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EDQM Standard Terms Implementation

Industry context & core steps to follow

Martti Ahtola | Jun 15, 2022

Easy and straightforward reports submission
From June 30, 2022, EudraVigilance users will need to report individual cases of suspected side effects using the ISO ICSR / ICH E2B R3 format and related ISO standard terminology for pharmaceutical form and route of administration. The new XCOMP system no longer accepts ICH E2B(R2) messages and the EDQM terms available for testing will not be periodically updated. Routes of Administration and Dosage Form terms in the EDQM Standard Terms database comply with the ISO 11239 standard. The content of the EDQM Standard Terms database is updated weekly with new or revised terms. EudraVigilance synchronizes the EDQM code lists every night so that the next day new terms are added and updates to existing terms are made. Marketing authorization holders and applicants, clinical trials sponsors, and national competent authorities need to regularly update their systems with the latest set of EDQM codes to avoid rejections of ICSR submissions. The new business rules became available in the EudraVigilance test environment (XCOMP) after Q1 2022 making it possible for us to test changes made to our own Tepsivo Safety Database.

Impacted Fields in R3

In the safety database context, we are talking about a relatively simple update. The fields below that have been part of the EU implementation of ICH E2B R3 structure for some time now, were updated from free text fields (this is how we had it in Tepsivo Safety Database, in other systems they might have been hidden and/or disabled) to dropdown menu fields.
  • Pharmaceutical Dose Form G.k.4.r.9.2b
  • Route of Administration G.k.4.r.10.2b
  • Route of Administration G.k.4.r.11.2b

What is EDQM?

European Directorate for the Quality of Medicines & Healthcare (EDQM) is probably best known for European Pharmacopoeia, but they provide other standardized information as well. EDQM Standard Terms lists and database were created at the request of the European Commission. They apply to both human and veterinary medicines and cover:
  • pharmaceutical dose forms (dosage forms),
  • routes and/or methods of administration,
  • units of presentation,
  • and containers, closures and delivery devices
The database contains equivalents of over 900 terms in 35 languages. Standard Terms are used in marketing authorization applications, labeling (including SmPCs), electronic communications and now also in adverse event reporting. ICH published supplementary information on the use of terms for dose forms and routes of administration as specified in the ISO standard 11239 for use in the electronic exchange of ICSRs according to the ICH E2B(R3) Implementation Guide for Electronic Transmission of Individual Case Safety Reports (ICSRs). The ICH guide specifies the use of terminology for pharmaceutical dose forms and routes of administration as published in the EDQM Standard Terms. The EU Individual Case Safety Report (ICSR) Implementation Guide contains specific technical information on using EDQM terms in ICSRs submitted in E2B R3 format. A code-list mapping the EU ICH-E2B(R2) Dosage forms to EDQM terms is also available.

How EDQM falls into ISO IDMP implementation and SPOR?

EMA is in the process of implementing the standards developed by the International Organization for Standardization (ISO) for the identification of medicinal products (IDMP). ISO IDMP standards specify the use of standardized definitions for the identification and description of medicinal products for human use. Purpose of the standards is to facilitate the reliable exchange of medicinal product information. Goal is interoperability across global regulatory and healthcare communities, enabling accurate analysis and unambiguous communication. Implementation of the standards takes place in a phased program based on the four domains of master data in pharmaceutical regulatory processes: substance, product, organization and referential (SPOR) master data.
  • Substance Management Service (SMS)
  • Product Management Service (PMS)
  • Organisation Management Service (OMS)
  • Referentials Management Service (RMS)
Referentials management service synchronizes with EDQM Standard Term database and the dosage form and routes and methods of administration lists are available through the SPOR RMS user interface and they can be retrieved using the SPOR RMS application programming interface (API).

How SPOR RMS works?

SPOR RMS is used to distribute lists of standardized terms for use in other systems in the SPOR context. Mostly, it will be used for standardization of product information once Product Management Service is fully implemented and replaces the current system (XEVMPD and XEVPRM). The EDQM Standard Terms for dose forms and routes of administration as specified in the ISO standard 11239 for use in the electronic exchange of ICSRs are examples of those standardized lists in the RMS. EDQM publishes updates as soon as terms are approved and SPOR RMS loads these updates once they are published. EudraVigilance synchronizes weekly, on Sundays, with SPOR RMS.

