This is an archived version. Please see the current version here: Q. QUALITY CHANGES – Q.II. FINISHED PRODUCT

B.II.a) Description and composition

B.II.a.1 Change or addition of imprints, bossing or other markings including replacement, or addition of inks used for product marking.

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

B.II.a.3 Changes in the composition (excipients) of the finished product

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

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

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

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B.II.a.1 Change or addition of imprints, bossing or other markings including replacement, or addition of inks used for product marking.	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Changes in imprints, bossing or other markings	1, 2, 3, 4	1, 2	IA_IN
b) Changes in scoring/break lines intended to divide into equal doses		1, 2, 3	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 or NTA volume 6B format for veterinary products, as appropriate), including a detailed drawing or written description of the current and new appearance, and including revised product information as appropriate.
2. Samples of the finished product where applicable (see NTA, Requirements for samples in the Member States).
3 Results of the appropriate Ph. Eur tests demonstrating equivalence in characteristics/correct dosing.

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B.II.a.2 Change in the shape or dimensions of the pharmaceutical form	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Immediate release tablets, capsules, suppositories and pessaries	1, 2, 3, 4	1, 4	IA_IN
b) Gastro-resistant, modified or prolonged release pharmaceutical forms and scored tablets intended to be divided into equal doses		1, 2, 3, 4, 5	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 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 or NTA volume 6B format for veterinary products, as appropriate), 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 (Human or Veterinary) guidance on Bioavailability). For herbal medicinal product comparative disintegration data may be acceptable.
3. Justification for not submitting a new bioequivalence study according to the relevant (Human or Veterinary) guidance on Bioavailability.
4. Samples of the finished product where applicable (see NTA, Requirements for samples in the Member States).
5. Results of the appropriate Ph. Eur tests demonstrating equivalence in characteristics/correct dosing.
Note: For B.II.a.2.c Applicants are reminded that any change to the “strength” of the medicinal product requires the submission of an Extension application.

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B.II.a.3 Changes in the composition (excipients) of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Changes in components of the flavouring or colouring system
1. Addition, deletion or replacement	1, 2, 3, 4, 5, 6, 7, 9, 11	1, 2, 4, 5, 6	IA_IN
2. Increase or reduction	1, 2, 3, 4, 11	1, 2, 4	IA
3. Biological veterinary medicinal products for oral use for which the colouring or flavouring agent is important for the uptake by target animal species			II
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, 7	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 medicinal product			II
3. Change that relates to a biological/immunological product			II
4. Any 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
5. Change that is supported by a bioequivalence study			II
6. Replacement of a single excipient with a comparable excipient with the same functional characteristics and at a similar level		1, 3, 4, 5, 6, 7, 8, 9, 10	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 an excipient which currently makes 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/VICH 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 Directives (e.g. Directive 94/36/EC of the European Parliament and of the Council and Comission Directive 2008/128/EC for colours for use in foodstuffs and Directive 88/388/EEC 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 (Human or Veterinary) guidance on Bioavailability). 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/immunological medicinal product.
11. For veterinary medicinal products for oral use, the change does not affect the uptake by target animal species.
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 identification method for any new colorant, where relevant, and including revised product information as appropriate.
2. A declaration 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).
3. 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 shelf life (with proposed action).
4. Sample of the new product, where applicable (see Notice to Applicants Requirements for samples in the Member States).
5. 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).
6. Data to demonstrate that the new excipient does not interfere with the finished product specification test methods, if appropriate.
7. Justification for the change/choice of excipients etc. must be given by appropriate development pharmaceutics (including stability aspects and antimicrobial preservation where appropriate).
8. 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.
9. Justification for not submitting a new bioequivalence study according to the current Note for Guidance on The Investigation of Bioavailability and Bioequivalence.
10. For veterinary medicines intended for use in food producing animal species, proof that the excipient is classified according to Article 14(2)(c) or, if not, justification that the excipient does not have pharmacological activity at the dose at which it is administered to the target animal.

