Cheryl Barton is director of PharmaVision, 

Cheryl Barton

Landkarte *** Europa | Image credit: ©beugdesign - Stock.adobe.com

In March 2025, the European Medicines Agency (EMA) published a three-year work plan (2025–2027) for the Good Manufacturing and Distribution Practice (GMDP) Inspectors Working Group (IWG), focusing on the Network Strategy and Regulatory Science Strategy (RSS) goals. The work plan emphasized the importance of supply chain integrity and resilience, product quality, and the potential impact of new manufacturing technologies on the supply chain(1). The overall objectives of the plan included:

Analyze the possible implications of new manufacturing technologies to regulate the new supply chains needed

Enhance inspector capacity building at the European Union and international levels

Enhance traceability, oversight, and security in the human/veterinary medicine supply chain

Encourage supply chain resilience and review long-term risks resulting from dependency on a limited number of manufacturers and sites

Reinforce the responsibility for product quality by harmonising and reinforcing guidance (1).

On 7 July 2025, the GMDP-Inspectors Working Group, in cooperation with the Pharmaceutical Inspection Co-operation Scheme (PIC/S), launched a public consultation regarding the revision of the EU’s good manufacturing practice (GMP) guidelines

, Annex 11 and Chapter 4, along with the introduction of a dedicated Annex 22 on artificial intelligence (AI) (2). The revision of Chapter 4 and Annex 11 will expand the scope of documentation requirements and raise the bar on digital system validation and oversight. Whilst the addition of Annex 22 sets clear boundaries for the safe and acceptable use of AI and machine learning (ML) in a regulated GMP environment, it will help to ensure regulatory harmonization in the manufacturing of medicines (3).

The revised Chapter 4 includes changes that emphasize the importance of documentation in GMP compliance and support the adoption of new technologies, hybrid solutions, and services for managing documentation (4). Risk-management principles are now central and integrated into the data governance system to ensure the accuracy, integrity, availability, and readability of documents in all formats. All documentation, whether in text, image, video, or audio form, must remain complete and legible throughout its lifecycle. The guideline also clarifies the requirements for managing electronic records, signatures, and data integrity, and aligns with the recent revision of Annex 11.

The revised Annex 11 establishes improved requirements for managing the entire lifecycle of computerized systems, requiring that quality risk management (QRM) principles be thoroughly applied at all stages to ensure product quality, patient safety, and data integrity. The updated provisions strengthen obligations related to defining and continuously maintaining system requirements, as well as overseeing suppliers and external service providers (5). Additionally, the Annex enhances controls for ensuring data integrity, audit trails, electronic signatures, system security, as well as backup and archiving.

The new annex on AI sets requirements for using AI/ML in manufacturing active substances and medicinal products (6). It details how to select, train, and validate AI models and places emphasis on defining the intended use of the model, establishing performance metrics, ensuring the quality of training data, and managing test data. Annex 22 requires ongoing oversight of AI systems, including change control, performance monitoring, and procedures for human review when needed. The document does not apply to generative AI and large language models, and these models should not be used in critical GMP applications.

By 2026, the updates to Chapter 4 and Annex 11, along with the introduction of Annex 22, will bring about a significant transformation in European GMP regulations for the pharmaceutical industry. These revisions could enforce tighter controls and redefine standards, setting the stage for a new era in GMP compliance.

In response to these changes, pharmaceutical companies will need to review their documentation processes and platforms and reevaluate and validate their legacy systems (such as quality control, laboratory information management systems, or commercial off-the-shelf applications) to ensure compliance with the updated traceability and audit trail requirements. Overall, organizations will need to plan for system lifecycle governance and supplier management. If activities are outsourced, they must ensure regulatory accountability remains in-house. Additionally, companies deploying AI technologies in a GMP environment will need to develop robust internal capabilities to ensure data science governance and validate AI models (3).

The pharmaceutical industry must act swiftly to align with the evolving regulatory expectations. The stakeholder consultation closes on October 7, 2025, so there is still time to submit opinions on the three documents that will shape the future of GMP in Europe (7–9).

The 3-Year Work Plan for the Inspectors Working Group 2025-2027

Stakeholders’ Consultation on EudraLex Volume 4 - Good Manufacturing Practice Guidelines: Chapter 4, Annex 11 and New Annex 22. 

Preparing for EMA's 20226 Good Manufacturing Practice (GMP) Revisions: Chapter 4, Annex 11 & Annex 22.

Cheryl Barton is founder and director of PharmaVision, Pharmavision.co.uk.

Articles

The deadline for stakeholder consultation submissions on the new and updated regulations is Oct. 7, 2025. 

