Post-Authorisation

Variations, Renewals, Marketing Authorisation Transfer

Following an initial Marketing Authorisation (MA), there are various post-authorisation procedures that are necessary in order to maintain the licence or to incorporate any changes that are required. The three key procedures are  

• Variations
• Renewals
• Marketing Authorisation Transfers

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• Variations

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  Variations to an MA are required for a number of reasons; additional data or information on the product may become available or manufacturing changes may be necessary. These changes are implemented via a specific classification of variation procedures, depending on the complexity of the change, and are subject to the approval of the European Medicines Agency (EMA) or National Competent Authority (NCA). The classification of variations (Type IAIN, type IA, type IB and type II variations, Extension of an MA, or Article 61(3) notification) determines the length of the variation procedure and the level of assessment that is required.

  How can we help?

  The EUDRAC team has extensive experience in writing and submitting variation procedures for a wide range of products; we provide support to our clients for:

  • Variation classifications and data requirements
  • Filing strategy (e.g. grouping, worksharing)
  • Document writing and publication of initial application and Request for Further Information (RFI) 
  • Submission of variation and RFI
  • Follow up activities incl. Article 57(2) database maintenance

• Renewals

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  An initial MA is valid for five years and then has to be renewed (Conditional MAs granted under Article 14(7) of Regulation (EC) No 726/2004 have to be renewed annually). The renewal application has specific documentation and submission requirements. The application undergoes a formal assessment procedure during which there may be an RFI before a renewal is granted.

  How can we help?

  EUDRAC regularly submit renewal applications for its clients and provide procedural support when an earlier renewal is an option.

   

• Marketing Authorisation Transfers

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  An MA Transfer is the procedure by which the MA is transferred to a new MAH; this is a different person/legal entity. For licences granted via the DeCentralised Procedure (DCP) or Mutual Recognition Procedure (MRP) such a transfer of ownership is granted nationally and the regulatory requirements and timelines are based on the national legislation in the Member States (MS). For licences granted via the Centralised Application Procedure (CAP), the transfer is granted via the EMA.
  There are often consequential changes due to an MA Transfer e.g. name change of the medicinal product, submission of the summary of the pharmacovigilance system of the new MAH; if these changes are subject to the variation regulations, they then have to be implemented by the relevant variation procedures.

  How can we help?

  EUDRAC has completed MA Transfers for many of its clients and has also prepared;the subsequent variations so that they have been implemented with minimal disruption to the marketing of the product.

   

• Publishing

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  In order for efficient production and review of documents transmitted between Agencies, NCAs and the pharmaceutical industry, standardisation is required. The Common Technical Document (CTD) describes the organisation of modules, sections and documents to be used, by MAAs and MAHs, for a medicinal product in each country of the European Union (EU), Japan and the United States (US). 

  How can we help?

  For every module of the CTD, EUDRAC has specialist and experienced writers, reviewers and publishers. We undertake the management, authoring, publishing and submission of a complete MAA; including any module adaptations for the US and other regions. 
  EUDRAC’s established review and tracking systems ensure the writing and publishing of the initial MAA and future responses and procedures are fully compliant and of exceptional quality.
  Additional services include: gap analyses; Package Leaflet User Testing; artwork, braille and Linguistic Review.

  Please see our Publishing page for more details.

Linguistic Review

Linguistic Review is the translation and review process for all new and updated Product Information (PI) that is required post-opinion for all products authorised by the CAP. This is a standardised 25-day process, covering 25 European languages and is required for new MAAs and any variations to the MA that affect the PI.

How can we help?

EUDRAC have very well-established systems and procedures for Linguistic Reviews. Our Labelling group work with a translation team who are experienced and trained in the requirements of the EMA Working Party for Quality Review of Documents (QRD) which include QRD template requirements, policies, guidance, as well as all standard terms and formatting conventions. We also publish and submit the translations to the MS and QRD group throughout the procedure.

EUDRAC have now conducted over 140 Linguistic Reviews following all types of regulatory procedures.

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• Translations

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  EUDRAC work with a translation team who have been trained to prepare swift, accurate translations according to the QRD convention. They understand the tight timelines of the Linguistic Review procedure and the need to liaise with the client and the MS at the different stages of the procedure.

  How can we help?

  EUDRAC undertake Linguistic Review for the complete spectrum of regulatory procedures; we often work at very short notice and always meet the prescribed timelines. We have developed procedures for all types of Linguistic Review and our procedures are very streamlined. EUDRAC routinely conduct Regulatory Intelligence updates and so are immediately aware of any changes in the requirements of the Linguitic Review procedure.

  EUDRAC also produce translations in all EU languages for associated educational materials and other regulatory documents.

• Publishing

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  In order for efficient production and review of documents transmitted between Agencies, NCAs and the pharmaceutical industry, standardisation is required. The Common Technical Document (CTD) describes the organisation of modules, sections and documents to be used by MAHs and MAAs for a medicinal product in each of the countries of European Union (EU), Japan and the United States. 

  EUDRAC have a full Publishing Service for all regulatory and PV procedures; we also manage electronic submissions to NCA and the EMA.