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B.II.a.4 Change in coating weight of oral dosage forms or change in weight of capsule shells	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Solid oral pharmaceutical forms	1, 2, 3, 4	1, 2	IA
b) Gastro-resistant, modified or prolonged release pharmaceutical forms where the coating 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.
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 or NTA volume 6B format for veterinary products, as appropriate).
2. A declaration 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). In addition, where relevant, photo-stability testing should be performed.

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

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

B.II.b) Manufacture

B.II.b.1 Replacement or addition of a manufacturing site for part or all of the manufacturing process of the finished product

B.II.b.2 Change to importer, batch release arrangements and quality control testing of the finished product

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

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

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

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B.II.b.1 Replacement or addition of a manufacturing site for part or all of the manufacturing process of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Secondary packaging site	1, 2	1,3, 8	IA_IN
b) Primary packaging site	1, 2, 3, 4, 5	1, 2, 3, 4, 8, 9	IA_IN
c) Site where any manufacturing operation(s) take place, except batch release, batch control, and secondary packaging, for biological/ immunological medicinal products, or for pharmaceutical forms manufactured by complex manufacturing processes			II
d) Site which requires an initial or product specific inspection			II
e) Site where any manufacturing operation(s) take place, except batch-release, batch control, primary and secondary packaging, for non- sterile medicinal products		1, 2, 3, 4, 5, 6, 7, 8, 9	IB
f) Site where any manufacturing operation(s) take place, except batch release, batch control, and secondary packaging, for sterile medicinal products (including those that are aseptically manufactured) excluding biological/ immunological medicinal products		1, 2, 3, 4, 5, 6, 7, 8	IB
Conditions
1. Satisfactory inspection in the last three years by an inspection service of one of the Member States of the EU/EEA or of a country where an operational Good Manufacturing Practice (GMP) mutual recognition agreement (MRA) exists between the country concerned and the EU.
2. Site appropriately authorised (to manufacture the pharmaceutical form or product concerned).
3. Product concerned is not a sterile product.
4. Where relevant, for instance for suspensions and emulsions, 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.
5. Product concerned is not a biological/immunological medicinal product.
Documentation
1. Proof that the proposed site is appropriately authorised for the pharmaceutical form or product 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.
2. Where relevant, the batch numbers, corresponding batch size and the manufacturing date of batches (³ 3) used in the validation study should be indicated and the validation data presented, or validation protocol (scheme) to be submitted.
3. The variation application form should clearly outline the “present” and “proposed” finished product manufacturers as listed in section 2.5 of the application form.
4. Copy of approved release and end-of-shelf life specifications if relevant.
5. 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).
6. 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 appropiate imaging technique.
7. i) If the new manufacturing site uses the active substance as a starting material – A declaration by the Qualified Person (QP) at the site responsible for batch release that the active substance is manufactured in accordance with the detailed guidelines on good manufacturing practice for starting materials as adopted by the Union. ii) In addition, if the new manufacturing site is located within the EU/EEA and uses the active substance as a starting material – A declaration by the Qualified Person (QP) of the new manufacturing site that the active substance used is manufactured in accordance with the detailed guidelines on good manufacturing practice for starting materials as adopted by the Union.
8. 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).
9. If the manufacturing site and the primary 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 Qualified Person is at the disposal of a manufacturing authorisation holder according to Art. 41 of Directive 2001/83/EC and Article 45 of Directive 2001/82/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 (1) of Directive 2001/83/EC and Article 50a (1) of Directive 2001/82/EC, manufacture includes complete or partial manufacture, import, dividing up, packaging or presentation prior to its incorporation into a medicinal 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 of the European Parliament and of the Council.

