ema Archives - European Industrial Pharmacists Group (EIPG)

A concept paper on the revision of Annex 11


This concept paper addresses the need to update Annex 11, Computerised Systems, of the Good Manufacturing Practice (GMP) guideline. Annex 11 is common to the member states of the European Union (EU)/European Economic Area (EEA) as well as to Read more

What happens after IP loss of protection


by Giuliana Miglierini What does it happen under a competitiveness perspective once intellectual property (IP) protection for medicinal products expired? And what is the impact of the new entries on generics and biosimilars already in the market? The role of competitor Read more

The FDA warns about the manufacture medicinal and non-pharmaceutical products on the same equipment


by Giuliana Miglierini A Warning Letter, sent in September 2022 by the US FDA to a German company after an inspection, addresses the possibility to use the same equipment for the manufacturing of pharmaceutical and non-pharmaceutical products. The FDA reject Read more

A concept paper on the revision of Annex 11

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This concept paper addresses the need to update Annex 11, Computerised Systems, of the Good Manufacturing Practice (GMP) guideline. Annex 11 is common to the member states of the European Union (EU)/European Economic Area (EEA) as well as to the participating authorities of the Pharmaceutical Inspection Co-operation Scheme (PIC/S). The current version was issued in 2011 and does not give sufficient guidance within a number of areas. Since then, there has been extensive progress in the use of new technologies.

Reasons for the revision of Annex 11 include but are not limited to the following (in non-prioritised order):

  • The document should be updated to replace relevant parts of the Q&A on Annex 11 and the Q&A on Data Integrity on the EMA GMP website
  • An update of the document with regulatory expectations to ‘digital transformation’ and similar newer concepts will be considered
  • References should be made to ICH Q9
  • The meaning of the term ‘validation’ (and ‘qualification’), needs to be clarified
  • Guidelines should be included for classification of critical data and critical systems
  • Important expectations to backup processes are missing e.g. to what is covered by a backup, what types of backups are made, how often backups are made, how long backups are, retained, which media is used for backups, or where backups are kept
  • The concept and purpose of audit trail review is inadequately described
  • Guidelines for acceptable frequency of audit trail review should be provided
  • There is an urgent need for regulatory guidance and expectations to the use of artificial intelligence (AI) and machine learning (ML) models in critical GMP applications as industry is already implementing this technology
  • FDA has released a draft guidance on Computer Software Assurance for Production and Quality System Software (CSA). This guidance and any implication will be considered with regards to aspects of potential regulatory relevance for GMP Annex 11

The current Annex 11 does not give sufficient guidance within a number of areas already covered, and other areas, which are becoming increasingly important to GMP, are not covered at all. The revised text will expand the guidance given in the document and embrace the application of new technologies which have gained momentum since the release of the existing version.

If possible, the revised document will include guidelines for acceptance of AI/ML algorithms used in critical GMP applications. This is an area where regulatory guidance is highly needed as this is not covered by any existing regulatory guidance in the pharmaceutical industry and as pharma companies are already implementing such algorithms.

The draft concept paper approved by EMA GMP/GDP IWG (October 2022) and by PIC/S (November 2022) and released for a two-months consultation until 16 January 2023.



ACT EU’s Workplan 2022-2026

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by Giuliana Miglierini

The implementation phase of the Accelerating Clinical Trials in the EU (ACT EU) initiative, launched in January 2022 by the European Commission, started with the publication of the2022-2026 Workplan jointly drafted by the Commission, the European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA).

The final target is to renew how clinical trials are designed and managed, so to improve the attractiveness of Europe for clinical research and the integration of results in the current practice of the European health system.

The 2022-2026 Workplan details the actions and deliverables planned according to the ten priorities identified by ACT EU. The drafting of the document took as primary reference also the recommendations of the European Medicines Regulatory Network (EMRN) strategy to 2025 and the European Commission’s Pharmaceutical Strategy for Europe.

Steps towards the full implementation of the CTR

The first priority of action should see the completion by the end of 2022 of the mapping of already existing initiatives within the EMRN and ethics infrastructure. This exercise represents a fundamental step to achieve a detailed picture of the current clinical trials regulatory landscape, characterised by the presence of various expert groups working in different areas.

The results of the mapping will form the basis to plan and implement a new strategy for the governance of the entire framework governing clinical trials, including the clarification of roles and responsibilities to the Network and its stakeholders. The expected outcome is the rationalisation and better coordination of the work done by different expert groups and working parties, as reflected by a new regulatory network responsibility assignment (RACI) matrix. The analysis and setting up of the new framework should start from the core governance bodies (Clinical Trials Coordination and Advisory Group (CTAG), Clinical Trials Coordination Group (CTCG), Commission Expert Group on Clinical Trials (CTEG) and Good Clinical Practice Inspectors Working Group (GCP IWG)), to then extend to other parts of the Network further.

