Human medicinal products Archives - European Industrial Pharmacists Group (EIPG)

Approval of the Data Governance Act, and EMA’s consultation on the protection of personal data in the CTIS


by Giuliana Miglierini The Data Governance Act (DGA) was approved and adopted in May 2022 by the European Council, following the positive position of the EU Parliament; the new legislation will entry into force after being signed by the presidents Read more

The transition towards EMA's new Digital Application Dataset Integration (DADI) user interface


by Giuliana Miglierini The Digital Application Dataset Integration (DADI) network project is aimed to replace the current PDF-based electronic applications forms (eAFs) used for regulatory submissions with new web-forms accessible through the DADI user interface. The European Medicines Agency (EMA) has Read more

IVD regulation in force: new MDCG guidelines and criticalities for innovation in diagnostics


by Giuliana Miglierini The new regulation on in vitro diagnostic medical devices (IVDR, Regulation (EU) 2017/746) entered into force on 26 May 2022. The new rules define a completely renewed framework for the development, validation and use of these important Read more

The transition towards EMA’s new Digital Application Dataset Integration (DADI) user interface

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by Giuliana Miglierini

The Digital Application Dataset Integration (DADI) network project is aimed to replace the current PDF-based electronic applications forms (eAFs) used for regulatory submissions with new web-forms accessible through the DADI user interface.

The European Medicines Agency (EMA) has released the updated timeline for the implementation of the project, which will at first affect variation forms for human medicinal products. The ongoing phase of User Acceptance Testing (UAT) by members of the DADI Subject Matter Expert (SME) Group (including representatives of EMA, national competent authorities and the industry) is expected to close in August 2022, followed by a second round of testing with external users, representatives of the different stakeholders.

The final release of the new form is currently scheduled for October 2022; a six month transition period shall then apply, during which both the PDF eAF and the web-based form can be used in parallel. Further information of the scope and implementation of the new DADI interface is available in the Q&A document published by EMA. An updated Fast Healthcare Interoperability Resources (FHIR) mapping spreadsheet is also available, containing all attributes that are required by the Notice to Applicants; the attributes have been made consistent with the ISO Identification of Medicinal Products (IDMP), so that the DADI form also supports the submission of structured data to EMA’s Product Management Service (PMS).

A short history of the project

The DADI project is aimed to improve the interoperability of data; it builds upon the Common European Single Submission Portal (CESSP) Phase 1 project (2016-2020). Seven national competent authorities (NCAs), from Austria, Germany, Spain, Ireland, the Netherlands, Norway and Sweden are also collaborating to the setting up of the DADI project.

Some results from the Horizon 2020’s UNICOM project (with no contractual obligations for EMA towards the UNICOM Consortium and the European Commission) also supported the DADI’s development; UNICOM is specifically targeted to ensure the availability of pan-European ISO IDMP compliant forms and IDMP implementation at national agencies.

The use of ISO IDMP rules is compulsory as for Commission Implementing Regulation (EU) 520/2012 (articles 25 and 26) for both marketing authorisation holders (MAHs), EMA and member states. These standardised definitions for the identification and description of medicinal products for human use shall facilitate the reliable exchange of information between the different parties involved in the regulatory processes. However, it should be noted that ISO IDMP covers human medicinal products only, not veterinary ones, and refers to the entire product lifecycle, including development. This differs from the PMS module, which covers only the Authorised Medicinal product part of IDMP.

How the DADI interface works

EMA’s plan is to gradually replace during 2022 and 2023 all the eAF forms for the various types of regulatory procedures, starting with the variation form for human medicinal products, so to achieve the availability of standard product master data for human and veterinary medicinal products. It is important to note that both the old forms based on the PDF format and the new web-forms are “electronic application forms”; EMA warns to expect that “the web-based forms will still be called electronic application forms (eAF)”, while in DADI communications, reference can be made to web-based application forms to distinguish them from the current PDF-based eAFs.

The implementation of the FHIR data exchange standard shall make possible to generate human- readable output (PDF files, with an attached FHIR XML) as well as machine-readable output for digital processing. Exchangeable contents based on FHIR are called “resources”. They all share some common characteristics, including how they are defined and represented on the basis of reusable patterns of elements, a common set of metadata, and a human readable part.

Some form fields could also be pre-populated with available product master data from the PMS for human medicines and the Union Product Database (UPD) for veterinary ones, so to facilitate applicants with the filling of the form. Additional metadata may be included in the FHIR XML backbone in order to facilitate regulatory activities.

Users will be able to download forms containing relevant product data, but it won’t be possible to export only product data nor to perform bulk exports in the web UI. Digital signature tools should be used to sign the PDF rendition of the web-form (details will follow from EMA).

Other expected benefits include shorter times to load substances drop down lists and a lower administrative burden for regulators, so to speed up the validation of applications and lowering the number of errors and discrepancies.

