Regulatory Affairs Archives - Page 2 of 3 - European Industrial Pharmacists Group (EIPG)

Environmental sustainability: the EIPG perspective


Piero Iamartino Although the impact of medicines on the environment has been highlighted since the 70s of the last century with the emergence of the first reports of pollution in surface waters, it is only since the beginning of the Read more

How AI is Changing the Pharma Industry and the Industrial Pharmacist's Role


Svala Anni, Favard Théo, O´Grady David The pharmaceutical sector is experiencing a major transformation, propelled by groundbreaking drug discoveries and advanced technology. As development costs in the pharmaceutical industry exceed $100 billion in the U.S. in 2022, there is a Read more

Generative AI in drug development


by Giuliana Miglierini Generative AI is perhaps the more advanced form of artificial intelligence available today, as it is able to create new contents (texts, images, audio, video, objects, etc) based on data used to train it. Applications of generative Read more

EMA/EFSA joint report on human dietary exposure to residues of veterinary medicines, pesticides and feed additives

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By Giuliana Miglierini

The presence of residues of veterinary medicines, feed additives and pesticides in food of animal origin may pose exposure risks for human health. The topic has been historically approached under different perspectives according to the specific reference legislative framework and the respective authority involved in regulating and monitoring the products. The European Medicines Agency (EMA) and the European Food Safety Authority (EFSA) are among the main regulators involved in setting and verifying the legally binding maximum residue limits (MRLs) for chemical substances, together with the European Chemicals Agency (ECHA).

EMA and EFSA received in 2020 a mandate by the European Commission to work at the development of a harmonised approach to the assessment of dietary exposure to residues of veterinary medicines in food of animal origin. The comparison of the current situation run by the two agencies included only exposure assessment methods used in the regulatory areas, which are all based on traditional deterministic approaches. The resulting recommendations have recently been published in the form of a joint report.

EMA/EFSA experts focused on key concepts and features in order to provide a general agreement on the basic “building blocks” of a recommendable harmonised methodology, leaving the setting up of more detailed methodological aspects targeted to the different sectorial applications to a further phase of discussion. The document shall now be assessed by the European Commission and, if adopted, may request the implementation of specific action targeted to the different sectors to reach a better harmonisation. The Technical Report to be submitted to the Commission may also contain other elements to be considered.

Meanwhile, on 9 February 2023 the Commission implementing Regulation (EU) 2022/1255 designating antimicrobials or groups of antimicrobials reserved for treatment of certain infections in humans entered into force. The regulation lists a wide range of antibiotic, antiviral and antiprotozoal active substances. Those use is from now on excluded to treat animals, so to preserve their efficacy in humans. The measure is part of the broader approach against antimicrobial resistance, and it aims to promote a more prudent and responsible use of antimicrobial medicinal products in animals, including very strict rules on their veterinary prescription for prophylactic and metaphylactic use.

The main issues examined by the EMA/EFSA report

Sectorial legislations in the field of medicinal products (managed by EMA), food (EFSA) and chemicals (ECHA) may greatly differ from one another in the approach and methodologies chosen to define exposure limits and to run risk assessments referred to residues of veterinary medicinal products, feed additives, pesticides and biocides. This lack in harmonisation may lead to significantly different outcomes in the assessment of the same active substance, especially when it is characterised by a dual use for applications in different sectors.

There are several pieces of legislation in place aimed to guarantee a high level of protection of both human and animal health and the environment [Commission Regulation (EU) 2018/7829, Regulation (EC) No 1107/200910 and Commission Regulation (EC) No 429/2008], as well as sectorial legislations in the pharmaceutical, food, and feed additives fields that may diverge at the level of data requirements, purpose of the required studies, methodologies for exposure assessment, consumption models, etc.

In general terms, exposure studies are usually run using radiolabeling to trace the fate of a substance and to characterise its metabolites and their concentration in edible tissues/food commodities from target animals. The “residue of concern” (RoC) considered in the dietary exposure assessment is most commonly estimated assuming that metabolites have the same pharmacological/ toxicological potential as the parent compound. The difficulty of measuring the concentration of all compounds in residue monitoring often leads to the selection of a marker residue to be traced.

Health Based Guidance Values (HBGVs, or Reference Values) corresponds to the concentration of a chemical that may present hazards for the human, animal or environmental health; they are listed in the EFSA Open Food Tox Database, as well as in similar WHO and US-EPA databases.

