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A new member within EIPG


The European Industrial Pharmacists Group (EIPG) is pleased to announce the Romanian Association (AFFI) as its newest member following the annual General Assembly of EIPG in Rome (20th-21st April 2024). Commenting on the continued growth of EIPG’s membership, EIPG President Read more

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

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Steps towards the final approval of the IP action plan

December 10, 2021 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

By Giuliana Miglierini

The end of 2021 may see the final approval of many pieces of the new legislative framework announced in November 2020 by the European Commission. An important piece of this puzzle is represented by the IP Action Plan, governing the protection of intellectual property (IP); a step forward in this direction is represented by the resolution of 11 November 2021 on the Own-initiative report of the European Parliament.

The final text licensed in single reading is the result of the examination of the initial draft report – issued in May 2020 by the Committee for Legal Affairs, rapporteur Marion Walsmann – by several other Committees (IMCO, DEVE, CULT, AGRI).

The main points of the resolution

The resolution recognises the importance for the European economy of a balanced protection and enforcement of intellectual property rights (IPR). In years 2012-2016, the knowledge-intensive industries generated almost 30% of all jobs and almost 45% of total economic activity (in terms of Gross Domestic Product, GDP) in the EU; the IPR-intensive industries account for 93% of total EU exports of goods.

Europe’s recovery and resilience capacity is also highly impacted, as demonstrated by the pandemic when shortages of certain medicinal products and vaccines occurred. The EU Parliament acknowledges the role played by intellectual property in increasing the overall value of companies,especially the small-and-medium size ones (SMEs).

A current limitation to IP protection in Europe is represented by the still fragmented situation across different member states, which often leads to parallel national validation procedures and litigation for European patents. To this instance, the Parliament suggests the establishment of an IP coordinator at European level, to harmonise the approach to EU IP policy and enhance cooperation between the different bodies involved in the process (i.e. national IP authorities, Commission Directorates-General, EPO, EUIPO, WIPO, etc).

The Parliament also recognised the role IP plays in the pharmaceutical sector, where the availability of incentives greatly favours the development of new and innovative treatments. The resolution asks the Commission to support the innovative potential of European companies “on the basis of a comprehensive IP regime”, so to guarantee effective protection for R&D investments and favour fair returns through licensing. The availability of open technology standards has been valued as an important competitive element on the wider, global scenario.

Many different types of incentives are suggested by the Parliament’s resolution as useful to support micro-enterprises and SMEs in filing and managing their intellectual property, including IP vouchers, IP Scan and other Commission and EUIPO initiatives to support simple registration procedures and low administrative fees. The newly created European IP Information Centre may represents a fundamental reference point to increase knowledge in the field. The Parliament also suggests to introducing an EU-level utility model protection, not yet available, as a possible fast and low-cost protection tool to protect technical inventions.

Unitary patents and improved market competition

Still missing members states are urged to adhere to the enhanced cooperation scheme for the creation of a Unitary Patent Protection (UPP) and to ratify the Protocol to the Agreement on a Unified Patent Court on provisional application (PPA). The activation of this unique Court in charge of the examination of litigations would allow for a more efficient process and for lowering legal costs and improving legal certainty.

Fragmentation remains an issue also with respect to Supplementary Protection Certificates (SPCs): to this instance, the resolution asks the Commission to issue guidelines for member states and to provide a legislative proposal based on an exhaustive impact assessment. A major criticality to be solved is represented by the unitary patent not providing a unique SPC title valid across the EU; the own-initiative report also suggests the extension of the EPO’s mandate, so that examination of SPC applications could be carried out on the basis of unified rules.

Other important points needing attention to improve the presence of generic and biosimilar medicines in the EU are the abuse of divisional patent applications and patent linkage, which should also see an intervention by the Commission. The Parliament also opened the possibility of a revision of the Bolar exemption, which allows clinical trials on patented products needed to reach marketing authorisation of a generic or biosimilar version not to be regarded as infringements of patent rights or SPCs. This may also support the immediate market entry after the expiration of patent rights and SPCs. The Commission is called also to ensure the effectiveness and better coordination of compulsory licensing in order to provide access to medicines needed in case of health emergencies.

