Your eCTD Questions Answered

Acorn Regulatory’s publishing team are eCTD experts.  We have assisted many companies in their eCTD projects in recent years.  Many visitors to our website submit questions on regulatory issues and in this blog post Eileen Ryan, our Regulatory Publishing Manager, looks at some of the most common issues that have manifested themselves for eCTD users and she gives solutions to those problems.

1. UUID number complications

UUID numbers can be generated quite easily; therefore, extreme caution should be used not to regenerate a UUID number for a dossier already submitted to the authorities. Some of the current validator tools can catch this error before submission by running a check against the UUID number to the sequence previous.  However, when the submissions are submitted close together, then it is possible to have a valid submission on the last sequence if the UUID number was changed two sequences prior.

Solution: What can be done if a UUID number was changed and submitted to the authorities in error?  The authorities should be notified immediately of the UUID number problem and to discuss what can be done to correct the issue.  In many cases the sequence that had the incorrect UUID number can be amended with the correct UUID number and resubmitted to the authorities to upload.

2. Lifecycle management complications

If you come across some eCTD dossiers that the lifecycle was not maintained, then it could be very difficult going forward to bring some order back into the dossier.

Solution: A possible suggestion is to correct the lifecycle at the next regulatory opportunity.  Of course, all changes will need to be outlined so the authorities are fully aware of the situation.

3. National translations

National translations should be handled outside the eCTD in both an MRP and DCP. If the national translations for a MR/DC procedure were included in existing eCTDs, then the CMDh have outlined the following solution to resolve the issue:

Solution: The CMDh recommend that applicants delete the national translations in the eCTD with the next submitted sequence or, at the latest, when the translations become obsolete.  Preferably, this should be clarified in the cover letter.

4. Uploading eCTD complications

As more and more sequences are created and software or providers change, then you may come across a problem with uploading previously submitted sequences. There are a number of issues that could explain why these sequences wont upload; however, the most common would be if there was a structural issue within the sequence for upload.

Solution: Run a validation report on the sequence to be uploaded.  See what kind of issue you are dealing with before proceeding with the upload.  If the validation report comes up valid, then proceed with uploading and review the upload report as it appears for the complication description.  If the validation report is not valid, then the report should be assessed for the complication.  Structural damage in the sequence itself could cause issues when uploading.  If a forced manual upload is done, then please be aware that this could cause complications down the line.  For instance, files could be missing from within the eCTD dossier or floating folders created.  Structural damage unfortunately does not have a clear-cut solution in many cases.

5. Country specific envelopes still visible for withdrawn marketing authorisations

You may come across a situation where a marketing authorisation is still visible after a marketing authorisation has been withdrawn.  What can be done in this situation?  Would it be acceptable to delete the envelope not in use or does it still need to be maintained?

Solution: Yes, if the marketing authorisation has been withdrawn, then you can delete the country specific envelope.  However, be sure to leave the module 1 documentation as it will serve as the history of the product.

6. MD5 checksum issues

Checksum issues can arise for many different reasons. To provide possible solutions to this issue we need to clarify what a MD5 checksum is and why is it important in eCTD?

An MD5 checksum or Message-Digest algorithm 5 checksum is a calculated value that is used to determine the integrity of the file.  What does this mean?  The checksum is an algorithm that a computer programme calculates to verify that the file has not been altered or changed in any way.  This is especially useful for competent authorities when moving files from one location to another.  In fact, it is so useful that it became a requirement for the eCTD sequence to have checksums for each individual file including a checksum file for the eCTD XML.   Therefore, when an eCTD sequence is sent or electronically transmitted via CESP to the authorities it will contain an MD5checksum summary.   The authorities can then calculate the checksum of the received eCTD sequence with the same algorithm used in this summary.  If the checksums do not match up, then it is evident that a transmission error has occurred and not all files/information has been received.

So, what happens if you change a document or even something as small as adding a letter after a sequence has been exported from your eCTD software?  If anything is changed in the file no matter how small the change may seem, this will cause a validation error to occur as the MD5 checksum will not match.

Solution:  If you have changed a file yourself after exporting out an eCTD sequence before submitting to the authorities, then the issue can be corrected rather easily before submission.  The eCTD sequence will need to be opened inside your eCTD software and the changed file will need to be officially replaced.  The sequence can now be finalised and exported out again.  Validation should now be corrected as the md5 checksum will now align. 

Please keep in mind that changing a file is not the only scenario where you can see an MD5checksum problem.  For instance, if a sequence was copied and moved to another location with a very long file path, then it is possible that a problem could occur during the copy where not every file had copied over to the new location due to the long file path used.  As a result, the sequence when validated will show a MD5checksum errors.   

Solution: Export the sequence out to a shorter file path and validation again.  The sequence should now be valid.

Acorn Regulatory can provide a range of eCTD services that could assist you in the transition to eCTD.  We have a dedicated electronic publishing team that can help with any of your eCTD publishing requirements or queries.  Talk to us today by calling 00353(0)52 61 76706 or completing the webform below.