Q.I.a) Manufacture
#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. | |||
Q.I.b) Control of active substance
#qib1
| Q.I.b.1 Change in the specification attribute and/or acceptance criteria of an active substance, starting material/reagent/intermediate used in the manufacturing process of the active substance | Conditions to be fulfilled | Documentation to be supplied | Procedure type |
| a) Change within the specification acceptance criteria for finished product subject to Official Control Authority Batch Release | 1, 2, 3 | 1, 2 | IAIN |
| b) Change within the specification acceptance criteria | 1, 2, 3, 4 | 1, 2 | IA |
| c) Addition of a new specification attribute with its corresponding analytical procedure and acceptance criteria | 1, 2, 4, 5, 6 | 1, 2, 3, 4, 5 | IA |
| d) Deletion of a non-significant or an obsolete specification attribute | 1, 2, 4, 7, 8 | 1, 2, 6 | IA |
| e) Deletion of a specification attribute which may have a significant effect on the overall quality of the active substance and/or the finished product | II | ||
| f) Change outside of the specification acceptance criteria for the active substance | II | ||
| g) Change outside of the specification acceptance criteria for starting material/reagent/intermediate which may have a significant effect on the overall quality of the active substance and/or the finished product | II | ||
| h) Change outside of the specification acceptance criteria for starting material/reagent/intermediate | 1, 2, 4, 5 | IB | |
| i) Change in specification attribute for the active substance from in-house to a non-official Pharmacopoeia/Pharmacopoeia of a third country where there is no monograph in the European Pharmacopoeia or the national pharmacopoeia of a Member State | 1, 2, 3, 4, 5 | IB | |
| j) Change of the analytical marker or widening of the acceptance criteria of the analytical marker (other extracts) for a herbal active substance | 1, 2, 3, 4, 5 | IB | |
| k) Change in the testing of specification attribute of the active substance, from routine to skip/periodic testing and vice versa | 1, 2, 7 | IB | |
| l) Replacement of a specification attribute with its corresponding analytical procedure | 1, 2, 3, 4 | IB | |
| Conditions | |||
| 1. The change is not a consequence of any commitment from previous assessments to review specification acceptance criteria (e.g. made during the procedure for the marketing authorisation application or a Type II variation procedure). | |||
| 2. The change does not result from unexpected events arising during manufacture and is not as a result of a safety or quality issue (e.g. new unqualified impurity, change in total impurity limits). | |||
| 3. The analytical procedure remains the same. | |||
| 4. The change is fully described in the open (‘applicant’s’) part of an Active Substance Master File, if applicable. | |||
| 5. For any material, the change does not concern a genotoxic impurity (including nitrosamines). If it involves the final active substance, other than for residual solvents which must be in line with ICH limits, any new impurity control should be in line with the Ph. Eur. or national pharmacopoeia of a Member State. | |||
| 6. Any new analytical procedure does not concern a novel non-standard technique or a standard technique used in a novel way. | |||
| 7. The change is not related to a revision of the control strategy with an intention to minimise testing of parameters and attributes (critical or non-critical). | |||
| 8. The specification attribute does not concern a critical attribute, for example: – identity test, – assay, – purity, – impurities (except when a solvent is no longer used in the manufacture of the active substance), – a critical physical characteristics (for example: polymorphism, particle size, bulk or tapped density), – or water content. | |||
| Documentation | |||
| 1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format). | |||
| 2. Comparative table of current and proposed specifications. | |||
| 3. Details of any new analytical procedure and validation data, where relevant. | |||
| 4. Batch analysis data on two production batches [3 production batches (unless otherwise justified) for biologicals]) of the relevant substance for all specification attributes. | |||
| 5. Justification from the marketing authorisation holder or ASMF holder as appropriate of the new specification attribute and the acceptance criteria. | |||
| 6. Justification/risk assessment from the marketing authorisation holder or the ASMF holder, as appropriate, that the specification attribute is non-significant, or that the specification attribute is obsolete. | |||
| 7. Justification from the marketing authorisation holder or the ASMF holder for the change in the testing of specification attribute. A change from routine testing to skip/periodic testing is warranted when the manufacturing process is under control and supported by sufficient amount of historical data compliant with the specification or as foreseen by relevant guidelines. A change from skip/periodic testing to routine testing should be supported by analytical data demonstrating failure to meet the approved acceptance criteria for the skip tested specification. | |||