HBGV, as well as acceptable daily intake (ADI) in case of chronic risk and the acute reference dose (ARfD) in case of acute risk, can be used in association with the estimated dietary exposure to the RoC to evaluate the risk of exposure.

The report initially discusses the different approaches and models currently in use by EMA, EFSA, the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and the Joint Meeting on Pesticide Residues (JMPR). Reference is made to the alternative definitions for the establishment of residue limits related to veterinary medicinal products charactering the different sectorial legislation, as well as to methods to assess the related hazard.

The Theoretical Maximum Daily Intake model (TMDI, or diet-based approach), for example, is used by EMA to estimate the risk from life-long exposure to residues in food commodities from animals treated with veterinary medicinal products. This model has been already abandoned by JECFA and EFSA, that switched respectively to the Feed Additives Consumer Exposure (FACE) and Pesticide Residue Intake Model (PRIMo 4), as better suited to estimate age-dependent exposure scenarios based on individual food consumption data. The report also discusses the Global Estimated Chronic Dietary Exposure (GECDE) model, and the International Estimated Daily Intakes (IEDI) model. This last one is based on the WHO GEMS Food Cluster diets, estimating average per capita consumption figures based on international trade and production statistics of foods.

A further level of complexity in the assessment has to be considered for substances with dual uses, such as veterinary medicines and pesticides. In such instances, it is important to note that maximum residue limits/levels may vary for the same substance in the same animal commodity, as their concentration may differ in different tissues and/or organs (i.e., muscle, fat, liver, kidney, eggs, or milk). This may result in uncertainties at the level of the enforcement of the appropriate level and residue definition by different authorities.

The recommendations for future harmonization

The analysis and evaluation of the performance of the many available methods led EMA and EFSA to conclude that the observed differences in exposure assessment could be primarily attributed to the type and use of consumption and occurrence data. Other possible elements impacting on the obtained result may include the chosen calculation model and exposure model, the exposure to residues from multiple uses, and the use of commodity definitions and combined exposure from multiple species. Different timelines in the implementation of scientific innovation may have also contributed to the observed divergences.

The final goal of the exercise was to obtain a most realistic exposure assessment possible based on the available methodologies. The so identified “preferred methodology” focuses on data sources and models, includes also alternative proposals on a number of items, and it might represent the “blueprint” for a future harmonised methodology. EMA and EFSA’s recommendations pay particular attention to exposure assessment as the first step of a risk assessment; as for risk characterisation, no specific recommendations have been developed during this round of discussions.



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.


MDCG, a position paper on the capacity of notified bodies

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by Giuliana Miglierini

The lack of a suitable capacity of notified bodies (NBs) is one of the main issues still pending after the entry into force of the new Medical Device Regulation (MDR) (EU) 2017/745 and In Vitro Diagnostic Regulation (IVDR) (EU) 2017/746. The Medical Devices Coordination Group (MDCG) discussed some suggestions on how to address the problem within a position paper published in August 2022.

Even if the document does not represent an official guideline, it describes some critical points to be considered by manufacturers and notified bodies in order to face the great challenge of the re-certification of medical devices and in vitro diagnostics according to the new rules. Should this not occur in time, many products may exit the market at the end of the transition period, potentially leading to a supply crisis greatly impacting on the health of patients and the normal functioning of healthcare institutions.

The MDCG position paper answers the request of EU Health ministers advanced during the EPSCO Council meeting on 14 June 2022 to figure out some immediate measures to face the problem. The final goal of the document is to improve the efficiency in the application of the current regulatory framework, with no reduction of requirements to be fulfilled by manufacturers. Waivers from applicable conformity assessments procedures should be considered only in relation to an interest of public health, patient’s safety, or health.

The position paper consists of nineteen points addressing the issue under its different perspectives, the first eleven of which refer to the increase of notified bodies’ capacity. The MDCG calls on all stakeholders to collaborate in order to smoothly implement the suggested actions, a process that will be monitored by the MDCG itself.

How to increase the capacity of NBs

Hybrid audits should be the elective tool notified bodies may use where appropriate to timely and efficiently run conformity assessment. Duplication of activities should be also avoided. To this instance, the suggestion is to “develop a framework for leveraging evidence, or components thereof, from previous assessments” run according to previous Directives. A pre-condition to activate this possibility is that the previous assessment has been judged “valid and properly substantiated also with regard to the MDR/IVDR requirements and the device” by a duly qualified notified body personnel.

