|Site:||EUPATI Open Classroom|
|Course:||Regulatory procedures- Marketing-Authorisations and their lifecycle management|
|Printed by:||Guest user|
|Date:||Tuesday, 6 June 2023, 2:35 AM|
1. The eCTD
(This section is organised in the form of a book, please follow the blue arrows to navigate through the book or by following the navigation panel on the right side of the page.)
The Common Technical Document (CTD) describes the organisation of modules, sections and documents to be used for a MAA for a medicine, agreed by the ICH. The electronic Common Technical Document (eCTD) allows for the electronic submission of the CTD from applicant to regulator. While the table of content is consistent with the harmonised CTD, the eCTD also provides a harmonised technical solution to implementing the CTD electronically. The eCTD is not merely a collection of PDF documents, and the documents cannot be gathered into one huge PDF file either.
Both the company and the assessors must be able to easily navigate in the dossier. Therefore, the eCTD is a standard that describes in detail the folder and file structure. Within a complete eCTD dossier, navigation is possible like in a normal directory on a computer. In other words, an eCTD is a standardized interface for the submission of PDF documents, stored in the eCTD directory structure, accessed through the XML backbone and with file integrity guaranteed by the MD5 Checksum.
What is CheckSum?
A checksum is a string of numbers and letters used to uniquely identify a file. Checksum is most commonly used to verify if a copy of a file is identical to an original.
How does CheckSum work?
A file is pushed through an algorithm, which outputs a unique alphanumeric string called a checksum, also known as a "hash". Different files, even those with minute differences, produce different checksum values.
There are multiple algorithms that can be used to produce a checksum value. The algorithm used for eCTD submissions within EU to provide checksum values is MD5. The MD5 message-digest algorithm is a widely used hash function producing a 128-bit hash value.
What circumstances would warrant verifying a CheckSum value?
Files may be changed during download, transmission, or storage. For example, if there is an issue with network connectivity at the time of download, the file may not download correctly. Issues with hard drive storage could also lead to file alteration.
CheckSum can be used to verify any type of file.
The eCTD format is mandatory to use for all submissions (e.g., MAAs, variations, paediatric, referrals, renewals, etc.) related to Marketing Authorisation for products within all EU procedures (i.e., Centralised, Decentralised and Mutual Recognition Procedures) and new regulatory activities in National Procedures.
The current version of the eCTD specification to be used for CTD modules 2-5 is the Electronic Common Technical Document Specification V3.2.2 (PDF). More information about the standard can be found at the ICH eCTD webpage. For eCTD submissions within the EU, covering the regional module 1 of the CTD, the EU Module 1 eCTD Specification (April 2021) should be used.
2. Electronic Application forms (eAF), eSubmission-Gateway and -Web Client and Common European Submission Platform (CESP)
In order to enable submission of applications for the various regulatory procedures, the respective application forms as well as submission portals have been put in place.
2.1. Electronic Application Forms (eAF)
The Electronic Application Forms offer a convenient, online alternative to the paper forms. In fact, the word-based application forms (AF) have been replaced by the electronic application forms (eAF), with new possibilities like electronic data import/export, data population within the form, online access to standardised catalogue terms, built in business rule validation, and support for validation of the form, etc.
The forms can be accessed at EU Electronic Application Forms eSubmission website and their use for EMA submissions is mandatory since 1 July 2015.
2.2. eSubmission Gateway and eSubmission Web Client
The eSubmission Gateway and the eSubmission Gateway Web Client are electronic submission channels that allow to submit documents supporting all types of applications related to the authorisation and maintenance of medicinal products to the EMA securely over the internet in structured and non-structured formats. They are based on the ESTRI (Electronic Standards for the Transfer of Regulatory Information) gateway standard, which defines a secure data exchange service for regulatory information. The web-based Gateway Web Client, available for all applicants, may be particularly relevant for Small and Medium sized Enterprises (SMEs) and companies with lower IT budgets and low submission volumes. The Gateway and the Web Client provide an automated confirmation of the technical validation feedback and an automated upload to the EMA’s eCTD review system. The use of the eSubmission Gateway and the Web Client is mandatory for all submissions.
2.3. Common European Submission Platform (CESP)
The HMA network (collaboration between Heads of Medicines Agencies in all member states) has developed the CESP mainly for national procedures (NPs, MRPs, DCPs).
CESP is an online delivery system with the following features:
- a simple and secure mechanism for exchange of information between stakeholders and agencies;
- allows submission of an application through one portal and distributing it to one or more agencies simultaneously (upload a dossier only once into the system);
- currently provides a delivery system for:
- MRP / DCP / National submissions.
- Clinical Trial Information;
- accepts all submission types and includes mechanisms to handle resubmitting of updated information;
- is a unidirectional system, from Industry to Regulator, with simple notification systems; CESP is purely a delivery system.
- can manage files and folders of varying sizes
- eliminates the effort for both Industry and Regulators in handling CD/DVD submissions
The CESP is optional for agencies to participate but is in operation in the majority of member states. All member states involved can extract the submission from the CESP repository.
The system will not perform validation, the respective agency will still validate the submission on receipt, but companies should carry out their own validation prior to submission.
For the interested
The progressive development of the electronic handling of regulatory processes between companies and regulatory authorities is an ongoing activity between the partners. An example are recent changes in Application Forms:
1) Implementation of mandatory use of the eAF is part of the HMA eSubmission roadmap. New version 188.8.131.52 of all eAFs is available for use from 1 October 2021. Mandatory use of these from 1 November 2021
2) The changes, in summary, are an updated section on Medical Devices in the human MAA form, addition of a new section on Medical Devices in the variation form, addition of new sections on parallel variations and on Harmonisation relating to National Variations.
Initial MAAs submitted to the EMA in the centralised procedure are subject to validation. The objective as stated by EMA is to make sure all essential regulatory elements required for scientific assessment are included in the MAA. Initial MAA validation has been centralised and is performed by a dedicated service within the EMA.
There are two elements to validation:
- the first is technical validation. This ensures that the structure of the submission is compliant with the EU CTD Module 1 Specification. An automated 'acknowledgement' email is sent from the system confirming:
- whether the submission has passed the relevant technical validation criteria
- has been uploaded to the EMA's review tool and
- made available via the Common Repository.
- If the eCTD submission results in an invalid Technical Validation the submission will not be accepted.
- the second element is regulatory and administrative content validation, which can only commence once the application has successfully passed technical validation.
If EMA requires additional data, information or clarification in order to complete its validation of the dossier, it will contact the applicant requesting to supply this information within a specific time limit.