public consultation Archives - European Industrial Pharmacists Group (EIPG)

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


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 Read more

EMA’s new Quality Innovation Expert Group (QIG)


by Giuliana Miglierini Innovative approaches to the development manufacturing and quality control of medicines are becoming the new paradigm to be faced both from an industrial and regulatory perspective. Not only innovative technologies for delivery, such as mRNA vaccines, many Read more

ICMRA report on best practices against antimicrobial resistance


by Giuliana Miglierini Antimicrobial resistance (AMR) is the consequence of mutations that allow microbes to survive pharmacological treatment. Resistant strains can often be tackled only by a limited number of therapeutic options: according to a systematic analysis published in The Read more

Comments to the draft ICH guidelines Q2(R2) and ICH Q14

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by Giuliana Miglierini

The public consultation on the two draft guidelines ICH Q2(R2) on the validation of analytical procedures and ICH Q14 on analytical procedure development closed at the end of July 2022.The European Medicines Agency published in August two documents summarising comments received (ICH Q2(R2) and ICH Q14).

Many industrial organisations contributed to the consultation with their point of view on the two draft guidelines. In the next phase of the procedure (step 3 of the ICH process), comments will be reviewed by the ICH Q2(R2)/ICH Q14 Expert Working Group (EWG). We summarise for readers some of the main comments received from industrial stakeholders. A webinar organised byEIPG on the implications and opportunities of the revision of ICHQ2 and the ICHQ14 was presented by Dr Phil Borman, Senior Fellow & Director Product Quality at GSK on 15thJune 2022 (recording and slides are available at the webinars page of EIPG’s website).

Key principles from the EIPG’s webinar

During the webinar, Dr Borman gave a comprehensive picture of the process of Analytical Quality by Design (QbD). The systematic approach to method development starts with the identification of the predefined objectives (Analytical Target Profile, ATP). The understanding and control of the analytical procedure are at the core of the process, and they should be pursued according to principles of ICH Q8. Analytical QbD covers both the drug product (ICH Q8) and the active ingredient (Q11). This means that a similar framework to ICH Q8 and Q11 can be applied also for analytical procedures. The ATP is made up of the sum of performance characteristics, precision, range (including sensitivity), and bias/accuracy.

According to ICH Q2(R1), published in 1994, the objective of validation of an analytical procedure is to demonstrate its suitability for the intended scope. Revision of both guidelines started in 2019, based on a Concept paper published in 2018. ICH Q2(R2) covers the validation of the analytical protocols and reports, while ICH Q14 refers to the development of the analytical procedure and its lifecycle management.

Key features of the new drafts include the fact that no additional expectations / mandated requirements for pharmaceutical analytical scientists are present, the possible use of “enhanced approaches” and the clear link between performance characteristics and their related criteria and the validation study. The Q2(R2) guideline shall apply to both small molecules and biologics and includes the possibility to use prior knowledge (e.g., from development or previous validation) as a part of the validation exercise. Assay for the determination of robustness can be conducted, for example, during development. Other key features highlighted by Dr Borman include the possible use of Platform analytical procedures to reduce the number of validation tests and the possibility to use any type of calibration model (including multivariate calibration).

The expected benefits refer to the possibility to reduce the existing burden associated with post-approval changes to analytical procedures and the use of Established Conditions.

As Dr Borman explained, the ATP could form the basis of a Post Approval Change Management Protocol (PACMP), thus favouring the reporting of changes between technologies at a lower reporting category. A more performance driven and flexible approach to validation is expected following the entry into force of the new ICH Q2(R2) guideline. The selection of validation tests shall be based on the concrete objective of the analytical procedure.

Comments to ICH Q2(R2)

The overview of comments relative to the draft ICH Q2(R2) published by EMA consists of a 72-page document, divided into a first section containing general comments and a second focused on specific comments.

APIC, representing manufacturers of active ingredients and API intermediates, focused on the fact that “uncertainty is not part of the validation whereas it has a reality in practice and part of the discussion between laboratories”. The measurement of uncertainty is also considered linked to the Total analytical error (TAE), a concept that would not be adequately addressed in the guideline.

EFPIA, on behalf of the biopharmaceutical industry, asked for a better connection between the two guidelines ICH Q2 and Q14, starting from the alignment of the respective titles. Improved consistency in the use of some terms was also suggested (e.g. ‘performance criteria’). Improved clarity and greater flexibility should be applied to the concept of working and reportable ranges. The association also asked to provide more examples for multivariate analytical procedures using different models to facilitate the understanding of their validation and lifecycle management.

Medicines for Europe, representing manufacturers of generic and biosimilars, asked to provide a more specific methodology for reportable range validation. The association requested some clarification about the possibility of using the minimal requirements of the performance characteristics for the addendum method validation strategy.