A flexible approach may also apply to the combination of audits for legacy devices and actions needed to guarantee their ‘appropriate surveillance’. Combined audits may be used particularly for legacy devices whose application for MDR/IVDR certification is under review by a NB, thus moving the focus more towards the assessment of compliance with the new rules. To this instance, the MDCG also announced the intention to produce a specific guidance on ‘appropriate surveillanceunder Article 110(3) IVDR and to update MDCG 2022-4.

Already existing guidance may also be reviewed to reduce the administrative burden for NBs, and remove limitations related to the scope of documentation not required by MDR/IVDR.

A fundamental piece of the new European infrastructure for medical devices and IVDs is represented by the centralised Eudamed database, which should be timely fed by NBs with all relevant information using machine-to-machine procedures. Double registrations should be avoided as much as possible.

New notified bodies are essential in order to increase capacity. To this instance, the MDCG suggests supporting training, coaching and internship activities for their personnel. The rationalisation of internal administrative procedures is also deemed important.

Time for re-assessment of NBs is undergoing a review by the European Commission, which is expected to result in the publication of new Delegated Acts. The proposal is to move from the current first re-assessment at three years after notification (and then every 4th year) to up to five years after notification, on the basis of a flexible approach. There are currently ten re-assessments planned in 2022, twelve in 2023 and 11 in 2024. According to the MDCG, the new timeframe for re-assessment would allow national designating authorities to free resources to assess new NBs, while existing ones could process higher numbers of first MDR/ IVDR certifications.

Assessment, designation and notification of conformity assessment bodies (including the European Commission) are also called to reduce their timeframes and improve the efficiency of their processes, keeping unaltered the requirements to be met. The possibility to add specific codes to the designation of NBs shall be also explored by the MDCG. The Group is also committed to prioritise some ongoing actions which may impact on NB’s capacity (i.e. revision of section III.6. of MDCG 2019-6 revision 3).

MDCG’s guidance documents should be seen as an aid “to apply the legal requirements in a harmonised way, providing possible solutions endorsed by the MDCG”. Nevertheless, demonstration of the compliance to requirements should always benefit of a certain flexibility. A reasonable time should also be granted to integrate the new guidance in the relevant systems and/ or to apply them, suggests the MDCG.

Suggestions for the manufacturers

Under the perspective of manufacturers of MDs and IVDs, costs to access NBs may play an important role, especially for small-and-medium companies (SMEs). The MDCG position paper recalls NBs to the obligation to make their standard fees publicly available, possibly in a way that might be easily compared. Specific access schemes should be also in place to make available some capacity to SMEs and other first-time applicants for conformity assessment.

Manufacturers should also refer to notice MDCG 2022-11 to ensure timely compliance with MDR requirements. IVDs should not left behind, even if this category of products benefits of one more year for the transition to new rules compered to medical devices.

Structured dialogue is the suggested tool to improve the collaboration between manufacturers and notified bodies along the entire process of conformity assessment aimed at regulatory procedures, should this approach turn to be useful in order to improve the overall efficiency and predictability.

A timely communication to manufacturers by mean of webinars, workshops, targeted feedback and informative sessions is also deemed important in order to allow for a better preparedness, with a particular attention to SMEs and first-time applicants. The MDCG also suggest NBs to develop common guidelines for manufacturers to assist them in the application phase, containing explicative examples of typical non-conformities and details on he preparation and content of technical documentation. National authorities and industry associations are called as well to contribute to the dissemination of relevant information across their stakeholders.

Specific guidance should be issued by the MDCG to support a simpler conformity assessment of some aspects of legacy and orphan devices denoted by a demonstrable track record of safety. The development of a specific definition of “orphan devices” is also planned.

An improved dialogue between NBs and medicines authorities, and cases where expedited review would be possible is also supported in order to speed up consultations on medical devices incorporating an ancillary medicinal substance and companion diagnostics.



