Current inspection trends and new approaches to the monitoring of post-inspection activities

July 8, 2022

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by Giuliana Miglierini

The European Federation of Pharmaceutical Industries and Associations (EFPIA) has published its Annual Regulatory GMP/GDP Inspection Survey 2021, highlighting the more recent trends in inspections and how the pandemic affected this critical verification process of pharmaceutical productions. Meanwhile, UK’s regulatory authority MHRA launched the Compliance Monitor Process pilot, aimed to use eligible consultants as Compliance Monitors to supervise companies in the delivery of actions identified in the Compliance Protocol agreed with the regulatory authority.

Main trends in inspections

The main effect of the lockdowns has been the implementation of new ways to run inspections. The recommendation resulting from EFPIA’s report is now for virtual tools combined with onsite presence; to this instance, data gathered in 2021 show that the two modalities of inspection have a similar duration (2.9 days for on-site inspections vs 2.8 days for virtual ones). The report also indicates there is still a backlog of inspections due in 2020, the critical period of the pandemic; suggestions to manage expiring GMP/GDP/ISO-certificates include a one-year prolongation of current certificates, a dedicated communication process between the industry and regulators in the case of issues with the registration in third countries, and a planning of inspections based on the quality history of the site.

Domestic inspections confirming the trend observed since 2016, are almost double of the number of foreign inspections. These last ones focused in 2021 on only 23 countries, compared to the 44 countries visited by inspectors in 2017. EU’s countries were the most visited ones, with some 350 inspections reported vs the 150 of US, confirming the importance of European pharmaceutical manufacturing. According to the report, 2021 saw an increased attention to GDP inspections, while the percentage of sites with no inspections remains stable for six years.

A new mix of inspection tools

The use of new tools, additional to physical on-site presence, has now become a routine possibility accepted by many regulatory authorities. Many different approaches have been tested during the pandemic, including different inspections tools. Different combinations of tools cannot be considered to be equivalent, according to EFPIA. In general, a mixture of physical presence, document review and virtual presence flanked by the sharing of experience, collaboration and reliance is deemed suitable to confirm compliance and capability while supporting a risk-based efficiency.

Data show that the number of virtual inspections was higher in 2020 compared to 2021; the last year saw an increase of on-site presence vs 2020 and a mixture of virtual and on-site inspections. According to the report, only seven European countries have experience with the implementation of virtual inspection tools (Germany, Denmark, Finland, Ireland, Italy, Poland and Sweden). As a consequence, the impact of mixed virtual and on-site domestic inspections in 2021 was lower in EU member states that, for example, in the US, Brazil, Russia and Singapore.

There is still space for improvement

EFPIA’s survey presents the respective advantages and disadvantages of on-site inspections vs virtual tools. The implementation of the new modalities is far from being accomplished, the process is still on the learning curve, says the document.

While the remote, virtual interaction allows for a greater flexibility of the inspection process, it may result stressful for some people; furthermore, it impacts on the way work is organised, as it needs a flexible schedule and time to prepare for the next day meetings. Also, the style of communication changes to become less natural and more focused. Overall, virtual inspections appear to be more efficient when performed in real-time, as it would be for on-site inspections. While being less costly, due to avoiding extensive travelling, virtual inspections require a careful preparation, including the availability of a suitable IT infrastructure and connectivity. Documents are also often required in advance of the meetings to be shared with regulators.

How to further improve inspections

According to EFPIA, the future of inspections calls for improved collaboration and reliance in order to increase the knowledge shared by the different inspectorates and overcome the limits intrinsic to self-dependency. The expected final outcome of the new approach to inspections is an improvement in the decision-making process. Inspection frequency may be set every 1 to 5 years on the basis of a risk-based evaluation.

Collaboration, reliance and delegation appear to be the new mantras to guide the actions of regulators: the focus suggested by EFPIA is on inspections run by domestic authorities, coupled to the implementation of Mutual Recognition Agreements (MRA) to avoid duplication of efforts. According to the report, it would be needed to harmonise the scope of existing MRAs and to establish new ones between the EU and PIC/S participating authorities (e.g. Argentina, Brazil, South Korea, Turkey and UK). The European legislation should be also updated to include the concept of listed third countries, as already in place for the importation of active substances under the provisions of the Falsified Medicines directive.

The report also suggests a qualitative tool that would fulfil the legal requirements for “inspections” and may prove useful to support inspection planning on the basis of the knowledge of the GMP compliance history of the site, the footprint history of critical and major deficiencies and the type of inspection to be run. These elements lead to the identification of the hazards to be considered, including the intrinsic risk and the compliance-related one. The final output of the tool takes the form of a risk-ranking quality metric, to be used to establish the frequency of inspection for a certain site and the number and level of expertise of the required inspectors, as well as the scope, depth and duration of routine inspections.

All these items may form the basis for the drafting of a GMP inspection “Reliance Assessment Report”, which would also include the statement about the name of the hosting national competent authority and the basis on which country reliance has been established. Such a document may be then used to support regulatory decisions. According to EFPIA, the suggested approach would benefit of a better knowledge of the site inspected by the local NCA, a better insight in the local culture and less barriers to the interaction, with optimisation of resources. A better transparency of the inspection process is also expected, as a non-compliant site may negatively impact on the reputation of local inspectorates. Identified pre-requisites to allow the implementation of such an approach are the availability of high-quality standards at the local level and the evaluation of national regulatory systems by and independent body (e.g. PIC/S or the WHO Global Benchmarking Tool).

UK’s pilot of a Compliance Monitor Process

A new approach that may represent a first example towards the new paradigm of collaboration and reliance has been undertaken in the UK, where the Medicines and Healthcare products Regulatory Agency (MHRA) launched in April 2022 a pilot project focused on the Compliance Monitor (CM) Process (see more here and here). The pilot is part of MHRA’s delivery plan 2021-2023 and will focus on the CM supervision process for appropriate GMP and GDP Inspection Action Group (IAG) cases.

According to the MHRA, the new process would allow companies to concentrate on the delivery of the required improvements without the need to use resources to manage MHRA supervision inspections to assess compliance remediation activities. On the regulatory side, the MHRA should be able to concentrate on the delivery of the routine risk-based inspection programme. The risk-based approach to supervision and monitoring is also expected to limit the number of potential shortages of supply.

The CM process is based on the figure of eligible consultants acting as Compliance Monitors (CM) in charge of working with the company to deliver the remediation actions identified in a Compliance Protocol (CP) agreed with the MHRA. The supervision by the CMs is expected to contribute to lower the need of on-site inspections with respect to the current process managed by the IAG. The CP also includes the transmission to MHRA of high-level updates at fixed intervals of time, which should include only exceptions to the agreed timelines or significant related compliance issues which were identified. Once completed the CP protocol, the CM informs the regulatory authority that the company is ready for inspection, so that the MHRA can verify onsite the possibility of its removal from IAG oversight.