#qib2
| Q.I.b.2 Change to analytical procedure for active substance or starting material/reagent/intermediate used in the manufacturing process of the active substance | Condition to be fulfilled | Documentation to be supplied | Procedure type |
| Change to analytical procedure for the active substance | |||
| (a) Minor change to an analytical procedure for the active substance | 1, 2, 3, 4 | 1, 2 | IA |
| (b) Deletion of an analytical procedure for the active substance if an alternative procedure is already authorised | 4, 5 | 1 | IA |
| (c) Introduction, replacement or substantial change to a biological/immunological/immunochemical analytical procedure for an active substance | II | ||
| (d) Other change to an analytical procedure (including replacement or addition) for the active substance | 1, 2 | IB | |
| Change to analytical procedure for starting material/reagent/intermediate used in the manufacturing process of the active substance | |||
| (e) Minor change to an analytical procedure for starting material/reagent/intermediate | 1, 2, 3, 4 | 1, 2 | IA |
| (f) Deletion of an analytical procedure for a starting material/reagent/intermediate, if an alternative analytical procedure is already authorised | 4, 5 | 1 | IA |
| (g) Introduction, replacement or change to a biological/immunological/immunochemical analytical procedure for starting material /reagent /intermediate, used in the manufacturing process of an active substance | 1, 2 | IB | |
| (h) Other change to an analytical procedure (including replacement or addition) for a starting material/reagent/intermediate | 1, 2, 4, 6, 7 | 1, 2 | IA |
| Conditions | |||
| 1. Appropriate validation studies have been performed in accordance with the relevant guidelines and show that the updated analytical procedure is at least equivalent to the former analytical procedure. | |||
| 2. There have been no changes of the total impurity limits; no new unqualified impurities are detected. | |||
| 3. The method of analysis should remain the same (e.g. a change in column length or temperature, but not a different type of column or method). | |||
| 4. The change is fully described in the open (‘applicant’s’) part of an Active Substance Master File, if applicable. | |||
| 5. An alternative analytical procedure is already authorised for the specification attribute. | |||
| 6. Any new analytical procedure does not concern a novel non-standard technique or a standard technique used in a novel way. | |||
| 7. The analytical procedure is not a biological/immunological/immunochemical procedure. | |||
| Documentation | |||
| 1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format), including a description of the analytical methodology, a summary of validation data, revised specifications. | |||
| 2. Comparative validation results, or if justified comparative analysis results showing that the current analytical procedure and the proposed one are equivalent. This requirement is not applicable in case of an addition of a new analytical procedure unless the new analytical procedure is added as an alternative procedure to a current one. | |||
#qib3
| Q.I.b.3 Change to an in-house reference standard/preparation for a biological active substance | Condition to be fulfilled | Documentation to be supplied | Procedure type |
| (a) Replacement of an in-house reference standard/preparation not covered by an approved qualification protocol (1) | II | ||
| (b) Replacement of an in-house reference standard/preparation not covered by an approved qualification protocol, where comparability test results using current and proposed reference standard/preparation material are available | 1, 2 | IB | |
| (c) Introduction of a qualification protocol for the preparation/replacement of an in-house reference standard or preparation (2) | II | ||
| (d) Substantial change to the qualification protocol for the preparation/replacement of an in-house reference standard or preparation which may have a significant impact on the quality, safety or efficacy of the active substance | II | ||
| (e) Other change to the qualification protocol for the prepartation/replacement of an in-house reference standard or preparation | 1 | IB | |
| Documentation | |||
| 1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format), including a description of the manufacturing and qualification of the new in-house reference standard. | |||
| 2. Comparative test results, showing that the current in-house reference standard and the proposed one are equivalent. | |||
Q.I.c) Container closure system
Q.I.c.1 Change in immediate packaging of the active substance
Q.I.c.3 Change in analytical procedure for the immediate packaging of the active substance
#qic1
| Q.I.c.1 Change in immediate packaging of the active substance | Condition to be fulfilled | Documentation to be supplied | Procedure type |
| (a) Change in immediate packaging of non-liquid active substance | 1, 2, 3 | 1, 2, 3, 4 | IA |
| (b) Change in immediate packaging of sterile liquid active substance | II | ||
| (c) Change in immediate packaging of nonsterile liquid active substance | 1, 2, 4, 5 | IB | |
