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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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European Council’s conclusions on the European Innovation Agenda and research infrastructures

January 6, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

The European socio-economic framework is undergoing a profound transformative moment, as a result of the new vision impressed by the von der Leyen Commission, with its goals in the field of the Digital and Green transitions. The subsequent crisis caused by the Covid pandemic and the following war at the boundaries of the European Union deeply impacted the already fragile economy, asking for new measures to sustain its competitiveness and ability to innovate.

A major goal of the Commission’s Agenda is to reposition the EU as a global leader in innovation. The European Council endorsed this vision at the beginning of December 2022, by adopting the Conclusions on the New European Innovation Agenda.

“The recent crises have shown the need for the EU to support an open strategic autonomy in order to curb the dependencies and vulnerabilities that affect our industry. We have to strengthen the EU’s own capacity in strategic areas. This will not be possible without ambitious investments in innovation”, said Vladimír Balaš, Czech Minister for Education, Youth and Sport, commenting the document.

The European Council also adopted its new Conclusions on research infrastructures (RIs), which complement and complete the framework to support innovation and set the basis for the full development of the European Research Area (ERA).

According to the European Commission, almost two thirds of the EU’s growth is driven by innovation. Despite this, the EU still positions behind other countries as for Gross domestic product expenditure on R&D activities (2.18%, vs 4.52% of South Korea, 3.28% of Japan and 2.82% of the US. Only China slightly follows at 2.14%). The same trend applies also to business enterprise investments in R&D (EU 1.45%, vs 3.63% of South Korea, 2.6% Japan, 2.05% of the US, and 1.66% of China).

The new Innovation Agenda

The Conclusions on the New European Innovation Agenda are the result of a work started in November 2021, when the Council’s Recommendation on a Pact for Research and Innovation (R&I) in Europe highlighted the importance of synergies with sectorial policies and industrial policy, as well as the coordination of R&I policies and programmes to support the development of breakthrough and incremental innovations across the Union. The New European Innovation Agenda was announced by the Commission in July 2022 and is intended to fully exploit the potential of deep tech innovations. In September 2022, the Czech Presidency of the Council started the drafting of the conclusions, and the final text adopted by the Competitiveness Council (Research) at its meeting of 2 December 2022.

All types of innovation play a critical role in driving EU’s competitiveness, states the document, with a particular emphasis on research-driven innovation, deemed able of shaping and creating new markets. Incremental and breakthrough innovation are both essential to maximise the societal and economic value of the resulting outcomes. Investing in higher education and R&I is thus essential to achieve these goals, and to position the EU as a global R&I leader. Social sciences and humanities should also be part of the comprehensive approach to innovation described by the Conclusions.

The diversification of supplies and the mitigation measures to tackle strategic dependencies on external suppliers are critical issues to be faced to compete in the complex global geopolitical scenario. An open approach to international R&I cooperation is still the goal of the European institutions, requiring shared fundamental values and principles with other countries and a balanced and reciprocal approach.

At the regulatory level, flexibility, fit-for-purpose, forward-looking and innovation-friendly remain the preferred keywords to characterise the new framework. The development of breakthrough, deep-tech and disruptive innovations should be supported by standardisation and accreditation, and regulatory adaptation and experimentation.

The Council also supports the role of private R&I investments and strategic use of intellectual assets as a fundamental part of the undergoing transition, as well as further policy reforms at Union, national and regional levels to better encourage the full development and implementation of new technologies, including testing and demonstration facilities.

The European Innovation Council (EIC) Fund has been confirmed as the tool to support investments in innovation. Among others, the Conclusions ask the Commission to implement the EIC’s Scale Up 100 action and to facilitate access to capital for innovative start-ups and SMEs through the InvestEU Programme.

Conclusions on Research Infrastructures

The second document approved in December 2022 updates the vision of the European RI ecosystem, with a particular focus on the system of integrated research infrastructures. Access to RIs is deemed fundamental to support innovation by private, large and medium-small companies. It can take different forms, i.e. proprietary access to RIs, contractual research, joint R&I, training and industrial, supply of top-class products and services to RIs. Research infrastructures are also important to sustain regional development and support the availability of a wide range of skills and relating jobs.

