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EMA : Guideline on quality aspects of phage therapy medicinal products
The European Medicines Agency Publishes Draft Guideline on Quality Aspects of Phage Therapy Medicinal Products: A Landmark in the Regulation of Bacteriophage Therapeutics
Introduction
This 15-page document represents the first comprehensive regulatory framework in the European Union specifically addressing the quality, manufacturing, and control requirements for bacteriophage-based medicinal products intended for human use.
The release of this draft guideline is a significant milestone in the development of phage therapy as a legitimate, standardised, and potentially widely accessible treatment modality for bacterial infections, particularly in the context of the global antimicrobial resistance (AMR) crisis.
The Rising Need for Regulatory Clarity in Phage Therapy
The exponential rise of antibiotic-resistant bacterial pathogens has become a pressing public health concern. The World Health Organization classifies antimicrobial resistance among the top ten global health threats, with resistant infections causing hundreds of thousands of deaths each year and imposing substantial societal and economic costs.
In this context, bacteriophages—viruses that specifically infect and lyse bacteria—have gained renewed interest as precision antimicrobial agents capable of targeting pathogenic bacteria with species- or strain-level specificity, while sparing the commensal microbiota.
Despite their therapeutic potential, phage-based medicines have long faced regulatory uncertainty. While the European Union’s pharmaceutical legislation recognises bacteriophages as biological medicinal products under Directive 2001/83/EC, no dedicated guideline existed to clarify the expectations for their quality, manufacturing, or control data. The absence of harmonised standards has historically limited the development and authorisation of phage therapy products within the EU, confining most applications to compassionate use or magistral preparations at hospital level.
The 2025 draft guideline directly addresses this gap, aiming to establish a scientifically robust and regulatory-compliant foundation for the marketing authorisation of phage therapy medicinal products (PTMPs).
Scope and Legal Basis
The draft guideline applies to strictly lytic (virulent) bacteriophages—those that exclusively undergo the lytic cycle and are incapable of lysogeny—used in the treatment of bacterial infections in humans. Both naturally occurring and genetically or chemically modified phages are covered, provided they are propagated in bacterial hosts under controlled conditions.
The guideline explicitly excludes:
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temperate phages capable of lysogeny,
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phage-derived enzymes (e.g., lysins or depolymerases),
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patient-specific or magistral preparations not intended for centralised marketing authorisation, and
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cell-free production systems, although it acknowledges that the general principles may apply to such technologies in future.
Where genetic modification results in characteristics aligning with gene therapy, the product may fall under the regulatory category of Advanced Therapy Medicinal Products (ATMPs), requiring additional oversight by the Committee for Advanced Therapies (CAT).
The document builds upon a comprehensive network of legal and scientific references, including Directive 2001/83/EC, Regulation (EC) No 1234/2008, and the full suite of relevant ICH guidelines (Q2, Q5D, Q6B, Q11, Q14) as well as European Pharmacopoeia (Ph. Eur.) general chapters.
Quality Requirements for Phage Therapy Medicinal Products
1. Active Substance
The active substance in a PTMP is defined as a phage population derived from a single clonal lineage, propagated in a bacterial production strain to ensure genetic and phenotypic homogeneity.
The manufacturing process must deliver a phage preparation of consistent quality, potency, purity, and stability, in compliance with GMP principles applicable to biological medicinal products.
Control of Materials
A dual seed lot system is recommended for both the bacterial production strain and the phage itself.
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Bacterial Master and Working Cell Banks (MCB/WCB) must undergo complete genomic sequencing and annotation to confirm identity, purity, absence of prophages, toxins, virulence factors, and antibiotic resistance genes.
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Phage Master and Working Seed Lots must similarly be fully sequenced, annotated, and assessed for detrimental genetic elements, ensuring the use of strictly lytic phages free of lysogeny or transducing potential.
This systematic genomic characterisation, employing next-generation sequencing (NGS) and bioinformatics analysis, reflects a modern approach to establishing traceability and quality consistency across phage production batches.
Process Validation and Genetic Stability
The guideline mandates process validation studies to confirm reproducibility and robustness of phage manufacturing. In accordance with the EMA’s process validation principles for biotechnology-derived substances, the genetic stability of the phage must be verified by comparing the full genomic sequences of production batches against the master seed lot reference.
Characterisation
Characterisation serves to define the critical quality attributes (CQAs) of the phage active substance. A range of orthogonal analytical methods—including electron microscopy for morphological assessment, plaque assays for lytic activity, and sequencing for genetic identity—should be employed.
The guideline specifically requires:
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Plaque phenotype documentation, including morphology and clarity;
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Host range determination, covering multiple strains of the target species and clinically relevant isolates;
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Potency measurement, typically expressed in plaque-forming units (PFU/mL);
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Evaluation of generalised transduction capacity, to mitigate potential gene transfer risks;
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Assessment of impurities, including host cell proteins (HCP), host cell DNA, pyrogens, and process-derived residues.
These requirements align phage characterisation with established biotechnology standards while addressing the unique biological behaviours of phages, such as self-replication and host specificity.
Specifications and Analytical Methods
Release and shelf-life specifications must be defined for identity, potency, purity, and microbiological quality.
Analytical methods must comply with ICH Q14 and Q2 guidelines, with the possibility of adopting platform methods across related phages when scientifically justified. Reference materials should be established and qualified for potency and system suitability testing.
Stability
Stability studies should follow ICH stability principles, identifying relevant parameters such as potency, pH, and appearance, to establish a scientifically justified shelf life for the phage active substance.
