Explore the challenges and latest developments in standardising manufacturing of microbiome-based drugs
Currently, fermentation is a commonly used method to manufacture commercial probiotic strains such as Lactobacillus spp. or Bifidobacterium spp. The advantage is that it can be easily scaled-up at relatively low cost, but the challenge is do it while respecting good manufacturing practices (GMP). When working to obtain cGMP certification, costs increase rapidly: in the case of manufacturing microbiome therapeutics, increased cost resolve around large batch fermenting vessels and anaerobic chambers for manipulation. This means that new strategies will have to be developed to enable large scale probiotic manufacturing.
Some of the systems being explored currently include disposable or low capital cost bioreactor designs, dynamically changing growth conditions and inoculation strategies reducing batch-to-batch variability as well as novel, low-cost media components. But companies in this space are realistic, and a number of challenges will need to be addressed. In July 2019, Informa polled 89 executives operating in the microbiome space. When asked what the biggest challenge they are facing specifically around manufacturing and scaling up, three issues dominated: the importance of viability, potency and purity was the biggest challenge for 30% of respondents, followed by creating new standards (25%) and limited choice of CDMOs for certain types of bacteria (20%).iii
While interest in microbiome therapeutics is growing rapidly, it is still a relatively new space of research and study, and there are multiple issues that need to be addressed in this space including data collection and sequencing. Data collection issues include variability as well as complexity of the data. Indeed, one of the biggest challenges when dealing with the microbiome is that it is not easy to extract significant data samples. Often, we are not dealing with a singular fungible unit, but rather a collection of organisms, or sometimes even a whole ecosystem.
This poses quite a challenge when using traditional sampling processes, as extracting large representative samples is often unfeasible, if not impossible. Furthermore, when the microbiome is studied in a specific point in time, it reduces our understanding of its variability. As such, scientists are often limited to studying individual microbiotic species, in a single point and time, rather than studying the interaction between multiple species and the human system over a prolonged period.
This also means that some data sets that we collect in one area of the body is not necessarily significant for other parts of the body. For example, some microbes might have a specific role in one part of our body, and a different one in another part.
Furthermore, while the technologies we have are able to detect and identify specific species, they often have issues when trying to identify different strains of the same species. This is especially troublesome, as some of these strains might have a different impact on our health.
In an effort to avoid limited data sets, some might be tempted to collect large, all-encompassing data sets. This leads to another relevant issue, the one relative to data analysis and quality of data. Overall, this means that, using our current existing technologies, it is quite challenging to monitor, catalog and identify individual members of a specific microbiome, as well as understanding how microbiota communities interact and influence their host-pathogen over prolonged period of times. Limited data sets create a very narrow window of understanding while larger data sets are often impossible to analyze. As such, some companies are hoping that artificial intelligence might be able to assist in data analytics of the more complex data sets. Eagle Genomics is one such company. They are developing IT platform solutions for the microbiomics space. They have even partnered with Microsoft Genomics in the hope of being able to scale they current products and solutions.
Microbiome therapeutics has long been the playground of small biotech companies. But as recent investments have shown, big pharma has been quite interested in entering the game. For example, AstraZeneca invested $20 million in Seres Therapeutics to work on microbiome medicines in immuno-oncology while AbbVie has elected to collaborate with Synlogic to target the inflammatory bowel disease market. As pharma get more implicated in the microbiome space, their involvement becomes key to the development of a regulatory framework.
In the US, the current regulatory pathway for microbiome therapeutics is still being defined. While three drugs are going through phase III trials: two have done so by using an orphan drug status (SER-109 by Seres Therapeutics and RBX-2660 by Rebiotix which are specifically indicated for the treatment of C. difficile infection) while the third, RP-G28 (Ritter Pharmaceuticals) is in trials for the treatment of lactose intolerance. The orphan drug regulatory strategy, while enabling product approval, has a significant downside for even when these microbiome therapeutics are approved, they will achieve an orphan drug status. This means they will be available uniquely for a specific indication, and end up being priced accordingly. Developing more encompassing regulatory pathways for microbiome therapeutics is necessary going forward, but our understanding of the microbiome is limited, which has complicated the development of a distinct regulatory framework. Relying on innovative data points (such as real-world data) to demonstrate value might be a valuable strategy to reduce regulatory agency anxiety.iv
Its important to note that regulatory bodies are usually quite willing to work early with innovators to develop standardized regulatory frameworks, and usually look to industry to assist in the preparation of practical real-world frameworks. For big pharma, this will mean developing frameworks for two key requirements. First, a framework to work on the characterisation of microbiome products and second, frameworks for well-designed clinical studies with defined endpoints.
