#qiii1
| Q.III.1 Submission of a new or updated Ph. Eur. certificate of suitability or deletion of Ph. Eur. certificate of suitability: – for an active substance – for a starting material/reagent/intermediate used in the manufacturing process of the active substance – for an excipient | Conditions to be fulfilled | Documentation to be supplied | Procedure type |
| (a) European Pharmacopoeial certificate of suitability to the relevant Ph. Eur. Monograph (*4) | |||
| 1. New certificate of suitability (CEP) (including replacement or addition) | 1, 2, 3, 4, 5, 6, 9 | 1, 2, 3, 4, | IAIN |
| 2. Update of an approved certificate of suitability (CEP) | 1, 2, 3, 4, 5, 9 | 1, 2, 3, 4, | IA |
| 3. Deletion of certificate(s) of suitability (CEP) | 8 | 2 | IA |
| 4. New certificate of suitability (CEP) for a non-sterile active substance that is to be used in a sterile finished product, where water is used in the last steps of the synthesis and the material is not claimed to be endotoxin free | 1, 2, 3, 4, 5 | IB | |
| 5. New or updated certificate of suitability (CEP) for a herbal active substance | 1, 2, 4, 6 | IB | |
| (b) European Pharmacopoeial TSE certificate of suitability for an active substance/starting material/reagent/intermediate/or excipient | |||
| 1. New TSE certificate for an active substance (including replacement or addition) | 4, 7 | 1, 2, 3, 4 | IAIN |
| 2. New TSE certificate for a starting material/reagent/intermediate/excipient (including replacement or addition) | 4, 7 | 1, 2, 3, 4, | IA |
| 3. Update of an approved TSE certificate | 4, 7 | 1, 2, 3, 4 | IA |
| 4. Deletion of TSE certificate(s) | 8 | 7 | IA |
| 5. New/updated TSE certificate using materials of human or animal origin for which an assessment of the risk with respect to potential contamination with adventitious agents is required | II | ||
| Conditions | |||
| 1. The impact of the new source of the active substance, or changes to the active substance, on the finished product has been evaluated by the holder/finished product manufacturer and there is no change in Critical Quality Attributes or composition of the finished product (e.g. API mix). The finished product release and end of shelf life specifications remain the same. | |||
| 2. The holder/finished product manufacturer active substance specification for impurities is unchanged. This applies to organic impurities, residual solvents, mutagenic impurities (including nitrosamines) and elemental impurities. Tightening of impurity limits, changes to specifications for impurities according to the Ph. Eur. and/or residual solvents according to ICH Q3C, are excluded. | |||
| 3. The holder/finished product manufacturer active substance specification is unchanged for any other specific requirements that may impact finished product quality, such as polymorphism, hydration state, particle size profile. | |||
| 4. The manufacturing process of the active substance, starting material/reagent/intermediate does not include the use of materials of human or animal origin for which an assessment of viral safety data is required, or if it does, the update of the CEP/TSE Certificate is only due to administrative changes. | |||
| 5. For active substance only, it will be tested immediately prior to use if no retest period is included in the Ph. Eur. certificate of suitability or if data to support a retest period is not already provided in the dossier. | |||
| 6. The active substance/starting material/reagent/intermediate/excipient is not sterile. | |||
| 7. If gelatin manufactured from bones is to be used in a finished product for parenteral use, it should only be manufactured in compliance with the relevant country requirements. | |||
| 8. At least one manufacturer for the same substance remains in the dossier. | |||
| 9. If the active substance is a not a sterile substance but is to be used in a sterile finished product then according to the CEP it must not use water during the last steps of the synthesis or if it does the active substance must comply with the guideline on water for pharmaceutical use regarding bacterial endotoxins and microbiological quality. | |||
| Documentation | |||
| 1. Copy of the current (updated) Ph. Eur. certificate of suitability (CEP) and the letter of access (where available). | |||
| 2. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format). This should include: – Updated consolidated holder/finished product manufacturer list of manufacturers of the active substance (Section 3.2.S.2.1). – Updated single compiled holder/finished product manufacturer active substance specification, including analytical methods and method validation (where the finished product manufacturer uses analytical procedures which are different from the Ph. Eur. monograph or from those used by the CEP holder), and batch results from testing carried out by the holder/finished product manufacturer (Section 3.2.S.4.1-3.2.S.4.4). | |||
