Topic/Scope of changes

Variation

Page

E.

ADMINISTRATIVE CHANGES

1 -5

28

Q.

QUALITY CHANGES

30

Q.I.

Active Substance

30

1 -6

31

1 -3

39

1 -4

43

1

46

1 -8

47

Q.II.

Finished Product

51

1 -6

51

1 -5

57

1 -4

65

1 -3

69

1 -8

72

1

78

1 -8

80

1

83

Q.III.

CEP/TSE/monographs

1 -2

84

Q.IV.

Medical Devices

1 -3

88

Q.V.

Changes to a marketing authorisation resulting from other regulatory procedures

91

1 -2

92

1

94

C.

SAFETY, EFFICACY, PHARMACOVIGILANCE CHANGES

1 -12

93

M.

PMF/VAMF

1 -16

99

Cond. to be fulfilled

Docum. to be supplied

Proced. type

(a)

for centrally authorised medicinal products

1

1, 2

IAIN

(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.

Copy of the EMA letter of acceptance of the new (invented) name.

2.

Revised product information.

Cond. to be fulfilled

Docum. to be supplied

Proced. type

1

1, 2, 3

IAIN

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.

Cond. to be fulfilled

Docum. to be supplied

Proced. 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.

Cond. to be fulfilled

Docum. to be supplied

Proced. type

2

1, 2

IAIN

1

1, 2

IAIN

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’.

Cond. to be fulfilled

Docum. to be supplied

Proced. 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.

Cond. to be fulfilled

Docum. to be supplied

Proced. 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

IAIN

(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

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

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:

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).

Cond. to be fulfilled

Docum. to be supplied

Proced. 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.

Cond. to be fulfilled

Docum. to be supplied

Proced. 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.

Cond. to be fulfilled

Docum. to be supplied

Proced. 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:

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.

Cond. to be fulfilled

Docum. to be supplied

Proced. type

(a)

Replacement of the strain(s) in a seasonal, pre-pandemic or a pandemic vaccine against human influenza

II

Cond. to be fulfilled

Docum. to be supplied

Proced. 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.

Cond. to be fulfilled

Docum. to be supplied

Proced. type

(a)

Change within the specification acceptance criteria for finished product subject to Official Control Authority Batch Release

1, 2, 3

1, 2

IAIN

(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:

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.

Cond. to be fulfilled

Docum. to be supplied

Proced. 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.

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.

Cond. to be fulfilled

Docum. to be supplied

Proced. 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).

Cond. to be fulfilled

Docum. to be supplied

Proced. 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.

Cond. to be fulfilled

Docum. to be supplied

Proced. 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.

Cond. to be fulfilled

Docum. to be supplied

Proced. 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).

Cond. to be fulfilled

Docum. to be supplied

Proced. type

(a)

Re-test period/storage period

1

1, 2, 3, 4

IA

1, 2, 3

IB

II

1, 3

IB

2

1, 2, 3

IA

(b)

Storage conditions

1, 3

1, 2, 3

IA

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.

Cond. to be fulfilled

Docum. to be supplied

Proced. type

(a)

New design space for one or more unit operations in the manufacturing process of the active substance including the resulting in-process controls and/or analytical procedures

1, 2, 3

II

(b)

New design space for an analytical procedure for a starting material/reagent/intermediate and/or the active substance

1, 2, 3

IB

(c)

Changes to, or extension of, an approved design space for the active substance and/or an analytical procedure for a starting material/reagent/intermediate

1, 2, 3

IB

Documentation

1.

The design space has been developed in accordance with the relevant European and international scientific guidelines. Results from product, process and analytical development studies including risk assessment and multivariate studies or process modelling, as appropriate, demonstrating where relevant that a systematic understanding of how material attributes and process parameters impact the critical quality attributes of the active substance has been achieved.

2.

Description of the design space in tabular format, and/or in the form of mathematical equation, as relevant, including the variables (material attributes and process parameters, as appropriate) with their proposed ranges and limits.

3.

Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).

Cond. to be fulfilled

Docum. to be supplied

Proced. type

1, 2, 3

II

Documentation

1.

Detailed description for the proposed change.

2.

Post-approval change management protocol related to the active substance.

3.

Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).

Cond. to be fulfilled

Docum. to be supplied

Proced. type

1

1, 2

IA

Conditions

1.

The deletion of the post-approval change management protocol related to the active substance is not a result of unexpected events or out of specification results during the implementation of the change(s) described in the protocol and does not have any effect on the already approved information in the dossier.

Documentation

1.

Justification for the proposed deletion.

2.

Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).

Cond. to be fulfilled

Docum. to be supplied

Proced. 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.

Cond. to be fulfilled

Docum. to be supplied

Proced. type

(a)

Implementation of changes foreseen in a PACMP via Type IA notification

1

1, 2, 3

IA

(b)

Implementation of changes foreseen in a PACMP via Type IAIN notification

2

1, 2, 3, 4

IAIN

(c)

Implementation of changes 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 (*1)

3.

Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).

4.

Results of the studies performed in accordance with the post-approval change management protocol.

Cond. to be fulfilled

Docum. to be supplied

Proced. 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 (e.g. interaction of the different parameters, including risk assessment and multivariate studies, as appropriate) demonstrating where relevant that a systematic understanding of how material attributes and process parameters impact the critical quality attributes of the active substance has been achieved.

2.

The product lifecycle management document includes a description of the material attributes, quality attributes and process parameters (or analytical procedure parameters), their proposed limits and ranges, and future variation reporting categories, in a tabular format.

3.

Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format).

Cond. to be fulfilled

Docum. to be supplied

Proced. type

(a)

Major change to the active substance in line with an approved PLCM

1, 2, 3

II

(b)

Minor change to the active substance in line with an approved PLCM

1

1, 2, 3

IA

(c)

Minor change to the active substance in line with an approved PLCM

2

1, 2, 3

IAIN

(d)

Minor change to the active substance 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 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).

Cond. to be fulfilled

Docum. to be supplied

Proced. 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).

Cond. to be fulfilled

Docum. to be supplied

Proced. type

(a)

Changes in imprints, bossing (embossing/debossing) or other markings

1, 2, 3, 4

1

IAIN

(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.

Cond. to be fulfilled

Docum. to be supplied

Proced. type

(a)

Immediate release tablets, capsules, suppositories and pessaries

1, 2, 3, 4

1, 4

IAIN

(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.

Cond. to be fulfilled

Docum. to be supplied

Proced. 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

IAIN

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.

Cond. to be fulfilled

Docum. to be supplied

Proced. 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.

Cond. to be fulfilled

Docum. to be supplied

Proced. type

II

Cond. to be fulfilled

Docum. to be supplied

Proced. 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.

Cond. to be fulfilled

Docum. to be supplied

Proced. type

(a)

Addition or replacement of a site responsible for secondary packaging

1, 2

1, 7

IAIN

(b)

Addition or replacement of a site responsible for immediate packaging

1, 2, 3, 4

1, 2, 7, 8

IAIN

(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:

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.

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)).

Cond. to be fulfilled

Docum. to be supplied

Proced. 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

IAIN

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

IAIN

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:

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.

Cond. to be fulfilled

Docum. to be supplied

Proced. 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.

Cond. to be fulfilled

Docum. to be supplied

Proced. 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.