Annex tables

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

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

Annex tables

E. ADMINISTRATIVE CHANGES

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

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

E.3 Change in ATC Code

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

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

#e1

E.1 Change in the (invented) name of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) for centrally authorised medicinal products	1	1, 2	IA_IN
(b) for nationally authorised medicinal products		2	IB
Conditions
1. The check by the EMA on the acceptability of the new name has been finalised and was positive.
Documentation
1. A formal document from a relevant official body (e.g. Chamber of Commerce) in which the new name or new address is mentioned.
2. Revised product information.

#e2

E.2 Change in name of the active substance, excipient, medical device (part), or packaging component	Conditions to be fulfilled	Documentation to be supplied	Procedure type
	1	1, 2, 3	IA_IN
Conditions
1. The active substance/excipient/medical device/packaging component must remain unchanged.
Documentation
1. For active substance and excipients, proof of acceptance by WHO or copy of the INN list. If applicable, proof that the change is in line with the Ph. Eur. For herbal medicinal product, declaration that the name is in accordance with the guideline on declaration of herbal substances and herbal preparations in (traditional) herbal medicinal products. For medical devices, updated CE certificate and/or declaration of conformity, if available.
2. Revised product information, as appropriate.
3. Amendment of the relevant section(s) of the dossier.

#e3

E.3 Change in ATC Code	Conditions to be fulfilled	Documentation to be supplied	Procedure type
	1	1, 2	IA
Conditions
1. Change following granting of or amendment to ATC Code by WHO.
Documentation
1. Proof of acceptance (by WHO) or copy of the ATC Code list.
2. Revised product information.

#e4

E.4 Change in the name and/or address of the marketing authorisation holder, ASMF holder, storage site of the master and/or working cell bank, manufacturing site for an active substance, intermediate or finished product, primary and/or secondary packaging site, manufacturer responsible for batch release, site where quality control takes place, and/or supplier of a packaging component, medical device (part), starting material, reagent and/or excipient (when mentioned in the dossier)	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) The change in the name and/or address concerns the marketing authorisation holder	2	1, 2	IA_IN
b) The change in the name and/or address concerns a manufacturer(s)whose activities include batch release of the finished product	1	1, 2	IA_IN
c) The change in the name and/or address does not concern a manufacturer(s) whose activities include batch release of the finished product nor the marketing authorisation holder	1	1, 2, 3	IA
Conditions
1. The physical location of the concerned manufacturing site and all manufacturing operations must remain the same.
2. The marketing authorisation holder must remain the same legal entity.
Documentation
1. A formal document from a relevant official body (e.g. Chamber of Commerce, or if not available, from a competent authority) in which the new name and/or address is mentioned, or a copy of the modified manufacturing authorisation, if available.
2. Amendment of the relevant section(s) of the dossier, including revised product information as appropriate.
3. In case of change in the name of the holder of the Active Substance Master File, updated ‘letter of access’.

#e5

E.5 Deletion of manufacturing sites for an active substance, intermediate or finished product, storage of master and/or working cell bank, primary and/or secondary packaging site, manufacturer responsible for batch release, site where quality control takes place, and/or supplier of a packaging component, medical device (part), starting material, reagent and/or excipient (when mentioned in the dossier)	Conditions to be fulfilled	Documentation to be supplied	Procedure type
	1, 2	1	IA
Conditions
1. There should at least remain one site/manufacturer, as previously authorised, performing the same function as the one(s) concerned by the deletion. Where applicable, at least one manufacturer responsible for batch release that is able to certify the product testing for the purpose of batch release within the EU/EEA remains in the EU/EEA.
2. The deletion should not be due to critical deficiencies concerning manufacturing.
Documentation
1. Amendment of the relevant section(s) of the dossier, including revised product information as appropriate.

Q. QUALITY CHANGES

Q.I ACTIVE SUBSTANCE

Q.I.a) Manufacture

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

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

Q.I.a.3 Change in batch size (including batch size ranges) of active substance or intermediate used in the manufacturing process of the active substance

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

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

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

#qia1

Q.I.a.1 Change in the manufacturing site of a starting material/intermediate used in the manufacturing process of the active substance or change in the manufacturing site (including where relevant quality control testing sites) of the active substance	Conditions to be fulfilled	Documentation to be supplied	Procedure type
Manufacturing site of an active substance or starting material or intermediate
a) Addition or replacement of a manufacturing site of an active substance or intermediate	1, 2, 3	1, 2, 3, 4, 5, 6	IA_IN
b) Addition or replacement of a manufacturing site of an active substance or intermediate that requires significant update to the relevant active substance section of the dossier, e.g. where a substantially different route of synthesis or manufacturing conditions is used, which may have a potential to change important quality characteristics of the active substance, such as qualitative and/or quantitative impurity profile requiring qualification, or physico-chemical properties impacting on bioavailability			II
c) Addition or replacement of a manufacturing site of a starting material used in the manufacture of the active substance or reagent required to be mentioned in the dossier	1, 2, 3	1, 2, 3, 4, 6	IA
d) Addition or replacement of a manufacturing site of – a biological active substance or – a biological starting material/reagent/raw material/intermediate used in the manufacture of a biological active substance which may have a significant impact on the quality, safety or efficacy of the finished product or – a material for which an assessment is required of viral safety and/or TSE risk			II
e) Addition or replacement of a new herbal starting material supplier or of a new herbal active substance manufacturing site using the same or different plant production (i.e. cultivated or wild collection)		1, 4, 5, 6, 7, 8	IB
f) Addition of a manufacturing site of the active substance that is supported by an Active Substance Master File (ASMF)			II
g) Addition or replacement of a manufacturing site responsible for sterilisation of the active substance using a Ph. Eur. method		1, 2, 4, 9	IB
h) Addition or replacement of a manufacturing site responsible for micronisation of the active substance	2, 4	1, 4, 5	IA
Quality control testing arrangements for the active substance or starting material or intermediate
i) Addition or replacement of a batch control/testing site of the active substance or starting material/intermediate used in the manufacturing of a biological active substance, applying a biological/immunological/immunochemical analytical procedure		1, 9, 10	IB
j) Addition or replacement of a batch control/testing site of the – the active substance or – intermediate of an active substance or – starting material of a biological active substance applying physicochemical and/or microbiological analytical procedures	5, 6	1	IA
Other
k) Addition or replacement of a storage site of the Master Cell Bank and/or Working Cell Banks	7	1	IA
Conditions
1. For starting materials, the specifications and analytical procedures are identical to those already approved. For intermediates and active substances the specifications (including in process controls, analytical procedures), method of preparation (including batch size) and detailed route of synthesis are identical to those already approved. For herbal active substances, the geographical source, production of the herbal starting material/herbal substance and the manufacturing process of the herbal active substance are the same as those already approved.
2. The active substance is not a biological or sterile substance.
3. Where materials of human or animal origin are used in the process, the manufacturer does not use any new supplier for which assessment is required of viral safety or of compliance with the current Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products.
4. The particle size specification of the active substance and the corresponding analytical procedure remain the same.
5. Method transfer from the old to the new site has been successfully completed.
6. The analytical procedure is not a biological/immunological/immunochemical procedure.
7. For Master Cell Bank and/or Working Cell Banks the storage conditions are identical to those already approved.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).
2. A declaration from the marketing authorisation holder (and the ASMF holder, where applicable) that the starting material (specifications and analytical procedures) and that the synthetic route, quality control procedures and specifications of the active substance and of the intermediate used in the manufacturing process of the active substance are the same as those already approved. For herbal active substances, a declaration that the geographical source, production of the herbal starting material/herbal substance and the manufacturing process of the herbal active substance are the same as those already approved.
3. Either a TSE Ph. Eur. certificate of suitability for any new source of material or, where applicable, documentary evidence that the specific source of the TSE risk material has previously been assessed by the competent authority and shown to comply with the current Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products. The information should include the following: Name of manufacturer, species and tissues from which the material is a derivative, country of origin of the source animals, its use and previous acceptance. For the centralised procedure, this information should be included in an updated TSE table A (and B, if relevant).
4. Batch analysis data (in a comparative tabular format) for at least two batches (minimum pilot scale) (or 3 batches (unless otherwise justified) for biologicals) of the active substance/starting material from the current and proposed manufacturers/sites.
5. A declaration by the qualified person (QP) of each of the manufacturing authorisation holders listed in the application, where the active substance is used as a starting material, and a declaration by the qualified person of each of the manufacturing authorisation holders listed in the application as responsible for batch release. These declarations should state that the active substance manufacturer(s) referred to in the application operate in compliance with the detailed guidelines on good manufacturing practice for starting materials. A single declaration may be acceptable under certain circumstances (see the note under variation no Q.II.b.1).
6. Where relevant, a commitment of the manufacturer of the active substance to inform the marketing authorisation holder of any changes to the manufacturing process, specifications and analytical procedures of the active substance.
7. For herbal starting material, a detailed comparison regarding specifications and critical quality attributes of the herbal starting material. For herbal active substance, a detailed comparison regarding specifications and critical quality attributes (e.g. for extracts: reference to the herbal starting material (incl. scientific binominal name and plant part), physical state, extraction solvent (nature and concentration), drug extract ratio (DER) and manufacturing process (including a stepwise comparison of all manufacturing steps in tabular format).
8. For herbal starting material supplier, a GACP declaration from the new supplier (and updated QP declaration if the new supplier is also involved in the herbal active substance manufacture).
9. Valid proof that the proposed site is GMP compliant for the manufacturing and/or testing operation(s) concerned: – For a site within the EU/EEA: a copy of the current manufacturing authorisation or where no manufacturing authorisation exists a certificate of GMP compliance issued within the last 3 years by the relevant competent authority. A reference to the EudraGMP database will suffice. For a third country site where a GMP mutual recognition agreement (MRA) or other relevant agreement on GMP is in place between the country concerned and the EU: a proof of GMP compliance issued within the last 3 years by the relevant local competent authority. – For a third country site where no MRA or relevant agreement on GMP is in place: a GMP certificate issued within the last 3 years by an EEA Member State. A reference to the EudraGMP database will suffice.
10. The analytical procedure transfer protocols in accordance with Eudralex Volume 4 Chapter 6 Article 6.39 (which pre-define the acceptance criteria), from the old site to the new site (or new test laboratory).

#qia2

Q.I.a.2 Change in the manufacturing process of the active substance, intermediate of an active substance or starting materials for biological active substance	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Minor change in the manufacturing process	1, 2, 3, 4, 5	1, 2, 3, 4	IA
b) Major change to the manufacturing process which may have a significant impact on the quality, safety or efficacy of the finished product			II
c) Change in the geographical source of a herbal starting material and/or production of a herbal substance		1, 2, 3, 4, 5	IB
d) Minor change to the restricted part of an Active Substance Master File		1, 2, 3, 6	IB
e) Deletion of a manufacturing process	6, 7	1	IA
Conditions
1. No adverse change in qualitative and quantitative impurity profile or in physico-chemical properties.
2. For chemical active substance: the synthetic route remains the same, i.e. intermediates remain the same and there are no new reagents, catalysts or solvents used in the process. For herbal active substances: the geographical source, production of the herbal starting material/herbal substance and the manufacturing process of the herbal active substance remain the same. For biological active substance/starting material/intermediate: the manufacturing steps remain the same and there are no changes to the manufacturing parameters (critical and non-critical PPs and IPCs) or to the specifications of the starting materials, intermediates, or active substance. For all: there are no changes to the finished product.
3. The specifications of the active substance, or intermediates are unchanged.
4. The change is fully described in the open (‘applicant’s’) part of an Active Substance Master File, if applicable.
5. 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.
6. The deletion should not be due to critical deficiencies concerning manufacturing.
7. There should at least remain one manufacturing process, as previously authorised.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).
2. Batch analysis data (in comparative tabular format) of at least two batches (minimum pilot scale), of the active substance or intermediate as appropriate, manufactured according to the currently approved and proposed process.
3. Copy of approved specifications of the active substance (as annex to the application form).
4. A declaration from the marketing authorisation holder that an evaluation has been performed and the minor changes do not impact the quality, safety or efficacy of the active substance/finished product (e.g. minor amendments to process description without actual process change, such as details of reagents (e.g. buffers, media preparation). For herbal starting materials/active substances, this evaluation should include a detailed comparison regarding quality determining process characteristics (e.g. for extracts: extraction time, temperature, pressure).
5. In the case of herbal starting materials, an updated GACP declaration and a declaration from the marketing authorisation holder that the manufacturing process of the herbal active substance remains the same.
6. A declaration from the marketing authorisation holder (and the ASMF holder, where applicable) that there is no change in qualitative and quantitative impurity profile or in physico-chemical properties, that the synthetic route remains the same and that the specifications of the active substance or intermediates are unchanged.
Note for Q.I.a.2.b: For chemical active substances, this refers to substantial changes to the synthetic route or manufacturing conditions which may have a potential to change important quality characteristics of the active substance, such as qualitative and/or quantitative impurity profile requiring qualification, or physico-chemical properties impacting on bioavailability.