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B.II.b.2 Change to importer, batch release arrangements and quality control testing of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Replacement or addition of a site where batch control/testing takes place	2, 3, 4, 5	1, 2, 5	IA
b) Replacement or addition of a site where batch control/testing takes place for a biological/immunological product and any of the test methods performed at the site is a biological/immunological method			II
c) Replacement or addition of a manufacturer responsible for importation and/or batch release
1. Not including batch control/testing	1, 2,5	1, 2, 3, 4, 5	IA_IN
2. Including batch control/testing	1, 2, 3, 4, 5	1, 2, 3, 4, 5	IA_IN
3. Including batch control/testing for a biological/immunological product and any of the test methods performed at that site is a biological / immunological / immunochemical method			II
Conditions
1. The manufacturer responsible for batch release must be located within the EU/EEA. 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 product is not a biological/immunological medicinal product.
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) 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. For a site within the EU/EEA: Attach copy of manufacturing authorisation(s) or where no manufacturing authorisation exists a certificate of GMP compliance issued within the last 3 years by the relevant competent authority. For a manufacturing site outside the 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. Where no such agreement exists a GMP certificate issued within the last 3 years by a EU/EEA competent authority.
2. The variation application form should clearly outline the “present” and “proposed” finished product manufacturers, importer, batch control/testing and batch release sites as listed in section 2.5 of the application form for marketing authorisation.
3. For centralised procedure only: contact details of new contact person in the EU/EEA for product defects and recalls, if applicable.
4. 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. B.II.b.1.
5. 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 revised product information as appropriate.

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B.II.b.3 Change in the manufacturing process of the finished product, including an intermediate used in the manufacture of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Minor change in the manufacturing process	1, 2, 3, 4, 5, 6, 7	1, 2, 3, 4, 5, 6, 7, 8	IA
b) Substantial changes to a manufacturing process that may have a significant impact on the quality, safety and efficacy of the medicinal product			II
c) The product is a biological/immunological medicinal product and the change requires an assessment of comparability			II
d) Introduction of a non-standard terminal sterilisation method			II
e) Introduction or increase in the overage that is used for the active substance			II
f) Minor change in the manufacturing process of an aqueous oral suspension		1, 2, 4, 6, 7,8	IB
Conditions
1. No change in qualitative and quantitative impurity profile or in physico-chemical properties.
2. Either the change relates to an immediate release solid oral dosage form / oral solution and the medicinal product concerned is not a biological /immunological or herbal medicinal product; or the change relates to process parameter(s) that, in the context of a previous assessment, 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 and at least three months stability data are at the disposal of the applicant. Assurance is given that these studies will be finalised and that 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).
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 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 (Human or Veterinary) guidance on Bioavailability.
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.
7. Batch analysis data (in a comparative tabulated format) on a minimum of one batch manufactured to both the currently approved and the proposed process. 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).
8. Declaration that relevant stability studies have been started under ICH/VICH 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 and at least three months satisfactory stability data are at the disposal of the applicant at time of notification and that the stability profile is similar to the currently registered situation. 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).

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B.II.b.4 Change in the batch size (including batch size ranges) of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Up to 10-fold compared to the originally approved batch size	1, 2, 3, 4, 5, 7	1, 4	IA
b) Downscaling down to 10-fold	1, 2, 3, 4, 5, 6	1, 4	IA
c) The change requires assessment of the comparability of a biological/immunological medicinal product or the change in batch size requires a new bioequivalence study			II
d) The change relates to all other pharmaceutical forms manufactured by complex manufacturing processes			II
e) More than 10-fold increase compared to the originally approved batch size for immediate release (oral) pharmaceutical forms		1, 2, 3, 4, 5, 6	IB
f) The scale for a biological/immunological medicinal 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 conventional immediate release oral pharmaceutical forms or to non- sterile liquid based pharmaceutical forms.
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/immunological medicinal 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 or NTA volume 6B format for veterinary products, as appropriate).
2. Batch analysis data (in a comparative tabulated format) on a minimum of one production batch 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 MAH if outside specifications (with proposed action).
3. Copy of approved release and end-of-shelf life specifications.
4. Where relevant the batch numbers, corresponding batch size and the manufacturing date of batches (³3) used in the validation study should be indicated or validation protocol (scheme) be submitted.
5. The validation results should be provided
6. The results of stability studies that have been carried out under ICH/VICH conditions, on the relevant stability parameters, on at least one pilot or industrial scale batch, covering a minimum period of 3 months, and an assurance is given that these studies will be finalised, and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action). For biologicals/immunologicals: a declaration that an assessment of comparability is not required.

