Securing supply of pharmaceutical ingredients with synthetic biology
Christina Smolke, PhD, co-founder and CEO of Antheia, describes how biomanufacturing can provide sustainable, high-quality APIs and KSMs, and de-risk pharmaceutical production by localising and streamlining supply chains.
Global crises like pandemics, extreme weather events, and geopolitical conflicts have underscored the urgent need to secure and fortify supply chains, especially those of the active pharmaceutical ingredients (APIs) and key starting materials (KSMs) used in essential medicines. Many of these APIs and KSMs are derived from plants grown in specific environments across the world, making them especially susceptible to supply shortages on both the local and global scale.
Synthetic biology – the engineering of organisms, such as yeast, to produce a wide array of compounds – may be the ultimate solution to enable the production of APIs and KSMs at scale. Through robust bioprocesses such as fermentation, synbio as it is called, can insulate these key medical compounds from the risks and challenges of agriculture-based sourcing. Biomanufacturing provides sustainable, high-quality APIs and KSMs and can de-risk pharmaceutical production by localising and streamlining supply chains.
Q. Let’s start off by asking you to define biomanufacturing in the context of Antheia as we’ll be discussing it in depth later on.
A. Biomanufacturing is producing products at a commercial scale using a biological means of synthesis. I'm intentionally defining that very broadly because I view biomanufacturing as including things like chemoenzymatic synthesis where you're using enzymes outside of the cell to perform certain reactions. It also includes leveraging whole cells – such as yeast – for making products via fermentation processes.
Q. What are the biggest challenges facing pharmaceutical-grade production of plant-based ingredients today?
A. The number one challenge comes down to the latency and variability associated with these agricultural supply chains. From a latency perspective, harvesting pharmaceutical-grade compounds from plants means you have to grow and produce that biomass, and these production cycles can be on the order of several years.
Another aspect of latency is that many of these plants have very specific growth requirements – they tend to grow in very specific climates, regions, or times of the year. This results in a geographically concentrated supply chain that has inherent vulnerabilities, such as being susceptible to damage or disruption via climate change and geopolitical events. We’re seeing increasingly more vulnerability coming into those supply chains.
In terms of consistency, control, and variability – again due to the nature of growing plants out in the open – it is not a controlled process, meaning it's not done in a controlled environment or facility. You must manage variability from growing season to growing season and factors that are outside your control, which are also difficult to predict.
Q. What are the consequences of this latency and variability in securing plant-based ingredients for the pharma industry?
A. The consequences are straightforward: supply chains can break down and medicines are not available when most needed. Even the US can face shortages of medicines that we collectively take for granted as always being readily available in critical circumstances. One example is vinblastine, an alkaloid extracted from the Periwinkle plant, that’s used as a chemotherapeutic to treat a number of cancers, particularly in children. Because it is only extracted from this plant, it faces a lot of risks, and frequent supply chain shortages.
The issue with plant-based production is that we don’t have an agile supply chain or network of production. If crops are lost because of a fire or a war, as we’re seeing with food crops in Ukraine right now, then the supply of those compounds is reduced for an entire growing season.
The impacts of these shortages ripple throughout the entire world. Costs go up, supply chains are disrupted, and certain under-resourced regions or countries may no longer get access to these medicines, which ultimately leads to inequitable access to essential medicines and an increased potential for human suffering.
From the manufacturing perspective, are there additional challenges in obtaining ingredients from plants for medicinal use?
There are a lot of nuances to be aware of when we talk about plants being used for medicinal purposes. When we’re referring to the pharma industry, and active pharmaceutical ingredients, there are very particular quality metrics set by the regulatory authorities that must be met during sourcing and production. This is different from botanicals – plant extracts used in unregulated supplements and nutraceuticals. The pharma industry, generally, is very tightly regulated by comparison – it's all about quality control, safety, and consistency.
