Help Support Advise Guidance 21 11 19

You need to apply Type IA Annual Reporting in the EU in 2025

The Type IA Annual Update, also known as the “Annual report”, is a single submission of all the Type IA variations (not requiring immediate notification) which have been implemented during the previous twelve months.

The Annual report should be submitted as close to 12-month deadline as possible, but ultimately no earlier than 9 months and no later than 12 months after the first implementation date of the Type IAs included in the report.

 

Meaning of implementation for type-IA variations:

For quality changes, ‘implementation’ is when the company makes the change in its own quality system.

This implementation date must be carefully planned and recorded to facilitate submission of your Annual Reports.

 

How to plan the submission of your Annual Report:

As submission of the Annual report is dependent on the implementation of the first type IA variation, its submission date can change every year.

It is very important to note that the Type IA Annual report must fulfil the variation conditions for grouping (or super-grouping if it concerns more than one marketing authorisation).

It is expected that Type IA variations included in an Annual report will not be rejected. However, if rejected, Type IA variations from the annual report can be resubmitted as individual Type IAs immediately (outside of an annual report).

 

CMDh confirmed that although not specified in their guidance, Type IA variations implemented before 1 January 2025 can still be submitted as single type IA variations according to the current rules. The EMA confirmed that Type IA variations implemented in 2024 and not submitted to the Agency by 31 December may also be submitted by MAH no later than 12 months after implementation.

 

Therefore, Type IA variations implemented from 1 January 2025 should be submitted as part of the Annual report.

Type IAs can still be submitted outside the Annual report in the following cases:

  • If they are part of a grouped Type IB or Type II variation
  • If they are part of a super-grouping variation
  • If it involves the resubmission of a Type IA variation previously refused in the Annual report (12-month reporting period is criteria in this situation)
  • In exceptionally cases which should discussed and agreed with the EMA/NCAs.

 

eAF:

There are no current plans to amend the eAF to reflect Annual Reporting, instead, Applicants are advised to include a note in the cover letter and an additional note in the eAF scope to clarify that the application relates to the Annual Update of Type IA variations e.g. as foreseen in the updated Cover letter template:

<Annual update of type IA variation(s)

[X] We confirm that the annual update is submitted within 12 months following the implementation of the first type IA variation applied for in this notification. Implementation date of the first type IA variation:      >

 

If you need any assistance with planning and submission of your Annual Reports, contact us and we will be happy to help.

 

Written by

Fiona Downey

Fiona Downey 1

Fiona Downey 1

Corona virus image 11 05 20

COVID-19: Still on your Radar? Current vaccine approval status and what’s on the horizon

It is just over 2 years and 9 months since the WHO declared the COVID-19 outbreak a public health emergency of international concern.

In the EU we now have a variety of options to protect us from COVID-19. There are as follows:

Notably, the three initial vaccines that were granted ‘Conditional marketing authorisations’ in December 2020 and January 2021 (Comirnaty – developed by BioNTech & Pfizer, Spikevax – developed by Moderna and Vaxzevria – developed by AstraZeneca) were all issued as ‘Standard marketing authorisations’ in October 2022.

  • Four adaptive vaccines
    Adapted vaccines are intended to provide broader protection against different virus variants following initial vaccination. They include:
  • Comirnaty Original/Omicron BA.1
  • Comirnaty Original/Omicron BA.4-5
  • Spikevax bivalent Original/Omicron BA.1
  • Spikevax bivalent Original/Omicron BA.4-5

All these authorisations were just recently issued by the EMA, in September and October 2022.

Note that at the end of October 2022, the EMA published a useful visual summary of COVID-19 vaccines, including their platforms, strains, uses and target populations.

The majority were developed specifically to treat COVID-19. However, some were already marketed for other indications but have also been proven to be effective in treating COVID-19. These include several pharmaceutical forms i.e., tablets, injections and solutions for infusions.

Update on potential new COVID-19 vaccines:

With the continuous emergence of variants, it is difficult to keep vaccines fully equipped to match the variants in circulation. However, developing further adaptive vaccines will help to improve neutralisation against circulating strains.

The EMA are still reviewing two other adaptive vaccines which target other strains of the virus. These include the Sanofi Pasteur vaccine called Vidprevtyn containing the beta strain. A possible CHMP opinion of this vaccine is expected at the November meeting.
Another vaccine under review contains both alpha and beta strains. The EMA is still waiting on additional data from the company before a decision on this adaptive vaccine can be made.

Updates and comments on COVID-19 treatments:

With the rise of new omicron sub-variants, currently available monoclonal antibodies will lack activity. Due to this, the EMA is exploring, with developers and international regulators, pathways for rapidly approving new monoclonal antibodies based on an established platform that could be rapidly deployed to tackle emerging variants.

