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The risk of a biosimilar void in Europe


by Giuliana Miglierini The undergoing revision of the pharmaceutical legislation aims, among others, to redefine data protection to better support competitiveness of generics and biosimilars and to favour the timely access of patients to treatments. While the innovator pharma industry is Read more

The drug shortage situation - EIPG's point of view


by Maurizio Battistini The shortage of medicines has been a major concern in the countries of the European Union, and elsewhere, for more than 10 years, so much so that the Economic Community has devoted a great deal of effort Read more

EP’s draft position on Unitary SPC and SPC Regulation revision


by Giuliana Miglierini The Committee for Legal Affairs (JURI) of the European Parliament released the draft amendments to the Commission’s proposals aimed to establish a Unitary Supplementary Protection Certificate (SPC) (links to the document and to the procedure) and to Read more

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

November 3, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

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.


ECA’s guide to compliant equipment design

March 31, 2023 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

By Giuliana Miglierini

The legislative evolution of the last decades emphasised requirements for equipment used in pharmaceutical productions. This is even more true with the entry into force of the new Annex 1 to the GMPs, characterised by many new requirements impacting on different manufacturing processes (i.e. production of water for injection, sterilisation, Form-Fill-Seal and Blow-Fill-Seal technologies, single use systems, lyophilisation, etc.).

Each pharmaceutical process requires the careful design of the needed equipment in order to provide the expected efficiency and performance. Furthermore, some equipment may be used for different industrial applications (e.g. pharmaceutical, cosmetic or food), thus needing a fine tuning to reflect relevant requirements. In pharmaceutical manufacturing, a further step of complexity may be represented by the need to handle highly potent active pharmaceutical ingredients, requiring isolators to segregate production, etc.

To facilitate the correct design of equipment compliant to GMPs, a new guidance document has been published by the ECA Foundation. The document was initially drafted in German by a task force of experts in pharmaceutical technology and engineering and published by Concept Heidelberg, and it has now been translated in English

Elements relevant to reach compliance

The first part of the document discusses general requirements that should always be part of the design of GMP-compliant equipment. Four different points of attention are listed: the equipment must not adversely affect the product quality, it must be easy to clean, it must comply with applicable technical rules, and it must be fit for its intended use.

As for the first point, “The question is rather what is tolerable without adversely affecting the product quality”, states the guidance. Avoidance of contamination and cross-contamination are the main goals of cleaning activities, both for sterile and non-sterile medicinal products. There are several issues to be taken in mind from this perspective, including the presence of endotoxins, sealing points, the efficiency of cleaning-in-place (CIP) processes, or the presence of unreachable dead leg areas. According to the guidance, the 3D/6D rule for the prevention of dead legs in water systems often used for specification would not always be correctly applied, due to some confusion in terminology. Official GMPs are also deemed “very vague”, as they are not drafted by engineers and apply to an extremely wide range of different equipment and processes. “Consequently, the question is, which technical rules have to be followed or where the actual state of the art can be looked up”, says the document. Many different references are possible, from pharmacopeia monographs and regulatory guidelines, to ISO standards, and other documents published by international professional bodies.

Qualification and calibration of equipment should always be targeted to the specific product, as it is an essential in proving compliance to the intended use. Regulatory compliance of submitted documentation is not less important, and it greatly impacts on change control and implementation of new productive technologies.

Risk analysis (RA) is the tool introduced in 2005 by ICH Q9 to evaluate all items which may impact on the design of productive processes and related equipment. There is no standard methodology to run risk analysis, the choice depends on the process/product under assessment. According to the guidance, RA can be performed both from the perspective of the product and the equipment, the latter being also considered a GMP risk analysis.

