Communication Archives - European Industrial Pharmacists Group (EIPG)

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

Environmental sustainability: the EIPG perspective


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 Read more

European Council’s recommendations on R&I

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by Giuliana Miglierini

The end of 2023 saw some steps forward to better support the European framework on Research and Innovation (R&I). The Council of Europe approved on 8 December 2023 its conclusions on the impact of research and innovation (R&I) in policymaking. The Council also reached a political agreement on a recommendation of a framework supporting researchers and research careers in the EU. R&I is strategically important as one of the main tools to make Europe more attractive to young talents and to create a open and sustainable European labour market for researchers, innovators and entrepreneurs. We summarise the main features of the Council’s decisions.

How to support the European R&I

The Council conclusions were proposed by the Spanish Presidency (Ministry of Science, Innovation and Universities), and they represent one of its main priorities in the area of research and innovation.

Three mutually complementary dimensions have been identified as fundamental to the success of European R&I. Science plays an important role to reinforce the political process of decision making, which in turn is key to improve life conditions of EU citizens and strengthen democracy. To this instance, the inclusion of scientific evidence and knowledge in the regulatory process and a better coherence of policy initiatives in different areas are deemed important by the Council. According to the conclusions, such an inclusion should help to improve the response capacity of the EU and member states against both structural and cyclical or circumstantial challenges. The document also recalls the ‘Science for Policy’ concept and the EU’s long-standing tradition of relying on science and evidence-based knowledge in all disciplines to support decision-making.

The availability of strong R&I ecosystems in all member states is deemed fundamental to sustain EU’s competitiveness and should be supported among others by the implementation of open-science policies and new technologies and innovation, including social innovation.

The best available scientific evidence should also always be included in impact assessments, so to improve citizens’ trust in public action, as well as the added value of the legislation. To this instance, a rigorous methodological framework would be needed, even though uncertainties are still possible. Transparent and responsible communication would support a better dissemination of scientific outcomes at all levels. The Council also recommended the mapping of the existing practices of knowledge valorisation in policymaking and the national institutional scientific advisory systems and mechanisms. The Commission should also extend the use of the Technical Support Instrument and the Policy Support Facility to support public policymakers and strengthen public structures for scientific advice.

Local and regional innovation ecosystems and ERA’s R&I

R&I may also represent a boost to enhance cooperation and territorial cohesion, reduce R&I fragmentation and disparities between and within member states and to sustain the creation of regional and local innovation ecosystems. Their design should aim to build synergies between cohesion policy and R&I funds. To this regard, according to the Council the R&I framework programme (i.e. Horizon Europe) should continue to drive research excellence in all member states.

Regional centres of excellence may represent a particularly interesting tool to support the regional dimension, with a special attention to the less innovative ecosystems. This goal is part of the New European Innovation Agenda (NEIA), as well as the Regional Innovation Valleys and the pilot project of the Partnerships for Regional Innovation. Cross-border cooperation (especially between less and more innovative member states and regions) may also be key to support better economic, social, and territorial cohesion and reinforce R&I efficiency.

The third dimension is referred to the policy impact of the Recovery and Resilience Facility (RRF) on the design of R&I policies in the European Research Area (ERA) after the pandemic crisis. This last occurrence had a positive effect in enabling many actions at the national level, allowing for targeted investments and reforms. The new ERA should be based on trust, shared responsibilities, and societal engagement and diversity.

Many sectoral and R&I policies experienced a joint approach to their improvement, including the additionality of the Facility with other EU funds. The Council invited the Commission to run a separate study that complements the mid-term evaluation of the RRF, expected by February 2024. The exercise should consider the differences between the RRF and other EU funds.

The reform of research careers

The political agreement reached by the Council on the proposal of a European framework to attract and retain research, innovation and entrepreneurial talents in Europe updates the R1- R4 profiles for researchers, introduced in 2011. It also introduces the European Charter for Re-searchers (ECR), a revision of the 2005 ECR and the Code of Conduct for the Recruitment of Researchers.

The revised definition of researcher and the related research activities are expected to widen career options, thus making European R&I framework more attractive for both internal and foreign talents.

According to the proposal, the term “researcher” would identify professionals engaged in the conception or creation of new knowledge, active in basic or applied research, experimental development, operating research equipment, or project management within any sector of the economy or society (i.e.academia, business, governmental laboratories and the public administration, and the non-profit sector). Careers in research management are also included in the definition.