CMs will be selected by the involved company from a dedicated register and accepted as suitable for that case by the MHRA. At least five years’ experience in independent audits of GMP/ GDP companies is needed to be eligible as CM. Furthermore, not having been personally the subject of MHRA regulatory action and/or significant adverse findings in the previous three years, a suitable CV and the completion of a MHRA training as CM. All details on requirements for the CM role and application are available at the dedicated page of the MHRA website.

Suitability criteria to act as a CM for the specific case include as a minimum a sufficient experience of the dosage form manufactured, testing activities being performed, or distribution activity being carried out and a written confirmation of absence of Conflict of Interest. These criteria will be assessed by the company selecting the CM.

BIA’s view of the reliance in the UK medicines regulatory framework

The UK’s BioIndustry Association (BIA) contributed to the debate on the reliance in the UK medicines regulatory framework with a Reflection Paper. According to BIA, the MHRA has a well recognised status and history as a valued contributor to the global regulatory ecosystem and a point of reference for the regulatory decision-making which should be preserved also in the future.

BIA recalls the role played by the MHRA in the development of the concept of regulatory reliance at the EU level, as a way to support the agile management of resources and simultaneously focusing on core and innovative national activities across all stages in the product lifecycle. The central concept sees regulators from one country to rely on the decision and assessments of trusted authorities from another country in order to speed up the timeline of regulatory procedures. At the end of the process, each regulator remains fully responsible and accountable for all its decisions.

BIA also highlights the contribution of reliance to the advancement of good regulatory practices and international networks of regulators, so to better allocate resources potentially taking into account also the respective fields of specialisation. The proposal is for a list of accepted reference regulatory authorities as a way to recognise the evolution of partnerships over time. Examples of recognition pathways already active in the UK are the EC Decision Reliance Procedure (ECDRP) and international work-sharing through the Access Consortium and Project Orbis, through which the MHRA may act as the reference regulatory agency in many procedures.

BIA also warns about the risks of a sudden interruption at the end of 2022 of the reliance pathway, that would have a highly disruptive impact on companies and patients.

Approval of the Data Governance Act, and EMA’s consultation on the protection of personal data in the CTIS

June 24, 2022

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by Giuliana Miglierini

The Data Governance Act (DGA) was approved and adopted in May 2022 by the European Council, following the positive position of the EU Parliament; the new legislation will entry into force after being signed by the presidents of the Parliament and of the Council and twenty days after the publication in the Official Journal of the European Union. The new rules governing data collection and sharing will start to apply 15 months after the entry into force of the new regulation.

The protection of personal data is also central to the new transparency requirements established by the Clinical Trials Regulation (CTR). To support pharmaceutical companies dealing with personal data within the Clinical Trials Information System (CTIS), the drafting of a dedicated guideline is ongoing. The European Medicines Agency has published a document to support the public consultation which will remain open until 8 September 2022.

The Data Governance Act

The new DGA regulation is part of the European data strategy and aims to promote the availability of data within a trustworthy environment, with the final goal to improve their use for research and the creation of innovative services and products.

Central to the DGA are some categories of public-sector data that are subject to property rights (i.e. trade secrets, personal data and data protected by intellectual property rights), which were not covered by the previous Open Data Directive (2019). Under the new rules, the reuse of such data shall be permitted provided that the public-sector bodies allowing it are technically equipped to ensure the preservation of privacy and confidentiality.

The DGA will also parallel the General Data Protection Regulation (GDPR) in providing appropriate safeguards against the unlawful international transfer of or governmental access to non-personal data (as the GDPR does for the personal ones). Secondary legislation may be issued by the Commission, for example, to ensure specific non-EU countries provide appropriate safeguards for the use of non-personal data transferred from the EU, on the basis of the existence of local equivalent measures of a similar protection level to that existing in the EU.

The reuse of public-sector data shall be justified with respect to the provision of a service of general interest; exclusive arrangements are needed, with a duration of 12 months for new contracts and 30 months for the existing ones. The access to data will operate through a searchable electronic register of public-sector data to be established by the European Commission and available via national single information points. Model contractual clauses may be adopted by the Commission in order to support public-sector bodies and re-users with the transfer of nonpersonal data covered by the DGA to third countries.

Data intermediation services

Data intermediation services are the core of the new business model resulting from the Data Governance Act; they will be listed in a register to improve transparency and trust. The final target is to enable a secure environment for the sharing of data.

Digital platforms shall represent the reference point for voluntary data-sharing between companies; they should fulfil all data-sharing obligations at the European and national level. Individuals shall maintain full control over their personal data; service providers should support them in exercising their rights according to the GDPR. New tools may be introduced to facilitate sharing on the basis of data holder’s consent, i.e. personal data spaces or data wallets. Service providers won’t be able to share data for purposes other than the allowed ones, and cannot benefit from selling data, even though they can charge for the transactions the carry out.

Data altruism is another key concept of the DGA regulation, making possible to voluntary share its own data for the common good, for example in the field of medical research. Data altruism will apply to both individuals and companies; the access to data should be possible upon registration of the interested entities in a national register of recognised data altruism organisations. A specific logo will support the easy identification of both compliant providers of data intermediation services and data altruism organisations.

The new European Data Innovation Board (EDIB) will be in charge of assisting the EU Commission on issues relative to the interoperability of data intermediation services and the development of guidelines on the creation of data spaces.

Data protection in the regulatory field

EMA’s draft guideline provides a description of the Clinical Trials Information System, its components and functionalities, as well as the rules for the publication of clinical trials information submitted to the CTIS (chapter 2). The protection of both personal data and commercially confidential information (CCI) submitted to the CTIS is then discussed (chapters 3 and 4), together with the protection of personal data and CCI in inspection reports (chapter 5).

The CTR established the CTIS as the single entry point for the submission of data and documents relating to clinical trials; the corresponding EU Database contains such data and documents, and the two are jointly referred to as the EU Portal and Database (EUPD).

The EUPD is the first component of the CTIS, representing the Clinical Trial module providing secure domains accessible to regulatory authorities and sponsors along the entire life cycle of the medicinal product and a public website where to find public information. The second component of the CTIS is represented by the EudraVigilance (EV) safety module, consisting of the Repository of Annual Safety Reports (ASRs) and the Clinical Trial Module (EVCTM) for Individual Case Safety Reports (ICSRs) of suspected unexpected serious adverse reactions (SUSARs) related to Investigational Medicinal Products. The optimisation of regulatory data flow also involve the use of data contained in the Extended EudraVigilance Medicinal Product Dictionary (XEVMPD), in the Organisation Management Service (OMS), and in the Identity Access Management (IAM).

The CTR regulation establishes the rules preventing the access to data stored in the EU Database on the basis of confidentiality information. Is this the case, for example, of personal data falling under Regulation (EU) 2018/17255 governing the protection of natural persons and their personal data. Commercially confidential information may also fall under this provision, upon consideration of the status of the marketing authorisation and unless there is an overriding public interest in disclosure. This means no data from the clinical trial application dossier can be made public before the decision on the clinical trial has been taken.

