17 th Jul Understanding eCTD
eCTD (electronic Common Technical Document) is now the preferred method of submission to National Competent Authorities (NCA’s) and is becoming compulsory for European submissions, yet many pharmaceutical companies still find it challenging and costly to implement.
Within this report, TRAC seeks to introduce the main elements of the eCTD submission, covering discussion points including:
– What eCTD is
– Why use eCTD
– Creating the eCTD
– Lifecycle management
– Document preparation
– eCTD in the context of National, MRP/DCP and Centralised procedures
– Useful links for those making an eCTD submission.
What is eCTD?
eCTD is the electronic version of the Common Technical Document. It contains individual documents as PDF files arranged in a hierarchical folder structure reflecting that of the CTD. An ‘XML backbone’ links to each file and provides descriptive information about the submission, the files within it and their relationship to previous submissions. It allows you to see whether files are “new”, have been “deleted” or “replaced”.
On 1st January 2010 the European Medicines Agency (EMA) made eCTD format compulsory for all Centralised procedure submissions. This was then rolled out to new Marketing Authorisation Applications (MAA) submitted under the Decentralised procedure (DCP) in 2015 and new MAAs under the Mutual Recognition procedure (MRP) in 2017. Ultimately all DCP and MRP submissions will need to be in eCTD format from 1st January 2018.
The Heads of Medicines Agencies (HMA) eSubmission Roadmap includes an implementation date of 1st July 2018 for compulsory use of eCTD for MAAs using National procedures (NP) and all regulatory submissions under NP by 1st January 2019.
The EU Telematics Implementation Group – electronic submissions (TIGes) have published a harmonised guidance document on preparing eCTD submissions.
EMA starts to accept eCTD only submissions without the need for paper for Centralised procedure applications.
Electronic only submissions (eCTD and NeeS) is ‘strongly recommended’ by the EMA.
MHRA requires all initial MAAs in eCTD format
EMA ‘strongly recommends’ eCTD only submissions (no NeeS).
eCTD mandatory for all submissions through the Centralised procedure.
Best practise guidance on the use of eCTD in the Mutual Recognition/Decentralised procedures is published.
Final new major version of the EU Region eCTD Validation Criteria; v5.0, is adopted as mandatory for all eCTD submissions following extensive updates.
eCTD submissions for the Centralised procedure must be routed via the eSubmission Gateway and/or the Web Client.
eCTD mandatory for new marketing authorisation applications through the Decentralised procedure.
eCTD mandatory for new marketing authorisation applications through the Mutual Recognition procedure. This deadline also includes Repeat Use procedures (RUP) and duplicates of new or previously submitted applications through the Decentralised or Mutual Recognition procedure.
eCTD mandatory for all submissions through the Decentralised and Mutual Recognition procedures.
eCTD mandatory for new marketing authorisation applications using National procedures.
eCTD mandatory for all submissions using National procedures.
Why Use eCTD?
In addition to the fact eCTD is becoming mandatory for all EU procedures, in line with the HMA eSubmission Roadmap, there are many benefits associated with implementing the format for both industry and agencies.
The XML backbone allows agencies to automatically upload the sequence into their systems and hyper-linking allows for quick referencing of information. Since all files are submitted electronically there is no need for agencies to scan documents or industry to print, transport and store masses of paper. Changes and updates to the dossier are easy for reviewers to identify, and, with electronic submission portals, can be presented to the authorities within minutes of completion, drastically reducing processing time.
With acceptance of eCTD growing worldwide it also facilitates a global submission strategy, reducing publishing time over several markets.
A major advantage of eCTD is the product lifecycle tracking element, being a central archive of all submissions. The current view and lifecycle features gives the viewer the ability to quickly and unambiguously determine what is currently registered for a particular product, as well as showing when and what changes have been made during the eCTD lifetime. This facilitates easy version control and allows a whole company to access the documents simultaneously.
Creating the eCTD?
There are numerous tools available which are specifically designed to generate eCTD submissions. Using these tools you can import PDF documents, create hyperlinks between them, validate and export your eCTD. eCTD publishing tools can do a lot of the work for you but it is still very important to be familiar with the ICH eCTD specification 3.2.2 and the EU M1 specification (Europe only) as well as any country specific requirements that there might be.
Specialist eCTD publishing software is expensive both in terms of the software itself and the time involved in training staff initially and on an ongoing basis, so many companies choose to outsource their publishing as a cost-effective solution.
A finalised eCTD sequence does not need any specialist software to be viewed, just Adobe Reader to view the PDF files and a web browser to open the XML. However, this will only allow you to view each submission as an individual, standalone sequence. To view the integrated lifecycle of a product you will need to use a specialist reviewing tool. Again, there are many tools available including free versions such as Rosetta Phoenix eCTD view.