A central part of document is represented by the call to proceed with the implementation of the ERA Policy Agenda for the period 2022–2024 and, in particular, ERA Action 8 (“Strengthen sustainability, accessibility and resilience of RIs in the ERA”). To this instance, a major activity should aim to involve RIs in producing, collecting, processing, storing and providing quality certified scientific data in accordance with the FAIR (Findable, Accessible, Interoperable and Reusable) principles. This action is considered essential to facilitate the sharing and use of data across a broad range of disciplines as well as at the international level.

To improve the RIs’ framework, the invitation of the Council is for the European Strategy Forum on Research Infrastructures (ESFRI) to run a comparative study aimed to identify best practices and elaborate recommendations to national and regional RI stakeholders by the end of 2023. A common approach for the staff of the RIs, especially in the case of a European Research Infrastructure Consortium (ERIC), is also envisaged.

Research infrastructures can’t operate without the support of Technology Infrastructures (TIs); a mapping exercises of the last ones is considered essential in order to proceed with the implementation of the TI concept within the ERA Policy Agenda. Members states and the Commission should also work to better identify the role of RIs in the implementation of Horizon Europe (i.e. European Partnerships and Missions, industrial technology roadmaps, etc.). RIs may also contribute to designing new services based on their different missions and should be supported by long-term investments by member states with the support of the Commission. To this instance, the analysis of possible types of financial support throughout RIs’ life cycle, with identification of good practices and synergies of various funding resources, should be accomplished by ESFRI.

The Council also invited the Commission to present an initiative on a revised European Charter for Access to Research Infrastructures by the end of 2023. A better coordination between ESFRI and the European Open Science Cloud (EOSC) Steering Board would also be needed.


How to approach drug substance supply in new product introduction (NPI) processes

October 7, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

A key issue to be faced during pharmaceutical development refers to the supply of the active pharmaceutical ingredients and other raw materials to be used for the manufacturing of the first batches of investigational medicinal products, and then up to commercial production once approved.

Changes of specifications can frequently occur during experimentation, thus leading to the need to modify supply requirements for clinical programs. This is more true when dealing with biopharmaceutical investigational products, for which the traditional models for forecasting and demand processes may prove unfitted. The result is a lower robustness and predictability at early stages of the new product introduction (NPI) manufacturing processes. The complexity of the NPI supply chain is also impacting on manufacturing operations, with possible delays in the clinical program and launch schedule.

These issues have been addressed in the document “Guidelines for materials introduction supporting drug substance delivery”, published by the B2B organisation BioPhorum. A summary of its contents has been published in Bioprocess Online.

A good internal communication is fundamental

The ability to produce robust supply forecasts for new product introduction bases on a detailed knowledge of the planning of different activities to be run for a timely launch. Role and responsibilities have to be clear, as well as the information to be collected and timely shared between the manufacturing and commercial departments of biopharmaceutical companies.

The availability of such information is crucial to reduce the variability intrinsic in the NPI process for a biopharmaceutical product, which costs much more compared to a traditional smallmolecule based one. Reducing variability also impacts on the ability to better compete in the often highly dynamic market for biosimilars, or to address the launch of a new biotherapeutic under the correct perspective. Issues may be encountered also with respect to the regulatory approval processes, which may require different time lengths in different geographic areas or countries. This adds another uncertainty factor to estimates of the quantities of product to be manufactured.

Upon this considerations, the BioPhorum document identifies four key issues to be addressed to provide for a timely NPI process, including capacity and lead-time restrictions or oversupply, late change evaluation and implementation, governance issues and network complexity and in-licensed (or non-platform) products.