All personal data (such as the ones of trial participants) in documents submitted to the CTIS should follow the general principles on anonymisation and pseudonymisation of personal data. The draft guideline provides examples of the public information that should be made available with respect to a certain clinical trial. This should include as a minimum the main characteristics of the trial, the conclusion on Part I of the assessment report for the authorisation, the decision on the authorisation of a clinical trial, the substantial modification of a clinical trial, and the clinical trial results including reasons for temporary halt and early termination.

A dedicated module of the CTIS is meant for inspectors to manage all information relative to GCP inspections conducted under the CTR, including the uploading of the final report. To this instance, the guideline indicates no personal data should be included in the version of the inspection report due for publication.

PIC/S Annual Report 2021

May 20, 2022

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by Giuliana Miglierini

The Annual Report of the Pharmaceutical Inspection Co-operation Scheme (PIC/S) resumes the many activities and results achieved in 2021, despite the ongoing pandemic that required remote coordination and on-line virtual meetings. To this regard, a written procedure has been used to manage important decisions. PIC/S also supported the harmonisation of the distant assessment procedures used by the various regulatory authorities to run GMP inspections during the pandemic period.

The non-binding co-operative arrangement between international regulatory authorities aims to implement harmonised GMP standards and quality systems in support to harmonised inspection procedures. PIC/S’ new strategic plan for 2023-2027 will be presented at the PIC/S 50th anniversary in 2022. The PIC/S Committee has elected Paul Gustafson (Canada/ROEB) as the new Chairperson for the period 2022-2023; he takes the place of Anne Hayes (Ireland/HPRA).

New memberships and re-assessments

Last year saw the entry into the PIC/S scheme of the Brasilian Agência Nacional de Vigilância Sanitária (ANVISA), one of the main regulators of South America, representing the largest market for medicinal products for this geographic area. ANVISA is the 54th member of PIC/S.

Five other membership applications continued the process of assessment. These include the application of Armenia’s Scientific Center of Drug and Medical Technologies Expertise (SCDMTE), that was requested to update its documentation; the preliminary report should be issued soon.

The Bulgarian Drug Agency (BDA) will benefit of a partial assessment of its application, due to the fact the agency already went through an audit under the EMA Joint Audit Programme (JAP) whose report was shared with PIC/S. Health Canada will also collaborate to this assessment under a MRA procedure.

The Jordan Food and Drug Administration (JFDA) also filed a membership application, as well as another regulator from Africa, the Saudi Food & Drug Authority (SFDA), whose preliminary report is soon expected.

Particularly complex is the case of the application by several Competent Authorities of the Russian Federation that jointly submitted a complete membership application in December2020. A larger team, consisting of a Rapporteur and several Co-Rapporteurs, shall be nominated to better manage the procedure. The involved Russian authorities are the Ministry of Industry and Trade of the Russian Federation (Minpromtorg Russia), the Federal Service for Surveillance in Healthcare (Roszdravnadzor), including the “Information and Methodological Center for Expertise, Accounting and Analysis of Circulation of Medical Products” (FGBU “IMCEUAOSMP” of Roszdravnadzor),the Federal “State Institute of Drugs and Good Practices” (FSI “SID & GP”), and the Federal “Scientific Center for Examination of Medical Devices” of the Ministry of Health of the Russian Federation (FSBI ”SCEMD”).

Among authorities undergoing the pre-accession procedure is the Chinese regulatory agency National Medical Products Administration (NMPA), whose application will be assessed by Jacques Morenas (France/ANSM) as Rapporteur and Raphael Yeung (Hong Kong SAR, China/PPBHK) as Co-Rapporteur.

Reviewing of the pre-accession application is also ongoing for the Analytical Expertise Center (AEC) of the Ministry of Health of Azerbaijan, the Bangladesh’s Directorate General of Drug Administration (DGDA, this 2-year timeframe for the pre-accession expired in February 2021, and a new application was required) and the Drug Regulatory Authority of Pakistan (DRAP), that was invited to apply for membership subject to the implementation of the PIC/S GMP Guide.

PIC/S also run a Joint Reassessment Programme (JRP) in parallel with the EU’s JAP to re-evaluate its members for equivalence on a regular basis. In 2021 the JRP included the reassessment of regulatory authorities from Indonesia (NADFC), New Zealand (Medsafe), and South Africa (SAHPRA).

PIC/S also established new contacts in 2021 with other non-member authorities, including Cameroon’s Laboratoire National de Contrôle de Qualité des Médicaments et d’ Expertise, China’s Institute of Veterinary Drug Control, Cuba’s Centro para el Control Estatal de Medicamentos, Equipos y Dispositivos Médicos (CECMED), and Montenegro’s Institute for Medicines and Medical Devices.

New guidances and revisions of existing ones

Among the new guidances adopted in 2021 are the Annex 2A for the Manufacture of ATMP for Human Use and Annex 2B for the Manufacture of Biological Medicinal Substances and Products for Human Use, that entered into force on 1 May 2021 (PE 009-15). The documents were finalised by the PIC/S Working Group on the revision of Annex 2 of the PIC/S GMP Guide.

The Working Group on Data Integrity issued two other guidance documents that entered into force on 1 July 2021, the Guidance on Good Practices for Data Management and Integrity in Regulated GMP/GDP Environments (PI 041-1) and a restricted Aide Memoire on inspection of data management and integrity (PI 049).

PIC/S also issued the Good Practice Guidelines for Blood Establishments and Hospital Blood Banks (PE 005) and the related Aide Memoire to Inspections of Blood Establishments and Plasma Warehouses (PI 008), that entered into force on 1 June 2021. The dedicated Working Group will now address the revision of PI 019 (PIC/S Site Master File for Source Plasma Establishments) and PI 020 (PIC/S Site Master File for Plasma Warehouses).

PIC/S and EMA’s joint Working Group on Annex 1 reviewed the comments received to the second public consultation and drafted the final version of the Annex.

The Working Group on Harmonisation of the Classification of Deficiencies is finalising the revision of the PIC/S SOP on Inspection Report Format (PI 013-3) in order to align it with the abovementioned PI 040-1. The Working Group on Controlling Cross-Contamination in Shared Facilities is as well finalising the revision of its Guidance on Cross-Contamination in Shared Facilities (PI 043-1).

PIC/S is also working to harmonise its GMP Guide and Annexes to the rules established by the European Union, in collaboration with EMA through the PIC/S-EMA Joint Consultation Procedure. Many chapters and annexes of the PIC/S-EU GMP Guide were considered during 2021, including Chapter 1 (Pharmaceutical Quality System), Chapter 4 (Documentation) and Annex 11 (Computerised Systems), Annexes 4 and 5 (Veterinary Medicinal Products), Annex 13 (Investigational Medicinal Products), Annex 16 (Certification by an Authorised Person & Batch Release), and Annex21 (GMP Obligations for Importation to the EU).

Virtual training in the pandemic period

Four virtual training events were organised in 2021, among which a PIC/S webinar for inspectors on ICH Q12 (Pharmaceutical Product Lifecycle Management) that was attended by around350 participants from 50 agencies and 44 different jurisdictions.

The webinar on Distant assessment/Remote Virtual Inspection co-organised with the EU Commission Expert Sub-Group on Inspections in the Blood, Tissues and Cells Sectors (IES) was attended by around 325 participants.