The full implementation of the Clinical Trials regulation (Reg. (EU) 536/2014) by mean of the launch of monthly KPIs tracking of the planned activities is another key action. A survey to identify issues for sponsors and the consequent implementation of a process to prioritise and solve them are planned for the second half of 2022. The beginning of 2023 should see the launch of a scheme to better support large multinational clinical trials, particularly those run in the academic setting. One year later, at the beginning of 2024, a one-stop shop to support academic sponsors should also be launched.

An important action for the success of ACT EU should see the creation of a multi-stakeholder platform (MSP) to enable the interaction and regular dialogue of the many different stakeholders working in the field of clinical trials under different perspectives, both at the European and member state level. The platform should be launched by Q2 2023, with the first events run under its umbrella planned for Q3 and is expected to help in the identification of key advances in clinical trial methods, technology, and science.

Methodological updates in clinical trials

Another key step in the renewal of the European framework for clinical trials is linked to the updating of the ICH E6(R2) guideline on “Good Clinical Practice” (GCP). A targeted multi-stakeholder workshop on this theme is planned for Q1 2023, while the resulting changes should be implemented in EU guidance documents by Q3 2023. New GCPs should take into better consideration the emerging designs for clinical trials and the availability of new sources for data and are expected to “provide flexibility when appropriate to facilitate the use of technological innovations in clinical trials”. This action also includes the development of a communication and change management strategy to support the transition to the revised GCP guideline, and the updating of other relevant EU guidelines impacted by the change.

The opportunity to introduce innovative clinical trial designs and methodologies shall be addressed starting from decentralised clinical trials (DCT), with the publication of a DCT recommendation paper by the end of 2022. A workshop on complex clinical trials should be also organized to discuss issues linked to study design, such us umbrella trials and basket trials or master protocols. New technologies may support innovative approaches to the recruitment of eligible study participants and new ways to capture data during clinical trials. The publication of key methodologies guidance is an expected deliverable, together with a improved link between innovation and scientific advice.

A new EU clinical trials data analytics strategy is expected to be published by the end of 2022, while the first half of next year should see the development of a publicly accessible EU clinical trials dashboard and a workshop to identify topics of common interest for researchers, policy makers, and funders. These activities are targeted to fully exploit the opportunities offered by data analytics, so to identify complex trends from the large base of data about clinical trials collected by the EMRN. The existence of multiple data sources is a main barrier currently affecting the possibility to access, process and interpret these data.

Another priority is to plan and launch a targeted communication campaign to engage all enablers of clinical trials, including data protection experts, academia, SMEs, funders, Health Technology Assessment (HTA) bodies and healthcare professionals. Up to 2024, this action will also support sponsors in remembering the importance of training linked to the application of the CTR and the mandatory use of the Clinical Trials Information System (CTIS). All other communication needs across all priority actions will also be handled under this action.

Scientific advice, safety monitoring and harmonised training

The current framework sees the involvement of different actors who interact with sponsors at different stages of product development to provide them with scientific advice. A simplification of the overall process should be pursued by grouping of key actors in clinical trials scientific advice in the EU, “with the aim of critically analysing the existing landscape in line with stakeholder needs”. The Workplan indicates several pilot phases should be run to identify the better way to address this topic, which should benefit especially academic or SMEs sponsors that may have less experience of regulatory processes. Planned activities include a enhanced intra-network information exchange, the running of a survey among stakeholders and the operation of a first pilot phase by Q4 2024, to then optimise and expand the advice process upon results.

The establishment of clinical trial safety monitoring is another central theme of action, that should see member states involved in a coordinated work-sharing assessment. Key activities should include the identification of safe CT KPIs by the end of 2022 and a review of IT functionalities for safety, and it will be run in strict connection with the EU4Health Joint Action Safety Assessment Cooperation and Facilitated Conduct of Clinical Trials (SAFE CT). Training of safety assessors and the development of a harmonised curriculum thereof shall be also considered, as well as the alignment of safety procedures for emerging safety issues potentially impacting clinical trials.

The development of a training curriculum informed by regulatory experience should support the creation of a renewed educational ‘ecosystem’ characterised by bidirectional exchanges to enable training on clinical trials. This action is target mainly to better engage universities and SMEs, and it should include also training provided by actors other than the regulatory network.


Trends in Drug delivery and Formulation

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by Giuliana Miglierini

According to the 2021 Global Drug Delivery & Formulation Report, signed by Kurt Sedo, Vice President Operations, PharmaCircle LLC and published in a three-part series on Drug Development & Delivery, the Covid-19 pandemic seems to have had little impact on the regulatory approvals of new dosage forms and formulations. A positive sign from the pharmaceutical ecosystem, considering the difficulty to maintain normal operative conditions, the issues with international supply chains and the many hurdles to regulatory activities posed by the emergency.