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B.II.b.5 Change to in-process tests or limits applied during the manufacture of the finished product	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 test(s) and limits	1, 2, 5, 6	1, 2, 3, 4, 5, 7	IA
c) Deletion of a non-significant in-process test	1, 2, 7	1, 2, 6	IA
d) Deletion of an in-process test which may have a significant effect on the overall quality of the finished product			II
e) Widening of the approved IPC limits, which may have a significant effect on overall quality of the finished product			II
f) Addition or replacement of an in-process test as a result of a safety or quality issue		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 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 in-process test does not concern the control of a critical parameter. e.g.: assay, impurities (unless a particular solvent is definitely not used in the manufacture) any critical physical characteristics (particle size, bulk, tapped density, etc.) identity test (unless there is a suitable alternative control already present) microbiological control (unless not required for the particular dosage form)
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate).
2. Comparative table of current and proposed in-process tests and limits.
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 finished product for all specification parameters.
5. Where appropriate, comparative dissolution profile data for the finished product on at least one pilot batch manufactured using the current and new in-process tests. For herbal medicinal products, comparative disintegration data may be acceptable.
6. Justification/risk assessment showing that the in-process test is non-significant or that it is obsolete.
7. Justification of the new in-process test and limits.

B.II.c) Control of excipients

B.II.c.1 Change in the specification parameters and/or limits of an excipient

B.II.c.2 Change in test procedure for an excipient

B.II.c.3 Change in source of an excipient or reagent with TSE risk

B.II.c.4 Change in synthesis or recovery of a non- pharmacopoeial excipient (when described in the dossier) or a novel excipient

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B.II.c.1 Change in the specification parameters and/or limits of an excipient	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, 6, 7	1, 2, 3, 4, 6, 8	IA
c) Deletion of a non-significant specification parameter (e.g. deletion of an obsolete parameter)	1, 2, 8	1, 2, 7	IA
d) Change outside the approved specifications limits range			II
e) Deletion of a specification parameter which may have a significant effect on the overall quality of the finished product			II
f) Addition or replacement (excluding biological or immunological product) of a specification parameter with its corresponding test method, as a result of a safety or quality issue		1, 2, 3, 4, 5, 6, 8	IB
g) Where there is no monograph in the European Pharmacopoeia or the national pharmacopoeia of a Member State for the excipient, a change in specification from in-house to a non-official Pharmacopoeia or a Pharmacopoeia of a third country		1, 2, 3, 4, 5, 6, 8	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 (does not include standard pharmacopoeial microbiological methods)
7. The change does not concern a genotoxic impurity.
8. The specification parameter does not concern the control of a critical parameter. e.g.: impurities (unless a particular solvent is definitely not used in the manufacture of the excipient) any critical physical characteristics (particle size, bulk, tapped density, etc.) identity test (unless there is a suitable alternative control already present) microbiological control (unless not required for the particular dosage form)
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format 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 biological excipients,) of the excipient for all specification parameters.
5. Where appropriate, comparative dissolution profile data for the finished product on at least one pilot batch containing the excipient complying with the current and proposed specification. For herbal medicinal products comparative disintegration data may be acceptable.
6. Justification for not submitting a new bioequivalence study according to the relevant (Human, Veterinary) Guideline on Bioavailability, if appropriate.
7. Justification/risk assessment showing that the parameter is non-significant or that it is obsolete.
8. Justification of the new specification parameter and the limits.

#biic2

B.II.c.2 Change in test procedure for an excipient	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 if an alternative test procedure is already authorised	5	1	IA
c) Substantial change to or replacement of a biological/ immunological/ immunochemical test method or a method using a biological reagent			II
d) Other changes to a test procedure (including replacement or addition)		1, 2	IB
Conditions
1. Appropriate validation studies have been performed in accordance with the relevant guidelines and show that the updated 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 (does not include standard pharmacopoeial microbiological methods).
5. 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.

#biic3

B.II.c.3 Change in source of an excipient or reagent with TSE risk	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) From TSE risk material to vegetable or synthetic origin
1. For excipients or reagents not used in the manufacture of a biological / immunological active substance or in a biological / immunological medicinal product	1	1	IA
2. For excipients or reagents used in the manufacture of a biological / immunological active substance or in a biological / immunological medicinal product		1, 2	IB
b) Change or introduction of a TSE risk material or replacement of a TSE risk material from a different TSE risk material, not covered by a TSE certificate of suitability			II
Conditions
1. Excipient and finished product release and end of shelf life specifications remain the same.
Documentation
1. Declaration from the manufacturer or the marketing authorisation holder of the material that it is purely of vegetable or synthetic origin.
2. Study of equivalence of the materials and the impact on production of the final material and impact on behaviour (e.g. Dissolution characteristics) of the finished product.