Stakeholders’ Consultation on GMP Annex 11, Chapter 4, and New Annex 22 

The European Medicines Agency (EMA) is encouraging the use of new approach methodologies (NAMs) as an alternative to animal testing in the assessment of safety and efficacy of new medicines during non-clinical development (1). In the European Union (plus Norway), 8.48 million uses of animals for scientific purposes occurred in 2022 (2). In most countries, the use of animals for some safety tests is required. For instance, 

 requires marketing authorisation holders to integrate the 3Rs (replacement, reduction, refinement) and welfare standards for the treatment of animals in all aspects of the development, manufacture, and testing of medicines (3). In October 2023, EMA published a concept paper on the revision of the guideline on the principles of regulatory acceptance of 3Rs testing approaches (4). Such alternative methods as NAMs can be highly effective at modelling individual aspects of safety and efficacy and should help to reduce and/or replace animal testing in line with the 3Rs principles (5). These principles include:

Availability of a defined test methodology (protocol, endpoints)

Description of the proposed NAM context of use (i.e., the circumstances in which the NAM is applied in the development and assessment of human or veterinary medicinal products)

Establishment of the relevance within that particular context of use

Demonstration of NAM reliability and robustness (5).

NAMs will need to be phased in. EMA is working with NAM developers to facilitate regulatory acceptance of these methodologies through briefing meetings and discussions with its Scientific Advice Working Party. Companies can also apply for the Committee for Medical Products for Human Use qualification of NAMs and voluntarily submit data generated from NAMs to the EMA; however, these data can be excluded from the regulatory decision-making process (

 Regulatory interactions between the European Medicines Agency (EMA) and new approach methodologies (NAM) developers. CVMP is Committee for Veterinary Medicinal Products.

The European Federation of Pharmaceutical Industries and Associations (EFPIA) endorses EMA's actions and believes it is feasible to phase out animal testing, “providing there is cross-sector collaboration, robust funding and incentives, global harmonization and streamlined regulatory acceptance of nan-animal methods” (6). In June 2025, EFPIA published pharma-specific recommendations regarding the phasing out of animal testing for chemical safety assessment. These include:

Strengthen collaboration between industry, regulators, academia, and non-government organisations (NGOs) through targeted consortia and incentives that catalyse NAM development.

Improve data sharing by creating safe harbour mechanisms, secure databases, and fee waivers for exploring novel methods.

Update regulatory frameworks to recognise the “last resort” principle, incorporate flexible qualification pathways, and align the roadmap with ongoing legislative revisions.

Institutionalise regular guideline reviews (e.g., every three years) to continuously phase out legacy animal tests and accelerate acceptance of new methods.

Build public trust by raising awareness of cutting-edge, non-animal approaches that can yield superior, more human-relevant safety data (6).

NAMs encompass a range of techniques, such as high-throughput screening, 

 modelling, often utilizing artificial intelligence and machine learning. NAMs focus on identifying changes in biological function that occur before outward symptoms, allowing for a more mechanistic understanding of the biomolecular interactions along the pathway toward harm (7). For instance, adverse outcome pathways (AOPs) enable tiered testing at multiple biological levels, increasing the overall predictive power and providing more accurate evidence-based approaches for hazard and risk assessment (

). AOPs could potentially reduce the levels of drug attrition rates resulting from undesired effects later in product development (8–10).

Furthermore, some organoids, organ-on-a-chip (OOC) technologies, and multi-organ microphysiological systems can simulate native organ structure and function, providing a cost-effective and accurate model for pharmacokinetics, pharmacodynamics, and toxicity studies (11). OOCs allow the rapid screening of multiple drug development candidates on a single chip, improving regulatory safety assessments and reducing the number of animal-based screens (12). In addition, several 

 cell biotransformation assays (CTAs) can assess carcinogenicity and exhibit good correlation with rodent bioassays. The CTAs can detect genotoxic and non-genotoxic carcinogens and provide a quick and more cost-effective alternative to 

 carcinogen models (13). Large pharma companies, such as AstraZeneca, GSK, and Pfizer, have established partnerships with OOC and CTA companies to harness this technology in their preclinical drug development programmes (14–16).

There is a paradigm shift toward a more mechanistically driven approach to toxicity testing for safety assessment. During the past decade, significant progress has been made in the development and evaluation of AOPs, OOCs, and 

 modelling technologies that enable risk-free biomedical testing and reduce the need for animal-based models (2). Stakeholders will need to work together to phase in NAMs and phase out animal testing (6). The regulators are keen to embrace new methodologies that replace, reduce, or refine the use of animals in research and encourage NAM developers to share their data and knowledge to facilitate the regulatory acceptance of these methodologies and ensure the NAMs are scientifically sound and useful in regulatory decision-making for the future (1).

Regulatory Acceptance of New Approach Methodologies: How to Interact with EMA

Directive 2010/63/EU of the European Parliament and of the Council of 22 September 2010 on the Protection of Animals Used for Scientific Purposes Text with EEA Relevance

Concept Paper on the Revision of the Guideline on the Principles of Regulatory Acceptance of 3Rs (Replacement, Reduction, Refinement) Testing Approaches

Guideline on the Principles of Regulatory Acceptance of 3Rs (Replacement, Reduction, Refinement) Testing Approaches.

EFPIA Recommendations on Phasing Out Animal Testing for Chemical Safety Assessments.

Adverse Outcome Pathway Networks as the Basis for the Development of New Approach Methodologies: Liver Toxicity as a Case Study.