According to Kurt Sedo, products newly approved by the FDA and based on new chemical entities have been the less affected, as they reflect a larger benefit for patients. On the other hand, are generics, together with new dosage forms and new formulations. Simple dosage forms continue to represent the great part of new approvals, while biologics prevail in terms of NCEs for injection.

The FDA approved in 2021 a total of 31 new products under the Biologics Licence Application (BLA) procedure, slightly more than in the previous two years. The increase is mainly linked to the higher number of vaccines and cell and gene therapies, while approval of biologic medicines maintained stable.

Approval trends by category of product

A marked decrease characterised Abbreviated New Drug Approvals (ANDA) (627 in 2021, vs 903 in 2020 and 962 in 2019). New Drug Applications (NDA) also slightly decreased. Analysing this category by type of product, the decrement is marked for new molecular entities and new dosage forms, while an opposite trend can be observed for new active ingredients and new formulations/new manufacturers.

As for administration route, the report indicates a marked prevalence of injection in all geographic areas (US 55%, EU 36%, JP 59%); oral drugs also continue to be highly represented. The author warns about the difficulty to reliably interpret the figures for European and Japanese approvals, as “The European Medicines Agency (EMA) approvals relate only to specific classes of pharmaceutical products and don’t capture the full range of products. The Japanese Pharmaceutical Medical and Medical Devices Agency (PMDA) published approvals are hard to access and properly assess”.

Looking more in detail at the injection route of administration, intravenous injectable products remain the leading category (US 39%, EU 38%, JP 38%), followed by subcutaneous injection. Simple solutions with or without a dedicated delivery device were the most commonly approved injectable simple dosage forms in 2021. Tablets and capsules remained the favoured oral dosage forms, while granules and pellets are especially represented in paediatric formulations.

Small molecules are the more represented category of active ingredients (US 64%, EU 74%, JP 52%), followed by antibodies and peptides; this last category of API offer the advantage of a possible formulation as non-injectable dosage form.

A deeper insight on the main approvals

Part 2 of the series debates the main products approved in 2021. The trend hints to a higher interest towards products and technologies targeted to wider patient populations and more diverse applications. According to Sedo, mRNA and gene therapy platforms have decrease their appealing due to need of validation for applications different than vaccines in the first case and safety and durability concerns in the latter.

Skytrofa (Ascendis Pharma) is a pegylated form of the growth hormone lonapegsomatropin-tcgd for injection or subcutaneous administration, using the dedicated rechargeable and reusable auto-injector. The weekly administration is the main advantage, overruling the need of daily injections.

Invega Hafyera (Janssen Pharmaceuticals), containing paliperidone palmitate as the active ingredient, has been approved in the US to treat adult schizophrenia by intramuscular injection every 6 months. Despite the parent molecule has already lost its exclusivity, Kurt Sedo highlights the remarkable lifecycle management of the Invega family of products, which allowed Janssen to maintain significant revenues for almost 20 years.

Tyrvaya (Oyster Point Pharma) is indicated to treat dry eye using the nasal delivery route. The formulation containing varenicline is administered using the Aptar’s CPS Spray Pump, representing the first approval for this type of technology platform. The possibility to overcome issues in treating ocular conditions connected to the difficulty many patients may experience with the administration of classical ocular drops is the main point of innovation.

Acuvue Theravision (Johnson & Johnson Vision Care) are contact lenses firstly approved in Japan and containing ketotifen to treat allergic conjunctivitis. In this case too, the approach may be replicated to administer other types of drugs in the eye. Issues may be represented by the difficulty of patients in using contact lenses and the need to stabilise the active ingredient to prevent leaching.

Cabenuva Kit (ViiV Healthcare) contains the combination cabotegravir – rilpivirine to treat HIV infection. Firstly, approved in Canada, it is administered monthly by intramuscular injection. Long-acting formulations can prove interesting to overcome compliance issues which may result in serious consequences for patients, as already proved in the case of hepatitis.

The monoclonal antibody Susvimo (anibizumab; Genentech) is formulated as a refillable ocular implant to treat wet acute macular degeneration. After implantation, the intravitreal injections using the Port Delivery System (PDS) occur every 6 months.

Other relevant technologies mentioned among new 2021 approvals include the Medicago Virus Like Particles (VLP) technology, which uses tobacco-related plants as bioreactors to produce noninfectious VLP that mimic the target virus, and LICA technology (Ionis), based on Ligand Conjugated Antisense (LICA) to favour the interaction of ligands and their respective receptors.

The Denali Transport Vehicle (TV) platform uses specific antibodies, enzymes, oligonucleotides, or proteins to link to the transferrin receptor of the blood vessel wall in the brain, thus providing a way to pass the blood-brain barrier by endocytosis.