Design and choice of materials

Materials (and coating materials where relevant) used to build pharmaceutical equipment should be completely inert. Pharmaceutical equipment must comply with the EC Directive on Machinery 2006/42/EC and DIN EN ISO 14159. The ECA guidance discusses material selection (plastics or stainless steel); hygienic system design is also addressed by many different guidelines, e.g. those published by the European Hygienic Engineering and Design Group (EHEDG). An important item to consider is service life considerations for the materials used (EHEDG Document 32), as well as their chemical-physical characteristics and materials pairing.

Particularly critical are process contact surfaces, as they may impact product quality. Establishment of specific requirements is thus needed. The guidance focuses its attention on austenitic stainless steels (i.e. CrNiMo steels 1.4404 and 1.4435). The main elements to be assessed are the risk of corrosion, the risk of contamination of the product or process medium and the cleanability of the metallic surface. Topography, morphology and energy level are the main characteristics to be used to describe surfaces, addressing respectively the geometric shape, chemical composition and energy required per unit area to increase the size of the surface. The guidance provides a detailed discussion of all different aspects of surface treatment methods, and the hygienic design of open and closed equipment. Other sections discuss the optimal design of pipework and fittings, connections, welding and seam control. Detailed information is also provided on equipment of electrical engineering, measurement and control technology, as well as the process control technology (PCT) measurement and control functions.

A highly critical area within a pharmaceutical facility are cleanrooms, for which the design of the equipment and the choice of materials is even more stringent. Elements to be considered include stability/statics as concerns dynamic loads, smoothness of the floor, tightness of external façades and of enclosing surfaces of cleanrooms. Smooth nonporous surfaces are required, together with avoidance of molecular contamination, resistance to the intended cleaning or disinfection agents and the cleaning procedure, simple and tight integration of various fittings, efficient and rapid implementation of subsequent functional and technical changes. The ECA guidance document goes deeper into relevant requirements for all elements that are part of the design of a compliant cleanroom.

Documentation and automation

User requirement specifications (URS) are the key document to demonstrate equipment is fit for the intended use, as stated by GMP Annex 15 (2015). The ECA guidance suggests translating the URS in a technical version to be submitted to the potential equipment supplier, so to ensure the design would reflect product and quality-relevant requirements, being thus GMP compliant.

The management of documentation along the design life cycle of a new piece of equipment is also taken into consideration, with the different construction phases identified according to Good engineering practices (GEP): conceptual design, basic design/engineering, and detailed design/engineering.

The extensive use of data to monitor and document pharmaceutical manufacturing process represents another area of great attention. Requirements relevant to the design of validated computerised systems, data protection and data integrity must be kept in mind. ECA’s experts highlight the need to carefully delimitate areas subject to validation and their extention, particularly with reference to automated systems. Differences between qualification and validation of automated systems are also addressed, including equipment that might either be defined as “computerised” or “automated” system. Regulatory reference for validation is GAMP 5, while qualification refers to Annex 15.


EDQM, the RTEMIS scheme for remote inspections and new application forms for CEPs

April 9, 2022 , , , , , , , , , , , , , , , , , , , , , , , , , , , , , ,

by Giuliana Miglierini

Starting in 2022, the Real-Time Remote Inspections (RTEMIS) programme, established by the European Directorate for the Quality of Medicines & HealthCare (EDQM) as a pilot in November 2020 to provide a tool to face travel restrictions due to Covid-19, has turned permanent. Companies applying for Certificates of suitability to the monographs of the European Pharmacopoeia (CEPs) may thus receive a notification for a RTEMIS inspection, as a part of the activities of the EDQM. The Directorate is responsible in cooperation with the participating agencies, for assessing the GMP compliance and CEPs applications relative to manufacturing sites of active pharmaceutical ingredients (APIs). The final GMP certificate issued from the NCA incorporates, following the positive closure of a remote inspection clearly states that the inspection was performed as a “distant assessment”.