Four different profiles have been identified to describe the career steps of researchers. First Stage Researcher (R1) are doing research under supervision up to the point of a PhD or equivalent level of competence and experience. Recognised Researcher (R2) hold a PhD or equivalent level of competence and experience but are not yet fully independent in their ability to develop their own research, attract funding, or lead a research group. R1 and R2 refer to researchers at the beginning of their career in science. R3 and R4 refer to senior researchers. Established Re-searcher (R3) holds a PhD or equivalent level of competence and possesses sufficient experience to independently develop and run their own research. Leading Researcher (R4) are recognised as leading their research field by their peers.

The Council recommends that these profiles are referenced to by members states in all vacancies specifically addressed to researchers. Member states are also called to promote equal esteem and reward of the different paths of research careers, regardless of the sector of employment or activity. Appropriate measuring should support comparison of careers across member states, sectors, and institutions, so enabling their full interoperability. The Council recommendation also aims to reduce the precarity of research labour by promoting adequate social protection measures. Inter-sectoral mobility is also encouraged, as well as better equality in research careers, as a tool to respond to the request of highly skilled talents. The Council expects that all organisations employing or providing funding for researchers would provide endorsement of the new “European Charter for Researchers”.


EC Communication (part 2): a Critical Medicines Alliance to support European pharma supply chain

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by Giuliana Miglierini

After last week’s examination of the first part of the Commission’s Communication, specifically targeted to short-term actions to prevent and mitigate critical medicine shortages, in this second post we will address the announced mid- and long-term structural measures, focused on the creation of the Critical Medicines Alliance, the diversification of supply chains and the role of international partnerships.

The Critical Medicines Alliance

The second part of the Commission’s Communication details the structural measures to strengthen the secure supply of pharmaceuticals in the EU, with particular reference to critical medicines. An objective that, according to the Commission, may require the development of new pieces of legislation, such as the EU Critical Medicines Act. To this instance, the preparatory study should be launched by the end of 2023, and followed by the impact assessment.

In the meantime, the improved coordination of the industrial approach to the management of shortages in the EU should be pursued by the Critical Medicines Alliance, to be created in early 2024. The Alliance will bring together all involved stakeholders; its activities should start from a shared analysis of vulnerabilities in the supply chain of the critical medicines on the Union list (i.e over-dependency on a limited number of external suppliers, limited diversification possibilities, limited production capacities, etc).

The result of this exercise should be the identification of useful tools to address vulnerabilities of a limited number of critical medicines with the highest risk of shortages and impact on healthcare systems. To this regard, several lines of actions are identified in the Communication, starting from the issuing of a dedicated guidance and common criteria for the coordinated procurement of critical medicines (e.g. green production and prioritisation of supplies in Euro-pe at times of critical shortages). A better quantification of demand and the consequent possibility to compensate and incentivise industry for its effort in these directions are other expected outcomes.

Medium-term contractual incentives are proposed as a tool to improve predictability of supply and to attract new manufacturing investments in Europe, together with the use of capacity reservation contracts modelled on EU FABs. These last instruments were launched by the HERA Authority during the pandemic in order to reserve manufacturing capacities for vaccines and obtain a priority right for their manufacturing in case of a future public health emergency.

The second line of action of the Alliance would address the diversification of global supply chains for critical medicines, including the identification of priority countries to be involved in strategic partnerships on the security of supply (see also below).

The third pillar should see the Alliance involved in the coordination and harmonisation of efforts to identify security of supply needs for critical medicines, on the basis of the above-mentioned identified vulnerabilities. Actions cited by the Communication, such as the Services of General Economic Interest (SGEI) coordinated at the EU level, should be compatible with the state aid framework. The Alliance may also represent the dedicated location where member states may better discuss the possibility of a new Important Project of Common European Interest (IPCEI) focusing on sustainable manufacturing of critical medicines (including off patent medicines).

Stockpiling, skills and financial support

EU stockpiling of critical medicines is another area of activity of the Critical Medicines Alliance. The goal is to overcome current limitations typical of national stockpile programmes; the development of a common strategic approach and a Joint Action on stockpiling has been announced for the first half of 2024, based on the previously mentioned vulnerability analysis and on the experience of the Union Civil Protection Mechanism (UCPM, that will continue to be part of the EU approach) and the rescEU stockpile.