The 2021 PIC/S annual seminar was hosted by the Ministry Food and Drug Safety (MFDS) of the Republic of Korea, and saw the participation of 315 inspectors from 54 authorities.

The 2nd meeting of the PIC/S Expert Circle on Controlling Cross-Contamination in Shared Facilities (CCCISF) was virtually hosted and was attended by 375 participants.

Last year saw also the provision of new harmonised and standardised GMP training activities for inspectors under the PIC/S Inspectorates’ Academy (PIA) initiative, a web-based educational centre also involved in setting up a standardised qualification process of inspectors.

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

April 9, 2022

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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.

The Made in Europe partnership for manufacturing

March 18, 2022

business models, circular economy, collaborative product-service engineering, cybersecurity, data economy, digital transformation, EFFRA, environmental impact, European Commission, European Factories of the Future Research Association, European manufacturing system, green transformation, Horizon Europe, Made in China, Made in Europe, manufacturing sovereignty, manufacturing sustainability, manufacturing-as-a-service, member states, next-generation sustainable materials and products, partnership, re-manufacturing, reconfigurable production lines, recycling, resilience, Strategic Research and Innovation Agenda

by Giuliana Miglierini

The availability of a robust framework to support a sustainable European manufacturing system is undoubtedly a priority in the challenging times we are experiencing. In the pharmaceutical sector, the reshoring of productions of both active ingredients and finished medicinal products is already a key point of the new EU Pharmaceutical Strategy and of the consequent ongoing revision of the legislation governing the sector.

A broader action addressed to the entire European industrial system was launched in 2019 within the framework programme Horizon Europe (HE) 2021-2027: the Made in Europe manufacturing partnership aims to become the main driver for sustainable manufacturing in Europe. The partnership was modelled with the contribution of the European Commission, member states and the European Factories of the Future Research Association (EFFRA); the latter is also the leading entity in charge of coordinating the initiative, which include all actors taking part to the manufacturing ecosystem (i.e. academia, industry, non-governmental organisations and the public sector).

The main goals of the Made in Europe partnership

The two themes of ecological and digital transitions central to the policies of the von der Leyen Commission are the main source of inspiration for the Made in Europe partnership. The availability of a European manufacturing environment able to compete on global scenarios thanks to its technological leadership is the main objective of the initiative. Many challenges need to be faced to reach it, especially in the field of the integration of technologies based on artificial intelligence to fully exploit the potential of industrial data, the reshaping of a circular economy and a high flexibility in response to emerging trends and issues.

The Made in Europe partnership represents a common platform for national and regional manufacturing technology initiatives, including the required disciplines and technologies. The principles governing its actions are described in a guidance document available at the EFFRA website; a Strategic Research and Innovation Agenda (SRIA) is also available.

According to the guidance document, manufactured goods represented in 2018 83% of EU exports, and accounted for a annual trade surplus of 286 billion euro. Despite this very high surplus, the document warns it may be not sufficient to cover deficits arising from the purchase of non-manufactured goods and services. Also considering these factors, the balance moved from a surplus of € 22 billion in 2017 to a deficit of € 25 billion in 2018. This situation may now dramatically evolve further, due to the high increase of costs of energy and raw materials experienced in the last month, as a consequence of the war occurring at the Eastern boundaries of the EU. A situation that might make harder for the EU to also face the competition of Asiatic economies.

The guidance document identifies twelve challenges to be faced by the European manufacturing industry, starting from the need to strongly reduce to the minimal level its environmental impact. To this instance, optimisation of resource efficiency and the carbon intensity of the entire supply chains are among the main factors to be addressed, leading to the opportunity for European-made environmental-friendly but high-priced products. This switch also supports the development of circular models for the economy, and the use of next-generation sustainable materials and products, requiring to manage profound changes if the manufacturing systems and related supply chains. Recycling and re-manufacturing may play in the future an important role in redefining products’ life cycle. The resilience and agility of the European manufacturing industry shall be also tackled, in order to limit the impact of sudden crisis, as occurred with the Covid-19 pandemic or now with the Ukraine war. This goal calls for the availability of flexible and reconfigurable production lines within a country or region, suggests the document. The pharmaceutical sector already experienced criticalities during the Covid-19 arising from the dependence from extra-EU supplies; the same applies to all European industrial sectors, and according to the Made in Europe partnership it should be faced through achieving manufacturing sovereignty and technological leadership in key areas and critical value chains. A very challenging objective, that requires a coordinated European effort on manufacturing.

As for competition from other economies, the document warns that big public-private manufacturing partnerships are being launched also in Asia and America (i.e. Made in China). Environmental and social aspects should be jointly considered in the location/relocation of manufacturing companies, to account for the environmental sustainability of the businesses coupled to the requirements arising from a EU’s population mainly living in urban areas.

The challenges of digitalisation

Many of the above-mentioned targets identified by the Made in Europe partnership may benefit from the potential offered by the implementation of digital technologies to accelerate innovation and industrial transformation, thus leading to the improvement of the overall efficiency of manufacturing. Data are becoming a central driver for the creation of value, but companies are called to better understand the data economy also from a non-technological point of view. Cybersecurity should be also carefully addressed, as digitalisation is reflected by a higher vulnerability to cyber attacks.

Digitalisation also impacts on the availability of new business models, such as “manufacturing-as-a-service” and “collaborative product-service engineering”. Automated systems governed by artificial intelligence are now widely available in many industrial plants, and attention should be paid to modes of interactions between collaborative robots and human operators. Nevertheless, the availability of trained and skilled human staff is considered as a major barrier and threat by the Made in Europe partnership, particularly for SMEs.

The planned actions

Six different calls for actions in the field of green and digital transitions were launched by the Made in Europe manufacturing partnership within the Horizon Europe work programme 2021-2022. The total available budget is around € 1 billion. Topics of interest included AI enhanced robotic systems for smart manufacturing, zero-defect manufacturing towards zero-waste, laser-based technologies for green manufacturing, manufacturing technologies for bio-based materials, advanced digital technologies for manufacturing, and data-driven distributed industrial environments.

The Made in Europe partnership was also involved in calls about reconfigurable production process chains, products with complex functional surfaces, excellence in distributed control and modular manufacturing, intelligent work piece handling in a full production line, ICT Innovation for manufacturing sustainability in SMEs, and digital tools to support the engineering of a circular economy.

A consultation on possible topics to be included in the HE work programme 2023-2024 is still open to comments and can be accessed by the dedicated webpage at the EFFRA website. A summary document is also available presenting potential recommendations and discussion topics received up to now. New possible lines of actions may address the availability of “excellent, responsive and smart factories & supply chains” , how to achieve a circular products and climate- neutral manufacturing, new use models referred to new integrated business, product-service and production approaches, and models for a human-centered and human-driven manufacturing innovation.

