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The EU Parliament voted its position on the Unitary SPC


by Giuliana Miglierini The intersecting pathways of revision of the pharmaceutical and intellectual property legislations recently marked the adoption of the EU Parliament’s position on the new unitary Supplementary Protection Certificate (SPC) system, parallel to the recast of the current Read more

Reform of pharma legislation: the debate on regulatory data protection


by Giuliana Miglierini As the definition of the final contents of many new pieces of the overall revision of the pharmaceutical legislation is approaching, many voices commented the possible impact the new scheme for regulatory data protection (RDP) may have Read more

Environmental sustainability: the EIPG perspective


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

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EU’s Industrial Forum, the future of advanced manufacturing technologies

October 6, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The expert group “Industrial Forum” is a multistakeholder body created by the European Commission to support the implementation of the Industrial Strategy launched in March 2020 and its following update of May 2021. Its members include Member States authorities, NGOs, industrial representations, research institutions and social partners representing different industrial ecosystems.

Its recently published report is the result of the structured dialogue among members on how to accelerate the deployment of advanced manufacturing technologies (AMTs) across the European industry. Among members which participated in the drafting of the document is also EuropaBio on behalf of the biomanufacturing industry.

Europe is leader in advanced manufacturing

Advanced manufacturing is based on the integration and convergence of the most advanced industrial technologies, i.e. automation, robotics, artificial intelligence and digitally connected solutions. New processes, new products as well as new business models based on this new approach are deemed to represent a fundamental competitive factor in the next few years.

Europe is currently well position in the ranking on “future of production” readiness, with 18 out of 25 countries considered by the World Economic Forum to be leading the change in manufacturing. Despite this, according to the report many efforts are still needed to accelerate the implementation of advanced manufacturing technologies in the EU, so not to be superseded by other fast-evolving competitors.

In order to achieve this challenging goal, the Industrial Forum identified seven different areas of attention, each of which is addressed by specific recommendations based on a SWOT analysis.

The seven areas of recommendation

The transition to new manufacturing models should, first of all, meet the EU sustainability goals established by the European Green Deal: the “net-zero industry” plan for renewables and industrial efficiency technologies is confirmed as a priority action, together with the expansion of the use of REPowerEU. The Commission is working on new energy savings directives, which should be timely implemented. Circularity of manufacturing processes and products is another main goal of EU’s industrial policies, to be supported by a set of new fit-for-purpose rules. A more rapid uptake of advanced manufacturing technologies should also be supported by both the availability of specific public procurement guidance and a targeted communication of the environmental benefits of European clean technologies.

The second area of action addresses how to improve access to capital, a key factor in ensuring the timely implementation of advanced manufacturing technologies. This may include a better use of public investment, as well as a cautious application of state aid instruments specifically targeted at later stages in the innovation and deployment process. The potential of these new technologies for sustainability should also be recognised within the upcoming EU Taxonomy de-legated acts.

The resilience of supply chains could be tackled by the rapid implementation of AMTs. In order to achieve this goal, the Industrial Forum highlighted the need for workable and proportionate rules on Due Diligence. No less important is the negotiation and activation of new Free Trade Agreements with third countries (such as the EU-Mercosur FTA). A critical area refers to the improvement of EU semiconductor capacity. According to the report, incentives and funding aimed to increase the supply chain resilience should be exempt from directing specific outcomes. The European institutions should also better support the local and regional industrial supply chains. Secure access to critical raw materials should be pursued by leveraging the trade policy.

The building of an EU Single Market is a main goal of the European Commission, also in the pharmaceutical field. Its freedoms should be safeguarded by narrowing down the scope of the Single Market Emergency Instrument, while promoting mitigation measures for advanced manufacturing. The Industrial Forum also recommends the availability of a single platform to provide companies with all the needed information to expand and/or export. Furthermore, a Single Market test should be included in the impact assessments of national laws to minimise the occurrence of gold-plating phenomena. New standards for AMTs would also be needed, an area which according to the Industrial Forum should conjugate an enhanced flexibility in standardisation requests and timely delivery in standard setting. Digital product standardisation should also be promoted, and adhesion to the New Legislative Framework should be ensured.

Data is a fundamental asset of the new economy. Recommendations in this area include supporting existing initiatives to create a strong European manufacturing data space, as well as ad-dressing the protection of both personal data and intellectual property rights and trade secrets. As artificial intelligence (AI) will assume an increasingly relevant role in future advanced manufacturing processes, the Forum recommends the development of clear, focused criteria on high-risk AI, while avoiding unnecessary regulation of industrial AI.

The availability of data should be pursued through the identification of a method for data collection in the advanced manufacturing category. It would also be important to generate trusted data sets at the European level for advanced manufacturing deployment, global competitive position, and economic / environmental / societal gains.

Many new skills will be needed in the next few years to handle the expansion of AMTs. To this instance, the Industrial Forum highlighted the importance to promote the harmonisation of Vocational Education and Training (VET) practices and qualification systems and to encourage women and girls to study STEM subjects and working in manufacturing. Other recommendations re-fer to the possibility of developing a Pact for Skills partnership and the proposal of a Blueprint Alliance for Advanced Manufacturing. A better entrepreneurial culture in Europe should also be promoted, as well as capitalisation on European creative industries.

Examples of biomanufacturing

Weaknesses to biomanufacturing identified by the Industrial Forum include the fact that it is still an emerging production process compared to chemical manufacturing. The report also mentions existing regulatory barriers, mainly linked to a process rather than product approvals pathway. Furthermore, significant investments in biomanufacturing are primarily located outside Europe. Possible risks identified by the report also refer to biomanufacturing being excluded or overlooked in key policymaking e.g. taxonomy supporting biomanufacture and sustainable financing.

