#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. | |||
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