| 3. Where applicable, a document providing information of any materials falling within the scope of the Note for Guidance on Minimising the Risk of Transmitting Animal Spongiform Encephalopathy Agents via Human and Veterinary Medicinal Products, including those which are used in the manufacture of the active substance/excipient. The following information should be included for each such material: Name of manufacturer, species and tissues from which the material is a derivative, country of origin of the source animals and its use. For the centralised procedure, this information should be included in an updated TSE table A (and B, if relevant). | |||
| 4. Where applicable, for active substance, 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 QP of each of the manufacturing authorisation holders listed in the application as responsible for batch release. | |||
| 5. Suitable evidence to confirm compliance of either the water used in the final steps of the synthesis of the active substance, or the active substance, itself with the corresponding requirements of the guideline on quality of water for pharmaceutical use regarding bacterial endotoxins and microbiological quality. | |||
| 6. For herbal active substances 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). | |||
| 7. Amendment of the relevant section(s) of the dossier (presented in the EU-CTD format). | |||
| (*4) Note: For active substances supported by a certificate of suitability (CEP), a separate variation is required under category Q.I. scope in the following scenarios: – to register or amend sites (e.g. micronisation or control/testing sites) if these sites are not included on the CEP (Q.I.a), – to register or amend in-house analytical procedures used by finished product manufacturer if these analytical procedures are not included on the CEP (Q.I.b), – to register or amend a re-test period if the re-test period is not included on the CEP (Q.I.d). | |||
#qiii2
| Q.III.2 Change to comply with Ph. Eur. or with a national pharmacopoeia of a Member State for active substances, reagents, intermediates, excipients, immediate packaging materials and active substance starting materials (*5) | Conditions to be fulfilled | Documation to be supplied | Procedure type |
| (a) Change of specification(s) of a former non-EU Pharmacopoeial substance to fully comply with the Ph. Eur. or with a national pharmacopoeia of a Member State | |||
| 1. Active substance | 1, 2, 3, 4 | 1, 2, 3, 4 | IAIN |
| 2. Excipient/active substance starting material/reagent/intermediate/immediate packaging material | 1, 2, 3, 4 | 1, 2, 3, 4 | IA |
| (b) Change to comply with an update of the relevant monograph of the Ph. Eur. or national pharmacopoeia of a Member State | 1, 2, 4 | 1, 2, 3, 4 | IA |
| (c) Change in specifications from a national pharmacopoeia of a Member State to the Ph. Eur. | 1, 4 | 1, 2, 3, 4 | IA |
| (d) Change related to a herbal active substance or herbal starting material | 1, 2, 3, 4, 5 | IB | |
| Conditions | |||
| 1. The change is made exclusively to fully comply with the pharmacopoeia. All the analytical procedures in the specification need to correspond to the pharmacopoeial standard after the change, except any additional supplementary procedures. | |||
| 2. Additional specifications to the pharmacopoeia for product specific properties are unchanged (e.g. particle size profiles, polymorphic form, bioassays or aggregates). | |||
| 3. No significant changes in qualitative and quantitative impurities profile unless the specifications are tightened. | |||
| 4. Suitability of the new or changed pharmacopoeial analytical procedure has been confirmed under the actual condition of use. | |||
| 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. Batch analysis data (in a comparative tabulated format) on two production batches of the relevant substance for all analytical procedures in the new specification and additionally, where appropriate, comparative dissolution profile data for the finished product on at least one pilot batch. For herbal finished products, comparative disintegration data may be acceptable. | |||
| 4. Data to demonstrate the suitability of the monograph to control the substance (e.g. a comparison of the potential impurities with the transparency note of the monograph). | |||
| 5. For herbal active substances/herbal starting materials a detailed comparison regarding their characteristics (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 the manufacturing process) should be provided. | |||
| (*5) Note: There is no need to notify the competent authorities of an updated monograph of the European pharmacopoeia or a national pharmacopoeia of a Member State in the case that reference is made to the ‘current edition’ in the dossier of an authorised finished product. | |||
One response to “Q.III CEP/TSE/Monographs”
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