Companies can adhere to the RTEMIS programme on a voluntary basis; the tool will complement the other modalities available to the EDQM to inspect manufacturers of pharmaceutical active ingredients, i.e. on-site inspections and documentation-based GMP assessment. As for on-site inspections, RTEMIS is also subject to the payment of fees. According to the Directorate, remote inspections cannot replace the on-site ones in terms of value and effectiveness, but many prove useful to assess GMP compliance for companies which have been already inspected. The RTEMIS scheme will thus form the third pillar for the supervision of GMP compliance of API manufacturers registered in the EDQM’s CEP scheme.

To qualify for an RTEMIS inspection, the concerned company should make available a suitable IT infrastructure and hardware to support the remote interaction with the EDQM’s team. To this regard, the notification letter will also include details about the expected infrastructural requirements; interested companies can contact the EDQM HelpDesk for further information.

The pilot phase to validate the RTEMIS scheme for remote inspections ran by the EDQM with reference to several manufacturing sites in India, selected on the basis of their GMP compliance history and a risk assessment, and which participated to the project on a voluntary basis. According to EDQM, suitable Corrective and Preventative Action Plans were developed by the inspected companies to address minor and major deficiencies identified during the inspections, leading to a degree in GMP conformity that the Directorate indicates as “satisfactory”.

Key factors for remote inspections

The pilot phase of the RTEMIS programme closed at the end of 2021 and led to the identification of several key factors to be respected in order to guarantee the success of remote inspections. During this period, RTEMIS inspections ran by the EDQM with the support of European Economic Area (EEA) inspectorates.

At a minimum, an appropriate IT infrastructure and hardware at the inspected site should be available to support a stable connection with the EDQM’s inspectors. During the preparatory phase of the inspection great attention should be paid to choose a suitable web conference application, running connectivity tests before the established date for the inspection, as well as a secure platform for the sharing of all relevant documentation (often in advance of the inspection). The selection of the IT tool to be used can benefit of the initial support from the EDQM’s IT department. Another important feature that should be always kept in mind refers to the possibility to run parallel sessions of discussion between the inspectors’ team and the staff and experts of the inspected company.

In remote inspections, participants are often located far apart, for example EDQM’s inspectors based in Strasbourg (F) may interact with an inspected company in China or India. The great difference in time zone requires a great flexibility on both sides to set the schedule for connections. Flexibility is also needed to face the many challenges posed by remote inspections, often requiring approaches significantly different from the traditional ones used for on-site inspections. Digital connected tools such as smart glasses may be used, for example, by the staff at the inspected site to allow inspectors to perform a real-time virtual tour of the plants.

New forms for CEPs applications

The EDQM also updated all forms to be used to apply for the release of Certificates of Suitability to the European Pharmacopoeia monographs. The forms to be used in case of a new application, revisions and sister files are available at the dedicated page of the EDQM’s website

The revision is intended to facilitate the transfer of data the EDQM’s new IT tools, which have been implemented starting 1 April 2022. The new forms also better reflect data available within the EMA’s SPOR – Organisation Management Services (OMS) system, including company details, names and addresses. The EDQM recommend communicating other additional data linked to the ones present in EMA’s website, i.e. the ORG_ID and LOC_ID.

 Applicants should also insert localisation data for their manufacturing sites, in the form of GPS coordinates. To this instance, the internationally recognised WGS 84 system should be used, using latitude and longitude (with the + and – symbols) expressed in degrees to at least five decimal places, as described in policy document PA/PH/CEP (10) 118.

Tables detailing the marketed medicinal products containing a certain active substance and the respective list of accepted Active Substance Master Files/Drug Master Files (ASMFs/DMFs) have been also updated, in order to better reflect the commercialisation history of the products and the quality assessments already performed.

EDQM also advises companies to use the form “change of contact details” as the preferred tool to inform the Directorate about the change of the contact person for one or more CEP dossiers (ref. policy document PA/PH/CEP (10) 86).

EDQM’s website is also undergoing a complete revision, aimed to improve the user experience and to ensure a quick and easy access to all relevant information. The new version of the site will be accessible from the same web address www.edqm.eu and is expected to be online in April 2022.