The resolution also addresses the theme of standard essential patents, which currently often leads to litigations, and it calls for the revision of the 20-years old system for design protection. Transparency on results obtained from publicly funded R&D is also recommended. The Parliament suggests artificial intelligence (AI) and blockchain technologies may play an important role in tackling counterfeiting practices and guarantee traceability of goods, as they may contribute to a better enforcement of intellectual property rights along the whole supply chain. The Commission should also work to establish clearer criteria for the protection of inventions created by the AI, without human intervention.

Comments from the industry

“The European Parliament has clearly voted for a strong and fair IP system by underlining the importance of timely generic and biosimilar medicine competition. The misuse of divisional patents, the need to enlarge the scope of bolar to include API and all regulatory and administrative steps, and the long overdue ban anti-competitive patent linkage are well known problems that the Commission should address in the IP Action Plan. The Parliament has voted; the Commission must act.”, said Adrian van den Hoven, Director General at Medicines for Europe.

A major point in the implementation of the new European policies is represented by the review the Commission is going to conduct in 2024 to assess the effective achievement of goals of the SPC manufacturing waiver, which entered into force in July 2019 and is expected to start producing effects in the second half of 2022.

Many of the themes discussed in the Parliament’s resolution were debated during a webinar organized by Medicines for Europe, with the participation of representatives from the European Commission and the European Patent Office.

EFPIA, representing the innovator pharmaceutical industry, focused its attention on the impact of past EU Free Trade Agreements (FTAs) on drug spending, timing of countries’ access to new medicines after global launch, investments overall and in pharmaceuticals, and clinical trial participation. A report by IQVIA published in the Federation’s website addresses the impact of IP protection on these elements. Results confirm the central role of the pharmaceutical sector as the most R&D intensive industry in the world, with R&D spending averaging over 15% of revenue. A strong IP protection framework available at the level of EU FTAs favours the attractiveness for investments in the EU and its FTA partner countries. According to the report, an expanded IP protection appears not to be linked to the generation of a higher pharmaceutical spending; drugs’ share of healthcare spending is claimed to stay flat or fall after an FTA, and prices for medicines to rise more slowly than the level of inflation. A stronger IP index, adds IQVIA, is also correlated with increased clinical trial activity in a country, bringing both clinical and economic benefits.


Automation of aseptic manufacturing

October 29, 2021 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giliana Miglierini

The pharmaceutical industry is often the last industrial sector to implement many new manufacturing and methodological procedures. One typical example is Lean production, those concepts were developed in the automotive industry well before their adoption in the pharmaceutical field. The same may also apply to automation: it appears time is now mature to see an increasing role of automated operations in the critical field of aseptic manufacturing, suggests an article by Jennifer Markarian on PharmTech.com.

The main added value of automation is represented by the possibility to greatly reduce the risk of contamination associated to the presence of human operators in cleanrooms. A goal of high significance for the production of biotech, advanced therapies, which are typically parenterally administered. Automation is already taking place in many downstream processes, for example for fill/finish operations, packaging or warehouse management.

The advantages of the automation of aseptic processes

“The biggest challenges engineers face when designing isolated fill lines are fitting the design into a small, enclosed space; achieving good operator ergonomics; and ensuring all systems and penetrations are leak-tight and properly designed for cleanability and [hydrogen peroxide] sterilization,” said Joe Hoff, CEO of robotics manufacturer AST, interviewed by Jennifer Markarian.

The great attention to the development of the Contamination Control Strategy (CCS) – which represents the core of sterile manufacturing, as indicated by the new Annex 1 to GMPs – may benefit from the insertion of robots and other automation technologies within gloveless isolators and other types of closed systems. This passage aims to completely exclude the human presence from the cleanroom and is key to achieve a completely segregated manufacturing environment, thus maximising the reduction of potential risks of contamination.

