Brexit Drug Supply
Brexit – is the after Brexit drug supply in Europe at risk?
The German Federal Association of Pharmaceutical Manufacturers (BAH) sees the Brexit drug supply in Europe at risk, when Britain leaves the EU on the 29.3.2019. Neither the UK itself nor the EU, in the opinion of the BAH, are well enough prepared. Accordingly, one of the tasks of the industry, is therefore to check whether their approval processes are currently underway with the participation of Great Britain.
So “who” and “what” in the Brexit drug supply is affected and “in which way”?
EMA moving to Amsterdam
One of the consequences of the Brexit is that the EMA will relocate to Amsterdam, Netherlands, where it will be operational by 30 March 2019 at the latest. The move is connected to a new building in Amsterdam and follows a tight schedule. Find here the milestones that the EMA has set itself for this project and the current status.
Source image: EMA Relocation to Amsterdam Main milestones
Brexit preparedness: EMA to further temporarily scale back and suspend activities
Next phase of business continuity plan aimed at securing essential public and animal health activities
The EMA will launch the next phase of its business continuity plan on 1 October 2018. This will allow the Agency to safeguard core activities related to the evaluation and supervision of medicines, while it has to intensify its preparations for the physical move to Amsterdam in March 2019 and cope with significant staff loss. The temporary cuts in activities are required because it has also become clear that the Agency will lose more staff than initially anticipated. Staff who will not relocate to Amsterdam have already started to leave the Agency and this trend is expected to ccelerate.
In addition, due to the employment rules in the Netherlands, 135 short-term contract staff will no longer be able to work for EMA. Overall, EMA expects a staff loss of about 30%, with a high degree of uncertainty regarding mid-term staff retention.
Authorisation holder of national approved human medicinal products
Subject to any transitional arrangements that may be included in a possible withdrawal agreement, the EU rules on medicinal products for human use and veterinary medicinal products are no longer applicable to the UK after Brexit. In particular, this has the following consequences in the different areas of EU pharmaceutical legislation:
EU law requires that license holders be established in the EU (or in the EEA);
Some activities have to be carried out in the EU (or in the EEA), e.g. Pharmacovigilance, batch release, etc .;
In a note from the European Medicines Agency (EMA), the EMA warned license holders to respond far in advance and proactively in order to avoid drug implications.
Authorisation Holder of centrally approved medicinal products
The EMA has made the necessary changes in the processes of centrally authorised medicines in a list of questions and answers (Q & A) on the topic. You can download the Q & A list here.
Overview of concerned MAH and Admission Processes
EMA carried out a Brexit-preparedness survey in 2018 to gather information from marketing authorisation holders for centrally authorised products on their plans to update their marketing authorisations in preparation for Brexit.
The main objective was to to gather information on the timelines for submission of the necessary regulatory changes and identify any centrally authorised products potentially at risk of supply shortages.
EMA sent the survey to marketing authorisation holders of 694 centrally authorised products (661 human and 33 veterinary products) either located in the UK or with an important step in their regulatory processes in the UK, such as quality control, batch release and/or import manufacturing sites, QPPV and pharmacovigilance system master file (PSMF).
According to EU law, the marketing authorisation holder, the QPPV, the PSMF and certain manufacturing sites need to be based in the EEA for a company to be able to market a medicine in the EU.
The companies analysed were based in the United Kingdom (UK) or perform the following functions in the UK:
- quality control
- Master file of the pharmacovigilance system (PSMF)
It is strongly recommended that pharmaceutical companies affected by the Brexit report the necessary changes to maintain EMA approval as early as possible and no later than the end of the fourth quarter of 2018 to ensure timely processing.
SMS, G-SRS, GINAS, EU-SRS Current Status of the IDMP Substance Submodel Implementations in Europe and the US
By Dieter Schlaps for IDMP1-News July 2018
FDA’s G-SRS System
In FDA2‘s G-SRS1 system, the substance is registered per type, as defined in the IDMP4 standard (e.g. chemicals, proteins, polymers, structurally diverse, nucleic acid, etc.) and then, certain criteria apply to distinguish substances in each category from one another (e.g., chemical structure, DNA sequence etc.). When enough information is available and validated, a substance is assigned a unique identification (UNII- Unique Ingredient Identifier) code, which can be used as a quick way to refer to that substance in the future. Until the UNII code is defined, the substance exists in G-SRS as a “concept”.
