This is an archived version. Please see the current version here: Q.I ACTIVE SUBSTANCE

B.I.a) Manufacture

B.I.a.1 Change in the manufacturer of a starting material/reagent/intermediate used in the manufacturing process of the active substance or change in the manufacturer (including where relevant quality control testing sites) of the active substance, where no Ph. Eur. Certificate of Suitability is part of the approved dossier

B.I.a.2 Changes in the manufacturing process of the active substance

B.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

B.I.a.4 Change to in-process tests or limits applied during the manufacture of the active substance

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

B.I.a.6 Changes to the active substance of a vaccine against human coronavirus (This section is introduced with Addendum to the Variations Guidelines (2021/C 215 I/01))

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B.I.a.1 Change in the manufacturer of a starting material/reagent/intermediate used in the manufacturing process of the active substance or change in the manufacturer (including where relevant quality control testing sites) of the active substance, where no Ph. Eur. Certificate of Suitability is part of the approved dossier	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) The proposed manufacturer is part of the same pharmaceutical group as the currently approved manufacturer	1, 2, 3	1, 2, 3, 4, 5, 6, 7	IA_IN
b) Introduction of a manufacturer of the active substance supported by an ASMF			II
c) The proposed manufacturer uses a substantially different route of synthesis 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			II
d) New manufacturer of material for which an assessment is required of viral safety and/or TSE risk			II
e) The change relates to a biological active substance or a starting material/reagent/intermediate used in the manufacture of a biological/immunological product			II
f) Changes to quality control testing arrangements for the active substance-replacement or addition of a site where batch control/testing takes place	2, 4	1, 5	IA
g) Introduction of a new manufacturer of the active substance that is not supported by an ASMF and requires significant update to the relevant active substance section of the dossier			II
h) Addition of an alternative sterilisation site for the active substance using a Ph.Eur. method		1, 2, 4, 5, 8	IB
i) Introduction of a new site of micronisation	2, 5	1, 4, 5, 6	IA
j) Changes to quality control testing arrangements for a biological active substance: replacement or addition of a site where batch control/testing including a biological / immunological / immunochemical method takes place			II
k) New storage site of Master Cell Bank and/or Working Cell Banks		1, 5	IB
Conditions
1. For starting materials and reagents the specifications (including in process controls, methods of analysis of all materials), are identical to those already approved. For intermediates and active substances the specifications (including in process controls, methods of analysis of all materials), method of preparation (including batch size) and detailed route of synthesis are identical to those already approved.
2. The active substance is not a biological/immunological substance or sterile.
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. Method transfer from the old to the new site has been successfully completed.
5. The particle size specification of the active substance and the corresponding analytical method remain the same.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate), if applicable.
2. A declaration from the marketing authorisation holder or the ASMF holder, where applicable, that the synthetic route (or in case of herbal medicinal products, where appropriate the method of preparation, geographical source, production of herbal drug and manufacturing route) quality control procedures and specifications of the active substance and of the starting material/reagent/intermediate in the manufacturing process of the active substance (if applicable) 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) of the active substance from the current and proposed manufacturers/sites.
5. The variation application form should clearly outline the “present” and “proposed” manufacturers as listed in section 2.5 of the application form for marketing authorisation.
6. 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 (QP) 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. B.II.b.1.
7. Where relevant, a commitment of the manufacturer of the active substance to inform the MA holder of any changes to the manufacturing process, specifications and test procedures of the active substance.
8. Proof that the proposed site is appropriately authorised for the pharmaceutical form or product or manufacturing operation concerned, i.e.: 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 manufacturing site outside the EU/EEA where an operational GMP mutual recognition agreement (MRA) exists between the country concerned and the EU: a GMP certificate issued within the last 3 years by the relevant competent authority. For a manufacturing site outside the EU/EEA where no such mutual recognition agreement exists: a GMP certificate issued within the last 3 years by an inspection service of one of the Member States of the EU/EEA. A reference to the EudraGMP database will suffice.