The new approach supports the pharmaceutical industry also in overcoming the often observed reluctance to innovate manufacturing processes: automation is now widely and positively perceived by regulators, thus contributing to lowering the regulatory risks linked to the submission of variations to the CMC part of the authorisation dossiers. High costs for the transitions to automated manufacturing – that might include the re-design of the facilities and the need to revalidate the processes – still represent significant barriers to the diffusion of these innovative methodologies for pharmaceutical production.

The elimination of human intervention in aseptic process was also a requirement of FDA’s 2004 Guideline on Sterile Drug Products Produced by Aseptic Processing and of the related report on Pharmaceutical CGMPs for the 21st Century: A Risk-Based Approach. According to Morningstar, for example, the FDA has recently granted approval for ADMA Biologics’ in-house aseptic fill-finish machine, an investment aimed to improve gross margins, consistency of supply, cycle times from inventory to production, and control of batch release.

Another advantage recalled by the PharmTech’s article is the availability of highly standardized robotics systems, thus enabling a great reduction of the time needed for setting up the new processes. The qualification of gloves’ use and cleaning procedures, for example, is no longer needed, impacting on another often highly critical step of manufacturing.

Easier training and higher reproducibility of operative tasks are other advantages offered by robots: machines do not need repeated training and testing for verification of the adherence to procedures, for example, thus greatly simplifying the qualification and validation steps required by GMPs. Nevertheless, training of human operators remains critical with respect to the availability of adequate knowledge to operate and control the automated systems, both from the mechanical and electronic point of view.

Possible examples of automation in sterile manufacturing

Robots are today able to perform a great number of complex, repetitive procedures with great precision, for example in the handling of different formats of vials and syringes. Automatic weighing stations are usually present within the isolator, so to weight empty and full vials in order to automatically adjust the filling process.

This may turn useful, for example, with respect to the production of small batches of advanced therapy medicinal products to be used in the field of precision medicine. Robots can also be automatically cleaned and decontaminated along with other contents of the isolator, simplifying the procedures that have to be run between different batches of production and according to the “Cleaning In Place” (CIP) and “Sterilisation In Place” (SIP) methodologies.

The design and mechanical characteristics of the robots (e.g. the use of brushless servomotors) make the process more smooth and reproducible, as mechanical movements are giving rise to a reduced number of particles.

Examples of gloveless fully sealed isolators inclusive of a robotic, GMP compliant arm were already presented in 2015 for the modular small-scale manufacturing of personalised, cytotoxic materials used for clinical trials.

Maintenance of the closed system may be also, at least partly, automated, for example by mean of haptic devices operated by remote to run the procedure the robotic arm needs to perform. Implementation of PAT tools and artificial intelligence algorithms offers opportunities for the continuous monitoring of the machinery, thus preventing malfunctioning and potential failures. The so gathered data may also prove very useful to run simulations of the process and optimization of the operative parameters. Artificial intelligence may be in place to run the automated monitoring and to detect defective finished products.

Automated filling machines allow for a high flexibility of batch’s size, from few hundreds of vials per hour up to some thousands. The transfer of containers along the different stations of the process is also automated. The implementation of this type of processes is usually associated with the use of pre-sterilised, single-use materials automatically inserted within the isolator (e.g. primary containers and closures, beta bags and disposal waste bags).

Automation may also refer to microbial monitoring and particle sampling operations to be run into cleanrooms, in line with the final goal to eliminate the need of human intervention.

Comparison of risks vs manual processes

A comparison of risks relative to various types of aseptic preparation processes typically run within a hospital pharmacy and performed, respectively, using a robot plus peristaltic pump or a manual process was published in 2019 in Pharm. Technol. in Hospital Pharmacy.

Production “on demand” of tailor-made preparations has been identified by authors as the more critical process, for which no significant difference in productivity is present between the manual and automated process. The robotic process proved to be superior for standardised preparations either from ready to use solutions or mixed cycles. A risk analysis run using the Failure Modes Effects and Criticality Analysis (FMECA) showed a lower level of associated risk.