The report includes two examples of AMTs linked to the health and agrifood sector. Chimeric antigen receptor T cells (CAR-T) represent one of the main areas of innovation in cancer treatment over the past two decades, in which the patient’s immune cells are engineered to produce the final immunotherapy. Many pharmaceutical companies are building specialised manufacturing facilities for CAR-T therapies within Europe, a biomanufacturing process which is highly complex and patient-specific, and requires long term investments, skills development, and integration into the European Union industrial base.

Biomanufacturing may also be applied to the production of vitamin B2 (riboflavin), that multi-step chemical synthesis is complex, requires hazardous agents and has low yields (~60%). Biotechnologies allow for the one-step production of vitamin B2, starting from vegetables as carbon sources and using a genetically modified bacterium (Bacillus subtilis) or fungus (Ashbya gossypii).


EMA’s reflection paper on AI in the pharmaceutical lifecycle

September 22, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The rapidly evolving role of artificial intelligence (AI) and its possible application in the pharmaceutical field led the European Medicines Agency (EMA) to publish a draft Reflection paper on the use of AI along the entire lifecycle of both human and veterinary medicines.

The Reflection paper summarises the current view on the possible use of AI and machine leaning (ML) technologies and is open to public consultation until 31 December 2023. Comments, together with the outcomes of the joint HMA/EMA workshop to be held on 20-21 November 2023, will support its finalisation, as well as the possible development of new guidance. The initiative aims to identify the aspects of AI/ML use that would fall within the remit of EMA or of the single National Competent Authorities (NCAs) in charge of the dossiers’ assessment.

The document is part of the effort to improve the European Medicines Regulatory Network’s capability in data-driven regulation set forth by the joint HMA-EMA Big Data Steering Group (BDSG), and it has been developed in coordination with EMA’s CHMP and CVMP committees.

“The use of artificial intelligence is rapidly developing in society and as regulators we see more and more applications in the field of medicines. AI brings exciting opportunities to generate new insights and improve processes. To embrace them fully, we will need to be prepared for the regulatory challenges presented by this quickly evolving ecosystem” said Jesper Kjær, Director of the Data Analytics Centre at the Danish Medicines Agency and co-chair of the BDSG.

“With this paper, we are opening a dialogue with developers, academics, and other regulators, to discuss ways forward, ensuring that the full potential of these innovations can be realised for the benefit of patients’ and animal health” added Peter Arlett, EMA’s Head of Data Analytics and Methods, co-chair of the BDSG.

The main contents of the Reflection paper

The Reflection paper addresses the use of AI/ML with a dedicated chapter for each one of the steps, part of the overall lifecycle of a medicinal product. The interactions with regulators are then explored, as well as the different technical aspects to be taken into consideration. The final chapters discuss the governance of AI/ML applications, the integrity, and ethical aspects to be considered and how to address data protection.

The increasing use of AI technologies is based on the wide availability of big amounts of data produced and captured in electronic format on a routine basis. This data can be analysed by machine learning algorithms to inform the training of other systems able to analyse data and take actions with some degree of autonomy in order to achieve specific goals. These latter systems are the truly intended AI algorithms, those use is under discussion also in the field of regulatory decision making.

The Reflection paper recalls how the diffusion of these new technologies carries with it also some new risks, due to the “exceptionally great numbers of trainable parameters arranged in non-transparent model architectures”. Measures should thus be taken to ensure the safety of patients and the integrity of data, as well as to avoid the integration of bias into AI/ML applications.

The contents of the Reflection paper may also refer to combinations between a medicinal pro-duct and AI/ML-including medical device, as in such occurrence EMA is involved in the assessment of the characteristics of the device.

In general terms, existing guidelines, best practices, and recommendations relative to model in-formed drug development and biostatistics also apply to AI/ML; the adjacent methodology guidelines which may be relevant to this instance are listed in the document. The Reflection paper warns readers about the differences between the human and veterinary regulatory domains, suggesting that another reflection document specific for veterinary may be developed in future.

A risk-based approach

The usual risk-based approach typical of pharmaceutical development should be used to identify risks throughout the entire AI/ML tool lifecycle, including regulatory impact. According to the Reflection paper, the level of risk may depend also on the context of use and the degree of influence the AI technology exerts.

Developers should always seek early regulatory interaction and scientific advice, especially in cases where the AI/ML system may impact on the benefit-risk ratio of the medicinal product un-der development. To this instance, the EMA Innovation Task Force (ITF) is responsible for pro-viding early interaction on experimental technology, while scientific advice and qualification of novel methodologies in medicines development is provided by the Scientific Advice Working Parties (SAWP) of the CHMP for human medicines and of the CVMP for the veterinary ones.

As for all other steps of pharmaceutical lifecycle, the final responsibility for the suitability and use made of AI/ML algorithms, as well as their compliance to ethical, technical, scientific, and regulatory standards (GxP standards) and to current EMA scientific guidelines falls under the Marketing Authorisation Holders (MAHs) or applicants.

According to the Reflection paper, risks referred to in the discovery step may be limited, but they may impact the final evidence presented for regulatory review, thus principles for non-clinical development should be followed. This second step may include, for example, AI/ML modelling approaches according to the 3R principles. Regulators would expect to receive Standard Operating Procedures (SOPs) for AI/ML applications in preclinical studies; advisory documents on Application of GLP Principles to Computerised Systems and GLP Data Integrity should be also considered where appropriate. A pre-specified analysis plan would be needed for preclinical data potentially relevant for the assessment of the benefit-risk balance.