The Faculty of Pharmacy in Brno is once again a part of Masaryk University

February 28, 2022

Aleš Franc, Brno, Czech Pharmaceutical Society, Czech Rebublic, Department of Applied Pharmacy, Department of Chemical Drugs and Department of Molecular Pharmacy, Department of Natural Drugs, Department of Pharmaceutical Technology, Department of Pharmacology and Toxicology, Faculty of Pharmacy, Masaryk University

by Aleš Franc

In 2020, the Faculty of Pharmacy of the Veterinary and Pharmaceutical University Brno was transferred to the framework of Masaryk University (both are located in Brno, Czech Republic). This short communication discusses the background to this event.

Faculty of Pharmacy, Masaryk University (1952 – 1960)
The Faculty of Pharmacy was established at Masaryk University (MU) based on a 1952 government decree. It had eight departments divided into groups. A Garden of Medicinal Plants and a Faculty Pharmacy were also built for the needs of the faculty in Brno. According to statistics from 1956, 75 % of graduates went to work in pharmacies and 5-7 % found employment in the pharmaceutical industry. However, based on a government decree, the faculty was abolished in 1960, and the study was merged with the Faculty of Pharmacy of Comenius University in Bratislava, which has existed since 1952 and became the only pharmaceutical faculty in Czechoslovakia. In 1969, the Faculty of Pharmacy of Charles University was established with its seat in Hradec Králové. In 1991, shortly after the collapse of socialism in Czechoslovakia, the Faculty of Pharmacy in Brno was renewed within the University of Veterinary and Pharmaceutical Sciences Brno.

Faculty of Pharmacy, Masaryk University (2019 – present)
Masaryk University was founded in 1919 as the second Czech university. According to the number of students in accredited study programs, it is the second-largest university in the Czech Republic. It has ten faculties and operates, among others, its Mendel Museum, the Scala University Cinema, the University Center in Telč, and the Antarctic Polar Station. According to QS Top Universities, Masaryk University has long been ranked among the top universities.
In 2019, negotiations were started between MU and University of Veterinary and Pharmaceutical Sciences on the inclusion of the faculty back into the MU framework. The move took place in July 2020. Teaching continues in the existing premises on the UVPS campus, which MU rented for five years. In the future, the faculty is to become part of the university campus. For current students and employees, the transition to MU means the possibility of cooperation with other faculties, such as the Faculty of Medicine and the Faculty of Science.
Thanks to the transfer to Masaryk University, the Faculty of Pharmacy will be able to use the facilities of teaching hospitals and the close contact with patients; also very strong scientific research facilities with the perspective of further development of pharmaceutical sciences. For example, Masaryk University has a Centre for Medicinal Plants, which has been connected to the Garden of Medicinal Plants since the 1950s, when the faculty was still part of MU. Other pharmaceutical disciplines can significantly enrich the research topics addressed at MU in the direction of biologically active substances of various origins, their production, and especially processing into modern pharmaceutical forms. At the same time, there is scope for the development and commercial exploitation of various activities, especially in the field of preclinical contract research.

Department of Pharmaceutical Technology
Currently, the Faculty of Pharmacy has six departments: Department of Applied Pharmacy, Department of Natural Drugs, Department of Pharmaceutical Technology, Department of Pharmacology and Toxicology, Department of Chemical Drugs and Department of Molecular Pharmacy.
The Department of Pharmaceutical Technology, which is closest to the pharmaceutical industry and whose employee is also the author of this article, operates within the Faculty of Pharmacy. It deals with the formulation, preparation, manufacture, evaluation, protection, and other aspects associated with pharmaceutical dosage forms. Regarding the focus on the pharmaceutical industry, a new program has been opened for cooperation with partners from the commercial sector. Oncomed manufacturing a.s. and medac GmbH became the first general partners.

The above has been processed according to materials available on the websites of the Faculty of Pharmacy MU and Masaryk University, Brno, Czech Republic.

Aleš Franc is Associate professor, Department of Pharmaceutical Technology at Masaryk University

ICMRA published a Reflection paper on remote inspections

January 21, 2022

aseptic manufacturing, collaborative inspections, CROs, deficiencies, digital technologies, distant assessment, GCP, GMP, health emergencies, hybrid inspections, ICRMA, inspections, inspectors, investigator sites, manufacturing site, on-site inspections, potent active ingredients, quality risk managemet, read-only access, real-time translation services, Reflection paper, regulatory authorities, regulatory compliance, remote assessment, remote inspections, virtual tours

by Giuliana Miglierini

Remote inspections have become a widely used approach since the last two years to ensure the oversight of the compliance of pharmaceutical productions to regulatory requirements, as the prolonged lockdown periods determined by the pandemic made very difficult the maintenance of the regular schedule for on-site inspections.

A Reflection paper on the so gathered experience has been recently published by the International Coalition of Medicines Regulatory Authorities (ICMRA); the document addresses from the point of view of regulatory authorities the many issues encountered to establish appropriate modalities to interact at distance with the industrial counterparts by mean of digital technologies and suggests the best practices for the future. The analysis focused especially on remote GCP and GMP inspections.

The Reflection paper was drafted by a working group chaired by the UK MHRA and inclusive of representatives from the US FDA, EMA, Health Canada, Swiss-medic, HPRA Ireland, AEMPS Spain, ANSM France, PEI Germany, MHLW/PMDA Japan, TGA Australia, ANVISA Brazil, HSA Singapore, WHO and Saudi FDA.

The lack of a uniform definitions and approaches

Each national competent authority adopted during the pandemic its own approach to remote inspections, evaluating this type of opportunity on a case-by-case basis, making use of established quality risk management principles and tools to reach their decision (par. 3 of the Reflection paper enlists the more widely used parameters for risk assessment and management).Among the factors entering this preliminary evaluation are the regulatory compliance history of the inspectee, the scope of the inspection (pre-approval, routine or for cause), and the inherent risk associated with the activities conducted by the site, the types of products and the need for the product.

The term used to identify the at distance interaction with the company to be inspected also assumed a quite wide variability; “distant assessment”, “remote evaluation”, “desktop assessment” or “remote assessment” are other frequent declinations used to define oversight procedures run by using digital technologies, both at the national and international level.

The choice of the specific term to identify this sort of practice depends upon many different factors, including the type of inspection and of the involved facilities, and the local national legal frameworks governing inspections as well as protection of personal data. The specific areas or sites to be included in the official review of activities, documents, facilities, records, etc. have proved also highly variable, as they may include not only the manufacturing site, but also investigator sites of a clinical trial, the sponsor’s and/or contract research organisation’s (CRO’s) facilities, or any other establishments deemed appropriate by the regulatory authority running the inspection.

Should the preliminary risk assessment had discouraged the possibility to conduct a remote inspection, the on-site inspections were usually postponed until the termination of lockdown measures in the interested countries. Hybrid or collaborative inspections represent another opportunity used to handle critical cases: the first ones involve the assessment or inspection to be conducted using a mix of remote and on-site activities, the second see two or more regulatory authorities collaborating to perform a conjunct inspection of a specific site.