#biic4

B.II.c.4 Change in synthesis or recovery of a non- pharmacopoeial excipient (when described in the dossier) or a novel excipient	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Minor change in synthesis or recovery of a non- pharmacopoeial excipient or a novel excipient	1, 2	1, 2, 3, 4	IA
b) The specifications are affected or there is a change in physico-chemical properties of the excipient which may affect the quality of the finished product.			II
c) The excipient is a biological/immunological substance			II
Conditions
1. The synthetic route and specifications are identical and there is no change in qualitative and quantitative impurity profile (excluding residual solvents, provided they are controlled in accordance with ICH/VICH limits), or in physico-chemical properties.
2. Adjuvants 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. Batch analysis data (in a comparative tabulated format) of at least two batches (minimum pilot scale) of the excipient manufactured according to the old and the new process.
3. Where appropriate, comparative dissolution profile data for the finished product of at least two batches (minimum pilot scale). For herbal medicinal products, comparative disintegration data may be acceptable.
4. Copy of approved and new (if applicable) specifications of the excipient.

B.II.d) Control of finished product

B.II.d.1 Change in the specification parameters and/or limits of the finished product

B.II.d.2 Change in test procedure for the finished product

B.II.d.3 Variations related to the introduction of real-time release or parametric release in the manufacture of the finished product

#biid1

B.II.d.1 Change in the specification parameters and/or limits of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Tightening of specification limits	1, 2, 3, 4	1, 2	IA
b) Tightening of specification limits for medicinal products subject to Official Control Authority Batch Release	1, 2, 3, 4	1, 2	IA_IN
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 such as odour and taste or identification test for a colouring or flavouring material)	1, 2, 9	1, 2, 6	IA
e) Change outside the approved specifications limits range			II
f) Deletion of a specification parameter which may have a significant effect on the overall quality of the finished product			II
g) Addition or replacement (excluding biological or immunological product) 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
h) Update of the dossier to comply with the provisions of an updated general monograph of the Ph. Eur for the finished product*	1, 2, 3, 4, 7, 8	1, 2	IA_IN
i) Ph. Eur. 2.9.40 Uniformity of dosage units is introduced to replace the currently registered method, either Ph. Eur. 2.9.5 (Uniformity of mass). or Ph. Eur. 2.9.6 (Uniformity of content)	1, 2,10	1, 2, 4	IA
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 the supporting documentation has been already assessed and approved within another 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.
7. The change does not concern any impurities (including genotoxic) or dissolution.
8. The change concerns the updating of the microbial control limits to be in line with the current Pharmacopoeia, and the currently registered microbial control limits (present situation) are in line with the pre January 2008 (non harmonised) situation and does not include any additional specified controls over the Pharmacopoeia requirements for the particular dosage form and the proposed controls are in line with the harmonised monograph.
9. The specification parameter or proposal for the specific dosage form does not concern a critical parameter for example: assay, impurities (unless a particular solvent is definitely not used in the manufacture of the finished product) any critical physical characteristics (hardness or friability for uncoated tablets, dimensions, etc.) a test that is required for the particular dosage form in accordance with the general notices of the Ph. Eur.; any request for skip testing.
10. The proposed control is fully in line with the Table 2.9.40.-1 of Ph. Eur. 2.9.40 monograph, and does not include the alternative proposal for testing uniformity of dosage units by Mass Variation instead of Content Uniformity when the latter is specified in Table 2.9.40.-1.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format 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 finished product for all specification parameters
5. Where appropriate, comparative dissolution profile data for the finished product on at least one pilot batch complying with the current and proposed specification. For herbal medicinal products, comparative disintegration data may be acceptable.
6. Justification/risk assessment showing that the parameter is non-significant or that it is obsolete.
7. Justification of the new specification parameter and the limits
* Note: There is no need to notify the competent authorities of an updated monograph of the European pharmacopoeia or a national pharmacopoeia of a Member State in the case that reference is made to the ‘current edition’ in the dossier of an authorised medicinal product. This variation therefore applies to cases where no reference to the updated monograph of the pharmacopoeia was contained in the technical dossier and the variation is made to make reference to the updated version.