MedRing (Ligalli) is a smart vaginal insert containing a miniaturised liquid formulation drug container with pump, battery, antenna, electronics, and sensors to monitor various biometric parameters (e.g. glucose or ovulation status).

Q-Sphera (Midatech Pharma) provides a bioencapsulation process using a microfluidic device to obtain discrete droplets without use of surfactants, toxic solvents, biphasic mixtures, shear, or heat forces.

Products in the pipelines

Part 3 of the series addresses the expectations for new approvals of products still in the pipelines The trend shows a higher percentage of early-stage products (research and pre-clinical phases), which is attributed to the higher interest of investors towards new companies able to fill the pipelines with early stage projects. The impact of Covid-19 has proved to be more relevant on projects at the clinical stage.

Small molecules still represent the main focus of development (59% in 2021/22), even if a drop has been observed from values recorded in 2015/16 (66%). Biological products may pose issues due to their highly speculative nature, suggests the report, while oligonucleotide and RNA products still represent only the 2% of the total in the pipelines; a more mature technology are antibodies (12%).

Cancer continues to be the leading therapeutic area of development, followed by infectious diseases and drugs to treat the central nervous system. The report indicates a very high attrition rate for anti-infectives under development, while many anti-cancer therapeutics in the pipelines may be me-too products pursuing validated therapeutic mechanisms. As seen above, injectable formulations maintain the leading position also for products under development (52%), followed by oral formulations.


EMA’s Industry stakeholders group (ISG)

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by Giuliana Miglierini

The Industrial Stakeholder Group (ISG) is a new initiative recently launched by the European Medicines Agency (EMA) in order to favour the dialogue with the industrial stakeholders. The first meeting of the ISG, the 21 June 2022, focused on the mandate of the Group and on the three priority topics to be addressed during the pilot phase: the Emergency Task Force (ETF), the issue of shortages of medicines and medical devices and the medical device expert panels.

The initiative is part of the activities planned by EMA for the implementation of its extended mandated, as for Regulation (EU) 2022/123.

The mandate of the ISG

The main scope of the ISG is to provide a dedicate forum to capture the industrial point of view and proactively inform on open issues during the implementation of EMA’s extended mandate. The ISG will focus on human medicines and will complement other existing tools, such as industry platform meetings, bilateral meetings, topic or project related meetings. The outcomes obtained from the pilot phase will form the basis of an analysis to evaluate if to extend the scope to other initiatives.

The Chair of the ISG is nominated by the Agency’s Executive Director; the group is composed by one member and one alternate from selected EU industry organisations relevant to the subject of discussion, on the basis of a call for expression of interest. Additional representatives of selected organisations and observers may also participate to specific meetings, according to the topics on the agenda. Observers include the European Commission, EMA’s committees (e.g. CHMP, ETF, CMDh, SPOC WP, SMMG), the EU Network, Notified bodies; ad-hoc observers may be also invited from member states and stakeholder groups.

Appointed members will be responsible to liaise with the respective industrial rganisations, so to contribute the discussion with their point of view and to keep them updated on the outcomes of the ISG meetings. The current schedule includes four quarterly meetings per year; the next two are fixed for the 26 September and 22 November 2022. The summary report of each meeting will be available in EMA’s website.

The Emergency Task Force

The new Emergency Task Force (ETF) builds upon the experience gathered during the pandemic and acts within EMA to advise and support on medicines for public health emergencies and preparedness.

The ETF is in charge of coordinating all efforts following the declaration of a public health emergency by health authorities, in strict coordination with all other relevant bodies including the European Health Emergency preparedness and Response Authority (DG HERA), the European Centre for Disease Prevention and Control (ECDC), the WHO and the European Commission.

The new ETF started operating on the new mandate on 22 April. Its composition is based on expertise, and it includes representatives of EMA’s Scientific Committees and Working Parties as well as selected patients and healthcare professionals and clinical trials experts from various member states.

There are three distinct area of activities for the Task Force. Scientific advice and support to clinical trials for the development of medicines to be used during the emergency will be directly managed and assessed by the ETF, free of charge and flowing a fast-track procedure. The new streamlined procedure should lead to the outcome in 20 days; deceleration criteria are also considered, i.e. premature evidence to address the medical need, high workload or lack of urgency. Expected benefits include the reduction of the use of medicines with insufficient evidence of efficacy and the increase of safe and harmonised use across the EU of new products from the pipelines ahead of authorisation. Activities of the ETF will cover all stages of development, from pre-authorisation (e.g. rolling applications or paediatric plans) to post-authorisation (e.g. major changes), investigational products and compassionate use.

