public consultation Archives - European Industrial Pharmacists Group (EIPG)

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

The first Union list of critical medicines

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by Giuliana Miglierini

The first version of the Union list of critical medicines was published on 12 December 2023 by the European Commission, the European Medicines Agency (EMA) and the Heads of medicines Agencies (HMA).

The initiative is part of the actions planned according to the Pharmaceutical Strategy and the Communication on addressing medicine shortages in the EU. A Q&As documentwas also published to illustrate the main features of the list, together with the methodology to identify critical medicinesto be included in the list (see the dedicated webpage of EMA’s website). The first version of the Union list of critical medicines is comprehensive of approx. 200 active substances, selected starting from a pool of more than 600 referred to in the national lists of critical medicines of Finland, France, Germany, Portugal, Spain, and Sweden. These six countries were chosen as their lists were based on criteria aligned with those agreed for the Union list. The process also comprised consultations of key stakeholders, including patients and healthcare professionals’ organisations and industry associations.

The list will be updated annually, and further references will be added in 2024. The final list will also include the separate assessment of the vulnerability of the supply chains to be run by the European Commission.

The Union list will not replace existing national lists of critical medicines, that will continue to support national policy decisions. EU member states may also use the Union list to create their own national lists, if not yet available.

Ensuring an uninterrupted supply of critical medicines is essential for a strong European Health Union. With the publication of the first Union list of critical medicines today, we are delivering on our promise to accelerate work in this area and to take every possible measure to avert the risk of shortages for our citizens”, said Stella Kyriakides, Commissioner for Health and Food Safety.

A list to prevent shortages

The Union list of critical medicines represents a warning about the importance of avoiding shortages for specific medicines, as they would highly impact both patients and healthcare systems. No immediate effect is expected on shortages, but the risk might decrease in the longer term.

The Union list specifies human medicines (both innovators and generics, vaccines, and medicines for rare diseases) those continued supply is considered a priority in the EU. It will be used by the EU Commission, EMA and HMA for the definition of proactive measures to strengthen the supply chain and minimise the risk of supply disruptions (see more on EMA’s webpage on Availability of critical medicines).

The Union list of critical medicines will also serve as the basis for the Commission to run the analysis of vulnerabilities, followed by recommendation of suitable measures in consultation with the Critical Medicines Alliance (we wrote about this part 1 and part 2). The Commission may issue recommendations for companies to diversify suppliers or increase production within the EU. Incentives to invest may also be used to favour the resilience of European manufacturing. As for procurement, strong contractual obligations for delivery may apply.

Medicines included in the Union list will also be prioritised for actions by the European medicines regulatory network, in charge of monitoring their availability and implementing measures to minimise the risk of supply disruptions. To this instance, existing processes and structures will be used as defined in the mandate of EMA’s Medicine Shortages Single Point of Contact (SPOC) Working Party and EMA’s Executive Steering Group on Shortages and Safety of Medicinal Products (MSSG).

No additional obligations have been introduced by now for marketing authorisation holders and national competent authorities. This will be a topic of discussions during the final phase of negotiations on the proposed revision of the EU pharmaceutical legislation.

The methodology to select critical medicines

The therapeutic indication and the availability of alternative medicines are the two main criteria for the insertion of a certain medicinal product in the Union list of critical medicines. Additionally, it has to be classified as critical in at least one-third (33%) of EU/EEA (European Eco-nomic Area) member states.

National lists of critical medicines may differ from one another, reflecting differences of the internal evaluation criteria used to assess criticality. For example, some products are marketed just in some countries, or alternatives are available in some countries and not in others. Furthermore, the Union list is still incomplete, as some important medicines have not yet been assessed at the central level. The Union list does not include as well products mentioned in the WHO list of essential medicines. Orphan medicines are included in the Union list if they meet the above-mentioned assessment criteria.

The document on methodology further clarifies the governance of the process and the matrix for identifying medicines to be included in the Union list of critical medicines. The methodology was created starting in 2021 (European Commission Structured Dialogue initiative), finalised by the HMA/EMA Task Force on the availability of authorised medicines for human and veterinary use (HMA/EMA TF-AAM), and finally adopted in June 2023.