#biid2

B.II.d.2 Change in test procedure for the finished product	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 if an alternative method is already authorised	4	1	IA
c) Substantial change to, or replacement of, a biological/ immunological/ immunochemical test method or a method using a biological reagent or replacement of a biological reference preparation not covered by an approved protocol			II
d) Other changes to a test procedure (including replacement or addition)		1, 2	IB
e) Update of the test procedure to comply with the updated general monograph in the Ph. Eur.	2, 3, 4, 5	1	IA
f) To reflect compliance with the Ph.Eur. and remove reference to the outdated internal test method and test method number*	2, 3, 4, 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. 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 (does not include standard pharmacopoeial microbiological methods).
5. The registered test procedure already refers to the general monograph of the Ph. Eur. and any changes are minor in nature and require update of the technical dossier.
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.
* Note: There is no need to notify the competent authorities of an updated monograph of the European pharmacopoeia in the case that reference is made to the ‘current edition’ in the dossier of an authorised medicinal product.

#biid3

B.II.d.3 Variations related to the introduction of real-time release or parametric release in the manufacture of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
			II

B.II.e) Container closure system

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

B.II.e.2 Change in the specification parameters and/or limits of the immediate packaging of the finished product

B.II.e.3 Change in test procedure for the immediate packaging of the finished product

B.II.e.4 Change in shape or dimensions of the container or closure (immediate packaging)

B.II.e.5 Change in pack size of the finished product

B.II.e.6 Change in any part of the (primary) packaging material not in contact with the finished product formulation (such as colour of flip-off caps, colour code rings on ampoules, change of needle shield (different plastic used))

B.II.e.7 Change in supplier of packaging components or devices (when mentioned in the dossier)

#biie1

B.II.e.1 Change in immediate packaging of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Qualitative and quantitative composition
1. Solid pharmaceutical forms	1, 2, 3	1, 2, 3, 4, 6	IA
2. Semi-solid and non-sterile liqui pharmaceutical forms		1, 2, 3, 5, 6	IB
3. Sterile medicinal products and biological/ immunological medicinal products.			II
4. The change relates to a less protective pack where there are associated changes in storage conditions and/or reduction in shelf life.			II
b) Change in type of container or addition of a new container
1. Solid, semi-solid and non-sterile liquid pharmaceutical forms		1, 2, 3, 5, 6, 7	IB
2. Sterile medicinal products and biological/ immunological medicinal products			II
3. Deletion of an immediate packaging container that does not lead to the complete deletion of a strength or pharmaceutical form	4	1, 8	IA
Conditions
1. The change only concerns the same packaging/container type (e.g. blister to blister).
2. The proposed packaging material must be at least equivalent to the approved material in respect of its relevant properties.
3. Relevant stability studies have been started under ICH/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 e.g. thicker blister packaging, the three months’ stability data do not yet have to be available. These studies must be finalised and the data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
4. The remaining product presentation(s) must be adequate for the dosing instructions and treatment duration as mentioned in the summary of product characteristics.
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 revised product information as appropriate.
2. Appropriate data on the new packaging (comparative data on permeability e.g. for O2, CO2 moisture).
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 pharmacopoeial requirements or legislation of the Union on plastic material and objects in contact with foodstuffs.
4. A declaration 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 shelf life (with proposed action).
6. Comparative table of the current and proposed immediate packaging specifications, if applicable.
7. Samples of the new container/closure where applicable (see NTA, Requirements for samples in the Member States/EMA).
8. Declaration that the remaining pack-size(s) is/are consistent with the dosage regimen and duration of treatment and adequate for the dosing instructions as approved in the summary of product characteristics.
Note: For B.II.e.1.b) applicants are reminded that any change which results in a “new pharmaceutical form” requires the submission of an Extension application.