Currently authorised antiviral treatments such as Paxlovid or Veklury, don’t target the spike protein but target other parts of the virus. This makes it more likely that they will remain effective as other viral proteins are less effective. However, it will be important to confirm their activity is not impacted by all these variants that are still emerging.

New antivirals that can be administered orally are currently under development and may provide a wider range of antiviral agents for treating COVID-19 patients in the future.

For further details contact us.

Written by

Claire Brown

Claire Brown

Changing medicine 24 02 21

When will DADI application forms replace the current eAFs?

The electronic application forms (eAFs) we are familiar with are in the process of being replaced later this year by a web based digital application form in a new eAF portal. The new eAF portal will look somewhat similar to the current IRIS portal.

This project, known as DADI (Digital Application Dataset Integration), is intended to be used for both CAP (Centrally Authorised Products) & NAP (Nationally Authorised Products) applications to make the future of form-filling and submission-handling more efficient at an EU level.

The Human medicinal product Variation application form will be the first to go live in DADI format. Every person involved in drafting an eAF will need to have an EMA account and user access. Companies who use consultants to prepare eAFs will need to make sure that they assign an EMA role to the consultant.

The next stages of DADI will cover the

  • Veterinary variation application form
  • Initial MAA form for Human and Veterinary products
  • Renewal form for Human and Veterinary products

 How will it work?

  1. The eAF will be filled in using the new eAF portal (via user interface).
  2. The user will then finalise the eAF by generating a PDF rendition
  3. This PDF version must still be included in the eCTD submission, as before.
  4. It will not be possible to submit the form directly from the eAF portal

 When will it happen?

As outlined in the EMA roadmap (link provided below) the two immediate key deliverables are as follows:

Key deliverables Go-Live Time Lines
Year Quarter
Launch of Human variations web-form (parallel use of old and new variation forms as part of a Transition period) 2022 Q4 (October)
Use of variation web form only 2023 Q2 (April)

It is important for all industry stake-holders to keep up to date with the development of these new web-based forms by consulting the EMA website for updates at the various launch stages.

Where can I find information?

  • DADI Network Project Webinar – 18/01/2022 – Live broadcast is available here.
  • The updated DADI roadmap, including key milestones, is available here.
  • The updated version of the DADI Questions and Answers documents is available here.
  • The “Common factors in the Fast Healthcare Interoperability Resources (FHIR) data standard for Art57(2) and eAF”documents are available in the following link.

The project will be implemented in phases, through a set of projects known as SPOR (Substances, Products, Organisations and Referentials) data management services for Human products. The Union Product Database will be the source of data for Veterinary products.

What is SPOR?

SPOR datasets Description of data types Status
Substance Management Services (SMS) Harmonised data and definitions to uniquely identify the ingredients and materials that constitute a medicinal product. Under Development
Product Management Services (PMS) Harmonised data and definitions to uniquely identify a medicinal product based on regulated information (e.g. marketing authorisation, packaging and medicinal information). Under Development
Organisations Management Services (OMS) Data comprising organisation name and location address, for organisations such as marketing authorisation holders, sponsors, regulatory authorities and manufacturers. Operational
Referentials Management Services (RMS) List of terms (controlled vocabularies) to describe attributes of products, e.g. lists of dosage forms, units of measurement and routes of administration. Operational

Once the above PMS and SMS are in place, pharmaceutical companies should start preparing to replace their current data submission format in Article 57 Database from the eXtended EudraVigilance Product Report Message (XEVPRM) format to the new ISO IDMP compatible format (HL7 FHIR). Webinars and training will be provided by EMA in due course.

 What do Marketing Authorisation Holders have to do at this stage?

  • Marketing authorisation holders need to check their data in SPOR (OMS) to ensure it is accurate and up to date. For CAPs the use of OMS data in the current eAF is already mandatory.
  • Marketing authorisation holders with authorised MA(s) need to check their data in Article 57 database (xEVMPD) to ensure it is accurate and up to date.

 Should you need any support at this stage in getting ready for the new Application Form format please feel free to contact us & the Ivowen team will be here to help.

Written by Marian Winder

marian 150x150 1

EMA

Are you ready for the Clinical Trials Information System (CTIS) implementation?

The Clinical Trials Information System is a harmonised and simplified end-to-end single entry point for clinical trials information in the European Union and in the European Economic Area and will go live on 31 January 2022.

As a single entry point, it will be used for the submission, management and assessment of information throughout the life cycle of a clinical trial. The exchange of information between sponsors and Member States will be fully electronic.

In a recent EMA training webinar, the EMA advise the following to prepare for the CTIS go live date:

EMA has launched the CTIS training webpage containing a substantial amount of training materials and information for the users and organisations to facilitate their preparedness.

Should you need any support in clinical trial application just contact us and the Ivowen team will be here to help.