Pathways-Based Approach Across the Biosciences–Toward Application in Practice

Adverse Outcome Pathways Can Drive Non-Animal Approaches for Safety Assessment

Organoids and Organs-on-Chips: Recent Advances, Applications in Drug Development, and Regulatory Challenges

Liver-on-a-Chip: Considerations, Advances, and Beyond

Cell Transformation Assays for Prediction of Carcinogenic Potential: State of the Science and Future Research Needs.,

Medera’s Novoheart Releases Latest Cardiac Screening Innovation, CTScreen v1.5 to Advance High-Throughput, Automated Human-Based Drug Testing

GEN. Engineered Heart-on-a-Chip Replicates Drug Responses Found in Adult Humans. 8 Aug. 2019.

Scientists Mimic Human Organs on Microscopic ‘Chips’ That Enable Drug Testing

Cheryl Barton, PhD, is founder and director of PharmaVision, Pharmavision.co.uk.

The European Medicines Agency (EMA) is promoting new approach methodologies (NAMs) to reduce animal testing in drug development, aligning with the 3Rs principles of replacement, reduction, and refinement. NAMs, including high-throughput screening, in vitro assays, and in silico modeling, offer mechanistic insights into drug safety and efficacy. The European Federation of Pharmaceutical Industries and Associations (EFPIA) supports phasing out animal testing through collaboration, funding, and regulatory updates. Techniques like organ-on-a-chip and cell transformation assays are advancing, providing cost-effective, human-relevant models for pharmacokinetics and toxicity studies.

EMA is phasing out animal testing and is asking pharmaceutical companies to use new approach methodologies.

EMA Encourages Use of New Approach Methodologies to Reduce Animal Testing 

The mRNA or messenger Ribonucleic Acid white text for medical or outbreak concept 3d rendering | Image Credit: ©niphon - adobe.stock.com

During the past decade, messenger RNA (mRNA)-based therapeutics have shown great promise in immunotherapy (e.g., cancer and vaccines), and non-immunogenic applications (e.g., protein replacement/supplementation therapy, regenerative medicine therapy, and genetic editing) (1). Several types of mRNA-based vaccines have emerged, namely non-replicating linear mRNAs (NRM), self-amplifying mRNAs (saRNAs), and circular mRNAs (circRNAs). Each mRNA type offers advantages and disadvantages (

 Types of messenger RNA (mRNA)-based vaccines. LNP is lipid nanoparticle.

Technological advances in the design and delivery of mRNA have catalysed the rapid development of mRNA COVID-19 vaccines by Pfizer-BioNTech and Moderna Therapeutics (3–4). Now, mRNA vaccines can be quickly created against different antigenic targets by changing the mRNA sequence, and companies are looking beyond COVID-19 at other infectious diseases, including Epstein-Barr virus, influenza, and Zika 

 In May 2024, the US Food and Drug Administration (FDA) approved Moderna’s next-generation base-modified mRNA-lipid nanoparticle (LNP) respiratory syncytial virus (RSV) vaccine mRESVIA (mRNA-1345) in adults aged 60 years and older with lower respiratory tract disease (5).

 Immunogenic messenger RNA (mRNA) vaccines and therapies in development.

In addition, manufacturers have begun to evaluate next-generation vaccine modalities in cancer (6). Although therapeutic mRNA-based cancer vaccines have yet to be approved, encouraging results have been reported by CureVac with CVGBM, its LNP-SAM mRNA vaccine CV0905010 in Phase I for glioblastoma (7). Some companies are combining mRNA vaccines with programmed cell death protein 1 (PD-1) inhibitors to activate the immune system and elicit tumour-specific T-cell responses. These include BioNTech/Regeneron with BNT111 plus Libtayo (cemiplimab) for patients with melanoma and Merck & Co./Moderna with LNP-delivered mRNA-4157/V940 in combination with Keytruda (pembrolizumab) also for melanoma (8–9).

Historically, production costs for mRNA therapies have been high, stability has been poor, and products have been associated with high immunogenicity. However, new strategies in mRNA modification, purification, and sequence design have led to the development of next-generation mRNA-based therapies 

In 2018, following decades of research and development, the first RNA-based therapy, Onpattro (patisiran), from Alnylam Pharmaceuticals reached the market (10). The LNP-encapsulated small interfering RNA (siRNA) was approved by FDA for the treatment of hereditary transthyretin amyloidosis (ATTR), and this opened the door for mRNA-based drugs in many applications. Numerous mRNA technologies are currently under evaluation at various stages of drug development, including Intellia Therapeutics NTLA-2001, an 

 gene-editing clustered regularly interspaced short palindromic repeats (CRISPR) agent and associated Cas9 endonuclease (CRISPR-Cas9) therapy that uses an mRNA-LNP system to inactivate the TTR gene to treat ATTR amyloidosis (11).

 Non-immunogenic mRNA therapies in development.

European biotech is leading the field in mRNA technologies

Several European biotech companies are leading the field in mRNA technology, including BioNTech, CureVac, eTheRNA, and Ethris. These companies compete with innovative biotech companies in the United States, such as ADARx Pharmaceuticals, Dicerna Pharmaceuticals, Greenlight Biosciences, Orna Therapeutics, Regulus Therapeutics, and Sirnaomics, as well as Abogen Biosciences and Stemirna Therapeutics in Asia.