#biie2

B.II.e.2 Change in the specification parameters and/or limits of the immediate packaging of the finished product	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).
2. The change does not result from unexpected events arising during manufacture
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 showing that the parameter is non-significant or that it is obsolete.
6. Justification of the new specification parameter and the limits.

#biie3

B.II.e.3 Change in test procedure for the immediate packaging of the finished product	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 validation studies 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. 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.
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.

#biie4

B.II.e.4 Change in shape or dimensions of the container or closure (immediate packaging)	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Non-sterile medicinal products	1, 2, 3	1, 2, 4	IA
b) The change in shape or dimensions concerns a fundamental part of the packaging material, which may have a significant impact on the delivery, use, safety or stability of the finished product			II
c) Sterile medicinal products		1, 2, 3, 4	IB
Conditions
1. No change in the qualitative or quantitative composition of the container.
2. The change does not concern a fundamental part of the packaging material, which affects the delivery, use, safety or stability of the finished product.
3. In case of a change in the headspace or a change in the surface/volume ratio, stability studies in accordance with the relevant guidelines have been started and relevant stability parameters have been assessed in at least two pilot scale (three for biological/immunological medicinal products) or industrial scale batches and at least three months (six months for biological/immunological medicinal products) stability data are at the disposal of the applicant. Assurance is given that these studies will be finalised and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate) ,including description, detailed drawing and composition of the container or closure material, and including revised product information as appropriate.
2. Samples of the new container/closure where applicable (see NTA, Requirements for samples in the Member States).
3. Re-validation studies have been performed in case of sterile products terminally sterilised. The batch numbers of the batches used in the re-validation studies should be indicated, where applicable.
4. In case of a change in the headspace or a change in the surface/volume ratio, a declaration that the required stability studies have been started under ICH/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 for a Type IA notification and time of submission of a Type IB notification, and that the available data did not indicate a problem. Assurance should also be given that the studies will be finalised and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action).

#biie5

B.II.e.5 Change in pack size of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Change in the number of units (e.g. tablets, ampoules, etc.) in a pack
1. Change within the range of the currently approved pack sizes	1, 2	1, 3	IA_IN
2. Change outside the range of the currently approved pack sizes		1, 2, 3	IB
b) Deletion of pack size(s)	3	1, 2	IA
c) Change in the fill weight/fill volume of sterile multidose (or single-dose, partial use) parenteral medicinal products, including biological/ immunological medicinal products.			II
d) Change in the fill weight/fill volume of non- parenteral multi-dose (or single-dose, partial use) products		1, 2, 3	IB
Conditions
1. New pack size should be consistent with the posology and treatment duration as approved in the Summary of Product Characteristics.
2. The primary packaging material remains the same.
3. The remaining product presentation(s) must be adequate for the dosing instructions and treatment duration as mentioned in the Summary of Product Characteristics.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate) including revised product information as appropriate.
2. Justification for the new/remaining pack-size, showing that the new/remaining size is/are consistent with the dosage regimen and duration of treatment as approved in the summary of product characteristics
3. Declaration that stability studies will be conducted in accordance with the relevant guidelines for products where stability parameters could be affected. Data to be reported only if outside specifications (with proposed action).
Note: For B.II.e.5.c) and d), applicants are reminded that any changes to the ‘strength’ of the medicinal product require the submission of an Extension application.

#biie6

B.II.e.6 Change in any part of the (primary) packaging material not in contact with the finished product formulation (such as colour of flip-off caps, colour code rings on ampoules, change of needle shield (different plastic used))	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Change that affects the product information	1	1	IA_IN
b) Change that does not affect the product information	1	1	IA
Conditions
1. The change does not concern a part of the packaging material, which affects the delivery, use, safety or stability of the finished product.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate), including revised product information as appropriate.

#biie7

B.II.e.7 Change in supplier of packaging components or devices (when mentioned in the dossier)	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Deletion of a supplier	1	1	IA
b) Replacement or addition of a supplier	1, 2, 3, 4	1, 2, 3	IA
c) Any change to suppliers of spacer devices for metered dose inhalers			II
Conditions
1. No deletion of packaging component or device.
2. The qualitative and quantitative composition of the packaging components/device and design specifications remain the same.
3. The specifications and quality control method are at least equivalent.
4. The sterilisation method and conditions remain the same, if applicable.
Documentation
1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate).
2. For devices for medicinal products for human use, proof of CE marking.
3. Comparative table of current and proposed specifications, if applicable.

