Robust Approaches for the Production of Active Ingredient and Drug Product for Human Phage Therapy

Abstract

To be successful, academic and commercial efforts to reintroduce phage therapy must ensure that only safe and efficacious products are used to treat patients. This raises a number of manufacturing, formulation, and delivery challenges. Since phages are biologics, robust manufacturing processes will be crucial to avoid unwanted variability in each step of the process. The quality standards themselves need to be developed, as patients are currently being treated with phages produced under quality standards ranging from cGMP for clinical trials in EMA and FDA regulated environments to no standards at all in some last resort treatments. In this short review, we will systematically review the literature covering technical issues and approaches to increase robustness at every step of the production process: the identity of the phage and bacterial production strains, the fermentation process and purification, the formulation of the drug product, the quality controls and the documentation standards themselves. We conclude that it is possible to control cost at the same time, which is critical to re-introduce phage therapy to western medicine.

Current challenges and future opportunities of phage therapy

“…For broad medical applications, phages would need to be produced in large scale under Good Manufacturing Practices (GMP) approved by regulatory agencies (Regulski, Champion-Arnaud and Gabard 2018). Although the production of phages for therapy must comply with the strict regulations that are usually applied for pharmaceutical products to ensure the high quality standards appropriate for their intended use, no clear guidelines were yet developed specifically for phage manufacturing (Mutti and Corsini 2019). To address this issue, a group of phage researchers have set some quality and safety requirements for sustainable phage therapy products (Pirnay et al 2015).…”

“…It is important to note that as phages are biological entities, the development of robust manufacturing processes in compliance with GMP is also essential to avoid variability among phage preparations (García et al 2019;Mutti and Corsini 2019). Another important aspect is the quality control of phage stock preparations.…”

Bacteriophage Therapy of Bacterial Infections: The Rediscovered Frontier

“…Understanding the interactions between host bacteria and bacteriophages is a crucial step in estimating the risks in production, including possible mutations in either microorganism [32]. The production process may also be affected by the nutrient composition, oxygenation, temperature and pH [33].…”

“…The process of removing endotoxins from phages is complex because lipopolysaccharide forms micelles that have approximately the same size as phages. Therefore, extra purification methods such as ion exchange, affinity chromatography and solvent extraction are needed for lysates of phage-infected Gram-negative bacteria [33].…”

“…Because phages break down bacterial DNA, the presence and concentration of nucleic acid residues in final products should be determined. qPCR can be used for this purpose [33].…”