The systematic assessment of the available evidence on medicines will be the focus of the scientific reviews, while recommendations will target medicines not yet authorised or topics of particular scientific or public interest. These may include, for example, the monitoring of new outbreaks and epidemics and the information on potential radiological, chemical or bioterrorism agents.

All lists of medicines under assessment to address a declared emergency will be made public to increase transparency, as well as the CHMP opinions on the use of medicines not yet authorised, Product Information, EPARs end Risk Management Plans.

Two dedicated mailboxes are also available, the first for sponsors of clinical trials to request EMA/ETF support for facilitating CTA and approval and sponsors agreement to conduct larger multinational trials ([email protected]), the second for manufacturers to discuss with EMA/ETF their development programs or plans for scientific advice prior to any kind of formal submission ([email protected]).

Shortages of medicines

EMA’s extended mandate in this area include the monitoring and mitigation of shortages of critical medicines and medical devices, and the setting up, maintenance and management of the European Shortages Monitoring Platform (ESMP). The action also includes the establishment of the Medicines Shortages Steering Group (MSSG), which will be supported by the Working Party of singles points of contacts in the members states (the EU SPOC Network) and a network of contact points from pharmaceutical companies (the i-SPOC system). A corresponding Executive Steering Group on Shortages of Medical Devices (MDSSG), to be created by February 2023, will be in charge of adopting the list of categories of critical medical devices and to monitor their supply and demand.

According to Regulation (EU) 2022/123, pharmaceutical companies are required to identify a i-SPOC to act as the reference contact for EMA should the Marketing Authorisation Holder (MAH) have medicinal products be included in the lists of critical medicines. All information has to be provided through the IRIS platform; the registration process opened on 28 June 2022 and is comprehensive of two steps (the IAM preliminary requirement for the creation of the account and the following IRIS submission).

Scheduled milestones will see the establishment of a list of the main therapeutic groups for hospital care (due by 2 August 2022), the registration of i-SPOCs from MAHs (by 2 September 2022), and the definition of shortages of medical devices and in vitro diagnostics (by 2 February 2023). The ESMP platform is expected to go live by 2 February 2025, and will represent a single reference point to make information available on shortages, supply and demand of medical products, including the marketing status and cessation.

Expert panels on medical devices

Regulation (EU) 2022/123 establishes the hangover of expert panels on medical devices from the Joint Research Centre (JRC) to EMA, thus adding a completing new type of activity for the Agency.

The new Secretariat is coordinating the activities of the Screening panel composed by 70 experts in charge of the decision whether to provide a scientific opinion, eleven thematic expert panels and expert panels sub-groups (for a total of approx. 130 experts), and a Coordination Committee inclusive of the Chair and vice-Chair of all the expert panels.

The main task of the expert panels is to provide opinion to the notified bodies for certain high-risk medical devices and in-vitro diagnostic, for the assessment of their clinical and/or performance evaluation. EMA is specifically involved in the coordination of the Clinical Evaluation Consultation Procedure (CECP) for medical devices and Performance Evaluation Consultation Procedure (PECP) for in-vitro diagnostics. Further details on the procedures and their interfaces with the ETF is available here.



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.


EMA’s consultation on draft Q&As on remote certification of batches by QP

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by Giuliana Miglierini

The last two years saw the implementation of a high degree of regulatory flexibility as a mean to respond to the many challenges posed by the travel bans consequent to the pandemic. After this “experimental” phase, regulatory authorities are now considering the possibility to allow the routine implementation of some remote procedures in the field of pharmaceutical production.

It is the case of the remote certification/confirmation of batches by the Qualified Person (QP): after the publication of a draft guideline in the form of Q&As (EMA/INS/169000/2022), the European Medicines Agency (EMA) has launched a short public consultation which will remain open up to 13 June 2022. Comments may be sent by email.

The guideline offers EMA’s point of view on the requirements for the physical attendance at the authorised manufacturing site applying to QPs in order to routinely run the remote certification of batches, outside emergency situations. The document has been drafted by the GMDP Inspectors Working Group; it is composed of four questions and their relative answers and it addresses some considerations arising from the experience gained on the application of the guidelines for human and veterinary medicines issued during the pandemic. These last ones were elaborated in cooperation between the European Commission, the Coordination group for Mutual recognition and Decentralised procedures – human (“CMDh”), the Inspectors Working Group, the Coordination group for Mutual recognition and Decentralised procedures – veterinary (“CMDv”) and EMA.

The Agency also warns that the contents proposed by new Q&As’ guideline may be subject to any other interpretation by the European Court of Justice, which is the ultimate responsible for the interpretation of the EU legislation.

The contents of the Q&As

The routine remote certification or confirmation of batches may in future apply to the activities carried out by the QPs within the EU and European Economic Area (EEA), with reference to manufactured or imported human and veterinary medicinal products and investigational medicinal products.

