#qia1
| Q.I.a.1 Change in the manufacturing site of a starting material/intermediate used in the manufacturing process of the active substance or change in the manufacturing site (including where relevant quality control testing sites) of the active substance | Conditions to be fulfilled | Documentation to be supplied | Procedure type |
| Manufacturing site of an active substance or starting material or intermediate | |||
| a) Addition or replacement of a manufacturing site of an active substance or intermediate | 1, 2, 3 | 1, 2, 3, 4, 5, 6 | IAIN |
| b) Addition or replacement of a manufacturing site of an active substance or intermediate that requires significant update to the relevant active substance section of the dossier, e.g. where a substantially different route of synthesis or manufacturing conditions is used, which may have a potential to change important quality characteristics of the active substance, such as qualitative and/or quantitative impurity profile requiring qualification, or physico-chemical properties impacting on bioavailability | II | ||
| c) Addition or replacement of a manufacturing site of a starting material used in the manufacture of the active substance or reagent required to be mentioned in the dossier | 1, 2, 3 | 1, 2, 3, 4, 6 | IA |
| d) Addition or replacement of a manufacturing site of – a biological active substance or – a biological starting material/reagent/raw material/intermediate used in the manufacture of a biological active substance which may have a significant impact on the quality, safety or efficacy of the finished product or – a material for which an assessment is required of viral safety and/or TSE risk | II | ||
| e) Addition or replacement of a new herbal starting material supplier or of a new herbal active substance manufacturing site using the same or different plant production (i.e. cultivated or wild collection) | 1, 4, 5, 6, 7, 8 | IB | |
| f) Addition of a manufacturing site of the active substance that is supported by an Active Substance Master File (ASMF) | II | ||
| g) Addition or replacement of a manufacturing site responsible for sterilisation of the active substance using a Ph. Eur. method | 1, 2, 4, 9 | IB | |
| h) Addition or replacement of a manufacturing site responsible for micronisation of the active substance | 2, 4 | 1, 4, 5 | IA |
| Quality control testing arrangements for the active substance or starting material or intermediate | |||
| i) Addition or replacement of a batch control/testing site of the active substance or starting material/intermediate used in the manufacturing of a biological active substance, applying a biological/immunological/immunochemical analytical procedure | 1, 9, 10 | IB | |
| j) Addition or replacement of a batch control/testing site of the – the active substance or – intermediate of an active substance or – starting material of a biological active substance applying physicochemical and/or microbiological analytical procedures | 5, 6 | 1 | IA |
| Other | |||
| k) Addition or replacement of a storage site of the Master Cell Bank and/or Working Cell Banks | 7 | 1 | IA |
| Conditions | |||
| 1. For starting materials, the specifications and analytical procedures are identical to those already approved. For intermediates and active substances the specifications (including in process controls, analytical procedures), method of preparation (including batch size) and detailed route of synthesis are identical to those already approved. For herbal active substances, the geographical source, production of the herbal starting material/herbal substance and the manufacturing process of the herbal active substance are the same as those already approved. | |||
| 2. The active substance is not a biological or sterile substance. | |||
| 3. Where materials of human or animal origin are used in the process, the manufacturer does not use any new supplier for which assessment is required of viral safety or of compliance with the current Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products. | |||
| 4. The particle size specification of the active substance and the corresponding analytical procedure remain the same. | |||
| 5. Method transfer from the old to the new site has been successfully completed. | |||
| 6. The analytical procedure is not a biological/immunological/immunochemical procedure. | |||
| 7. For Master Cell Bank and/or Working Cell Banks the storage conditions are identical to those already approved. | |||
| Documentation | |||
| 1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format). | |||
| 2. A declaration from the marketing authorisation holder (and the ASMF holder, where applicable) that the starting material (specifications and analytical procedures) and that the synthetic route, quality control procedures and specifications of the active substance and of the intermediate used in the manufacturing process of the active substance are the same as those already approved. For herbal active substances, a declaration that the geographical source, production of the herbal starting material/herbal substance and the manufacturing process of the herbal active substance are the same as those already approved. | |||