In the field of clinical trials, ICH E6 and VICH GL9 on human and veterinary GCPs should also be applied to the use of AI/ML. In particular, regulators expect the full model architecture and description of the data processing pipeline would be made fully available for comprehensive assessment should a model be generated for clinical trial purposes, as they would be considered parts of the clinical trial data or trial protocol dossier.

From precision medicine to pharmacovigilance

Particular considerations may be needed for applications of AI/ML in precision medicine, to individualise treatment according to the patient’s characteristics. AI/ML application supporting indication or posology decisions should be referenced in the Summary of product characteristics and their assessment falls under medicines regulation, representing a high-risk use both from the patient and regulatory perspectives. Close human supervision is also expected for AI applications used to draft or translate product information documents.

Many are the possible applications of AI/ML in the manufacturing of medicinal products, where they should follow the usual quality risk management principles (ICH Q8, Q9 and Q10) to guarantee safety, quality, and data integrity. New recommendations are also expected from EMA.

In the post-authorisation phase, AI/ML tools can effectively support efficacy and safety studies and post-marketing surveillance studies for veterinary medicines, as well as pharmacovigilance activities. Good pharmacovigilance practices should always be respected, and the used model should be validated, monitored and documented under the responsibility of the MAH. For conditional marketing authorisations, AI/ML applications should be discussed within a regulatory procedure unless details are agreed already at time of authorisation.


The EU Commission proposal of the new pharmaceutical legislation

May 5, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

By Giuliana Miglierini

After a five-months delay, the European Commission has announced on 26 April 2023 its proposal for the revision of the European pharmaceutical legislation. The package is comprehensive of a Directive governing authorisations and other regulatory procedures, and a Regulation focused on central authorisation procedures. A Council Recommendation on antimicrobial resistance is also included. The entire reform package shall now undergo the scrutiny of both the European Parliament and Council in order to gain final approval and adoption.

In this first article, we will resume the main features of this highly complex reform, leaving to following posts a more detailed discussion of the single lines of intervention.

The experienced delays acknowledge of the many difficulties encountered by the Commission in reaching a balance between forces representing different perspectives within the pharmaceutical sector. Among the main areas of debate was the exclusivity protection: an issue not yet re-solved, judging from the first reactions from industrial associations, and that should be addressed during the incoming negotiations at the EU Parliament and Council.

A single market for medicines

Central to the entire reform package is the creation of a single European market for medicines, aimed to facilitate the fair and rapid access to patients of all member states. Regulatory procedures for approval of generic and biosimilar medicines should be simplified. Patients are also expected to benefit from more innovative medicines, thanks to a wide array of incentives, and from the repurposing of products already on the market.

Patient centricity should also address rare diseases and new therapeutic options for paediatric patients, including the creation of a EU network of representatives of patients associations, academics, developers and investigators. Patient representatives should be appointed to the EMA Committees, and thus involved in the approval of new medicines. A more extensive use of electronic Product Information is expected to facilitate access to updated information, while reducing costs for manufacturers.

A greater transparency on public funding for R&D should better support price negotiations with national authorities, so to make medicines more affordable to patients.

The long lasting issue of medicines shortages should be tackled from different perspectives. Pharmaceutical companies should be responsible for the emission of earlier warnings on shortages and withdrawals, and for the establishment of prevention plans. European authorities should create a list of critical medicines, to be used to identify supply chain vulnerabilities and improve security of supply. National and central competent authorities are called to a better monitoring of shortages, while EMA should play a stronger guiding role on security of supply.

The One Health approach should inspire actions to improve the environmental sustainability of medicines. From this perspective, the proposed reform includes a strengthened environmental risk assessment for all medicines, including those already on the market. Actions to improve environmentally friendly production technologies and to reduce the release of drugs into the environment are also considered.

Actions supporting innovation

The reform package completely redesigns the duration of regulatory protection, reducing the standard length to 8 years (6 years of data protection + 2 years of market protection), but offering a wide range of incentives to reach a cumulative maximum of up to 12 years of protection. The true novelty is the 2-year incentive for companies launching a new product in all EU markets at the same time. Other incentives are targeted to unmet medical needs (6 months), comparative clinical trials (6 months), and for a new indication to treat another disease (1 year).

The standard market exclusivity should reach 9 years for medicines for rare diseases. In this case too, a wide range of incentives may extend protection to up to 13 years.

The Transferable data exclusivity voucher is the tool identified to support the development of new antimicrobial medicines: the voucher would be transferred to another of the company’s products, extending its protection by 1 year. The Commission plans to issue no more than 10 vouchers over a 15 year period, under strict conditions, so to limit the impact of the measure on healthcare systems. Reshoring of pharmaceutical productions and EU’s strategic autonomy are not included in the reform. A number of other actions are ongoing to support specific lines of intervention, i.e. the EU FAB flexible manufacturing network of vaccines producers, HERA’s Joint Industrial Cooperation Forum on vulnerabilities along the supply chain, and the Important Project of Common European Interest on Health to allocate state aid to support for innovative EU projects.

A more flexible regulatory framework

A higher regulatory flexibility should support fast approval of medicines. Regulatory assessment for centralised procedures should shorten to 180 days (from the current 210); the time should be reduced further to 150 days for products needed for health emergencies.

Simplification of procedures will include full electronic submission of applications. Rolling re-views and temporary emergency marketing authorisations at the EU level for public health emergencies will fully enter the set of available procedures. Simplification should also include the abolishing of the marketing authorisation renewal in most cases.

A reform of EMA’s Committees is also envisaged: only the Committee for Human medicinal pro-ducts (CHMP) and the Safety Committee (PRAC) should continue to exist, while the orphan, paediatric and ATMP committees would be abolished.