#qia3

Q.I.a.3 Change in batch size (including batch size ranges) of active substance or intermediate used in the manufacturing process of the active substance	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) An increase to the originally approved batch size	1, 2, 3, 4, 5, 6, 7	1, 2, 3	IA
b) Downscaling of the approved batch size	1, 2, 3, 4, 5, 6, 8	1, 2, 3	IA
c) The change in batch size of a biological active substance/intermediate requires assessment of the comparability			II
d) The scale for a biological active substance/intermediate is increased/decreased without process change (e.g. duplication of line)		1, 2, 4	IB
Conditions
1. Any changes to the manufacturing methods are only those necessitated by scale-up or downscaling, e.g. use of different-sized equipment.
2. Test results of at least two batches according to the specifications should be available for the proposed batch size.
3. The active substance is not a biological substance.
4. The change does not adversely affect the reproducibility of the process.
5. The change is fully described in the open (‘applicant’s’) part of an Active Substance Master File, if applicable.
6. The specifications of the active substance/intermediates remain the same and the control strategy for impurities has been reviewed and remains appropriate.
7. The active substance is not sterile.
8. The change should not be the result of unexpected events arising during manufacture or because of stability concerns.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).
2. Batch analysis data (in a comparative tabulated format) on a minimum of two production batches of the active substance or intermediate, as appropriate, manufactured to both the currently approved and the proposed sizes. Batch analysis data of 3 batches (unless otherwise justified) for biological active substance, should be available for the proposed batch size.
3. A declaration from the marketing authorisation holder (and the ASMF holder as appropriate) that the changes to the manufacturing methods are only those necessitated by scale-up or downscaling, e.g. use of different-sized equipment, that the change does not adversely affect the reproducibility of the process, that it is not the result of unexpected events arising during manufacture or because of stability concerns and that the specifications of the active substance/intermediates remain the same.
4. For biological active substance, a justification that an assessment of comparability is not required.

#qia4

Q.I.a.4 Change to in-process controls applied during the manufacture of the active substance, intermediate of an active substance or starting materials for biological active substance	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Minor change of in-process control limits	1, 2, 3, 4, 5	1, 2	IA
b) Addition of new in-process control and limits with its corresponding analytical procedure	1, 2, 5, 6	1, 2, 3, 4, 5	IA
c) Deletion of a non-significant or obsolete in-process control	1, 2, 5, 7, 8	1, 2, 6	IA
d) Widening of the approved in-process control limits, which may have a significant effect on the overall quality of the active substance			II
e) Deletion of an in-process test which may have a significant effect on the overall quality of the active substance			II
f) Change of an analytical procedure for an in-process control	2, 4, 5, 9, 10	1	IA
g) Replacement of an in-process control with its corresponding analytical procedure		1, 2, 3, 4, 5	IB
Conditions
1. The change is not a consequence of any commitment from previous assessments to review in-process control limits (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, and is not as a result of a safety or quality issue (e.g. new unqualified impurity detected, or a change in total impurity limits).
3. Any change should be within the range of currently approved limits.
4. The analytical procedure remains the same, or changes in the analytical procedure are minor (e.g. a change in column length or temperature could be allowed, but not a different type of column or method).
5. The change is fully described in the open (‘applicant’s’) part of an Active Substance Master File, if applicable.
6. Any new analytical procedure does not concern a novel non-standard technique or a standard technique used in a novel way.
7. The in-process control does not concern a critical attribute, for example: – assay, – purity, – impurities (except when a solvent is no longer used in the manufacture of the active substance), – a critical physical characteristic (for example: particle size, bulk or tapped density), – identity test, – or water content.
8. 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).
9. The new analytical procedure is not a biological/immunological/immunochemical procedure.
10. Appropriate 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.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).
2. Comparative table of current and proposed in-process controls and limits.
3. Details of any new non-pharmacopoeial analytical method and validation data, where relevant.
4. Batch analysis data on two production batches of the active substance for all specification attributes.
5. Justification from the holder or ASMF holder as appropriate for the new in-process control and limits.
6. Justification/risk assessment from the marketing authorisation holder or the ASMF holder, as appropriate, that the in-process controls are non-significant, or that the in-process controls are obsolete.

#qia5

Q.I.a.5 Changes to the active substance of a seasonal, pre-pandemic or pandemic vaccine against human influenza	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Replacement of the strain(s) in a seasonal, pre-pandemic or a pandemic vaccine against human influenza			II

#qia6

Q.I.a.6 Changes to the active substance of a vaccine against human coronavirus or other vaccine that has the potential to address a public health emergency in the Union	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Replacement or, upon agreement of the relevant authorities, addition of a serotype, strain, antigen or coding sequence or combination of serotypes, strains, antigens or coding sequences for a human coronavirus vaccine or other vaccine that has the potential to address a public health emergency in the Union			II
b) Deletion of a serotype, strain, antigen or coding sequence or combination of serotypes, strains, antigens or coding sequences for a human coronavirus vaccine or other vaccine that has the potential to address a public health emergency in the Union		1, 2, 3, 4	IB
Documentation
1. Declaration that the remaining product presentation(s) are adequate for the dosing instructions and duration as mentioned in the summary of product characteristics, and the deletion has been agreed in principle with the Agency.
2. Amendment of the relevant section(s) of the dossier, as appropriate.
3. Declaration that the serotype, strain, antigen or coding sequence is no longer appropriate in relation to the epidemiological evolution of the human virus of concern.
4. Revised product information.

Q.I.b) Control of active substance

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

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

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

#qib1

Q.I.b.1 Change in the specification attribute and/or acceptance criteria of an active substance, starting material/reagent/intermediate used in the manufacturing process of the active substance	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Change within the specification acceptance criteria for finished product subject to Official Control Authority Batch Release	1, 2, 3	1, 2	IA_IN
b) Change within the specification acceptance criteria	1, 2, 3, 4	1, 2	IA
c) Addition of a new specification attribute with its corresponding analytical procedure and acceptance criteria	1, 2, 4, 5, 6	1, 2, 3, 4, 5	IA
d) Deletion of a non-significant or an obsolete specification attribute	1, 2, 4, 7, 8	1, 2, 6	IA
e) Deletion of a specification attribute which may have a significant effect on the overall quality of the active substance and/or the finished product			II
f) Change outside of the specification acceptance criteria for the active substance			II
g) Change outside of the specification acceptance criteria for starting material/reagent/intermediate which may have a significant effect on the overall quality of the active substance and/or the finished product			II
h) Change outside of the specification acceptance criteria for starting material/reagent/intermediate		1, 2, 4, 5	IB
i) Change in specification attribute for the active substance from in-house to a non-official Pharmacopoeia/Pharmacopoeia of a third country where there is no monograph in the European Pharmacopoeia or the national pharmacopoeia of a Member State		1, 2, 3, 4, 5	IB
j) Change of the analytical marker or widening of the acceptance criteria of the analytical marker (other extracts) for a herbal active substance		1, 2, 3, 4, 5	IB
k) Change in the testing of specification attribute of the active substance, from routine to skip/periodic testing and vice versa		1, 2, 7	IB
l) Replacement of a specification attribute with its corresponding analytical procedure		1, 2, 3, 4	IB
Conditions
1. The change is not a consequence of any commitment from previous assessments 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 and is not as a result of a safety or quality issue (e.g. new unqualified impurity, change in total impurity limits).
3. The analytical procedure remains the same.
4. The change is fully described in the open (‘applicant’s’) part of an Active Substance Master File, if applicable.
5. For any material, the change does not concern a genotoxic impurity (including nitrosamines). If it involves the final active substance, other than for residual solvents which must be in line with ICH limits, any new impurity control should be in line with the Ph. Eur. or national pharmacopoeia of a Member State.
6. Any new analytical procedure does not concern a novel non-standard technique or a standard technique used in a novel way.
7. 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).
8. The specification attribute does not concern a critical attribute, for example: – identity test, – assay, – purity, – impurities (except when a solvent is no longer used in the manufacture of the active substance), – a critical physical characteristics (for example: polymorphism, particle size, bulk or tapped density), – or water content.
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. Batch analysis data on two production batches [3 production batches (unless otherwise justified) for biologicals]) of the relevant substance for all specification attributes.
5. Justification from the marketing authorisation holder or ASMF holder as appropriate of the new specification attribute and the acceptance criteria.
6. Justification/risk assessment from the marketing authorisation holder or the ASMF holder, as appropriate, that the specification attribute is non-significant, or that the specification attribute is obsolete.
7. Justification from the marketing authorisation holder or the ASMF holder for the change in the testing of specification attribute. A change from routine testing to skip/periodic testing is warranted when the manufacturing process is under control and supported by sufficient amount of historical data compliant with the specification or as foreseen by relevant guidelines. A change from skip/periodic testing to routine testing should be supported by analytical data demonstrating failure to meet the approved acceptance criteria for the skip tested specification.

#qib2

Q.I.b.2 Change to analytical procedure for active substance or starting material/reagent/intermediate used in the manufacturing process of the active substance	Condition to be fulfilled	Documentation to be supplied	Procedure type
Change to analytical procedure for the active substance
(a) Minor change to an analytical procedure for the active substance	1, 2, 3, 4	1, 2	IA
(b) Deletion of an analytical procedure for the active substance if an alternative procedure is already authorised	4, 5	1	IA
(c) Introduction, replacement or substantial change to a biological/immunological/immunochemical analytical procedure for an active substance			II
(d) Other change to an analytical procedure (including replacement or addition) for the active substance		1, 2	IB
Change to analytical procedure for starting material/reagent/intermediate used in the manufacturing process of the active substance
(e) Minor change to an analytical procedure for starting material/reagent/intermediate	1, 2, 3, 4	1, 2	IA
(f) Deletion of an analytical procedure for a starting material/reagent/intermediate, if an alternative analytical procedure is already authorised	4, 5	1	IA
(g) Introduction, replacement or change to a biological/immunological/immunochemical analytical procedure for starting material /reagent /intermediate, used in the manufacturing process of an active substance		1, 2	IB
(h) Other change to an analytical procedure (including replacement or addition) for a starting material/reagent/intermediate	1, 2, 4, 6, 7	1, 2	IA
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. There have been no changes of the total impurity limits; no new unqualified impurities are detected.
3. 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).
4. The change is fully described in the open (‘applicant’s’) part of an Active Substance Master File, if applicable.
5. An alternative analytical procedure is already authorised for the specification attribute.
6. Any new analytical procedure does not concern a novel non-standard technique or a standard technique used in a novel way.
7. The analytical procedure is not a biological/immunological/immunochemical procedure.
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, revised specifications.
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 unless the new analytical procedure is added as an alternative procedure to a current one.

#qib3

Q.I.b.3 Change to an in-house reference standard/preparation for a biological active substance	Condition to be fulfilled	Documentation to be supplied	Procedure type
(a) Replacement of an in-house reference standard/preparation not covered by an approved qualification protocol (1)			II
(b) Replacement of an in-house reference standard/preparation not covered by an approved qualification protocol, where comparability test results using current and proposed reference standard/preparation material are available		1, 2	IB
(c) Introduction of a qualification protocol for the preparation/replacement of an in-house reference standard or preparation (2)			II
(d) Substantial change to the qualification protocol for the preparation/replacement of an in-house reference standard or preparation which may have a significant impact on the quality, safety or efficacy of the active substance			II
(e) Other change to the qualification protocol for the prepartation/replacement of an in-house reference standard or preparation		1	IB
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format), including a description of the manufacturing and qualification of the new in-house reference standard.
2. Comparative test results, showing that the current in-house reference standard and the proposed one are equivalent.

Q.I.c) Container closure system

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

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

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

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

#qic1

Q.I.c.1 Change in immediate packaging of the active substance	Condition to be fulfilled	Documentation to be supplied	Procedure type
(a) Change in immediate packaging of non-liquid active substance	1, 2, 3	1, 2, 3, 4	IA
(b) Change in immediate packaging of sterile liquid active substance			II
(c) Change in immediate packaging of nonsterile liquid active substance		1, 2, 4, 5	IB
(d) Deletion of one of the authorised immediate packagings of the active substance	4	1	IA
Conditions
1. The proposed packaging material must be at least equivalent to the approved material in respect of its relevant properties.
2. 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, 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 shelf life/retest period (with proposed action).
3. The active substance is not a sterile active substance or biological active substance.
4. There should be at least one remaining packaging adequate for the storage of the active substance at the authorised conditions.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).
2. Appropriate data on the new packaging (e.g. comparative data on permeability e.g. for O2, CO2 moisture). Where appropriate, proof must be provided that no interaction between the content and the packaging material has no impact on the active substance quality (e.g. no migration of components of the proposed material into the content and no loss of components of the product into the pack), including confirmation that the material complies with relevant pharmacopoeia requirements or legislation of the Union on plastic material and objects in contact with foodstuffs.
3. A declaration from the marketing authorisation holder or the ASMF holder as appropriate 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. Comparison of the current and proposed immediate packaging specifications, if applicable.
5. 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 retest period (with proposed action).

#qic2

Q.I.c.2 Change in the specification attribute and/or acceptance criteria of the immediate packaging of the active substance	Condition to be fulfilled	Documentation to be supplied	Procedure type
(a) Change of specification acceptance criteria	1, 2, 3, 4	1, 2	IA
(b) Addition of a new specification attribute to the specification with its corresponding analytical procedure	1, 2, 5	1, 2, 3, 4	IA
(c) Deletion of a non-significant or obsolete specification attribute	1, 2, 6	1, 2, 5	IA
(d) Replacement of a specification attribute with its corresponding analytical procedure		1, 2, 3	IB
Conditions
1. The change is not a consequence of any commitment from previous assessments to review specification acceptance criteria (e.g. made during the procedure for the marketing authorisation application or a Type II variation procedure) unless it has been previously assessed and agreed as part of a follow-up measure.
2. The change does not result from unexpected events arising during manufacture of the packaging material or because of stability concerns during storage of the active substance, 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 analytical 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 from the marketing authorisation holder or the ASMF Holder, as appropriate, of the new specification attribute and the acceptance criteria.
5. Justification/risk assessment from the marketing authorisation holder or the ASMF Holder, as appropriate, that the specification attribute is non-significant, or obsolete.