The availability of a good NPI process may avoid to incur many problems once operations are in place; all the needed master data information to support the use of raw materials should also be present and correct. BioPhorum’s suggestion is to include NPI processes in the creation of master service and supply agreements for the supply of raw materials, as they help to reach clarity on what a supplier can deliver and what it cannot.

A four steps methodology and roadmap

The document by the BioPhorum describes the results of a project aimed to develop a materialsbased methodology and roadmap to support improved NPI processes, on the basis of a collaborative industry approach to identify and implement best practices.

The result is a four steps process referring to the different activities needed to set up materials introduction and supply. The proposed different steps include the establishment of product lifecycle materials requirements, materials evaluation, supplier selection and qualification, and a manufacture and business review. Each of them should be supported by specific tools and checklists to be developed internally by the company. The governance of the process should involve senior supplier/manufacturer nominees to formally approve the package of deliverables at each stage gate.

Establishing product lifecycle material requirements

For each of the four steps of the NPI process, the BioPhorum document offers detailed lists of information to be collected and of expected outcomes.

Stage gate 1 addresses the establishment of product lifecycle material requirements, usually corresponding to the activation of first time in human studies (FTIH). Data to be collected include specifications of raw materials (e.g. order of magnitude, grade, supply options, environmental-health-safety (EHS) or geographic issues, etc.) as well as master data such as recipe information, plant diagram, list of equipment and process information. At the clinical level, information on the demand sensitivities on indication and clinical milestones and decision points should support the first estimates of the supply and demand plan, to be then expanded to agree on lifecycle forecasts.

The output may take the form of a ‘Product Lifecycle Demand and Supply Strategy’, a document discussing the long-term supply, demand and manufacturing of the product. Starting from the initial planning, the strategy should evolve through the creation of a data store specific for biopharmaceuticals, and the execution of gap analysis for in-licensed products. The strategy should also include a rough capacity modelling and description of ownership and the definition of a RACI matrix (responsible, accountable, consult, inform) to clarify roles and responsibilities with respect to each task, deliverable, or action. Information should be also available on high level technology requirements (both at the internal and external level). Strategic suppliers should be involved in early activities and materials risk analysis should be initiated.

Materials evaluation

Stage gate 2 refers to the information to be gathered from suppliers on the basis of requests for information (RFI) on materials. This should include all the different aspects relevant to the selection of the supplier, including capacity and costs, contacts, technical specifications and audit history, availability of samples, EHS aspects and business systems (e.g. availability of an appropriate ERP system).

This information should facilitate the identification of supplier that might be able to support the predicted or proposed growth of the product over its lifecycle. Stage gate 2 is also part of the risk management process to be run to validate the activation of full production.

Outputs include the sharing of forecasts and sensitivities with suppliers as needed, the establishment of a standard industrial master data set for biopharmaceuticals, as well as of business acceptance criteria.

Supplier selection and qualification

Stage gate 3 addresses the qualification process to finally select the most suitable suppliers and close the corresponding material supply agreements. The RFI and other information gathered in the previous step represent the basis of this exercise, aimed to develop a supply chain resilience strategic approach. The signature of the initial contracts is the final mark of formal selection, and should be supported by an agreement with the supplier on forecast and schedule for the supply, as well as of the business acceptance criteria.

Manufacture and business review

Stage gate 4 refers to the assessment of the operational performance of the supply chain for raw materials, a key activity in order to ensure continuity of supply and to promptly intercept any emerging issue on the basis of trends analysis.

Tools needed to this instance include the definition of appropriate metrics to monitor supplies (e.g. adherence to schedule, “On time in full”-OTIF, “Cost of poor quality”-COPQ). Information on the innovation potential of the supplier and the provision of a feedback on its performance is also deemed important. Any issue should be timely discussed between the supplier and the biopharmaceutical company, and confirmation of the production schedule agreed upon.


ICMRA, two pilot programmes to optimise regulatory assessment and inspections

July 22, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

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

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

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

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

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

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

The general objectives

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

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

Hybrid inspections

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

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

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

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

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

Collaborative assessment

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

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

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

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

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

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