CEP and QP declaration, as appropriate.

45

Submission of a new Ph. Eur. CEP from a new manufacturer (replacement or addition) for a non-sterile:

| — | active substance; |
| --- | --- |

—

active substance;

| — | starting material, reagent or intermediate used in the manufacturing process of the active substance; |
| --- | --- |

—

starting material, reagent or intermediate used in the manufacturing process of the active substance;

| — | excipient |
| --- | --- |

—

excipient

The finished product release and end of shelf life specifications shall remain the same.

The change shall not have the potential to affect the identity, quality, purity, potency or physical characteristics of the active substance, starting material, reagent or intermediate used in the manufacturing process of the active substance, or of the excipient.

No additional data shall be required.

The manufacturing process of the active substance, starting material, reagent, intermediate or excipient shall not include the use of material from human or animal origin.

For a herbal substance or a herbal preparation the manufacturing route, physical form, extraction solvent and drug extract ratio (DER) shall remain the same.

The manufacturer shall already be incorporated in the Union IT systems storing and providing organisational data.

Amendment of the relevant section(s) of the dossier, including a copy of the updated Ph. Eur. CEP and QP declaration, as appropriate.

46

Submission of a new or updated Ph. Eur. TSE CEP for a non-sterile:

| — | active substance; |
| --- | --- |

—

active substance;

| — | starting material, reagent, intermediate used in the manufacturing process of the active substance; |
| --- | --- |

—

starting material, reagent, intermediate used in the manufacturing process of the active substance;

| — | excipient |
| --- | --- |

—

excipient

The change shall not have the potential to affect the identity, quality, purity, potency or physical characteristics of the active substance, starting material, reagent or intermediate used in the manufacturing process of the active substance, or of the excipient.

The change shall not impact the risk of extraneous agents contamination (e. g. no change of country of origin).

The manufacturer shall already be approved and incorporated in the Union IT systems storing and providing organisational data.

Amendment of the relevant section(s) of the dossier including a copy of the updated Ph. Eur. CEP, QP declaration and TSE information, as appropriate.

47

Change to comply with Ph. Eur. or with a national pharmacopoeia of a Member State:

The change shall be made exclusively to fully comply with the pharmacopoeia. All the tests in the specification shall correspond to the pharmacopoeial standard after the change, except any additional tests.

Additional validation of a new or changed pharmacopoeial method shall not be required.

For a herbal substance or a herbal preparation the manufacturing route, physical form, extraction solvent and drug extract ratio (DER) shall remain the same.

Amendment of the relevant section(s) of the dossier (4).

Comparative table of the former and new specifications, if applicable.

a)

| — | change of specification(s) of a former non EU Pharmacopoeial active substance, excipient or active substance starting material to fully comply with the Ph. Eur. or with a national pharmacopoeia of a Member State |
| --- | --- |

—

change of specification(s) of a former non EU Pharmacopoeial active substance, excipient or active substance starting material to fully comply with the Ph. Eur. or with a national pharmacopoeia of a Member State

Additional specifications to the pharmacopoeia for product specific properties shall be unchanged (e.g. particle size profiles, polymorphic form, bioassays or aggregates).

The change shall not concern significant changes in qualitative and quantitative impurities profile unless the specifications are tightened.

Batch data and data demonstrating the suitability of the monograph to control the substance.

b)

| — | change to comply with an update of the relevant monograph of the Ph. Eur. or national pharmacopoeia of a Member State |
| --- | --- |

—

change to comply with an update of the relevant monograph of the Ph. Eur. or national pharmacopoeia of a Member State

Additional specifications to the pharmacopoeia for product specific properties shall be unchanged (e.g. particle size profiles, polymorphic form, bioassays or aggregates).

c)

| — | change in specifications from a national pharmacopoeia of a Member State to the Ph. Eur. |
| --- | --- |

—

change in specifications from a national pharmacopoeia of a Member State to the Ph. Eur.

Amendment of the relevant section(s) of the dossier, including batch data and data demonstrating the suitability of the monograph to control the substance.

d)

| — | to reflect compliance with the Ph. Eur. by removing reference to the internal test method and test method number |
| --- | --- |

—

to reflect compliance with the Ph. Eur. by removing reference to the internal test method and test method number

48

Addition or replacement of a measuring or administration device which is not an integrated part of the primary packaging

The change shall not affect the delivery, use, safety or stability of the finished product.

The change shall be only applicable to a device with CE marking.

The new measuring or administration device shall accurately deliver the required dose for the product concerned in line with the approved posology, and results of such studies shall be available.

The new device shall be compatible with the veterinary medicinal product.

The change shall not lead to substantial amendments of the product information.

Amendment of the relevant section(s) of the dossier.

49

Change in specification parameters or limits of a measuring or administration device:

The change shall not be a consequence of any commitment from previous assessments to review specification limits (e.g. made during the procedure for the marketing authorisation application or a variation procedure according to Article 62 of Regulation (EU) 2019/6) unless it has been previously assessed and agreed as part of a follow-up measure in a previous procedure under Regulation (EU) 2019/6.

The change shall not be the result of unexpected events arising during manufacture.

Amendment of the relevant section(s) of the dossier.

Comparative table of former and new specification parameters and limits.

a)

| — | tightening of specification limits |
| --- | --- |

—

tightening of specification limits

The change shall be within the range of currently approved limits.