#qic3

Q.I.c.3 Change in analytical procedure for the immediate packaging of the active substance	Condition to be fulfilled	Documentation to be supplied	Procedure type
(a) Minor change to an approved analytical procedure	1, 2, 3	1, 2	IA
(b) Other change to an analytical procedure (including replacement or addition)	1, 3	1, 2	IA
(c) Deletion of an analytical procedure if an alternative procedure is already authorised	4	1	IA
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 procedure.
2. The analytical procedure 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. There is still an analytical procedure registered 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.

#qic4

Q.I.c.4 Change of a secondary packaging component of the active substance (including replacement, addition or deletion), when mentioned in the dossier	Condition to be fulfilled	Documentation to be supplied	Procedure type
	1, 2, 3, 4	1	IA
Conditions
1. The secondary packaging does not play a functional role on the stability of the active substance, 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 active substance 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 because of stability concerns during storage of the active substance.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).

Q.I.d) Stability

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

#qid1

Q.I.d.1 Change in the re-test period/storage period or storage conditions of the active substance or intermediates used in the manufacturing process of the biological active substance	Condition to be fulfilled	Documentation to be supplied	Procedure type
(a) Re-test period/storage period
1. Reduction of re-test period/storage period	1	1, 2, 3, 4	IA
2. Introduction of re-test period/storage period		1, 2, 3	IB
3. Extension of the re-test period/storage period based on extrapolation or stability modelling not in accordance with relevant stability guidelines			II
4. Extension of re-test period/storage period supported by real time data not in accordance with an approved stability protocol or an extension based on extrapolation of stability data in accordance with relevant stability guidelines		1, 3	IB
5. Extension of a re-test period/storage period supported by real time data fully in line with the stability protocol	2	1, 2, 3	IA
(b) Storage conditions
1. Change to more restrictive storage conditions	1, 3	1, 2, 3	IA
2. Change in storage conditions		1, 2, 3	IB
(c) Change to an approved stability protocol	1, 4	1, 4	IA
Conditions
1. The change should not be the result of unexpected events arising during manufacture or because of stability concerns.
2. Stability studies have been performed in accordance with a currently approved stability protocol. Real time data are submitted. All batches meet their pre-defined specification at all time points. No unexpected trends have been observed.
3. The physical state of the active substance has not changed.
4. The changes do 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.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format). This must contain results of appropriate real time stability studies, conducted in accordance with the relevant stability guidelines on three pilot or production scale batches of the active substance or intermediate in the authorised packaging material.
2. Confirmation that stability studies have been done to the currently approved protocol. The studies must show that the agreed relevant specifications are still met.
3. Copy of approved specifications of the active substance (as annex to the application form).
4. Justification for the proposed changes.

Q.II. FINISHED PRODUCT

Q.II.a) Description and composition

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

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

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

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

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

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

#qiia1

Q.II.a.1 Change or addition of imprints, bossing (embossing/debossing) or other markings including replacement, or addition of inks used for product marking	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Changes in imprints, bossing (embossing/debossing) or other markings	1, 2, 3, 4	1	IA_IN
(b) Changes in scoring/break lines intended to divide into equal doses		1, 2	IB
Conditions
1. Finished product release and end of shelf life specifications have not been changed (except for appearance).
2. Any ink must comply with the relevant pharmaceutical legislation.
3. The scoring/break lines are not intended to divide into equal doses.
4. Any product markings used to differentiate strengths should not be completely deleted.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format), including a detailed drawing or written description of the current and new appearance, and including revised product information as appropriate.
2. Results of the appropriate Ph. Eur tests demonstrating equivalence in characteristics/correct dosing.

#qiia2

Q.II.a.2 Change in the shape or dimensions of the pharmaceutical form	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Immediate release tablets, capsules, suppositories and pessaries	1, 2, 3, 4	1, 4	IA_IN
(b) Gastro-resistant, modified or prolonged release pharmaceutical forms and scored tablets intended to be divided into equal doses		1, 2, 3, 4	IB
(c) Addition of a new kit for a radiopharmaceutical preparation with another fill volume			II
Conditions
1. If appropriate, the dissolution profile of the reformulated product is comparable to the old one. For herbal medicinal products, where dissolution testing may not be feasible, the disintegration time of the new product compared to the old one.
2. Release and end of shelf life specifications of the product have not been changed (except for shape or dimensions).
3. The qualitative or quantitative composition and mean mass remain unchanged.
4. The change does not relate to a scored tablet that is intended to be divided into equal doses.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format), including a detailed drawing of the current and proposed situation, and including revised product information as appropriate.
2. Comparative dissolution data on at least one pilot batch of the current and proposed dimensions (no significant differences regarding comparability see the relevant guideline on Investigation of Bioequivalence). For herbal medicinal product comparative disintegration data may be acceptable.
3 Justification for not submitting a new bioequivalence study according to the relevant guideline on Investigation of Bioequivalence.
4. Results of the appropriate Ph. Eur tests demonstrating equivalence in characteristics/correct dosing.
Note: For Q.II.a.2.c Applicants are reminded that any change to the ‘strength’ of the finished product requires the submission of an Extension application.

#qiia3

Q.II.a.3 Change in the composition (excipients) of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Change in components of the flavouring or colouring system
1. Addition, deletion or replacement	1, 2, 3, 4, 5, 6, 7, 9	1, 2, 4, 5	IA_IN
2. Increase or reduction	1, 2, 3, 4,	1, 2	IA
(b) Other excipients
1. Any minor adjustment of the quantitative composition of the finished product with respect to excipients	1, 2, 4, 8, 9, 10	1, 2, 6	IA
2. Qualitative or quantitative changes in one or more excipients that may have a significant impact on the safety, quality or efficacy of the finished product (for example, biological excipients or a new excipient that includes the use of materials of human or animal origin for which assessment is required of viral safety data or TSE risk)			II
3. Change that is supported by a bioequivalence study			II
4. Replacement of excipient(s) with comparable excipient(s) with the same functional characteristics		1, 3, 4, 5, 6, 7, 8	IB
Conditions
1. No change in functional characteristics of the pharmaceutical form (e.g. disintegration time, dissolution profile).
2. Any minor adjustment to the formulation to maintain the total weight should be made by one or more excipient(s) which currently make(s) up a major part of the finished product formulation.
3. The finished product specification has only been updated in respect of appearance/odour/taste and if relevant, deletion of an identification test.
4. Stability studies have been started under ICH conditions (with indication of batch numbers) 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 for Type IAs and at time of notification for Type IBs) and that the stability profile is similar to the currently registered situation. 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 specification at the end of the approved shelf life (with proposed action). In addition, where relevant, photo-stability testing should be performed.
5. Any new proposed components must comply with the relevant Union legislation (e.g. Regulation (EC) No 1333/2008 of the European Parliament and of the Council (³), Commission Regulation (EU) No 231/2012 (⁴) on food additives and Regulation (EC) No 1334/2008 of the European Parliament and of the Council (⁵) for flavours).
6. Any new component does not include the use of materials of human or animal origin for which assessment is required of viral safety data or compliance with the current Note For Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products.
7. Where applicable, the change does not affect the differentiation between strengths and does not have a negative impact on taste acceptability for paediatric formulations.
8. The dissolution profile of the new product determined on a minimum of two pilot scale batches is comparable to the old one (no significant differences regarding comparability, see the relevant guideline on Investigation of Bioequivalence). For herbal medicinal products where dissolution testing may not be feasible, the disintegration time of the new product is comparable to the old one.
9. The change is not the result of stability issues and/or should not result in potential safety concerns i.e. differentiation between strengths.
10. The product concerned is not a biological finished product.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format), and revised product information as appropriate.
2. 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).
3. 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).
4. 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 should 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. For the centralised procedure, this information should be included in an updated TSE table A (and B, if relevant).
5. Data to demonstrate that the new excipient does not interfere with the finished product specification analytical procedures, if appropriate.
6. Justification for the change/choice of excipients etc. must be given by appropriate development pharmaceutics (including stability aspects and antimicrobial preservation where appropriate).
7. For solid dosage forms, comparative dissolution profile data of at least two pilot scale batches of the finished product in the new and old composition. For herbal medicinal products, comparative disintegration data may be acceptable.
8. Justification for not submitting a new bioequivalence study according to the current guideline on Investigation of Bioequivalence.
Notes: (³) Regulation (EC) No 1333/2008 of the European Parliament and of the Council of 16 December 2008 on food additives (OJ L 354, 31.12.2008, p. 16, ELI: http://data.europa.eu/eli/reg/2008/1333/oj). (⁴) Commission Regulation (EU) No 231/2012 of 9 March 2012 laying down specifications for food additives listed in Annexes II and III to Regulation (EC) No 1333/2008 of the European Parliament and of the Council (OJ L 83, 22.3.2012, p. 1, ELI: http://data.europa.eu/eli/reg/2012/231/oj). (⁵) Regulation (EC) No 1334/2008 of the European Parliament and of the Council of 16 December 2008 on flavourings and certain food ingredients with flavouring properties for use in and on foods and amending Council Regulation (EEC) No 1601/91, Regulations (EC) No 2232/96 and (EC) No 110/2008 and Directive 2000/13/EC (OJ L 354, 31.12.2008, p. 34, ELI: http://data.europa.eu/eli/reg/2008/1334/oj).

#qiia4

Q.II.a.4 Change in coating weight of oral dosage forms or change in weight of capsule shells	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Solid oral pharmaceutical forms	1, 2, 3, 4	1, 2	IA
(b) Gastro-resistant pharmaceutical forms where the coating or capsule shell is a critical factor for the release mechanism		1, 3, 4, 5, 6	IB
(c) Modified or prolonged release pharmaceutical forms where the coating or capsule shell is a critical factor for the release mechanism			II
Conditions
1. The dissolution profile of the new product determined on a minimum of two pilot scale batches is comparable to the old one. For herbal medicinal products where dissolution testing may not be feasible, the disintegration time of the new product is comparable to the old one.
2. The coating is not a critical factor for the release mechanism or for the control of other quality attribute(s).
3. The finished product specification has only been updated in respect of weight and dimensions, if applicable.
4. Stability studies in accordance with the relevant guidelines have been started with 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 the time of implementation and assurance that these studies will be finalised. 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).
2. 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). In addition, where relevant, photo-stability testing should be performed.
3. 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).
4. Comparative batch analysis data and comparative dissolution profile data of at least two pilot scale batches of the finished product in the current and proposed formulation. For herbal medicinal products where dissolution testing may not be feasible, comparative disintegration data should be provided.
5. Justification for not submitting a new bioequivalence study according to the current guideline on the Investigation of Bioequivalence.
6. Declaration that the finished product specification has only been updated in respect of weight and dimensions.

#qiia5

Q.II.a.5 Change in concentration of a single-dose, total use parenteral product, where the amount of active substance per unit dose (i.e. the strength) remains the same	Conditions to be fulfilled	Documentation to be supplied	Procedure type
			II

#qiia6

Q.II.a.6 Deletion of the solvent/diluent container from the pack	Conditions to be fulfilled	Documentation to be supplied	Procedure type
		1, 2	IB
Documentation
1. Justification for the deletion, including a statement regarding alternative means to obtain the solvent/diluent as required for the safe and effective use of the finished product.
2. Revised product information.