The main expected changes

No changes in the process to apply for or submit marketing authorisation applications will occur following the implementation of the DADI project. The current PDF output will remain, as well as the content of the output form included in the application.

The DADI project was developed on the basis of the Safe Agile principles of the Network Portfolio, and it will impact both centralised, decentralised, mutual recognition and national procedures. Ownership of the new web-forms is shared between EMA and NCAs, to acknowledge the collaborative work done to develop them.

At the level of national competent authorities, the new FHIR compliant XML shall be implemented by NCAs which are currently using the PDF forms’ Extensible Markup Language (XML) functionalities.

Specific guidance, training and webinars on the use of the new variation form should be made available by EMA close to its final adoption. Support in the use of the new web-forms will be available through the EMA Service Desk; the existing eAF Maintenance Group shall also continue its activities and act as an expert body.

Access to the new DADI interface should be based on EMA’s Identity and Access Management (IAM) system, and make use of specific access privileges. Consultants may be granted access by marketing authorisation holders (MAHs) to all products from that MAH, or only to specific applications containing products.

EMA also clarifies that the new DADI portal will remain distinct from the IRIS platform supporting product-related scientific and regulatory procedures, and it will be governed differently.

The challenges for the industry

The challenges and opportunities for the pharmaceutical industry linked to the implementation of the new DADI interface by April 2023, at the end of the transition period, has been addressed by an article by Amy Williams in Pharmaceutical Online.

Namely, the decision to implement the DADI has overwritten the expected publication of the IDMP’s EU Implementation Guide 2.2, thus asking the industry an effort to redefine its priorities along its entire regulatory portfolio to include all types of EU procedures. Submission of structured PMS data should also be accelerated by the adoption of the DADI, thus asking for an improved approach to data capture and alignment across the entire company. The need to resubmit post-approval data using EMA’s Extended EudraVigilance Medicinal Product Dictionary (xEVMPD) should be also considered.

The new phase of the DADI implementation indicates that “full IDMP-based regulatory data exchange, via a system-to-system interface between pharmaceutical companies and EMA, now won’t come into effect any time soon”, writes Renato Rjavec in Pharmaceutical Technology Europe. Compliance to data granularity requirements of IDMP should also be ensured, together with the availability of tools to extract relevant information from complex IDMP data model to appropriately generate the xEVPRM format of data exchange.


The new Annex 21 to GMPs

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by Giuliana Miglierini

The new Annex 21 to GMPs (C(2022) 843 final) that EIPG gave a significant contribution in reviewing the original draft and thoroughly presented it within a webinar to its members on August 2020, was published by the European Commission on 16 February 2022; the document provides a guideline on the import of medicinal products from extra-EU countries. The new annex will entry into force six months after its publication, on 21 August 2022. Its contents should be read in parallel with the EU Guide to Good Manufacturing Practice for Medicinal Products and its other annexes, those requirements continue to apply as appropriate.

Annex 21 details the GMP requirements referred to human, investigational and/or veterinary medicinal products imported in the European Union and European Economic Area (EEA) by holders of a Manufacturing Import Authorisation (MIA). The new Annex does not apply to medicinal products entering the EU/EEA for export only, as they do not undergo any process or release aimed to place them on the internal market. Fiscal transactions are also not considered as a part of the new annex.

The main principles

According to Annex 21, once a batch of a medicinal product has been physically imported in a EU/EEA country, including clearance by the custom authority of the entrance territory, it is subject to the Qualified Person (QP) certification or confirmation. Manufacturing operations in accordance with the marketing authorisation or clinical trial authorisation can be run on imported bulk and intermediate products prior to the QP certification/confirmation. To this regard, all importation responsibilities for both medicinal products and bulks/intermediates must be carried out at specific sites authorised under a MIA. These include the site of physical importation and the site of QP certification (for imported medicinal products) or QP confirmation (for bulk or intermediate products undergoing further processing).

Marketing authorisation holders (MAHs) for imported products authorised in the EU remain in any case the sole responsible for placing the products in the European/EEA market. Annex 21 requires sites responsible for QP certification to verify an ongoing stability program is in place at the third country site where manufacturing is performed. This last one has to transmit to the QP all the information needed to verify the ongoing product quality, and relevant documentation (i.e. protocols, results and reports) should be available for inspection at the site responsible for QP certification. QP’s responsibilities also extend to the verification that reference and retention samples are available in accordance to Annex 19 of the GMPs, and that safety features are placed on the packaging, if required.

Importation sites should be adequately organised and equipped to ensure the proper performance of activities on imported products. More specifically, a segregated quarantine area should be available to store the incoming products until the occurrence of release for further processing or QP certification/confirmation.

