Q.II.c.1 Change in the specification attribute and/or acceptance criteria of an excipient
#qiic1
| Q.II.c.1 Change in the specification attribute and/or acceptance criteria of an excipient | Conditions to be fulfilled | Documentation to be supplied | Procedure type |
| (a) Change within the approved specification acceptance criteria | 1, 2, 4 | 1, 2 | IA |
| (b) Addition of a new specification attribute to the specification with its corresponding analytical procedure | 1, 2, 5, 6 | 1, 2, 3, 4, 5, 7 | IA |
| (c) Deletion of a non-significant or obsolete specification attribute | 1, 2, 3, 7 | 1, 2, 6 | IA |
| (d) Change outside of the approved specification acceptance criteria | II | ||
| (e) Deletion of a specification attribute which may have a significant effect on the overall quality of the finished product | II | ||
| (f) Change in specification of an excipient 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, 7 | IB | |
| (g) Replacement of a specification attribute with its corresponding analytical procedure | 1, 2, 3, 4, 7 | 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 or because of stability concerns and is not as a result of a safety or quality issue, e.g. new unqualified impurity; change in total impurity limits. | |||
| 3. The change is not related to a revisions of the control strategy with an intention to minimise redundant testing of parameters and attributes (critical or non-critical). | |||
| 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 does not concern a genotoxic impurity. | |||
| 7. The specification attribute does not concern the control of a critical attribute, for example: – assay, – purity, – impurities (except when a solvent is no longer used in the manufacture of the excipient), – a critical physical characteristic (for example: particle size, bulk or tapped density) – identity test (unless there is a suitable alternative control already present), – water content – 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). | |||
| 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 of the excipient for all specification attributes [3 production batches (unless otherwise justified) for biological excipients or novel excipients]. | |||
| 5. Justification for not submitting a new bioequivalence study according to the relevant Guideline on The Investigation of Bioequivalence, if appropriate. | |||
| 6. Justification/risk assessment showing that the attribute is non-significant or that it is obsolete. | |||
| 7. Justification of the new specification attribute and the acceptance criteria. | |||
#qiic2
| Q.II.c.2 Change in analytical procedure for an excipient | Conditions to be fulfilled | Documentation to be supplied | Procedure type |
| (a) Minor change to an approved analytical procedure | 1, 2, 3 | 1, 2 | IA |
| (b) Deletion of an analytical procedure if an alternative analytical procedure is already authorised | 4 | 1 | IA |
| (c) Introduction, replacement or substantial change to a biological/immunological/immunochemical analytical procedure for an excipient | II | ||
| (d) Other changes to an analytical procedure (including replacement or addition) | 1, 2 | IB | |
| 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. An alternative analytical procedure is already authorised 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, revised specifications. | |||
| 2. Comparative validation results or if justified comparative analysis results showing that the current analytical and the proposed one are equivalent. This requirement is not applicable in case of an addition of a new analytical procedure. | |||
#qiic3
| Q.II.c.3 Change in source of an excipient or reagent with TSE risk, which is used in the manufacture of an active substance or in a finished product | Conditions to be fulfilled | Documentation to be supplied | Procedure type |
| (a) Change in the source of an excipient or reagent from a TSE risk material to a material of vegetable or synthetic origin | 1 | 1, 2, 3 | IA |
| (b) Change in the source of an excipient or reagent which is unlikely to present any risk of TSE contamination | 1, 2 | 1, 3 | IA |
| (c) Change in the source of a TSE risk material, or introduction of a TSE risk material, not covered by a European Pharmacopoeial TSE certificate of suitability | II | ||
| Conditions | |||
| 1. Excipient and finished product release and end of shelf life specifications remain the same. | |||
| 2. Compliance with the conditions formulated in the Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products has to be ensured. | |||
| Documentation | |||
| 1. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format. | |||
| 2. Declaration from the manufacturer or the marketing authorisation holder of the material that it is purely of vegetable or synthetic origin. | |||
| 3. Confirmation of equivalence of the materials and that there is no impact on the quality of the finished product. | |||
#qiic4
| Q.II.c.4 Change in synthesis, manufacturing or recovery of an excipient (when described in the dossier) | Conditions to be fulfilled | Documentation to be supplied | Procedure type |
| (a) Minor change in synthesis, manufacturing or recovery of an excipient | 1, 2, 3 | 1, 2, 3, 4 | IA |
| (b) Change in the manufacturing site, synthesis, manufacturing or recovery of the excipient which may affect the quality, safety or efficacy of the finished product | II | ||
| (c) Deletion of one manufacturing process of an excipient | 4, 5 | 1 | IA |
| (d) Addition or replacement of a site responsible for the manufacture or testing of an excipient, when required to be described in the dossier | 1, 2 | IB | |
| Conditions | |||
| 1. The synthetic route/manufacturing process and specifications are identical and there is no change in qualitative and quantitative impurity profile (excluding residual solvents, provided they are controlled in accordance with ICH limits), or in physico-chemical properties. | |||
| 2. Adjuvants are excluded. | |||
| 3. The excipient is not a biological substance. | |||
| 4. The deletion should not be due to critical deficiencies concerning manufacturing. | |||
| 5. 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 a comparative tabulated format) of at least two batches (minimum pilot scale) (or 3 production batches (unless otherwise justified) for biological excipients) of the excipient manufactured according to the present and proposed process, or by the present and proposed manufacturer, as applicable. | |||
| 3. Where appropriate, comparative dissolution profile data for the finished product of at least two batches (minimum pilot scale). For herbal medicinal products, comparative disintegration data may be acceptable. | |||
| 4. Copy of approved and new (if applicable) specifications of the excipient (as annex to the application form). | |||
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