According to the Reflection paper, it thus appears highly unlikely that a unique and fully harmonized approach to remote inspections in all scenarios might be developed for the future. “While the ICMRA group have found remote inspections an enabling tool to maintain at least a minimal regulatory oversight during the pandemic, it is not the view of the group that remote inspections would fully replace an on-site inspection programme”, states the document.

The main issues encountered

The possibility to conduct inspections, evaluations or assessments at a distance/virtually is based on the implicit availability of a robust IT and communication infrastructure; this has proved a fundamental requirement to smoothly share and review all the relevant documentation and ensure access from remote to systems and plants. Virtual tours of the manufacturing facilities are a typical example, for which the availability of solid “hardware and software that can provide an appropriate field of vision, clarity and stabilisation of the picture, while simultaneously facilitating conversation between the inspector and tour host” is essential to enable the real-time transmission of images and sounds captured by the in charge on-site staff by mean of smart devices or more advanced systems as smart-glasses.

In international inspections, the difference in time-zone and the availability of real-time, online translation services have also proved critical in many instances, especially if parallel sessions of discussion were needed. The possibility for inspectors to access on-line the relevant documentation requires the availability of the inspected company to provide credentials to enter in a read-only mode its proprietary document management systems and repositories. To this instance, confidentiality issues often led many companies to provide access to IT systems by mean of a specifically appointed member of the staff, in charge of accessing in real-time the systems and made available all the documentation as indicated by the inspectors.

The main areas of attention

The Reflection paper identifies four different areas for which remote assessment/inspection proved to be particularly useful during the pandemic period.

In the case of virtual tours, the indication coming from ICRMA experts is to limit the use of prerecorded video tours only in exceptional circumstances, and never for inspection of high-risk activities, as the inspector may not be in the right conditions to effectively verify all details needed to evaluate the suitability of the facility.

“Direct access to documentation by inspectors is an expectation, electronically or otherwise, whether the inspection is on-site or remote”, states the Reflection paper. The alternative intervention of site staff may be acceptable, but it should not negatively impact the results of the assessment. Furthermore, this modality may also prove quite time consuming for both the inspector and the inspected company. ICRMA also supports the possibility for regulators to access documentation after the closure meeting, and upon the formal closure of the inspection, in order to facilitate the drafting of the report or to clarify a deficiency already raised.

GCP and GMP inspections

Specific issues for both GCP and GMP inspections are addressed in two dedicated chapters of ICRMA’s Reflection paper.

“It should be noted that within the EU remote inspections at investigator sites are not considered to be feasible”, writes ICRMA. The motivation has to be found mainly in the need to avoid any further impact on the clinical sites during an health emergency like the pandemic, andin the issues posed by local frameworks for data protection. The Reflections paper provides a list of clinical areas not suitable for remote inspection.

As for GMP inspections, not all regulatory authorities adopted the same approach during the pandemic; in general terms, this sort of practice has been judged acceptable by ICRMA to handle emergency situations with restrictions to travels in place, but it cannot fully substitute onsite inspections of manufacturing sites. More specifically, the experience of the past two years shows that remote inspection proved unfeasible for sites requiring detailed observation, as those performing aseptic manufacturing or handling potent active ingredients with low Permitted Daily Exposure.

A study on medicines shortages from the European Commission

December 24, 2021

critical shortages, digital leaflets, Directive 2001/83/EC, emergency imports, essential medicines, EU list, EU pharmaceutical legislation, European Commission, exceptional circumstances, export restrictions, generics, inequitable distribution, intra-EU trade, legal obligations, legislative framework, MAHs, mandatory reporting, manufacturing issues, market withdrawals, marketing authorisation holders, medicines for human use, medicines shortages, national competent authorities, NCAs, off-patent medicines, parallel distribution, Pharmaceutical Strategy, Rebecca Guntern, regulatory flexibility, Repeat Use Procedure, shortage registries, shortage reporting, supply, wholesale distributors

by Giuliana Miglierini

The study on medicines shortages commissioned in March 2020 by the European Commission upon request of the European Parliament and Council has been published; the document, prepared by a consortium led by Technopolis, suggests 16 possible policy measures – both legislative and not-legislative – that the Commission may consider while drafting a new legislative proposal to govern the issue, expected to be announced at the end of 2022.

According to the current EU pharmaceutical legislation (Directive 2001/83/EC), marketing authorization holders (MAHs) have to submit – two months before the temporary or permanent interruption of supply of a certain medicinal product – a pre-notification to the relevant national competent authorities (NCAs) (Article 23a, a part in the case of exceptional circumstances).

The mandate to continue supply to cover the needs of patients, and respective responsibilities of MAHs and wholesale distributors are established by Article 81 of the same directive.

The new study will support some of the achievements set forth in the Pharmaceutical Strategy; another action undertaken to reduce the impact of shortages in the EU is represented by the EU Executive Steering Group on Shortages of Medicines Caused by Major Events, an initiative set up in March 2020 with the contribution of the Commission, EMA and member states.

“The Commission study on shortages by Technopolis confirms that current market framework conditions for off-patent medicines play against supply resilience – said Rebecca Guntern, President ad-interim of Medicines for Europe, commenting the release of the study –. As long as healthcare systems only focus on the cheapest possible price for off-patent medicines and do not reward investments to ensure robust supply chains, the only option for companies is to be the cheapest or to leave the market.”

The main outcomes of the study

The study on shortages focused its attention on medicines for human use marketed in the EU/ EEA in the period 2004-2020. The main objectives of the exercise include the identification of shortages’ root causes and specific characteristics, the assessment of the adequacy of the current framework (at EU and national level) and of possible solutions to address the problem.

Data from the shortages registries kept by national competent authorities (NCAs) of 22 EU’s countries was only available for years 2007-2020. Commercial data on pharmaceutical sales from IQVIA MIDAS was also used, and extensive consultation with stakeholders was run under different formats.

Central to the 16 recommendations highlighted in the study is the establishment of a centralized and harmonised EU-wide definition of medicine shortages, as well as of harmonised reporting criteria. The latter should aim to collect sufficiently detailed information on key parameters (e.g. product details, MAH, details on the shortage and impact).

Different definitions, systems for notifications and type of information requested are currently in use in the various member states; even the definition of “shortage” agreed in 2019 by EMA and HMA was not considered by stakeholders adequate to differentiate between critical and non-critical shortages. According to the report, this fragmented situation doesn’t allow for the sharing of data and comparative analysis between countries, thus resulting in the overall inefficiency of the system.

Attention should be paid also to the creation of a EU-wide list of medicines subject to critical shortages; specific policies and regulations may be developed on this basis to improve their availability. Medicines typically experiencing shortages are older, off-patent and generics drugs with low profit margins; the main therapeutic areas involved include pain, hypertension, infections and oncology.

The creation of dialogue platforms at the national level is also envisaged, where to exchange the point of view of different supply chain stakeholders (including patients and healthcare providers). The study highlights the high burden shortages create on pharmacists and physicians looking for the best possible treatment alternative for their patients. A possible way to address this issue would see the availability of information about alternative medicines in shortage databases. In many cases, this type of occurrence is referred just to some countries within the EU, thus suggesting inequitable distribution and access rather than global supply issues may play a major role in shortages.