The opportunity for repurposing of oncology medicines

September 10, 2021 , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

Rare cancers, which account for approx. 22% of new cases in Europe, represent an area of low business interest for the pharmaceutical industry, due to the limited number of patients compared to the very high costs to develop targeted treatments. It is thus important to consider the possibility for already existing medicines to be repurposed for a new indication. Lower costs of development and risk of failure, and a shorter time frame to reach registration are upon the main advantages of repurposing compared to de novo development, highlights the Policy Brief presented during the Joint meeting of EU Directors for Pharmaceutical Policy & Pharmaceutical Committee of 8 and 9 July 2021.
The experts addressed more specifically the possibility to achieve non-commercial repurposing of off-patent cancer medicines, which are commonly used off-label to treat patients not responsive to other more innovative types of therapies.

The issue of non-commercial development
The request of a new indication for an already marketed medicine has to be submitted by the Marketing authorisation holder (MAH). This greatly hampers the access to noncommercial repurposing by independent research institutions, as they would need to find an agreement with the MAH, the only responsible for all the interactions with regulatory authorities, at the central (EMA) or national level.
Considering the issue from the industrial point of view, this type of external request may prove difficult to be answered positively, when taking into consideration the very low return on investment that can be expected from a repurposed off-patent medicine. Even EU incentives schemes, such as those on data exclusivity and orphan designation, may not be sufficiently attractive for the industry. Current incentives schemes, for example, allow for an additional year of exclusivity in case of a new indication for a well-established substance, a 10-year market exclusivity
plus incentives in case of an authorised medicine granted with orphan designation, or the extension of the supplementary protection certificate for paediatric studies (plus 2 years market exclusivity for orphans).
The following table summarises the main issues and potential solutions involved in the setting of a specific reference framework for the repurposing of off-patent medicines for cancer, as reported in the WHO’s Policy Brief.

Table: Short overview of issues and solutions in repurposing of off-patent medicines for cancer
(Source: Repurposing of medicines – the underrated champion of sustainable innovation. Copenhagen: WHO Regional Office for Europe; 2021. Licence: CC BY-NC-SA 3.0 IGO)

Many projects active in the EU
The European Commission started looking at the repurposing of medicines with the 2015-2019 project Safe and Timely Access to Medicines for Patients (STAMP). A follow-up phase of this initiative should see the activation in 2021 of a pilot project integrated with the new European Pharmaceutical Strategy.
Several other projects were also funded in the EU, e.g. to better train the academia in Regulatory Science (CSA STARS), use in silico-based approaches to improve the efficacy and precision of drug repurposing (REPO TRIAL) or testing the repurposing of already marketed drugs (e.g. saracatinib to prevent the rare disease fibrodysplasia ossificans progressive, FOP). A specific action aimed to build a European platform for the repurposing of medicines is also included in Horizon Europe’s Work programme 2021 –2022; furthermore, both the EU’s Beating Cancer Plan and the Pharmaceutical Strategy include actions to support non-commercial development for the repurposing of medicines.

According to the WHO’s Policy Brief, a one-stop shop mechanism could be established in order for selected non-commercial actors, the so-called “Champions”, to act as the coordination point for EU institutions involved in the funding of research activities aimed to repurposing. This action may be complemented by the support to public–private partnerships involving research, registration and manufacturing and targeted to guarantee volumes for non-profitable compounds.
Among possible non-profit institutions to access funding for repurposing research in cancer are the European Organisation for Research on Cancer (EORTC) and the Breast Cancer International Group. An overview of other existing initiatives on repurposing has been offered during the debate by the WHO’s representative, Sarah Garner.

