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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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Reform of pharma legislation: the debate on regulatory data protection

April 1, 2024 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

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 on the entire European pharmaceutical and healthcare sectors. In the meantime, the Committee for Legal Affairs of the European Parliament approved the amendment to the Regulation proposed by the Commission to govern the issuing of Union compulsory licences for the manufacturing of medicinal products during crisis.

The initial proposal on regulatory data protection

To resume the main features of the EU Commission proposal on incentives referred to regulatory data protection (RDP), the current 8+2(+1) scheme would be remodulated to grant a standard 6-year period of regulatory data protection, valid for all newly approved medicines. This might be followed by extension periods of different length, depending on specific conditions (see here the impact report, Chap. VII).

The proposed additional criteria may support an RDP duration up to 12 years, as for example in the case of medicines for orphan diseases or unmet medical needs. But the more debated criteria proposed by the Commission is perhaps the request to the holders of marketing authorisations (MAH) to market newly approved medicinal products in all EU members states at the same time, within 2 years from the date of the MA. Should this occur, the MAH may benefit from a 2-year extension of the RDP.

New chemical substances undergoing clinical testing against a relevant and evidence-based comparator may also benefit of a 6-month extension of the RDP. Should the product be already in the market, the approval of a new indication coupled to the provision of a significant clinical benefit may extend regulatory data protection for 1 year. The same extension applies to products that changed their prescription status on the basis of significant non-clinical tests or clinical studies. Repurposed medicinal products may benefit from a 4-year extension of regulatory data protection in case of a new therapeutic indication not previously authorised in the EU.

The RDP is critical for the EU’s competitiveness

According to the Director General of EFPIA, Nathalie Moll, there are three key areas to be kept in mind while reaching the final decision: the positive net financial impact of regulatory data protection for both patients, the EU and member states, the R&D attractiveness at the EU and national level, and the fact the US has currently a more attractive RDP than the EU (see here more).

The regulatory data protection scheme proposed by the Commission might greatly reduce the number of new medicines available in Europe in the next 15 years, says EFPIA. The Commission’s estimate of €1.2 billion/year of additional costs for members states for every additional year of regulatory data protection would be wrong, it adds, as it is based on the List Prices of medicines. But many EU countries have clawback-type mechanisms to reduce this type of impact, which should be added to the indirect impact innovative medicines may exert in reducing other costs supported by healthcare systems. Thus, the final economic impact calculated by EFPIA would be €2 billion/year.

The attractiveness for R&D investments of a certain geographical area may prove also important, especially in the case of advanced therapies and complex types of therapeutics or to support research targeted to unmet medical needs.

As for the duration of regulatory data protection in the US, according to EFPIA this reaches 12 years (including market protection) for biologics and around 6-7 years of market protection for small molecules. ”RDP for non-biologics is the only element of IP where Europe leads on the US and is in the control of EU policy makers”, wrote Nathalie Moll.

On the other side of the game, Medicines for Europe on behalf of the generic and biosimilar industry also addressed a note to the rapporteur and shadow-rapporteur of the EU pharmaceutical legislation.

The key message is that there might have been a misunderstanding about the concrete impact of the extensions of regulatory data protection proposed by the EU Parliament, which received a strong political support, due to the complex interactions between the pharma legislation and the IP and SPC legislations.

The correct understanding of the dual track of pharmaceutical incentives (regulatory and patent/ SPCs) should be thus the key area of attention during the final set up of the new provisions. According to Medicines for Europe, some parliamentary amendment would extend the duration of regulatory data protection well beyond the duration of SPC, thus further extending the global protection (up to 13.5 or 18 years, depending on the specific proposal) and preventing the entry of generics and biosimilars in the European market.

The analysis run by the industrial association also calculated the potential impact on pharmaceutical budgets corresponding to the possible different lengths of regulatory data protection, and how the same budget might be used to potentiate the resources of healthcare system in terms of available nurses and doctors. The calculated range spans from €2.5-5.35 bln for the three countries considered (France, Germany, Spain) up to €19.5 bln to the entire EU in the case of 13.5 year extension, and it reaches, respectively, €13.2-24 bln and €99.5 bln in the case of the 18 years extension.

A strong critical voice in support of a true competition

The European Social Insurance Platform (ESIP) published a note at the end of February signed by its Director, Yannis Natsis. “Let us be clear that these protection periods are not companies’ rights, but privileges granted to the manufacturers by the European legislators, and they come at a significant cost for public budgets”, wrote Mr. Natsis.

The extension of regulatory data protection would thus result in a possible distortion of competition, and in a delay of patients’ access to treatments. Mr. Natsis also identified the “elephant in the room” of the European healthcare system, i.e. the extremely high prices of medicines in many therapeutic areas. An issue that ESIP’s Director considers a systemic problem.

The note supports the proposed 6-year standard regulatory data protection, with extensions that should not exceed the current situation. Incentives for orphan medicines should go in favour of truly rare diseases and unmet medical needs. ESIP also supports the availability of alternative incentive mechanisms to reward development of new antibiotics, instead of the Transferable exclusivity vouchers (TEVs) that should be replaced.

ESIP’s Director also wrote that “Put simply, we need to take these industry threats with a pinch of salt”, with reference to the pharmaceutical industry having repeatedly threatened to leave Europe since the beginning of the revision of the pharma legislation. “In any case, we cannot afford to end up with a reform which hands a free-for-all incentives “menu” to the companies. These are very expensive “carrots”. Such an outcome will be counter-productive for patients and self-defeating for healthcare systems across Europe”, commented Yannis Natsis.