. German biotech, BioNTech, is developing next-generation personalised therapies, focusing on oncology, cerebral diseases, and COVID-19 vaccines. It co-developed Comirnaty, the COVID-19 vaccine in partnership with Pfizer, and is gearing up for the commercial launch of its variant-adapted COVID-19 vaccine for the 2025/2026 season, pending regulatory approval. It is also developing BNT165e, an RNA-based vaccine for the prevention of 

 However, FDA has placed the Phase I/II trial on hold, and BioNTech is taking actions to address FDA’s requests and will work with the agency to assess the next steps.

In oncology, the company is leveraging its proprietary cancer vaccine platforms FixVac and iNeST to tailor treatment, and its RiboMab, RiboCytokine, and intratumoural immunotherapy platforms to target tumours directly. It is currently developing multivalent mRNA cancer Immunotherapeutics, which include BNT111 (Phase II, advanced melanoma), BNT113 (Phase II, metastatic head and neck cancer), BNT116 (Phase II metastatic NSCLC), BNT142 (Phase I/II, multiple solid tumours), and combination therapies, such as mRNA-based cancer immunotherapies for the early, adjuvant setting, and an anti-PDL1/ vascular endothelial growth factor A (VEGF-A) bispecific antibody candidate BNT327/PM8002 for the treatment of advanced solid tumours.

The company is developing modified RNA that includes methyl-pseudouridine modifications, nucleoside modifications, saRNAs, and trans-amplifying mRNA, with an improved immunogenetic profile. It is also developing novel delivery formulations to improve the targeted delivery of mRNA; these include lipoplex, LNPs, and polyplexes (12).

BioNTech has collaborations with Bayer, Genentech, Genevant, Fosun Pharma, Pfizer, and Regeneron. In February 2025, BioNTech completed the acquisition of Biotheus to obtain full global rights to BNT327 and all other pipeline candidates for US$800 million, plus additional performance-based payments of up to US$150 million (12). It signed a $1.5 billion strategic partnership in June 2025 with Bristol Myers Squibb to co-develop and co-commercialize next-generation bispecific antibody BNT327 targeted to PDL1 and VEGF-A for multiple solid tumours (13).

 German biopharmaceutical company CureVac N.V. was founded in 2000 and specialises in the development of mRNA-based vaccines and therapeutics. CureVac leverages its proprietary mRNA technology, with advanced omics and computational tools, to design and develop off-the-shelf and personalised precision immunotherapies to treat cancer (14). The company has been issued more than 1000 patents and is currently involved in patent litigation with BioNTech regarding the application of poly-A tail technology in mRNA constructs (15). In the US, seven patents are being assessed, and the trial is expected to start in September 2025.

CureVac has a broad product portfolio, which includes CVGBM, an off-the-shelf precision immunotherapy in Phase I for glioblastoma, and CVHNLC, a multiepitope mRNA-based precision immunotherapy in Phase I for squamous non-small cell lung cancer. It is also developing prophylactic vaccines for urinary tract infections and influenza/COVID-19, the latter being co-developed by GlaxoSmithKline (14).

The company has established collaborations with myNEO Therapeutics and MD Anderson Cancer Center in the oncology field, CRISPR Therapeutics on the development of gene-based medicines, and Acuitas Therapeutics to develop novel LNP delivery systems and LNP-formulated mRNA candidates. In February 2023, CureVac closed a US$250 million public offering and has a strong cash position to continue the development of its promising pipeline (14, 16).

. Belgium-based eTheRNA was founded in 2013 and developed mRNA and LNP technologies. In 2022, the company raised €39 million in a series B round that included the participation of Chien and Dekkers, co-founders of Dropshot Therapeutics. The company’s lead programme is a triple combination mRNA cancer vaccine that targets cytokines IL-21 and IL-7 and the membrane-bound co-stimulator 4-1BBL, which has shown promising results in triple-negative breast cancer (17). The LNPs provide targeted delivery of the mRNA directly to tumours, resulting in strong immune activation, tumour elimination, and durable immunological responses.

In January 2025, eTheRNA established a collaboration with Dropshot Therapeutics to develop RNA-based therapeutics for multiple new drug candidates across several indications in cardiac and renal diseases. The company will receive up to US$950 million, which includes an upfront payment plus milestone payments and tiered royalties following product launch (18). eTheRNA is working with Hasselt University on autoimmune mRNA therapeutics and Almirall on a multi-target alliance in medical dermatology (19–20).

Ethris GmbH was founded in Germany in 2009 and is a clinical-stage biotechnology company developing next-generation RNA therapeutics and vaccines based on non-immunogenic messenger RNA (SNIM RNA) and lipidoid nanoparticle (SNaPL). Its lead candidate, ETH47, is a broad-spectrum antiviral with a virus and mutation-independent mechanism, encoding interferon lambda. The product uses the SNaPL technology for inhalation or intranasal delivery and can be combined with existing antivirals to improve clinical outcomes in respiratory diseases such as uncontrolled asthma. In May 2025, the company was awarded a €10 million EU4Health Grant to support clinical development and expand antiviral applications of ETH47 and US$5 million from Coalition for Epidemic Preparedness Innovations (CEPI) and US$5 million from the Gates Foundation to develop its next-generation RNA therapeutics and vaccines (21–23). Etheris has collaborations with Lonza to develop spray-dried mRNA vaccines for respiratory diseases and HEQET Therapeutics to develop RNA-based therapeutics for heart attack and heart failure (24-25).