EDQM Standard Terms implementation

EMA has published plenty of material to support the implementation. However, the core steps might get lost in all that information. The EU ICSR implementation guide along with the published ICH guidance contains detailed guidance on how to implement EDQM terms in E2B(R3) files. In addition to these documents, the following support files have been updated to include support for EDQM terms and codes. The high-level steps for the implementation of the EDQM Standard Terms to the above-mentioned fields in Tepsivo Safety Database:
  1. We explored technical details of SPOR RMS API and how the EDQM data could be synchronized regularly.
  2. Updated the relevant fields and prepared Tepsivo Safety Database to send calls to SPOR RMS API and to receive the XML responses from the authority system.
  3. Registered new dedicated user account for testing and production using EMA Account Management.
  4. API connection was established and tested with SPOR RMS to obtain the EDQM code lists
  • API connection test was required as part of the registration process.
  • EMA has not specified which tests are required from the software vendors or pharmaceutical companies using their own software.
  • Based on our experience with the implementation, it is sufficient to perform tests 16, 17, and 18.
  • The results and proof of testing are provided in the registration. Further registrations can refer to this testing documentation.
Then,
  • Received access to the production version of the SPOR RMS API.
  • Tested the production connection.
  • Tested the functionality of the new fields with the new EV Test files from EMA.

Exploring technical details

We started the implementation process by exploring technical details of SPOR RMS API and how the EDQM data could be synchronized: how to create new terms and, most importantly, how to amend existing terms.

Preparing the relevant fields and rest of the system

We planned how the terms would be implemented to the backend and frontend parts of Tepsivo Safety Database. As a result, the user of Tepsivo Safety Database will be able to select EDQM Standard Terms in the ICSR fields, the system stores them in the database and submits (xml generation) them to EudraVigilance. EDQM Standard Terms data can potentially be updated daily based on the requests from authorities and companies, and EudraVigilance is updated every Sunday, so it makes sense to synchronize the data at least weekly.

Registering a dedicated account for the connection

First, we registered a dedicated technical account using EMA Account Management Portal and the test version of EMA Account Management Portal. The account was used to request SPOR roles Industry User role. The organization needs to have a SPOR industry super user assigned (both production and UAT) before the requests are submitted. The usernames and passwords created in the production and test versions of the Account Management Portal are used later for the API connection as well.

Establishing API connection

API connection needs to be established to SPOR RMS to obtain the EDQM code list. Access for the test environment (UAT) API connection of SPOR RMS should be obtained first. We determined that this needed to be done as soon as possible because the API connection would be required since the beginning of the development of the EDQM implementation.

We prepared Tepsivo Safety Database to send API calls to SPOR RMS and to receive the XML responses. API connection test is required as part of the registration process.

To gain access to the SPOR RMS API we firstly filled in the SPOR API Access Request Form and raised a service desk ticket for SPOR API access.

Importantly, Tepsivo database software needed to have an IP address that could be used for this purpose. The IP address(es) are whitelisted by EMA during the registration process.

An overview of the registration process is given in Figure 2 from EMA guidance

API connection testing

There are also specific API connection tests that should be performed based on the organization’s needs. EMA had not specified which tests are required from the software vendors or pharmaceutical companies using their own software. Based on our experience with the implementation, it is sufficient to perform tests 16, 17, and 18 which test the following aspects of the API:

  • 16: Export all terms that begins with “Cough” having translations in French (country France)
  • 17: Export specific terms with IDs 100000000369, 100000000370, 100000000371, 100000000372, 100000093541
  • 18: Get all terms in the latest version of the list Pharmaceutical dose form

The results and proof of testing were provided in the registration. Further registrations (by companies using Tepsivo Safety Database) can refer to this testing documentation created by us.

Testing with EMA test cases

We performed testing with new EudraVigilance Test xml files from EMA that include EDQM Standard Terms. The testing of the field functionality was performed in XCOMP environment via Tepsivo Safety Database cloud application. This also ensured that the fields are working as expected when xml files are imported from EudraVigilance.

 Registering customers

When the registration and testing was complete for the test instance of Tepsivo Safety Database and us as a SPOR OMS organization, we moved to deploying the updates to customer instances of our software and registering our pharmacovigilance service customers for whom we manage both the safety database and the pharmacovigilance system.

Because we had already completed the testing, the registration of a customer instance of Tepsivo Safety Database was much faster. Again, we raised a ticket at the service desk attaching the registration form, reference to the previously completed testing (issue IDs) and appointment letter of Tepsivo as the service provider of the organization. After whitelisting of the customer instance IPs and testing the API connection with simple calls, the registration was complete and the new version of Tepsivo Safety Database with EDQM Standard Term fields was deployed to the customer instances.

High-level solution of EDQM integration in Tepsivo Safety Database

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