From the perspective of statutory payers, a well-functioning generic competition allows to treat larger groups of patients at lower prices, while the pricing and business strategies of pharma companies often would limit the possibility to treat patients with most severe conditions. The request for the Parliament is thus to reach a well-balanced text. “There needs to be a renewed social contract between the pharmaceutical industries and the society at large”, wrote Yannis Natsis.

The JURI Committee amendments to the proposed Regulation on the Union compulsory licensing

In the meantime, the Committee for Legal Affairs (JURI) of the EU Parliament approved on 13 February 2024 (17 votes in favour, 6 against) the report detailing the amendments to the proposed Regulation on the Union compulsory licensing during crisis and emergencies for the public health.

The Report also include the opinion given by the Committee on International Trade, and the list of entities or persons that provided input to the rapporteur (Adrián Vázquez Lázara) in the preparation of the report, among which are many industrial associations.

The Explanatory Note by the rapporteur highlights the need to maintain the equilibrium between innovation and rapid access to essential products. The JURI Committee has identified several aspects of the proposed Regulation that should be better clarified to ensure legal certainty, and which were addressed within the approved amendments.

The definition of “crisis” raised many concerns; the proposed amendments refer to a cross-border effect in the UE with involvement of two or more member states. Measures put in place should be proportionate, and not unnecessarily and disproportionally affecting the rights of citizens or the protection of intellectual property rights of businesses.

Union compulsory licenses might be issued only after the rights-holder has the time to negotiate a voluntary license with a potential licensee. To this instance, the Parliament has indicated 4 weeks as a suitable period for the Commission to wait for the results of ongoing negotiations. Furthermore, the Union compulsory licensing should remain a last resort instance and should have a duration strictly in line with that of the crisis, with a maximum of 12 months unless otherwise needed.

According to the JURI Committee, the definition of the know-how necessary for the manufacturing of certain products should be also clarified, as it is key to activate an expanded production capacity during crises. A new proposed recital indicates the Commission should have the authority to oblige rights-holders to provide all needed information, including know-how, especially for highly complex pharmaceuticals such as vaccines.

The Committee also highlighted the need for a better definition of the role of the advisory board. The proposed amendment indicates the inclusion as observers of other crisis relevant bodies at the UE level to ensure consistency with the measure, and of representatives of national authorities responsible for issuing compulsory licenses under the national patent laws.

Rights-holders should be able to provide their comments and other pertinent information to the advisory board prior to the final issuing of the Union compulsory licence. The procedure should start with the identification of the intellectual property rights concerned, and of potential licensees. The Commission should not grant any compulsory licences should the rights-holders not have been completely identified.

The JURI Committee also amended the text of the proposal to indicate the remuneration for the rights-holders should be determined, among others, considering the total gross revenue gene-rated by the licensee from the pertinent activities governed by the Union compulsory licence.

Remuneration should be also provided in cases where the rights-holder should disclose the trade secrets strictly necessary to achieve the purpose of the licence. A new amendment asks the Commission to assess the list of crisis modes or emergency modes reported in the Annex to the Regulation every two years from its entry into force, or without undue delay in case of exceptional threats to public safety or national security.


Environmental sustainability: the EIPG perspective

March 25, 2024 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

Piero Iamartino

Although the impact of medicines on the environment has been highlighted since the 70s of the last century with the emergence of the first reports of pollution in surface waters, it is only since the beginning of the 2000s that specific regulatory interventions have been designed to promote the identification of the different sources of pollution and the determination of possible actions to be taken.

The obligation to submit the result of an environmental risk assessment of a medicinal product at the same time as the application for marketing authorisation was introduced only after the publication of the Environmental Risk Assessment (ERA) guideline issued by EMA in 2006, which sets out the guidelines and describes a series of standard tests to be performed. However, this first piece of legislation immediately highlighted limitations as it was applied only to the marketing of medicines from that moment on, without considering the contribution of medicines with the same active ingredient and neglecting the evaluation of those already authorised and on the market.

Over the following years, the problem of the environmental impact of medicines was tackled more extensively with the launch of several projects promoted by the European Commission in partnership with the EFPIA (IMI: Chem21, iPiE and Premier) which have deepened the characterisation of environmental risks, with the identification of priority criteria to be assigned to interventions and the development of models and tools to measure the sustainability of the processes of manufacture, in particular of active substances.

These important projects in recent years have been added to the initiatives undertaken at the European level with the publication in 2020 of the new European pharmaceutical strategy which defines some specific objectives for the mitigation of the environmental impact of medicines that will be reflected in the upcoming revision of European pharmaceutical legislation and which are part of the broader regulatory acts for the ecological transition envisaged by the Green Deal European.

In light of the above, a gradual transformation of some processes and operating methods carried out by the European pharmaceutical industry is envisaged, starting from the development of a new medicinal product to its distribution and, similarly, adequate regulatory interventions will have to be envisaged on the management of the correct use and disposal of medicinal products since the environmental impact of this last phase of the life cycle of a medicinal product is predominant.

Although these changes involve all professionals working in the pharmaceutical industry, a key role is played by the industrial pharmacist who, due to his professional profile dictated by his university curriculum, has the fundamental knowledge bases to occupy different positions in the industry, covering the entire path of medicine from its conception and manufacture as an active ingredient, its development as a medicinal product and its distribution on the market.