Generic and biosimilar medicines shall also benefit from simpler rules for approval, while regulatory sandboxes are the tool to support testing of particularly new and innovative therapies. These may also benefit of additional early scientific advice and regulatory support by EMA, particularly for unmet needs. Dedicated pathways are also planned to support repurposing, especially for SMEs and not-for-profit organisations.

Clinical development may be improved thanks to a wider use of adaptive clinical trials, real world evidence and health data. The reform is also expected to make easier the interaction with other relevant healthcare frameworks, e.g. for medical devices and health technology assessment.

The first comments from interested parties

A very negative opinion on the proposed reform has been issued by the European Federation of Pharmaceutical Industrial Associations (EFPIA), representing the innovator industry.

“Unfortunately, today’s proposal manages to undermine research and development in Europe while failing to address access to medicines for patients”, said EFPIA’s Director General Nathalie Moll. The main point of criticism is the 2-year incentive for the contemporary launch of a new medicine in all 27 member states, that for EFPIA would represent an impossible target for companies. According to President Hubertus von Baumbach, “the ‘net’ impact of policies set out across these proposals, in their current form, puts European competitiveness at risk: overall, it weakens the attractiveness for investment in innovation and hampers European science, research and development”. A comprehensive competitiveness checks on the impact of the revised pharmaceutical legislation is EFPIA’s request.

The Association also published a series of reports supporting its vision on the availability of new medicines throughout Europe, as its first action to stimulate the debate in view of the assessment of the proposal by the EU Council and Parliament.

“We strongly support the proposal’s intention to stop the well documented patent games manship and evergreening and the adaptation of incentives to necessary equity of access across the EU. Moreover, there should not be an accumulation of regulatory incentives that would extend the regulatory data protection period beyond the existing system (8 years) which is already the longest in the world. Regarding AMR, the Commission proposal for a reserve fund is the correct alternative to transferable vouchers and most efficient policy to protect against future risks”, wrote in a note Medicines for Europe, representing the generic, biosimilar and value added medicines industry. “The central role of the off-patent medicines industry for the patient is clearly reflected in the intentions of the draft legislation. We are still lacking an industrial strategy to strengthen the European off- patent sector and improve open strategic autonomy in health”, said Medicines for Europe President Elisabeth Stampa.

EuropaBio, on behalf of the biotech sector, welcomed the provisions improving the EU’s regulatory framework and promoting novel technologies. In this case too, the main concern is the proposed new set of incentives, that according to EuropaBio may undermine the predictability and stability of the European landscape for innovation. “It is essential that EU policies meaningfully improve patient access to medicines across the EU without undermining the EU’s attractiveness for life science investments”, said EuropaBio Healthcare Public Affairs Director Vlad Olteanu.

“AESGP supports the revision of the EU pharmaceutical legislation in principle. While we welcome the regulatory simplifications introduced by the revision, we are voicing some concerns on behalf of non-prescription medicines manufacturers that may have unintended negative consequences”, said Jurate Svarcaite, AESGP Director General. The Association resumed its worries in a statement published in its site.

These include the proposed two new prescription criteria for antimicrobial products and medicines containing an active substance which may have an environmental impact. As for incentives, according to AESGP a longer data exclusivity period (3 years instead of 1) should be considered in cases where new, pivotal evidence is generated, for switching from prescription to non-prescription status. Other points of concern refer to how environmental risks for medicines are to be assessed. “Decisions to minimise the environmental impact should always lead to proportional risk mitigation measures and never interfere with clinical priorities and benefit/ risk assessments that ensure EU citizens get access to the healthcare products they need”, wrote AESGP.

Improvement to the Commission’s proposal would also be needed with regard to the adoption of electronic Product Information, where a phased and harmonised approach to digitalisation is suggested. A better definition of real-world evidence/data would also be needed. As for shortages, mitigation measures should be proportionate and aimed at the critical medicines that do not have alternatives and have concentrated supply chains. AESGP supports the extension of the proposed approach to Risk Management Plans exemption also to medicinal products of well-established use, as for generics and biosimilars.

“We appreciate the proposals aimed at streamlining and digitalising regulatory procedures, yet we are concerned that other provisions will undermine R&D, innovation, and EU competitiveness. These will be especially detrimental to the small and mid-sized innovative companies that Eucope represents. The proposal introduces more risk and unpredictability into the system while reducing incentives for innovation and investment, which will negatively impact patient access”, wrote the association in its comments to the proposal of reform.

“The Commission’s revision includes troubling proposals, such as the introduction of (High) Unmet Medical Need, which risk reducing the EU’s global competitiveness in life sciences, thereby limiting the development and availability of innovative therapies”, said Eucope Secretary General Alexander Natz.


ECA’s guide to compliant equipment design

March 31, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

By Giuliana Miglierini

The legislative evolution of the last decades emphasised requirements for equipment used in pharmaceutical productions. This is even more true with the entry into force of the new Annex 1 to the GMPs, characterised by many new requirements impacting on different manufacturing processes (i.e. production of water for injection, sterilisation, Form-Fill-Seal and Blow-Fill-Seal technologies, single use systems, lyophilisation, etc.).

Each pharmaceutical process requires the careful design of the needed equipment in order to provide the expected efficiency and performance. Furthermore, some equipment may be used for different industrial applications (e.g. pharmaceutical, cosmetic or food), thus needing a fine tuning to reflect relevant requirements. In pharmaceutical manufacturing, a further step of complexity may be represented by the need to handle highly potent active pharmaceutical ingredients, requiring isolators to segregate production, etc.