Understanding the root causes

Limited reporting is a key point to be solved in order to improve the understanding of root causes of shortages. According to the study, a reductionist approach to reporting is often used; this makes fully evident just acute causes (e.g. a problem at the production site), but leaves unattended more systemic issues (e.g. consolidation of manufacturing, resulting in a very limited number of production sites) and market-related factors (e.g. single-winner procurement practices).

Quality and manufacturing issues account for approx. half of all cases of shortages, suggest the report; among commercial reasons are market withdrawals and unexpected increases in demand. The information available for the analysis was judged insufficient to exactly asses the potential risks linked to outsourcing of manufacturing activities (including the production of APIs) and parallel distribution.

The proposed recommendations ask for greater transparency of industry supply quotas as well as parallel traders’ and wholesalers’ transactions. Suppliers should establish adequate shortage prevention and mitigation plans; legal obligations for MAHs and wholesalers are suggested in order to maintain a safety stock of (unfinished) products for medicines of major therapeutic interest at EU-level.

A new legislation to tackle shortages

The provisions set forth by Articles 23a and 81 of the Directive have been transposed differently into the single national legislations, often well before the establishment of the shortages registries. Several EU’s countries have acted on their own to strengthen the system, for example establishing mandatory reporting on stock levels and export restrictions. Nevertheless, according to the study available data are not sufficient to draw final conclusions on the costs and efficacy of stock keeping obligations on the level of (notified) shortages in the countries where they were introduced.

A more pro-active approach to the management of medicines shortages by MAHs and distributors may be supported by the availability of a EU-wide and uniform legislation governing financial sanctions to be applied if notification requirements and/or supply responsibilities are not met. Other suggestions include the adoption of common principles for the introduction of national restrictions on intra-EU trade, and the availability of greater flexibilities for emergency imports of specific products in case of market withdrawals and other critical shortages. As for procurement, the study indicates the opportunity to address public procurement tenders also considering the incorporation of requirements for more diversified, multiple tenderers and thereby supply sources.

From a regulatory perspective, the document highlights the opportunity to reduce costs and simplify administrative procedures for the submission of post-approval changes. The availability of an accelerated mutual recognition procedure (MRP) within the EU is also suggested, together with a more efficient use of the Repeat Use Procedure. Improved flexibility should be a target also with respect to the EU-wide regulation governing medicines packaging and labelling, so to allow for the use of digital leaflets and multi-country/multi-language packaging and labelling.

Steps forward towards the new framework for HTA

November 26, 2021

added value, administrative procedures, choice of comparators, Council of Europe, data appropriateness, disease prevention, Dominique Le Guludec, early dialogue, early exchange, economic evidence generation plan, ema, EUnetHTA 21, feasibility study, HaDEA, HAG, Heads of Agencies Group, HTA, HTA agencies, HTA regulation, HTA White Paper, Joint Clinical Assessments, joint consortium, Joint Scientific Consultations, JSC, medical devices, national competent authorities, non-binding scientific advice, Open Call, patient groups, pharmaceutical industry, pivotal clinical trials, proof of concept, quality of life, relevant outcomes, scientific advice, Service Contract, study design, Technology Assessment, Trygve Ottersen

By Giuliana Miglierini

The long-waited European regulation on Health Technology Assessment (HTA) was adopted by the Council of Europe on November 9, and it has now to pass through the final endorsement of the European Parliament as the last step before publication in the EU Official Journal. The regulation will entry into force three years and twenty days after publication.

The first proposal of a new HTA regulation was made in January 2018 by the EU Commission; the final political agreement between the Council and the EU Parliament was reached in June 2021. The position of the Council of Europe on the draft regulation at first reading was also published.

The provisions of the new HTA regulation will apply to medicinal products, medical devices (for example pacemakers, dialysis equipment or infusion pumps) or medical and surgical procedures, as well as measures for disease prevention, diagnosis or treatment used in healthcare.

“The adoption of this law is another demonstration of how EU countries, when acting together, can achieve very practical results for their citizens. This new law will benefit patients, producers of health technologies and our health systems.”, said Janez Poklukar, the Slovenian minister for health.

Cooperation and joint activities

Joint clinical assessments and joint scientific consultations are central concepts of the HTA regulation: a target that would require the active cooperation of all member states in order to efficiently identify emerging health technologies. Administrative procedures shall be greatly simplified and become more cost-efficient, as manufacturers of health technologies (especially small companies) should be required to submit once-only all data and documentation for a certain technology at the EU level. These will form the basis for national competent authorities to run all joint activities, including scientific advice and clinical assessment.

The added value of new health technologies compared to the existing ones will be a main driver to guide the assessment activities, so to take informed decisions on pricing or reimbursement.

Joint scientific consultations may also include the exchange of relevant information between national authorities and manufacturers on development plans for the technology under assessment, so to favour the availability of all the evidence required to meet regulatory expectations.

The new Heads of Agencies Group

While waiting for the formal adoption of the new HTA regulation by the EU Parliament, other activities are ongoing to set up the operative framework needed to guarantee the smooth activation of all planned collaborative efforts.

The newly formed Heads of Agencies Group (HAG) is an initiative aimed to support the implementation of common joint work approach on all HTA activities at the EU level, according to the new model of cooperation among national authorities established by the regulation.

The new HTA-focused collaborative network for high-level strategic exchange and discussion was launched on 29 September 2021 by the heads of 19 European HTA agencies, which elected Prof. Rui Santos Ivo (INFARMED, Portugal) as its Chair, and Prof. Dominique Le Guludec (HAS, France) and Dr. Trygve Ottersen (NIPH, Norway) as Vice-Chairs. The secretariat of the Group has been established at the Dutch Health Care Institute (ZIN).

All HAG’s activities will be based on a joint Memorandum of Understanding. The Group will work during the next three years to support national systems to be prepared for the entry into force of the HTA regulation, including the availability of the needed capacity. HAG will also support the joint technical and scientific work performed by HTA bodies across Europe, and it will advise policymakers and other relevant institutions – both at the EU and national level – on issues related to cooperation in HTA.

Current members of the group include the following national authorities involved in HTA activities: AEMPS (Spain), AIFA (Italy), AGENAS (Italy), AIHTA (Austria), INFARMED (Portugal), KCE (Belgium), NIPH (Norway), G-BA (Germany), HAS (France), HIQA (Ireland), IQWiG (Germany), FIMEA (Finland), NCPE (Ireland), REDETS (Spain), RER (Italy), RIZIV-INAMI (Belgium), NOMA (Norway), TLV (Sweden) and ZIN (The Netherlands).

The EUnetHTA 21 consortium

After the closing of its third Joint Action (2016-2020), which paved the way to the permanent HTA working structure for Europe (encompassing more than 80 HTA bodies), the European Network for Health Technology Assessment (EUnetHTA) has published a HTA White Paper as the final document resuming lessons learned up to now that may prove relevant for the implementation of the next phase of the HTA joint cooperation.