The Alliance should also address the need for new and updated skills to work in the pharmaceutical sector, so to cope with the increasing impact of digitalisation, the evolution of the regulatory environment and the green transition. Pharmacists are cited in the Communication, as their curricula could be easily adjusted to accommodate education and training on new skills. Attention should be paid to increasing STEM (Science, Technology, Engineering and Mathematics) graduates. A Pact for Skills is the measure identified to actively involve key actors in educational and training activities aimed to fill industry skills gaps.

The Alliance would also play a significant role in better leverage and align EU and national funding: a goal deemed important in order to support improved long-term investment predictability for the private sector, and to avoid duplication of efforts. Among other tools cited by the Communication to reach it, the proposed Strategic Technologies for Europe Platform (STEP) is also inclusive of pharmaceuticals, biotechnologies and medical technologies. The creation of a Sovereignty Seal to promote synergies amongst existing programmes, and the Technical Support Instrument to enhance the administrative capacity of member states in managing shortages and producing critical medicines are among other proposed tools.

Diversification of supply chains

A second, fundamental line of action identified by the Commission addresses how to better diversify the complex, global pharmaceutical supply chain, also by means of new international partnerships with third countries. According to the Communication, the EU industry needs to have access to a broad range of essential inputs; to this regard, new strategic partnerships with third countries for production of critical medicines and active ingredients should be based on concrete actions of mutual interest.

The EU has 42 preferential trade agreements in place with 74 different trading partners, and a new one is under negotiation with India. The Commission also recalled the importance of bilateral meetings with China on issues affecting access to medicines supply chains, and of the dialogue with Latin America.

An improved regulatory convergence is another main objective of the planned actions at the international level, so to increase GMP compliance of medicinal products marketed in the EU and manufactured by extra-UE partners. To this instance, the Communication mentions the work of international bodies such as the ICH (International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use) and ICMRA (International Coalition of Medicines Regulatory Authorities) for the harmonisation of standards for pharmaceuticals, and the WHO support to improved regulatory convergence. Many free trade and mutual recognition agreements (MRAs) signed by the EU also contain this type of obligation, and in some cases the sharing of non-sensitive market knowledge to anticipate possible problems too.

A new network of international partners should be created by the Commission within a year, in conformity with applicable state aid and antitrust rules. The network activities would focus on crisis preparedness and supply diversification. The Communication mentions also different international initiatives already in place, such as the Global Gateway to support local manufacturing of health products and announced another Team European Initiative in Africa on health security and pandemic preparedness and response. Another ongoing initiative is the EU-Latin America and Caribbean Partnership on manufacturing and access to vaccines, medicines and health technologies. The EU will also continue to support the provision of critical medicines in humanitarian contexts.


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

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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.


Current inspection trends and new approaches to the monitoring of post-inspection activities

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by Giuliana Miglierini

The European Federation of Pharmaceutical Industries and Associations (EFPIA) has published its Annual Regulatory GMP/GDP Inspection Survey 2021, highlighting the more recent trends in inspections and how the pandemic affected this critical verification process of pharmaceutical productions. Meanwhile, UK’s regulatory authority MHRA launched the Compliance Monitor Process pilot, aimed to use eligible consultants as Compliance Monitors to supervise companies in the delivery of actions identified in the Compliance Protocol agreed with the regulatory authority.

Main trends in inspections

The main effect of the lockdowns has been the implementation of new ways to run inspections. The recommendation resulting from EFPIA’s report is now for virtual tools combined with onsite presence; to this instance, data gathered in 2021 show that the two modalities of inspection have a similar duration (2.9 days for on-site inspections vs 2.8 days for virtual ones). The report also indicates there is still a backlog of inspections due in 2020, the critical period of the pandemic; suggestions to manage expiring GMP/GDP/ISO-certificates include a one-year prolongation of current certificates, a dedicated communication process between the industry and regulators in the case of issues with the registration in third countries, and a planning of inspections based on the quality history of the site.

Domestic inspections confirming the trend observed since 2016, are almost double of the number of foreign inspections. These last ones focused in 2021 on only 23 countries, compared to the 44 countries visited by inspectors in 2017. EU’s countries were the most visited ones, with some 350 inspections reported vs the 150 of US, confirming the importance of European pharmaceutical manufacturing. According to the report, 2021 saw an increased attention to GDP inspections, while the percentage of sites with no inspections remains stable for six years.