The medicinal product criticality is evaluated on the basis of a risk assessment. As for therapeutic indications (criterion 1), all authorised medicines in a member state should be classified, irrespective of their marketing status. Criterion 2 refers to the availability of alternatives, and only authorised medicines marketed in the respective member state should be classified.

A low, medium or high-risk level is assigned for each of the two above-mentioned criteria, thus resulting in a risk matrix. The exercise allows to assign the medicine in one of the following categories: critical medicines, medicines at risk, other medicines.

Medicines considered at high risk with respect to their therapeutic indication refers to products those use may have very serious implications for the health of individual patients or public health (general life-threatening acute conditions, specific life-threatening acute conditions, or irreversibly progressive conditions). Evaluation parameters include the fact the disease is potentially fatal, irreversibly progressive or, if left untreated, will pose an immediate threat to the patients. Furthermore, the treatment must be administered immediately or within regular dosing intervals, and the product has to be part of a national disease control program.

Appropriate alternatives are identified according to the fact they are authorised for the same therapeutic indication and are available on the market in the respective member state. Furthermore, alternative treatment has to be clinically possible, without negative impact on the patient’s health and providing the same quality of care standard. As for criterion 2, high risk cri-tical medicines refer to products for which no appropriate alternative is available, or only one appropriate alternative (product) on ATC level 4 or 5 (same active substance or alternative is within the same ATC level 4 group or in another ATC level 4 group) is available.

Public consultation for the review of HERA

We inform all interested EIPG’s members that the public consultation for the review of the Health Emergency Preparedness and Response Authority (HERA) is open until 19 February 2024 and it can be accessed through the dedicated webpage of the EU Commission website.

The consultations aim to assess how HERA’s mandate and tools contributed to achieve EU’s political objectives, and how the Authority complements the work of other EU bodies and responds to the current health challenges.


Reactions to the proposed ban of PFAS

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by Giuliana Miglierini

A proposal to ban around 10,000 per- and polyfluoroalkyl substances (PFAS) was submitted in January 2023 to the European Chemicals Agency (ECHA) by authorities of Germany, Denmark, the Netherlands, Norway, and Sweden. The proposal was published on ECHA website on 7 February 2023.

The focus is the so-called “forever chemicals”, i.e. very high persistence PFAS typically characterised by bioaccumulation (also in plants), great mobility and a long range transport potential, and potential endocrine activity.

This landmark proposal by the five authorities supports the ambitions of the EU’s Chemicals Strategy and the Zero Pollution action plan. While the evaluation of such a broad proposal with thousands of substances, and many uses, will be challenging, we are ready.”, said Peter van der Zandt, ECHA’s Director for Risk Assessment.

The proposal was open to public consultation on 22 March 2023, giving rise to the collection of 5,600 comments. Opinions will be issued by ECHA’s scientific committees for Risk Assessment (RAC) and for Socio-Economic Analysis (SEAC), to be then forwarded to the EU Commission for final decision.

 The current role of PFAS

PFAS are characterised by the presence of alkyl groups in which many or all the hydrogen atoms have been replaced with fluorine. The main carbon chain of these substances may have different lengths, from small molecules to long chain PFAS and polymers, and may carry a very wide variety of other functional groups. The strength of the carbon-fluorine bond is the root cause of PFAS persistence, leading to these substances remaining in the environment for decades to centuries.

Per- and polyfluoroalkyl substances are currently used in many different industrial sectors, thanks to their useful technical properties. Among others, PFAS can be used to repel water, oil and dirt from surfaces, and is characterised by a high durability under extreme conditions of temperature, pressure, radiation, and chemicals. PFAS also present electrical and thermal insulation properties.

The main features of the restriction proposal

According to the authorities that submitted the proposal, around 4.4 million tons of PFAS would end up in the environment over the next 30 years in the case of no action. Ban would refer to manufacture, placing on the market and use as such, as constituent in other substances or in mixture as well as in articles.

