While the microbiome therapeutics industry is still in its infancy, the lack of defined standards remains a major challenge affecting projects, across R&D and manufacturing. Companies have yet to identify the best processes to produce a high-quality medicinal product under regulatory scrutiny. Demonstrating reproducibility in live culture compositions is one hurdle yet to be overcome by standardisation, among many more.
How long is the road to defining the standards required? What steps are yet to be made, and could some solutions be right under our noses? Five industry experts gave us their view.
David Daboush, CEO, MyBiotics
The microbiome is a complex system consisting of multiple conditions and organism interactions, the most significant clinical outcomes are often related to multiple bacterial consortia and not to specific strain. Setting the standard for producing such complex communities will probably require much more scientific know-how combined with production and regulatory experience.
I believe that the clinical potential and clinical results will be the engine for setting up the margins and requirements as we see today in the case of FMT compared to new strain approval. The scientific community tends to underestimate the gaps in the end product formulation and focus on the culturing and pre clinical outcome, this will be the ground for innovation as we expect companies with unique capabilities to take the lead to market.
Delphine Lauté-Caly, PhD, Molecular Microbiology Team Lead, 4DPharma
Manufacturing represents a key hurdle for microbiome therapeutics, as with any new modality. 4D pharma recognised this and invested in our internal capabilities, with cGMP certification and capacity to supply all our ongoing clinical trials. Before considering how far off, it is worth asking whether Live Biotherapeutics necessitate new standards, or are sufficiently covered by existing legislation for medicines, particularly biologics? There are clearly additional considerations when working with live bacteria, but standards may be covered by existing legislation regarding consistency, purity, contamination and process, for example. The European Pharmacopoeia issued quality standards for LBPs which came into effect in 2019, however these do not explicitly cover manufacturing. In the US, the FDA has issued guidelines on clinical development of LBPs but not manufacturing. As the field matures, industry input into any discussion around standards for manufacturing, or any other aspect of microbiome therapeutics, will be vital.
Sam Westreich, Microbiome Specialist and Bioinformatician, DNAnexus
I believe that there is still a hurdle to overcome when it comes to defining manufacturing standards, a hurdle imposed by the limitations of our scientific understanding of the microbiome. We have not fully determined how deeply we must examine a microbiome in order to be reasonably confident in our predictions of its functions and outcomes for a patient or product. Until we can confidently state the minimum level of detail that we need, we won't be able to set consistent manufacturing standards. Hopefully, identification of therapeutic uses will provide us with a benchmark that we can use to determine the minimum accuracy thresholds, and thus set standards for manufacturing and production.
Lita M Proctor, PhD [V], NHGRI/NIH, HMP, NIH
Over a decade ago, the human microbiome field was catalysed by the application of sequencing technologies. The microbiome field benefited greatly from our ability to directly sequence the microbes of the microbiomes from the human body. Sequence analysis formed the cornerstone for this field and sequence-based standards are currently under development by several government agencies and by commercial entities for the analysis and interpretation of sequence data. In that regard, I believe the microbiome therapeutics industry is very close indeed to having defined standards for manufacturing purposes.
However, I believe that inherent in this question is the assumption that only one class of standard – for sequence analysis and interpretation – will be needed for industry. In fact, it is becoming abundantly clear that sequence data will not be the only metric needed to evaluate the efficacy of any microbiome-based product or intervention. This is because simply ‘naming the microbe’ will not be sufficient to determine the efficacy of many future microbiome-based products. For example, some products will be focused on a specific microbe, where sequence standards may be sufficient, but other products will be focused on specific metabolic properties or on specific cellular properties of the microbe or microbes in the product. As such, we will need functional data, such as the analysis of specific microbial properties of the microbe or microbes in a product, to evaluate the efficacy of that product. This means that standards will need to be developed for other classes of technologies, such as metabolomics or other HTP technologies, for manufacturing purposes. Most of the current attention in this field has been on sequence data but if this field – and any applications or products which may emerge from this field – is to advance, we will need to develop standards which are tailored for each class of microbiome-based product.
ALAIN SOURABIÉ, Science, Technology & Innovation Director, Procelys by Lesaffre
Industrial microbiome therapeutics manufacturing strategies are a critical step and a key challenge towards the commercialization which need to be addressed in the most efficient way. Are these therapeutics likely to be regulated in the same way as other pharmaceuticals, food additives or nutritional/dietary supplements? This will be the basis to define specific manufacturing standards inclusive of safety, purity, consistency and reliability.
Before defining standardization however, live biotherapeutics manufacturing technology need to be developed at scale and which is currently lacking. Indeed, most of microbiota origin strains are strict anaerobes, highly sensitive to environmental stresses encountered during processes, with complex, often unknown nutrient requirements, and limited or variable growth.