The future of mRNA vaccines and therapies

The global mRNA therapeutics and vaccines market is estimated at US$64.5 billion in 2024 and is forcasted to reach US$71.7 billion by 2034, exhibiting a compound average growth rate of 1.2% during 2025–2034 (26). The market will be driven by the rising incidence of chronic diseases and increasing awareness of the widespread potential of mRNA technology, the emergence of next-generation immunotherapy and non-immunotherapy drugs, and vaccines. Leading pharma and biotech companies, such as AstraZeneca, Daiichi Sankyo, GlaxoSmithKline, Moderna, Pfizer, Sangamo Therapeutics, and Sanofi, have made significant investments in this field, and numerous mRNA therapies and vaccines have entered clinical development (27).

To date, mRNA-based products have demonstrated great potential in combating a broad range of diseases either as monotherapies or in combination with approved agents. mRNA technology is constantly evolving, and the next-generation circRNA and saRNAs are likely to supersede mRNA linear formats in vaccine development due to increased immunogenicity and durability. However, the successful implementation of these next-generation products will rely on the development of targeted delivery vehicles and may also require additional modification to the mRNA molecule to improve safety and efficacy.

Progress and Prospects of mRNA-based Drugs in Pre-clinical and Clinical Applications

Current Landscape of mRNA Technologies and Delivery Systems for New Modality Therapeutics. 

Pfizer’s COVID-19 Vaccine Secures First Full FDA Approval.

Moderna Receives Full U.S. FDA Approval for COVID-19 Vaccine Spikevax.

Mullard, A. FDA Approves mRNA-based RSV Vaccine. 

Dolgin, E. Personalized Cancer Vaccines Pass First Major Clinical Test. 

CureVac’s CVGBM Cancer Vaccine Induces Promising Immune Responses in Phase 1 Study in Glioblastoma Presented at the ESMO 2024 Congress

BNT111/Cemiplimab Combo Significantly Improves ORR in Unresectable Melanoma

Moderna & Merck Announce 3-Year Data For mRNA-4157 (V940) in Combination With KEYTRUDA(R) (pembrolizumab) Demonstrated Sustained Improvement in Recurrence-Free Survival & Distant Metastasis-Free Survival Versus KEYTRUDA in Patients With High-Risk Stage III/IV Melanoma Following Complete Resection

Alnylam Pharmaceuticals Press Release | Aug 10, 2018 | Alnylam Announces First-Ever FDA Approval of an RNAi Therapeutic, ONPATTRO™ (patisiran) for the Treatment of Hereditary Transthyretin-Mediated Amyloidosis in Adults

Intellia Therapeutics Announces First Patient Dosed in the Phase 3 MAGNITUDE Study of NTLA-2001 as a Single-Dose CRISPR-Based Treatment for Transthyretin Amyloidosis with Cardiomyopathy.

BioNTech Announces First Quarter 2025 Financial Results and Corporate Update | BioNTech

BioNTech and Bristol Myers Squibb Announce Global Strategic Partnership to Co-Develop and Co-Commercialize Next-generation Bispecific Antibody Candidate BNT327 Broadly for Multiple Solid Tumor Types.

CureVac Announces Financial Results for the Fourth Quarter and Full-Year 2024 and Provides Business Update.

CureVac Receives Additional Positive Validity Decision from European Patent Office in Ongoing Litigation Against BioNTech SE

CureVac Announces Closing of $250 million Follow-on Public Offering of Common Shares

The Discovery of mRNA Therapy that Eradicates Tumours in Preclinical Trials

Strategic Multi-target Collaboration with Dropshot Therapeutics.

Etherna and Hasselt University Announce Autoimmune mRNA Therapeutics Research Collaboration

Almirall and Etherna Enter into a Multi-target Alliance to Develop mRNA-based Therapies in Medical Dermatology.,

$5M CEPI Grant for Spray-dried Mucosal Vaccines.

mRNA Vaccines and Therapeutics Market Report and Forecast 2025-2034.

Top 8 mRNA Vaccines and Therapeutics Companies

mRNA technologies offer great promise in immunotherapy and non-immunogenic applications.

Looking Beyond mRNA-based COVID-19 Vaccines to Innovative Therapeutics

On 14 Apr. 2025, the European Medicines Agency (EMA) published strategic recommendations designed to strengthen the supply chain of radiopharmaceuticals (1). In the recommendations, the Executive Steering Group on Shortages and Safety of Medicinal Products (MSSG) highlighted key areas of vulnerability and proposed measures to mitigate the impact of shortages in the European Union (EU).

Radiopharmaceuticals are specialised drugs that contain radioactive isotopes and are used primarily in nuclear medicine. The production and distribution of radiopharmaceuticals involves several critical processes that must adhere to stringent regulatory guidelines to ensure the safety and efficacy of these products (2). As of 2024, all radiopharmaceutical products are considered medicines in the EU, and industrially prepared products must be authorized as pharmaceuticals (3). However, country-level regulation is diverse, and the different regulatory and Health Technology Assessment (HTA) systems have led to significant differences in the use and availability of radiopharmaceuticals across the EU (4–5).

