The holder of a Certificate of suitability shall inform the EDQM of any change to the information in the certification dossier by sending an application form and all necessary documents demonstrating that the conditions laid down in the present guideline are met.
Classification of changes
The changes have been classified in three categories (notification/minor/major) depending on the potential impact of the change on the quality of the final substance. These three categories are based on those (IA-IAIN/IB/II) of the Commission Regulation (EC) No 1234/2008 concerning the examination of variations to the terms of marketing authorisation for medicinal products for human use and veterinary medicinal products.
Any change not classified as a notification or a major change should be classified as a minor change except in the following cases where a new application should be submitted:
- addition of a new route of synthesis and/or a new manufacturing site where the specifications of the final substance are different from the one already approved
- transfer to a new holder that is not the same legal entity as the approved one, where the transfer does not occur because of a merger or because the company is sold, and where the manufacturer does not take out the Certificate of suitability in their own name.
The changes related to Ph. Eur. monograph revisions or any other regulatory requirements are treated separately and generally initiated by the EDQM.
For any revision the documentation should consist of:
- a cover letter
- the application form, duly filled and listing all the changes applied for
- a description of each change together with a justification
- data showing, when applicable, that the conditions have been met
- updat-e of the relevant section(s) of the dossier (presented in EU-CTD format).
- the specific documents described below for each change and supporting the change
- supportive information, including comparative data with the previous version of the dossier (in tabular format), showing the approved and the proposed section and highlighting the changes
Consequential changes should be identified and the relation between the changes should be described.
Each time batch data are needed:
- they should be in accordance with the specifications of the current Ph. Eur. monograph and when relevant with the additional requirements included in the Certificate of suitability
- the manufacturing site, the manufacturing date and the size of the batches should be specified.
- quantitative results should be presented numerically (i.e. not in general terms such as “complies”) and with the appropriate number of decimal places.
- Typical minor revisions for Certificates of suitability for chemical purity and microbiological quality or for TSE Certificates of suitability
- Major revisions (MAJ)
- Renewal
- Transfer of holdership
Editorial changes should not be submitted as separate variations but should be reported at the same time as changes concerning the respective part of the dossier. In any case, a declaration should be provided that the content of the concerned part of the dossier has not been changed by the editorial changes (except for the change itself).
IN3) Deletion of any manufacturing site for the final substance (former N3)
Conditions:
- the deletion should not be due to critical deficiencies concerning manufacturing.
Specific Documentation:
- the justification of the deletion.
IN4) Change or addition of a manufacturer of a starting material or intermediate used in the manufacturing process of the final substance when the proposed manufacturer is part of the same group as the currently approved manufacturer
Conditions:
- the specifications and the route of synthesis (including In-Process Controls, methods of analysis of all materials used) of the concerned material are identical to those already approved
- the final substance is not a biological substance or a sterile substance.
Specific Documentation:
- a declaration from the holder of the Certificate of suitability that the specifications of the final substance are the same as those already approved
- a declaration from the holder of the Certificate of suitability that the synthetic route (or in case of herbal material, where appropriate, the method of preparation, geographical source and production), the specifications and the quality control procedures of the starting material or intermediate are the same as those already approved
- a list of approved and proposed sites
- batch analysis data (in a comparative tabular format) for at least two batches (minimum pilot scale) of the final substance from the approved and proposed sites.
IN5) Change or addition of a manufacturing site/workshop for the final substance when the proposed manufacturer is part of the same group as the currently approved manufacturer
Conditions:
- the specifications of the final substance (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
- the final substance is not a biological substance or a sterile substance.
Specific Documentation:
- a declaration from the holder of the Certificate of suitability that the synthetic route (or in case of herbal material, where appropriate the method of preparation, geographical source and production), quality control procedures and specifications of the final substance are the same as those already approved
- a list of approved and proposed sites
- batch analysis data (in a comparative tabular format) for at least two batches (minimum pilot scale) of the final substance from the approved and proposed sites
- updat-ed declarations of manufacture in accordance with the dossier and according to GMP rules and of willingness to be inspected for the new site.
IN7) Minor changes to a test procedure for the final substance. Editorial changes to a method description annexed to a certificate of suitability (former N7)
Conditions:
- appropriate validation studies have been performed in accordance with the relevant guidelines and show that the updat-ed test procedure is at least equivalent to the former test procedure
- there have been no changes of the total impurity limits; no new unqualified impurities are detected
- 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)
- the test method is not a biological method, or a method using a biological reagent for a biological substance (does not include standard pharmacopoeial microbiological methods).
Specific Documentation:
- updat-ed description of the method in a format to be appended to the certificate of suitability
- amendment of the relevant section(s) of the dossier, including description of the analytical method, summary of validation data,..
- comparative validation results, or if justified comparative analysis results showing that the approved test and the proposed one are equivalent.
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