How to address repurposing
Looking for a new indication is just one of the possible points of view from which to look at the repurposing of a medicine. Other possibilities include the development of a new administration route for the same indication, the setup of a combination form instead of the use of separated medicinal products, or the realisation of a drug-medical device combination.
A change of strategy in the war on cancer may be useful, according to Lydie Meheus, Managing Director of the AntiCancer Fund (ACF), and Ciska Verbaanderd.
Keeping cancer development under control may bring more efficacy to the intervention than trying to cure it, said ACF’s representatives. The possible approaches include a hard repurposing, with a medicine being transferred to a completely new therapeutic area on the basis of considerations about the tumor biology and the immunological, metabolic and inflammatory pathways, or a soft repurposing within the oncology field, simply looking to new indications for rare cancers.
From the regulatory point of view, a possible example for EMA on how to address the inclusion of new off-label uses of marketed medicines is given by the FDA, which may request a labeling change when aware of new information beyond the safety ones.

The Champion framework
The Champion framework, proposed as a result of the STAMP project, is intended to facilitate data generation and gathering compliant to regulatory requirements for a new therapeutic use for an authorised active substance or medicine already free from of intellectual property and regulatory protection.
A Champion is typically a not-for-profit organisation, which interacts with the MAH in order to include on-label what was previously off-label, using existing regulatory tools (e.g innovation offices and scientific and/or regulatory advice). The Champion shall coordinate research activities up to full industry engagement and would be responsible for filing the initial request for scientific/regulatory advice on the basis of the available data. The pilot project to be activated to test the framework will be monitored by the Repurposing observatory group (RepOG), which will report to the Pharmaceutical Committee and will issue recommendations on how to deal with these types of procedures.

AI to optimise the chances of success
Artificial intelligence (AI) may play a central role in the identification of suitable medicines to be repurposed for a target indication, as it supports the collection and systematic analysis of very large amounts of data. The process has been used during the Covid pandemic, for example, when five supercomputers analysed more than 6 thousand molecules and identified 40 candidates for repurposing against the viral infection.
AI can be used along drug development process, making it easier to analyse the often complex and interconnected interactions which are at the basis of the observed pharmacological effect (e.g drug-target, protein-protein, drug-drug, drug-disease), explained Prof. Marinka Zitnik, Harvard Medical School.
To this instance, graphic neural networks can be used to identify a drug useful to treat a disease, as it is close to the disease in “pharmacological space”. The analysis may also take into account the possible interactions with other medicines. This is important to better evaluate the possible side effects resulting from co-prescribing; annual costs in treating side effects exceed $177 billion in the US alone, according to Prof. Zitnik.


Artificial intelligence in medicine regulation

August 20, 2021 , , , , , , , , , , , ,

The International Coalition of Medicines Regulatory Authorities (ICMRA) sets out recommendations to help regulators to address the challenges that the use of artificial intelligence (AI) poses for global medicines regulation, in a report published on 16 August 2021.

AI includes various technologies (such as statistical models, diverse algorithms and self-modifying systems) that are increasingly being applied across all stages of a medicine’s lifecycle: from preclinical development to clinical trial data recording and analysis, to pharmacovigilance and clinical use optimisation. This range of applications brings with it regulatory challenges, including the transparency of algorithms and their meaning, as well as the risks of AI failures and the wider impact these would have on AI uptake in medicine development and patients’ health.

The report identifies key issues linked to the regulation of future therapies using AI and makes specific recommendations for regulators and stakeholders involved in medicine development to foster the uptake of AI. Some of the main findings and recommendations include:

  • Regulators may need to apply a risk-based approach to assessing and regulating AI, which could be informed through exchange and collaboration in ICMRA;
  • Sponsors, developers and pharmaceutical companies should establish strengthened governance structures to oversee algorithms and AI deployments that are closely linked to the benefit/risk of a medicinal product;
  • Regulatory guidelines for AI development, validation and use with medicinal products should be developed in areas such as data provenance, reliability, transparency and understandability, pharmacovigilance, and real-world monitoring of patient functioning.

The report is based on a horizon-scanning exercise in AI, conducted by the ICMRA Informal Network for Innovation working group and led by EMA. The goal of this network is to identify challenging topics for medicine regulators, to explore the suitability of existing regulatory frameworks and to develop recommendations to adapt regulatory systems in order to facilitate safe and timely access to innovative medicines.

The implementation of the recommendations will be discussed by ICMRA members in the coming months.

Source: EMA


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