- The final versions of the ISO Standard 11238 on Substances (https://www.iso.org/standard/69697.html ) and its Implementation Guideline 19844 (https://www.iso.org/standard/71965.html ) with all annexes are published in this month (July 2018)
- Version 2.2 of G-SRS is now in productive use at the FDA
- The version 2.2 of the public G-SRS will be released in a few weeks, watch website https://tripod.nih.gov/ginas/#/.
- The currently available version 2.1 of the public G-SRS already hosts more than 100.000 substances and concepts.
- Programmatic communication with the G-SRS database is possible through the GINAS RESTful API (https://tripod.nih.gov/ginas/#/gsrs/api ), allowing substance searching, registration, browsing, updating. Figure 1 shows and example that downloads substances with all details in a simple query.
- Version 2.2 allows individual configuration by the registered user, e.g. which properties of a substance and which substance types are to be listed in the G-SRS views.
- With version 2.2, G-SRS has become more modular and more extendable than previously, which also should make interfacing and synchronization with other substance databases easier.
- For the production versions, from now on FDA will only support UNIX-based platforms, however. But Windows-based systems will be available for test and/or development environments.
At the same time, interested parties, that would be interested to develop and maintain a Windows-based G-SRS are welcome and should contact FDA’s GINAS team.
Figure 1: G-SRS API: Example Download of substance details in JSON format. The URL <uri>https://ginas.ncats.nih.gov/ginas/app/api/v1/substances?view=full</uri> retrieves the full data of the first ten substances as a single JSON file.
The following figure shows a screenshot of FDA’s internal G-SRS system, that links information about the product, its registrations and the substance information in a common interface.
Figure 2: FDA’s internal G-SRS System, where product registration information is linked to IDMP substance information ()
An updated G-SRS data set will be available end of July.
For versions 2.3ff. FDA now plans to address the following topics :
- Inclusion of Orphan Drug Application Codes, indications and other product-related information
- Develop modules for Specified Substance Groups 2-4
- Start entering Specified Substance Group 1 information
- Continue to develop better forms and presentation of data
- Expand quality (impurities) and pharmacology (targets, metabolite, cyp and transporter information)
- Deploy full instances with all public data at Open FDA and NLM
- Establish mechanism for system-system communication
- Integrate G-SRS into a clinical trial registry system (C-DISC)
European Activities around SMS and EU-SRS
The following activities concerning the SMS, G-SRS, GINAS, EU-SRS Current Status are carried out in Europe:
Substance Pilots to assess the validity of Article 57 substances and carry out mappings to G-SRS:
In Europe with the (IDMP-non-compliant) substance information being available in Article 57 database, there is first-of-all the need to map these information into the IDMP data model, to clean-up the data and then to match it against the G-SRS system.
The following figure shows how the EMA team led by Dr. Herman Diederik (Medicines Evaluation Board, Amsterdam, Netherlands) is carrying out this challenging task:
Figure 3: Substance mapping from xEVMPD/ Article 57 to G-SRS ()
Business Case and Implementation of a European Substance Registration System (EU-SRS)
The business case that was presented to the 92nd Heads of Medicines Agencies (HMA) (19 – 21 June 2018, Sofia, Bulgaria) describes why an IDMP-compliant Substance Management System is regarded indispensable for a successful implementation of SPOR, the European Framework for IDMP. Without unique identification and reliable characterization of substances used in product compositions, extensive additional efforts will be continuously be spent to check, correct and communicate substance data provided by industry to regulatory agencies.
The data lists that are used today for the selection of the substances and/or the declaration of strength for product composition in electronic Application Form (eAF), as currently provided by EUTCT / EudraVigilance are highly error-prone and not unambiguous.
At last, the HMA meeting endorsed the business case which now allows to start the EU-SRS project.
The Dutch Medicines Evaluation Board will lead the implementation of EU-SRS.
European Substances Validation Group (SVG)
The HMA meeting also endorsed the establishment of the European Substances Validation Group (SVG), which will assemble European (NCA/EMA) substance experts that will govern the contents and enable Europe-wide use of substance information, and it also endorsed the full cleansing of the current substances list to a baseline of quality that supports the required processes.
The role of SMS vs. EU-SRS
The Substance Management Service (SMS) within SPOR will be the “substance list” that is to be used when substances are to be selected for an electronic submission. It will hold a key set of fields on substances for use in related regulatory use cases (SPOR). In contrast to SMS, EU-SRS will support unique identification of substances using a more extensive data model, validation rules as well as validated content. EU-SRS will generate the final identifier to the substance and will distribute this to SMS for use in regulatory processes.
EU-SRS will also be the primary tool for the SVG and will enable alignment and synchronization with the FDA substance system (G-SRS) to allow for maximal re-use of already characterized substances. 
