Questions and answers on active substance and finished product manufacturer
This Q&A aims to address the commonly-asked questions regarding correct submission of documentation in eCTD format for active substance and finished product manufacturers.
Can the front page of an ASMF be omitted when the ASMF is submitted in eCTD format?
No. The ASMF is still required to have an individual and unique version number for the AP and RP in order to unambiguously identify the version of the AP or RP.
The version number and date should clearly be stated on the front page of the Applicant’s Part (AP), the Restricted Part (RP), the QOS on the Applicant’s Part and the QOS on the Restricted Part (four individual front pages). The front pages should be included in module 2 for the QOS and in module 3 for the AP and RP.
If it is difficult to include the front page as a separate document in the Applicant’s Part, the front page could be included as the first page in module 3.2.S.1.1. The same can be done for the Restricted Part i.e. module 3.2.S.2.1.
When a new version of the ASMF is submitted, the front pages should be updated and submitted accordingly.
Should the version number of the ASMF be visible on each page of the ASMF?
Yes. The version number of the ASMF should be visible on each page of the ASMF.
This means in the ASMF module 2 for the QOS for Applicant’s Part (AP) and QOS for the Restricted Part (RP) and module 3 for the AP and RP.
Is it acceptable to only provide a response to the issues raised on an ASMF with a commitment to update the ASMF at a later time point?
No. Along with the responses to questions to an ASMF, the updated modules /sections of the ASMF, related to raised questions, should be provided.
Is it sufficient to only have one folder for the Restricted Part (3.2.S.2), with no sub-folders (i.e. not including 3.2.S.2.1, 3.2.S.2.2, 3.2.S.2.3, etc), if each document is named according to the eCTD-format?
No. The Restricted Part should include sub-folders named 3.2.S.2.1, 3.2.S.2.2, 3.2.S.2.3, 3.2.S.2.4, 3.2.S.2.5 and 3.2.S.2.6.
Each document should be placed in the relevant sub-folder.
When is it acceptable to have one active substance module (section 3.2.S) per active substance manufacturer?
In relation to the active substance documentation, it must be differentiated between:
- The active substance manufacturer´s documentation on the active substance
- The finished product manufacturer’s documentation on the active substance
The active substance manufacturer’s documentation covers how the active substance is manufactured and controlled by the active substance manufacturer to ensure the quality of the active substance.
The documentation on the active substance can be presented in the MA dossier as part of the full file, be covered by an ASMF or by a CEP.
It is acceptable that the active substance manufacturer’s documentation is presented in the MA dossier in one active substance module per active substance manufacturer.
The finished product manufacturer’s documentation covers how the active substance is controlled by the finished product manufacturer to ensure the quality of the active substance.
Only one active substance module (section 3.2.S) per active substance should be provided regardless of the number of active substance manufacturers or finished product manufacturers.
The finished product manufacturer’s active substance specification (also referred to as the MAH/Applicant active substance specification in guidance), should be compiled per active substance covering all active substance manufacturers proposed.
When is it acceptable to have one finished product module (module 3.2.P) per finished product manufacturer?
In most cases, it is not acceptable to have one finished product module (module 3.2.P) per finished product manufacturer. There can only be one quality of the finished product in one marketing authorisation and consequently only one composition and one manufacturing process.
It is acknowledged that there can be minor technical adaptions in the manufacturing process at two different finished product manufacturing sites i.e. due to slightly different equipment. However, there can still only be one finished product module and one description of the manufacturing process.
Any difference between the two manufacturing sites has to be indicated in one described manufacturing process. Accordingly, there should only be one list of in-process controls, not one list per manufacturing site.
The aforementioned requirements are outlined in the Guideline on manufacture of the finished product EMA/CHMP/QWP/245074/2015 dated 4 July 2017 under the subheading Technical adaptations in the manufacturing process.
Examples
One compiled finished product module
If two or more finished product manufacturers are proposed for a film-coated tablet, there should only be one compiled finished product module (3.2.P) covering all manufacturing sites.
It is not acceptable to have one finished product module per finished product manufacturer.
Two separate finished product modules
As stated in ICH Topic M4Q Location issues for Common Technical Document for the Registration of Pharmaceuticals for Human Use – Quality Questions and Answers (CPMP/ICH/4680/02): a “drug product supplied with a reconstitution diluent should be presented in separate Drug Product sections for the drug product and the reconstitution diluent. These could be titled 3.2.P (Drug Product) and 3.2.P (Diluent).”