| 3. Either a TSE Ph. Eur. certificate of suitability for any new source of material or, where applicable, documentary evidence that the specific source of the TSE risk material has previously been assessed by the competent authority and shown to comply with the current Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products. The information should include the following: Name of manufacturer, species and tissues from which the material is a derivative, country of origin of the source animals, its use and previous acceptance. For the centralised procedure, this information should be included in an updated TSE table A (and B, if relevant). | |||
| 4. Batch analysis data (in a comparative tabular format) for at least two batches (minimum pilot scale) (or 3 batches (unless otherwise justified) for biologicals) of the active substance/starting material from the current and proposed manufacturers/sites. | |||
| 5. A declaration by the qualified person (QP) of each of the manufacturing authorisation holders listed in the application, where the active substance is used as a starting material, and a declaration by the qualified person of each of the manufacturing authorisation holders listed in the application as responsible for batch release. These declarations should state that the active substance manufacturer(s) referred to in the application operate in compliance with the detailed guidelines on good manufacturing practice for starting materials. A single declaration may be acceptable under certain circumstances (see the note under variation no Q.II.b.1). | |||
| 6. Where relevant, a commitment of the manufacturer of the active substance to inform the marketing authorisation holder of any changes to the manufacturing process, specifications and analytical procedures of the active substance. | |||
| 7. For herbal starting material, a detailed comparison regarding specifications and critical quality attributes of the herbal starting material. For herbal active substance, a detailed comparison regarding specifications and critical quality attributes (e.g. for extracts: reference to the herbal starting material (incl. scientific binominal name and plant part), physical state, extraction solvent (nature and concentration), drug extract ratio (DER) and manufacturing process (including a stepwise comparison of all manufacturing steps in tabular format). | |||
| 8. For herbal starting material supplier, a GACP declaration from the new supplier (and updated QP declaration if the new supplier is also involved in the herbal active substance manufacture). | |||
| 9. Valid proof that the proposed site is GMP compliant for the manufacturing and/or testing operation(s) concerned: – For a site within the EU/EEA: a copy of the current manufacturing authorisation 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. | |||
| 10. The analytical procedure transfer protocols in accordance with Eudralex Volume 4 Chapter 6 Article 6.39 (which pre-define the acceptance criteria), from the old site to the new site (or new test laboratory). | |||
#qia2
| Q.I.a.2 Change in the manufacturing process of the active substance, intermediate of an active substance or starting materials for biological active substance | Conditions to be fulfilled | Documentation to be supplied | Procedure type |
| a) Minor change in the manufacturing process | 1, 2, 3, 4, 5 | 1, 2, 3, 4 | IA |
| b) Major change to the manufacturing process which may have a significant impact on the quality, safety or efficacy of the finished product | II | ||
| c) Change in the geographical source of a herbal starting material and/or production of a herbal substance | 1, 2, 3, 4, 5 | IB | |
| d) Minor change to the restricted part of an Active Substance Master File | 1, 2, 3, 6 | IB | |
| e) Deletion of a manufacturing process | 6, 7 | 1 | IA |
| Conditions | |||
| 1. No adverse change in qualitative and quantitative impurity profile or in physico-chemical properties. | |||
| 2. For chemical active substance: the synthetic route remains the same, i.e. intermediates remain the same and there are no new reagents, catalysts or solvents used in the process. For herbal active substances: the geographical source, production of the herbal starting material/herbal substance and the manufacturing process of the herbal active substance remain the same. For biological active substance/starting material/intermediate: the manufacturing steps remain the same and there are no changes to the manufacturing parameters (critical and non-critical PPs and IPCs) or to the specifications of the starting materials, intermediates, or active substance. For all: there are no changes to the finished product. | |||
| 3. The specifications of the active substance, or intermediates are unchanged. | |||
| 4. The change is fully described in the open (‘applicant’s’) part of an Active Substance Master File, if applicable. | |||
| 5. The change does not result from unexpected events arising during manufacture or because of stability concerns, and is not as a result of a safety or quality issue. | |||