The first answer clarifies that it could be possible for the QP to routinely run remote batch certification or confirmation only if this type of practice is accepted by the relevant national competent authority (NCA) of the member state where the authorised site is located. To this instance, it should be noted that some NCAs may request some specific requirements to authorise the routine remote certification procedure, for example with reference to the location of the QPs.

Should the remote certification be allowed on a routine basis, specific requirements should be met in order to validate this practice, starting from its full compliance to the EU legislation and EU GMP guidelines.

The answer to question 2 specifies that all activities should take place in an EU/EEA country, and that the time spent by the QP at the authorised site should be commensurate with the risks related to the processes” hereby taking place. To this instance, it is of paramount importance the ability to demonstrate that the QP acting from remote has maintained full knowledge of the products, manufacturing processes and pharmaceutical quality system (PQS) involved in the remote certification/confirmation of batches. That also means that the QP should be highly reliant on the PQS of the authorised site, and this would be only possible by spending an adequate time on-site to verify the adequacy of the PQS with respect to the processes of interest. The pharmaceutical quality system should also include details of all the procedures used for the routine remote certification/confirmation of batches. The possible use of this type of remote procedure by the QP should be also clearly mentioned in the technical agreement governing the relationship between the authorisation holder and the QP, which should also specify all cases requiring the presence on-site of the QP. A robust IT infrastructure should be in place to guarantee the remote access of the QP to all the relevant documentation in the electronic format needed to achieve bath certification/confirmation, according to the provisions described in Annex 16 to the GMPs (Certification by a Qualified Person and Batch Release). To this instance, presence on-site should be always considered to solve issues that cannot properly be addressed from remote. The demonstration of the presence on-site of the QP falls under the responsibility of the Manufacturing/Importers Authorisation (MIA) holders.

These are also responsible to make available to the QPs all the hardware and software needed to guarantee the remote access to the relevant documentation (e.g. manufacturing executions systems, electronic batch records system, laboratory information systems etc.) as well as batch registers. All IT systems used for remote batch release should comply with the requirements of Annex 11 to the GMP (Computerised Systems).

On the same basis, it should be possible for NCAs to contemporaneously access for inspection all documentation and batch registers involved in routine remote certification/confirmation at the authorised site of batch release. MIA holders should also guarantee the QP is the only allowed person to access the batch certification/confirmation function and batch register, that the transferred data are complete and unchanged, and that an adequate system for electronic signatures is in place.

Question 3 simply clarifies that some members states may have some specific requirements about the country of residence of the QP, for example it should be the same where the authorised site involved in the remote certification procedure is located.

The last question discusses technical requirements linked to IT-security and data integrity for remote access, a type of procedure presenting a higher intrinsic risk in comparison to the same activities carried on-site. Here again, the main reference is Annex 11; all equipment and software used for remote certification of batches should always reflect the current technological developments.

Among the suggestions made by the Q&A draft guideline is the precise identification of all hardware transferred off-site to the QP, that should be inventoried and kept updated. Hard disks should be encrypted, and ports not required, disabled.

Attention should also be paid to the configuration of any virtual private network (VPN) used by the QP to improve the security of the connection to the IT infrastructure of the authorised site and to prevent unauthorised accesses. Authentication should be based on recognised industry standards (e.g. two-factor or multifactor authentication, with automatic date of expiry). The transfer of data should be secured by strong transport encryption protocols; assignment of individual privileges and technical controls falls under the responsibility of the MIA holder


EDQM, the RTEMIS scheme for remote inspections and new application forms for CEPs

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by Giuliana Miglierini

Starting in 2022, the Real-Time Remote Inspections (RTEMIS) programme, established by the European Directorate for the Quality of Medicines & HealthCare (EDQM) as a pilot in November 2020 to provide a tool to face travel restrictions due to Covid-19, has turned permanent. Companies applying for Certificates of suitability to the monographs of the European Pharmacopoeia (CEPs) may thus receive a notification for a RTEMIS inspection, as a part of the activities of the EDQM. The Directorate is responsible in cooperation with the participating agencies, for assessing the GMP compliance and CEPs applications relative to manufacturing sites of active pharmaceutical ingredients (APIs). The final GMP certificate issued from the NCA incorporates, following the positive closure of a remote inspection clearly states that the inspection was performed as a “distant assessment”.

Companies can adhere to the RTEMIS programme on a voluntary basis; the tool will complement the other modalities available to the EDQM to inspect manufacturers of pharmaceutical active ingredients, i.e. on-site inspections and documentation-based GMP assessment. As for on-site inspections, RTEMIS is also subject to the payment of fees. According to the Directorate, remote inspections cannot replace the on-site ones in terms of value and effectiveness, but many prove useful to assess GMP compliance for companies which have been already inspected. The RTEMIS scheme will thus form the third pillar for the supervision of GMP compliance of API manufacturers registered in the EDQM’s CEP scheme.