With this in mind, EIPG has started the preparation of a document that analyses the main critical areas of the entire production process of a medicinal product and sets out its position on the interventions considered a priority in a perspective of changes that will lead to the inclusion of new methods alternative material resources and will require new skills.

The first critical area examined is the manufacture of the active ingredient, both for its impact as such on the environment and for the process applied to its manufacture. The problem is particularly relevant for small molecules, while it is substantially insignificant for large molecules and even less so for products based on the use of cellular tissues or biological structures (ATMPs). The fundamental parameters to be considered are the environmental toxicity and the bio-degradability of the product. The problem is how to reconcile these two parameters with the chemical-physical and biopharmaceutical characteristics that an active ingredient must possess to be administered, absorbed and then carry out the desired pharmacological activity. The effort required in the design and screening phase of a new small molecule is the identification of a structural parameter that makes it more eco-friendly without compromising its purpose. Although this criticality does not arise in the case of large molecules and ATMPs, for these active ingredients the environmental impact due to higher energy consumption attributable to the need for low-temperature storage conditions may prevail.

About the production process of small molecules, which today still represent the largest percentage of active ingredients in development and on the market, it is essential to definitively introduce the application of the principles of Green Chemistry, as highlighted by the most recent studies (IMI Premier Project). The prospect is that of a progressive change in the synthesis processes with the use of reagents and less toxic solvents that are entirely recyclable and reusable, as well as the development of a synthesis route that allows the least number of operations, generating the least amount of waste and maintaining the best possible efficiency. It is desirable to increase biocatalysis processes as well as the introduction of more incisive treatments in the management of industrial wastewater to accentuate chemical degradation before their transfer to eternity.

A second large critical area where important changes are expected is the manufacturing processes of the medicine from the active substance to its availability for distribution on the market. Also in this area, interventions can be identified to optimize the use of the resources used, with particular reference to energy consumption and the use of water. These two parameters are already the subject of numerous studies for the development of new energy containment processes with the introduction of innovative plant solutions, and further improvements are expected considering the benefits that derive from them in terms of efficiency and therefore costs.

Among the parameters closely linked to the medicinal product that shows a significant environmental impact, attention must be paid to the packaging materials used in the pharmaceutical industry. A priority intervention must focus on certain widely used plastic materials that are difficult to dispose of and not recyclable, identifying alternative materials with the consequent need to study their compatibility with the medicinal product, especially if used in direct contact, and their impact on the stability profile of the same, as required by the reference standards. Other objectives should be the choice of secondary packaging materials that can be easily recycled by the end user, as well as the reduction of their volume, also favoured by the digitization of the information materials related to them. The implementation of these interventions will require adjustments both to the packaging lines used in the pharmaceutical industry and to the alternative ways of managing products in the transport and distribution phase, with a marked increase in studies for the reuse of packaging materials in line with the principles of the circular economy.

The prospects of the expected changes in the path from the active substance to the medicine will have to be accompanied by an assessment of the possibilities of intervening in the supply chain used by the pharmaceutical industry involving suppliers of active ingredients, materials and medicines. The regulatory guidelines and commitments on actions to improve environmental sustainability will require a progressive review in the management and evaluation of suppliers according to their ability to apply the ecosustainability criteria of their processes, giving preference to those who take this path.

The above analysis, limited to the areas of greatest environmental criticality, highlights the transformations that are expected in the pharmaceutical industry in the coming years with the implementation of the provisions that will be progressively adopted at the European level. We think there should be good coordination between the impositions for environmental sustainability and the need to adhere to pharmaceutical regulatory requirements to facilitate the implementation of changes. This coordination is essential as innovation will be the guiding criterion for the introduction of the required changes to meet the sustainability objectives.


Reactions to the proposed ban of PFAS

November 10, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

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 for “a 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.


EC Communication (part 1): How to address critical medicines shortages

October 27, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

As announced on 3 October in the speech given by Commissioner Stella Kyriakides at European Parliament Plenary Session, the EU Commission has published on 24 October its Communication on medicine shortages and strategic healthcare autonomy.

The planned actions are firstly targeted to prevent and mitigate on the short-term critical medicine shortages, thus avoiding the reoccurrence of situations such as those experienced in the 2022. Mid- and long-term actions have been also addressed to support the strategic autonomy of the European pharmaceutical supply chain. Among these is the creation of a Critical Medicines Alliance, to start operations in early 2024.

“Improving the management of critical shortages of medicines and ensuring a steady security of supply for the EU has been our priority since day one. We need a single market for medicines in the EU and a new approach to better tackle shortages of critical medicines. Today we are putting forward collective actions to work closer with the industry and help Member States improve the security of supply for the coming winter and in the long-term.” said Stella Kyriakides, Commissioner for Health and Food Safety.

In this first post, we will examine actions in the field of medicines shortages, leaving the medium and long-term ones to a following article (part 2).

Prepared for future winters

The first goal of the EU Commission is to avoid situations of shortages of critical antibiotics such as those that occurred last year. To this instance, the Health Emergency Preparedness and Response Authority (HERA) and the European Medicines Agency (EMA) have already identified key antibiotics potentially at risk of critical shortages in the winter season, also in future years.

Immediately after the release of the Communication by the Commission, EMA published the details of the announced new European Voluntary Solidarity Mechanism for medicines, the MSSG Solidarity Mechanism.