A new mix of inspection tools

The use of new tools, additional to physical on-site presence, has now become a routine possibility accepted by many regulatory authorities. Many different approaches have been tested during the pandemic, including different inspections tools. Different combinations of tools cannot be considered to be equivalent, according to EFPIA. In general, a mixture of physical presence, document review and virtual presence flanked by the sharing of experience, collaboration and reliance is deemed suitable to confirm compliance and capability while supporting a risk-based efficiency.

Data show that the number of virtual inspections was higher in 2020 compared to 2021; the last year saw an increase of on-site presence vs 2020 and a mixture of virtual and on-site inspections. According to the report, only seven European countries have experience with the implementation of virtual inspection tools (Germany, Denmark, Finland, Ireland, Italy, Poland and Sweden). As a consequence, the impact of mixed virtual and on-site domestic inspections in 2021 was lower in EU member states that, for example, in the US, Brazil, Russia and Singapore.

There is still space for improvement

EFPIA’s survey presents the respective advantages and disadvantages of on-site inspections vs virtual tools. The implementation of the new modalities is far from being accomplished, the process is still on the learning curve, says the document.

While the remote, virtual interaction allows for a greater flexibility of the inspection process, it may result stressful for some people; furthermore, it impacts on the way work is organised, as it needs a flexible schedule and time to prepare for the next day meetings. Also, the style of communication changes to become less natural and more focused. Overall, virtual inspections appear to be more efficient when performed in real-time, as it would be for on-site inspections. While being less costly, due to avoiding extensive travelling, virtual inspections require a careful preparation, including the availability of a suitable IT infrastructure and connectivity. Documents are also often required in advance of the meetings to be shared with regulators.

How to further improve inspections

According to EFPIA, the future of inspections calls for improved collaboration and reliance in order to increase the knowledge shared by the different inspectorates and overcome the limits intrinsic to self-dependency. The expected final outcome of the new approach to inspections is an improvement in the decision-making process. Inspection frequency may be set every 1 to 5 years on the basis of a risk-based evaluation.

Collaboration, reliance and delegation appear to be the new mantras to guide the actions of regulators: the focus suggested by EFPIA is on inspections run by domestic authorities, coupled to the implementation of Mutual Recognition Agreements (MRA) to avoid duplication of efforts. According to the report, it would be needed to harmonise the scope of existing MRAs and to establish new ones between the EU and PIC/S participating authorities (e.g. Argentina, Brazil, South Korea, Turkey and UK). The European legislation should be also updated to include the concept of listed third countries, as already in place for the importation of active substances under the provisions of the Falsified Medicines directive.

The report also suggests a qualitative tool that would fulfil the legal requirements for “inspections” and may prove useful to support inspection planning on the basis of the knowledge of the GMP compliance history of the site, the footprint history of critical and major deficiencies and the type of inspection to be run. These elements lead to the identification of the hazards to be considered, including the intrinsic risk and the compliance-related one. The final output of the tool takes the form of a risk-ranking quality metric, to be used to establish the frequency of inspection for a certain site and the number and level of expertise of the required inspectors, as well as the scope, depth and duration of routine inspections.

All these items may form the basis for the drafting of a GMP inspection “Reliance Assessment Report”, which would also include the statement about the name of the hosting national competent authority and the basis on which country reliance has been established. Such a document may be then used to support regulatory decisions. According to EFPIA, the suggested approach would benefit of a better knowledge of the site inspected by the local NCA, a better insight in the local culture and less barriers to the interaction, with optimisation of resources. A better transparency of the inspection process is also expected, as a non-compliant site may negatively impact on the reputation of local inspectorates. Identified pre-requisites to allow the implementation of such an approach are the availability of high-quality standards at the local level and the evaluation of national regulatory systems by and independent body (e.g. PIC/S or the WHO Global Benchmarking Tool).

UK’s pilot of a Compliance Monitor Process

A new approach that may represent a first example towards the new paradigm of collaboration and reliance has been undertaken in the UK, where the Medicines and Healthcare products Regulatory Agency (MHRA) launched in April 2022 a pilot project focused on the Compliance Monitor (CM) Process (see more here and here). The pilot is part of MHRA’s delivery plan 2021-2023 and will focus on the CM supervision process for appropriate GMP and GDP Inspection Action Group (IAG) cases.

According to the MHRA, the new process would allow companies to concentrate on the delivery of the required improvements without the need to use resources to manage MHRA supervision inspections to assess compliance remediation activities. On the regulatory side, the MHRA should be able to concentrate on the delivery of the routine risk-based inspection programme. The risk-based approach to supervision and monitoring is also expected to limit the number of potential shortages of supply.