Q.II.b) Manufacture

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

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

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

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

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

#qiib1

Q.II.b.1 Change in the manufacturing site for part or all of the manufacturing process of the finished product (except for batch release and batch control testing sites)	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Addition or replacement of a site responsible for secondary packaging	1, 2	1, 7	IA_IN
(b) Addition or replacement of a site responsible for immediate packaging	1, 2, 3, 4	1, 2, 7, 8	IA_IN
(c) Addition or replacement of a site responsible for any manufacturing operation(s) of finished product manufactured by novel or complex manufacturing processes			II
(d) Addition or replacement of a site which requires an initial or product specific GMP inspection			II
(e) Addition or replacement of a site responsible for any manufacturing operation(s) of a finished product		1, 2, 4, 5, 6, 7, 8	IB
(f) Addition or replacement of a site responsible for the assembly of a finished product containing an integral medical device		1, 2, 3, 4, 7	IB
Conditions
1. Satisfactory inspection in the last three years by an inspectorate of one of the Member States of the EU/EEA or for sites located in a country where an operational Good Manufacturing Practice (GMP) mutual recognition agreement (MRA) or other relevant agreement exists between the country concerned and the EU, by that concerned international partner authority.
2. Site appropriately authorised (to manufacture the pharmaceutical form or product concerned).
3. Product concerned is not a sterile product.
4. Where relevant, validation scheme is 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.
Documentation
1. Valid proof that the proposed site is GMP compliant for the manufacturing and/or testing operation(s)concerned: – For a manufacturing site within the EU/EEA: a copy of the current manufacturing authorisation. A reference to the EudraGMP database will suffice; – For a third country site where a GMP mutual recognition agreement (MRA) or other relevant agreement is in place between the country concerned and the EU: a proof of GMP compliance issued within the last 3 years by the relevant local competent authority; – For a third country site where no MRA or relevant agreement on GMP is in place: a GMP certificate issued within the last 3 years by an EEA Member State relevant international authority. A reference to the EudraGMP database will suffice.
2. Where relevant, the batch numbers, corresponding batch size and the manufacturing date of batches (≥ 3) used in the validation study should be indicated and the validation data presented, or validation protocol (scheme) to be submitted.
3. Copy of approved release and end-of-shelf life specifications if relevant (as annex to the application form).
4. Batch analysis data on one production batch and two pilot scale batches simulating the production process (or two production batches) and comparative data on the last three batches from the previous site; batch data on the next two production batches should be available on request or reported if outside specifications (with proposed action). Batch analysis data of 3 batches (unless otherwise justified) of the biological finished product, manufactured from the current and proposed manufacturers/sites.
5. For semisolid and liquid formulations in which the active substance is present in non-dissolved form, appropriate validation data including microscopic imaging of particle size distribution and morphology or any other appropriate imaging technique.
6. (i) If the new manufacturing site uses the active substance as a starting material – A declaration by the qualified person at the site responsible for batch release that the active substance is manufactured in accordance with the detailed guidelines on good manufacturing practice for starting materials as adopted by the Union. (ii) In addition, if the new manufacturing site is located within the EU/EEA and uses the active substance as a starting material – A declaration by the qualified person of the new manufacturing site that the active substance used is manufactured in accordance with the detailed guidelines on good manufacturing practice for starting materials as adopted by the Union.
7. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).
8. If the manufacturing site and the immediate packaging site are different, conditions of transport and bulk storage should be specified and validated.
Notes: In case of a change in or a new manufacturing site in a country outside the EU/EEA without an operational GMP mutual recognition agreement with the EU, marketing authorisation holders are advised to consult the relevant competent authorities first before making the submission of the notification and to provide information about any previous EU/EEA inspection in the last 2-3 years and/or any planned EU/EEA inspection(s) including inspection dates, product category inspected, supervisory authority and other relevant information. This will facilitate the arrangement for a GMP inspection by an inspection service of one of the Member States if needed. QP Declarations in relation to active substances Manufacturing authorisation holders are obliged to only use as starting materials active substances that have been manufactured in accordance with GMP so a declaration is expected from each of the manufacturing authorisation holders that use the active substance as a starting material. In addition, as the QP responsible for batch certification takes overall responsibility for each batch, a further declaration from the QP responsible for batch certification is expected when the batch release site is a different site from the above. In many cases only one manufacturing authorisation holder is involved and therefore only one declaration will be required. However, when more than one manufacturing authorisation holder is involved rather than provide multiple declarations it may be acceptable to provide a single declaration signed by one QP. This will be accepted provided that: The declaration makes it clear that it is signed on behalf of all the involved QPs. The arrangements are underpinned by a technical agreement as described in Chapter 7 of the GMP Guide and the QP providing the declaration is the one identified in the agreement as taking specific responsibility for the GMP compliance of the active substance manufacturer(s). Note: These arrangements are subject to inspection by the competent authorities. Applicants are reminded that a QP is at the disposal of a manufacturing authorisation holder according to Art. 41 of Directive 2001/83/EC and located in the EU/EEA. Therefore, declarations from personnel employed by manufacturers in third countries, including those located within MRA partner countries are not acceptable. According to Article 46a of Directive 2001/83/EC, manufacture includes complete or partial manufacture, import, dividing up, packaging or presentation prior to its incorporation into a finished product, including re-packaging or re-labelling as carried out by a distributor. A declaration is not required for blood or blood components, they are subject to the requirements of Directive 2002/98/EC (Directive 2002/98/EC of the European Parliament and of the Council of 27 January 2003 setting standards of quality and safety for the collection, testing, processing, storage and distribution of human blood and blood components and amending Directive 2001/83/EC (OJ L 33, 8.2.2003, p. 30, ELI: http://data.europa.eu/eli/dir/2002/98/oj)).

#qiib2

Q.II.b.2 Change to batch release arrangements and batch control testing of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Addition or replacement of a batch control/testing site applying physicochemical and/or microbiological analytical procedures for the finished product	2, 3, 4, 5	1, 4	IA
(b) Addition or replacement of a batch control/testing site applying a biological/immunological/immunochemical analytical procedure for a biological finished product		1, 4, 5	IB
(c) Addition or replacement of a site responsible for batch release (QP certification)
1. Not including batch control/testing	1, 2, 5	1, 2, 3, 4, 6	IA_IN
2. Including batch control/testing applying physicochemical and/or microbiological analytical procedures for the finished product	1, 2, 3, 4, 5	1, 2, 3, 4 6	IA_IN
3. Including batch control/testing applying a biological/immunological/immunochemical analytical procedure for a biological finished product		1, 2, 3, 4, 5, 6	IB
Conditions
1. The manufacturer responsible for batch release must be located within the EU/EEA and hold a valid manufacturing authorisation for the proposed operations issued by the relevant competent authority of the EU/EEA Member State. At least one batch release site remains within the EU/EEA that is able to certify the product testing for the purpose of batch release within the EU/EEA.
2. The site is appropriately authorised.
3. The analytical procedure is not a biological/immunological/immunochemical procedure.
4. Method transfer from the old to the new site or new test laboratory has been successfully completed.
5. At least one batch control/testing site remains within the EU/EEA or in a country where an operational and suitably scoped GMP mutual recognition agreement (MRA) or other relevant agreement exists between the country concerned and the EU, that is able to carry out product testing for the purpose of batch release within the EU/EEA.
Documentation
1. Valid proof that the proposed site is GMP compliant for the manufacturing and/or testing operation(s) concerned: – For a site within the EU/EEA: a copy of manufacturing authorisation(s) or where no manufacturing authorisation exists a certificate of GMP compliance issued within the last 3 years by the relevant competent authority. A reference to the EudraGMP database will suffice. – For a third country site where a GMP mutual recognition agreement (MRA) or other relevant agreement on GMP is in place between the country concerned and the EU: a proof of GMP compliance, issued within the last 3 years by the relevant local competent authority. – For a third country site where no MRA or relevant agreement on GMP is in place: a GMP certificate issued within the last 3 years by an EEA Member State. A reference to the EudraGMP database will suffice.
2. For centralised procedure only: contact details of new contact person in the EU/EEA for product defects and recalls, if applicable.
3. A declaration by the qualified person (QP) responsible for batch certification stating that the active substance manufacturer(s) referred to in the marketing authorisation operate in compliance with the detailed guidelines on good manufacturing practice for starting materials. A single declaration may be acceptable under certain circumstances (see the note under variation no. Q.II.b.1).
4. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format), as appropriate.
5. The analytical procedure transfer protocols in accordance with Eudralex Volume 4 Chapter 6 Article 6.39 (which pre-define the acceptance criteria), from the old site to the new site (or new test laboratory).
6. Revised product information.

#qiib3

Q.II.b.3 Change in the manufacturing process of the finished product, including an intermediate used in the manufacture of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Minor change in the manufacturing process	1, 2, 3, 4, 5, 6, 7, 8	1, 2, 3, 4, 5, 6, 7, 8, 9	IA
(b) Major change to a manufacturing process of the finish product that may have a significant impact on the quality, safety and efficacy of the finished product			II
(c) Introduction of a non-standard terminal sterilisation method			II
(d) Introduction of, or change in, an overage that is used for the active substance			II
(e) Change in the holding time and/or storage conditions of an intermediate or bulk product used in the manufacture of the finished product		1, 6, 10	IB
Conditions
1. No change in qualitative and quantitative impurity profile or in physico-chemical properties.
2. The change relates to immediate release oral pharmaceutical forms or to non-sterile solutions or the change relates to non-critical process parameter(s), i.e. process parameter(s) that, in the context of a previous assessment by the competent authority, have been considered to have no impact on the quality of the finished product (regardless of the type of product and/or dosage form).
3. The manufacturing principle including the single manufacturing steps remain the same (e.g. processing intermediates and there are no changes to any manufacturing solvent used in the process).
4 The currently registered process has to be controlled by relevant in-process controls and no changes (widening or deletion of limits) are required to these controls.
5. The specifications of the finished product or intermediates are unchanged.
6. The new process must lead to an identical product regarding all aspects of quality, safety and efficacy.
7. Relevant stability studies in accordance with the relevant guidelines have been started with at least one pilot scale or industrial scale batch. Assurance is given that these studies will be finalised and that 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).
8. 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.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format), including a direct comparison of the present process and the new process.
2. For semi-solid and liquid products in which the active substance is present in non-dissolved form: appropriate validation of the change including microscopic imaging of particles to check for visible changes in morphology; comparative size distribution data by an appropriate method.
3. For solid dosage forms: dissolution profile data of one representative production batch and comparative data of the last three batches from the previous process; data on the next two full production batches should be available on request or reported if outside specification (with proposed action). For herbal medicinal products, comparative disintegration data may be acceptable.
4. Justification for not submitting a new bioequivalence study according to the relevant guidance on Investigation of Bioequivalence.
5. For changes to process parameter(s) that have been considered to have no impact on the quality of the finished product, declaration to this effect reached in the context of the previously approved risk assessment.
6. Copy of approved release and end-of-shelf life specifications (as annex to the application form).
7. Batch analysis data (in a comparative tabulated format) on a minimum of two batches manufactured to both the currently approved and the proposed process.
8. Declaration that relevant stability studies have been started under ICH conditions, as appropriate, (with indication of the batch numbers concerned) and relevant stability parameters have been assessed in at least one pilot scale or industrial scale batch. Assurance is given that these studies will be finalised and that 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).
9. A declaration from the marketing authorisation holder that an evaluation of the concerned manufacturing step(s) has been performed and the minor change does not impact the quality, safety or efficacy of the finished product.
10. Data to validate the proposed change in holding time and/or storage conditions of the intermediate or bulk product (minimum of two batches at pilot or commercial scale). Composition of the intermediate or bulk container should be described and its specification stated. If pilot scale batches are provided, a commitment to verify these data on commercial scale batches. Declaration that the finished product shelf life is set in accordance with the Note for guidance on start of shelf life of the finished dosage form, or otherwise justified.

#qiib4

Q.II.b.4 Change in the batch size (including batch size ranges) of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Up to 10-fold increase compared to the originally approved batch size	1, 2, 3, 4, 5, 7	1, 3	IA
(b) Downscaling down to 10-fold	1, 2, 3, 4, 5, 6	1, 3	IA
(c) The change requires assessment of the comparability of a biological finished product or the change in batch size requires a new bioequivalence study			II
(d) The change relates to all other pharmaceutical forms manufactured by novel or complex manufacturing processes			II
(e) More than 10-fold increase/decrease compared to the originally approved batch size		1, 2, 3, 4, 5, 6	IB
(f) The scale for a biological finished product is increased/decreased without process change (e.g. duplication of line)		1, 2, 3, 4, 5, 6	IB
Conditions
1. The change does not affect reproducibility and/or consistency of the product.
2. The change relates to immediate release oral pharmaceutical forms or to non-sterile solutions.
3. Any changes to the manufacturing method and/or to the in-process controls are only those necessitated by the change in batch-size, e.g. use of different sized equipment.
4. Validation scheme is available or validation of the manufacture has been successfully carried out according to the current protocol with at least three batches at the proposed new batch size in accordance with the relevant guidelines.
5. The product concerned is not a biological finished product.
6. The change should not be the result of unexpected events arising during manufacture or because of stability concerns.
7. The batch size is within the 10-fold range of the batch size foreseen when the marketing authorisation was granted or following a subsequent change not agreed as a Type IA variation.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).
2. Batch analysis data (in a comparative tabulated format) on a minimum of two production batches manufactured to both the currently approved and the proposed sizes. Batch analysis data of 3 batches (unless otherwise justified) for biological finished product should be available for the proposed batch size.
3. Where relevant the batch numbers, corresponding batch size and the manufacturing date of batches (≥ 3) used in the validation study should be indicated or validation protocol (scheme) be submitted.
4. The validation results should be provided.
5. The results of stability studies that have been carried out under ICH conditions, on the relevant stability parameters, on at least one pilot or industrial scale batch, 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).
6. For biological finished products, a justification that an assessment of comparability is not required.

#qiib5

Q.II.b.5 Change to in-process control or limits applied during the manufacture of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Minor changes of in-process control limits	1, 2, 3, 4	1, 2	IA
(b) Addition of new in-process control and limits with its corresponding analytical procedure	1, 2, 5	1, 2, 3, 4, 6	IA
(c) Deletion of a non-significant or obsolete in-process control	1, 2, 7, 9	1, 2, 5	IA
(d) Deletion of an in-process control which may have a significant effect on the overall quality of the finished product			II
(e) Widening of the approved in-process control limits, which may have a significant effect on overall quality of the finished product			II
(f) Change of an analytical procedure for an in-process control	2, 4, 6, 8	1, 7	IA
(g) Replacement of an in-process control with its corresponding analytical procedure		1, 2, 3, 4, 5	IB
Conditions
1. The change is not a consequence of any commitment from previous assessments to review in-process control (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, e.g. new unqualified impurity detected, or a change in total impurity limits.
3. Any change should be within the range of currently approved limits.
4. The analytical procedure remains the same, or changes in the procedure are minor (e.g. a change in column length or temperature could be allowed, but not a different type of column or method).
5. Any new analytical procedure does not concern a novel non-standard technique or a standard technique used in a novel way.
6. The analytical procedure is not a biological/immunological/immunochemical procedure.
7. The in-process control does not concern the control of a critical attribute for example: – assay, – purity, – impurities (except solvent is no longer used in the manufacture), – a critical physical characteristic (for example: particle size, bulk or tapped density), – identity test (unless there is a suitable alternative control already present), – microbiological control (unless not required for the particular dosage form).
8. Appropriate studies have been performed in accordance with the relevant guidelines to show that the updated analytical procedure is at least equivalent to the former analytical procedure.
9. 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 in-process control and limits.
3. Details of any new analytical procedure and validation data, where relevant.
4. Batch analysis data on two production of the finished product for all specification attributes.
5. Justification/risk assessment showing that the in-process control is non-significant or that it is obsolete.
6. Justification of the new in-process control and limits.
7. Comparative study results or 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.