Conclusion and Outlook to the SMS, G-SRS, GINAS, EU-SRS Current Status
In the first half year of 2018 there has been significant progress in IDMP substance management activities around the globe:
The IDMP standard and implementation guidelines for Substances 11238 and 19844 are in process of being published by the International Standards Organisation (ISO), FDA has made some significant achievements in the implementation of their G-SRS system and EMA has now finally endorsed a project to establish Europe’s first IDMP-compatible Substance Management System (EU-SRS).
The implementation of EU-SRS will last probably one year or more, but will ultimately lead to a better and more effective regulatory decision making in the Network, from which patients, regulators and industry will profit.
References: Overview of ISO IDMP, Substances and HL7 Patient Care WG (allergy-intolerance)
Joint HL7 Biomedical Research & Regulation WG and Patient Care WG Meeting, May 10, Madrid, Spain
Panagiotis Telonis (EMA), Christian Hay (ISO/GS1), Herman Diederik (EMA/CBG),
Larry Callahan (FDA), Frank Switzer (FDA), Tyler Peryea (NCATS/NIH), Noel Southall
(NCATS/NIH). Link: http://wiki.hl7.org/images/2/2d/PT_CH_LC_HD_IDMP_HL7_Joint_BRR-PC_May_2017.pdf  Business case for implementation of EU-SRS – IDMP compliant substance management.
92nd Meeting of Heads of Medicines Agencies (HMA) (19 – 21 June 2018, Sofia, Bulgaria)
 GINAS is the project name of FDA’s substance database project and stood originally for “Global Ingredient Archiving System”. The system’s name name has been changed in the meantime into G-SRS, “Global Substance Registration System”, but the old project name is still in use.
 FDA: Food and Drug Administration
 NCATS: National Center for Advancing Translational Sciences
 IDMP: ISO Standard for the Identification of Medicinal Products
 RESTful: The REST (“Representational State Transfer”) architecture has been defined to allow “stateless” machine-to-machine communication between clients and web-based applications. “Stateless” means that all information that is needed to conclude the API request must be contained in the url (“uniform resource locator”) string. Methods like “GET”, “PUT”, “POST” etc. are provided by G-SRS for that purpose. The web application therefore does only need minimum access rights management and no further session management due to its stateless character.
 API: Application Program Interface – Set of functions for communication and data exchange with the G-SRS database
 IDMP Group 1 Specified Substances are multiple substance materials (Coatings, Colorants, Flavorants); Physical Form; Extracts
Using OMS data in eAF
(EMA SPOR webinar, 14 June 2018)
- About OMS
- Using OMS in eAF/CESP
- Submission of OMS Change Requests (CRs)
- Key messages
- OMS support & guidance
- Download Webinar (PDF)
1.) About OMS
2.) Using OMS in eAF/CESP
3.) Submission of OMS Change Requests (CRs)
4.) Key messages to Using OMS data in eAF
Using OMS data in eAF in a nutshell:
- OMS dictionary (list of organisations with associated physical locations) can be used to support regulatory business processes
- OMS content is growing and data quality is expected to improve over time
- Business owner of the process using OMS data decides how/when to use it and mandates its use. OMS team will work closely with the business process owners
- eAF will not mandate the use of OMS data, free text will still be available
- CESP will mandate the use of OMS data in the form. Organisation data will have to be pre-registered in OMS and can be selected in CESP. This is not planned before Q3-2019 for Initial MA Applications
- Applicants are advised to familiarise themselves with the use of OMS data and with the process before the use of OMS data will be mandated
- Applicants and MAHs are responsible to register/update organisation data in OMS before regulatory submissions (e.g. Initial MAA, Var, Renewal)
- Submission of OMS Change Requests for Veterinary MAH & MAAs for NAPs starts from September 2018
5.) OMS support & guidance
Reference documents accessible from the SPOR portal
- OMS web user manual – guidance on OMS services, e.g. searching, exporting data, requesting CRs
- SPOR user registration manual (how to register for SPOR)
- SPOR affiliation template (to register the first industry super user)
- Change Request (CR) Validation in OMS
- Organisation data quality standards in OMS
- SPOR SLAs (SLA are indicative and will be reviewed in future)
EMA Account Management Portal
To create a new EMA account in order to obtain access to EMA systems (including SPOR). To request SPOR user role.
EMA Service Desk Portal
Service requests, issues, requests for technical support shall be submitted through the Service Desk Portal.