| (d) Deletion of one of the authorised immediate packagings of the active substance | 4 | 1 | IA |
| Conditions | |||
| 1. The proposed packaging material must be at least equivalent to the approved material in respect of its relevant properties. | |||
| 2. Relevant stability studies have been started under ICH conditions and relevant stability parameters have been assessed in at least two pilot scale or industrial scale batches and at least three months satisfactory stability data are at the disposal of the applicant at time of implementation. However, if the proposed packaging is more resistant than the existing packaging, the three months’ stability data do not yet have to be available. These studies must be finalised and the data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the shelf life/retest period (with proposed action). | |||
| 3. The active substance is not a sterile active substance or biological active substance. | |||
| 4. There should be at least one remaining packaging adequate for the storage of the active substance at the authorised conditions. | |||
| Documentation | |||
| 1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format). | |||
| 2. Appropriate data on the new packaging (e.g. comparative data on permeability e.g. for O2, CO2 moisture). Where appropriate, proof must be provided that no interaction between the content and the packaging material has no impact on the active substance quality (e.g. no migration of components of the proposed material into the content and no loss of components of the product into the pack), including confirmation that the material complies with relevant pharmacopoeia requirements or legislation of the Union on plastic material and objects in contact with foodstuffs. | |||
| 3. A declaration from the marketing authorisation holder or the ASMF holder as appropriate that the required stability studies have been started under ICH conditions (with indication of the batch numbers concerned) and that, as relevant, the required minimum satisfactory stability data were at the disposal of the applicant at time of implementation and that the available data did not indicate a problem. Assurance should also be given that the studies will be finalised and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved shelf life (with proposed action). | |||
| 4. Comparison of the current and proposed immediate packaging specifications, if applicable. | |||
| 5. The results of stability studies that have been carried out under ICH conditions, on the relevant stability parameters, on at least two pilot or industrial scale batches, covering a minimum period of 3 months, and an assurance is given that these studies will be finalised, and that data will be provided immediately to the competent authorities if outside specifications or potentially outside specifications at the end of the approved retest period (with proposed action). | |||
#qic2
| Q.I.c.2 Change in the specification attribute and/or acceptance criteria of the immediate packaging of the active substance | Condition to be fulfilled | Documentation to be supplied | Procedure type |
| (a) Change of specification acceptance criteria | 1, 2, 3, 4 | 1, 2 | IA |
| (b) Addition of a new specification attribute to the specification with its corresponding analytical procedure | 1, 2, 5 | 1, 2, 3, 4 | IA |
| (c) Deletion of a non-significant or obsolete specification attribute | 1, 2, 6 | 1, 2, 5 | IA |
| (d) Replacement of a specification attribute with its corresponding analytical procedure | 1, 2, 3 | IB | |
| Conditions | |||
| 1. The change is not a consequence of any commitment from previous assessments to review specification acceptance criteria (e.g. made during the procedure for the marketing authorisation application or a Type II variation procedure) unless it has been previously assessed and agreed as part of a follow-up measure. | |||
| 2. The change does not result from unexpected events arising during manufacture of the packaging material or because of stability concerns during storage of the active substance, and is not as a result of a safety or quality issue. | |||
| 3. Any change should be within the range of currently approved acceptance criteria. | |||
| 4. The analytical procedure remains the same, or changes in the analytical procedure are minor. | |||
| 5. Any new analytical procedure does not concern a novel non-standard technique or a standard technique used in a novel way. | |||
| 6. The change is not related to a revision of the control strategy with an intention to minimise testing of parameters and attributes (critical or non-critical). | |||
| Documentation | |||
| 1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format). | |||
| 2. Comparative table of current and proposed specifications. | |||
| 3. Details of any new analytical procedure and validation data, where relevant. | |||
| 4. Justification from the marketing authorisation holder or the ASMF Holder, as appropriate, of the new specification attribute and the acceptance criteria. | |||