To facilitate the correct design of equipment compliant to GMPs, a new guidance document has been published by the ECA Foundation. The document was initially drafted in German by a task force of experts in pharmaceutical technology and engineering and published by Concept Heidelberg, and it has now been translated in English

Elements relevant to reach compliance

The first part of the document discusses general requirements that should always be part of the design of GMP-compliant equipment. Four different points of attention are listed: the equipment must not adversely affect the product quality, it must be easy to clean, it must comply with applicable technical rules, and it must be fit for its intended use.

As for the first point, “The question is rather what is tolerable without adversely affecting the product quality”, states the guidance. Avoidance of contamination and cross-contamination are the main goals of cleaning activities, both for sterile and non-sterile medicinal products. There are several issues to be taken in mind from this perspective, including the presence of endotoxins, sealing points, the efficiency of cleaning-in-place (CIP) processes, or the presence of unreachable dead leg areas. According to the guidance, the 3D/6D rule for the prevention of dead legs in water systems often used for specification would not always be correctly applied, due to some confusion in terminology. Official GMPs are also deemed “very vague”, as they are not drafted by engineers and apply to an extremely wide range of different equipment and processes. “Consequently, the question is, which technical rules have to be followed or where the actual state of the art can be looked up”, says the document. Many different references are possible, from pharmacopeia monographs and regulatory guidelines, to ISO standards, and other documents published by international professional bodies.

Qualification and calibration of equipment should always be targeted to the specific product, as it is an essential in proving compliance to the intended use. Regulatory compliance of submitted documentation is not less important, and it greatly impacts on change control and implementation of new productive technologies.

Risk analysis (RA) is the tool introduced in 2005 by ICH Q9 to evaluate all items which may impact on the design of productive processes and related equipment. There is no standard methodology to run risk analysis, the choice depends on the process/product under assessment. According to the guidance, RA can be performed both from the perspective of the product and the equipment, the latter being also considered a GMP risk analysis.

Design and choice of materials

Materials (and coating materials where relevant) used to build pharmaceutical equipment should be completely inert. Pharmaceutical equipment must comply with the EC Directive on Machinery 2006/42/EC and DIN EN ISO 14159. The ECA guidance discusses material selection (plastics or stainless steel); hygienic system design is also addressed by many different guidelines, e.g. those published by the European Hygienic Engineering and Design Group (EHEDG). An important item to consider is service life considerations for the materials used (EHEDG Document 32), as well as their chemical-physical characteristics and materials pairing.

Particularly critical are process contact surfaces, as they may impact product quality. Establishment of specific requirements is thus needed. The guidance focuses its attention on austenitic stainless steels (i.e. CrNiMo steels 1.4404 and 1.4435). The main elements to be assessed are the risk of corrosion, the risk of contamination of the product or process medium and the cleanability of the metallic surface. Topography, morphology and energy level are the main characteristics to be used to describe surfaces, addressing respectively the geometric shape, chemical composition and energy required per unit area to increase the size of the surface. The guidance provides a detailed discussion of all different aspects of surface treatment methods, and the hygienic design of open and closed equipment. Other sections discuss the optimal design of pipework and fittings, connections, welding and seam control. Detailed information is also provided on equipment of electrical engineering, measurement and control technology, as well as the process control technology (PCT) measurement and control functions.

A highly critical area within a pharmaceutical facility are cleanrooms, for which the design of the equipment and the choice of materials is even more stringent. Elements to be considered include stability/statics as concerns dynamic loads, smoothness of the floor, tightness of external façades and of enclosing surfaces of cleanrooms. Smooth nonporous surfaces are required, together with avoidance of molecular contamination, resistance to the intended cleaning or disinfection agents and the cleaning procedure, simple and tight integration of various fittings, efficient and rapid implementation of subsequent functional and technical changes. The ECA guidance document goes deeper into relevant requirements for all elements that are part of the design of a compliant cleanroom.

Documentation and automation

User requirement specifications (URS) are the key document to demonstrate equipment is fit for the intended use, as stated by GMP Annex 15 (2015). The ECA guidance suggests translating the URS in a technical version to be submitted to the potential equipment supplier, so to ensure the design would reflect product and quality-relevant requirements, being thus GMP compliant.

The management of documentation along the design life cycle of a new piece of equipment is also taken into consideration, with the different construction phases identified according to Good engineering practices (GEP): conceptual design, basic design/engineering, and detailed design/engineering.

The extensive use of data to monitor and document pharmaceutical manufacturing process represents another area of great attention. Requirements relevant to the design of validated computerised systems, data protection and data integrity must be kept in mind. ECA’s experts highlight the need to carefully delimitate areas subject to validation and their extention, particularly with reference to automated systems. Differences between qualification and validation of automated systems are also addressed, including equipment that might either be defined as “computerised” or “automated” system. Regulatory reference for validation is GAMP 5, while qualification refers to Annex 15.


What happens after IP loss of protection

November 11, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

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

The role of competitor entry on the market has been analysed in a report by IQVIA.

The document focuses on loss of protection (LOP), thus including in the analysis all products that are free from any form of IP rights (patent protection, SPCs, RDP, market exclusivity/loss of exclusivity, data exclusivity, orphan/paediatric drug exclusivity). According to the report, there are many elements to be considered while assessing the impact of IP rights, among which are regulatory issues, prices policies, competitiveness landscapes. Finally, all the previously mentioned issues are today facing a higher pressure due to the incumbent global situation, characterised a generalised economic crisis especially in Europe. One of the main goals of the EU Commission is to increase the attractiveness of the internal market as a key innovative region for investment in the pharmaceutical sector.