ICMRA, two pilot programmes to optimise regulatory assessment and inspections

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by Giuliana Miglierini

New flexible modalities for the management of regulatory procedures are becoming progressively accepted even for routine activities, upon the experience built during the pandemic. Efforts are ongoing at the global level in order to better harmonise the new approaches. To this instance, the International Coalition of Medicines Regulatory Authorities (ICMRA) has launched two pilot programmes focused, respectively, on the collaborative assessments of chemistry, manufacturing and control (CMC) and Post-Approval Change (PAC) submissions and related regulatory actions and on hybrid inspections.

Each programme is expected to last 1-1.5 years and should see the involvement of at least two regulatory regions, each one conducting three assessments or collaborative hybrid inspections. Recommendations resulting from the pilots shall be published in 2023, representing the basis of an initial common framework for collaborative assessment and hybrid inspections. The initiative follows the results of a workshop organised by ICMRA in July 2021, during which emerged the need for more convergence and reliance across regulatory authorities in order to support the timely supply of critical medicines.

ICRMA has invited industrial sponsors to participate to the initiative, with particular reference to those planning to file an application for a new product or for post approval changes of already approved products to more than one regulatory agency. All details and the procedure for application are available at this link.

Therapeutics which may be object of the submission include both small molecules and biological products. The submission may refer to products for the treatment of Covid-19, other medically necessary/critical medicines or products granted for access to fast-track procedures such as the Breakthrough (US), PRIME (EU) or Sakigake (JP) schemes.

Interested sponsors are required to check with the involved facility’s management to ensure readiness for inspection and possibility to host a collaborative hybrid inspection, with a particular attention to the availability of suitable IT infrastructures and interpretation services, and the possibility to coordinate at least two inspectorates across different time-zones.

Applications are open since 15 June 2022 and have to be forwarded using the EudraLink secure file transfer application provided by EMA. After a rolling review of the applications, starting of the first pilot is scheduled for September 2022.

The general objectives

The main goals of the initiative include the definition of best practices and standards in the quality assessment of CMC-related post-approval changes and collaborative hybrid inspections. A single list of questions to the sponsor or manufacturer should also be delivered, and answers be shared with the participating quality assessors and inspectors.

The exercise should lead to the identification of misalignments and potential areas of harmonization across participating regulatory regions. An improved convergence and collaboration among regulators in specific data expectations and assessment approaches for the assessment of manufacturing facilities for Pre-Approval and Pre-License Applications (PAIs & PLIs) and reviewing PACs and PAC Management Protocols may also be supported by the analysis of the data acquired during the two programmes.

Hybrid inspections

Hybrid inspections are based on the collaboration of at least two different National Regulatory Authorities (NRAs), one of which in charge of the on-site inspection activities, the second acting as a remote inspectorate. The respective tasks shall be coordinated and run using virtual technologies, so to enable real-time collaboration in the inspection activities, which should target facilities and products of interest for multiple regulatory agencies (see more details here and here).

The pilot is expected to reduce the need of multiple inspections or facility assessments and to support the identification of the best virtual platforms and information technology (i.e., video) to facilitate concurrent on-site inspection and distant assessment. Focus on the development of a common framework to accommodate time zone differences between the facility location and the distant inspectorates is also expected.

Best practices to prepare and conduct the hybrid inspection are another important outcome, as both the on-site and distant inspectorates needs to obtain from the activities all the information needed to run their respective assessments.

In the critical field of GMP expectations, a possible target of the pilot may be represented by how the inspection is reported and how deficiencies are classified by different regulators. Aligned reports and protocols may also support the sharing of information with other interested ICRMA inspectorates. In any case, each participating authority remains the sole responsible for the evaluation of the outcomes of the inspection and the enforcement of any consequent action, according to its own reference legal framework.

A final protocol describing how to execute a hybrid inspection is a main expected outcome of the fist pilot, to be then applied by the Working Group to evaluate at least 3-5 facilities with at least two regulatory agencies involved in the hybrid assessment.

Collaborative assessment

The second pilot aims to run collaborative quality assessment for a minimum of three different applications and a minimum of three regulatory agencies involved each time. The initial phase of the pilot should see a limited number of regulatory agencies (3-5) participating to the project, on the basis of specific confidentiality agreements.

Sponsors participating to the pilot shall submit a single application for the proposed CMC changes for assessment by multiple regulatory authorities; the initial focus is expected to be on post-approval change management protocols (PACMPs; chapter 4 of ICH Q12) for Covid-19 therapeutics. More in detail, participating regulatory agencies will agree on the procedure to be used for the collaborative assessment. They are expected to share and discuss in advance any information request or comment, prior to the interaction with the applicant. Any participating authority can maintain its independence to issue information requests, but in any case, the so obtained answers shall be shared with other NRAs and assessed on the basis of a common approach, so to avoid the need of multiple independent lists of clarification seeking comments.

