This is an archived version. Please see the current version here: Q. QUALITY CHANGES – Q.I ACTIVE SUBSTANCE – Q.I.a) Manufacture
B.I.a.2 Changes in the manufacturing process of the active substance
B.I.a.4 Change to in-process tests or limits applied during the manufacture of the active substance
B.I.a.6 Changes to the active substance of a vaccine against human coronavirus (This section is introduced with Addendum to the Variations Guidelines (2021/C 215 I/01))
#bia1
| B.I.a.1 Change in the manufacturer of a starting material/reagent/intermediate used in the manufacturing process of the active substance or change in the manufacturer (including where relevant quality control testing sites) of the active substance, where no Ph. Eur. Certificate of Suitability is part of the approved dossier | Conditions to be fulfilled | Documentation to be supplied | Procedure type |
| a) The proposed manufacturer is part of the same pharmaceutical group as the currently approved manufacturer | 1, 2, 3 | 1, 2, 3, 4, 5, 6, 7 | IAIN |
| b) Introduction of a manufacturer of the active substance supported by an ASMF | II | ||
| c) The proposed manufacturer uses a substantially different route of synthesis 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 | II | ||
| d) New manufacturer of material for which an assessment is required of viral safety and/or TSE risk | II | ||
| e) The change relates to a biological active substance or a starting material/reagent/intermediate used in the manufacture of a biological/immunological product | II | ||
| f) Changes to quality control testing arrangements for the active substance-replacement or addition of a site where batch control/testing takes place | 2, 4 | 1, 5 | IA |
| g) Introduction of a new manufacturer of the active substance that is not supported by an ASMF and requires significant update to the relevant active substance section of the dossier | II | ||
| h) Addition of an alternative sterilisation site for the active substance using a Ph.Eur. method | 1, 2, 4, 5, 8 | IB | |
| i) Introduction of a new site of micronisation | 2, 5 | 1, 4, 5, 6 | IA |
| j) Changes to quality control testing arrangements for a biological active substance: replacement or addition of a site where batch control/testing including a biological / immunological / immunochemical method takes place | II | ||
| k) New storage site of Master Cell Bank and/or Working Cell Banks | 1, 5 | IB | |
| Conditions | |||
| 1. For starting materials and reagents the specifications (including in process controls, methods of analysis of all materials), are identical to those already approved. For intermediates and active substances the specifications (including in process controls, methods of analysis of all materials), method of preparation (including batch size) and detailed route of synthesis are identical to those already approved. | |||
| 2. The active substance is not a biological/immunological substance or sterile. | |||
| 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. Method transfer from the old to the new site has been successfully completed. | |||
| 5. The particle size specification of the active substance and the corresponding analytical method remain the same. | |||
| 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), if applicable. | |||
| 2. A declaration from the marketing authorisation holder or the ASMF holder, where applicable, that the synthetic route (or in case of herbal medicinal products, where appropriate the method of preparation, geographical source, production of herbal drug and manufacturing route) quality control procedures and specifications of the active substance and of the starting material/reagent/intermediate in the manufacturing process of the active substance (if applicable) 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) of the active substance from the current and proposed manufacturers/sites. | |||
| 5. The variation application form should clearly outline the “present” and “proposed” manufacturers as listed in section 2.5 of the application form for marketing authorisation. | |||
| 6. 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 (QP) 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. B.II.b.1. | |||
| 7. Where relevant, a commitment of the manufacturer of the active substance to inform the MA holder of any changes to the manufacturing process, specifications and test procedures of the active substance. | |||
| 8. Proof that the proposed site is appropriately authorised for the pharmaceutical form or product or manufacturing operation 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. | |||
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| B.I.a.2 Changes in the manufacturing process of the active substance | Conditions to be fulfilled | Documentation to be supplied | Procedure type |
| a) Minor change in the manufacturing process of the active substance | 1, 2, 3, 4, 5, 6, 7 | 1, 2, 3 | IA |
| b) Substantial change to the manufacturing process of the active substance which may have a significant impact on the quality, safety or efficacy of the medicinal product | II | ||
| c) The change refers to a biological / immunological substance or use of a different chemically derived substance in the manufacture of a biological/immunological substance, which may have a significant impact on the quality, safety and efficacy of the medicinal product and is not related to a protocol | II | ||
| d) The change relates to a herbal medicinal product and there is a change to any of the following: geographical source, manufacturing route or production | II | ||