Demand for radiopharmaceuticals increasing

Radiopharmaceuticals play important roles in medical imaging, diagnosis, and treatment. Several radiopharmaceuticals have received regulatory approval for therapeutic use, and many more are in clinical development (

). The global radiopharmaceutical market is estimated to be worth US$6.97 billion in 2024 and is forecast to reach US$11.06 billion by 2034, as market demand increases and innovative agents reach the market (6).

 Regulatory-approved radiopharmaceuticals for therapeutic use. Modified from KPMG. Leveraging Opportunities in Radiopharmaceuticals. Kpmg.com. 21 Mar. 2025.

Whilst the demand for radiopharmaceuticals is steadily increasing, the manufacturing capacity in Europe is limited, and many research reactors are ageing (8).

Manufacture of radiopharmaceuticals is complex

The production of radiopharmaceuticals relies on stable isotopes and other materials, which are mainly sourced from China, Russia, and other geopolitically sensitive areas (9). Importantly, high-assay-low-enriched uranium (HALEU), used as fuel for research reactors, is currently not produced in the EU and can only be imported from Russia or the United States. Additionally, the supply chain of these medicines, including how to transport them safely, is complex (1).

Most radiopharmaceuticals used for diagnostic purposes are produced at the time of use because they begin to decay the moment they are made (10). Manufacturers are unable to stockpile radioisotopes, which means that small fluctuations in the global supply of some isotopes can have a significant impact on manufacturing. As a result, strong supplier relationships and risk-based plans for transporting raw materials and finished radiopharmaceuticals are essential (10).

Large pharma companies, such as Bayer AG, Bracco Imaging, Cardinal Health, Curium Pharma, Eli Lilly, Lantheus Holdings, Novartis AG, and Nordion, provide radiopharmaceuticals to healthcare facilities that include hospitals, ambulatory surgical centres, clinics, and specialty hospitals (6). Companies are forming partnerships with contract development and manufacturing organisations (CDMOs) and other manufacturers to expand their reach and ensure a reliable supply chain.

MSSG recommendations for radiopharmaceuticals

To mitigate supply chain issues, the MSSG recommends:

enhancing domestic production capabilities, including the development of EU-based HALEU enrichment and metallization facilities

continuation and expansion of the European Radioisotope Valley Initiative (ERVI), alongside optimizing existing production installations

harmonization of transport procedures and extended monitoring to additional radioisotopes, ensuring preparedness for rising demand

diversifying sources of key materials to reduce geopolitical risks

investing in modernizing and expanding EU-based production facilities

enhancing collaborative efforts among Member States for coordinated responses (1, 11).

The MSSG has provided specific recommendations and invited EU Member States to assess national supply chains, address transport issues, include new radiopharmaceuticals in horizon scanning activities, and provide regulatory support (12). The recommendations also encourage EMA to offer regulatory support, assist Member States with horizon scanning, and coordinate related activities to ensure efficiency and avoid duplication of efforts (12). All stakeholders are invited to cooperate and share relevant information to help secure the EU supply of medical radioisotopes.

The ERVI is reviewing the EU's production capacity for metallic HALEU. It is also looking at ways to enhance the production of enriched stable isotopes, strengthen medical radionuclide production, expand the European medical radionuclide programme, and develop more reliable monitoring of supply and demand (1).

The Euratom Supply Agency (ESA) is responsible for securing the supply of source materials for radioisotopes production and is involved in theStrategic Agenda for Medical Ionising Radiation Applications, or SAMIRA. This is a comprehensive action plan to support safe, high-quality, and reliable use of radiological and nuclear technology in healthcare (13). ESA also monitors the production chain of medical radioisotopes through the European Observatory on the Supply of Medical Radioisotopes.

Given the increasing demand for isotopes and the geopolitical uncertainties surrounding supply, diversification is essential (9). The European Association of Nuclear Medicine welcomed the EMA's recommendations and was “pleased to see such a political commitment to the supply of medical radioisotopes at the highest level. As the demand for radiopharmaceuticals grows, ensuring their consistent availability is paramount for patient care across Europe” (12).

The European Parliament has already been proactive in addressing supply chain issues associated with the production of APIs and finished medicines (14), and it is now up to the MSSG to align radiopharmaceutical supplies with the EU demands through the Medicine Shortages Single Point of Contact Working Party (15).

Efforts are underway in Europe to expand stable isotope enrichment capabilities outside of Russia to help reduce dependency and enhance long-term security. In addition, new technologies are emerging that may provide alternative approaches to reactor-based production, and the construction of new research reactors, such as the PALLAS reactor in the Netherlands, will expand capacity for medical isotope production (9). However, legislative changes, such as the implementation of the Critical Medicines Act, are essential to minimize the risk of medicine shortages and safeguard the health of EU citizens moving forward (16).

Tackling Vulnerabilities in the Supply Chain of Radiopharmaceuticals in the EU

Regulatory Radiopharmaceutical Production.