To qualify for an RTEMIS inspection, the concerned company should make available a suitable IT infrastructure and hardware to support the remote interaction with the EDQM’s team. To this regard, the notification letter will also include details about the expected infrastructural requirements; interested companies can contact the EDQM HelpDesk for further information.

The pilot phase to validate the RTEMIS scheme for remote inspections ran by the EDQM with reference to several manufacturing sites in India, selected on the basis of their GMP compliance history and a risk assessment, and which participated to the project on a voluntary basis. According to EDQM, suitable Corrective and Preventative Action Plans were developed by the inspected companies to address minor and major deficiencies identified during the inspections, leading to a degree in GMP conformity that the Directorate indicates as “satisfactory”.

Key factors for remote inspections

The pilot phase of the RTEMIS programme closed at the end of 2021 and led to the identification of several key factors to be respected in order to guarantee the success of remote inspections. During this period, RTEMIS inspections ran by the EDQM with the support of European Economic Area (EEA) inspectorates.

At a minimum, an appropriate IT infrastructure and hardware at the inspected site should be available to support a stable connection with the EDQM’s inspectors. During the preparatory phase of the inspection great attention should be paid to choose a suitable web conference application, running connectivity tests before the established date for the inspection, as well as a secure platform for the sharing of all relevant documentation (often in advance of the inspection). The selection of the IT tool to be used can benefit of the initial support from the EDQM’s IT department. Another important feature that should be always kept in mind refers to the possibility to run parallel sessions of discussion between the inspectors’ team and the staff and experts of the inspected company.

In remote inspections, participants are often located far apart, for example EDQM’s inspectors based in Strasbourg (F) may interact with an inspected company in China or India. The great difference in time zone requires a great flexibility on both sides to set the schedule for connections. Flexibility is also needed to face the many challenges posed by remote inspections, often requiring approaches significantly different from the traditional ones used for on-site inspections. Digital connected tools such as smart glasses may be used, for example, by the staff at the inspected site to allow inspectors to perform a real-time virtual tour of the plants.

New forms for CEPs applications

The EDQM also updated all forms to be used to apply for the release of Certificates of Suitability to the European Pharmacopoeia monographs. The forms to be used in case of a new application, revisions and sister files are available at the dedicated page of the EDQM’s website

The revision is intended to facilitate the transfer of data the EDQM’s new IT tools, which have been implemented starting 1 April 2022. The new forms also better reflect data available within the EMA’s SPOR – Organisation Management Services (OMS) system, including company details, names and addresses. The EDQM recommend communicating other additional data linked to the ones present in EMA’s website, i.e. the ORG_ID and LOC_ID.

 Applicants should also insert localisation data for their manufacturing sites, in the form of GPS coordinates. To this instance, the internationally recognised WGS 84 system should be used, using latitude and longitude (with the + and – symbols) expressed in degrees to at least five decimal places, as described in policy document PA/PH/CEP (10) 118.

Tables detailing the marketed medicinal products containing a certain active substance and the respective list of accepted Active Substance Master Files/Drug Master Files (ASMFs/DMFs) have been also updated, in order to better reflect the commercialisation history of the products and the quality assessments already performed.

EDQM also advises companies to use the form “change of contact details” as the preferred tool to inform the Directorate about the change of the contact person for one or more CEP dossiers (ref. policy document PA/PH/CEP (10) 86).

EDQM’s website is also undergoing a complete revision, aimed to improve the user experience and to ensure a quick and easy access to all relevant information. The new version of the site will be accessible from the same web address www.edqm.eu and is expected to be online in April 2022.  


Revision of the PIC/S GMP Guide: Annex 13 and Annex 16

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by Giuliana Miglierini

The entry into force of EU Regulation 536/2014 “Clinical trials”, at the end of January, resulted in the parallel updating of some international guidelines. In particular, a new version of the GMP Guide PE016 was published by PIC/S (Pharmaceutical Inspection Co-operation Scheme) on 1st February 2022. The revision included Annex 13 on the manufacturing of Investigational Medicinal Products (IMPs), and the new Annex 16 on the certification and batch release to be performed by Authorised Persons (AP) (click here to access all PIC/S guidance related to GMP). The revision of PIC/s guidelines is aimed to reflect the last changes occurred in the corresponding EMA documents, so to maintain the alignment between the two regulatory references (as established by the cooperation agreement between EMA and PIC/S). PIC/S has invited all non- EEA Participating Authorities and applicants to transpose the new Annexes 13 and 16 into their own GMP Guides.