| e) Minor change to the restricted part of an Active Substance Master File | 1, 2, 3, 4 | IB | |
| Conditions | |||
| 1. No adverse change in qualitative and quantitative impurity profile or in physico-chemical properties. | |||
| 2. 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. In the case of herbal medicinal products, the geographical source, production of the herbal substance and the manufacturing route remain the same. | |||
| 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 active substance is not a biological / immunological substance. | |||
| 6. The change does not refer to the geographical source, manufacturing route or production of a herbal medicinal product. | |||
| 7. The change does not refer to the restricted part of an Active Substance Master File. | |||
| 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), and of the approved Active Substance Master File (where applicable), including a direct comparison of the present process and the new process. | |||
| 2. Batch analysis data (in comparative tabular format) of at least two batches (minimum pilot scale) manufactured according to the currently approved and proposed process. | |||
| 3. Copy of approved specifications of the active substance. | |||
| 4. A declaration from the marketing authorisation holder or 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 B.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. | |||
#bia3
| B.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) Up to 10-fold increase compared to the originally approved batch size | 1, 2, 3, 4, 6, 7, 8 | 1, 2, 5 | IA |
| b) Downscaling down to 10-fold | 1, 2, 3, 4, 5 | 1, 2, 5 | IA |
| c) The change requires assessment of the comparability of a biological/immunological active substance | II | ||
| d) More than 10-fold increase compared to the originally approved batch size | 1, 2, 3, 4 | IB | |
| e) The scale for a biological/immunological active substance is increased / decreased without process change (e.g. duplication of line) | 1, 2, 3, 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 product concerned is not a biological/immunological medicinal product. | |||
| 4. The change does not adversely affect the reproducibility of the process. | |||
| 5. The change should not be the result of unexpected events arising during manufacture or because of stability concerns. | |||
| 6. The specifications of the active substance/intermediates remain the same. | |||
| 7. The active substance is not sterile. | |||
| 8. 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. The batch numbers of the tested batches having the proposed batch size. | |||
| 3. Batch analysis data (in a comparative tabulated format) on a minimum of one production batch of the active substance or intermediate as appropriate, 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 marketing authorisation holder if outside specification (with proposed action). | |||
| 4. Copy of approved specifications of the active substance (and of the intermediate, if applicable). | |||
| 5. A declaration from the marketing authorisation holder or 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. | |||
#bia4
| B.I.a.4 Change to in-process tests or limits applied during the manufacture of the active substance | 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 in-process test and limits | 1, 2, 5, 6 | 1, 2, 3, 4, 6 | IA |
| c) Deletion of a non-significant in-process test | 1, 2, 7 | 1, 2, 5 | IA |
| d) Widening of the approved in-process test 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) Addition or replacement of an in-process test as a result of a safety or quality issue | 1, 2, 3, 4, 6 | IB | |
| Conditions | |||
| 1. The change is not a consequence of any commitment from previous assessments to review specification limits (e.g. made during the procedure for the marketing authorisation application or a type II variation procedure). | |||
| 2. The change does not result from unexpected events arising during manufacture 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 specification parameter does not concern a critical parameter for example any of the following: assay, impurities (unless a particular solvent is definitely not used in the manufacture of the active substance), any critical physical characteristics e.g. particle size, bulk or tapped density, identity test, water, any request for changing the frequency of testing. | |||
| Documentation | |||
| 1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format or NTA volume 6B format for veterinary products, as appropriate). | |||
| 2. Comparative table of current and proposed in-process tests. | |||
| 3. Details of any new non-pharmacopoeial 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 active substance for all specification parameters. | |||
| 5. Justification/risk assessment from the marketing authorisation holder or the ASMF Holder, as appropriate, that the in-process tests are non-significant, or that the in-process tests are obsolete. | |||
| 6. Justification from the MAH or ASMF Holder as appropriate for the new in-process test and limits. | |||
#bia5
| B.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 |
This section is introduced with Addendum to the Variations Guidelines (2021/C 215 I/01)
#bia6
| B.I.a.6 Changes to the active substance of a vaccine against human coronavirus | Conditions to be fulfilled | Documentation to be supplied | Procedure type |
| a) Replacement or addition of a serotype, strain, antigen or coding sequence or combination of serotypes, strains, antigens or coding sequences for a human coronavirus vaccine | II |