For the revision or renewal of a Certificate of Suitability to the monographs of the European Pharmacopoeia (CEP) the CEP holder must submit documents to the EDQM in a format that guarantees a fast examination and processing of the dossier by the authority. In the past this has not always been the case and the EDQM has found it necessary to publish the "Guidance on frequent changes to applications for Certificates of Suitability (CEPs)". With this document the authority wants to limit requests for additional information from the applicants and to reduce the time for the processing of the dossiers submitted.
The guidance contains clarifications regarding the most common notifications of changes and defines the terms "notification", "major revision" and "minor revision" in the relevant contexts. The following briefly summarises the document's topics:
1. Format of the documentation
You can find detailed information on the document's format and structure in this section. The EDQM explicitly warns against non-compliance with these requirements, since this may block the processing of the dossier.
2. Technical aspects
At the beginning of this section the term "synthetic route" is defined. According to EDQM's understanding this term includes all starting materials, intermediates, process steps and all the reagents, solvents and catalysts used.
2.1. Changes to the manufacturing process
Notification: there is a change without a possible impact on the quality of the product.
Major revision: the synthetic route has been changed in accordance with the definition mentioned above. The change impacts the impurity profile of the substance and thus its quality. The replacement of a Class 2 solvent by a Class 3 solvent also is a major revision.
Minor revision: there is neither a notification nor a major revision. Example: A solvent is used in a later step of the synthesis.
2.2. Changes to a manufacturer/manufacturing site
2.2.1. Changes to a manufacturer/manufacturing site of the final substance or an intermediate
Notification: the other manufacturer/site is of the same group; the synthetic route, the quality control procedures and the specifications of the intermediates and the final step of synthesis remain unchanged.
Major revision: change to the synthetic route, to the quality control procedures or to the specifications.
Minor revision: example: the alternative manufacturer is not part of the same group or changes the batch size using the same synthetic route.
2.2.2. Changes to a manufacturer/manufacturing site of starting materials
Notification: the other manufacturer/site is of the same group; the synthetic route, the quality control procedures and the specifications of the starting materials remain unchanged.
Major revision: the synthetic route or the specifications are changed.
Minor revision: such as: addition of a new manufacturer that is not part of the same group. The synthetic route and the specifications, however, remain unchanged.
2.3. Changes to specifications (concerns changes to specifications of starting materials, intermediates or final substances and changes in in-process controls)
Notification: the change to specifications does not result from deviations in the manufacturing process. Example: deletion of a non-significant test that tests a parameter without significant relevance for the product quality.
Major revision: the limits of significant parameters are widened.
Minor revision: the limits of significant parameters listed in the Ph. Eur. monograph are widened but remain within the limits of that monograph.
2.4. Changes to analytical procedures
Notification: the procedure remains essentially the same. The changes are within the ranges allowed by the general chapter 2.2.46 Chromatografic separation techniques of the Ph. Eur.
2.5. Changes to the packaging material
Notification: changes to the secondary packaging material.
Minor revision: the primary packaging material is changed to be less protective than the one approved before.
The EDQM explicitly points out that this Guidance should be considered as an explicative note and that it should be read jointly with the Guideline on Requirements for Revision/Renewal of Certificates of Suitability to the European Pharmacopoeia monographs (PA/PH/CEP (04) 2).
For further information please see the new EDQM document entitled "Guidance on frequent changes to applications for Certificates of Suitability (CEPs)".
Information: You can receive actual information on the CEP procedure by an EDQM representative at the"15th APIC/CEFIC European Conference on Acitve Pharmaceutical Ingredients" taking place from 7-9 November 2012 in Budapest.
Dr. Gerhard Becker
CONCEPT HEIDELBERG (a service provider entrusted by the ECA Foundation)