Document Granularity within the eCTD Structure

Deciding where a document should begin and end is one of the key considerations when drafting certain documents which are to be submitted as part of an eCTD submission. For the most part, the eCTD structure allows no legroom when deciding where and how to include a document as part of an eCTD.  For example, your Cover Letter (section 1.0) and Application Form (section 1.2) cannot be submitted as one merged PDF document in either section.

In some sections of Modules 2 and 3, there is some scope to choose how to submit your documents. For example, it is possible to submit one document in 2.3 which covers all CTD sections below this level; or you may submit one document per CTD section (e.g. 2.3.S.1, 2.3.S.2…). The second approach is said to be the more “granular” approach as documents are broken down into smaller sections. Document granularity, therefore, means the level into which documents are broken down for submission. The screenshot below displays the documents which can be submitted at more than one level.

Also, it is possible to submit documents such as QP and GMP certificates separately (per certificate) or merged together.

Similarly, in Modules 4 and 5, study reports can be submitted either with all appendices attached to the study itself, or as separate documents within the same document section. The latter may be preferable in the case of documents which, when combined with annexes, would exceed the applicable size limits for individual files.

Before deciding the appropriate granularity for your documents, it’s worth considering some of the practical eCTD implications of adopting either approach.

For example - You decide to submit a complete 2.3 QoS section as one document in your initial eCTD sequence. If at some point you need to update only section 2.3.S Drug Substance, it would not be possible to submit in the new sequence only the updated Drug Substance section. This is because it’s not possible to replace a complete 2.3 with only a 2.3.S – If you were to do this, all of the other non-Substance related data (e.g. 2.3.P, 2.3.A and 2.3.R) would be deleted from the eCTD current view. You would therefore have to update the entire 2.3 document with only the changes made in 2.3.S, and replace the ‘old’ 2.3 document in the eCTD.

The real advantage to this ‘less granular’ approach is that the overall number of documents to be submitted will be kept to a minimum, improving the manageability of the CTD sections.

There are however, quite a few disadvantages to this approach…

The first major disadvantage is the potential for more linking and bookmarking in sections which have not been updated but are still submitted as part of the greater ‘complete’ document. This may well increase the time it takes to publish a submission.

Secondly (and probably most importantly), where sections will be authored by more than one individual, updating only one document could lead to possible errors or omissions and an overall delay in the authoring process.

Thirdly, this approach provides more scope for publishing error. For example, if in your initial submission you submit three QP Declarations submitted as a merged document, one of which subsequently needs to be updated, your submissions specialist will need to: be aware of which certificate has been updated, delete the old certificate within the originally submitted PDF and insert the new certificate in its place, then replace the old document in the eCTD outline. If the certificates had been submitted separately there would be no need to manipulate the documents, but only to replace the old document in the eCTD outline.

Lastly, the time it takes to review the dossier will be longer if currently approved sections are included in the eCTD dossier. The reviewer will need to know which sections have been updated, and scroll through the pages of sections which haven’t.

You should consider various things carefully before deciding which method to adopt:

Is the dossier particularly large and complex?

Is there a need for multiple Drug Product or Drug Substance sections?
How often will the dossier need to be updated?

Without considering the particulars of any individual scenario, my preferred approach is to submit documents in a more granular fashion. In this way the potential for authoring and publishing errors is kept to a minimum, and one of the overall ideals of eCTD – that the dossier should be easy to review – is achieved.

If you would like advice regarding document granularity, or any other eCTD issues, please visit us at www.apexregulatory.co.uk, contact us using our contact form, or give us a call on the number at the top of the site.