The mechanism was developed by EMA’s Medicines Shortages Steering Group (MSSG), on the basis of the informal experience made during the pandemic. In case of critical shortages escalated to the MSSG for coordination at European level to request assistance, other member states may be of help through the rescEU stockpile mechanism to redistribute medicines from available stocks. The activation of the Union Civil Protection Mechanism (UCPM), via its 24/7 available European Response Coordination Centre (ERCC), aims to coordinate and logistically support the voluntary transfer of medicines, and it should represent the last resort, after the interested member state had exhausted all other possibilities.

The MSSG also developed a Toolkit including recommendations on how to tackle shortages of critical medicines. Among others are the monitoring of available stocks, supply and demand, interactions with marketing authorisation holders and manufacturers for increasing the manufacturing capacity and for the fair distribution of medicinal products, the implementation of regulatory flexibilities and actions aimed to improve communication to the public and international cooperation with other regulators to early identify critical shortages.

The other actions to tackle shortages

The first version of the Union list of critical medicines is expected to be released by the end of 2023. It will allow the development of further actions, on the basis of the analysis of the vulnerabilities of the supply chain of selected medicines to occur by April 2024.

In addition to the practical recommendations relative to demand forecasting at national level, the Commission is working on an EU Mechanism for Demand Signalling that should better support the collective EU public sector in its decisions. A new European Shortages Monitoring Platform for reporting information regarding available stocks and shortages of medicines is expected to start operating in 2025. Many future actions shall be supported using artificial intelligence to extract information about trends in demand and supply from existing data.

At the regulatory level, a new Joint Action has been announced for early 2024 to promote the effective use of flexibility as well as of measures applied at national level (i.e. magistral preparations of local pharmacies). Regulatory flexibilities may include, among others, the quick authorisation of alternatives, the approval of alternative suppliers of raw materials or finished products, or the temporary extension of shelf-life.

Another initiative announced for 2024 should see the issuing of an EU guidance on procurement of medicines, better detailing the already existing tools and practices supporting the security of supply. In the meantime, an EU joint procurement for antibiotics and treatments for respiratory viruses should be activated for the incoming winter.

The Communication contains some recommendations for member states and the pharmaceutical industry. The former are called to monitor and fully enforce the supply obligations of companies, to develop effective communication plans, and to consider how national procurement rules and criteria can increase security of supply. Industrial stakeholders should continuously monitor the evolution of demand and supply of critical medicines, assuring to the full the supply obligation under EU law. Early communication of critical situations to regulators should also occur, as well as the implementation of recommendations, both on regulatory flexibilities and on the elements of the pharmaceutical revision that could already be applied.

Comments from the stakeholders

The interested pharmaceutical associations promptly reacted to the EU Commission’s Communication.

EFPIA particularly welcomed the structural measures to address the industrial dimension of medicines shortages in the medium and long term, as the Critical Medicines Alliance. The development of solutions targeting the specific root causes of shortages, and measures aimed at mitigating shortages in the short term should be “proportionate and provide efficient, workable solutions that serve public health needs”. EFPIA asks for the industry to be included in the design and implementation of new processes and highlighted the “missed opportunity” represented by sharing of the information stored in the European Medicines Verification System (EMVS).

“In response to Member State and Parliament calls for a Critical Medicines Act, this communication is a positive first step for the security of supply of medicines. Medicines for Europe will partner with the EU to implement these important reforms”, said Medicines for Europe President, Elisabeth Stampa. The associations ask, among others, for a strategic EU reserve of essential medicines, and EU funds and State aid projects to incentivise investments in greener and more secure manufacturing processes for essential medicines and active pharmaceutical ingredients (APIs). Digitalisation of the regulatory system and harmonisation of pack sizes and presentations would be also helpful.

European community pharmacists also welcomed the Communication, as it may help to avoid new, severe medicine shortages like the one experienced last winter. “PGEU’s annual survey confirms that shortages exist in all EU countries across all types of medicines, causing detriment to patients’ health, waste of resources and frustration. Every day, we spend hours managing shortages and finding solutions to guarantee continuity of treatment for our patients”, commented PGEU President Koen Straetmans. As for the common strategic approach to stockpiling, according to PGEU it should be guaranteed that stocks will not be to such an extent as to jeopardize the general supply of medicines, nor they should generate unnecessary waste.

EuropaBio, representing the biotech industry, positively commented on the Communication and highlighted that EU actions should not be limited to essential medicines, but should target also the growing dependency on third countries for innovation medicines.


Webinar: Building a healthier and more environmentally sustainable future

October 19, 2023 , , , , , , , , , , , , , , , , , , , , ,

EIPG webinar

Next EIPG webinar is to be held on Thursday 26th of October 2023 at 17.00 CEST (16.00 BST) in conjunction with PIER and University College Cork. Kirsty Reid, Director for Science Policy at EFPIA, will discuss the various proactive initiatives and reactive activities undertaken by industry forming the basis behind building a healthier and more environmentally sustainable future within the healthcare sector. Kirsty holds a PhD in biology and for the past 18 years she has worked closely on research, EU public and regulatory affairs covering alternatives to animal testing, environment, health, safety and sustainability issues.

The European Green Deal, launched by the Commission in December 2019, is a package of policy initiatives, which aims to set the EU on the path to a green transition, with the ultimate goal of reaching climate neutrality by 2050. The pharmaceutical sector operations, the supply chain, pharmacies and patients will be impacted by the European Commission’s Green Deal initiative which focuses on climate, zero pollution, chemicals, and circular economy. Furthermore, there are ongoing decisions taking place to restrict certain substances or technologies which can potentially disrupt continuity of supply for specific products or platforms. The pharmaceutical package published on the 26 April, specifically calls out these legislations linking them to the environmental risk assessment of medicinal products.