| 6. The deletion should not be due to critical deficiencies concerning manufacturing. | |||
| 7. There should at least remain one manufacturing process, as previously authorised. | |||
| Documentation | |||
| 1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format). | |||
| 2. Batch analysis data (in comparative tabular format) of at least two batches (minimum pilot scale), of the active substance or intermediate as appropriate, manufactured according to the currently approved and proposed process. | |||
| 3. Copy of approved specifications of the active substance (as annex to the application form). | |||
| 4. A declaration from the marketing authorisation holder that an evaluation has been performed and the minor changes do not impact the quality, safety or efficacy of the active substance/finished product (e.g. minor amendments to process description without actual process change, such as details of reagents (e.g. buffers, media preparation). For herbal starting materials/active substances, this evaluation should include a detailed comparison regarding quality determining process characteristics (e.g. for extracts: extraction time, temperature, pressure). | |||
| 5. In the case of herbal starting materials, an updated GACP declaration and a declaration from the marketing authorisation holder that the manufacturing process of the herbal active substance remains the same. | |||
| 6. A declaration from the marketing authorisation holder (and the ASMF holder, where applicable) that there is no change in qualitative and quantitative impurity profile or in physico-chemical properties, that the synthetic route remains the same and that the specifications of the active substance or intermediates are unchanged. | |||
| Note for Q.I.a.2.b: For chemical active substances, this refers to substantial changes to the synthetic route or manufacturing conditions which may have a potential to change important quality characteristics of the active substance, such as qualitative and/or quantitative impurity profile requiring qualification, or physico-chemical properties impacting on bioavailability. | |||
#qia3
| Q.I.a.3 Change in batch size (including batch size ranges) of active substance or intermediate used in the manufacturing process of the active substance | Conditions to be fulfilled | Documentation to be supplied | Procedure type |
| a) An increase to the originally approved batch size | 1, 2, 3, 4, 5, 6, 7 | 1, 2, 3 | IA |
| b) Downscaling of the approved batch size | 1, 2, 3, 4, 5, 6, 8 | 1, 2, 3 | IA |
| c) The change in batch size of a biological active substance/intermediate requires assessment of the comparability | II | ||
| d) The scale for a biological active substance/intermediate is increased/decreased without process change (e.g. duplication of line) | 1, 2, 4 | IB | |
| Conditions | |||
| 1. Any changes to the manufacturing methods are only those necessitated by scale-up or downscaling, e.g. use of different-sized equipment. | |||
| 2. Test results of at least two batches according to the specifications should be available for the proposed batch size. | |||
| 3. The active substance is not a biological substance. | |||
| 4. The change does not adversely affect the reproducibility of the process. | |||
| 5. The change is fully described in the open (‘applicant’s’) part of an Active Substance Master File, if applicable. | |||
| 6. The specifications of the active substance/intermediates remain the same and the control strategy for impurities has been reviewed and remains appropriate. | |||
| 7. The active substance is not sterile. | |||
| 8. The change should not be the result of unexpected events arising during manufacture or because of stability concerns. | |||
| Documentation | |||
| 1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format). | |||
| 2. Batch analysis data (in a comparative tabulated format) on a minimum of two production batches of the active substance or intermediate, as appropriate, manufactured to both the currently approved and the proposed sizes. Batch analysis data of 3 batches (unless otherwise justified) for biological active substance, should be available for the proposed batch size. | |||
| 3. A declaration from the marketing authorisation holder (and the ASMF holder as appropriate) that the changes to the manufacturing methods are only those necessitated by scale-up or downscaling, e.g. use of different-sized equipment, that the change does not adversely affect the reproducibility of the process, that it is not the result of unexpected events arising during manufacture or because of stability concerns and that the specifications of the active substance/intermediates remain the same. | |||
| 4. For biological active substance, a justification that an assessment of comparability is not required. | |||
#qia4
| Q.I.a.4 Change to in-process controls applied during the manufacture of the active substance, intermediate of an active substance or starting materials for biological active substance | Conditions to be fulfilled | Documentation to be supplied | Procedure type |
