"Sister File Procedure": New Fast-Track Procedure for the Application of Further CEPs for the Same API

In addition to an already existing Certificate of Suitability (CEP), a CEP holder may have good reasons to apply for a further CEP for the same substance, when for example: 

  • The specifications of the final substance obtained with an alternative process cannot be covered by the existing CEP (i.e. because the solvents used in the final purification steps have been changed, alternative crystallization, etc.)
  • The API will be additionally manufactured at another manufacturing site.
  • The API will be additionally manufactured in different qualities (higher or lower according to the intended use).

Instead of applying for a new CEP, it is possible to use the fast-track procedure for an API with an already approved reference CEP dossier. The approach is described in the "Guidance on applications for 'sister files'" published on 2 September 2013 by the EDQM. The procedure itself isn't really new and has already been set in a former version of this guideline. The newly released guidance has been updated and refined.
To be able to use this fast-track application procedure, the following conditions have to be fulfilled:

  • The additional API is the same as that covered by the original application.
  • The original CEP has already been approved and is valid.
  • The manufacturer is the same or belongs to the same company group.
  • The CEP holder is the same or belongs to the same company group.

The differences between the second application and the original one can be classified and hence treated as a revision of the original.
At least the significant key intermediates must be the same as those in the original application and the synthetic route should lead to the same finished products.

The manufacturing method described in the "sister file" should be from the same category as that indicated in the original application and should correspond to the definition section of the relevant monograph (i.e. synthetic, semisynthetic or by fermentation).

Process Analytical Technology (PAT) or Quality by Design concepts shouldn't be introduced in the second application if they have not already been approved in the original application.

How comprehensive should be the documentation of a "Sister Files"? The centrepiece of such a second application is a comparative table. This table should include and oppose all sections of the dossier and it needs to be detailed regarding the content of each section (e.g. manufacturing process, flow-chart, in-process controls, specifications, etc.). Changes must be reported and explained in an additional column of the table. If no changes have been made to a dossier chapter and/ or sections, this must be stated in the table.

Two (or more) CEPs approved for an API have their own life-cycle and are independent from each other with regard to updates and upkeep. In the event that a CEP is withdrawn by the holder, this has no effect on the remaining CEP(s).

The "Sister File" procedure doesn't apply to sterile or herbal APIs; it also can't be used for TSE applications. Applications for a "chemical" CEP and for a TSE-CEP regarding the same API must be processed as two independent CEP applications and thus undergo the respective standard application procedure.

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