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B.I.a.2 Changes in the manufacturing process of the active substance	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Minor change in the manufacturing process of the active substance	1, 2, 3, 4, 5, 6, 7	1, 2, 3	IA
b) Substantial change to the manufacturing process of the active substance which may have a significant impact on the quality, safety or efficacy of the medicinal product			II
c) The change refers to a biological / immunological substance or use of a different chemically derived substance in the manufacture of a biological/immunological substance, which may have a significant impact on the quality, safety and efficacy of the medicinal product and is not related to a protocol			II
d) The change relates to a herbal medicinal product and there is a change to any of the following: geographical source, manufacturing route or production			II
e) Minor change to the restricted part of an Active Substance Master File		1, 2, 3, 4	IB
Conditions
1. No adverse change in qualitative and quantitative impurity profile or in physico-chemical properties.
2. 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. In the case of herbal medicinal products, the geographical source, production of the herbal substance and the manufacturing route remain the same.
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 active substance is not a biological / immunological substance.
6. The change does not refer to the geographical source, manufacturing route or production of a herbal medicinal product.
7. The change does not refer to the restricted part of an Active Substance Master File.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate), and of the approved Active Substance Master File (where applicable), including a direct comparison of the present process and the new process.
2. Batch analysis data (in comparative tabular format) of at least two batches (minimum pilot scale) manufactured according to the currently approved and proposed process.
3. Copy of approved specifications of the active substance.
4. A declaration from the marketing authorisation holder or 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 B.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.

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B.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) Up to 10-fold increase compared to the originally approved batch size	1, 2, 3, 4, 6, 7, 8	1, 2, 5	IA
b) Downscaling down to 10-fold	1, 2, 3, 4, 5	1, 2, 5	IA
c) The change requires assessment of the comparability of a biological/immunological active substance			II
d) More than 10-fold increase compared to the originally approved batch size		1, 2, 3, 4	IB
e) The scale for a biological/immunological active substance is increased / decreased without process change (e.g. duplication of line)		1, 2, 3, 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 product concerned is not a biological/immunological medicinal product.
4. The change does not adversely affect the reproducibility of the process.
5. The change should not be the result of unexpected events arising during manufacture or because of stability concerns.
6. The specifications of the active substance/intermediates remain the same.
7. The active substance is not sterile.
8. 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 or NTA volume 6B format for veterinary products, as appropriate).
2. The batch numbers of the tested batches having the proposed batch size.
3. Batch analysis data (in a comparative tabulated format) on a minimum of one production batch of the active substance or intermediate as appropriate, manufactured to both the currently approved and the proposed sizes. Batch data on the next two full production batches should be made available upon request and reported by the marketing authorisation holder if outside specification (with proposed action).
4. Copy of approved specifications of the active substance (and of the intermediate, if applicable).
5. A declaration from the marketing authorisation holder or 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.

#bia4

B.I.a.4 Change to in-process tests or limits applied during the manufacture of the active substance	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Tightening of in-process limits	1, 2, 3, 4	1, 2	IA
b) Addition of a new in-process test and limits	1, 2, 5, 6	1, 2, 3, 4, 6	IA
c) Deletion of a non-significant in-process test	1, 2, 7	1, 2, 5	IA
d) Widening of the approved in-process test 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) Addition or replacement of an in-process test as a result of a safety or quality issue		1, 2, 3, 4, 6	IB
Conditions
1. The change is not a consequence of any commitment from previous assessments to review specification limits (e.g. made during the procedure for the marketing authorisation application or a type II variation procedure).
2. The change does not result from unexpected events arising during manufacture e.g. new unqualified impurity; change in total impurity limits.
3. Any change should be within the range of currently approved limits.
4. The test procedure remains the same, or changes in the test procedure are minor.
5. Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way.
6. The new test method is not a biological/immunological/immunochemical method or a method using a biological reagent for a biological active substance (does not include standard pharmacopoeial microbiological methods).
7. The specification parameter does not concern a critical parameter for example any of the following: assay, impurities (unless a particular solvent is definitely not used in the manufacture of the active substance), any critical physical characteristics e.g. particle size, bulk or tapped density, identity test, water, any request for changing the frequency of testing.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate).
2. Comparative table of current and proposed in-process tests.
3. Details of any new non-pharmacopoeial analytical method and validation data, where relevant.
4. Batch analysis data on two production batches (3 production batches for biologicals, unless otherwise justified) of the active substance for all specification parameters.
5. Justification/risk assessment from the marketing authorisation holder or the ASMF Holder, as appropriate, that the in-process tests are non-significant, or that the in-process tests are obsolete.
6. Justification from the MAH or ASMF Holder as appropriate for the new in-process test and limits.