| a) Minor change of in-process control limits | 1, 2, 3, 4, 5 | 1, 2 | IA |
| b) Addition of new in-process control and limits with its corresponding analytical procedure | 1, 2, 5, 6 | 1, 2, 3, 4, 5 | IA |
| c) Deletion of a non-significant or obsolete in-process control | 1, 2, 5, 7, 8 | 1, 2, 6 | IA |
| d) Widening of the approved in-process control limits, which may have a significant effect on the overall quality of the active substance | II | ||
| e) Deletion of an in-process test which may have a significant effect on the overall quality of the active substance | II | ||
| f) Change of an analytical procedure for an in-process control | 2, 4, 5, 9, 10 | 1 | IA |
| g) Replacement of an in-process control with its corresponding analytical procedure | 1, 2, 3, 4, 5 | IB | |
| Conditions | |||
| 1. The change is not a consequence of any commitment from previous assessments to review in-process control limits (e.g. made during the procedure for the marketing authorisation application or a Type II variation procedure). | |||
| 2. The change does not result from unexpected events arising during manufacture, and is not as a result of a safety or quality issue (e.g. new unqualified impurity detected, or a change in total impurity limits). | |||
| 3. Any change should be within the range of currently approved limits. | |||
| 4. The analytical procedure remains the same, or changes in the analytical procedure are minor (e.g. a change in column length or temperature could be allowed, but not a different type of column or method). | |||
| 5. The change is fully described in the open (‘applicant’s’) part of an Active Substance Master File, if applicable. | |||
| 6. Any new analytical procedure does not concern a novel non-standard technique or a standard technique used in a novel way. | |||
| 7. The in-process control does not concern a critical attribute, for example: – assay, – purity, – impurities (except when a solvent is no longer used in the manufacture of the active substance), – a critical physical characteristic (for example: particle size, bulk or tapped density), – identity test, – or water content. | |||
| 8. The change is not related to a revision of the control strategy with an intention to minimise testing of parameters and attributes (critical or non-critical). | |||
| 9. The new analytical procedure is not a biological/immunological/immunochemical procedure. | |||
| 10. Appropriate studies have been performed in accordance with the relevant guidelines and show that the updated analytical procedure is at least equivalent to the former analytical procedure. | |||
| Documentation | |||
| 1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format). | |||
| 2. Comparative table of current and proposed in-process controls and limits. | |||
| 3. Details of any new non-pharmacopoeial analytical method and validation data, where relevant. | |||
| 4. Batch analysis data on two production batches of the active substance for all specification attributes. | |||
| 5. Justification from the holder or ASMF holder as appropriate for the new in-process control and limits. | |||
| 6. Justification/risk assessment from the marketing authorisation holder or the ASMF holder, as appropriate, that the in-process controls are non-significant, or that the in-process controls are obsolete. | |||
#qia5
| Q.I.a.5 Changes to the active substance of a seasonal, pre-pandemic or pandemic vaccine against human influenza | Conditions to be fulfilled | Documentation to be supplied | Procedure type |
| a) Replacement of the strain(s) in a seasonal, pre-pandemic or a pandemic vaccine against human influenza | II |
#qia6
| Q.I.a.6 Changes to the active substance of a vaccine against human coronavirus or other vaccine that has the potential to address a public health emergency in the Union | Conditions to be fulfilled | Documentation to be supplied | Procedure type |
| a) Replacement or, upon agreement of the relevant authorities, addition of a serotype, strain, antigen or coding sequence or combination of serotypes, strains, antigens or coding sequences for a human coronavirus vaccine or other vaccine that has the potential to address a public health emergency in the Union | II | ||
| b) Deletion of a serotype, strain, antigen or coding sequence or combination of serotypes, strains, antigens or coding sequences for a human coronavirus vaccine or other vaccine that has the potential to address a public health emergency in the Union | 1, 2, 3, 4 | IB | |
| Documentation | |||
| 1. Declaration that the remaining product presentation(s) are adequate for the dosing instructions and duration as mentioned in the summary of product characteristics, and the deletion has been agreed in principle with the Agency. | |||
| 2. Amendment of the relevant section(s) of the dossier, as appropriate. | |||
| 3. Declaration that the serotype, strain, antigen or coding sequence is no longer appropriate in relation to the epidemiological evolution of the human virus of concern. | |||
| 4. Revised product information. | |||
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