At the end of this webinar attendees will be able to:

  1. Appreciate the April 2023 Pharmaceutical Package in relation to the European Commission’s Green Deal.
  2. Discuss the multiple ongoing actions to reduce emissions.
  3. Assist in the development of initiatives for your company’s Environmental Risk Assessments of medicinal products.

Please register by filling out the Registration Form. Keep a record of the streaming details of the event that will be shown on your screen at the time of your registration.


The New Pharmaceutical Legislation

September 15, 2023 , , , , , , , , , , , , , , , , , , , ,

by Jane Nicholson

To celebrate the 70th Anniversary of the foundation of the Belgian Association of Industrial Pharmacists (UPIP-VAPI) a Seminar on “The New Pharmaceutical Legislation” was held on 8th September in the European Parliament. The meeting was arranged in conjunction with the General Assembly of the European Industrial Pharmacists Group (EIPG) with attendance from participants of at least 15 European countries.

Frank Peeters, President of UPIP-VAPI opened the meeting and Alexia Rensonnet, a Board Member, described the new legislation as the largest reform in the past 20 years. The existing directive and regulations are to be replaced by new legislation with the objective of creating a single market to ensure all patients have timely and equitable access to safe, effective and affordable medicines whilst continuing to offer an attractive and innovation friendly market for suppliers.

Lilia Luchianov, Policy Officer at DG Sante – European Commission, said that the new legislation envisaged a leaner regulatory environment through simplification, regulatory modernisation and digitalisation. There will be access to both innovative and established medicines and incentives for innovation so that European companies remain globally competitive. Regulatory responsibilities will be shared between the EU and Member States. As well as changes to the General Pharmaceutical Legislation there will be changes to the Orphan and Paediatric legislation. Pre-authorisation support and a faster approval process including “targeted approach” rather than the current “one size fits all” are proposed.

The proposed reduction of protection for innovative products and the market launch conditions were questioned by several participants. Some of the current challenges for the Commission were said to be that pricing, reimbursement and procurement are a national competence.

In response to the current growing concerns on shortages, the Commission’s suggestions include the publication of an EU list of critical medicines, improved coordination of monitoring, earlier industry notification of shortages and withdrawals, improved industry shortage prevention plans, stronger coordination by the EMA and more legislative powers for the Member States and the Commission. During the discussion period Maggie Saykali, Director of the European Fine Chemical Group challenged the Commission to provide economic conditions for the manufacture in Europe of raw materials used by the pharmaceutical industry. Rather than dependence on China or India, European supply of raw materials would enormously improve security of supply of pharmaceuticals as well as improve worldwide environmental sustainability.

Par Tellner, Director of Regulatory, Drug Development and Manufacturing for the European Federation of Pharmaceutical Industries and Associations presented EFPIA’s views on the proposed revision to the pharmaceutical legislation. Whilst he welcomed the opportunities for regulatory modernisation such as simplification of the EMA structure by reducing the Scientific Committees from 5 to 2 and abolishing product licence renewals there are a number of challenges ahead. These include the notable reduction of research and development incentives, the added burden for industry to implement environmental risk assessments and the actual root causes of non-availability of medicinal products in the markets of Europe.

Jean-Paul Pirnay, head of LabMCT, Queen Astrid Military Hospital presented the past present and future of bacteriophage therapy. Wherever you find bacteria, you find phages which have been used since 1923 with the establishment of the Phage Institute in Tblisi (GEO). Although abandoned in the West many years ago, the Russian USSR has kept using phage therapy. Some isolated laboratories have been further developing and using phages and it has been shown that you need a handful of phages to target one bacterial spp.

Jean-Paul’s laboratory has helped establish a phage bank in a controlled environment. A single phage API can be produced according to a monograph. Individual phages can then be mixed together to target a particular bacterium. 100 seriously ill patients with resistant bacteria have been treated in 35 hospital of 29 cities and 26 phages were found to be needed. Eradication of the target bacterial infection was found in 61% of cases. In addition, phages were found to be synergistic when used with antibiotics. Jean-Paul considers commercially viable broad spectrum phage cocktails may be produced in the future.”

Geert Verniers (Lector SCM and Researcher BM-expertise center VIVES University) and his colleague described the use of Drones in the transportation of medicinal products,biological samples and tissues. With traffic congestion on roads causing gridlock around many hospital centres and personalised medicines needing urgent delivery from one area to another, the use of drones for professional transportation is compelling. Various significant points for consideration were discussed. These included the type of drone, drone pilots and Cargo Ports, the design of routes and the complexity of regulation, environmental impact, vibration problems and temperature control.

Following a lengthy discussion period, Frank Peeters thanked the speakers for their interesting contributions and all those responsible for this meeting being held in the European Parliament.


The proposals of the EU Commission for the revision of the IP legislation

May 12, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

By Giuliana Miglierini

In parallel to the new pharmaceutical legislation, on 27 April 2023 the EU Commission issued the proposal for the new framework protecting intellectual property (IP). The reform package impacts on the pharmaceutical industry, as it contains proposals on Supplementary Protection Certificates(SPCs) and compulsory licensing (CL) in crisis situations. It also includes a new Regulation on Standard Essential Patents(SEPs).