The main trends of the past six years

The IQVIA’s report takes into consideration the group of medicines that have lost protection across the past six years (2016–2021), for a total of 118 molecules; it also analysed the impact of the alignment of the regulatory data protection (RDP) rules in Europe occurred in late 2005, as well as the entry of new countries in the EU occurred in 2004 (Czech Republic, Estonia, Cyprus, Latvia, Lithuania, Hungary, Malta, Poland, Slovakia and Slovenia). EU’s enlargement also included Romania (2007), Bulgaria (2007), and Croatia (2013). Many of the products considered in the analysis were innovative medicines, representing approx. 13% of the total European pharmaceutical expenditure at their peak.

According to IQVIA’s data, the total European pharmaceutical market at list prices valued € 1 trillion in 2016-2021. Over the same period, all protected products counted for 37% of total expenditure on pharmaceuticals (€ 377 billion). Medicinal products that lost protection represented roughly 10% of the total EU market value (€103 billion).

Forms of IP protection

Just more than a half (51%) of products that lost protection in years 2016-2021 were subject to a Supplementary Protection Certificate (SPC), while the RDP mainly refers to older cardiovascular, or combination medicines. Eleven years is the current average length of protection in Europe (-4.2 years; it was 15.2 years for authorisations granted in 1999-2005); the decrease can be attributed to the entry into force of the European centralised system, that diminished the impact of delays to LOP. Market exclusivity also depends on the specific form of IP protection chosen, as it may vary the calculation from different starting dates for IP filing.

IQVIA’s data show that SPC represents 32% of the final form of protection; this sums to 19% of SPC followed by paediatric extension. SPC provides a maximum of 15 years of protection, with an average of 14.4 years. Medicines under regulatory data protection are 31% of total (8 years data exclusivity + 2 years market exclusivity +1 year for a significant new indication), the patented ones 11%. Smaller fractions are covered by orphan drug exclusivity (5%) or orphan drug extension followed by paediatric extension (2%). Considering sales values, the preferred constraining form of protection for small molecules is SPC (93%), followed by RDP (83%); SPC plus paediatric extension occurs in 50% of cases for biologics. Small molecules are also often subject (80%) to patent plus other forms of exclusivity (orphan/paediatric extension). According to IQVIA, the undergoing discussion on the review of the European IP legislation may lead to an alignment of the RDP duration to the US standard (5 years for small molecules, 12 years for biologics).

The impact of the different legislation governing patent litigation in the EU vs the US should also be taken into consideration.

Access and competition

Access of new generic and biosimilar medicines in the European market is a long debated issue, as historically it often proved difficult to determine the precise date of patent expiry and to find an alignment between different countries on this fundamental issue.

According to IQVIA’s report, in the years 2016-2021 the duration of access to major EU markets was 36 days. Competition for small molecules has reduced the cost by approx. 41%, with a volume growth of ~27%; the overall savings for the payer was -8% CAGR for the years 2016-2021. Biologics also increased their volumes year-on-year (23%). Less evident are savings for payers (8% increase in 2016-2021), but many biologics benefit of confidential discounts for hospital supplies.

Competition is very peculiar to the European market landscape, with 92% of molecules having competitors recorded by sales value. A very small niche (2%) of small, low value products proved to be less attractive; the remaining 6% refers to products under development. The biosimilar sector is particularly challenging, as only the largest molecules are attractive from the competition point of view; about 30% of products without a competitor in development are biologics.

Central and Eastern Europe countries are still the preferred ones for early access to competitors, compared to the EU4 markets (Germany, France, Italy, Spain), due to dates for LOP that are in many cases still subject to some variation. On the contrary, EU4 markets account for 89% of sales of available molecules; many countries have no recorded sales for 25% of the available originator molecules.

Data by IQVIA indicates that, at a macro-level, the system has reduced the cost of medicines open to competition by 28%, while the volume of treatment increased 27%. Despite this encouraging trend, treatment paradigms shifting were also observed before LOP.

As for therapeutic areas, RDP protected medicines that underwent LOP were mainly referring to anti-hypertensive (73%) and combination products (61%). The higher proportion of SPC protected products was found in systemic anti-fungals (60%), oncology medicines and HIV/anti-virals (45% each). Immunology and lipid regulators are often protected using SPC plus paediatric extension (60% and 50%, respectively)

The importance of intellectual property rights

Estimates of investments in pharmaceutical R&D are approx. €39 billion/year, according to the report. Return on investment relies heavily on IP rights, a theme that is central also to the ongoing review of the EU’s pharmaceutical and IP legislations. Many new treatments are on their way towards approval, especially in the field of advanced therapies; according to IQVIA, more than 60% are first-in-class therapeutics.

Two core concepts support the current European framework for intellectual property rights: a period of exclusivity applying to new compounds (patent protection + SPC), followed by open competition once all IP expired. At this stage, competitors can access open data and manufacturing formulations. Prices are often regulated at the national level to incentivise competition and to positively impact on treatment opportunities available to patients.

The current fragility of supply chains for pharmaceutical productions may pose many challenges to originator companies which remain the sole provider of a medicine after loss of protection. A risk highlighted by IQVIA’s report is a too pronounced decrease of prices to support competition, and thus the sustainability of the market.

Access to innovative medicines is another challenge identified, referring to countries where the originator did not launch its product, and neither the competitors did. Furthermore, competitor entry often refers to low-value medicines. This despite future loss of protection for the years 2026-2030 should refer mainly (55%) to biologic molecules, compared to 43% for the period 2021-2025.


The European Medicines Regulatory Network Data Standardisation Strategy

January 28, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The availability of interoperable data is a “must” to ensure the smooth sharing, use and re-use of data along the entire regulatory process. A new document – the European Medicines Regulatory Network Data Standardisation Strategy – has been issued by the European Medicines Agency (EMA) and the Heads of Medicines Agencies (HMA) to provide guidance to all authorities members of the European Medicines Regulatory Network (EMRN) on how to approach issues related to the definition, adoption and implementation of international data standards.