#bia5

B.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

This section is introduced with Addendum to the Variations Guidelines (2021/C 215 I/01)

#bia6

B.I.a.6 Changes to the active substance of a vaccine against human coronavirus	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Replacement or addition of a serotype, strain, antigen or coding sequence or combination of serotypes, strains, antigens or coding sequences for a human coronavirus vaccine			II

B.I.b) Control of active substance

B.I.b.1 Change in the specification parameters and/or limits of an active substance, starting material / intermediate / reagent used in the manufacturing process of the active substance

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

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B.I.b.1 Change in the specification parameters and/or limits of an active substance, starting material / intermediate / reagent used in the manufacturing process of the active substance	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Tightening of specification limits for medicinal products subject to Official Control Authority Batch Release	1, 2, 3, 4	1, 2	IA_IN
b) Tightening of specification limits	1, 2, 3, 4	1, 2	IA
c) Addition of a new specification parameter to the specification with its corresponding test method	1, 2, 5, 6, 7	1, 2, 3, 4, 5, 7	IA
d) Deletion of a non-significant specification parameter (e.g. deletion of an obsolete parameter)	1, 2, 8	1, 2, 6	IA
e) Deletion of a specification parameter which may have a significant effect on the overall quality of the active substance and/or the finished product			II
f) Change outside the approved specifications limits range for the active substance			II
g) Widening of the approved specifications limits for starting materials/intermediates, which may have a significant effect on the overall quality of the active substance and/or the finished product			II
h) Addition or replacement (excluding biological or immunological substance) of a specification parameter with its corresponding test method as a result of a safety or quality issue		1, 2, 3, 4, 5, 7	IB
i) Where there is no monograph in the European Pharmacopoeia or the national pharmacopoeia of a Member State for the active substance, a change in specification from in-house to a non- official Pharmacopoeia or a Pharmacopoeia of a third country		1, 2, 3, 4, 5, 7	IB
Conditions
1. The change is not a consequence of any commitment from previous assessments to review specification limits (e.g. made during the procedure for the marketing authorisation application or a type II variation procedure).
2. The change does not result from unexpected events arising during manufacture e.g. new unqualified impurity; change in total impurity limits.
3. Any change should be within the range of currently approved limits.
4. The test procedure remains the same, or changes in the test procedure are minor.
5. Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way.
6. The test method is not a biological/immunological/immunochemical method or a method using a biological reagent for a biological active substance (does not include standard pharmacopoeia microbiological methods).
7. For any material, the change does not concern a genotoxic impurity. If it involves the final active substance, other than for residual solvents which must be in line with ICH/VICH limits, any new impurity control should be in line with the Ph. Eur. or National Pharmacopoeia of a Member State.
8. The specification parameter does not concern a critical parameter, for example any of the following: assay, impurities (unless a particular solvent is definitely not used in the manufacture of the active substance), any critical physical characteristics e.g. particle size, bulk or tapped density, identity test, water, any request for skip testing.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate).
2. Comparative table of current and proposed specifications.
3. Details of any new analytical method and validation data, where relevant.
4. Batch analysis data on two production batches (3 production batches for biologicals, unless otherwise justified) of the relevant substance for all specification parameters.
5. Where appropriate, comparative dissolution profile data for the finished product on at least one pilot batch containing the active substance complying with the current and proposed specification. For herbal medicinal products, comparative disintegration data may be acceptable.
6. Justification/risk assessment from the marketing authorisation holder or the ASMF Holder, as appropriate, that the in-process parameter is non-significant, or that the in-process parameter is obsolete.
7. Justification from the MAH or ASMF Holder as appropriate of the new specification parameter and the limits.

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B.I.b.2 Change in test procedure for active substance or starting material/reagent/intermediate used in the manufacturing process of the active substance	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Minor changes to an approved test procedure	1, 2, 3, 4	1, 2	IA
b) Deletion of a test procedure for the active substance or a starting material/reagent/ intermediate, if an alternative test procedure is already authorised.	7	1	IA
c) Other changes to a test procedure (including replacement or addition) for a reagent, which does not have a significant effect on the overall quality of the active substance	1, 2, 3, 5, 6	1, 2	IA
d) Substantial change to or replacement of a biological/ immunological/ immunochemical test method or a method using a biological reagent for a biological active substance			II
e) Other changes to a test procedure (including replacement or addition) for the active substance or a starting material/intermediate		1, 2	IB
Conditions
1. Appropriate validation studies have been performed in accordance with the relevant guidelines and show that the updated test procedure is at least equivalent to the former test procedure.
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 test method is not a biological/immunological/immunochemical method, or a method using a biological reagent for a biological active substance. (does not include standard pharmacopoeial microbiological methods).
5. Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way.
6. The active substance is not biological/immunological.
7. An alternative test procedure is already authorised for the specification parameter and this procedure has not been added through IA/IA(IN) notification.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate), including a description of the analytical methodology, a summary of validation data, revised specifications for impurities (if applicable).
2. Comparative validation results, or if justified comparative analysis results showing that the current test and the proposed one are equivalent. This requirement is not applicable in case of an addition of a new test procedure.