The new Annex 16

Annex 16 represents a completely new addition to the PIC/S GMP guide; the EU Annex 16 (part of the EU GMP Guide) was initially considered to be too EU-specific and difficult to transpose for PIC/S purposes. Following a consultation in 2017, PIC/S Participating Authorities agreed to make an attempt to transpose EU Annex 16, as the adaptation may support a better harmonisation of GMP standards at the international level.

Annex 16 refers to both human and veterinary medicinal products which are subject to the PIC/S Participating Authority or are made for export. Furthermore, the Annex applies to investigational medicinal products for human use, “subject to any difference in the legal provisions and more specific guidance published by PIC/S Participating Authorities under national law”. With reference to imported medicinal products, each PIC/S Participating Authority may independently and voluntary decide whether to adopt the guidance as a legally-binding standard.

Certain types of medicinal products (e.g. blood and immunological products) are not addressed by the Annex, as they are regulated by national laws and fall under the competences of National authorities; to this instance, Annex 16 applies to the certification process performed by the AP and to the subsequent release of the batches.

The marketing authorisation holder (MAH) remains the sole responsible for the safety, quality and efficacy of the marketed products. Authorised Persons are required to check each single batch to verify compliance to national and GMP requirements, as well as to those detailed within the marketing authorisation (MA). After certification by the AP, batches of finished products can be transferred to saleable stock and/or export. Specific and documented agreements are needed should this require transfer to a site different from the certification’s one. Authorised Persons should be clearly identifiable, with reference to any quality defect leading to investigation or batch recall. APs certifying the release of the finished product are responsible for verifying the conditions of storage and transport for the batch and the sample, if sent separately, and of all testing required upon importation (including sampling, where needed).

A formal Quality Risk Management (QRM) process is required when sampling is performed at a manufacturing site located in another jurisdiction; Annex 16 provides detailed guidance on the elements to be considered in this exercise. Documentation of the continuous training received by the AP in charge of certification and batch release should be always available, with specific reference to the product type, production processes, technical advances and changes to GMP.

Annex 16 provides detailed guidance on how to conduct the process of certification of each batch of finished product, independently of the number of sites involved. With reference to specific manufacturing or control steps performed at different sites, their respective AP has to provide confirmation of the performed activities, sharing responsibilities with the AP in charge of the final batch release.

The certification process should take into consideration the entire supply chain of both the active substance and the finished product, including manufacturing sites of the starting and packaging materials. The AP responsible for certification should be able to access results of the audits performed at the sites involved, in order to check the consistency of all activities with those described in the MA and within GMPs. Audits run by third parties should reflect requirements set forth in Chapter 7 of the PIC/S GMP Guide.

In particular, suppliers of active substances should comply with GMP and GDP requirements relating to the supply of the active ingredient used to the finished product manufacturing. Excipients should also fulfil GMP requirements, and be possibly manufactured and supplied in accordance with the PI 045-1 guideline. Specific guidance may also apply for other types of products, i.e. biological active substances and medicinal products for human use or radiopharmaceuticals. Annex 16 provides templates for the confirmation letters to be used for the partial manufacturing of a medicinal product and for the content of Batch Certificates.

The revision of Annex 13

Annex 13 has been revised in order to reflect the contents of the new EU Regulation n. 536/2014 on clinical trials, which will replace EU Annex 13. PIC/S Annex 13 discusses the manufacturing of Investigational Medicinal Products (IMP), apart from the reconstitution phase, which is not considered to be part of the process. Provisions set forth by Annex 13 should be taken into consideration with reference to the re-labelling or re-packaging of IMPs and to the preparation of radiopharmaceuticals used as diagnostic investigational medicinal products, occurring in hospitals, health centres or clinics and performed by pharmacists or other persons legally authorised in the country concerned.

All activities should refer to an appropriate Pharmaceutical Quality System to be in place, according to requirements set forth in Chapter 1 of Part 1 of the PIC/S GMP Guide.

 The characteristics of IMPs may intrinsically evolve along the development process, as new data become available that may require changes to, for example, the formulation or the dosage form. This has to be reflected into the respective product specifications and manufacturing instructions, that should also evolve in parallel and be fully traceable and documented. Annex 13 indicates that all deviations should be registered and investigated, and preventive and corrective actions put in place. The new Annex provides detailed guidance on the different items to be considered within the product specification file, as well as for the proper management of personnel, premises and equipment.

All the documentation generated during the clinical development phases should fulfil requirements specified by the PIC/S GMP Guide, Part I, Chapter 4. To this instance, relevant documentation includes specifications and instructions, orders, manufacturing formulae and processing instructions, packaging instructions and batch records. Detailed guidance is provided also for production, including packaging materials and manufacturing operations, the modification of comparator products, blinding operations, and the packaging and labelling of the IMP. Annex 13 also offers guidance on how to perform quality control and batch release, and how to address outsourced operations, complaints and recalls and or the destruction of batches of IMP products.