The proposed reform, which is part of the EU Industrial Strategy, will now undergo the scrutiny of the European Parliament and Council. It aims to improve European competitiveness, innovation and technological sovereignity, with a special attention to the role played by SMEs. The proposal is based on comments received during the consultation on the Action Plan on Intellectual Property issued in November 2020. The IP legislative framework will complement the Unitary Patent system, that will fully entry into force on 1 June 2023.

Supplementary Protection Certificates

Central to the reform of the SPC system is the creation of a unitary SPC to complement the Unitary Patent. The aim is to reduce the current fragmentation in the issuing of SPCs at the national level, which often leads to complex interpretation of patents’ expiry dates, and consequent legal uncertainty. The new system would not replace the existing national SPC schemes.

Procedures should be simplified, with a single application to be submitted to the EU Intellectual Property Office (EUIPO), which would be responsible for its central examination in close cooperation with EU national IP offices. The process would lead to national SPCs granted for each of the designated member states (MS), plus a unitary SPC if required by the applicant (here the Q&As).

According to the Commission, approx. 25% of current SPC procedures have contradictory outcomes. The mean number of annual SPC applications is 81 per MS, with a total cost of €192,000 over the 5 years of duration (compared to roughly €3,000 in the US and €4,200 in Japan). Savings from the new procedures may amount to up €137,000 for the EU27 wide, five years long SPC protection. A central SPC database is also planned in order to increase transparency.

The proposed reform is comprehensive of a Regulation specific to medicinal products and a second one focusing on plant protection products, plus parallel recasting regulations to review the current legislative provisions (i.e. Regulation (EC) No 469/2009). Innovators would be incentivised to use unitary SPCs, since otherwise a unitary patent could be extended at higher costs only by means of national SPCs. Infringements of unitary SPCs would fall under the judgement of the UPC Court.

The Commission expects the development and access to generic medicines will be facilitated. In particular, SMEs will be able to submit observations during the examination of a centralised SPC application, and to file an opposition in order to centrally challenge the validity of the SPC protection, if justified. The new framework complements the proposed pharmaceutical legislation, for example on the Bolar exception. This should allow the generic industry to perform research and testing for preparing regulatory approval also while a patent/SPC is still in force.

Compulsory licensing

Compulsory licensing may be used during crisis in order to provide access to relevant products and technologies, should result in impossible (or not adequate) to close voluntary licensing agreements with owners of IP rights. The current fragmentation of procedures at the national level results in a wide legal uncertainty (see also the published Q&As). The new framework would complement other EU crisis tools, such as the Single Market Emergency Instrument, HERA regulations and the Chips Act.

According to the proposal, a Union compulsory licence can only be granted after activation of an emergency or crisis mode at EU level. Instruments to trigger this fundamental passage are listed in an Annex, so to improve legal certainty. A remuneration scheme for IPR holders is also included, on the basis of successive steps in the activation and termination of compulsory licensing.

The existing national frameworks on compulsory licensing will continue to operate, and they may be used to manage local crisis. Compulsory licensing of exported products would not be allowed.

Standard Essential Patents

SEPs refer to technologies essential for the implementation of a technical standard adopted by a standard developing organisation. They are typical of the ITC industrial sector, and central to building the Internet of Things.

To improve the transparency and legal certainty of SEPs, the proposal aims to ensure innovation would be run in the EU by both EU SEP owners and implementers. End users would benefit from products based on the latest standardised technologies at fair and reasonable prices. SEPs licensing is based on the FRAND scheme (fair, reasonable and non-discriminatory) for the remuneration of patent holders.

Comments from the stakeholders

EFPIA granted positive feedback on the simplification and harmonisation of the SPC system and to the opportunities offered by the unitary SPC. On the other hand, the proposals on compulsory licensing didn’t find the agreement of the research-based pharmaceutical industry.

According to a note, voluntary licensing would be the preferred instrument for innovators, as it allows for the choice of the best-positioned and trusted partners to speed up production and distribution of medicinal products during health crisis. On the contrary, compulsory licensing is seen as a threat to investment stability of the EU’s IP system and to the overall innovation pipeline.

“Protecting the EU’s intellectual property framework could not be more important if we are to close the investment gap between Europe, the US and increasingly China and continue to offer patients the best possible treatments. Yet we are seeing multiple proposals emerging from the European Commission in the pharmaceutical legislation and patent package which tend towards the opposite”, said EFPIA Director General Nathalie Moll.

Medicines for Europe (MfE), on behalf of the generic and biosimilar industry, said that while “voluntary licensing agreements are relevant for health crises, we will contribute constructively to the EU-wide compulsory licensing system”. The request to the Commission is to make it a remedy also for anti-competitive abuses of the patent system, according to art. 31(k) of the TRIPS Agreement.

As for new SPCs, MfE highlights the new regime would extend their geographical scope from the current 20 out of 27 MS covered on average. “The proposal for a reform in the SPC system has the potential to reduce fragmentation in Europe but the legislation must ensure improved quality and transparency of granting procedures to prevent misuse by right holders to delay competition”, said MfE Director General Adrian van den Hoven.

Critics of the proposed scheme for compulsory licensing also came from EUCOPE, representing pharmaceutical entrepreneurs. According to the Confederation, the Commission’s proposal would further weakening the value of intellectual property rights within the EU. “Together with the proposal on the revision of the general pharmaceutical legislation, it is another indicator that the development of an innovation-friendly environment is not a priority, contrary to statements in the Intellectual Property Action Plan”, it states in a note.