B.I.c) Container closure system

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

B.I.c.2 Change in the specification parameters and/or limits of the immediate packaging of the active substance

B.I.c.3 Change in test procedure for the immediate packaging of the active substance

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B.I.c.1 Change in immediate packaging of the active substance	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Qualitative and/or quantitative composition	1, 2, 3	1, 2, 3, 4, 6	IA
b) Qualitative and/or quantitative composition for sterile and non-frozen biological/immunological active substances			II
c) Liquid active substances (non sterile)		1, 2, 3, 5, 6	IB
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/VICH 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. Sterile, liquid and biological/immunological active substances are excluded.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate).
2. Appropriate data on the new packaging (e.g. comparative data on permeability e.g. for O2, CO2 moisture), including a confirmation that the material complies with relevant pharmacopoeial requirements or legislation of the Union on plastic materials and objects in contact with foodstuffs.
3. Where appropriate, proof must be provided that no interaction between the content and the packaging material occurs (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.
4. A declaration from the marketing authorisation holder or the ASMF holder as appropriate that the required stability studies have been started under ICH/VICH 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).
5. The results of stability studies that have been carried out under ICH/VICH 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).
6. Comparison of the current and proposed immediate packaging specifications, if applicable.

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B.I.c.2 Change in the specification parameters and/or limits of the immediate packaging of the active substance	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Tightening of specification limits	1, 2, 3, 4	1, 2	IA
b) Addition of a new specification parameter to the specification with its corresponding test method	1, 2, 5	1, 2, 3, 4, 6	IA
c) Deletion of a non-significant specification parameter (e.g. deletion of an obsolete parameter)	1, 2	1, 2, 5	IA
d) Addition or replacement of a specification parameter as a result of a safety or quality issue		1, 2, 3, 4, 6	IB
Conditions
1. The change is not a consequence of any commitment from previous assessments to review specification limits (e.g. made during the procedure for the marketing authorisation application or a 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 during storage of the active substance.
3. Any change should be within the range of currently approved limits.
4. The test procedure remains the same, or changes in the test procedure are minor.
5. Any new test method does not concern a novel non-standard technique or a standard technique used in a novel way.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate).
2. Comparative table of current and proposed specifications.
3. Details of any new analytical method and validation data, where relevant.
4. Batch analysis data on two batches of the immediate packaging for all specification parameters.
5. Justification/risk assessment from the marketing authorisation holder or the ASMF Holder, as appropriate, that the in-process parameter is non-significant, or that the in-process parameter is obsolete.
6. Justification from the marketing authorisation holder or the ASMF Holder, as appropriate, of the new specification parameter and the limits.

#bic3

B.I.c.3 Change in test procedure for the immediate packaging of the active substance	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Minor changes to an approved test procedure	1, 2, 3,	1, 2	IA
b) Other changes to a test procedure (including replacement or addition)	1, 3, 4	1, 2	IA
c) Deletion of a test procedure if an alternative test procedure is already authorised	5	1	IA
Conditions
1. Appropriate validation studies have been performed in accordance with the relevant guidelines and show that the updated test procedure is at least equivalent to the former test procedure.
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 test method does not concern a novel non-standard technique or a standard technique used in a novel way.
4. The active substance/ finished product is not biological/immunological.
5. There is still a test procedure registered for the specification parameter and this procedure has not been added through a IA/IA(IN) notification.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate), 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 test and the proposed one are equivalent. This requirement is not applicable in case of an addition of a new test procedure.