Two options for restriction have been considered, a full ban or specific derogations for certain industries, based on the analyses of alternatives, efforts put in place for switching to them, and socio-economic considerations. The ban would be effective above a set concentration limit; a transition period of 18 months should occur between final adoption and entry into force. Use-specific, time-limited derogation might refer, for example, to a 5-year period in the case of food contact materials for industrial food and feed production (as alternatives are already under development, but are not yet available to entry into force), or to a 12 years for implantable medical devices (for which identification, development and certification of alternatives is still needed).

During the public consultation phase, comments were received from more than 4,400 organisations, companies and individuals, to be reviewed by both the RAC and SEAC committees and the five proposing countries. Sweden, Germany and Japan are the countries that contributed the higher number of comments, well in advance of Belgium, China, Italy and the US. Companies provided more than the half of the comments (58,7%), followed by individuals (27,3%), and industrial or trade associations (9,8%). The full list of entities participating to the consultation is available at the consultation webpage.

EFPIA response to ECHA’s consultation

The European Federation of Pharmaceutical Industries and Associations (EFPIA) contributed to the consultation with a detailed document. Another joint ISPE-EFPIA document particularly addressed the use of fluoropolymers and fluoroelastomers in medicinal product manufacturing facilities.

While we support the need to restrict certain PFAS, we need to find the right approach to ensure the continued manufacturing and availability of medicines in Europe. A total ban would see medicines’ manufacturing in the EU grind to a halt in under three years. It would also jeopardise the production of all pharmaceutical substances in Europe and would conflict with the EU’s strategy of reducing dependency on nations outside of the EEA in the event of shortages or pandemics.”, said EFPIA’s director general, Nathalie Moll.

EFPIA’s consultation documents highlights the many different uses of PFAS in the pharmaceutical industry, ranging from active pharmaceutical ingredients (API) falling within the definition of PFAS used in the proposal, to building blocks and raw materials used within chemical synthesis of PFAS and non-PFAS medicines. Other reagents and equipment might also fall within the scope of the ban, as well as packaging materials or combination products such as pre-filled syringes. The ban would also affect the manufacturing process, where PFAS materials are used in a wide variety of applications.

It might thus result in the disappearance from the market of a large number of important medicines, warns EFPIA, due to the unavailability of replacement materials, and the time required to obtain regulatory re-approval of alternatives. The supply chain of pharmaceuticals would be also impacted at many stages, thus possibly exacerbating shortages.

In its analysis, EFPIA highlights how some PFAS are considered of low concern by the OECD, and in particular “those used in actual medicines have no or low identified risk through medicines risk benefit or environmental risk assessments”.

A patient access impact analysis was also jointly developed by the involved industrial associations (AESGP, EFCG, EFPIA, Medicines for Europe and Vaccines Europe), showing that the current proposal would lead to at least 47,677 global marketing authorisations being affected by the ban. More than 600 medicines from the WHO Essential Medicines List would be at risk; restrictions would greatly impact also the European Member State’s “Critical Medicines lists”.

EFPIA submitted also a socio-economic assessment of the proposal, according to which a broad restriction of PFAS used in the production of human medicines would have disproportionate negative impacts on the European economy and society. “Without additional derogations, the entire pharmaceutical industry would no longer be able to manufacture active pharmaceutical ingredients (APIs) (whether classified as PFAS or non-PFAS APIs) or associated medicinal products in the EEA”, writes EFPIA, resulting in APIs production to necessarily move out of the European Economic Area.

The position of the medical device sector

MedTech Europe also published a position paper on the PFAS restriction proposal and called fora realistic transition pathway to non-PFAS alternatives that are both reliable and feasible for medical technologies (including their manufacturing and supply chain) to avoid shortages of medical technologies for patients and practitioners”.

The position paper presents many PFAS use cases in the field of medical devices, together with the criticalities posed by the proposed transition. In particular, broad derogations should be considered to allow sufficient time to first “identify all PFAS uses in medical technologies and to subsequently move to alternatives where these are proven to be technically viable, available besides in conformity with the sector-specific MD and IVD Regulations so as fit for the intended purpose”. In this case too, the need to manage complex supply chains would require a realistic timeline in order to address dependencies, and long development timelines and steps to ensure compliance with the sectorial legislation.