For EUCOPE, the proposed SPC regime would not amend the substantive elements of the current system. Furthermore, a centralised SPC application would only be possible on the basis of a European patent, including a unitary patent, and for products with a centralised marketing authorisation. EUCOPE position goes for an optional EU-wide SPC, so to allow flexibility for IP owners in deciding their strategy for the protection of IP rights.


Webinar: ICH Q12 Product Lifecycle Management – open road or dead end?

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Next EIPG webinar is to be held on Tuesday 18th April 2023 at 17.00 CEST (16.00 BST) in conjunction with PIER and University College Cork. Graham Cook, former Pfizer’s Quality Intelligence and Compliance Information team leader and chair of EFPIA’s Manufacturing and Quality Expert Group (MQEG) will explain the context for the development of the ICH Q12 guideline on Product Lifecycle Management.

The ICH Q12 Product Lifecycle Management guideline reached step 4 in the ICH process in November 2019 – where are we with the adoption of this guideline? This webinar will provide an overview of the content, and discuss the opportunities and implications for implementation of Q12 by industry and regulators.

Graham Cook is a pharmacist with a Ph.D. in pharmaceutics. He was appointed to the British Pharmacopoeia Commission between 2010 and 2021 and chairs the Medicinal Chemicals (MC2) Expert Advisory Group and the Analytical Quality by Design Working Party. Between 2012-2018 he was Chairman of the American Society for Testing Materials (ASTM) International E55 Technical Committee developing pharmaceutical manufacturing standards and continues to serve as a member of the E55 Executive Committee. He was a past chair of Pfizer’s Quality by Design Council and previous roles include Technical Director supporting Wyeth Europa Manufacturing and External Supply, and Director Formulation Development for Wyeth Consumer Healthcare (Richmond, Virginia, USA).

This is an event for members of EIPG member organisations. Contact your national association EIPG representative for further information.


Review of the pharmaceutical legislation, the proposals of the industrial associations

February 10, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

By Giuliana Miglierini

The Staff Working Document on “Vulnerabilities of the global supply chains of medicines” published by the European Commission on 17 October 2022 identified several issues related to the current, often difficult situation experienced by pharmaceutical supply chains. Among these are the increasing complexity and specialisation, challenges linked to the production process and technologies, the lack of geographical diversification and other dependencies, the need to unlock the potential of data to improve supply and demand predictability, and a perceived regulatory complexity.

The same issues have been widely debated under different perspectives during recent months as a possible contribution to the current revision of the pharmaceutical legislation, a major goal of the EU Commission’s Pharmaceutical Strategy for Europe together with the New Industrial Strategy for Europe.

The structured dialogue with stakeholders has been the tool chosen to facilitate the interaction and exchange of opinions in order to optimise the development and implementation of the new pieces of legislation. We resume some of the latest proposals arising from the main industrial associations on how to better achieve this very challenging objective.

EFPIA proposals for action

In November 2022, the European Federation of Pharmaceutical Industry Associations published a report to illustrate its proposals for action to tackle shortages of medicines and to improve the efficiency and robustness of the supply chain.

Five key principles form the basis of nine operative proposals. A standard definition of a shortage and an interoperable IT European monitoring/notification system would be needed in order to build a harmonised EU prevention and mitigation system. Epidemiological data are deemed essential to better analyse patient demand, so to improve transparency in the overall supply chain by means of the European Medicines Verification System (EMVS). Targeted shortage prevention plans (SPP) should be developed to prevent the risk of shortages for critical products and to manage safety stocks on a risk-based approach. Regulatory mitigation measures for shortages would also be of help in improving flexibility. At the global level, the maintenance of global open supply chains should be the goal, supported by the strong existing EU manufacturing and R&D footprint, and where appropriate, targeted incentives for the diversification of supply chains.

“The current revision of EU pharmaceutical legislation is a golden opportunity to reverse the trends of the last 25 years. It is our once-in-a-generation chance to reinvent the regulatory framework to ensure we have a modern approach that matches our ambition to be a hub of medical innovation”, writes EFPIA’s director general Nathalie Moll in a recent post, published on the association’s website.

In its Regulatory roadmap to Innovation of January 2023, EFPIA focused on how to achieve a more agile and streamlined regulatory framework, so to shorten the period needed for approval of a new active substance (currently 426 days, vs 244 days in the USA, 306 in Canada, 313 in Japan or 315 in Australia). Innovative approaches to clinical trials, including complex clinical trials (CCTs) and decentralised trials (DCTs), and the development of clear guidance on the use and regulatory acceptance of real-world data (RWD) and real-world evidence (RWE) are among the eight areas of possible immediate actions identified by EFPIA.

A dynamic regulatory assessment pathway based on early and iterative dialogue on data, international data standards and technology, and cloud-based submission modalities would support EMA and HTAs in accepting iterative data generation as part of the evaluation procedures.

As for drug-device combinations and in-vitro diagnostics, EFPIA suggests adopting an integrated EU pathway for the assessment, including the possibility for parallel advice with Notified Bodies. A clearer definition of unmet medical need would also be needed, as well as the full digitalisation of regulatory processes. A common definition of shortage coupled to the setting up of a European reporting system (possibly the already existing EMVS) would support the collection of real-time information and activation of alerts. Epidemiological data should be elaborated and released by the European Centre for Disease Control (ECDC).

