Quality and Safety Requirements for Sustainable Phage Therapy Products

Abstract

The worldwide antibiotic crisis has led to a renewed interest in phage therapy. Since time immemorial phages control bacterial populations on Earth. Potent lytic phages against bacterial pathogens can be isolated from the environment or selected from a collection in a matter of days. In addition, phages have the capacity to rapidly overcome bacterial resistances, which will inevitably emerge. To maximally exploit these advantage phages have over conventional drugs such as antibiotics, it is important that sustainable phage products are not submitted to the conventional long medicinal product development and licensing pathway. There is a need for an adapted framework, including realistic production and quality and safety requirements, that allowsa timely supplying of phage therapy products for ‘personalized therapy’ or for public health or medical emergencies. This paper enumerates all phage therapy product related quality and safety risks known to the authors, as well as the tests that can be performed to minimize these risks, only to the extent needed to protect the patients and to allow and advance responsible phage therapy and research.

Paenibacilluslarvae-Directed Bacteriophage HB10c2 and Its Application in American Foulbrood-Affected Honey Bee Larvae

“…On the basis of experience with therapeutic phages for almost a century and because phages are abundant in natural ecosystems, they are regarded as inherently safe (5). However, rigorous research is required to determine the efficacy of respective therapeutic phages and to confirm their anticipated safety (29). Critical issues that have to be taken into consideration are the following.…”

A century of bacteriophage research and applications: impacts on biotechnology, health, ecology and the economy!

“…The situation is quite different when large bacterial infection outbreaks are to be dealt with . In this context, at the Eliava Institute in Tbilisi, Georgia, fermenter vessels up to 500 L volume are in use . In order to produce phages on a larger scale, the pathogenic host bacterial cells must first be cultivated in fermenter vessels under strictly contained conditions.…”

“…The overall regulatory approval of a phage preparation remains a major hurdle in addition to patenting it as well, because phages are considered neither a chemical nor a living cell. As of now, no regulatory framework deals with these aspects adequately …”

Microencapsulation of Clostridium difficile specific bacteriophages using microfluidic glass capillary devices for colon delivery using pH triggered release

“…Phages have been recommended as good candidates for antibacterial therapy [8] because: (i) they are highly specific with a defined host range and therefore they do not disrupt beneficial natural microbiota in the way broad spectrum antibiotics do [9]; (ii) in the presence of an accessible host, they self-amplify in situ thereby increasing their dose at the infection site, which may be advantageous for difficult to access infection sites e.g. bacterial biofilms [10] (this dose amplification is however highly dependent on the concentration of both the phage and actively growing bacteria [11], [12]); (iii) they are generally considered to be nontoxic to animals including humans [13], [14] and have minimal impact on non-target bacteria or body tissues when delivered orally [14]; (iv) they may potentially penetrate and kill bacteria within biofilms through production of depolymerases and other enzymes [15–17]; (v) they could be relatively inexpensive to produce using well understood fermentation and downstream processing technology, however, existing lab based manufacturing processes are poorly optimised for producing phage in large quantities thereby incurring high costs if produced under GMP standards required for therapeutic use [18]; (vi) for many species, they can be isolated from accessible sources and they can be modified (using forced phage evolution techniques, under laboratory conditions) to counter phage resistance or alter their inherent properties, and thus if resistance develops, or if a greater spectrum of activity is required, the phage pipeline can be added to without having to start a whole new programme of activity [19]; (vii) they are capable of infecting bacteria which have developed resistance to antibiotics [5]. …”