The CM process is based on the figure of eligible consultants acting as Compliance Monitors (CM) in charge of working with the company to deliver the remediation actions identified in a Compliance Protocol (CP) agreed with the MHRA. The supervision by the CMs is expected to contribute to lower the need of on-site inspections with respect to the current process managed by the IAG. The CP also includes the transmission to MHRA of high-level updates at fixed intervals of time, which should include only exceptions to the agreed timelines or significant related compliance issues which were identified. Once completed the CP protocol, the CM informs the regulatory authority that the company is ready for inspection, so that the MHRA can verify onsite the possibility of its removal from IAG oversight.

CMs will be selected by the involved company from a dedicated register and accepted as suitable for that case by the MHRA. At least five years’ experience in independent audits of GMP/ GDP companies is needed to be eligible as CM. Furthermore, not having been personally the subject of MHRA regulatory action and/or significant adverse findings in the previous three years,  a suitable CV and the completion of a MHRA training as CM. All details on requirements for the CM role and application are available at the dedicated page of the MHRA website.

Suitability criteria to act as a CM for the specific case include as a minimum a sufficient experience of the dosage form manufactured, testing activities being performed, or distribution activity being carried out and a written confirmation of absence of Conflict of Interest. These criteria will be assessed by the company selecting the CM.

BIA’s view of the reliance in the UK medicines regulatory framework

The UK’s BioIndustry Association (BIA) contributed to the debate on the reliance in the UK medicines regulatory framework with a Reflection Paper. According to BIA, the MHRA has a well recognised status and history as a valued contributor to the global regulatory ecosystem and a point of reference for the regulatory decision-making which should be preserved also in the future.

BIA recalls the role played by the MHRA in the development of the concept of regulatory reliance at the EU level, as a way to support the agile management of resources and simultaneously focusing on core and innovative national activities across all stages in the product lifecycle. The central concept sees regulators from one country to rely on the decision and assessments of trusted authorities from another country in order to speed up the timeline of regulatory procedures. At the end of the process, each regulator remains fully responsible and accountable for all its decisions.

BIA also highlights the contribution of reliance to the advancement of good regulatory practices and international networks of regulators, so to better allocate resources potentially taking into account also the respective fields of specialisation. The proposal is for a list of accepted reference regulatory authorities as a way to recognise the evolution of partnerships over time. Examples of recognition pathways already active in the UK are the EC Decision Reliance Procedure (ECDRP) and international work-sharing through the Access Consortium and Project Orbis, through which the MHRA may act as the reference regulatory agency in many procedures.

BIA also warns about the risks of a sudden interruption at the end of 2022 of the reliance pathway, that would have a highly disruptive impact on companies and patients.


Revision of the CDMh’s Q&As document on nitrosamine impurities

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by Giuliana Miglierini

The review process of medicinal products started in 2018 to assess the presence of nitrosamine impurities is still ongoing. The Coordination Group for Mutual Recognition and Decentralised Procedure (CMDh) last updated in December2021 its Questions & Answers document (Q&A) proving guidance on how to approach the revision procedure.

The US’s Food and Drug Administration (FDA) also updated its guidance on how to minimise the risks related to nitrosamine through formulation design changes. We summarise the latest news of the topic of nitrosamine impurities.

The CMDh’s update of the Q&A document

The CMDh Questions & Answers document (CMDh/400/2019, Rev.5) specifically refers to the implementation of the outcome of Art. 31 referral on angiotensin-II-receptor antagonists (sartans) containing a tetrazole group. According to the indications released in November 2020 by EMA’s human medicines committee (CHMP), these outcomes should now be aligned with those issued for other classes of medicines. This provision impacted on the allowed limits for nitrosamines, which are now applied to the finished products instead than to the active ingredient. The limits are determined on the basis of internationally agreed standards (ICH M7(R1)).

Companies are called to implement an appropriate control strategy to prevent or limit the presence of nitrosamine impurities as much as possible and to improve their manufacturing processes where necessary. A risk assessment should be run to evaluate the possible presence of N-nitrosamines in medicinal products, and tests carried out if appropriate.

Four different conditions (A-D) are set for the marketing authorisation (MA) of tetrazole sartans, with specific dates to be met for their fulfilment by marketing authorisation holders (MAHs). Revision 5 of the Q&As document specifically addresses conditions B and D.