Q.II.c) Control of excipients

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

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

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

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

#qiic1

Q.II.c.1 Change in the specification attribute and/or acceptance criteria of an excipient	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Change within the approved specification acceptance criteria	1, 2, 4	1, 2	IA
(b) Addition of a new specification attribute to the specification with its corresponding analytical procedure	1, 2, 5, 6	1, 2, 3, 4, 5, 7	IA
(c) Deletion of a non-significant or obsolete specification attribute	1, 2, 3, 7	1, 2, 6	IA
(d) Change outside of the approved specification acceptance criteria			II
(e) Deletion of a specification attribute which may have a significant effect on the overall quality of the finished product			II
(f) Change in specification of an excipient from in-house to a non-official Pharmacopoeia/Pharmacopoeia of a third country where there is no monograph in the European Pharmacopoeia or the national pharmacopoeia of a Member State		1, 2, 3, 4, 5, 7	IB
(g) Replacement of a specification attribute with its corresponding analytical procedure		1, 2, 3, 4, 7	IB
Conditions
1. The change is not a consequence of any commitment from previous assessments 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, e.g. new unqualified impurity; change in total impurity limits.
3. The change is not related to a revisions of the control strategy with an intention to minimise redundant testing of parameters and attributes (critical or non-critical).
4. The analytical procedure remains the same, or changes in the analytical 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 does not concern a genotoxic impurity.
7. The specification attribute does not concern the control of a critical attribute, for example: – assay, – purity, – impurities (except when a solvent is no longer used in the manufacture of the excipient), – a critical physical characteristic (for example: particle size, bulk or tapped density) – identity test (unless there is a suitable alternative control already present), – water content – microbiological control (unless not required for the particular dosage form).
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. Batch analysis data on two production batches of the excipient for all specification attributes [3 production batches (unless otherwise justified) for biological excipients or novel excipients].
5. Justification for not submitting a new bioequivalence study according to the relevant Guideline on The Investigation of Bioequivalence, if appropriate.
6. Justification/risk assessment showing that the attribute is non-significant or that it is obsolete.
7. Justification of the new specification attribute and the acceptance criteria.

#qiic2

Q.II.c.2 Change in analytical procedure for an excipient	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Minor change to an approved analytical procedure	1, 2, 3	1, 2	IA
(b) Deletion of an analytical procedure if an alternative analytical procedure is already authorised	4	1	IA
(c) Introduction, replacement or substantial change to a biological/immunological/immunochemical analytical procedure for an excipient			II
(d) Other changes to an analytical procedure (including replacement or addition)		1, 2	IB
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. There have been no changes of the total impurity limits; no new unqualified impurities are detected.
3. 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).
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, revised specifications.
2. Comparative validation results or if justified comparative analysis results showing that the current analytical and the proposed one are equivalent. This requirement is not applicable in case of an addition of a new analytical procedure.

#qiic3

Q.II.c.3 Change in source of an excipient or reagent with TSE risk, which is used in the manufacture of an active substance or in a finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Change in the source of an excipient or reagent from a TSE risk material to a material of vegetable or synthetic origin	1	1, 2, 3	IA
(b) Change in the source of an excipient or reagent which is unlikely to present any risk of TSE contamination	1, 2	1, 3	IA
(c) Change in the source of a TSE risk material, or introduction of a TSE risk material, not covered by a European Pharmacopoeial TSE certificate of suitability			II
Conditions
1. Excipient and finished product release and end of shelf life specifications remain the same.
2. Compliance with the conditions formulated in the Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products has to be ensured.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format.
2. Declaration from the manufacturer or the marketing authorisation holder of the material that it is purely of vegetable or synthetic origin.
3. Confirmation of equivalence of the materials and that there is no impact on the quality of the finished product.

#qiic4

Q.II.c.4 Change in synthesis, manufacturing or recovery of an excipient (when described in the dossier)	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Minor change in synthesis, manufacturing or recovery of an excipient	1, 2, 3	1, 2, 3, 4	IA
(b) Change in the manufacturing site, synthesis, manufacturing or recovery of the excipient which may affect the quality, safety or efficacy of the finished product			II
(c) Deletion of one manufacturing process of an excipient	4, 5	1	IA
(d) Addition or replacement of a site responsible for the manufacture or testing of an excipient, when required to be described in the dossier		1, 2	IB
Conditions
1. The synthetic route/manufacturing process and specifications are identical and there is no change in qualitative and quantitative impurity profile (excluding residual solvents, provided they are controlled in accordance with ICH limits), or in physico-chemical properties.
2. Adjuvants are excluded.
3. The excipient is not a biological substance.
4. The deletion should not be due to critical deficiencies concerning manufacturing.
5. There should at least remain one manufacturing process, as previously authorised.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).
2. Batch analysis data (in a comparative tabulated format) of at least two batches (minimum pilot scale) (or 3 production batches (unless otherwise justified) for biological excipients) of the excipient manufactured according to the present and proposed process, or by the present and proposed manufacturer, as applicable.
3. Where appropriate, comparative dissolution profile data for the finished product of at least two batches (minimum pilot scale). For herbal medicinal products, comparative disintegration data may be acceptable.
4. Copy of approved and new (if applicable) specifications of the excipient (as annex to the application form).

Q.II.d) Control of finished product

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

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

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

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Q.II.d.1 Change in the specification attribute and/or acceptance criteria of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Change within the specifications acceptance criteria	1, 2, 4	1, 2	IA
(b) Change within the specification acceptance criteria for finished products subject to Official Control Authority Batch Release	1, 2, 4	1, 2	IA_IN
(c) Addition of a new specification attribute with its corresponding analytical procedure and acceptance criteria	1, 2, 5, 6	1, 2, 3, 4, 6	IA
(d) Deletion of a non-significant or obsolete specification attribute (e.g. deletion of odour and taste or identification test for a colouring or flavouring material)	1, 2, 3, 7	1, 2, 5	IA
(e) Change outside of the specification acceptance criteria of the finished product			II
(f) Deletion of a specification attribute which may have a significant effect on the overall quality of the finished product			II
(g) Update of the dossier to comply with the provisions of an updated general monograph of the Ph. Eur(²).	1, 2, 4, 6	1, 2	IA_IN
(h) Ph. Eur. 2.9.40 Uniformity of dosage units is introduced to replace the currently registered method, either Ph. Eur. 2.9.5 (Uniformity of mass) or Ph. Eur. 2.9.6 (Uniformity of content)	1, 2, 8	1, 2, 4	IA
(i) Change in the testing of specification attribute, from routine to skip/periodic testing and vice versa		1, 2, 7	IB
(j) Replacement of a specification attribute with its corresponding analytical procedure		1, 2, 3, 4, 6	IB
Conditions
1. The change is not a consequence of any commitment from previous assessments to review specification acceptance criteria (e.g. made during the procedure for the marketing authorisation application or a Type II variation procedure), unless the supporting documentation has been already assessed and approved within another procedure.
2. The change does not result from unexpected events arising during manufacture or because of stability concerns, or as a result of a safety or quality issue, e.g. new unqualified impurity; change in total impurity acceptance criteria.
3. 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).
4. The analytical procedure remains the same.
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 does not concern any impurities (including genotoxic) or dissolution.
7. The specification attribute or proposal for the specific dosage form does not concern a critical attribute, for example: – identity, – assay, – purity, – impurities (except solvent is not used in the manufacture of the finished product), – critical physical characteristics (for example: hardness or friability for uncoated tablets, dimensions) – a test that is required for the particular dosage form in accordance with the general notices of the Ph. Eur., – any request for skip testing.
8. The proposed control is fully in line with the Table 2.9.40.-1 of Ph. Eur. 2.9.40 monograph, and does not include the alternative proposal for testing uniformity of dosage units by Mass Variation instead of Content Uniformity when the latter is specified in Table 2.9.40.-1.
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. Batch analysis data on two production batches (3 production batches (unless otherwise justified) for biologicals) of the finished product for all specification attributes.
5. Justification/risk assessment showing that the attribute is non-significant or that it is obsolete.
6. Justification of the new specification attribute and the acceptance criteria.
8 7. Justification from the holder for the change in the testing of specification attribute. A change from routine testing to skip/periodic testing is warranted when the manufacturing process is under control and supported by a sufficient amount of historical data compliant with the specification. A change from skip/periodic testing to routine testing should be supported by analytical data demonstrating failure to meet the approved acceptance criteria for the skip tested specification.
(²) Note: Upon approval of the variation for the qualification protocol, the introduction of a new reference standard for a biological active substance/finished product or the extension of its re-test period/storage period, according to the approved qualification protocol will be covered by the existing quality assurance system and hence, there will be no need to file a variation as long as all approved acceptance criteria are met.

#qiid2

Q.II.d.2 Change to analytical procedure for the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Minor change to an approved analytical procedure	1, 2, 3	1, 2	IA
(b) Deletion of an analytical procedure if an alternative procedure is already authorised	4	1	IA
(c) Introduction, replacement, or substantial change to a biological/immunological/immunochemical analytical procedure for a finished product			II
(d) Other change to an analytical procedure for a finished product (including replacement or addition)		1, 2	IB
(e) Update of the analytical procedure to comply with the updated general monograph in the Ph. Eur.	2, 3, 5, 6	1	IA
(f) To reflect compliance with the Ph. Eur. and remove reference to the outdated internal analytical procedure and analytical procedure number	2, 3, 5, 6	1	IA
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 procedure.
2. There have been no changes of the total impurity limits; no new unqualified impurities are detected.
3. 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).
4. An alternative analytical procedure is already authorised for the specification attribute.
5. The registered analytical procedure already refers to the general monograph of the Ph. Eur. and any changes are minor in nature and require update of the technical dossier.
6. The analytical procedure is not a biological/immunological/immunochemical procedure.
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, revised specifications.
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 unless the new analytical procedure is added as an alternative procedure to a current one.

#qiid3

Q.II.d.3 Variations related to real-time release testing in the manufacture of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
Introduction, replacement, or substantial change of a real-time release testing procedure			II
Note: For changes to in-house reference standard/preparation for a biological finished product, refer to category Q.I.b.3 Change to an in-house reference standard/preparation for a biological active substance.

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

#qiie1

Q.II.e.1 Change in immediate packaging of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Change in qualitative and quantitative composition of an approved container
1. Solid pharmaceutical forms	1, 2, 3, 5, 6	1, 2, 3, 5	IA
2. Semi-solid and non-sterile liquid pharmaceutical forms		1, 2, 4, 5	IB
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, 5	IB
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 form	4	1, 6	IA
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.

#qiie2

Q.II.e.2 Change in shape or dimensions of the container or closure (immediate packaging) of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Non-sterile finished products	1, 2, 3	1, 3	IA
(b) Sterile finished products		1, 2, 3	IB
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).

#qiie3

Q.II.e.3 Change in any part of the (primary) packaging material not in contact with the finished product formulation (such as colour of flip-off caps, colour code rings on ampoules)	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Change that affects the product information	1	1	IA_IN
(b) Change that does not affect the product information	1	1	IA
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.

#qiie4

Q.II.e.4 Change in the specification attribute and/or acceptance criteria of the immediate packaging of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Change of specification acceptance criteria	1, 2, 3, 4	1, 2	IA
(b) Addition of a specification attribute to the specification with its corresponding analytical procedure	1, 2, 5	1, 2, 3, 5	IA
(c) Deletion of a non-significant or obsolete specification attribute	1, 2, 6	1, 2, 4	IA
(d) Replacement of a specification attribute with its corresponding analytical procedure		1, 2, 3	IB
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.

#qiie5

Q.II.e.5 Change in analytical procedure for the immediate packaging of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Minor change to an approved analytical procedure	1, 2, 3	1, 2	IA
(b) Other changes to an analytical procedure (including replacement or addition)	1, 3	1, 2	IA
(c) Deletion of an analytical procedure if an alternative analytical procedure is already authorised	4	1	IA
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.

#qiie6

Q.II.e.6 Change in pack size of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure 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 sizes	1, 2	1, 3	IA_IN
2. Change outside the range of the currently approved pack sizes		1, 2, 3	IB
(b) Deletion of pack size(s)	3	1, 2	IA
(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, 3	IB
(e) Addition of or change to a calendar package for a pack size already registered in the dossier	2	1	IA_IN
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.

#qiie7

Q.II.e.7 Change in manufacturer, sterilisation process or supplier of packaging components (when mentioned in the dossier)	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Addition or replacement of a manufacturer or supplier	1, 2, 3, 4	1, 2	IA
(b) Addition or replacement of a site responsible for sterilisation of a packaging component, and/or a change to the sterilisation process		3, 4	IB
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.

#qiie8

Q.II.e.8 Change of a secondary packaging component of the finished product (including replacement or addition or deletion), when mentioned in the dossier	Conditions to be fulfilled	Documentation to be supplied	Procedure type
	1, 2, 3, 4	1	IA
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).