| 5. Justification/risk assessment from the marketing authorisation holder or the ASMF Holder, as appropriate, that the specification attribute is non-significant, or obsolete. | |||
#qic3
| Q.I.c.3 Change in analytical procedure for the immediate packaging of the active substance | Condition to be fulfilled | Documentation to be supplied | Procedure type |
| (a) Minor change to an approved analytical procedure | 1, 2, 3 | 1, 2 | IA |
| (b) Other change to an analytical procedure (including replacement or addition) | 1, 3 | 1, 2 | IA |
| (c) Deletion of an analytical procedure if an alternative procedure is already authorised | 4 | 1 | IA |
| Conditions | |||
| 1. Appropriate validation studies have been performed in accordance with the relevant guidelines and show that the updated analytical procedure is at least equivalent to the former procedure. | |||
| 2. The analytical procedure should remain the same (e.g. a change in column length or temperature, but not a different type of column or method). | |||
| 3. Any new analytical procedure does not concern a novel non-standard technique or a standard technique used in a novel way. | |||
| 4. There is still an analytical procedure registered for the specification attribute. | |||
| Documentation | |||
| 1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format), including a description of the analytical methodology, a summary of validation data. | |||
| 2. Comparative validation results or if justified comparative analysis results showing that the current analytical procedure and the proposed one are equivalent. This requirement is not applicable in case of an addition of a new analytical procedure. | |||
#qic4
| Q.I.c.4 Change of a secondary packaging component of the active substance (including replacement, addition or deletion), when mentioned in the dossier | Condition to be fulfilled | Documentation to be supplied | Procedure type |
| 1, 2, 3, 4 | 1 | IA | |
| Conditions | |||
| 1. The secondary packaging does not play a functional role on the stability of the active substance, or if it does, it is not less protective than the approved one. | |||
| 2. The changed packaging component must be adequate for the storage of the active substance at the authorised conditions. | |||
| 3. The change should not be due to critical deficiencies of the former packaging component. | |||
| 4. The change is not a result of any unexpected events arising during manufacture or because of stability concerns during storage of the active substance. | |||
| Documentation | |||
| 1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format). | |||
Q.I.d) Stability
#qid1
| Q.I.d.1 Change in the re-test period/storage period or storage conditions of the active substance or intermediates used in the manufacturing process of the biological active substance | Condition to be fulfilled | Documentation to be supplied | Procedure type |
| (a) Re-test period/storage period | |||
| 1. Reduction of re-test period/storage period | 1 | 1, 2, 3, 4 | IA |
| 2. Introduction of re-test period/storage period | 1, 2, 3 | IB | |
| 3. Extension of the re-test period/storage period based on extrapolation or stability modelling not in accordance with relevant stability guidelines | II | ||
| 4. Extension of re-test period/storage period supported by real time data not in accordance with an approved stability protocol or an extension based on extrapolation of stability data in accordance with relevant stability guidelines | 1, 3 | IB | |
| 5. Extension of a re-test period/storage period supported by real time data fully in line with the stability protocol | 2 | 1, 2, 3 | IA |
| (b) Storage conditions | |||
| 1. Change to more restrictive storage conditions | 1, 3 | 1, 2, 3 | IA |
| 2. Change in storage conditions | 1, 2, 3 | IB | |
| (c) Change to an approved stability protocol | 1, 4 | 1, 4 | IA |
| Conditions | |||
| 1. The change should not be the result of unexpected events arising during manufacture or because of stability concerns. | |||
| 2. Stability studies have been performed in accordance with a currently approved stability protocol. Real time data are submitted. All batches meet their pre-defined specification at all time points. No unexpected trends have been observed. | |||
| 3. The physical state of the active substance has not changed. | |||
| 4. The changes do not concern a widening of the acceptance criteria in the parameters tested, a removal of stability indicating parameters or a reduction in the frequency of testing. | |||
| Documentation | |||
| 1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format). This must contain results of appropriate real time stability studies, conducted in accordance with the relevant stability guidelines on three pilot or production scale batches of the active substance or intermediate in the authorised packaging material. | |||
| 2. Confirmation that stability studies have been done to the currently approved protocol. The studies must show that the agreed relevant specifications are still met. | |||
| 3. Copy of approved specifications of the active substance (as annex to the application form). | |||
| 4. Justification for the proposed changes. | |||
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