Written by Fiona Downey

Capsule Biological medicine 25 08 20

Guidance to avoid Nitrosamines in Biological Medicines

Following the outcome of the Article 31 referral on sartans with a tetrazole ring and the knowledge acquired on N-nitrosamines in medicinal products, EMA together with the EU Network and international partners has continued the review to identify if there are any consequences for medicinal products outside the class of sartans.

Taking into account that N-nitrosamines have been found in sartans with a tetrazole ring but also in other API/medicinal products in September 2019 the CHMP’s opinion was sought by the EMA’s Executive Director in accordance with Article 5(3) of Regulation (EC) No 726/2004 regarding the detection, management and prevention of presence of N-nitrosamines in medicinal products for human use.

The CHMP adopted a scientific opinion in June 2020, which recommended reviewing biological medicines in addition to medicines containing chemically synthesised active substances.

The risk of presence of nitrosamines must be evaluated by the MAHs/Applicants. In case of risk, confirmatory testing must be performed.

  • A risk evaluation/risk assessment for the presence of nitrosamines must be submitted for new marketing authorization applications at the time of submission, and for already authorized medicinal products containing chemically synthesised active pharmaceutical ingredients (APIs) as per the ‘call for review’:

https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-information-nitrosamines-marketing-authorisation-holders_en.pdf

And for biological medicinal products in a similar exercise, as per instructions to be published in a ‘Questions and Answers document’:

https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-questions-answers-information-nitrosamines-marketing-authorisation_en.pdf

  • The approach for risk evaluation/risk assessment should cover manufacturing processes of active substance and finished product in consideration of the root-causes, and subsequent confirmatory testing in the finished product in case a risk is identified
  • Although the overall risk of presence of nitrosamines in biological medicinal products is considered very low, the following risk factors should be taken into consideration:
    • Biologicals containing chemically synthesized fragments, where risk factors similar to chemically synthesized active substances are present,
    • Biologicals using processes where nitrosating reagents are deliberately added,
    • or those packaged in certain primary packaging material, such as blister packs containing nitrocellulose.

For details see CHMP – Assessment Report: https://www.ema.europa.eu/en/documents/referral/nitrosamines-emea-h-a53-1490-assessment-report_en.pdf

If you need any clarification or support to help implement the responsibilities of an MAH with regard to Nitrosamines reporting contact us and Ivowen will gladly assist you in a timely manner.

Written by Nanda Naik

Nanda Naik

Water image 10 08 20

New pharmaceutical water quality guideline from February 2021

In 2018 the EMA had a public consultation (15th Nov 2018 – 15th May 2019) on draft guidance for industry on the pharmaceutical use of different grades of water in the manufacture of active substances and medicinal products. This consultation has resulted in an update to the old 2002 guidelines and the new guideline will come into effect from February 2021. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-quality-water-pharmaceutical-use_en.pdf

Within the guideline, it is stated that the European Pharmacopoeia (Ph. Eur.) has set quality standards for three grades of water: water for injections (WFI), purified water and water for preparation of extracts. EMA also notes that potable water, while not covered by a pharmaceutical monograph, “is the prescribed source feed water for the production of pharmacopeial grade waters,” and must comply with the regulations on water intended for human consumption of a quality equivalent to that defined in Directive 98/83/EC or laid down by the competent authority.

The guideline itself provides recommendations for the minimum acceptable quality of water to be used for different uses and applications, including the manufacture of sterile and nonsterile medicinal products, active substances and water used for cleaning and rinsing equipment and container/closures for medicinal products.

The note for guidance has been updated to reflect the following changes in the European Pharmacopoeia:

  • revised monograph for Water for Injections (0169) allowing the possibility to use methods other than distillation for producing water of injectable quality (this change brings the Ph. Eur. more closely in line with the US Pharmacopeia and the Japanese Pharmacopoeia, allowing production of WFI by distillation or by a purification process proven “equivalent or superior to distillation”, and “by distillation or by reverse osmosis and/or ultrafiltration”, respectively);
  • new monograph for Water for preparation of extracts (2249);
  • suppression of the monograph for Water, highly purified (1927).

The guideline has also been updated to reflect current expectations for the minimum acceptable quality of water used in the manufacture of active substances and medicinal products for human and veterinary use.

The guideline can be read in conjunction with the questions and answers on production of water for injections by non-distillation methods – reverse osmosis and biofilms and control strategies https://www.ema.europa.eu/en/documents/other/questions-answers-production-water-injections-non-distillation-methods-reverse-osmosis-biofilms_en.pdf and the comments received on the draft guideline https://www.ema.europa.eu/en/documents/comments/overview-comments-received-draft-guideline-quality-water-pharmaceutical-use-ema/chmp/cvmp/qwp/496873/2018_en.pdf

Written by Emily Fletcher

Emily Fletcher

Need help with all the regulatory jargon?

Check out our updated GLOSSARY OF ABBREVIATIONS AND ACRONYMS.

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