Q.II.f) Stability

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

#qiif1

Q.II.f.1 Change in the shelf life or storage conditions of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Reduction of the shelf life of the finished product
1. As packaged for sale	1, 6	1, 2, 3, 4	IA_IN
2. After first opening	1, 6	1, 2, 3, 4	IA_IN
3. After dilution or reconstitution	1, 6	1, 2, 3, 4	IA_IN
(b) Extension of the shelf life of the finished product
1. As packaged for sale (supported by real time data, fully in line with the stability protocol)	3, 4, 5	1, 2, 3	IA_IN
2. After first opening (supported by real time data)		1, 2, 3	IB
3. After dilution or reconstitution (supported by real time data)		1, 2, 3	IB
4. Extension of the shelf life of the finished product based on extrapolation or stability modelling not in accordance with relevant stability guidelines			II
5. Extension of the shelf life of the finished product based on extrapolation of stability data in accordance with relevant stability guidelines		1, 2, 3	IB
(c) Change in storage conditions of a biological finished product			II
(d) Change in storage conditions of the finished product or the diluted/reconstituted product		1, 2, 3	IB
(e) Change to an approved stability protocol of the finished product	1, 2	1, 4	IA
Conditions
1. The change should not be the result of unexpected events arising during manufacture or because of stability concerns.
2. The change does 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.
3. Stability studies have been performed in accordance with a currently approved stability protocol. Real time data are submitted. All batches meet their pre-defined specification at all time points. No unexpected trends have been observed.
4. Product is not a biological or herbal finished product.
5. Product is an immediate release film-coated tablet.
6. Product is not on the Union list of critical medicines or similar national list (where applicable).
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format). This must contain results of appropriate stability studies conducted in accordance with the relevant stability guidelines on three pilot scale batches(³) of the finished product in the authorised packaging material and/or two batches after first opening or reconstitution, as appropriate. Where applicable, results of appropriate microbiological testing should be included.
2. Revised product information.
3. Copy of approved end of shelf life finished product specification and where applicable, specifications after dilution/reconstitution or first opening (as annex to the application form).
4. Justification for the proposed change(s).
(³) Regulation (EC) No 1333/2008 of the European Parliament and of the Council of 16 December 2008 on food additives (OJ L 354, 31.12.2008, p. 16, ELI: http://data.europa.eu/eli/reg/2008/1333/oj).

Q.II.g) Additional regulatory tools

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

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

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

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

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

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

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

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

#qiig1

Q.II.g.1 Introduction of a new design space or extension of an approved design space for the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) New design space for one or more unit operations in the manufacturing process of the finished product including the resulting in-process controls and/or analytical procedures		1, 2, 3	II
(b) New design space for an analytical procedure for an excipient/intermediate and/or the finished product		1, 2, 3	IB
(c) Changes to, or extension of, an approved design space for the finished product and/or an analytical procedure for excipients/intermediates and/or the finished product		1, 2, 3	IB
Documentation
1. The design space has been developed in accordance with the relevant European and international scientific guidelines. Results from product and process development studies (including risk assessment and multivariate studies, as appropriate) demonstrating that a systematic understanding of material attributes and process parameters to the critical quality attributes of the finished product has been achieved.
2. Description of the design space in tabular format, and/or in the form of mathematical equation, as relevant, including the variables (material attributes and process parameters, as appropriate) with their proposed ranges and limits.
3. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).

#qiig2

Q.II.g.2 Introduction of a post-approval change management protocol related to the finished product (PACMP)	Conditions to be fulfilled	Documentation to be supplied	Procedure type
		1, 2, 3	II
Documentation
1. Detailed description for the proposed change.
2. Post-approval change management protocol related to the finished product.
3. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD).

#qiig3

Q.II.g.3 Deletion of a post-approval change management protocol (PACMP) related to the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
	1	1, 2	IA
Conditions
1. The deletion of the post-approval change management protocol related to the finish product is not a result of unexpected events or out of specification results during the implementation of the change(s) described in the protocol and does not have any effect on the already approved information in the dossier.
Documentation
1. Justification for the proposed deletion.
2. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).

#qiig4

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

#qiig5

Q.II.g.5 Implementation of changes foreseen in a post-approval change management protocol (PACMP)	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) The implementation of changes foreseen in a PACMP via Type IA notification	1	1, 2, 3, 4	IA
(b) The implementation of changes foreseen in a PACMP via Type IA_IN notification	2	1, 2, 3 4	IA_IN
(c) Implementation of change foreseen in a PACMP via Type IB notification		1, 2, 3, 4	IB
Conditions
1. The proposed change has been performed fully in line with the post-approval change management protocol, which requires its notification within 12 months following implementation.
2. The proposed change has been performed fully in line with the post-approval change management protocol, which requires its immediate notification following implementation.
Documentation
1. Reference to the post-approval change management protocol.
2. Declaration that the change is in accordance with the post-approval change management protocol and that the study results meet the acceptance criteria specified in the protocol (*).
3. Results of the studies performed and any other supporting documentation in accordance with the post-approval change management protocol.
4. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).
Note: (*) In case the acceptance criteria and/or other conditions in the protocol are not met, the change cannot be implemented as a variation of this category and should instead be submitted as variation of the applicable category without PACMP.

#qiig6

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

#qiig7

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

#qiig8

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

Q.II.h) Adventitious Agents Safety

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

#qiih1

Q.II.h.1 Update to the ‘Adventitious Agents Safety Evaluation’ information (Section 3.2.A.2)	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Studies related to manufacturing steps investigated for the first time for one or more adventitious agents			II
(b) Replacement of obsolete studies related to manufacturing steps and adventitious agents already reported in the dossier
1. with modification of risk assessment resulting in higher risk			II
2. with modification of risk assessment resulting in equivalent or lower risk		1, 2, 3	IB
3. without modification of risk assessment		1, 3, 4	IB
Documentation
1. Amendment of the relevant section(s) of the dossiers including the introduction of the new studies to investigate the capability of manufacturing steps to inactivate/reduce adventitious agents.
2. Justification that the studies modify the risk assessment resulting in equivalent or lower risk.
3. Amendment of product information (where applicable).
4. Justification that the studies do not modify the risk assessment.

Q.III CEP/TSE/Monographs

Q.III.1 Submission of a new or updated Ph. Eur. certificate of suitability or deletion of Ph. Eur. certificate of suitability:

– for an active substance

– for a starting material/reagent/intermediate used in the manufacturing process of the active substance

– for an excipient

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

#qiii1

Q.III.1 Submission of a new or updated Ph. Eur. certificate of suitability or deletion of Ph. Eur. certificate of suitability: – for an active substance – for a starting material/reagent/intermediate used in the manufacturing process of the active substance – for an excipient	Conditions to be fulfilled	Documentation to be supplied	Procedure type
*(a) European Pharmacopoeial certificate of suitability to the relevant Ph. Eur. Monograph (^4)**
1. New certificate of suitability (CEP) (including replacement or addition)	1, 2, 3, 4, 5, 6, 9	1, 2, 3, 4,	IA_IN
2. Update of an approved certificate of suitability (CEP)	1, 2, 3, 4, 5, 9	1, 2, 3, 4,	IA
3. Deletion of certificate(s) of suitability (CEP)	8	2	IA
4. New certificate of suitability (CEP) for a non-sterile active substance that is to be used in a sterile finished product, where water is used in the last steps of the synthesis and the material is not claimed to be endotoxin free		1, 2, 3, 4, 5	IB
5. New or updated certificate of suitability (CEP) for a herbal active substance		1, 2, 4, 6	IB
(b) European Pharmacopoeial TSE certificate of suitability for an active substance/starting material/reagent/intermediate/or excipient
1. New TSE certificate for an active substance (including replacement or addition)	4, 7	1, 2, 3, 4	IA_IN
2. New TSE certificate for a starting material/reagent/intermediate/excipient (including replacement or addition)	4, 7	1, 2, 3, 4,	IA
3. Update of an approved TSE certificate	4, 7	1, 2, 3, 4	IA
4. Deletion of TSE certificate(s)	8	7	IA
5. New/updated TSE certificate using materials of human or animal origin for which an assessment of the risk with respect to potential contamination with adventitious agents is required			II
Conditions
1. The impact of the new source of the active substance, or changes to the active substance, on the finished product has been evaluated by the holder/finished product manufacturer and there is no change in Critical Quality Attributes or composition of the finished product (e.g. API mix). The finished product release and end of shelf life specifications remain the same.
2. The holder/finished product manufacturer active substance specification for impurities is unchanged. This applies to organic impurities, residual solvents, mutagenic impurities (including nitrosamines) and elemental impurities. Tightening of impurity limits, changes to specifications for impurities according to the Ph. Eur. and/or residual solvents according to ICH Q3C, are excluded.
3. The holder/finished product manufacturer active substance specification is unchanged for any other specific requirements that may impact finished product quality, such as polymorphism, hydration state, particle size profile.
4. The manufacturing process of the active substance, starting material/reagent/intermediate does not include the use of materials of human or animal origin for which an assessment of viral safety data is required, or if it does, the update of the CEP/TSE Certificate is only due to administrative changes.
5. For active substance only, it will be tested immediately prior to use if no retest period is included in the Ph. Eur. certificate of suitability or if data to support a retest period is not already provided in the dossier.
6. The active substance/starting material/reagent/intermediate/excipient is not sterile.
7. If gelatin manufactured from bones is to be used in a finished product for parenteral use, it should only be manufactured in compliance with the relevant country requirements.
8. At least one manufacturer for the same substance remains in the dossier.
9. If the active substance is a not a sterile substance but is to be used in a sterile finished product then according to the CEP it must not use water during the last steps of the synthesis or if it does the active substance must comply with the guideline on water for pharmaceutical use regarding bacterial endotoxins and microbiological quality.
Documentation
1. Copy of the current (updated) Ph. Eur. certificate of suitability (CEP) and the letter of access (where available).
2. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format). This should include: – Updated consolidated holder/finished product manufacturer list of manufacturers of the active substance (Section 3.2.S.2.1). – Updated single compiled holder/finished product manufacturer active substance specification, including analytical methods and method validation (where the finished product manufacturer uses analytical procedures which are different from the Ph. Eur. monograph or from those used by the CEP holder), and batch results from testing carried out by the holder/finished product manufacturer (Section 3.2.S.4.1-3.2.S.4.4).
3. Where applicable, a document providing information of any materials falling within the scope of the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products, including those which are used in the manufacture of the active substance/excipient. The following information should 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. For the centralised procedure, this information should be included in an updated TSE table A (and B, if relevant).
4. Where applicable, for active substance, a declaration by the qualified person (QP) of each of the manufacturing authorisation holders listed in the application where the active substance is used as a starting material and a declaration by the QP of each of the manufacturing authorisation holders listed in the application as responsible for batch release.
5. Suitable evidence to confirm compliance of either the water used in the final steps of the synthesis of the active substance, or the active substance, itself with the corresponding requirements of the guideline on quality of water for pharmaceutical use regarding bacterial endotoxins and microbiological quality.
6. For herbal active substances a detailed comparison regarding specifications and critical quality attributes (e.g. for extracts: reference to the herbal starting material (incl. scientific binominal name and plant part), physical state, extraction solvent (nature and concentration), drug extract ratio (DER) and manufacturing process (including a stepwise comparison of all manufacturing steps in tabular format).
7. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).
(^4) Note:* For active substances supported by a certificate of suitability (CEP), a separate variation is required under category Q.I. scope in the following scenarios: – to register or amend sites (e.g. micronisation or control/testing sites) if these sites are not included on the CEP (Q.I.a), – to register or amend in-house analytical procedures used by finished product manufacturer if these analytical procedures are not included on the CEP (Q.I.b), – to register or amend a re-test period if the re-test period is not included on the CEP (Q.I.d).

#qiii2

Q.III.2 Change to comply with Ph. Eur. or with a national pharmacopoeia of a Member State for active substances, reagents, intermediates, excipients, immediate packaging materials and active substance starting materials (^*5)	Conditions to be fulfilled	Documation to be supplied	Procedure type
(a) Change of specification(s) of a former non-EU Pharmacopoeial substance to fully comply with the Ph. Eur. or with a national pharmacopoeia of a Member State
1. Active substance	1, 2, 3, 4	1, 2, 3, 4	IA_IN
2. Excipient/active substance starting material/reagent/intermediate/immediate packaging material	1, 2, 3, 4	1, 2, 3, 4	IA
(b) Change to comply with an update of the relevant monograph of the Ph. Eur. or national pharmacopoeia of a Member State	1, 2, 4	1, 2, 3, 4	IA
(c) Change in specifications from a national pharmacopoeia of a Member State to the Ph. Eur.	1, 4	1, 2, 3, 4	IA
(d) Change related to a herbal active substance or herbal starting material		1, 2, 3, 4, 5	IB
Conditions
1. The change is made exclusively to fully comply with the pharmacopoeia. All the analytical procedures in the specification need to correspond to the pharmacopoeial standard after the change, except any additional supplementary procedures.
2. Additional specifications to the pharmacopoeia for product specific properties are unchanged (e.g. particle size profiles, polymorphic form, bioassays or aggregates).
3. No significant changes in qualitative and quantitative impurities profile unless the specifications are tightened.
4. Suitability of the new or changed pharmacopoeial analytical procedure has been confirmed under the actual condition of use.
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. Batch analysis data (in a comparative tabulated format) on two production batches of the relevant substance for all analytical procedures in the new specification and additionally, where appropriate, comparative dissolution profile data for the finished product on at least one pilot batch. For herbal finished products, comparative disintegration data may be acceptable.
4. Data to demonstrate the suitability of the monograph to control the substance (e.g. a comparison of the potential impurities with the transparency note of the monograph).
5. For herbal active substances/herbal starting materials a detailed comparison regarding their characteristics (e.g. for extracts: reference to the herbal starting material (incl. scientific binominal name and plant part, physical state extraction solvent (nature and concentration), drug extract ratio (DER) and the manufacturing process) should be provided.
(^5) Note:* 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 finished product.

Q.IV Medical devices

Note: changes to medical devices should be submitted under the appropriate Q.IV classification, even if the medical device also acts as container closure system.