European GMP rules or equivalent standards shall be followed for the manufacturing of medicinal products in third countries due to be imported in the EU. The manufacturing process has to comply to the one described in the Marketing Authorisation (MA), the clinical trial authorization (CTA) and the relevant quality agreement in place between the MAH and the manufacturer. The respect of EU GMP rules or equivalent standards should be documented through regular monitoring and periodic on-site audits of the third country manufacturing sites, to be implemented by the site responsible for QP certification or by a third party on its behalf.

The QP of the importation site is also responsible for the verification of testing requirements, in order to confirm the compliance of the imported products to the authorised specifications detailed in the MA. The verification of testing requirements can be avoided only in the case a Mutual Recognition Agreement (MRA) or an Agreement on conformity assessment and acceptance of industrial products (ACAA) is in place between the European Union and the third country where the production of the medicinal product is located.

All agreements between the different entities involved in the manufacturing and importation process, including the MAH and/or sponsor, should be in the written form, as indicated by Chapter 7 of the EU GMP Guide.

The Pharmaceutical Quality System of the importing site

According to the European legislation (Chapter 1 of the EU GMP Guide), all activities performed in the EU with reference to the manufacturing and distribution of pharmaceutical products should fall under to umbrella of the company’s Pharmaceutical Quality System (PQS). This is also true for sites involved with importation activities, those PQS should reflect the scope of the activities carried out. A specific procedure should be established to manage complaints, quality defects and product recalls.

More in detail, the new Annex 21 establishes that sites responsible for QP certification of imported products (including the case of further processing before export with the exception of investigational medicinal products) have to run periodic Product Quality Reviews (PQR). In this case too, the respective responsibilities of the parties involved in compiling the Reviews should be specified by written agreements. Should the sampling of the imported product be conducted in a third country (in accordance with Annex 16 of the GMPs), the the PQR should also include an assessment of the basis for continued reliance on the sampling practice. A review of deviations encountered during transportation up to the point of batch certification should be also available, and a comparison should be run to assess the correspondence of analytical results from importation testing with those listed by the Certificate of Analysis generated by the third country manufacturer.

Full documentation available at MIA sites

The QP’s certification/confirmation step for an imported batch has to be paralleled by the availability of the full batch documentation at the corresponding MIA holder’s site; in case of need, this site may also have access to documents supporting batch certification, according to Annex 16. Other MIA holders involved in the process may access batch documentation for their respective needs and responsibilities, as detailed in the written agreements. A risk assessment is needed to justify the frequency for the review of the full batch documentation at the site responsible for QP certification/confirmation; the so established periodicity should be included in the PQS.

Annex 21 also lists the type of documents that should be available at the importation sites, including the details of transportation and receipt of the product, and relevant ordering and delivery documentation. This last one should specify the site of origin of the product, the one of physical importation and shipping details (including transportation route, temperature monitoring records, and customs documentation). Appropriate documentation should be also available to confirm reconciliation of the quantities of batches which underwent subdivision and were imported separately.

Requirements set forth in Chapter 4 of the GMPs apply to the retention of the documentation; the availability at the third country manufacturing site of an adequate record retention policy equivalent to EU requirements shall be assessed by the site responsible for QP certification. Should it be appropriate, translations of original documents and certificates should be provided to improve understanding.


Draft Guideline on the acceptability of names for human medicinal products

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The scope of this guideline is to provide information on the overall procedure for submitting and reviewing the acceptability of proposed (invented) names for human medicinal products processed through the centralised procedure, as well as detailed guidance on the criteria applied by the Name Review Group (NRG) when reviewing the acceptability of names. The main aim is to promote patient safety as an essential principle.

Based on the experience gathered by the NRG since the last revision of the guideline in May 2014, it became apparent that some areas of the guideline would benefit from further clarifications, in particular with regards to the requirements for acceptability of proposed (invented)1 names of medicinal products processed through the centralised procedure.

This 7th update of the guideline further clarifies specific aspects of the criteria applied to address safety and public health concerns, international non-proprietary names issues and product-specific concerns in proposed (invented) names. This update also provides further information on the conditional acceptability of invented names and the process for bilateral negotiations and proposes changes to the duration of the validity of an (invented) name and the review process of the NRG.

Consultation dates: 16/12/2021 to 16/03/2022

Reference number: EMA/CHMP/287710/2014 Rev. 7


EMA’s OMS has turned mandatory for centrally authorised products

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by Giuliana Miglierini

Since November 1st, 2021, the use of the Organisation Management Service (OMS) became mandatory for all Centrally Authorised Products (CAPs). The European Medicines Agency (EMA) has published a Questions & Answers document to better explain the new procedures, that will impact the source of data to be used to exactly identify the organisations filing CAP procedures with EMA.

