ESMP Archives - European Industrial Pharmacists Group (EIPG)

Webinar: ICH Q12 Product Lifecycle Management – open road or dead end?


Next EIPG webinar is to be held on Tuesday 18th April 2023 at 17.00 CEST (16.00 BST) in conjunction with PIER and University College Cork. Graham Cook, former Pfizer’s Quality Intelligence and Compliance Information team leader and chair of Read more

Draft ICH M13A guideline on bioequivalence open for consultation


By Giuliana Miglierini The draft ICH M13A harmonised guideline “Bioequivalence for immediate-release solid oral dosage forms” was endorsed by the International Council for Harmonisation on 20 December 2022 and is now open for consultation. Comments can be forwarded until 26 Read more

The Windsor Framework


On 27 February 2023, UK Prime Minister Rishi Sunak and the European Commission President Ursula von der Leyen announced that agreement had been reached on changes to the operation of the Protocol on Ireland/Northern Ireland. The Protocol has been in Read more

HERA reports on stockpiling of antimicrobials

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By Giuliana Miglierini

The European Health Emergency Preparedness and Response Authority (HERA) has published the two final reports, prepared by McKinsey Solutions for the European Commission, describing respectively the results obtained during the first and second phases of the antimicrobial resistance (AMR) feasibility study on stockpiling.

Antibiotic resistance represents a major threat for human health, as many active substances are losing efficacy towards many bacterial species. The first report (deliverables D1–D5) focuses on the mapping exercise run during the project and aimed to assessing the current situation, identifying vulnerabilities, and reviewing the stockpiling systems currently available in the EU and at the global level.

The second report (deliverables D6-D7) discusses the vulnerabilities identified in the previous phase and the potential tools and solutions to address them, including the assessment of available options for stockpiling of antimicrobials at EU level.

Mapping of the current situation

According to the first report, 32 classes of antibiotics were identified as critical with respect to the need to ensure continued access to patients in order to offer sufficient therapeutic and prophylactic options against systemic bacterial infections.

The analysis proceeded further to identify narrower sets of antibiotics most useful to treat infections due to common pathogens with acquired antibiotic resistance: a first subset of 20 substances was indicated as specially relevant as first- or last-line/reserve therapies against AMR pathogens, and from this a shorter sublist of 13 was identified as last-line/reserve therapies for severe and potentially lethal infections.

The report did not identified any critical market withdrawal of antibiotic substances from the EU market, even though some criticalities may occur in some member states. Alternatives with better efficacy and/or safety profiles are still available on the market for the six substances identified as fully withdrawn.

According to the report, stockpiling at the EU level might not have a direct impact on the mitigation of market-driven trends. Improved monitoring of potentially critical future withdrawals would be needed to enable early detection of shortages and establishment of counteractions.

Innovation in the field of new antibiotics is still largely insufficient, with only six substances currently in phase 3 clinical development. These might prove useful especially as the ultimate reserve line of therapy after exhaustion of the currently available therapeutic options. The report suggests that, upon reaching approval, these innovative substances could be considered for future stockpiling or incentives to facilitate launch in the EU.

The analysis of supply chain vulnerabilities aimed to identify higher priority antibiotics as possible candidates for stockpiling. The report highlights that the analysis was “significantly limited by a lack of outside-in transparency”. Potential single points of failure and/or past disruptions in most supply chains were identified for the 32 critical antimicrobial classes, but the lack of capacity data made the in-depth analysis particularly difficult.

Six representative sets of antibiotic substances were assessed, for five of which less than 25% of API manufacturing occurs in the EU. Similar trends have been also observed for the remaining 26 classes. The supply of critical intermediates (i.e., 6-APA and 7-ACA) appears particularly worrying and may potentially lead to a future shortage of that specific antibiotic/class in the case of a shock. HERA report warns against the possible risks related to potential vulnerability to trade disruptions and unforeseen geopolitical shocks, which may lead to a significant shortage in case of failure of just a single manufacturing site, independent of its location.

The feasibility study also mapped the already existing or planned stockpiling systems, so to use this information to better design the new, EU-level stockpiling system. Four different levels were identified, ranging from the EU’s and member states’ systems to multilateral and/or international NGO stockpiles, stockpiles/inventories in the commercial value chain, and extra-EU national stockpiles.