As data contains the higher informative value, regulatory procedures are undergoing a phase of deep rethinking in order to pay greater attention to the underlying data, leaving behind the traditional assessment of regulatory documents prepared using those data. Furthermore, the secondary use of data may support optimised regulatory decision-making processes.

The EMRN Data Standardisation Strategy – one of the main deliverables of the HMA-EMA Joint Big Data Steering Group (BDSG) workplan – builds upon the EU Data Strategy and the goals of the EMRN Strategy 2025. The FAIR principles (Findable, Accessible, Interoperable and Reusable) have been identified to govern the acquisition, conservation and use of data.

A more standardised approach to be adopted by the EMRN shall make possible to reduce the current manual and technical workload needed to manage regulatory documents and data, which are often submitted using a variety of different formats. According to the Strategy, a review of the mechanisms of data governance is also needed to include the responsibilities for oversight of data standardisation work and for the periodic updating of the EMRN data strategy. Further assessment of the expected costs and benefits is needed to make available the final roadmap for the implementation and prioritisation of measures suggested by the Data Standardisation Strategy.

Adopt, adapt, develop

The document was drafted on the basis of initial internal consultations on current practices for the management of scientific data; the inventory of the current IT systems in use by members of the EMRN was also created. In a second phase, a public survey was conducted among all stakeholders; current and new standards under development were identified by analysis of a selection of Standards Development Organisations (SDOs) active in the healthcare sector.

The exercise led to the identification of three different categories of actions, respectively referred to the adoption by the EMRN of currently available standards, the adaptation of available standards to include additional requirements, and the development of entirely new standards.

A total of eight principles have been identified to guide the standardisation of data to be used for regulatory purposes. First of all, high-quality data standards developed by accredited SDOs should always be adopted, on the basis of voluntary and consensus-based processes. EMA-HMA’s suggestion is to use such standards in place of (unique) local or proprietary standards, unless not compatible with the EU legislation or otherwise impractical. This would also support the creation of the European Health Data Space (part of the EU digital strategy) and facilitate the sharing and re-use of data and the governance of data privacy according to the draft EU Data Governance Act. The principles of data protection and data ethics by design are another fundamental requirement, as well as the collaboration with stakeholders in order to be informed about their needs. An alignment and consolidation of requirements from other regulations and guidelines is also envisaged; assessment of requirements for both human and veterinary regulatory practices should be run in order to avoid duplication of efforts or creation of competing standards.

Four domains for the management of data

The EMRN Data Standardisation Strategy identifies four different domains for the adoption of common standards: Medicinal Product, Healthcare & study data, Safety & risk management and Submissions. Recommendations for each of the four domains are discussed in the document.

The Medicinal Product domain includes product information, substance information, manufacturing and quality information.

Standards such as the ISO IDMP (IDentification of Medicinal Products) – based on the HL7 FHIR (Fast Healthcare Interoperability Resources) standard – are already in place, for example, to feed EMA’s SPOR system, but additional FHIR resources would be needed to structure key product information in already existing projects. To this regard, the Strategy suggests to implement and adapt ISO IDMP specified substance group levels 2 and 4 by the associated HL7 FHIR message exchange format, so to capture active substances and excipients in a structured format. This approach would also better support inspections (together with the availability of a standardised template for all inspections data), traceability of the origin of all substances used to manufacture a certain medicinal product, and the adoption of risk-based tracking procedures to assess the interactions between product quality and inspections of manufacturing sites.

The Healthcare and study data domain refers to data acquired during clinical development (i.e. data from interventional and/or observational studies) and the development of a common data model (CDM) for individual patient data and mobile health (mHealth) devices.

Many projects are already active, e.g. the ICH M11: Clinical electronic Structured Harmonised Protocol (CeSHarP), an initiative that would need further tuning to include some additional requirements. The possible use of raw data from interventional studies is also under assessment (e.g. CDISC SDTM – Study Data Tabulation Model, and ADaM-Analysis Data Model).

A new CDM standard would also be needed to exploit the full and harmonised potential of real-world data (RWD) and metadata obtained from healthcare records and disease registries. To this instance, a particular attention should be paid to mHealth applications installed on personal smart-devices, a fast-growing segment giving rise to the availability to big quantities of data.

The Safety and risk management domain refers to pharmacovigilance activities and includes Individual case safety reports (ICSR), Product safety update reports (PSUR), and environmental risk assessment (ERA) and risk management plans (RMP).

ICSR might be optimised by adoption of the HL7 FHIR based messaging standard and the inclusion of -omics data (genomics, proteomics and metabolomics) of patients. According to the Strategy, a new structured, electronic format for PSURs built upon the ICH E2C (R2) periodic benefit- risk evaluation report guidelines would be also beneficial for the work of regulatory authorities. The CDISC SDTM8 standard for data collection of risk assessment data represents a possible option to better handle data referred to environmental risk assessments. A structured, electronic risk management plan (eRMP) format should be also created to overcome the current paper template format; the new standard may find inspiration in the ICH E2E Pharmacovigilance Planning guideline and the EU Guideline on good pharmacovigilance practices (GVP) Module V – Risk management systems.

The Submissions domain includes the dossier management and the structured application form. Version 4.0 of the electronic Common Technical Document (eCTD v4.0) is more flexible compared to the previous one; for example, it supports the re-use of Pdf documents across sequences and eCTD dossiers and the submission of other data formats within the dossiers. The wider use of structured data will make the use of Pdf files less common, in favour of electronic Application Forms (eAF) based on data exchange standards such as HL7 FHIR to manage regulatory application along the entire life cycle of a medicine.