2. Finished Product
The guideline differentiates between single-phage products (monophage) and multi-phage products (phage cocktails).
A multiphage formulation is defined as a qualitatively and quantitatively characterised combination of individual monophage components.
Applicants must:
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Provide a full qualitative and quantitative composition of the product;
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Demonstrate compatibility among combined phages and excipients;
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Justify the scientific rationale for combining phages; and
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Provide in-use stability and compatibility data, particularly when mixing is required prior to administration.
For multiphage products, individual potency testing of each phage component is mandatory, unless a scientifically robust justification for composite testing is accepted. Stability studies must also monitor the infectious titre of each component over time.
The guideline also requires manufacturers to perform pharmaceutical development studies, define the quality target product profile (QTPP), identify critical process parameters, and demonstrate comparability between clinical and commercial formulations.
3. Control of the Finished Product
Finished product specifications must include tests for appearance, potency, identity, pH, osmolality, visible and subvisible particles, microbiological quality, and any other relevant physical attributes.
Potency testing follows Ph. Eur. general chapter 2.7.38 (“Bacteriophage Potency Determination”), currently under development, which will provide harmonised assay principles for determining the infectious titre.
Microbiological quality testing depends on the intended route of administration, with sterility testing required for sterile products. Analytical validation summaries should be provided for all test methods.
4. Reference Materials and Stability
Reference materials for potency testing should be established in accordance with ICH requirements and monitored for stability.
Finished product stability studies should follow ICH guidelines, considering factors such as temperature, pH, agitation, and container closure systems.
Regulatory and Lifecycle Management Considerations
The guideline addresses a critical question in phage therapy regulation: how to manage changes in the composition of a phage product after marketing authorisation.
Under current EU law, phage therapy products fall under the same legal framework as other biological medicines. Consequently, any modification of the active substance composition—such as replacing or adding a new phage to a cocktail—constitutes an extension of the marketing authorisation under Regulation (EC) No 1234/2008.
Such changes must be justified through quality, non-clinical, and clinical data, demonstrating that the new or replacement phage maintains comparable safety and efficacy profiles. This approach underscores the importance of genomic and phenotypic consistency within authorised phage compositions.
The guideline also encourages the use of prior knowledge and platform data—for example, standardised manufacturing and analytical platforms across multiple phage products—provided that the relevance and applicability of the supporting data are scientifically justified. Nonetheless, it stresses that each product must maintain a product-specific dossier, ensuring regulatory rigour and traceability.
Defining Key Terminology
A dedicated definitions section provides harmonised terminology for phage therapy, including:
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Bacteriophage (phage): virus infecting bacteria, with a genome encapsulated in a protein capsid;
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Lytic bacteriophage: phage that exclusively replicates through bacterial lysis;
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Multiphage product (phage cocktail): combination of multiple monophage components;
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Host range: taxonomic diversity of bacterial strains a phage can infect;
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Transduction: transfer of bacterial DNA by phage particles;
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Generalised transduction: random packaging and transfer of host DNA;
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Phage therapy medicinal product (PTMP): preparation of phages used to treat bacterial infections in humans.
This standardisation of language represents a crucial step toward ensuring clarity and consistency across regulatory submissions and scientific literature.
Consultation Process and Next Steps
The public consultation period for the draft guideline runs from 23 October 2025 to 30 April 2026. Stakeholders—including academic researchers, pharmaceutical developers, regulatory experts, and healthcare institutions—are invited to provide input via the EMA’s EUSurvey platform.
Following consultation, the CHMP will review feedback and adopt the final version of the guideline, which is expected to become a cornerstone reference for both regulators and developers of phage-based medicinal products.
Significance and Innovation: A Regulatory Turning Point
The publication of the EMA’s draft guideline on phage therapy medicinal products is more than a regulatory formality; it represents a paradigm shift in the European approach to novel biological therapies.
By formally recognising the unique nature of bacteriophages—living biological entities capable of self-replication and evolution—the EMA has taken a decisive step toward integrating phage therapy into the mainstream of pharmaceutical regulation.
This framework provides, for the first time, a clear pathway for the standardisation, authorisation, and industrial-scale production of phage-based treatments.
The document’s emphasis on genomic characterisation, host range analysis, impurity control, and stability assessment sets a rigorous scientific foundation for ensuring the safety, efficacy, and quality of phage therapy products. At the same time, the guideline acknowledges the need for regulatory flexibility, encouraging scientific advice and adaptive approaches to account for the dynamic nature of phage biology.
In the broader context of antimicrobial innovation, this initiative could catalyse the emergence of a new class of precision antibacterials—phage therapies that complement or replace antibiotics in the treatment of multidrug-resistant infections.
By providing clarity to developers, investors, and clinicians, the EMA’s guidance is likely to accelerate the translation of phage research into clinically validated, authorised medicinal products available to patients across Europe.
Conclusion
The EMA’s 2025 draft Guideline on Quality Aspects of Phage Therapy Medicinal Products establishes, for the first time, a comprehensive and scientifically grounded regulatory framework for the development and approval of phage-based therapeutics in the European Union.
It signals a new era in which phage therapy transitions from experimental science to regulated medicine, guided by the same principles of quality, safety, and efficacy that underpin all biological medicinal products.
As antimicrobial resistance continues to escalate globally, the formal recognition of phage therapy within the European regulatory landscape may well prove to be one of the most consequential innovations in infectious disease therapeutics of this decade.
To take part in the modification of the draft, click here
Reference : https://www.ema.europa.eu/en/quality-aspects-phage-therapy-medicinal-products
To download the Draft guideline on quality aspects of phage therapy medicinal products, click here
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