Despite many years and efforts for the development of new antibiotics, antimicrobial resistance (AMR) still represents a major health challenge. According to the World Health Organisation (WHO), AMR is directly responsible for 133,000 deaths each year in the WHO European Region, plus an additional 541,000 indirect deaths. The estimated annual costs of dealing with AMR in the EU and European Economic Area is approx. €11.7 billion.
Antimicrobial resistance is characterised by the target microorganism developing mutations that render it impervious to available treatments. Among the most worrisome micro-organisms are the bacteria Klebsiella pneumoniae, often resistant to last-resort carbapenem antibiotics, Escherichia coli, which has developed resistance to fluoroquinolone antibiotics, and methicillin-resistant Staphylococcus aureus. The spread of antibiotic-resistant bacteria is of particular concern with regard to hospital infections, as it increases the risk of worse clinical outcomes for patients who are already suffering from severe conditions, such as cancer or immunological diseases.
The failure of the pharmaceutical industry to develop new antibiotics at sustainable costs has attracted attention to phage therapy, a new approach for the Western world that actually has an history spanning over a hundred years.
What are bacteriophages
Phage therapy is based on the use of the viruses known as bacteriophages, or phages. These are the most abundant commonly occurring natural viruses, and play a key role in controlling and regulating bacterial populations and ecosystems. Phages are also present in the human body, and are characterised by their ability to specifically infect only certain bacterial strains. Phages are harmless to humans as they do not infect human cells.
Therapeutic phages replicate using a lytic cycle, meaning that upon infecting bacterial cells, they cause lysis of the host cells in order to spread progeny. This prevents the diffusion of the bacterial infection. According to the WHO, phage therapy does not affect the normal human microbiota because the viruses only attack specific pathogenic bacteria. This is fundamental for the safety of the phage treatment, which does not cause significant side effects.
These characteristics make phages a form of “personalised medicine”. They can be used as monotherapy, with one phage type specifically directed against the target bacterial strain, or as a combination of different phages to address complex infections involving different bacteria. Phage therapy can also be used alongside antibiotics to overcome antibiotic resistance.
Phage therapy has been widely used in Eastern European countries since the beginning of the 20th century. These viruses were discovered in 1917 and soon found application to treat infections, but in Western countries their use rapidly declined after the discovery of penicillin. Conversely, phage therapy remained a common treatment in the Soviet Union and still remains so in many Eastern European countries today.
Many clinical trials on phage therapy have been launched in the West in recent years. One of the more significant initiatives refers to a retrospective observational analysis of the first 100 consecutive cases of personalised phage therapy of difficult-to-treat infections, those results were published in 2024 in Nature Microbiology. The project covered the period Jan. 2008 – Apr. 2022 and was coordinated by a Belgian consortium, with involvement of 35 hospitals, 29 cities and 12 countries. The results showed clinical improvement and eradication of the targeted bacteria in 77.2% and 61.3% of infections, respectively.
The new European regulatory guidelines
In the Western world, phage therapy has emerged in recent years as a potential solution to antimicrobial resistance, since phages can infect and kill antibiotic-resistant bacteria. According to the One Health paradigm, phages can also be useful also in treating veterinary conditions and potentially replacing the use of antibiotics in agriculture.
In October 2023, EMA published the first guideline on phage therapy specifically targeted at veterinary use. A few months later, in March 2024, the EDQM adopted the new general chapter “Phage therapy medicinal products” (5.31) of the Eur.Ph., which provides a framework of requirements for the production and control of phage therapy products.
On 17 October 2025, the European Medicines Agency (EMA) released the draft guideline on the quality aspects of phage therapy manufacturing for PTMPs for human use (link), which is now undergoing public consultation until 30 April 2026. Comments can be submitted via the dedicated EUSurvey webpage.
On 4 June 2025, the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) also published the document “Regulatory considerations for therapeutic use of bacteriophages in the UK”, that provides guidance on licensed and unlicensed phage therapies throughout their life cycle, from preclinical development to post-licensure pharmacovigilance activities.
EMA guideline on PTMPs for human use
According to the recently published EMA’s draft guideline, in Europe phage therapy medicinal products (PTMPs) should be classified as biological medicines under Directive 2001/83/EC. They could also be classified as advanced therapy medicinal products (ATMPs) if the phages have been genetically modified.
The guideline is structured according to the eCTD framework and covers the quality aspects of both phage-based active substances and finished medicinal products. It only covers the production of phages by propagation in bacterial cells, and not cell-free production systems, magistral formulae, patient-specific phages or phage-derived products (e.g. lysins and other enzymes).
Chapter 4 of the EMA’s draft guideline addresses the different aspects affecting the quality and efficacy of the PTMP active substance, that should be produced using a bacterial production strain via propagation of a phage seed lot derived from a single phage clone. General information on the PTMP active substance should cover its structure and general properties (e.g. taxonomic classification, target bacteria, potency, particle size and genome type and size, etc).
The name and address of each manufacturer and production site, together with their specific responsibilities, the batch scale or size or proposed range, should be provided. A detailed description of each manufacturing step should be also included, with identification of critical steps and intermediates and justification of hold times. Paragraph 4.4 specifically addresses the controls to be performed on the starting materials, including bacterial cell banks and phage seed lots.
Process validation should be carried out in accordance with the EMA’s guideline on biologically- derived active substances and the Ph.Eur. general chapter 5.31, paying particular attention to the genetic stability of the phages. Their structure, biological activity, purity and other relevant characteristics should be fully elucidated using state-of-the-art techniques. This should also include the profile of product-related and process-related impurities and parameters impacting on stability.
Information to be provided for the finished product (Chapter 5) include its qualitative and quantitative composition, also in terms of pharmaceutical development and choice of excipients. Justification should be provided for combinations of different phages. The manufacturing process must be described in detail and validated, and suitable controls should be established to assess the final quality and stability of the product.
Chapter 6 of the draft guideline provides indication on how to deal with change management of PTMPs, as for Annex I of the Variations regulations. Furthermore, despite the possibility of using prior knowledge to support marketing authorisation, a product-specific dossier is always required.