Manufacturing is one of the biggest bottlenecks faced by microbiome companies. Despite decades of experience growing bacteria to produce biologics, there is actual very limited experience in manufacturing live bacterial therapies within GMP environments, which is essential for pharmaceutical products.
For example, when Lonza formed a Joint Venture with Chr Hansen to accelerate development in the microbiome space, they quickly acquired microbiome expertise and capacity that might have taken them a lot of time to build organically; unfortunately, Chr Hansen’s experience is not in GMP environments but rather in manufacturing agricultural products, where being cGMP compliant was not necessary. This means Lonza and Chr Hansen will have to invest considerable sums to upgrade cGMP-compliant pharma production capabilities.v
This shortage of manufacturing capacity is especially important for companies working on intestinal microbiome strains, which represent the majority of companies in space. As gut microbes require low-oxygen culture conditions and produce spores that can contaminate other cultures, high standards must be applicated during production.
Developing manufacturing standards will be key in this space, as they will be highly scrutinised by regulatory authorities, especially when one considers the batch-to-batch variations that are implicit with living organisms. Live culture compositions will need to be standardised to demonstrate to regulatory bodies that reproducibility is possible. Other key concerns will likely include potency (the quantity of product require to obtain desired efficacy); purity (no detectable pathogens); and identity (the presence of certain organisms, especially when those being responsible for therapeutic effect are not identified).
Further requirements will most likely include additional containment areas to ensure “clean” areas remain sterile: as M. John Aunins, from Seres Therapeutics mentioned his presentation on manufacturing considerations for microbiome -based productsvi: “you really have to make sure that you've got unique facility designs that have appropriate classifications, that have appropriate pressure gradients, so that you can both keep bugs you don't want out, keep your bugs in.” Final considerations will have to be made to demonstrate that beneficial effects are still present when the product gets to the consumer and through to the expiration date of the product.
Going forward, some other ideas manufacturers can explore include minimising the use of reusable equipment (to limit the chance of cross contamination), use extensive decontamination procedures to make sure that they address concerns of cross-contamination and making sure the environmental testing will actually address the microbes being produced.
Australia Therapeutic Goods Administration (TGA) has proposed a framework for regulating faecal microbiota transplant (FMT) products by suggesting a risk-based approach to regulating FMT products. Under the proposal, the TGA will treat minimally manipulated FMT products as Class 1 or Class 2 biologicals, depending on whether they are manufactured in the treating hospital or remotely for shipping to a healthcare facility.
These regulations will form the basis of key, general requirements, such as the standards the TGA will require of hospital-based manufacturing facilities. As producers of Class 1 biologicals, hospitals will be exempt from good manufacturing practices, since it is believed that proximity and immediacy of the biological production unit to where it is used addresses key concerns around long-term stability of microbiotic therapeutics.vii
iNewman, Tim. “How 'good' viruses may influence health”, January 6th, 2020, https://www.medicalnewstoday.com/articles/327167 (Last Visited 18th of February 2020).
iiForbes and al. A Fungal World: Could the Gut Mycobiome Be Involved in Neurological Disease? Frontiers in Microbiology, January 9th, 2019. https://www.frontiersin.org/articles/10.3389/fmicb.2018.03249/full (Last Visited 18th of February 2020).
iiiBurrows, Andrew. The state of manufacturing and commercialization of microbiome therapeutics - Data report analysis, November 2019. https://informaconnect.com/manufacturing-commercialization-microbiome-therapeutics/ (Last Visited 18th of February 2020)
ivMoodley, Thunicia and Mistry, Erin. Could the Gut Microbiome Revolutionize Medical Care? Current Status and Initial Considerations for Successful Development and Commercialization of Microbiome Therapies. Syneos Health, April 2019. https://www.syneoshealth.com/sites/default/files/documents/Syneos_Health_Consulting_Microbiome_1_April_2019.pdf (Last Visited 18th of February 2020).
vPress Release, Bloomberg. “Lonza and Chr. Hansen in Joint Venture to Accelerate Momentum in Microbiome”, Bloomberg, Aril 2nd 2019. (Last Visited 10th of February 2020).
viUnited States Food and Drug Administration / National Institute of Allergy and Infectious Diseases. “Science and regulation of Live Microbiome-Based Products used to Prevent, Treat and Cure diseases in humans”, Rockville, Maryland, Friday, April 19, 2019 Website: https://www.fda.gov/media/128302/download (Last Visited 10th of February 2020).
viiTaylor, Nick. “Australia proposes manufacturing standards for faecal transplant products” 28th of November, 2019. Website: https://www.biopharma-reporter.com/Article/2019/11/28/Australia-proposes-manufacturing-standards-for-faecal-transplants (Last Visited 10th of February 2020).