The new MHRA’s framework for clinical studies

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By Giuliana Miglierini

The repositioning of the United Kingdom as a global leader for clinical development of medicinal products can now benefit of the complete renewal of the framework regulating clinical studies run in the country. Announced in March 2023 by the Medicines and Healthcare products Regulatory Agency (MHRA), the new set of measures represents the deepest reform of the sector in the last 20 years. The new package is based upon results of the public consultation run in Q1 2022 in partnership with the Health Research Authority (HRA) and the Department of Health in Northern Ireland, which collected more than 2,000 responses.

As stated in the foreword of the final document, which details the government’s consideration of responses to individual questions, the main objective of the reform is for the UK to capitalise on the opportunity offered by the country’s new position in the global clinical trial landscape. Furthermore, it represents just the initial step of UK’s new regulatory approach, which may include for example a wider use of real-world evidence, novel analytics and data tools. International collaborations are also deemed important, e.g. with the FDA’s Project Orbis and the Access Consortium (Australia, Canada, Singapore and Switzerland) and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals of Human Use.

Our world-first Covid-19 approvals showed how important it is to ensure that regulation is flexible and agile. This overhaul of the clinical trials legislation will do just this – it will move us away from a one-size-fits-all approach to the regulation of clinical trials and help to streamline approvals by removing granular and duplicative regulatory requirements”, said MHRA Chief Science and Innovation Officer Marc Bailey.

According to the Health and Social Care Secretary Steve Barclay, the reform will make the UK more attractive for scientists and researchers. “These changes will help speed up clinical trials, without compromising on safety, and encourage the development of new and better medicines for patients. They come after the government announced additional funding of £10 million for the MHRA to accelerate the delivery of cutting-edge treatments including cancer vaccines”, he said.

The main goals of the reform

Patients are central to the UK’s reform of clinical trials. While efficacy and safety of new medicines under development remain the main target, great attention should be paid to reduce health disparities. To this instance, the MHRA announced the issuing of new guidance on how to ensure diversity of participants enrolled in trials, so to overcome imposed targets or arbitrary quotas. The improved attention to diversity would also support the delivery of trial results more adherent to the effective prevalence and clinical need across the population.

Flexibility and proportionality of the regulatory environment is another key objective of the reform. According to the final document, regulatory requirements should adapt to the current risk of the trial, and researcher should become subject to an overarching duty to consider proportionate approaches to clinical development.

Simplification of regulatory procedures is also expected, for example in the case of studies characterised by a risk similar to that of standard medical care. In this instance, regulatory review of the study protocol should not be needed anymore, substituted by simple “notification scheme” to enable approval.

As said, the attractiveness of the UK as a leading destination for international trials should be supported by streamlined and efficient application processes. This goal should include a new legislative action to integrate the regulatory and ethics reviews of clinical trial applications. Results from a pilot phase will be taken into consideration, as they proved possible to halve the approval times and cut the time from application to recruiting a first patient by 40 days.

All activities relating to clinical development should reflect the ICH Good Clinical Practice (GCP) principles for trial conduct. Regulatory timelines for approval are expected to compete at the international level, so to encourage sponsors to choose the UK as the preferred site to conduct multinational trials. According to the MHRA, the review of an application should take a maximum of 30 days in general, with a maximum of 10 calendar days for a decision to be granted once the regulator has received any final information. As for GCPs, compliance should also extend to service providers of electronic systems that may impact on patient safety.

Sponsors should also benefit from greater flexibility to respond to questions raised by regulators. In particular, the reform aims to amend the Request for Information (RFI) receipt, so that the sponsor has access to RFIs as they are ready rather than waiting for all requests to be made together.

The reform takes in consideration also the possible impact of incoming innovation, for example different types of trials and innovative study designs (e.g. decentralised trials). New guidance should be provided to set out specific details, thus avoiding any duplication. Guidance should be also provided on how to involve patients; family members or carers having a direct experience of the health problem in the design and conduct of a trial.

Transparency of the entire process should be supported by the compulsory registration of the trial in a World Health Organisation public register. A summary of results should also be published within 12 months of the end of the trial, and trial findings should be mandatory shared with trial participants.