The European Association of Nuclear Medicine (EANM) focused its intervention of radiopharmaceuticals, a class of substances that should be considered a special case and therefore be excluded from the scope of the guidance. The request assumes that other approaches different that those discussed may be applicable and “acceptable with appropriate science-based justification”. The same request also applies to the draft ICH Q14 guideline. The EANM contribution also highlighted aspects specific to radiopharmaceuticals that should be considered, including the strength of the radioactivity content, the unavailability of radioactive standards of the active substance, and the need of specific techniques for radioactivity determination. The suggestion is to refer to the specific guideline on the validation of analytical methods for radiopharmaceuticals jointly developed by the EANM and the EDQM.

According to the International Society for Pharmaceutical Engineering (ISPE), there are many sections of the draft Q2(R2) guideline that may pose challenges due to lack of alignment and fragmentation of contents. A revision of the structure is thus suggested, together with the harmonisation of terms with those listed in the Glossary. ISPE also highlighted the opportunity to better clarify the distinction between validation elements and recommended data applicable to multivariate analytical procedures vs traditional analytical methods.

The ECA Foundation/European QP Association reported a very critical position on the two draft guidelines, clearly stating that ICH Q2 and Q14 should integrate with one another. According to ECA, the corresponding US guideline “USP <1220> is far superior”. Many of the points reported above with respect to the general section of the overview are discussed in more deep detail within the part of the document listing specific comments.

Comments to ICH Q14

The same structure of the document also applies to the 54-page overview summarising the results of the consultation on ICH Q14 guideline.

According to the Plasma Protein Therapeutics Association (PPTA), representing manufacturers of plasma-derived and recombinant analog therapies, the draft would be too focused on chemical methods, with just a residual attention to biological methods.

APIC asked for improved discussion of the capability (and uncertainty) of the method of analysis, a fundamental parameter to assess its appropriateness for the intended use within the defined specification range. According to the association, more specific reference should be made in relation to development data that can be/cannot be used as validation data.

ISPE suggested adopting a more detailed title for the guideline; something similar has also been suggested by EFPIA. ISPE also addressed the issue of reproducibility, that may be influenced by external factors across multiple laboratories. Multivariate analysis is also discussed, suggesting adopting additional requirements for the multivariate elements while maintaining the same approach to other analytical procedures.

EFPIA would prefer to avoid the use of the term “minimal” in favour of other expressions denoted by a less negative connotation (e.g., traditional, suitable/historic, classical, fit for purpose) with reference to the validation approach. The availability of training case studies is considered important to support the alignment between industry and regulatory agencies on expectations for regulatory change management, especially with reference to multivariate models. EFPIA asked that the paragraph discussing the relationship between ICH Q2 and Q14 should not address what should be submitted to regulatory agencies. Discussion of OMICS methods used in quality control of complex biological products should be included in the annexes.

ISPE asked to avoid reference to geographic regions, as the final goal is to reach harmonisation. A clearer statement of the scope would be advisable (a possible example is provided), as well as a better linkage to the ICH Q12 guideline on pharmaceutical product lifecycle management.

Specific comments include the suggestion of the PPTA to define all acronyms at first use in text and to include them in the Glossary. According to Medicines for Europe, it would be advisable to add characterisational assays (other than release/stability) for biosimilars. Furthermore, the scope of the guideline should focus on the risk assessment and availability of the analytical knowledge needed to select the most appropriate method for a specific application. Activities deemed to the submission of the regulatory CTD dossier should remain confined to the complementaryQ2 guideline.



Consultation on the reform of the European pharmaceutical legislation

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by Giuliana Miglierini

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

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

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

Details of the consultation

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

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

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

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

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

A brief overview of the legislative process

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

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

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


The Pact for Research and Innovation in Europe

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by Giuliana Miglierini

The roadmap to support the implementation of the new vision of the European Research Area (ERA) made a concrete step forward on 16 July 2021, with the adoption by the European Commission of the proposal for a Council Recommendation on “A Pact for Research and Innovation in Europe”. The chosen form of a Recommendation supports the final adoption of the Pact in the form of a single non-binding initiative.
The Commission’s proposal was drafted taking into consideration the results from the public consultation ran between 15 April and 13 May 2021, the views generated within the ERA Forum for Transition (set up as an informal Commission expert group), and the out-comings of workshops involving selected stakeholders.
“The pandemic has shown us the importance of uniting research and innovation efforts that swiftly bring results to the market. It has shown us the importance of investment in jointly agreed strategic priorities between Member states and the EU. The Pact for Research and Innovation we propose today, will facilitate better collaboration, and join our efforts to tackle research and innovation objectives that matter the most for Europe. And it will allow all of us to learn from each other”, said Margrethe Vestager, EU Commission’s Executive Vice-President for a Europe Fit for the Digital Age.
According to Mariya Gabriel, Commissioner for Innovation, Research, Culture, Education and Youth, “The objective of the Pact is to foster the future dialogue process with key actors putting a clear emphasis on sharing best practices and facilitating the collaboration of Member States to invest in and coordinate on common research and innovation objectives”.