A new role for EMA and a pilot project for the repurposing of medicines

November 12, 2021 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

A draft agreement was reached at the end of October between the Council of the European Union and the European Parliament to reinforce the mandate of the European Medicines Agency (EMA) with reference to crisis preparedness and management for medicinal products and medical devices. “EU-level preparation and coordination are two essential ingredients to fight future health crises. Thanks to this deal we are adding an essential new building block to upgrade the EU’s health architecture. It will allow the EU’s Medicines Agency to make sure we have the medicines needed to deal with public health emergencies”, said Janez Poklukar, the Slovenian minister for health.

The revision of EMA mandate is part of the broader activities announced by the EU Commission in November 2020 to achieve the European Health Union; these also include the reinforcement of the European Centre for Disease Prevention and Control and a draft law on cross-border health threats. The establishment of the new Health Emergency Preparedness and Response Authority (HERA), announced in September 2021, is also part of the package. The draft agreement shall now be endorsed both by the Council and the Parliament before entering into force.

Three new key targets for EMA

The draft agreement reached by the Council and Parliament negotiators focuses on three main areas. The first one refers to the definition of a major event and how to recognise it: these shall be events likely to pose a serious risk to public health in relation to medicinal products, as acknowledged by a positive opinion from the Medicines Shortages Steering Group, and which may trigger specific actions such as the adoption of a list of critical medicinal products to fight the health threat.

Solid funding from the Union budget shall be also provided to EMA in order to support the work of the new steering groups, task force, working parties and expert panels. The availability of provisions for adequate data protection is important to guarantee the full compliance to the GDPR regulation and other EU data protection rules, and the safe transfer of personal data relevant to EMA’s activities (e.g. data from clinical trials).

EMA shall play an improved role in the monitoring and management of shortages of medicines and medical devices, a critical activity for the availability of the products needed during public health emergencies. Other points of the agreement include the timely development of high-quality, safe and efficacious medicinal products, and the creation of a new EMA’s structure specific for expert panels in charge of the assessment of high-risk medical devices and of essential advice on crisis preparedness and management.

How to tackle shortages of medicines

According to the EU Parliament, two “shortages steering groups” (for medicines and medical devices, respectively) shall be created by EMA; if needed, these groups may also include expert advice from relevant stakeholders (e.g. patients and medical professionals, marketing authorization holders, wholesale distributors, etc.).

Parliament negotiators highlighted the importance to achieve a high transparency of the process, including avoidance of interests related to industry sectors for members of the two groups; summaries of the proceedings and recommendations shall be also made publicly available.

A European Shortages Monitoring Platform shall be created by EMA to facilitate the collection of information on shortages, supply and demand of medicinal products; a public webpage with information on shortages of critical medicines and medical devices shall be also made available.

As already occurred during the Covid pandemic, future public health emergencies may boost the development of new medicines and medical devices. Sponsors of clinical trials conducted during health emergencies will be required to make the study protocol publicly available in the EU clinical trials register at the start of the trial, as well as a summary of the results. Following the granting of the marketing authorisation, EMA will also publish product information with details of the conditions of use and clinical data received (e.g. anonymised personal data and no commercially confidential information).

“With this agreement, Parliament makes both the Agency and all actors in the supply chain more transparent, involving them more in the process and fostering synergies between EU agencies. Moreover, we pave the way to promoting clinical trials for the development of vaccines and treatments, boosting transparency on those issues. In short, more transparency, more participation, more coordination, more effective monitoring and more prevention”, said Rapporteur Nicolás González Casares (S&D, ES).

EMA’s pilot project for the repurposing of medicines

The repurposing of already approved and marketed medicines is another key action put in place to ensure improved response capacity in case of future health emergencies.

A new pilot project to support the repurposing of off-patent medicines has been launched by EMA and the Heads of Medicines Agencies (HMA), with special focus on not-for-profit organisations and the academia as the main actors to carry out research activities needed to support the regulatory submission for the new indication. The initiative follows the outcomes reached by the European Commission’s Expert Group on Safe and Timely Access to Medicines for Patients (STAMP).

Interested sponsors may access EMA’s specific scientific advice upon submission of the drug repurposing submission form to the e-mail address [email protected] by 28 February 2022. More information is available in a Question-and-Answer document. The pilot will last until scientific advice for the selected repurposing candidate projects; filing of an application by a pharmaceutical company for the new indication is another target. Final results of the project will be published by EMA.

Comments from the industry

The European Federation of Pharmaceutical Industry Associations (EFPIA) welcomed the proposed framework for the repurposing of authorised medicines. “This pilot launch comes at a timely moment to test whether a streamlined and more transparent regulatory pathway for repurposing of off-patent established products increases the chances of including existing scientific evidence into regulatory assessment. One of the goals of the pilot is to raise awareness regarding the standards required for regulatory-ready evidence on the road to further increase availability of authorised therapeutic use”, said the chair of EFPIA’s Regulatory Strategy Committee Alan Morrison.

Innovation on existing, well-known molecules through repurposing can deliver huge benefits for patients, according to Medicines for Europe. The Association of the generic and biosimilar industry supports the pilot project as a way to generate robust data packages and to translate research into access for patients. A sustainable innovation ecosystem for off-patent medicine is the expected final outcome, possibly including also reformulation of existing medicines, new strengths or adaptation for specific patient groups (i.e. paediatric populations). “These investments must also be recognised in pricing and reimbursement policies to make access a reality for all patients”, writes Medicines for Europe.