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

This is an archived version.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