B.I.d) Stability

B.I.d.1 Change in the re-test period/storage period or storage conditions of the active substance where no Ph. Eur. Certificate of Suitability covering the retest period is part of the approved dossier

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B.I.d.1 Change in the re-test period/storage period or storage conditions of the active substance where no Ph. Eur. Certificate of Suitability covering the retest period is part of the approved dossier	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Re-test period/storage period
1. Reduction	1	1, 2, 3	IA
2. Extension of the retest period based on extrapolation of stability data not in accordance with ICH/VICH guidelines*			II
3. Extension of storage period of a biological/ immunological active substance not in accordance with an approved stability protocol			II
4. Extension or introduction of a re-test period/storage period supported by real time data		1, 2, 3	IB
b) Storage conditions
1. Change to more restrictive storage conditions of the active substance	1	1, 2, 3	IA
2. Change in storage conditions of biological/ immunological active substances, when the stability studies have not been performed in accordance with a currently approved stability protocol			II
3. Change in storage conditions of the active substance		1, 2, 3	IB
c) Change to an approved stability protocol	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 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 or NTA volume 6B format for veterinary products, as appropriate). This must contain results of appropriate real time stability studies, conducted in accordance with the relevant stability guidelines on at least two (three for biological medicinal products) pilot or production scale batches of the active substance in the authorised packaging material and covering the duration of the requested re-test period or requested storage conditions.
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.
4. Justification for the proposed changes.
* Note: retest period not applicable for biological/immunological active substance

B.I.e) Design Space and post-approval change management protocols

B.I.e.1 Introduction of a new design space or extension of an approved design space for the active substance, concerning:

B.I.e.2 Introduction of a post approval change management protocol related to the active substance

B.I.e.3 Deletion of an approved change management protocol related to the active substance

B.I.e.4 Changes to an approved change management protocol

B.I.e.5 Implementation of changes foreseen in an approved change management protocol

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B.I.e.1 Introduction of a new design space or extension of an approved design space for the active substance, concerning:	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) One unit operation in the manufacturing process of the active substance including the resulting in- process controls and/or test procedures		1, 2, 3	II
b) Test procedures for starting materials/reagents/ intermediates and/or the active substance		1, 2, 3	II
Documentation
1. The design space has been developed in accordance with the relevant European and international scientific guidelines. Results from product, process and analytical development studies (e.g. interaction of the different parameters forming the design space have to be studied, including risk assessment and multivariate studies, as appropriate) demonstrating where relevant that a systematic mechanistic understanding of material attributes and process parameters to the critical quality attributes of the active substance has been achieved.
2. Description of the Design space in tabular format, including the variables (material attributes and process parameters, as appropriate) and their proposed ranges.
3. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate).

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B.I.e.2 Introduction of a post approval change management protocol related to the active substance	Conditions to be fulfilled	Documentation to be supplied	Procedure type
		1, 2, 3	II
Documentation
1. Detailed description for the proposed change.
2. Change management protocol related to the active substance.
3. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate).

#bie3

B.I.e.3 Deletion of an approved change management protocol related to the active substance	Conditions to be fulfilled	Documentation to be supplied	Procedure type
	1	1, 2	IA_IN
Conditions
1. The deletion of the approved change management protocol related to the active substance is not a result of unexpected events or out of specification results during the implementation of the change (s) described in the protocol and does not have any effect on the already approved information in the dossier.
Documentation
1. Justification for the proposed deletion.
2. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate).

#bie4

B.I.e.4 Changes to an approved change management protocol	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Major changes to an approved change management protocol			II
b) Minor changes to an approved change management protocol that do not change the strategy defined in the protocol		1	IB
Documentation
1. Declaration that any change should be within the range of currently approved limits. In addition, declaration that an assessment of comparability is not required for biological/immunological medicinal products.

#bie5

B.I.e.5 Implementation of changes foreseen in an approved change management protocol	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) The implementation of the change requires no further supportive data	1	1, 2, 4	IA_IN
b) The implementation of the change requires further supportive data		1, 2, 3, 4	IB
c) Implementation of a change for a biological/immunological medicinal product		1, 2, 3, 4, 5	IB
Conditions
1. The proposed change has been performed fully in line with the approved change management protocol.
Documentation
1. Reference to the approved change management protocol.
2. Declaration that the change is in accordance with the approved change management and that the study results meet the acceptance criteria specified in the protocol. In addition, declaration that an assessment of comparability is not required for biological/immunological medicinal products.
3. Results of the studies performed in accordance with the approved change management protocol.
4. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate).
5. Copy of approved specifications of the active substance.

B. QUALITY CHANGES – B.I ACTIVE SUBSTANCE (obsolete version)

B.I.a) Manufacture

B.I.b) Control of active substance

B.I.c) Container closure system

B.I.d) Stability

B.I.e) Design Space and post-approval change management protocols