At the EU and EFTA national level, 13 countries reported a national stockpile that includes antimicrobials, even if greatly differing as for the chosen model. The rescEU system was identified at the EU level as the most relevant mechanism potentially useful to complement and/or integrate with a publicly managed physical stockpile of antibiotics.

The Stop TB Partnership’s Global Drug Facility (GDF) was identified as one of the international models of interest, together with the US Strategic National Stockpile (SNS). The GDF includes more than 2,000 partners and acts as the largest purchaser and supplier of medicines to treat tuberculosis in the public sector globally. The suggestion is for HERA and the European Commission to collaborate with the GDF in case of a TB-related demand spike. The SNS may represent a significant example of how to address many of the criticalities highlighted by the report.

How to better address stockpiling of antibiotics

The second report builds on the above-mentioned observations to go deeper in analysing from different perspectives and targets the possible approaches to the stockpiling of antibiotics. The indication is for HERA to consider using existing initiatives (e.g., rescEU, the EU’s Joint Procurement Agreement and the Emergency Response Coordination Centre) and to work closely with EU member states and other EU agencies (i.e., EMA and the ECDC).

An important warning was also made: stockpiling is just “a short-term mechanism. It does not alter the fundamental market environment. It can only represent one part of any answer to the challenges faced by health agencies including HERA, whether AMR-related or otherwise”.

A sudden and unpredictable surge in demand and an interruption to supply are the two archetypes analysed to better identify how to address stockpiling.

More than 30 potential demand scenarios were considered, leading to the identification of one high priority stockpiling candidate (higher demand for anti-mycobacterial medicines due to a surge of imported tuberculosis cases) and other three important, but not yet prioritised scenarios. These include stockpiling against the accidental or deliberate release of a bacterial pathogen, treating bacterial super-infections due to a viral pandemic, and the potential rapid spread of an AMR pathogen in the current European context.

Stockpiling for supply chain disruptions was also assessed, leading to the conclusion that alternative products are available as substitutes in the great majority of cases. A point of attention is represented by cross-class substitution, that might provoke different side effects for different groups of patients and could represent a potential factor for the promotion of AMR. More complex treatment procedures (e.g., i.m. vs oral administration), higher costs for healthcare systems and organisational issues for providers should also be considered.

Virtual stockpiling to be managed through the new European Shortages Monitoring Platform (ESMP) or the existing European Medicines Verification System (EMVS) would increase transparency of the system. A mandate or incentives to support private sector physical stockpiling was considered as the most feasible option available. Efforts should be made by the EU Commission to better characterise the relationships between the economic sustainability of limited generics productions (e.g. oral formulations for paediatric use of narrow-spectrum genericised penicillins) and the risk of shortages.

Five lines of possible action

The second report identifies five possible lines for future action aimed to strengthen the antibiotic supply chain and improve the stockpiling feasibility. At first instance, it would be important to improve transparency and reporting, so to better enable the availability of targeted preparedness and response measures.

This might include the harmonisation and extension of mandatory reporting of medicine shortages across the EU, the possibility for HERA to access regulatory data from agencies and information from marketing authorisation holders on supply chain setup and inventories in the case of a healthcare emergency situation, the implementation of an opt-out mechanism from stockpiling obligations at final product level, and the introduction of a general extension of reporting requirements for the supply chain of antibiotic products sold in the EU.

The second line of possible action addresses how to lower wastage in existing private and public inventories and stockpiles. Available options include regulatory measures and limited financial support for drug stability studies or for packaging options able to maintain product quality over longer periods of time.

Facilitation and regulatory support for mutual recognition of national level approvals for antibiotics might help to improve the flexibility of existing inventories and stockpiles, so as to better mitigate the shortages occurring in some member states.

Other two complementary approaches have been identified as potentially useful to improve the supply chain resilience of the EU antibiotics market. On one hand, diversified and in-market antibiotic manufacturing capacities and capabilities could be supported by targeted incentives and investments. On the other, the maintenance of reserve/convertible manufacturing capacity for hard-to-make substances might be also supported, so to better face the need to rapidly compensate the increased requests from patients should disruptions occur.


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.