The test procedure shall remain the same, or changes in the test procedure shall be minor.

b)

| — | addition of a new specification parameter to the specification with its corresponding test method |
| --- | --- |

—

addition of a new specification parameter to the specification with its corresponding test method

Any new test method shall not concern a novel non-standard technique or a standard technique used in a novel way.

Amendment of the relevant section(s) of the dossier for method and validation and batch data.

50

Change in test procedure (including replacement or addition) of a measuring or administration device

Appropriate validation studies shall have been performed in accordance with the relevant guidelines and show that the updated test procedure is at least equivalent to the former test procedure.

Any new test method shall not concern a novel non-standard technique or a standard technique used in a novel way.

Amendment of the relevant section(s) of the dossier for method and validation and batch data.

51

Update of the quality dossier intended to implement the outcome of a Union interest referral procedure according to Article 83 of Regulation (EU) 2019/6:

This change shall only be applicable when no new or additional data is required for an assessment.

Amendment of the relevant section(s) of the dossier.

a)

| — | the finished product is covered by the defined scope of the procedure |
| --- | --- |

—

the finished product is covered by the defined scope of the procedure

b)

| — | the finished product is not covered by the defined scope of the procedure but the change(s) implements the outcome of the procedure |
| --- | --- |

—

the finished product is not covered by the defined scope of the procedure but the change(s) implements the outcome of the procedure

C

Changes to the safety, efficacy and pharmacovigilance part of the dossier

1

Change(s) in the name or address or contact details of a qualified person for pharmacovigilance (QPPV)

2

Change(s) in the Summary of Product Characteristics (SPC), labelling or package leaflet intended to implement the outcome of a Union interest referral procedure according to Article 83 of Regulation (EU) 2019/6

The veterinary medicinal product shall be covered by the defined scope of the referral.

This change shall only be applicable when no new or additional data is required for an assessment.

The proposed Summary of Product Characteristics, Labelling and Package Leaflet shall be identical for the concerned sections to that annexed to the Commission Decision on the referral procedure for the reference medicinal product.

3

Change(s) in the SPC, labelling or package leaflet of a generic or hybrid medicinal product following assessment of the same change(s) for the reference product

This change shall only be applicable when no new or additional data is required for an assessment.

The proposed changes to Summary of Product Characteristics, Labelling and Package Leaflet shall be identical to those changes approved for the reference medicinal product.

The reference product shall be approved in the Member State concerned.

4

Change(s) in the SPC, labelling or package leaflet intended to implement the outcome of a procedure or recommendation from the competent authority or the Agency concerning risk management measures in pharmacovigilance related to veterinary medicinal products

This change shall only be applicable when no new or additional data is required for an assessment.

The proposed changes to Summary of Product Characteristics, Labelling and Package Leaflet shall be identical to wording agreed by the competent authority or the Agency.

5

Change in the pharmacovigilance system master file (PSMF) location

6

Introduction of a summary of the PSMF or changes to the summary of the PSMF not already covered elsewhere in this Annex

Summary of pharmacovigilance system master file according to Article 8(1)(c) of Regulation (EU) 2019/6.

7

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

The wording shall be limited to that agreed by the competent authority or the Agency.

8

Implementation of changes in the SPC not already covered elsewhere in this Annex

This change shall only be applicable when no new or additional data is required for an assessment. The changes shall not affect the quality, safety or efficacy of the product.

Changes shall be minor in nature and shall be consistent with the information currently included in the SPC.

9

Editorial changes to SPC, package leaflet or labelling if inclusion in an upcoming procedure is not possible

The changes shall not affect the quality, safety or efficacy of the medicinal product.

10

Changes to the labelling or the package leaflet which shall not be connected with the SPC:

a)

| — | administrative information concerning the holder’s representative |
| --- | --- |

—

administrative information concerning the holder’s representative

b)

| — | other changes |
| --- | --- |

—

other changes

Changes shall be minor in nature and shall be consistent with the information included in the SPC.

The change shall not include the introduction of new batch release sites.

Changes shall not be promotional in nature and shall not have a negative impact on the legibility of the product information.

c)

| — | inclusion of traceability stickers in or on product carton |
| --- | --- |

—

inclusion of traceability stickers in or on product carton

Addition shall not have a negative impact on the legibility of the product information.

D

Changes to the vaccine antigen master file (VAMF) part of the dossier

1

Change in the name or address or contact details of the VAMF certificate holder for biological products

The marketing authorisation holder shall remain the same legal entity.

Amendment of the relevant section(s) of the dossier, as appropriate.

2

Inclusion of an already certified VAMF in the marketing authorisation dossier of a veterinary medicinal product. (VAMF 2
  nd
  step procedure)

Changes shall not affect the properties of the finished product.

Amendment of the relevant section(s) of the dossier.

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(1)  As per EDQM standard terms the system of names and terms published by the EDQM for marketing authorisation applications.

(2)  In cases where a given pharmaceutical form or strength has received an individual marketing authorisation which is separate to the marketing authorisation for other pharmaceutical forms or strengths of the same product, the deletion of the former will not be a variation but the withdrawal of the marketing authorisation.

(3)  In cases where a given pack size has received an individual marketing authorisation which is separate to the marketing authorisation for other pack sizes of the same product, the change of the former will not be a variation according to Article 61, but a variation according to Article 62 of Regulation (EU) 2019/6.

(4)  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 reference is made to the ‘current edition’ in the dossier of an authorised medicinal product. Applicants are reminded that compliance with the updated monograph should be implemented within six months. If implementation does not occur within 6 months from the publication date, this variation applies.

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