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.

Antimicrobial resistance in bacteria is an increasingly serious threat in every part of the world [1]. Without action, the world could be heading towards a post-antibiotic era in which common infections become fatal and currently routine surgeries become impossible. New initiatives to tackle the problem of antibiotic resistance are urgently needed.

One promising solution is the therapeutic use of bacteriophages – the viruses of bacteria, also known as phages – to treat bacterial infections. When discovered in the early twentieth century, phages were immediately applied in medicine (phage therapy) with variable success. After World War II, Western industry and policymakers preferred antibiotics, which at the time had obvious advantages in terms of breadth of coverage and ease of production and patentability, and phage therapy was pushed into the background. Today, phage therapy is again put forward as a potential way to address the current antibiotic crisis [2, 3].

Since time immemorial, phages have controlled bacterial populations on our planet, locked in an evolutionary arms race with their hosts (consisting of the repeated emergence of new phage infectivity and bacterial defense mutations). The capacity of bacteriophages to rapidly overcome bacterial resistance makes them suitable for flexible therapeutic applications. To maximally exploit this key advantage of phages over conventional ‘static’ drugs such as traditional small molecule-type antibiotics, it is important that sustainable phage products are not submitted to the conventional long medicinal product development and licensing pathway [4]. A key goal for the modern phage therapy community must be the development and validation of an expedited product development and licensing pathway in consultation with policymakers and competent authorities.

Georgian and Polish phage therapy centers maintain extensive therapeutic phage collections, which are regularly enriched with new phages, thus widening the total host range of the collection and adapting the collection to changing bacterial populations (with regard to host range and antibiotic resistance as well as phage resistance). Moreover, the effectiveness of phages can be readily improved by in vitro selection of (natural) phage mutants that exhibit an increased infectivity range. For example, it is possible to obtain potent lytic phages against problematic enteroaggregative Escherichia coli strains by isolation of new phages from the environment or by selection and adaptation of phages from an existing collection, and this often in a matter of days [5]. As such, phages could probably have been used to help control the O104:H4 (hybrid EAggEC STEC/VTEC pathotype) E. coli outbreak that caused the death of more than 50 patients in Germany in 2011. Unfortunately, authorized use of phages would not have been possible in this otherwise feasible context because under the existing medicinal product legislation such an anti-O104:H4 phage preparation would have taken years to develop, produce and register. Since phages are species and often even strain-specific, it is very likely that current O104:H4‑specific phage preparations will not be effective against future epidemic enteroaggregative E. coli strains. ‘Broad‑spectrum’ phage cocktails active against bacteria that are likely to cause problems in the future could be developed in advance and used as a first line treatment for acute healthcare problems (e.g., foodborne disease outbreaks and bacterial bioweapon threats). However, we need to keep in mind that some of these cocktails will not always work due to the greater biodiversity outside of the laboratory and the existing resistance to specific phages. The cocktails that initially work will need to be regularly updated (e.g., supplemented with new phages in response to the evolution of phage resistance and the involvement of new circulating bacterial strains). There are indications that bacterial resistance to phages, even to cocktails containing multiple potent phages, will inevitably occur [6].

Notwithstanding the Intellectual Property (IP) and regulatory hurdles, as well as the empirical evidence suggesting that stable and widely distributed phage preparations (prêt-à-porter) will need to be constantly updated, a few companies have picked up the gauntlet and are slowly moving along the elaborate and expensive conventional medicinal product licensing pathway. The development and marketing of phage medicinal products in the EU – including Good Manufacturing Practice (GMP) production, preclinical and Phase I, II and III clinical trials and centralized marketing authorization – is in fact technically possible (and indeed advisable for some products), providing some minor modifications and logical exemptions are made.

However, multiple discussions between experts, competent authorities and policymakers have led to an increasing awareness that sustainable (sur-mesure) phage therapy is not compatible with the conventional approaches to the development and application of medicinal products [4]. Next to the classical medicinal product pathway, which should be adjusted to support the industrial production of (first line) broad-spectrum phage cocktails or phage-derived products (e.g., phage endolysins), there is a need for a specific framework (including realistic production and quality and safety requirements) that allows a timely (rapid) supplying of adapted productions of natural bacteriophages for ‘personalized therapy’. This regulatory framework could be based on the Quality by Design (QbD) concept, which is increasingly applied to the development and production of biopharmaceutical molecules [7]. The QbD approach entails designing quality into the process and the product, and this in a science- and risk-based manner. Understanding patients’ needs and determining the specific science and quality characteristics of the product that are linked to safety and efficacy are crucial components of QbD. More research is urgently needed to gather the required data with regard to the efficacy of phage therapy and to broaden our understanding of bacteria-phage coevolution in nature and in the context of human disease [8, 9]. To avoid the mistakes of the past (which lead to the current antibiotic resistance crisis), phage therapy products should not exclusively be developed and marketed as antibiotics, i.e., applying current pharmacoeconomic principles. Ideally, phage therapy should be coordinated and standardized (in a first instance) by national phage therapy centers, which operate under the supervision of relevant public health authorities and in interaction with private stakeholders.

There are precedents for such a dedicated ‘non-medicinal product’ approach. In the European Union (EU), human tissues and cells that are not considered as ‘Advanced Therapy Medicinal Products (ATMPs)’ are procured, processed, tested and allocated by (or under the responsibility of) dedicated tissue establishments and are exclusively regulated by the EU Tissue and Cell Directives (EUTCDs). The EUTCDs consist of three Directives, the parent Directive (2004/23/EC), which provides the framework legislation, and two technical Directives (2006/17/EC and 2006/86/EC), which provide the detailed requirements of the EUTCD. The purpose of these Directives was to facilitate a safer and easier exchange of human tissues and cells between member states and to improve safety standards for European citizens. They set a benchmark for the standards that must be met when carrying out any activity involving tissues and cells for human application.

In view of further meetings with phage experts and representatives of the competent authorities and policymakers – coordinated by the European Commission Joint Research Centre, which acts in an advisory capacity to the Commission and its policy making directorates general –, a group of ‘phage experts’ (the authors of this paper) were asked through the intermediary of a not-for-profit organization (www.p-h-a-g-e.org) to set realistic quality and safety requirements for sustainable phage therapy products (Table I). These requirements are intended to apply to the production of phage therapy products (finished products), starting from banked characterized natural therapeutic bacteriophages (Master Seed lots), and possibly using intermediate bacteriophage products (Working Seed lots or Active Substances). They were roughly based on the EUTCD quality and safety standards for human cells and were defined by consensus among 32 phage experts (biologists, geneticists, bioengineers, quality managers, pharmacists and MDs) from 12 countries. This document enumerates all possible phage product related quality and safety risks known to the experts, 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. The exact tests used and limits applied will depend on the route of administration (e.g., topical or systemic) and the regulatory path the product is being used under. These requirements do not address efficacy aspects of phage therapy products.

Table I Expert Consensus Quality and Safety Requirements for Sustainable Phage Therapy Products

Should bacteriophages be used for a public health or medical emergency and no adequate finished products, Master Seed lots or Working Seed lots are available, then less stringent requirements could be considered, pending compliance (as quick as possible) to the quality and safety requirements.