6.) Download Webinar
Download SPOR API Documentation
Download SPOR API Documentation new edition ((version 1.14 published 9.1.2018) API schemas, OMS & RMS message formats and HL7) is accessible for interested parties for a free download in this website:
The latest version of the API specification incorporates the following additional information:
- A description of how an implementing system must retain rowid elements in the creation, and later management, of change requests in RMS.
- A description on the fields that have to be conditionally provided when dealing with both OMS and RMS change requests depending on the status and the data of such requests.
- An explanation on how OMS retains compatibility for searching elements based on identifiers, even after they have been merged, and how the current identifier, of an element, is highlighted in the response data.
- A description on what kind of change requests can be filed in OMS depending on the status of the referred organisation and/or location.
Please note that in the SPOR API specification, the services are set out in Section 6 and those that are OMS-specific are marked “O”, RMS-specific are marked “R”, and services shared by both RMS and OMS are marked as “RO”.
The documents have been shared with the SPOR Task Force and UAT testers.
Decision on EMA relocation has been published
The EMA is currently based in London’s Docklands business district but must move when Britain leaves the bloc in March 2019. EU agencies are not allowed to be based outside the union.
The fight for one of the most prised spoils of Brexit has come to a climax on Monday 20.11.2017 when 27 EU states picked the new host cities for the European Medicines Agency.
In a process only half-jokingly compared to the Eurovision Song Contest, ministers has voted on where to relocate the European Medicines Agency.
Out of a total of 19 candidates to be the new home of the EMA, the winner has been announced:
The European Medicines Agency goes to Amsterdam!
In an unusually complex procedure – even for the EU – each country had six points to distribute, including three to give to their first choice, two to their second and one to their third. The Dutch capital beat Milan in the lucky dip after three rounds of “Eurovision-style voting” had resulted in a dead heat.
Paris won the race to take the European Banking Authority from London, beating Dublin in the final, after the favourite Frankfurt was knocked out in the second round.
Starting from the 20th of November, the EMA has now less than 17 months to conclude its move and take up its operations in the new host city by end of March 2019.
Moving a large organisation such as EMA to a new location is a challenging undertaking under any circumstances. It is made even more complex by the ambitious timetable determined by the withdrawal of the United Kingdom (UK) from the European Union (EU) on 30 March 2019. Effective collaboration between EMA and the new host country on the basis of the commitments made in the offer to host EMA is essential for a successful move to a new location and EMA’s business continuity.
Find here the press release of EMA concerning the relocation to Amsterdam.
EMA launched Referentials Management Service
The RMS and OMS manage two of the four domains of substance, product, organisation and referential (SPOR) master data in pharmaceutical regulatory processes. They lay the data foundations for delivering the substance and product data management services.
Users can access information to these data services directly online via the SPOR portal.
EMA will invite national competent authorities and industry stakeholders to register their RMS and OMS users, starting with ‘super users’ who can authorise the registration of further users from the same organisation.
However, the timetable is different for different stakeholders:
National competent authorities:
EMA invited national competent authorities to begin registering their super users and to use the RMS from June 2017;
Update: EMA will invite industry stakeholders to begin registering their ‘super users’ from 15 December 2017 and other users from January 2018.
For more information see the Referentials Management Service (RMS) and Organisations Management Services (OMS) user on-boarding plan.
EMA Update on IDMP SPOR September 2017
4 September 2017, EMA/580454/2017, Information management division
The EMA update IDMP SPOR September 2017 envisaged additional post implementation releases of RMS and OMS data services to enhance functionality (please see the plan below). The first improvements to these data services were released on 10 August 2017 (release notes are available from the SPOR portal). Two more releases of RMS and OMS are planned for 2017:
- RMS & OMS version 2.2, planned for 16 October 2017;
- RMS & OMS version 2.3, planned for 17 November 2017.
Prior to the version 2.2 the EMA will run another round of OMS user acceptance testing (UAT), commencing 15 September 2017. The scope of this round of the OMS UAT will cover functional areas not tested, or which were unsuccessful, in the previous UAT held in March/April 2017.
Participation in this UAT is open only to those testers who participated in the previous round of UAT, plus those Industry Vendors who submitted a request during the recent Call for Expressions of Interest (closed Thursday 31 August).
The results of this round of UAT should be issued formally before the end of October 2017. Defects reported are expected to be fixed and included in version 2.3, due for release in November 2017.
A slide deck from the OMS UAT preparatory webinar held on 1 September 2017 can be accessed here (choose documents / view).
Following the October 2017 release (version 2.2), EMA will invite industry stakeholders to begin registering their Super Users and Users. Precise date will be communicated during October.