The project also aims to achieve a single regulatory decision regarding the joint assessment (see more details here and here).

More specifically, priorities to be addressed should include for example the evaluation of information or data on specifications, stability, and/or PACMP that support site changes or additions.

As for the hybrid inspections, expected outcomes are represented by the identification of the best practices and standards in the quality assessment of post approval changes, including PACMPs, and of potential areas for alignment or harmonisation across regions.

A forum of discussion should be also created in order to facilitate convergence on the basis of such best practices. Each evaluation should lead to the preparation of lessons-learned summaries to share the acquired knowledge; new quality assessment guidance and standards might also be proposed, where appropriate.


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.


Joint implementation plan for the IVDR regulation

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by Giuliana Miglierini

Regulation (EU) 2017/746 (IVDR), establishing the new legislative framework for in vitro diagnostic medical devices (IVDs), will entry into force on 26 May 2022. The Medical Device Coordination Group (MDCG) has published an updated version of the Joint implementation and preparedness plan, discussing the priority actions to be implemented and monitored at the level of member states, Commission and MDCG.

The implementation of the IVDR is highly complex, as it requires a strict coordination between all the different stakeholders, including manufacturers, notified bodies, authorised representatives and laboratories. The IVD regulation has introduced a completely new device classification system for in vitro diagnostics, as well as a greater involvement of notified bodies in conformity assessment and new regulatory structures such as the EU reference laboratories and expert panels.

The Joint implementation plan is aimed to support the harmonised implementation of the new framework, a process led by the Commission and where member states are called to ensure the new provisions are effectively applied and enforced at national level.

Ongoing actions and future goals

As of January 2022, six notified bodies were already designated and the examination of other applications is undergoing. The Unique Device Identifier system that will support the punctual tracing of the devices has also been set up, while the Eudamed database is still under development. From the regulatory perspective, a number of new common specifications are being drafted; some guidance documents are already available while others are under development.

To smooth the impact of the transition and to prevent disruption in the supply of essential IVDs, Regulation (EU) 2022/112 has established the calendar for the transition of different classes of devices, i.e. 26 May 2025 for IVDs that fall in class D under the IVDR, 2026 for class C, 2027 for class B and A sterile.

The Joint implementation plan identifies two sets of priorities to be tackled by the stakeholders, on the basis of public health’s goals, patient safety and transparency. Set A includes essential actions to enable IVDs to maintain access to the market. Set B includes the development of other new pieces of legislation and guidance documents needed to better support the transition and the designation of EU reference laboratories for high-risk IVDs.

Set A, essential actions

Contingency planning and monitoring are the first priority to be met under Set A essential actions, in order to anticipate possible risks of IVDs’ shortages arising from the transition to the new framework. The MDCG will closely follow this process to monitor its progress and identify systemic risks and mitigation actions, with a particular attention to the availability of particularly critical IVDs.

Regular updates are also expected from the industry and notified bodies to inform member states and the Commission about the need of specific actions. This type of activity would also support the identification of barriers that could result in shortages of devices, e.g. with reference to the designation of notified bodies or the certification process. Stakeholders are also requested to be ready to manage some uncertainty in areas where guidance is still not available, thus requiring the provision of sound justifications to maintain critical IVDs on the market.

The second highest priority is the availability of a sufficient number of notified bodies to support the expected very high volume of applications for the certification of medium and high-risk IVDs. The plan indicates the need to make available national experts for the joint assessment of notified bodies. Member states should also address the need to improve the notified body capacity, discussing this issue within the MDCG and its specialised working groups as well as with the Commission. According to the Joint plan, the percentage of IVDs requiring certification under the new IVDR will rise up to 80-90%, from approx. 10% devices requiring involvement of a notified body under Directive 98/79/EC.

To facilitate this part of the transition, Regulation (EU) 2022/112 establishes that certificates issued under the Directive 98/79/EC are valid, under certain conditions, until May 2025. Renewals of existing certificates by a set of nineteen notified bodies designated under the current Directive is possibile, if necessary, up to 26 May 2022.