Comments from the industry

We welcome the MHRA and HRA’s commitment to work with our industry to codevelop new regulatory guidance and their pragmatic approach to patient & public involvement and trial diversity. We look forward to working with them to make the UK an attractive destination for clinical trials.”, said Richard Torbett, ABPI Chief Executive.

On 19 May, ABPI further commented from is blog the current situation of clinical development in the UK. According to the association representing the British pharmaceutical industry, enrolment to industry trials decreased by 44% between 2017 and 2021, while UK’s global ranking for phase III trials dropped to the 10th place (from the previous 4th). ABPI also reports revenues and cost savings to NHS England from life sciences companies of more than £10,000 for every patient recruited onto an industry clinical trial between 2016 and 2018.

In view of the release of the independent review commissioned by the government to former innovation minister Lord O’Shaughnessy, ABPI has identified three main steps necessary to support the international competitiveness of UK’s clinical trials sector.

Rapid and smooth regulatory procedures are at the first place, with the request not to delay from the 60 days target for combined regulatory and ethics review, comprehensive of the administrative processes of costing and contracting a clinical trial. Early scientific and regulatory advice and sufficient resources for the MHRA to clear the current backlogs and codevelop new regulatory guidance would be also important.

ABPI also highlights the often-experienced difficulty in recruiting a sufficient number of patients. The suggestion for the government is to take inspiration from UK’s leading position in early-phase (phase I) industry trials in order to improve investment in late-phase trial infrastructure. To this instance, health real-world data may prove important to support the search for eligible patients in a larger population.

According to the industrial representative, the UK is also lacking a nationwide clinical research dashboard to describe its performance in clinical research to global sponsors. This should include metrics on volume, speed, quality, impact, and innovation.


Draft ICH M13A guideline on bioequivalence open for consultation

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By Giuliana Miglierini

The draft ICH M13A harmonised guideline Bioequivalence for immediate-release solid oral dosage forms” was endorsed by the International Council for Harmonisation on 20 December 2022 and is now open for consultation. Comments can be forwarded until 26 May 2023; publication of the final document is expected by May 2024.

The new guideline will then be implemented as a European guideline, replacing the current EMA guideline on the investigation of bioequivalence (BE) for oral dosage forms. The ICH M13A is the first of a planned series intended to address scientific and technical aspects of study design and data analysis, so to better support BE assessment both during development and post approval. The guideline covers immediate-release (IR) solid oral dosage forms delivering drugs to the systemic circulation (i.e. tablets, capsules, and granules/powders for oral suspension). Different approaches from those suggested in the guideline are possible, provided they are scientifically justified; applicants are thus encouraged to seek the advice of the relevant regulators in order to share a common approach to development.

Key concepts of the M13 series

The determination of bioequivalence to the originator is a fundamental step in the development of generic and biosimilar medicines. BE plays also an important role for some innovator products, as well as for post-approval changes of formulation and/or manufacturing process. BE is determined in terms of bioavailability of the products under comparison after administration, within predefined limits to ensure safety and efficacy. In vivo BE studies for certain orally administered IR solid oral dosage forms can be waived according to the ICH M9 guideline on Biopharmaceutics classification system (BCS)-based biowaiver, which has already superseded Appendix III of the EMA guideline.

The M13A guideline addresses study design containing multiple comparator products or test products, but not the acceptance of comparator products across different regulatory regions, as this greatly varies according to local legislations. The process of regulatory decision making based on BE is also excluded from the guideline.

The planned M13 series should also include the ICH M13B guideline, focused on biowaiver considerations for additional strengths not investigated in BE studies, and ICH M13C discussing data analysis and BE assessment for highly variable drugs, drugs with narrow therapeutic index, and complex BE study design. It should also address data analysis considerations, for example in the case of adaptive BE study design.

Pharmacokinetics (PK) bioequivalence studies and comparative in vitro dissolution studies are the main tools for BE determination for IR solid oral dosage forms with systemic action. These principles can be also applied to other non-orally administered drug products with immediate action (e.g., certain rectal, inhalation, and nasal drug products), provided BE may be derived from measures of systemic exposure.