The main features of the document
The goal of the Commission is to update the approach used to manage the European Research Area to the most recent models of R&I and financing of scientific research. The new model for ERA was already described in the “Communication on A New ERA for Research and Innovation” (COM(2020) 628 final) adopted on 30 September 2020.
Integration of national policies instead of a simple collaboration is one of the main points to achieve sharing of key principles and values and to guide joint actions in priority areas. These values and principles are now better detailed in the new Pact for Research and Innovation (R&I), which shall represent the basis for national authorities to reform their internal R&I frameworks in the direction of an improved harmonisation between different member states.
Coordination of efforts at the central and national level should benefit from a Union-level coordination and support mechanism, a common ERA policy agenda of jointly agreed ERA actions to be implemented, a dedicated ERA policy online platform for reporting, and a ERA score- board to monitor progress towards common objectives. Regular bilateral and multilateral policy dialogues between member states and the Commission is expected to favour the sharing of best practices and mutual learning exercises.

The inspiring values
Three different dimensions characterise the declination of the principles and values called to inspire future R&I activities. The “upholding values” include ethics and integrity of research and innovation, freedom of scientific research, gender equality and equal opportunities.
“Working better” values target the free circulation of researchers, excellence and value creation as a tool to support European excellence in science generation, together with early sharing of scientific knowledge through open science practices, attractive and merit-based careers, enhanced framework conditions for mobility and exchanges between academia and industry, and open access to research infrastructures, technology infrastructures and their services. The common goal of all these actions refers to the achievement of the highest quality of R&I activities, to be supported by new models of selection and funding; re-use of previous results should be also pursued during research management activities.
The “working together” dimension is based on the key principles of coordination, coherence, and commitment. Member states are called to coordinate their R&I policies and programmes in areas of common interest and to direct research and innovation investments and reforms to- wards achieving the ERA and speed up the green and digital transition. Global outreach should base on collaboration with partners from third countries and regions, while inclusiveness should support the exploitation of ERA’s full potential to compete at the global level. Furthermore, societal responsibility should aim to increase public trust in science and innovation.

Synergies of action
The Pact for R&I is expected to act in synergy with many other pieces of European legislation to achieve its goals. Challenge-based ERA actions should support the increased integration of the Commission and member states, including their regions, cities, and municipalities. The operative tools may be represented for example by collaborative projects to be run as a part of Horizon Europe Missions, European partnerships including EIT Knowledge and Innovation Communities (EIT KICs), joint programming initiatives or multilateral alliance. Inspiration can be obtained also from existing coordination initiatives, such as the Strategic Energy Technology Plan (SET Plan) or the ERAvsCorona initiative.
Integration with the EU Skills Agenda is also important to ensure the alignment of R&I with higher education, and synergies are expected between ERA and the European Higher Education Area (EHEA). Not less important are possible synergies with the EU’s Industrial Strategy, for example in the field of technology infrastructures, industrial Alliances, and common industrial technology roadmaps. A more active citizen and societal engagement in R&I is another target of the Pact.
At the financial level, the EU Commission looks at improved synergies between EU’s, national and regional funding programmes, with attention to favour the excellence-based integration of research-performing organisations from countries with lower R&I performance into EU’s scientific networks and innovation ecosystems.
The proposal adopted by the Commission provides insights on the expected level of investments in R&D: the total expenditure on research and development should reach the 3% target of EU GDP by 2030, with a total public effort on R&D up to 1.25% of EU GDP. The share of national public R&D expenditure committed to joint programmes, research infrastructures and European Partnerships should also reach 5% of national public R&D funding by the same year.
Voluntary targets for investments
A possible weak point in the vision of the Commission for the future of ERA may be represented by the voluntary adhesion member states are called to with respect to the expected level of expenditure on R&I activities. According to Science Business, the 3% target was achieved in 2019 only by Germany, Sweden, and Austria, while the EU average (2.2%) is below that of US, Japan, and Korea.
Critics to the current EU’s “boom and bust” approach to basic research funding came by the outgoing president of the European Research Council (ERC), Jean-Pierre Bourguignon, during a meeting of EU science ministers in Slovenia in July (see Science Business).
According to Bourguignon, basic R&D should be not necessarily targeted towards topics which represents the priority of action of the EU Commission, such as the green and digital agenda. Sufficient funding for bottom-up research should be always available in order to support curiosity-driven research.