Ensuring submission readiness in eCTD publishing

Paul Johnston, examines the eCTD format and its significance in submitting drug product regulatory information to Health Authorities (HAs).

The electronic Common Technical Document (eCTD) is now the standard format for providing drug product regulatory information such as applications, supplements, and reports to Health Authorities (HA).

eCTD is the mandatory submission format for large global markets such as the USA, EU, and Japan. The latest version, eCTD v.4.0, is currently being rolled out and will become mandatory in leading markets in this decade [1], with many more countries worldwide adopting the use of the eCTD format as the primary submission format.

Submission publishers must grasp how to comply with the eCTD requirements and guidelines set by the ICH (International Conference for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) (refer to [2] for EU eCTD Technical Guidance).

Regulatory submission publishers are responsible for tasks such as document authoring, submission assembly/maintenance, and HA submissions.

This article provides a high-level overview of the common tools used to publish complete submissions, ensuring adherence to regulatory requirements and preventing future rework & technical rejection by the HA.

A key component of submission publishing is maintaining an up-to-date view of the most current documents submitted to HA as eCTD submissions for each drug product.

This practice facilitates the strategic assembly of new eCTD submissions, preventing document duplication and ensuring the HA has quick access to the most recent documents. This streamlined process enhances the HA’s review experience, potentially reducing the time required for approval.

What is XML?

Extensible Markup Language, or XML, is a core element of eCTD submissions.

It acts as the 'backbone' file and contains structured information on the contents of the published submission [3].

Each submission is accompanied by an XML file, generated through a publishing tool (e.g., DocuBridge, Veeva), and submitted to the HA along with the comprehensive submission package.

The XML file functions as an electronic table of contents that summarizes the submission and contains vital information about the eCTD contents, including:

- Application and sequence metadata (including lifecycle operations)
- CTD file titles
- Hyperlinking and bookmarking information
- Document ID and version.

Publishers use validator tools to scan the submission and analyze the XML file, ensuring the submission is technically valid and adheres to ICH eCTD specifications. Further details on validation tools are discussed below.

What are lifecycle operations?

In the context of eCTD, lifecycle operations refer to metadata tags used during the compilation of documents for a new submission within publishing tools.

These are crucial in indicating the status of each document concerning what the HA has previously received in submissions for the same product.

As the publisher adds documents to their designated eCTD section (e.g., Module 1 – Cover Letter), they attach metadata tags, or lifecycle operations, to each document.

These tags serve as markers, providing insights into the document's status within the submission history.

Publishing tools have a ‘working/cumulative’ view which displays all content added to the eCTD structure across all previous sequences, and a ‘publishing/current’ view that only displays the content included in the submission currently being compiled by the user.

In compiling new application sequences, three common lifecycle operations are used [2]:

New: A document version that has never been submitted to the HA in previous eCTD submissions. For example, a cover letter is always added with the ‘New’ operation tag, as it is considered a new and unique document for each submission that summarizes the scope and purpose of the application.

Replace: A document that has a previous version submitted in past submission dossiers to the HA and is added with the ‘Replace’ operation. For example, the tracking table is always added to replace the previous sequence’s version, as an updated version will be included in every new application to reflect the new sequence in the product's application history.

Delete: A document that is to be completely removed from the current sequence is designated with a ‘Delete’ operation within the sequence. This operation is used in the re-publishing of a sequence to remove incorrectly added documents from the XML, instead of publishing the entire submission again.

Each document’s associated lifecycle operation is reflected in the XML and is validated by an eCTD validation tool that is either part of the publishing tool or an external application (e.g., Lorenz).

It is noteworthy that each new submission for the same drug product within the same country/region is referred to as a ‘sequence’. For instance, if ‘Drug A’ has been submitted to the HA 5 times, ‘Sequence 0000’ corresponds to the first submission, and ‘Sequence 0004’ is the latest in the series.

Hyperlinking

If hyperlinking the submission documents is the publisher’s responsibility, it can become one of the most time-consuming aspects of the publishing process.

The number of links required by the publisher varies based on factors such as the submission region, document size, and the quantity of sequences already published. It could range from just a few to thousands of links per submission.

These hyperlinks let the regulatory reviewer navigate the contents and facilitate easy access to documents that are text-referenced. For example, an ‘M3-Stability Summary and Conclusions’ document will contain multiple in-text links to the various ‘Stability Data’ that are present in the current or previous sequences.

To simplify this task, sponsors will often employ automated hyperlinking tools. These scan documents for blue text (as required by HA to identify hyperlinks) and generate a report that can be used to create and select the correct document destinations.

The use of hyperlinking tools not only significantly reduces publishing times, but also minimizes the risk of human error and avoids common mistakes such as missing or incorrect hyperlinks that can lead to delays in the approval timeline.

Validation tools

Validation tools, also known as ‘eValidators’, are software applications that scan the submission’s structure and XML file (e.g., Lorenz [4], Veeva Vault [5]). These tools generate a validation report that details where the submission has complied with ICH eCTD specification requirements and identifies areas of non-compliance.

The eValidator includes profiles for region-specific criteria (e.g., EU, US, AU, GCC, etc.) which can be chosen as required for each eCTD submission. This criterion is based on the eCTD validation criteria for the region and checks the submission and XML for adherence to requirements such as file sizes, expected documents, hyperlink validity, and metadata.

Validation criteria can be modified by the user to suit submission needs. For example, if the submission is in eSub format, which does not require an XML file, the criteria can be selected to scan only the submission’s PDF files. This prevents validation report errors due to a missing XML file.

Whilst eValidators are essential for ensuring technical compliance, manual review by publishers remains essential to confirm submission readiness.

Conclusion

The effectiveness of ensuring submission readiness as a publisher depends on a comprehensive understanding and knowledge of technical regulatory requirements and the strategic use of tools to streamline the publishing process.

Artificial Intelligence (AI) has been at the forefront of public and business consciousness in recent years.

It is foreseeable that all aspects of regulatory affairs will be transformed by AI and machine learning (ML) with the automation of routine tasks, allowing skilled professionals to focus on more high-value tasks.

While the practical applications of AI and ML in the regulatory space are evolving, it is easy to imagine the significant value that automated AI-driven tools will produce for publishing workflows and resource management.

References

[1] Ich official website site ICH. Available at: https://ich.org/page/ich-electronic-common-technical-document-ectd-v40

[2] EMA (2021) Harmonised technical guidance for ECTD submissions in the EU - europa.eu, europa.eu. Available at: https://esubmission.ema.europa.eu/tiges/docs/eCTD%20Guidance%20v4%200-20160422-final.pdf

[3] Industry guidance on ECTD submissions - who/OMS extranet systems (2023) Industry Guidance on eCTD submissions. Available at: https://extranet.who.int/prequal/sites/default/files/document_files/WHO%20eCTD%20Guidance%20for%20Industry%20v1.0.pdf

[4] Submission validation with Lorenz Evalidator Validation Software for eCTD and More | LORENZ eValidator. Available at: https://www.lorenz.cc/Solutions/eValidator/?gad_source=1&gclid=Cj0KCQiAwP6sBhDAARIsAPfK_wZiK-Zrxfxhob0s5XyZx1Z8YwXsAccfPQ2YqA53kDB47mSAWyasBxoaAk0JEALw_wcB

[5] Vault Submissions Publishing: Health Authority Gateway: Veeva Systems EU (2023) Veeva Systems Europe. Available at: https://www.veeva.com/eu/products/vault-submissions-publishing