  How can we help?

  EUDRAC continuously conduct Linguistic Review Procedures for our clients; for many of them, we do this as part of the full Labelling Service that we provide for them over their product lifecycle.

  EUDRAC routinely undertake the entire Linguistic Review Procedure on behalf of our clients and so publish the final Day 25 translations as they appear on the EMA website; we have developed software applications to apply the specific formatting requirements to all word and pdf documents.

• QRD

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  The EMA Working group on Quality Review of Documents (QRD) develop specific templates for the PI. These are updated on a regular basis with the purpose of maximising the linguistic accuracy and clarity of the information and scientific terminology contained within the PI. 

  How can we help?

  The EUDRAC Labelling team has a very high level of expertise and experience in dealing with the the linguistic requirements of the PI. Our translators are fully trained in the QRD requirements. EUDRAC also perform a Regulatory Intelligence Service so the Labelling team is always aware of any updates that are required for the Linguistic Review procedure.

Product Information and Labelling

The Product Information (PI) is the core document providing inforamtion on the medicinal product for the physician and the patient. It is a pivotal part of the MA and defines all Labelling, Educational Material, Advertising and Prescribing Information on the product. During the lifecycle of a medicine, any changes required to the MA are implemented via different regulatory procedures and many of these will affect the PI, which has to be updated as part of the procedure.

How can we help?

• The EUDRAC Labelling team fully manage and implement updates to the PI for its clients; this includes implementing local labelling requirements.
• We also manage any translation requirements and co-ordinate the Linguistic Review procedure when this is required.

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• Packaging Review

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  Packaging review includes the check of the labelling for packaging materials to make absolutely sure that it contains all the required details for accurate identification, storage and delivery of the medicinal product. In addition, the Package Leaflet provides patients/users with important information on the application and safety of the medicine. During the lifecycle of a medicinal product, any changes to the MA or safety information and changes in the legal requirements may affect the packaging which has to be revised accordingly.

  How can we help?

  • EUDRAC produce and review artwork for its clients. We have established the use of validation software to ensure complete accuracy is achieved during any review process.
  • EUDRAC consultants keep their expertise up-to-date with the current national and European laws and ensure all packaging artwork complies with legal requirements including local specifications.
  • We manage packaging review processes in compliance with the client’s procedures and liaise specifically with the client's team members who are responsible for medical information and packaging release.

CMC & Quality

After an MA has been granted, the MAH is responsible for maintaining the dossier and keeping it up-to-date. Updates may be required in relation to any new legislation or guidelines that are published and also any new information and data that become available on the product, as well as any changes that are made to the manufacturing process.

How can we help?

EUDRAC manage the complete range of post-authorisation Chemistry Manufacturing & Control (CMC) and Quality activities for its clients; the CMC team which works across our offices (in UK, France and Germany) work on a wide variety of post-approval CMC projects, from assessment of manufacturing site change controls to project management of complex technology transfers such as the switch to a new finished product manufacturing site. The team has experience with a wide range of different dosage forms, encompassing immediate and modified-release tablets and capsules, oral solutions, transdermal patches, sterile ophthalmic and auricular formulations, topical aerosols and solutions for intravenous administration. We work on many different small molecules and complex biological drug substances. 

A key area in in CMC is providing a link between the manufacturing site and the MA. At EUDRAC we conduct a thorough assessment of manufacturing site change controls for any regulatory impact and provide advice on new regulatory requirements. We are then able to propose a suitable regulatory strategy to implement necessary changes to the dossier. For many of our clients, we also author the updated sections of the dossier and publish and submit them via the appropriate regulatory procedure.

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• Strategic Development of Module 3

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  A well written Module 3 containing information on CMC and Quality can offer significant benefits in the post-authorisation phase of the product lifecycle. A key area of benefit is a potential reduction in the number of CMC changes that will have a regulatory impact; these changes can arise from diverse sources such as manufacturing sites and the suppliers of the active ingredient, excipient and packaging.

  How can we help?

  If the implementation of post-approval CMC changes is not well-managed it can adversely impact on commercial supplies. Updates to CMC sections of the dossier can also result in changes to other areas of the dossier such as the PI; an appreciation of these aspects is an consideration when assessing CMC changes and defining a strategy for implementation.

   

• Lifecycle Management

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  Changes to medicinal products in the EU are introduced via the relevant variation procedures. These changes are subject to the approval of the EMA or the NCA of the concerned MS and they are classified according to different categories (Type IAIN, type IA, type IB and type II variations, Extension of an MA or Article 61(3) notification); the classification depends on the level of risk to public health and the impact on the quality, safety and efficacy of the medicinal product concerned.

  How can we help?