The ICH E6 guideline on Good Clinical Practice should also be considered while conducting BE studies, in order to ensure the data integrity of all data generated in the trials.

The main contents of the ICH M13A

Chapter 2 of the ICH M13A guideline discusses the general principles to be used for the establishment of bioequivalence. These include the selection of the study population and the choice of the pharmacokinetic endpoint to be used in the BE studies. Healthy subjects should be the preferred choice, unless there are ethical concerns linked to the safety of the pharmaceutical products under assessment. In any case, inclusion and exclusion criteria should always be clearly reported in the study protocol. The main target of BE studies should be the detection of differences in the in vivo release characteristics between the products. Elements to be considered to select the study population are discussed in the draft guideline.

As for the study design, the recommended suggestion is for randomised, single-dose, two-period, two-sequence crossover studies comparing two formulations, as single-dose studies may better detect differences in the rate and extent of absorption. Multiple-dose studies may be conducted in patients should the single-dose design be not affordable for safety/tolerability or ethical reasons. A parallel design may be indicated for drugs with long elimination half-lives, requiring a prolonged washout period. Alternatives are also acceptable upon scientific justification.

The choice of the test product should be also discussed and justified, and it should be representative of the product to be marketed. As for the comparator, the selection of the batches to be used for BE studies should be based on assay content. The strength of the product to be used in the BE study depends on the dose proportionality in PK and solubility of the analyte.

The draft also indicates standardised fasting conditions should be the preferred choice to run BE studies, as they support a better discrimination between the PK profiles of the product and the comparator. Both fasting and fed BE studies should be conducted for high-risk products, due to their complex formulation design or manufacturing process that may impact differently on their in vivo performance, due to different gastrointestinal (GI) conditions. This is the case, for example, of low solubility drug substances formulated in the form of solid dispersions, microemulsions, lipid-based formulations, nanotechnologies, or other specialised technologies.

Analysis of the parent drug should be the preferred choice to demonstrated bioequivalence. Primary metabolites are considered acceptable in the case of pro-drugs which are rapidly eliminated. Stereoselective assays measuring individual enantiomers should be also considered while assessing chiral drugs.

Specific paragraphs address the setting up of sampling, the need to avoid occurrence of Cmax at the first post-dose sampling time point, the possibility to use truncated AUC for drugs with long half-life and considerations on early exposure.

How to analyse and present data

Specific sections of the guideline discuss how to present and report data obtained from BE studies. The study documentation should include the complete evidence of the protocol, conduct, and evaluation, and it should be written according to the ICH E3 guideline Structure and content of clinical study reports”.

Unadjusted, measured drug concentrations in a suitable biological fluid should be always provided for both the product and the originator, for each subject participating in the study. Any deviations should be clearly identified. A suggested list of PK’s parameters to be tabulated for each subject-formulation combination is provided, together with summary statistics to be reported. Not less important is the statistical analysis performed on raw data. To this instance, the model of choice for the analysis should be pre-specified in the study protocol. Cmax and AUC(0-t) should be the preferred PK parameters to establish BE.

Chapter 3 discusses specific topics that may impact on the determination of BE. Among these is the presence of endogenous compounds identical to the drug under evaluation, thus requiring the determination of their baseline concentration in the biological fluids of interest. The draft guideline also specifies that both orally disintegrating tablets (ODTs) and chewable tablets should be administered in BE studies according to the comparator product labelling with regard to intake of water. The comparator product labelling should also represent the main reference for BE studies involving tablets, granules, and powders labelled as being only intended to be dispersed in a liquid before administration as an oral suspension. Considerations are also provided for fixed-dose combination products and the dependance of the drug solubility on pH.


EDQM introduces a consultation phase in the management of CEP documents

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by Giuliana Miglierini

The new process implemented by the European Directorate for the Quality of Medicines and HealthCare (EDQM) for the elaboration of documents related to the Certification of Suitability  (CEP) procedure includes a newly inserted consultation phase. This new step, which may be public  or targeted to specific groups of stakeholders, aims to increase the transparency of the  elaboration process and offers stakeholders the possibility to forward comments to the draft documents  in order to optimise them.