The plan also takes into consideration the possible occurrence of new Covid-19 restrictions, that may highly impact the work of the notified bodies (for example, due to the need to run first-time audits of many manufacturers). The Commission and the MDCG are thus called to consider how notified bodies can perform conformity assessment activities in such circumstances.

Set B, high priority actions

Actions included in set B are not essential for manufacturers to market their IVDs, but their implementation would support a smoother transition.

The EU reference laboratories are a new type of independent scientific body designated by the Commission to carry out additional tests on the performance and compliance with any common specifications of class D devices, before placing them on the market. If the Commission would not designate a EU reference laboratory for a particular device in class D, those requirements are not applicable. According to the Joint plan, a call for application to member states and the Joint Research Centre shall be issued by the Commission to nominate candidate laboratories. New implanting acts on tasks and criteria and on fees to be levied by the EU reference laboratories are also expected.

According to the IVDR, the adoption of common specifications (CS) is optional; nevertheless, the Joint plan indicates the intention of the Commission to propose some sets of common specifi cations and reach an agreement on the text that should enter the first adoption round. This should also lead to the adoption of the first implementing act containing the common specifications. This round should include common specifications relative to Kidd and Duffy blood grouping, Chagas and syphilis, and cytomegalovirus/Epstein-Barr virus devices, for which the drafting process is at an advanced phase.

New common specifications should be targeted to class D devices and will be developed by the IVD sub-group of the MDCG. Already existing CS under the old Directive should be transposed without major modifications.

A new implementing act on the MDR/IVDR standardisation request should be adopted by the Commission and accepted by relevant bodies (CEN/Cenelec). The Commission should also adopt the implementing acts on the publication in the Official Journal of references of harmonised European standards in support of the IVDR requirements.

Set B of actions include also the drafting and endorsement of a guidance on notified body designation codes, as well as of guidance on batch testing for notified bodies. New guidance may be also developed on significant changes and on appropriate surveillance, as referred to in Article 110(3) of IVDR. The MDCG should also complete the issuing of a new guidance on clinical evidence for IVDs, which is part of the documents needed to support the evaluation of the devices’ performances and the work of expert panels.

To this instance, the plan also indicates the need for a clarification on what constitutes a “type of device” and on the process to be followed by notified bodies in context of views of the expert panel. A template for summary of safety and performance should be also released, together with a template for the application/notification of performance studies. The issuing of an IVDR-specific guidance on harmonised administrative practices and alternative technical solutions until Eudamed is fully functional is also planned.

The joint plan also includes sections on actions required in the field of companion diagnostics, legacy devices and in-house devices.


A new joint work plan to 2023 for EMA and EUnetHTA 21

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by Giuliana Miglierini

The new Regulation (EU) 2021/228 on Health Technology Assessment (HTA) will assume full validity in January 2025, at the end of the 3-year transition period. To this instance, it is time to define the actions needed to establish the new framework for HTA in the field of medicinal products.

A central point of the new approach is represented by joint scientific consultations (JSCs) to be carried out in coordination between the European Medicines Agency (EMA) and the bodies entitled of HTA at the level of single member states.

After the termination of the European Network for Health Technology Assessment (EUnetHTA) initiative, in 2021, the new consortium EUnetHTA 21 has been created grouping thirteen HTA agencies from The Netherlands, Spain, Italy, Austria, Germany, France, Portugal, Belgium, Ireland, Hungary and Norway. EUnetHTA 21 signed a contract service in 2021 with the Health and Digital Executive Agency (HaDEA) for the provision of joint health technology assessment up to September 2023.

On this basis, EMA and EUnetHTA 21 have now published a joint work plan of the activities to be put in place until 2023; the initiative represents the continuation of the EUnetHTA Joint Actions, started in 2010 and concluded in May 2021.

The document identifies the priority areas of future collaboration between regulators and HTA bodies at European level, with the final goal to “improve efficiency and quality of processes, whilst respecting the respective remits of different decision makers, and ensure mutual understanding and dialogue on evidence needs”.

The transition to the new legislative framework shall be based on a flexible approach to the different tasks; the work plan includes both methodological and operative actions, and it will be monitored in close cooperation with the EU Commission. Progresses will be discussed during the four bilateral meetings planned until September 2023.