The progression in the implementation of the new provisions

The use of the OMS system is now compulsory for all organisations filing CAP submissions, with the final goal to improve the interoperability of data and the overall efficiency of the regulatory process. Should applicants lack to use OMS data, the relevant applications will be filtered out of the EMA’a validation procedure and sent back to the applicant for remedial action.

The OMS data management service was launched in 2015, and applied to electronic application forms (eAFs) since 2017, and then to many other types of procedures. The availability of OMS data may prove critical to allow the smooth implementation, in early 2022, of the new Clinical Trial Information System (CTIS) and of the Clinical Trial application procedure; during the next year, EMA plans to integrate the OMS also with the Union Product Database (UPD), Variation applications (via DADI project) and Manufacturing/Importers Authorisations (MIAs), Good Manufacturing Practice (GMP) inspections and Wholesale distribution authorisations (via EudraGMDP).

Validated OMS data also need to be used with reference to the “applicant” and “contact person affiliated organisation” sections of pre-submission applications. With the new eAF release (eAF V.1.25.0.0) for Medical Devices, the compulsory use of OMS data will also refer to the “Device Manufacturer”, “Notified Body” and “Companion diagnostic” sections.

Remediation in case of lack to use OMS data includes the insertion of all relevant information in the OMS database before updating and re-submitting the application form. Should applicants not provide sufficient responses, the application may be completely or partially invalidated.

Discussions are undergoing to further extend the use of OMS data also to National Procedures (NP); according to EMA, this may be turn inevitable in the next couple of years, as current eAF forms will be progressively replaced by web-based application forms (through the DADI project), being the latter the same for centrally and nationally authorised products by design.

Any question on the use of the OMS can be sent to EMA’s e-mail addresses specified in the Q&As document.

What is new for applicants

The use of OMS master data (the so-called “OMS Dictionary”) is now mandatory for both Human and Veterinary centralised procedures, namely those making use of eAFs (initial marketing authorization applications, variations applications, and renewals) and well as other procedures (see the Q&A document for more detail). The name and contact details of the contact person are not OMS data, and do not need to be registered with the system; historical organisational data do not have to be registered as well.

To manage a CAP procedure, applicants now need to first register their organisation data with the OMS, or request the update of data already registered by submitting a “Change Request” before filing of the regulatory application.

All requests will be assessed by EMA OMS Data stewards, that will also update data in the systems if the requirements are met. This validation step is fundamental to avoid duplication of data, as all information is checked against the same reference sources (i.e. national business registry, DUNS and/or GMP/MIA certificates) and standardised according to the OMS rules agreed with the Network. The Service Level Agreement provide for EMA to process 75% of OMS requests within five working days and 90% within ten working days. Changes will become visible in the eAF the day after they had been processed, and only upon active refresh of the relevant lists.

The business process which makes use of OMS data is usually responsible to submit such a request, but it can arise also form other parties. More specifically, EMA advises the user who needs to use the data should take the lead in updating it. This may prove relevant, for example, to ensure all manufacturer organisations are included in the OMS Dictionary as needed.

EMA warns applicants to consider the turnaround time for processing the OMS change request when planning to submit applications: even if the application forms will not immediately change and everything may appear as usual, the background process has been now modified and may need additional activities to validate the change requests.

Changes in the eAF templates are planned to remove the free text fields for CAP applications, but until the new models will be available, the free text field for “organisations” should not be used. Planned availability and entry into force of the new versions are December 2021 for Human procedures (v1.26.0.0) and January 28th, 2022 for Veterinary procedures (in line with the veterinary regulation).

How to access the OMS

EMA’s data management system refers to four different domains of data, including the substance, the product, the organisation and referential (SPOR) master data in pharmaceutical regulatory processes.

The SPOR portal provides access to the respective four specific areas of service (e.g. SMS for substances, PMS for products, OMS for organisations and RMS for referential). SPOR is the mechanism used by EMA to implement the ISO IDMP standards, as required by articles 25 and 26 of the Commission Implementing Regulation (EU) No. 520/2012. Organisation master data, even if not covered by ISO IDMP, have been considered by EMA, National Competent Authorities and Industry in Europe to be essential in order to make the master data operating model work.

Applicants need to create an EMA account with SPOR user roles to conduct additional tasks, such as requesting changes to data, translating data or managing user preferences. Already granted credentials to access other active accounts for any EMA-hosted website or online application can also be used. OMS data can now no longer be captured in other EMA databases.

OMS master data include the organisation name and address, labelled by mean of unique identities (ID) (i.e. ‘Organisation_ID’ and ‘Location_ID’). Different categories of organisations are possible (i.e. ‘Industry’, ‘Regulatory Authority’ or ‘Educational Institution’), and of different size (i.e. ‘Micro’, ‘Small’, or ‘Medium’). The role played by a certain organisation is context-specific and cannot be defined within the OMS.