In the eCTD sequence, each file is given an attribute: New, Replace, Append or Delete. This defines its relationship to all other sequences in the product lifecycle. So, for an initial MAA, all files are ‘new’ and the sequence number is 0000. Subsequent regulatory activity might involve adding a document (new), changing a document (replace) or removing an obsolete document (delete). Subsequent submissions are numbered sequentially: 0001, 0002, 0003 and so on.
It is recommended that applicants avoid the use of ‘append’ (adding pages to an existing document) now due to the potential for increased lifecycle complexity.
Only documents that are new or have changed are submitted with each sequence. Unchanged documents are not resubmitted but can be hyperlinked for easy reference.
It is important not to think of the eCTD as merely the last step in publishing; creating a sequence begins in document preparation. This is because the eCTD specification has rules on the formatting of documents. Having procedures in place to create ‘submission ready documents’ in the first instance can avoid unnecessary delays caused by inadequate documents when it comes to publishing.
Files in the eCTD should be text searchable PDF files and cross referenced to other files in the submission using hyperlinks. Using Microsoft Word templates to author documents before converting them to PDF can help a great deal. Templates can take a lot of the work out by having standard fonts, formatting, headers and footers across all documents. The use of styles to automatically generate bookmarks and tables of contents can in particular save a lot of time by reducing the need to hyperlink the documents at a later stage.
If you have to work from any documents which have been scanned you must make sure that they are of an acceptable quality (300 dpi) and have been scanned using OCR (optical character recognition) so that they are text searchable.
Thought should be given to the level of granularity of documents as this will affect the lifecycle management of the eCTD. When changes are made, whole documents must be replaced, not just specific pages. A ‘finer’ granularity creates more documents which means more work initially but has benefits in terms of the reuse of documents and lifecycle management. A ‘coarser’ level of granularity means that there are fewer documents to deal with but you may need to replace large documents when only a couple of pages have been changed. The ICH M4 ‘Granularity Document’ on the organisation of the CTD details the acceptable levels of granularity.
– Make use of templates to author documents in MS Word
– Use standard fonts e.g. Times New Roman, Arial, Courier
– Use size 12 font wherever possible
– Convert files to PDF and save as version 1.5
– Do not password protect or add security settings to files
– The maximum file size for an individual PDF file is 100 MB
– Scanned documents should have a resolution of at least 300 dpi for text documents and 600 dpi for photographs
– Scan documents with OCR so that they are text searchable
Submitting an eCTD Sequence
eCTD submissions can be made via several means, including electronic portals, email or by posting a CD/DVD to the authority.
Centralised Submissions – The EMA now only accepts submissions in eCTD format. Since 1st March 2014 all eCTD submissions going through the Centralised procedure must be routed via the eSubmission Gateway or the Web Client; the secure electronic submission channels.
MRP/DCP Submissions – eCTD is now compulsory as the submission format in the MRP and DCP for MAAs, and applicable for all regulatory submissions using these procedures from 1st January 2018. Best practise guidance on the use of eCTD in MRP/DCP submissions has been published.
The Common European Submission Portal (CESP) has now been adopted by the majority of EU member states for most submission types, providing a secure platform for submissions and allowing a single delivery to multiple agencies, particularly valuable for MRP/DCP. However, it is important to understand each member states requirements as some markets still require paper and/or CD/DVD copies of documents in parallel with a CESP submission.
National Submissions – Although eCTD submission requirements in the EU are becoming more harmonised, and the format will become compulsory in January 2019 there are still market differences which you must adhere to under the National procedure. Most markets have clear guidance around this but if in doubt make contact with them prior to submission to prevent rejection or delays in processing.
The CESP has been adopted by a number of member states for National submissions, but some still have their own ‘portals’ or CD/DVD requirements, so again it is important to understand exactly what is required for the specific submission type.
Going forward, the CESP will be combined with the EMA eSubmission Gateway to form a Common European Single Submission Portal (CESSP). This platform will include a web based solution for application content so will replace the need for the current electronic application form. The first version of this new system will be available for use by Q1 2018.
In the rapidly changing world of eCTD it is important to keep up-to-date on submission requirements.
NeeS stands for “non-eCTD electronic submissions”. NeeS is basically an electronic submission following the same folder structure as eCTD but without the XML backbone. In place of this a PDF table of contents is included in each module and an overall dossier module listing. TIGes have published harmonised guidance on NeeS. NeeS format is very much an interim solution until industry and agencies are able to work completely in eCTD and companies are encouraged to switch to eCTD as soon as possible.
Glossary of Terms
electronic Common Technical Document
Non eCTD electronic Submission
International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use
Portable Document Format
eXtensible Markup Language
European Medicines Agency
Medicines and Healthcare products Regulatory Agency
National Competent Authority
Notice to Applicants
Optical Character Recognition
Marketing Authorisation Application
Mutual Recognition Procedure
Repeat Use Procedure