Radiopharmaceuticals Landscape in Europe: Commercial and In-House Production

Radiopharmaceutical Small-scale Preparation in Europe: Will We Be Able to Harmonize the Situation

The Regulatory Landscape of Radiopharmaceuticals: Ensuring Safety and Effectiveness

Leveraging Opportunities in Radiopharmaceuticals

EMA: Recommendations Regarding Vulnerabilities in the Supply Chain of Radiopharmaceuticals

The Geopolitical Tightrope of Medical Isotope Supply: Risks and Opportunities

. LinkedIn Post. LinkedIn.com. 19 Feb. 2025

Radiopharmaceuticals: A Guide for Manufacturers

EU Takes Action to Secure Radiopharmaceutical Supply Chains

EMA’s Recommendations to Address Vulnerabilities in the Supply Chain of Radiopharmaceuticals

. euratom-supply.ec.europa.eu/ (accessed May 2025).

Overreliance on Imports of Active Pharmaceutical Ingredients

Medicine Shortages Single Point of Contact (SPOC) Working Party

EMA has published recommendations to address potential radiopharmaceutical shortages.

EMA Is Tackling Vulnerabilities in the Supply Chain of Radiopharmaceuticals

On 29 Jan. 2025, the European Parliament (EP) held a public hearing to discuss ways to support the production of APIs and finished medicines within Europe (1). The European Union (EU) faces a growing challenge in securing its supply of essential pharmaceuticals, with the majority of its APIs and finished medicines currently imported from Asia, namely India and China.

This article was published in the May 2025 issue of 

APIs play a pivotal role in the pharmaceutical industry. They are essential for the efficacy and safety of drugs. The quality of APIs directly impacts the effectiveness of the final drug product (2). Whilst the globalization of the medicines supply chain has helped to increase access to cheap, high-quality medicines, the supply chain has grown longer, more complex, and fragmented, and countries have become more reliant on overseas API suppliers (2).

The European API sector is considered highly competitive, given its technical know-how and strong workforce capacities (3). API manufacturing is an important sector, generating €60 billion per year and employing more than 150,000 people throughout Europe (3). Over the past two decades, Europe’s API manufacturing capabilities have decreased from 42% share of the market in API Drug Master Files (DMFs) in 2000 to 10% in 2023, highlighting the long-term trend of decreasing API manufacturing activity within Europe (

). There has also been a shift of small-molecule APIs and related intermediates production towards Asia, and more than 74% of the European medicine value chain depends on imports (

Figure 1: Active API Drug Master Files by region, 2000, 2023. Figure courtesy of the author

Whilst India remains the market leader in API manufacturing, China has exhibited strong growth and expanded its role in global API production, accounting for almost one-third of all DMF filings in 2023 (4). These findings underscore the importance of monitoring the pharmaceutical supply chain to understand and adapt to market dynamics and reduce any perceived threats that the EU’s reliance on API imports may have on public health in the Member States.

Figure 2: European supply chain (base 100, 2023). Figure courtesy of the author.

Reshoring pharmaceutical production in Europe and promoting geographic diversity in API manufacturing will help reduce supply chain vulnerabilities and the risk of drug shortages (5). This was the conclusion of the Environment, Public Health and Food Safety report, Potential Measures to Facilitate the Production of Active Pharmaceutical Ingredients (APIs), published in March 2023 (5). The study confirmed that reshoring would require financial support from governments to the pharmaceutical industry, but this was not the only factor. Further solutions were proposed including agreements with local chemical suppliers (e.g., key materials), the consideration of fee or tax benefits, the development of new production technologies to accelerate automation and reduce labour costs, incentives to encourage the use of environmentally friendly technologies, the creation of training and programmes to develop workforce needs, and the alignment of existing policies (6).

On 11 Mar. 2025, the European Commission (EC) took the first step in this direction and proposed the Critical Medicines Act, setting out a plan to improve medicine procurement, provide subsidies for drug production, and improve supply chains to reduce the risk of drug shortages (7). But time is running out.

The EU needs to move quickly or risk a manufacturing exodus to the US

In April 2025, the European Federation of Pharmaceutical Industries and Associations issued a stark warning that “unless Europe delivers rapid, radical policy change, then pharma research, development, and manufacturing is increasingly likely to be directed towards the [United States]” (8). The CEOs of the research-based pharmaceutical industry called for immediate action on:

adopting a world-leading regulatory framework conducive to innovation

achieving a competitive EU market that attracts, values, and rewards innovation in line with other economies at the forefront of patient care

ensuring policy coherence across environmental and chemical legislation to secure a resilient manufacturing and supply chain of medicines in Europe

strengthening rather than weakening Europe’s intellectual property provisions (8).

In the meantime, the uncertainty created by the threat of US tariffs on pharmaceuticals means there are limited incentives for pharma to invest in the EU and a significant push to relocate to the US. In the past month, several pharmaceutical companies—Eli Lilly, Johnson & Johnson, Merck, Novo Nordisk, and Novartis—have announced their plans to expand manufacturing facilities in the US (9). Whilst it may take several years for these sites to become fully operational, it sends a clear message that market dynamics have changed, and the EU will need to move quickly and invest in its pharmaceutical ecosystem, or it will fall behind and be held to ransom by overseas suppliers (8).

EP. Overreliance on Imports of Active Pharmaceutical Ingredients. Committee of Public Health. 29 Jan. 2025.

