How can a CEP for a starting material be used in a CEP application for an API?

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28-30 March 2023

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Contents of the regulatory information in the ASMF and CEP

If you submit an application for a certificate of suitability (CEP) for an active substance to the EDQM, your dossier has to comprise extensive information on the quality of the active substance, its synthesis as well as on the used starting materials and intermediates. The document providing the specifications for this purpose, dates back to the year 2007 and is titled "content of the dossier for chemical purity and microbiological quality" (PA/PH/CEP (04) 1, 4R).) It says in the chapter "control of materials (3.2.S.2.3)":
 "In the case of a route of synthesis consisting of one or only a few steps, full details of the manufacture of the starting material(s) should be given and/or at least detailed specifications especially regarding the impurity profile including residual solvents and catalysts. Alternatively, for starting materials described in the European Pharmacopoeia certificates of suitability can be provided, if available."

So CEPs for raw materials can be used to apply for an API CEP which eliminates the need for the detailed description of the starting material in such an application.  But what are the exact conditions and requirements for such a procedure? A new EDQM document entitled "Use of a CEP to describe a starting material in on application for another CEP" (PA/PH/CEP (14) 06) provides some information. According to this document it is possible to use a starting material CEP in the application process under the following conditions:

• The raw material must be covered by the CEP application for the active ingredient. 
• The CEP for the raw material must already be granted and valid. 
• A copy of the CEP for the raw material must accompany the application for the active ingredient CEP. 
• As described in the API CEP application for the manufacture of the active ingredient the complete specifications of the raw material - as they are specified in the CEP - have to be applied.

Following further provisions in relation to the life cycle of the material or its CEP have to be noted:

• Immediately after any change or update of the CEP for the raw material the active ingredient CEP has to be revised as well. This is usually done as part of the annual notification. Exceptions are: a change in the specifications of the raw material (a minor revision by default has to be submitted) or a change of the production site without changing the specifications of the raw material (an immediate notification is required). 
• If the CEP for the raw material is suspended temporarily or permanently or if its validity period has expired, the active ingredient CEP has to be updated accordingly: all references to the invalid CEP of the raw material have to be removed, and instead references to a raw material CEP from another source have to be added. If the raw material from the alternative source has no CEP, its quality needs to be fully described accordingly.

In general detailed information has to be provided about all production sites involved in the manufacturing process for the raw material.