Condition B asks the MAH to submit a step 2 response in the general “call for review”. To lift the condition on the risk assessment for the finished product, and provided no nitrosamine was detected in step 2 or levels are below 10% of acceptable intake (AI), submission of the step 2 response must now be followed by the submission of the outcome of the risk assessment. To this instance, the relevant template “Step 2 – No nitrosamine detected response template” should be used to fill a type IA C.I.11.a variation.

A further amendment to Condition B refers to nitrosamines being detected in step 2 above 10% AI. In this case, a variation application should be submitted as appropriate to support changes to the manufacturing process and the possible introduction of a limit in the specification of the finished product.

Condition D now specifies that it applies only to N-nitrosodimethylamine (NDMA) and N nitrosodiethylamine (NDEA) impurities. Thus, to lift the condition on the change of the finished product specification, and if the MAH wants to apply for omission from the specification, supporting data and risk assessments should be submitted via a type IB C.I.11.z variation referring only to these two impurities. Should any other nitrosamine impurity be potentially present, data should be submitted under separate variation (also grouping them together). Conditions A and C remain unchanged. The former refers to the three different possibilities for lifting the condition on the risk assessment for the active substance and with specific reference to the manufacturing process used to prepare it, the second to lifting the condition on the control strategy.

The guidance from the FDA

The US regulatory agency Food and Drug Administration (FDA) released in February 2021 the first revision of the “Guidance for Industry Control of Nitrosamine Impurities in Human Drugs”, establishing a three-step process to demonstrate the fulfilment of requirements.

The guideline widely discusses the structure of nitrosamine impurities and the possible root causes for their presence in medicinal products. While not binding for manufacturers, recommendations contained in the document should be applied in order to evaluate the risk level for the contamination of both active ingredients and finished products. This exercise should be run on the basis of a prioritisation taking into consideration the maximum daily dose, the duration of treatment, the therapeutic indication, and the number of patients treated.

The FDA provides also the acceptable intake limits for a set of different nitrosamine impurities (NDMA, NDEA, NMBA, NMPA, NIPEA, and NDIPA); the approach outlined in ICH M7(R1) should be used to determine the risk associated with other types of nitrosamines.

Manufacturers do not need to submit the results of the risk assessment to the FDA, the relevant documentation has to be made available just upon specific request.

The second step refers to products showing a risk for the presence of nitrosamine impurities. In this case, highly sensitive confirmatory testing is needed to confirm the presence of the impurities.

The implementation of all changes to the manufacturing process for the API or final product have then to be submitted to the FDA in the form of drug master file amendments and changes to approved applications.

The Agency also provides specific guidance for API manufacturers to optimise the route of manufacturing in order to prevent the possible formation of nitrosamine impurities. API manufacturers should participate to the risk assessment run by the MAH; this last exercise should include the evaluation of any pathway (including degradation) that may introduce nitrosamines during drug product manufacture or storage.

Additional points to be considered

A Communication issued in November 2021 by the FDA specifies the terms for the recommended completion dates of the above mentioned three steps and adds some additional points to be considered in the evaluations. MAHs should have already completed by 31st March 2021 all risk assessments, while there is time up to 1st October 2023 for confirmatory testing and reporting changes. According to the FDA, the time left is enough to include in the development of the mitigation strategies also new considerations on how formulation design may prove useful to control nitrosamine levels in drug products.

More in particular, manufacturers are asked to evaluate the presence of nitrosamine drug substance-related impurities (NDSRIs), that may be produced if nitrite impurities are present in excipients (at parts-per-million amounts) or may be generated during manufacturing or shelf-life storage. Should NDSRIs be present, FDA recommends the mitigation strategy should include a supplier qualification program that takes into account potential nitrite impurities across excipient suppliers and excipient lots.

Formulation design is another possible approach to solve the issue. This may use, for example, common antioxidants – such as ascorbic acid (vitamin C) or alpha-tocopherol (vitamin E) – that according to the scientific literature inhibit the formation of nitrosamines in vivo. The kinetic of the reaction leading to the formation of nitrosamine impurities may be also addressed by using a neutral or basic pH for formulation, to avoid acidic conditions which favours the side reaction.

Formulation changes may be submitted to the FDA through supplements or amendments to the applications, also following a preliminary meeting with the Agency to better discuss the approach to be used. Should this be the case, applicants or manufacturers are asked to prepare a comprehensive meeting package with the appropriate regulatory and scientific data on the selected approach to be submitted to the FDA in advance of the meeting.