  The EUDRAC team has a broad experience in the management of post-approval changes such as variations and provides its clients with regulatory, procedural and technical support throughout the procedures including:

  • Variation classification and advice on data requirements
  • Variation filing strategy (e.g. grouping, worksharing)
  • Interaction with EMA or NCA
  • Document writing, compilation of application (e.g. eAF) and publishing (NeeS/eCTD)
  • Paper and eSubmissions (e.g. CESP, EMA Web Client, National Portals)
  • Follow up activities incl. Article 57(2) database maintenance

  EUDRAC’s Regulatory Intelligence Service ensures that our Consultants are always aware of the latest changes to regulatory guidelines which are relevant to all aspects of lifecycle management. The EUDRAC team always strives to provide its clients with a dossier that is both fit for submission in the current regulatory climate, but that has also considered potential changes that may be implemented in the future; this serves to minimise the work and cost of maintaining the dossier throughout the lifetime of a product.
   

• CMC Compliance: Module 3 vs Current Manufacturing Site Practices

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  Ensuring regulatory compliance and uninterrupted commercial supplies of a product is critical for any company. One of the most frequently observed issues, particularly for established products, is a divergence between actual manufacturing site practices and the registered details contained in Module 3, the CMC section, of the CTD dossier. Examples of this include the method of manufacture, analytical test methods and specification limits applied to excipients or the active substance. These can be caused by updates in compendial monographs, changes introduced by suppliers, a poorly written CMC section, or bu the company failing to ensure that regulatory commitments are fulfilled.

  How can we help?

  EUDRAc undertakes gap analyses for its clients to compare the currently registered dossier against technical documentation from the manufacturing, packaging and QC testing sites.

  The EUDRAC CMC team works to identify any differences between the different information sources. It then confirms if these discrepancies have any regulatory impact and proposes remediation strategies to ensure that required changes are implemented at a site level to ensure compliance. If this is not possible, it will propose a regulatory submission strategy to update the dossier in line with current practices. When reviewing the dossier, the team also takes the opportunity to propose additional updates to minimise further post-approval regulatory submissions. EUDRAC also have a Regulatory Intelligence Service to monitor and communicate all relevant regulatory changes to our teams and to our clients.

   

• Technical Writing and Authoring

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  The link between manufacturing site operations and Regulatory Affairs functions is crucial during product development and of equal importance in the post-authorisation phase. It is often necessary to review manufacturing site documentation or change controls, assess the regulatory impact and to extract a summary of the key information into a format suitable for regulatory submission.

  How can we help?

  The EUDRAC CMC team ensure the links between manufacturing and regulatory functions are clear and relevant when it is involved in authoring technical reports and the CTD. Many of our Consultants have prior experience gained via Research & Development roles in industry prior to a career in Regulatory Affairs.

  The CMC team has the necessary technical expertise required to review raw data or reports and extract critical information, together with the knowledge of relevant regulatory guidelines in order to summarise the information in a format ready for submission. We have previously prepared complete Module 3 dossier sections from manufacturing site documentation including pharmaceutical development reports, process validation summaries and analytical method summaries or validation reports.

   

Promotional & Educational Material

The promotion of a medicinal product starts with the initial press release following its authorisation.  Promotional material and activities are strictly regulated in all EU countries and the rules and requirements vary from country to country, e.g. some countries require that the material is reviewed by the NCA before it is used. Most promotional material needs to include Prescribing Information which also has to comply with specific national requirements.

Educational materials for the patient and physician are often required as additional Risk Minimisation Measures (RMM) to ensure the medicinal product is used correctly and safely.  These RMM must be clearly distinguished from promotional material. Educational material content, presentation and the mode of distribution also need to be approved by the NCA.

How can we help?

EUDRAC currently assists its clients to write and review both promotional and educational materials for their products.  We have Partners in all EU countries who prepare translations, implement local requirements and facilitate NCA review when this is required.

• We perform the regulatory review of promotional and educational material as part of our clients’ multi-disciplinary medical teams
• We implement local requirements for European materials
• We co-ordinate pan-European submission of materials to the NCAs

Clinical Trial Redaction - Policy 0070

The EMA has launched several initiatives to increase the transparency of information on medicinal products; there is growing demand from stakeholders for additional transparency, not only about the EMA’s deliberations and actions, but also about the clinical data on which regulatory decisions are based.

The EMA has taken the initiative to develop Policy 0070 on publication of clinical data in accordance with article 80 of Regulation (EC) No 726/2004. As a consequence, all MAAs in the EU must now publicly publish their clinical trial data following the final opinion of the Committee for Medicinal Products for Human Use (CHMP) whether it be positive or negative.

Clinical data comprises:

• Clinical overview
• Clinical summaries
• Clinical study reports (all phases)

Prior to publishing these data, the applicant must propose redactions of certain information to the EMA i.e. personal information and confidential company information.  The EMA then review these proposals for redactions and the detailed justifications made by the applicant.  Upon finalisation of the procedure the EMA will upload the information to the clinical trial data website.

How can we help?

EUDRAC has the capabilities and tools to aid applicants in the process of redacting the data. We utilise sophisticated software to scan for pre-defined phrases or patterns to highlight potential redactions, which reduces time and costs. Following that, our experienced consultants, who are very familiar with clinical data, review the redactions and include any additional redactions required. Using this process, the bulk of the redactions can be done in minimal time, whilst allowing for a thorough review by highly trained consultants.