The Variation Regulation is also under review by the EU Commission. EFPIA’s proposal is to incorporate the considerations for pharmaceutical product lifecycle management set forth by the ICH Q12 guideline, and to develop a vaccine-specific annex to the Variation guideline.

EFPIA also identified four areas requiring legislative change to accelerate pharmaceutical innovation in Europe. These include the possibility to redesign EMA’s committee structure in order to speed up the efficiency of regulatory assessment and decision-making process from EMA approval to EC decision.

Expedited regulatory pathways (ERP) are still of limited use in the EU, according to EFPIA. The suggestion is to embed the PRIME scheme in the new legislation to ensure its optimal use and allocation of sufficient resources. The creation of a new legal category for drug-device combination products, to be regulated as medicinal products, would also accelerate the approval of this increasingly important type of therapeutic option.

The transition from paper leaflets to electronic product information (ePI) should be also supported within the new pharmaceutical legislation, while considering the still present difficulties that may be experienced by elders and people not having access to computers or mobile devices. A new, centralised ePI repository/database would also be needed.

Medicines for Europe, focus on access and prevention of shortages

The 2022 of Medicines for Europe (MfE), representing the generic, biosimilar and value-added medicines industry, focused its lobbying activities mainly on access to medicines and prevention/ mitigation of shortages.

The economic and geopolitical crisis highly impacted the sector, which suffers strict price caps requirements in market policies. In a recent letter to the EU institutions, Medicines for Europe highlights the possible link between the shortages of amoxicillin and amoxiclav antibiotics and the low pricing and procurement policies in place in many EU member states.

“There are significant risks of more medicine shortages in 2023”, writes the association, which may be tackled by concrete policy reforms and industry commitments.

The economic model for generic medicines in Europe is identified as the structural root cause of shortages, requiring manufacturers to run their plants at the maximum capacity in order to “remain profitable as GMP rules require continuous investment in manufacturing plant upgrades”. This leaves little space to accommodate requests for increased production in order to face shortages. Other measures that, for MfE, impacted on the consolidation of supply chains and generic markets include the requests set forth by the Falsified medicines directive, as well as the Brexit, the Covid emergency and the current war scenarios.

The letter also identifies some possible short- and medium-term measures useful to mitigate the risk of shortages and improve the efficiency of the generic’s supply chains.

The first ones include the request for more regulatory flexibility for packaging, to facilitate the distribution of the available products in different member states. Clearer thresholds for nitrosamines and the need to avoid new regulations that may have a disproportionate impact on low margin medicines are also suggested. A better dialogue on immediate measures to tackle the cost of inflation on generic medicines would also be beneficial, says MfE, which also agrees on the need to better estimate demand surges on the basis of available data and epidemiological analysis.

The association of the generic and biosimilar industry shares also the importance of a rapid digitalisation of the medicines regulatory network in order to fully exploit the potential of big data. On the medium-term (2025), this may prove important to achieve objective related to the implementation of the ePI, the reduction of variations, the management of API sources, the harmonisation of packs and a better handling of requirements at national level.

Suggested actions at the legislative level include the introduction of legal guidance on the implementation of the criteria established by the Public Procurement Directive. The Transparency Directive may take example from Canada, where prices for generics varies according to the variation of the demand. A Medicine Security Act might represent the legislative tool to support investments in manufacturing diversification and greener technologies.

MfE also highlights some threats resulting from political choices such as national stockpiling requirements, that can increase costs and reduce cross-country solidarity. A preferred approach would be that of the European strategic reserve concept, based on rolling reserves. The real usefulness of joint procurement should also be better evaluated, especially with reference to OTC and other medicines directly dispensed by community pharmacies.

A note published in November 2022 focused on the still greatly unused potential of value-added medicines, a sector which according to MfE may benefit by a re-evaluation of the current innovation model, leading to a increased attention to the entire lifecycle of a medicine and on off-patent molecules. The request to the EU Commission is to fully acknowledge value added medicines in the EU pharmaceutical legislation as a separate group of medicines, with its own dedicated regulatory pathway and proportionate data exclusivity incentives.

The vision of the ATMP sector

The vision of the advanced therapies (ATMPs) sector, represented by the Alliance for Regenerative Medice (ARM), was illustrated in an event held in November 2022 at the European Parliament.

The declining competitiveness of the EU and how to ensure patients’ access to transformative treatments have been subjects of the debate. Many of the newly approved treatments fall under the ATMP categories of medicinal products (cell and gene therapies, tissue therapies), that according to ARM would require a better suited policy and regulatory framework to fully exploit their potential. “The same policies and approaches that brought us yesterday’s biomedical innovation simply will not work for the cell and gene therapies of today and tomorrow. The EU has led before — and can lead once again — but the time to act is now.” said Timothy D. Hunt, chief executive officer of ARM.

According to data by ARM, the number of ongoing industry clinical trials in Europe involving ATMPs is increasing very slowly (just 2% at the end of June 2022). More in detail, only one phase 1 study was initiated in Europe in the first half of 2022, says the association, and the region accounted for just 11% of new trials involving ATMPs and started in the same period. Many EU’s approved advanced therapies are also suffering, with 23 ATMPs withdrawn from the market. The reduced interest of the sector towards Europe is also acknowledged by the declining number of developers headquarters (-2% vs the previous five years): a trend opposite to that of North America and, especially, the Asia-Pacific region


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

November 25, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

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.


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