Public production of therapeutic bacteriophages
4 October 2023
B. Lapras1,4,5, C. Kolenda2,4, M. Medina2,4, M. Bonhomme2,4, C. Marchand1,4, C. Merienne1,4, T. Briot3,4, G. Leboucher3,4, F. Laurent2,4, F. Pirot1,4,51 FRIPHARM®, Pharmacie à usage intérieur, Groupement Hospitalier Centre - Hospices Civils de Lyon (HCL), France
2 Laboratoire de bactériologie, Centre national de référence des staphylocoques – HCL, France
3 Pharmacie à usage intérieur, Groupement Hospitalier Nord – HCL, France
4 Consortium PHAG-ONE – PHAGinLyon, France
5 UMR 5305: Laboratoire de Biologie Tissulaire et d’Ingénierie Thérapeutique, Institut de Biologie et Chimie des Protéines, CNRS/Université Claude Bernard Lyon 1, France
Introduction
To stern antibiotic resistance –the death toll of which is predicted to reach 10 million deaths per year by 2050- new strategies are explored such as phage therapy. It takes advantage of the ability of bacteriophages or phages –viruses of bacteria- to infect, replicate and lyse their host.
Objectives
PHAG-ONE project (20-PAMR-0009) allowed the creation of an Etablissement Français des Phages Thérapeutiques (EFPT) working with French hospitals to treat patients who reached therapeutic dead-ends. This work details the future approach for hospital production of phage suspensions.
Methods and results
Selection of production host: An in silico approach, based on a bioinformatics pipeline, is developed to select the bacterial strains the most free of virulence factors and resistances. This system reduces the risks associated with the necessary use of bacterial strains to amplify natural phages.
Selection of high therapeutic potential phages: Phages are sampled from their natural environment -e.g., wastewater plants; identified by genetic sequencing; their activity range is tested on a bacterial panel representative of the clinical and genetic diversity of the pathogen. Phages with broad activity spectrum and complementary activities are selected for further pharmaceutical development.
Production: After amplification on the selected hosts, phages are purified by tangential flow filtration and ultrafiltration. The output is qualified as an active pharmaceutical ingredient (API) authorized by the French regulatory health agency (ANSM). This API can enter hospital preparations.
Formulation and quality control: The excipients for the hospital preparations are selected to (i) enhance the phage suspension stability and (ii) be suitable for clinical use. The quality controls target (i) the phage identity and activity; (ii) the risks associated with the administration route; (iii) the risks associated with the production process. The hospital preparation’s stability is explored following both ICH and predictive approaches.
Discussion
The authorisations to produce phage API and hospital preparations of phage suspensions will be asked according respectively to the fabrication (part 2 and appendix 2) and preparation good practices and to the future general chapter “Phage therapy active substances and medicinal products for human and veterinary use (5.31)”.
Conclusion
Inspired by the French blood establishment, EFPT’s purpose will be to offer phage suspensions against multi resistant bacteria or to treat patients with infectious recurrences and other bacterial therapeutic dead ends in a personalised approach.