Transparency and efficiency are also the main goals inspiring the overall new elaboration process, which covers the entire pathway of CEP documents, from development, through consultation,  up to final adoption, publication and implementation.

A dedicated page on the EDQMs’s website will host the documents open to consultation, together with the respective instructions for the stakeholders wishing to submit comments. Announcements  on new documents available for consultation will be made on EDQM Certification webpages.  The CEP Steering Committee will be responsible for the elaboration process for CEP documents, in compliance with the EDQM document CEP Terms of Reference and Rules of Procedure (PA/PH/CEP (01) 1).

The elaboration process will cover both public documents (the main part), as well as those the CEP Steering Committee would indicate as restricted for use by the bodies involved in the CEP  procedure. The new process does not cover the Resolution on the Certification procedure, which falls under another specific process established by the Council of Europe.

A guidance to understand the new process

The management of CEP guidelines and operational documents for the CEP procedure has been described in a specific guidance issued in November 2022 by the EDQM’s Certification of Substances Department.

The guidance covers a broad range of documents participating from different perspectives to the CEP procedure. The elaboration of the different types of documents may slightly differ from one another, with possible exemptions from some steps, for example in the case of minor revisions (which in any case always have to be full justified and documented). All CEP documents will be drafted in English; the guidance provides indication of the format to be used to establish the unique reference code for governance documents and technical guidelines (PA/PH/CEP (XX)  YY), as well as for the revision number (ZR) where needed.

 The EDQM specifies that the implementation date of the newly approved CEP documents will be such to allow interested parties to have enough time to comply with the new or revised requirements.

Governance documents define procedural aspects for the practical implementation of the CEP procedure. The initial draft will be prepared by the EDQM and reviewed and agreed upon by the CEP Steering Committee before entering the consultation phase. Comments collected will serve as the basis to consolidate the final version of the document. A second round of consultation may be needed in case of critical comments preventing finalisation. The adoption of the final document falls under the responsibility of the CEP Steering Committee, which may also indicate the need to improve and re-submit the draft before adoption. Once the final version of the document is available, its publication on the EDQM’s website and implementation will close the process.

Technical guidelines inform about the requirements applicants should fulfil for the submission or evaluation of CEP applications. Their drafting may be initiated also by members of the relevant Technical Advisory Board (TAB), in addition to the EDQM. The TAB is also called to review and agree upon the draft document before the assessment and approval by the CEP Steering Committee and the following consultation phase can take place. The same applies to the consolidation of comments and finalisation of the document, that has to be approved by the relevant TAB. In this case too, a second round of consultation is possible should criticalities arise during the first one, followed by adoption by the CEP Steering Committee (and a possible second round of updating and approval by the TAB, if needed), and publication and implementation.

The management of specific aspects of the procedure can be supported by the issuing of administrative or operational documents. These documents fall under the responsibility of the EDQM, that may consult the CEP Steering Committee of other parties where necessary.

The consultation phase

A specific chapter of the EDQM’s guidance describes the newly inserted consultation phase, those details (type of process and duration) will be decided on a case-by-case basis by the CEP Steering Committee.

In the case of a public consultation, the draft document will be made available at the dedicated page of the EDQM website. The draft may also be sent to identified relevant stakeholder organisations, to ensure a better awareness of the ongoing process.

Targeted consultations aim to obtain feedback from selected stakeholders on specific areas of intervention. In such instances, the forwarding of the draft document will be restricted only to identified interested parties, including regulators and relevant industrial associations or other organisations.

According to the type of document and/or the topic under consultation, the consultation phase may vary in duration. To this instance, the guidance indicates a possible range between 3 weeks and 3 months, with the effective duration to be communicated as a part of the call for consultation.  A template will also be available to submit comments, which should be always justified and contain concrete proposals for action to tackle the issue under consideration. All comments and justifications received will be transmitted to the groups in charge of approving and adopting the documents.

At the end of the elaboration process, the final approved versions of CEP documents will be published on the EDQM’s website.   


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.