Q. QUALITY CHANGES – Q.II. FINISHED PRODUCT – Q.II.b) Manufacture

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

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

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

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

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

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

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

#qiib1

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

#qiib2

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

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

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

#qiib5

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

Q. QUALITY CHANGES – Q.II. FINISHED PRODUCT – Q.II.b) Manufacture

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