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

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

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

#qiv1

Q.IV.1 Changes to a device co-packaged with the medicinal product or referenced in the product information	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Addition or replacement of a co-packaged device or referenced device	1, 2, 3, 5	1, 2, 3	IA_IN
(b) Addition, replacement or other changes of a co-packaged or referenced device that may have a significant impact to the delivery, quality, safety and/or efficacy of the medicinal product			II
(c) Deletion of a co-packaged or referenced device	3, 4, 5	1, 4	IA_IN
(d) Minor change for a co-packaged device or referenced device that does not impact the delivery, quality, safety and/or efficacy of the medicinal product or the usability of the device	3, 5	1	IA
Conditions
1. The change does not have a significant impact on the delivery, quality, safety and/or efficacy of the medicinal product or the usability of the device.
2. Compatibility studies have been finalised and the device is compatible with the medicinal product.
3. The change should not lead to substantial amendments of the product information.
4. The medicinal product can still be safely and accurately delivered.
5. There is no impact to the Risk Management Plan of the medicinal product.
Documentation
1. Amendment of the relevant section(s) of the dossier, including description, drawing and composition of the device material, compatibility and usability studies as appropriate.
2. For the addition or replacement of a co-packaged medical device, evidence that relevant standards have been met e.g. EU declaration of conformity or, where applicable, EU certificate, or other appropriate documentation such as summary information confirming compliance with relevant General Safety and Performance Requirements.
3. Data to demonstrate performance, safety and compatibility of the device, as appropriate.
4. Justification for the deletion of the device.

#qiv2

Q.IV.2 Changes to an integral medical device (part)	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Addition or replacement of an integral device (part) or major change to the materials and/or design and/or performance characteristics of an integral device which may have a significant impact on the delivery or the quality, safety, or efficacy of the medicinal product			II
(b) Addition or replacement of an integral device (part) which does not have a significant impact on the performance, delivery, quality, safety or efficacy of the medicinal product		1, 2	IB
(c) Deletion of an integral medical device (part) that does not lead to the complete deletion of a strength or pharmaceutical form	1, 2	1	IA_IN
(d) Change of a material of a device (part) not in contact with the medicinal product	3, 4	1, 2	IA
(e) Change of a material of a device (part) in contact with the medicinal product that does not have a significant impact on the performance, safety, quality or efficacy of the medicinal product and does not contain materials of human or animal origin for which assessment is required of viral safety data or TSE risk		1, 2, 3, 4	IB
(f) Addition or replacement of a supplier/manufacturer of an existing device (part)	5, 6	1, 2	IA
(g) Addition or replacement of a site responsible for sterilisation of the device (part) and/or change to the sterilisation process of the device (part) when supplied as sterile		1, 2, 5, 6	IB
(h) Other minor change to an integral device (part)	3, 4	1, 2	IA
Conditions
1. The medicinal product can still be safely and accurately delivered.
2. The remaining product presentation(s) must be adequate for the dosing instructions and treatment duration as mentioned in the summary of product characteristics.
3. The change has no impact on the performance, delivery, safety or quality of the finished product. The functionality must remain the same.
4. There is no substantial amendment of the product information.
5. There is no change to the device (part).
6. The supplier/manufacturer does not perform sterilisation.
Documentation
1. Amendment of the relevant section(s) of the dossier, including revised product information as appropriate.
2. Justification for the absence of a Notified Body opinion/EU certificate/EU declaration of conformity, based on the risk-assessment performed, which concluded that the proposed change has no significant impact on the medicinal product.
3. 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).
4. Where appropriate, proof must be provided that no interaction between the medicinal product and the device (part) occurs (e.g. no migration of components of the proposed material into the content and no loss of components of the product into the device), including confirmation that the material complies with relevant pharmacopoeial requirements or legislation of the Union on plastic material and objects in contact with foodstuffs. Comparative data on permeability e.g. for O₂, CO₂ moisture should be provided as appropriate.
5. 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.
6. Description of the sterilisation method and sterilisation cycle. Validation of the sterilisation cycle should be provided if it does not use the reference conditions stated in Ph. Eur..

#qiv3

Q.IV.3 Changes to the dimensions, specification attributes and/or acceptance criteria or analytical procedures for an integral medical device (part)	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Minor change to the dimensions of a medical device (part)	1, 2, 3	1	IA
(b) Change to the specification for a medical device (part) that is not part of the final product specifications
1. Change to the specification acceptance criteria, including amendments to more accurately describe the appearance	1, 2, 4, 5	1	IA
2. Addition of a new specification attribute with its corresponding analytical procedure	1, 2, 8	1, 2, 3	IA
3. Replacement of a specification attribute with its corresponding analytical procedure		1, 2, 3	IB
4. Change outside of a specification acceptance criteria or deletion of a specification attribute that has a significant impact on the quality, safety, performance or usability of the device			II
(c) Change to an analytical procedure for the medical device (part)
1. Addition, replacement or other change to an approved analytical procedure	1, 6	1, 2, 4	IA
2. Deletion of an analytical procedure if an alternative an analytical procedure is already authorised	1, 7	1	IA
Conditions
1. The change does not impact the delivery, use, safety or stability of the finished product.
2. No change in the qualitative or quantitative composition of the device (part).
3. No change in the headspace or in the surface/volume ratio, or minor changes that do not impact the stability of the final product.
4. The change should be in the range of currently approved specification acceptance criteria.
5. The analytical procedure remains the same or changes to the analytical procedure are minor.
6. 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 (when appropriate).
7. An alternative analytical procedure is already authorised for the specification attribute.
8. The change is not the result of a safety or quality issue.
Documentation
1. Amendment of the relevant section(s) of the dossier.
2. Details of any new analytical procedure and validation, where relevant.
3. Justification of the specification attribute and its acceptance criteria.
4. 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.
Note: Q.IV.3 classification applicable to specifications and analytical procedures for the medical device (part) only (3.2.P.7). Analytical procedures and specifications that are part of the final product specification and control strategy (3.2.P.5) should be classified under the appropriate Q.II category.

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

Q.V.a) PMF/VAMF

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

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

#qva1

Q.V.a.1 Inclusion of a new, updated or amended Plasma Master File in the marketing authorisation dossier of a medicinal product. (PMF 2nd step procedure)	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) First-time inclusion of a new Plasma Master File affecting the properties of the finished product			II
(b) First-time inclusion of a new Plasma Master File not affecting the properties of the finished product		1, 2, 3, 4, 5	IB
(c) Inclusion of an updated/amended Plasma Master File when changes affect the properties of the finished product		1, 2, 3, 4, 5, 6	IB
(d) Inclusion of an updated/amended Plasma Master File when changes do not affect the properties of the finished product	1	1, 2, 3, 4, 5	IA
Conditions
1. The updated or amended Plasma Master File has been granted a certificate of compliance with legislation of the Union in accordance with Annex I of Directive 2001/83/EC.
Documentation
1. Declaration that the PMF Certificate and Evaluation Report are fully applicable for the authorised product, PMF holder has provided the PMF Certificate, Evaluation report and PMF dossier to the holder (where the marketing authorisation holder is different to the PMF holder), the PMF Certificate and Evaluation Report replace the previous PMF documentation for this marketing authorisation.
2. PMF Certificate and Evaluation Report.
3. An expert statement outlining all the changes introduced with the certified PMF and evaluating their potential impact on the finished products including product specific risk assessments.
4. The variation application form should clearly outline the ‘present’ and ‘proposed’ PMF EMA Certificate (code number) in the MA dossier. When applicable, the variation application form should clearly list also all the other PMFs to which the medicinal product refers even if they are not the subject of the application.
5. Updated product information whenever this is required by the relevant national legislation.
6. Updated affected sections of the dossier for the medicinal product.

#qva2

Q.V.a.2 Inclusion of a new, updated or amended Vaccine Antigen Master File in the marketing authorisation dossier of a medicinal product. (VAMF 2nd step procedure)	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) First-time inclusion of a new Vaccine Antigen Master File			II
(b) Inclusion of an updated/amended Vaccine Antigen Master File, when changes affect the properties of the finished product		1, 2, 3, 4	IB
(c) Inclusion of an updated/amended Vaccine Antigen Master File, when changes do not affect the properties of the finished product	1	1, 2, 3, 4	IA_IN
Conditions
1. The updated or amended Vaccine Antigen Master File has been granted a certificate of compliance with legislation of the Union in accordance with Annex I to Directive 2001/83/EC.
Documentation
1. Declaration that the VAMF Certificate and Evaluation Report are fully applicable for the authorised product, VAMF holder has submitted the VAMF Certificate, Evaluation report and VAMF dossier to the holder (where the marketing authorisation holder is different to the VAMF holder), the VAMF Certificate and Evaluation Report replace the previous VAMF documentation for this marketing authorisation.
2. VAMF Certificate and Evaluation Report.
3. An expert statement outlining all the changes introduced with the certified VAMF and evaluating their potential impact on the finished products including product specific risk assessments.
4. The variation application form should clearly outline the ‘present’ and ‘proposed’ VAMF EMA Certificate (code number) in the MA dossier. When applicable, the variation application form should clearly list also all the other VAMFs to which the medicinal product refers even if they are not the subject of the application.

Q.V.b) Referral

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

#qvb1

Q.V.b.1 Update of the quality dossier intended to implement the outcome of a Union referral procedure	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) The change implements the outcome of the referral	1	1, 2	IA_IN
(b) The harmonisation of the quality dossier was not part of the referral and the update is intended to harmonise it			II
Conditions
1. The outcome does not require further assessment.
Documentation
1. Attached to the cover letter of the variation application: A reference to the Commission Decision concerned.
2. The changes introduced during the referral procedure should be clearly highlighted in the submission.

C. SAFETY, EFFICACY, PHARMACOVIGILANCE CHANGES

General Note: In case of a change in therapeutic indication, posology or maximum daily dose, a review of quality documentation should be performed. Any resulting change to the quality documentation (for example, the need to change impurity limits) will require the submission of the appropriate quality variation under the Quality Changes chapter.

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

C.2 Change(s) in the summary of product characteristics, labelling or package leaflet of a generic/hybrid/biosimilar medicinal products following assessment of the same change for the reference product

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

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

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

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

C.7 Deletion of:

(a) a pharmaceutical form

(b) a strength

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

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

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

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

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

#c1

C.1 Change(s) in the summary of product characteristics, labelling or package leaflet intended to implement the outcome of a Union referral procedure	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) The medicinal product is covered by the defined scope of the procedure	1	1, 2, 3	IA_IN
(b) The medicinal product is not covered by the defined scope of the procedure but the change(s) implements the outcome of the procedure and no new additional data is required to be submitted by the holder		1, 2, 3	IB
(c) The medicinal product is not covered by the defined scope of the procedure but the change(s) implements the outcome of the procedure with new additional data submitted by the holder			II
Conditions
1. The variation implements the wording exactly as requested by the authority and it does not require the submission of additional information and/or further assessment.
Documentation
1. Attached to the cover letter of the variation application: a reference to the Commission Decision concerned or to the agreement reached by the CMDh (as applicable) with the annexed summary of product characteristics, labelling or package leaflet.
2. Confirmation that the proposed summary of product characteristics, labelling and package leaflet is identical for the concerned sections to that annexed to the Commission Decision or to the agreement reached by the CMDh (as applicable).
3. Revised product information.

#c2

C.2 Change(s) in the summary of product characteristics, labelling or package leaflet of a generic/hybrid/biosimilar medicinal products following assessment of the same change for the reference product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Implementation of change(s) for which no new additional data is required to be submitted by the holder		1, 2, 3	IB
(b) Implementation of change(s) which require to be further substantiated by new additional data to be submitted by the marketing authorisation holder (e.g. comparability)			II
Documentation
1. Attached to the cover letter of the variation application: EMA/NCA request, if applicable.
2. Revised product information.
3. For the biosimilar medicinal product aligning the product information with an indication of the reference medicinal product: a justification that the comparability exercise performed for the biosimilar medicinal product is valid for the applied indication.

#c3

C.3 Change(s) in the summary of product characteristics, labelling or package leaflet intended to implement the outcome of a procedure concerning PSUR or PASS, or the outcome of the assessment done by the competent authority under Article 45 or 46 of Regulation (EC) No 1901/2006, or the outcome of a PRAC signal recommendation, or to adapt to a joint recommendation of EU competent authorities (e.g. a Core SmPC, or following the assessment of an Urgent Safety Restriction etc.)	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Implementation of the agreed wording	1	1, 2	IA_IN
(b) Implementation of the agreed wording that requires additional minor assessment (e.g. translations are not yet agreed upon)		1, 2	IB
(c) Implementation of change(s) which require to be further substantiated by new additional data to be submitted by the MAH			II
Conditions
1. The variation implements the wording exactly as requested, including agreed national translations, and it does not require the submission of additional information and/or further assessment.
Documentation
1. Attached to the cover letter of the variation application: reference to the agreement/assessment of the competent authorities.
2. Revised product information.

#c4

C.4 Change(s) in the summary of product characteristics, labelling or package leaflet due to new quality, preclinical, clinical or pharmacovigilance data.	Conditions to be fulfilled	Documentation to be supplied	Procedure type
			II

#c5

C.5 Change in the legal status of a medicinal product for centrally authorised medicinal products	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) For generic/hybrid/biosimilar medicinal products following an approved legal status change of the reference medicinal product		1, 2	IB
(b) All other legal status changes			II
Documentation
1. Attached to the cover letter of the variation application: proof of authorisation of the legal status change (e.g. reference to the Commission Decision concerned).
2. Revised product information.
Note: for nationally authorised medicinal products approved via MRP/DCP, the change of the legal status is to be handled at national level (not via a MRP variation).