This new phase in the life of the Network, that now goes under the name of EUnetHTA 21, is no more a Joint Action; a joint consortium has been created instead, led by the Dutch HTA body ZIN and including the following HTA agencies: AEMPS (Spain), AIFA (Italy), AIHTA (Austria), GBA (Germany), HAS (France), INFARMED (Portugal), IQWIG (Germany), KCE (Belgium), NCPE (Ireland), NIPN (Hungary), NOMA (Norway) and TLV (Sweden). The consortium will provide support to the future European HTA system to be established according to the upcoming regulation.

EUnetHTA 21 is funded by a two-years’ Service Contract for the Provision of Joint Health Technology Assessment (HTA) Work Supporting the Continuation of EU Cooperation on HTA, signed on 17 September 2021 by the European Health and Digital Executive Agency (HaDEA).

The first Stakeholder Kick-Off online meeting of the consortium is scheduled on 3 December

2021; the discussion will focus on the illustration of the governance principles, the planned interactions with stakeholders in the form of public consultations and the presentation of deliverables planned for the next two years.

The first Open Call for consultation

EUnetHTA 21 has already launched its first Open Call , targeted to the pharmaceutical industry with reference to four different Joint Scientific Consultations (JSC, previously referred to as Early Dialogues). The Call is open until 7 December 2021; some other four slots for JSC are expected to be activated during the period of activities of EUnetHTA 21.

The medicinal products to access these four first slots will be selected on the basis of the results of the Open Call, within two weeks from its closure; the following Joint Scientific Consultations are expected to start in January 2022. According to EUnetHTA, the procedure to be used for JSC shall remain essentially unchanged, with just minor adjustments; an updated guidance document should be soon available.

JSCs are a pillar of the new HTA regulation, aimed to provide non-binding scientific advice to developers of new products, after completion of the feasibility or proof of concept studies and prior to the activation of pivotal clinical trials, in order to improve the quality and appropriateness of the data to be used for future HTA assessment. This type of evaluation will run in parallel to EMA’s scientific advice procedures.

Early exchange of relevant information between applicants and both regulatory (EMA) and HTA agencies represents the core of the process, so to optimise the integration of the different requirements to be included in the study design across multiple European member states. These might refer, for example, to the choice of comparators or relevant outcomes, to the quality of life and/or patient groups (both for pivotal trials and post-launch studies), as well as to the economic evidence generation plan.

Consultation on the reform of the European pharmaceutical legislation

October 15, 2021

affordable medicines, antimicrobial resistance, competitiveness, consultation strategy, crisis preparedness, environmental challenges, EU Health Data Space, European Commission, evaluation roadmap, Health Technology Assessment, incentives for innovation, Inception Impact Assessment, manufacturing, medicines for human use, online questionnaire, Pharmaceutical Strategy for Europe, public consultation, quality, rare diseases, regulatory framework, repurposing, response mechanisms, secure supply chains, shortages of medicines, unmet medical needs

by Giuliana Miglierini

A new step in the review of the overall framework governing the pharmaceutical sector has been announced by the European Commission on September 28th: the launch of a first phase of public consultation will enable to collect opinions from all the stakeholders of the pharmaceutical sector as a pre-requisite for the revision of the existing general pharmaceutical legislation on medicines for human use.

The initiative builds on the previous public consultation which represented the basis for the drafting of the Pharmaceutical Strategy for Europe released by the Commission in November 2020. The final target is the creation of a future-proof and crisis-resilient regulatory framework for the pharmaceutical sector. The pharmaceutical industry represents one of the main contributors to the European economy, with 800.000 direct jobs and €109.4 billion trade surplus in 2019, and €37 billion contribution to research investment.

“Today we take an important step for the reform of EU’s pharmaceutical legislation by the end of next year. A regulatory framework for pharmaceuticals, which is modernised and fit for purpose, is a key element of a strong European Health Union and crucial to addressing the many challenges this sector is facing. I call on all interested citizens and stakeholders to help us shape EU rules for the future, responding to patients’ needs and keeping our industry innovative and globally.”, said the Commissioner for Health and Food Safety, Stella Kyriakides.

Details of the consultation

The consultation is open until 21 December 2021 and is published in the form of an online questionnaire to be filled in by stakeholders and members of the general public, including patients and patient’s organisations, pharmacists and doctors, associations active in public health, healthcare professionals and providers, academia, researchers, regulators, EU’s institutions and the pharmaceutical industry. A combined evaluation roadmap/Inception Impact Assessment published in April 2021 is also available at the consultation’s webpage, together with a document on the consultation strategy (link).

The main issues touched by the consultation include all the 4 pillars of the Pharmaceutical Strategy, for each of which both legislative and non-legislative actions are envisaged.

A main area of interest looks to address unmet medical needs and ensure access to affordable medicines for patients, namely in the areas of antimicrobial resistance and rare diseases. The commitment to respond to environmental challenges is another key point of attention. New incentives for innovation and future-proofing the regulatory framework for novel products shall support the availability of next-generation therapeutics for European citizens and the competitiveness of the European markets. Quality and manufacturing of medicines, and the repurposing of older products are other topics looking for innovative approaches to be defined within the revision of the pharmaceutical legislation.

The Covid pandemia showed the importance to developed measures to enhance crisis preparedness and response mechanisms in all European countries, and to ensure diversified and secure supply chains are in place to reduce dependency of supply from extra-EU countries. A stronger EU voice on the theme of medicines shortages shall be also pursued by promoting a high level of quality, efficacy and safety standards.

The consultation aims to better understanding of all implications of the possible policy options, and to provide evidence to the Commission on the functioning and delivery of the current legislation with respect to its initial objectives. The impact of new potential options on the different stakeholders shall be also assessed. The exercise aims to identify areas of broad agreement among stakeholders as well as differences of views on other topics, and the causes of contention.

A brief overview of the legislative process

The revision of the pharmaceutical legislation is just one of the many legislative actions undertaken by the von der Leyen Commission in order to completely innovate the reference framework for medicines’ development, production, authorisation, commercialisation and postmarketing monitoring. The last revision of the pharmaceutical legislation occurred almost 20 years ago.

The Pharmaceutical Strategy defines the general targets, to be then synergistically implemented by mean of actions specific to the different fields. The revision of the general pharmaceutical legislation is one of the main flagship initiatives towards this target, and it is also being supported by an ongoing study run by an external contractor and expected to close in Q1 2022.

Among other actions which shall contribute to the goals of the Strategy are the proposal of the new regulation on Health Technology Assessment, the EU Health Data Space, the revision of the current legislation on rare diseases and paediatric medicines and actions to address shortage of medicines in the EU’s market.

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EU Focus Archives - Page 2 of 3 - European Industrial Pharmacists Group (EIPG)

Current inspection trends and new approaches to the monitoring of post-inspection activities

PIC/S Annual Report 2021

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

The Made in Europe partnership for manufacturing

The Faculty of Pharmacy in Brno is once again a part of Masaryk University

ICMRA published a Reflection paper on remote inspections

A study on medicines shortages from the European Commission

Steps forward towards the new framework for HTA

Consultation on the reform of the European pharmaceutical legislation

News from EIPG