Under the new framework, high priority HTA activities related to the service contract will be delivered by EUnetHTA 21. Other voluntary activities can be actioned through individual HTA bodies from a European (EU/EEA) member state that expressed their interest to participate. Should this be the case, the work plan clarifies that the position is that of the individual HTA body, not of EUnetHTA 21. A public consultation on deliverables part of the EUnetHTA’s mandate is also planned.

Actions in support of JSCs

Joint scientific consultations are the core of the new approach to HTA, aimed to generate a robust evidence relative to the entire life cycle of medicinal products, including the post-licensing and launch.

The work plan establishes a new European process of “parallel joint scientific consultation” involving both HTA bodies and EMA, that will take the place of the current procedures of parallel scientific advice, parallel consultation and early dialogue. This action shall make available a single assessment process, reflecting both regulatory and HTA’s needs.

Interested parties can apply to access the EMA/EUnetHTA parallel JSC procedure; a joint guidance on how to apply and the dates of EMA’s Scientific Advice Working Party (SAWP) meetings are available at the dedicated page of the Agency’s website, together with the template of the parallel consultation briefing document and submission deadlines. The joint guideline also provides details for applicants on how to respond to a EUnetHTA 21 open call for joint scientific consultation.

Exchange of information

The setting up of the JSC procedure includes the optimisation of the use of registries to facilitate post-licensing evidence generation (PLEG) and/or launch evidence to support decision making. To this instance, and depending on the specific products selected during the JSC, advice may be provided on requirements for data collection and analysis of disease registries in the context of development plans, or for qualification of registries in disease areas of particular mutual interest (including advanced therapies, ATMPs).

This exchange of information between EMA and EUnetHTA 21 may lead to discussions in order to monitor progress in the identification of PLEG. Under this action, a voluntary pilot might be activated to explore the feasibility of earlier engagement with an HTA agency during regulatory assessment, including evidence sharing and managing of uncertainties. A main outcome of this area of cooperation shall see the initial drafting of the rules for the exchange of information on the preparation and update of joint clinical assessment of medicinal products.

Capturing patient relevant data and information

The ability to generate patient relevant data and information is key to support the process of decision making. The joint work plan aims to develop new methodologies to improve reliance of patient relevant data. To this instance, the cooperation with EUnetHTA is expected to contribute to EMA’s initiative to establish an EU network of experts on Patient Reported Outcomes (PROs). The work plan also includes voluntary actions focused on the discussion and exchange of relevant data in bilateral meetings, in parallel with the development of the respective guidelines, and a workshop on patient experience data planned in June 2022.

The work plan shall also favour a better engagement of patients and healthcare professionals in areas of mutual interest. To this regard, EMA and EUnetHTA 21 will share their best practices as for compensation for expert participation and how to incorporate the input received in regulatory and HTA deliverables.

Preparedness for future challenges

The need to better understand challenges arising from the development of innovative treatments will benefit the sharing of horizon scanning activities between EMA and EUnetHTA 21. This may include, on a voluntary basis, joint discussions on data requirements and preparative measures relative to high-impact innovative medicines for patients with high unmet needs. Other voluntary activities by individual HTA bodies may focus on the optimisation of regulatory assessment reports in order to facilitate the uptake of their outcomes as part of the HTA process. Sharing of experience and guidance on the optimisation of information on subpopulations (e.g. labelling and EPARs) may also be considered, as well as the improvement of Orphan Medicines Assessment Reports (OMARs). Under the methodological perspective needed to make real-world evidence more available, a main goal of the plan shall achieve HTA representation in the advisory board of Darwin EU, the Data Analysis and Real World Interrogation Network established and coordinated by EMA to provide timely and reliable evidence on the use, safety and effectiveness of medicines for human use from real-world healthcare databases across the EU.

Other voluntary activities in this area may include multi-stakeholder discussions aimed to optimise the design, quality and utilisation of disease registries and the training on new guidance on registry-based studies. Joint methodological work may be also carried out to identify key concepts supporting the acceptance of extrapolation and/or evidence transfer, and to share best practices and experiences in the field of the integrated assessment of companion diagnostics, or other diagnostics for targeting therapeutics not directly related to the use of specific medicines.


The new Annex 21 to GMPs

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by Giuliana Miglierini

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

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

The main principles

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

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

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

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

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

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

The Pharmaceutical Quality System of the importing site

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

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

Full documentation available at MIA sites

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

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

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