B.II.f) Stability

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

#biif1

B.II.f.1 Change in the shelf-life or storage conditions of the finished product	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) Reduction of the shelf life of the finished product
1. As packaged for sale	1	1, 2, 3	IA_IN
2. After first opening	1	1, 2, 3	IA_IN
3. After dilution or reconstitution	1	1, 2, 3	IA_IN
b) Extension of the shelf life of the finished product
1. As packaged for sale (supported by real time data)		1, 2, 3	IB
2. After first opening (supported by real time data)		1, 2, 3	IB
3. After dilution or reconstitution (supported by real time data)		1, 2, 3	IB
4. Extension of the shelf-life based on extrapolation of stability data not in accordance with ICH/VICH guidelines*			II
5. Extension of the shelf-life of a biological/ immunological medicinal product in accordance with an approved stability protocol.		1, 2, 3	IB
c) Change in storage conditions for biological medicinal products, when the stability studies have not been performed in accordance with an approved stability protocol			II
d) Change in storage conditions of the finished product or the diluted/reconstituted product		1, 2, 3	IB
e) Change to an approved stability protocol	1, 2	1, 4	IA
Conditions
1. The change should not be the result of unexpected events arising during manufacture or because of stability concerns.
2. The change does not concern a widening of the acceptance criteria in the parameters tested, a removal of stability indicating parameters or a reduction in the frequency of testing.
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 (covering the entire shelf life) conducted in accordance with the relevant stability guidelines on at least two pilot scale batches¹ of the finished product in the authorised packaging material and/or after first opening or reconstitution, as appropriate; where applicable, results of appropriate microbiological testing should be included. ¹Pilot scale batches can be accepted with a commitment to verify the shelf life on production scale batches.
2. Revised product information
3. Copy of approved end of shelf life finished product specification and where applicable, specifications after dilution/reconstitution or first opening.
4. Justification for the proposed change(s).
*Note: extrapolation not applicable for biological/immunological medicinal product.

B.II.g) Design Space and post approval change management protocol

B.II.g.1 Introduction of a new design space or extension of an approved design space for the finished product, concerning:

B.II.g.2 Introduction of a post approval change management protocol related to the finished product

B.II.g.3 Deletion of an approved change management protocol related to the finished product

B.II.g.4 Changes to an approved change management protocol

B.II.g.5 Implementation of changes foreseen in an approved change management protocol

#biig1

B.II.g.1 Introduction of a new design space or extension of an approved design space for the finished product, concerning:	Conditions to be fulfilled	Documentation to be supplied	Procedure type
a) One or more unit operations in the manufacturing process of the finished product including the resulting in-process controls and/or test procedures		1, 2, 3	II
b) Test procedures for excipients / intermediates and/or the finished product.		1, 2, 3	II
Documentation
1. Results from product and process development studies (including risk assessment and multivariate studies, as appropriate) demonstrating that a systematic mechanistic understanding of material attributes and process parameters to the critical quality attributes of the finished product has been achieved.
2. Description of the design space in tabular format, 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).

#biig2

B.II.g.2 Introduction of a post approval change management protocol related to the finished product	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 finished product.
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).

#biig3

B.II.g.3 Deletion of an approved change management protocol related to the finished product	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 finish product is not a result of unexpected events or out of specification results during the implementation of the change (s) described in the protocol and does not have any effect on the already approved information in the dossier.
Documentation
1. Justification for the proposed deletion.
2. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate).

#biig4

B.II.g.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.

#biig5

B.II.g.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, which requires its immediate notification following implementation.
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 finished product.

B.II.h) Adventitious Agents Safety

B.II.h.1 Update to the “Adventitious Agents Safety Evaluation” information (section 3.2.A.2)

#biih1

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

B. QUALITY CHANGES – B.II FINISHED PRODUCT (obsolete version)