SEQENS. Enhancing Drug Development: A Comprehensive Guide to API Manufacturing. Seqens.com. 17 Jan. 2025. (accessed 15 Apr. 2025).

Medicines for Europe. EP Hearing on “Overreliance on imports of Active Pharmaceutical Ingredients (APIs)”. Committee for Public Health (SANT) European Parliament. 25 Jan 2025.

Quality Matters. Global Manufacturing Capacity for Active Pharmaceutical Ingredients Remains Concentrated. U.S. Pharmacopeia Blog. 6 Nov. 2024

CHESSMEN. Identifying the Root Causes of Observed Shortages of Medicines. 2024. Ja-chessmen.eu (accessed 16 April 2025).

ENVI. Potential Measures to Facilitate the Production of Active Pharmaceutical Ingredients (APIs). March 2023.

EC. Proposal for a Critical Medicines Act. EC.europa.eu. 11 Mar. 2025

EFPIA. Pharma CEOs Alert President von der Leyen to Risk of Exodus to the US. Efpia.eu. 8 Apr. 2025.

POLITICO. Trump Says Pharma Tariffs Will Entice Back Drug Production. They Won’t. Politico.eu. 14 Mar. 2025.

When referring to this article, please cite it as Barton, C. EU to Support the Production of APIs and Finished Medicines within Europe. 

The European Union is discussing ways to reduce Europe’s over-reliance on imports of APIs.

EU to Support the Production of APIs and Finished Medicines within Europe  

In the past two decades, significant advances in immunology have improved our understanding of immune checkpoint mechanisms and the role of T-cell receptors (TCRs) recognizing tumour antigens and tumour cell eradication (1). This knowledge has led to the development of several immune checkpoint inhibitors (ICIs) such as anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) treatments. Although ICIs have cured many cancer patients, some patients fail to respond to ICIs due to the limited presence of tumour-specific effector T cells (2).

This article was published in the April 2025 issue of 

Adoptive T-cell therapies (ACTs), which include chimeric antigen receptor T cells (CAR-T), tumour-infiltrating lymphocytes (TILs), and engineered T-cell receptor-T cells (TCR-Ts), have the potential to overcome these shortfalls. To date, six CAR-T therapies targeting CD19 or B cell maturation antigen have been approved by the regulators and have shown encouraging results in haematological cancers; however, their clinical impact on solid tumours has been modest due to antigen scarcity, tumour heterogeneity, and immunosuppression within the tumour microenvironment (TME) (3–4). Thus, companies have been exploring other ACT approaches to overcome these issues (5–6).

Engineered T-cell receptor-T cell therapies

TCR-T increases the flexibility for targeting solid tumours, particularly those with a high mutational burden (HMB). Unlike TILs, one does not need access to the primary tumour, which allows the use of upstream sources of material, for example, peripheral blood. Importantly, TCR-T cells can target inside the cell surface and recognize a broader range of epitopes than CAR-T cells and up to 90% of cellular proteins, including:

tumour-associated antigens (TAAs) that are over-expressed in cancer cells compared with normal tissues. For example, tissue differentiation antigens (TDAs) such as melanoma antigen recognized by T 1 (MART-1) and gp100, and cancer germline antigens (CGAs) such as melanoma-associated antigen A (MAGE-A) protein family, New York oesophageal squamous cell carcinoma-1 (NY-ESO-1), and preferentially expressed antigen in melanoma (PRAME)

tumour-specific antigens (TSAs) or neoantigens (NAs) that are exclusively expressed in tumour cells. For example, TP53 and Kirsten rat sarcoma virus (KRAS)

viral antigens, for instance, antigens stemming from viral-induced cancers such as Epstein-Barr virus (EBV), human papillomavirus (HPV), hepatitis B virus (HBV), and Merkel cell polyomavirus (MCPyV).

Importantly, TCR-T cells exhibit high antigen sensitivity that could result in improved tumour cell detection and removal, and they are associated with a high level of T cell persistence (7). More than 30 clinical trials are underway exploring the potential of TCR-T cells in haematological and solid tumours (

Table I. TCR-T cell therapies in clinical development.

Allogeneic “off-the-shelf” solutions are emerging

The use of gene editing in autologous (patient-derived) CAR-T and TCR-T cell therapies is dictated by the compatibility of the highly polymorphic HLA molecules between donors and recipients, which can lead to graft-versus-host disease (GVHD) and rejection. Academic researchers and biotechs are looking at ways to generate “off-the-shelf” or allogeneic (universal) solutions using virus-specific T cells, lipid-restricted (CD1) T cells, MR1-restricted T cells, and γδ-TCR T cells (8). This approach could enable TCR-T therapies to be produced more cost-effectively and be made available to a broader patient population. For instance, researchers at Princess Máxima Center for Paediatric Oncology, Utrecht, The Netherlands, have engineered allogeneic cord blood-derived CD8+ T cells with a specific TCR targeting the tumour-associated antigen WT1 to achieve high efficiency and potent cytotoxicity against AML cells (9).

European biotech investing in TCR-T therapies

New TCR-T cell therapies look promising in the treatment of haematological and solid tumours.