#c6

C.6 Change(s) to therapeutic indication(s)	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Addition of a new therapeutic indication or modification of an approved one			II
(b) Deletion of a therapeutic indication		1	IB
Documentation
1. Amendment of the relevant section(s) of the dossier, including revised product information.
Note: where the change takes place in the context of the implementation of the outcome of a referral procedure, or – for a generic/hybrid/biosimilar product – when the same change has been done for the reference product, variations C.1 and C.2 apply, respectively.

#c7

C.7 Deletion of:	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) a pharmaceutical form		1, 2	IB
(b) a strength		1, 2	IB
Documentation
1. Declaration that the remaining product presentation(s) are adequate for the dosing instructions and treatment duration as mentioned in the summary of product characteristics.
2. Revised product information.
Note: in cases where a given pharmaceutical form or strength has received a marketing authorisation which is separate to the marketing authorisation for other pharmaceutical forms or strengths, the deletion of the former will not be a variation but the withdrawal of the marketing authorisation.

#c8

C.8 Introduction of a summary of pharmacovigilance system for medicinal products	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Introduction of a summary of pharmacovigilance system after a change of the holder		1, 2	IA_IN
Documentation
1. Summary of the pharmacovigilance system:. Proof that the holder has at its disposal a qualified person responsible for pharmacovigilance and a statement signed by the holder to the effect that it has the necessary means to fulfil the tasks and responsibilities listed in Title IX of Directive 2001/83/EC.
2. PSMF number (if available).
Note: This variation is only applicable to nationally authorised medicinal products.

#c9

C.9 Introduction of, or change(s) to, the obligations and conditions of a marketing authorisation, including the risk management plan	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Implementation of changes to reflect the outcome of previous assessment	1	1, 2	IA_IN
(b) Implementation of changes which require additional minor assessment (e.g. change to the due date of obligations and conditions of a marketing authorisation and required pharmacovigilance activities in the risk management plan, including changes to the due date of study milestones, and template updates)		2	IB
(c) Implementation of change(s) which require to be further substantiated by new additional data to be submitted by the holder where significant assessment by the competent authority is required			II
Conditions
1. The variation implements the action requested, including the exact agreed wording and the agreed national translations, and it does not require the submission of additional information and/or further assessment.
Documentation
1. Attached to the cover letter of the variation application: A reference to the relevant decision of the competent authorities.
2. Update of the relevant section of the dossier.
Note: This variation covers the situation where the only change introduced concerns the conditions and/or obligations of the marketing authorisation, including the risk management plan and the conditions and/or obligations of marketing authorisations under exceptional circumstances and conditional marketing authorisation.

#c10

C.10 Inclusion or deletion of black symbol and explanatory statements for medicinal products in the list of medicinal products that are subject to additional monitoring	Conditions to be fulfilled	Documentation to be supplied	Procedure type
	1	1, 2	IA_IN
Conditions
1. The medicinal product is included or removed from the list of medicinal products that are subject to additional monitoring (as applicable).
Documentation
1. Attached to the cover letter of the variation application: A reference to the list of medicinal products that are subject to additional monitoring.
2. Revised product information.
Note: This variation covers the situation where the inclusion or deletion of the black symbol and explanatory statements is not done as part of another regulatory procedure (e.g. renewal or variation procedure affecting the product information).

#c11

C.11 Submission of results of assessments carried out on target patient groups in order to comply with Article 59(3) of Directive 2001/83/EC and any resulting change(s) to the package leaflet.	Conditions to be fulfilled	Documentation to be supplied	Procedure type
		1, 2	IB
Documentation
1. Results of consultation with target patient groups (user test or bridging report).
2. Revised product information.

#c12

C.12 Other variations not specifically covered elsewhere in this Annex which involve the submission of studies, including bioequivalence studies, to the competent authority	Conditions to be fulfilled	Documentation to be supplied	Procedure type
			II
Note: This variation scope includes the submission of studies where no changes to the summary of product characteristics, labelling or package leaflet are initially proposed by the MAH. . In cases where the assessment by the competent authority of the data submitted leads to a change of the summary of product characteristics, labelling or package leaflet, the relevant amendment to the summary of product characteristics, labelling or package leaflet is covered by the variation.

M. PMF/VAMF

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

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

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

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

M.5 Deletion or change of status (operational/non-operational) of establishment(s)/centre(s) used for blood/plasma collection or in the testing of donations and plasma pools

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

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

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

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

M.10 Addition or replacement of blood and plasma tests

M.11 Change of inventory hold procedure

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

M.13 Change in storage/transport

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

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

M.16 Change in the steps that would be taken if it is found retrospectively that donation(s) should have been excluded from processing (‘look-back’ procedure)

#m1

M.1 Change in the name and/or address of the certificate holder	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) PMF certificate holder	1	1	IA_IN
(b) VAMF certificate holder	1	1	IA_IN
Conditions
1. The certificate holder must remain the same legal entity.
Documentation
1. A formal document from a relevant official body (e.g. Chamber of Commerce) in which the new name or new address is mentioned.

#m2

M.2 Change or transfer of the current PMF certificate holder to a new PMF certificate holder, i.e. different legal entity	Conditions to be fulfilled	Documentation to be supplied	Procedure type
		1, 2, 3, 4, 5, 6	IA_IN
Documentation
1. A document including the identification (name and address) of the current PMF holder (transferor) and the identification (name and address) of the person to whom the transfer is to be granted (transferee) together with the proposed implementation date – signed by both companies.
2. Copy of the latest PMF Certificate page ‘EMA Plasma Master File (PMF) certificate of compliance with Community legislation’.
3. Proof of establishment of the new holder (Excerpt of the commercial register and the English translation of it) – signed by both companies.
4. Confirmation of the transfer of the complete PMF documentation since the initial PMF certification to the transferee – signed by both companies.
5. Letter of Authorisation including contact details of the person responsible for communication between the competent authority and the PMF holder – signed by the transferee.
6. Letter of Undertaking to fulfil all open and remaining commitments (if any) – signed by the transferee.

#m3

M.3 Change in the name and/or address of a blood establishment and/or blood/plasma collection centres	Conditions to be fulfilled	Documentation to be supplied	Procedure type
	1, 2	1, 2, 3	IA
Conditions
1. The blood establishment must remain the same legal entity.
2. The change must be administrative.
Documentation
1. Signed declaration that the change does not involve a change of the quality system within the blood establishment.
2. Signed declaration that there is no change in the list of the collection centres.
3. Updated relevant sections and annexes of the PMF dossier.

#m4

M.4 Addition or relocation of a blood/plasma collection centre within a blood establishment already included in the PMF	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Relocation	1, 2, 3	2, 3	IA
(b) Addition		1, 2, 3	IB
Conditions
1. It remains the same legal entity.
2. Inspection authorities have issued new inspection approval status.
3. The blood/plasma collection centre should retain the same quality system.
Documentation
1. Epidemiological data for viral markers related to the blood/plasma collection centre to be provided as requested in the Guideline on epidemiological data on blood transmissible infections.
2. Statement that the centre is working under the same conditions as the other centres belonging to the blood establishment, as specified in the standard contract between blood establishment and PMF holder.
3. Updated relevant sections and annexes of the PMF dossier including also inspections and audit information.

#m5

M.5 Deletion or change of status (operational/non-operational) of establishment(s)/centre(s) used for blood/plasma collection or in the testing of donations and plasma pools	Conditions to be fulfilled	Documentation to be supplied	Procedure type
1. Deletion.	1	1	IA
2. Change of status.
(a) from operational to non-operational	1	1	IA
(b) from non-operational to operational	2, 3, 4	1, 2, 3, 6	IA
(c) from non-operational to operational when epidemiological data has not been annually submitted or there have been other than administrative changes in blood establishment or centres since there were moved to non-operational (e.g. blood bags, testing kits)		1, 4, 5, 6	IB
Conditions
1. The deletion or change of status should not relate to a GMP issue or other safety reasons.
2. The establishments(s)/centre(s) should comply with the legislation in terms of inspections.
3. There have been no other than administrative (Type IA) changes in blood establishment or centres since they were moved to non-operational (e.g. blood bags, testing kits) and standard contract between blood establishment and PMF holder is in place.
4. For collection centres epidemiological data have been annually submitted and evaluated in the PMF annual update.
Documentation
1. Updated relevant sections and annexes of the PMF dossier including inspections and audit information, as needed.
2. Confirmation no changes other than administrative (Type IA) have been implemented.
3. Declaration that, while the establishment(s)/centre(s) has remained in non-operational, the epidemiology data have been submitted annually.
4. Updated epidemiological data for viral markers related to the blood/plasma collection centre.
5. Declaration of changes introduced, and variation applications submitted.
6. Confirmation that standard contract between blood establishment/centre and PMF holder is in place.

#m6

M.6 Addition of a new blood establishment for the collection of blood/plasma not included in the PMF	Conditions to be fulfilled	Documentation to be supplied	Procedure type
			II

#m7

M.7 Addition or relocation of a centre/laboratory for testing of donations and/or plasma pools within an establishment already included in the PMF	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Relocation	1, 2, 3	1, 2	IA
(b) Addition		1, 2	IB
(c) Link existing collection centres to another existing or new blood/plasma testing centres in PMF		2	IA
Conditions
1. It remains the same legal entity.
2. Inspection authorities have issued new inspection approval status.
3. The centre/laboratory should retain the same staff, equipment and quality system.
Documentation
1. Statement that the testing is performed following the same SOPs and/or analytical procedures as already accepted.
2. Updated relevant sections and annexes of the PMF dossier including inspections and audit information.

#m8

M.8 Addition of a new laboratory for testing of donations and/or plasma pool not included in the PMF	Conditions to be fulfilled	Documentation to be supplied	Procedure type
			II

#m9

M.9 Changes of an establishment or centre(s) in which storage of plasma is carried out or organisation(s) involved in the transport of plasma	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Relocation of storage establishment or centre	1, 2	1, 2	IA
(b) Addition of storage establishment/centre or transport organisation		2	IB
(c) Deletion of storage establishment/centre or transport organisation	3	2	IA
Conditions
1. It remains the same legal entity.
2. Inspection authorities have issued new inspection approval status.
3. The reason for deletion should not be related to GMP issues.
Documentation
1. Statement that the storage centre is working following the same SOPs as the already accepted establishment.
2. Updated relevant sections and annexes of the PMF dossier including inspections and audit information, as needed.

#m10

M.10 Addition or replacement of blood and plasma tests	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) Test kit for individual donations (serology markers and NAT)
1. CE-marked	1	1, 2	IA
2. Non-CE-marked, not previously been approved in the PMF for any blood centre for testing of donations			II
3. Non-CE-marked, previously approved in the PMF for other blood centre(s) for testing of donations		1, 2	IB
(b) Test for mini-pools NAT
1. CE-marked	1	1, 2	IA
2. Non-CE-marked			II
(c) Test for plasma pools (antibody, antigen or NAT test)			II
Conditions
1. The new test kit is CE-marked and used in line with instructions of use.
Documentation
1. List of testing site(s) where the test is currently used and a list of testing centre(s) where the kit will be used.
2. Updated relevant sections and annexes of the PMF dossier, including updated information on testing as requested in the ‘Guideline on the scientific data requirements for a PMF’.

#m11

M.11 Change of inventory hold procedure	Conditions to be fulfilled	Documentation to be supplied	Procedure type
		1	IA
Documentation
1. Updated relevant sections of the PMF dossier.

#m12

M.12 Addition or replacement of blood containers (e.g. bags, bottles)	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) The new blood containers are CE-marked	1	1	IA
(b) The new blood containers are not CE-marked and there is no impact on the quality criteria of the blood in the container		1, 2, 3, 4	IB
(c) The new blood containers are not CE-marked and there is potentially an impact on the quality criteria of the blood in the container			II
Conditions
1. The quality criteria of the blood in the container remain unchanged.
Documentation
1. Updated relevant sections and annexes of the PMF dossier, including the name of container, manufacturer, anticoagulant solution specification, confirmation of CE-mark and the name of the blood establishments where the container is used.
2. Confirmation and data demonstrating compliance with equivalent quality standard as CE-mark as requested in the ‘Guideline on the scientific data requirements for a PMF’.
3. Confirmation that any anticoagulant solution complies with Ph. Eur. requirements.
4. Justification that there is no impact on the quality criteria of the blood in the container.

#m13

M.13 Change in storage/transport	Conditions to be fulfilled	Documentation to be supplied	Procedure type
(a) storage and/or transport conditions	1	1	IA
(b) maximum storage time for the plasma	1, 2	1	IA
Conditions
1. The change should tighten the conditions and be in compliance with Ph. Eur. requirements for Human Plasma for Fractionation.
2. The maximum storage time is shorter than previously.
Documentation
1. Updated relevant sections and annexes of the PMF dossier, including detailed description of the new conditions, confirmation of validation of storage/transport conditions and the name of the blood establishment(s) where the change takes place (if relevant).

#m14

M.14 Introduction of test for a new viral marker when this will have significant impact on the viral risk assessment	Conditions to be fulfilled	Documentation to be supplied	Procedure type
			II

#m15

M.15 Change in the plasma pool preparation (e.g. manufacturing method, pool size, storage of plasma pool samples)	Conditions to be fulfilled	Documentation to be supplied	Procedure type
		1	IB
Documentation
1. Updated relevant sections of the PMF dossier.

#m16

M.16 Change in the steps that would be taken if it is found retrospectively that donation(s) should have been excluded from processing (‘look-back’ procedure)	Conditions to be fulfilled	Documentation to be supplied	Procedure type
			II