Extracting active ingredients from plants adds a layer of complexity to pharmaceutical manufacturing. You start with a mixture of a lot of different compounds from that plant and you look to extract and purify a single compound. It’s challenging to control what that mixture looks like from growing season to growing season, and there are times when API manufacturers see variability from season to season. This requires more work and effort on the manufacturing side to make the API or ingredient consistent in its formulation.
The pharma industry has shifted to synthetic approaches for production as much as possible, including leveraging fermentation-based biomanufacturing, because they yield more consistent and controlled methods that fit better within the demanding framework of pharma.
Q. What are the benefits of fermentation in addressing all these challenges associated with the plant-based production of critical pharma ingredients?
A. Fermentation allows for agility in manufacturing. What has typically taken several years now can take two to three weeks at whatever scale is needed with fermentation biomanufacturing, and the infrastructure is quite consistent. It’s very agile and flexible, so the industry can respond to different events – be they geopolitical or environmental – addressing the latency challenge directly, or circumventing it entirely in the controlled environment of a bioreactor.
This addresses another major issue: building resiliency into our supply chains. We cannot and should not rely on one or two countries to do all the production. Fermentation facilities can be set up globally to reduce dependence on faraway geographical regions with particular climates for farming specialised crops. Fermentation can be done wherever these compounds are needed.
Q. Fermentation seems like the obvious solution – we’ve been able to produce therapeutics like insulin and other drug APIs via fermentation for decades – what has prevented us from doing this for current plant-derived therapeutic APIs?
A. This comes down to limitations on the technology side. Fermentation has been around for millennia, while genetic engineering has been around only for decades. It began with taking a recombinant gene product, insulin, and expressing that in a microorganism, like bacteria or yeast. That’s fine for a single gene product, but trying to make complex compounds like those found in plants changes the scale of genetic engineering.
For complex plant-based compounds like vinblastine, it’s no longer one protein – it takes 20-30 or even more proteins to make one molecule. The challenging part is identifying the processes that the plant and other organisms in nature possess that perform these interesting chemistries. Once these are identified, then we have to figure out a way to put it all together into yeast, our tiny fermentation factory, which is a very different environment than a plant cell – in a way that’s functional and more efficient. While fermentation is an obvious solution to the challenges posed by plant-based production, we are still limited by the technology in executing and building out this solution.
Only recently has this scale of genetic engineering become feasible through synthetic biology. If you look at the synthetic biology industry, most of the products that are scaled on the market are, in comparison, simpler than this in terms of the engineering challenge. Those may be on a scale of five or six proteins, so successfully taking the 20 or 30 proteins that are necessary for these very complex plant-based active pharmaceutical ingredients has been a big step for the field. It’s a challenge that Antheia has been uniquely able to execute, and where we believe that our technology adds value.
Q. How does synthetic biology-enabled biomanufacturing compare to traditional industrial biotech in overcoming these manufacturing limitations?
A. Looking at insulin, this was originally extracted from pigs, prior to Genentech’s engineered E. coli strain. This solved a major manufacturing problem for the pharmaceutical industry, and it was discovered that the microbial production was quite advantageous. The story of Antheia at this stage is quite similar. Our synthetic biology products are the results of advances in manufacturing, and are able to address challenges in global supply chains and manufacturing platforms in general.
The other way synthetic biology can be used is to produce new molecules and new products. The whole process of synthetic biology is identifying proteins that can catalyse these reactions and build from the bottom up in the same way synthetic chemistry does – we’re just using different catalysts and tools. Because we’re building from the bottom up, we can access new chemical space which, in healthcare, means developing new molecules and compounds to address indications and targets that are currently difficult to drug.
Q. What are the current limitations of biomanufacturing enabled by synthetic biology and how can we overcome those?
A. One of the limitations of biomanufacturing is that there are certain reactions where it’s simply not going to be commercially feasible to leverage synthetic biology. From a commercial perspective, even if something is technically or scientifically feasible, the costs once the process is scaled make it hard to be sustainable. We have to think about what is feasible at scale from a commercial perspective from the start. I find the industry oftentimes focuses on what we can produce but not how to scale the fermentation and downstream process with commercial viability.
Taking a step back – and being trained as a chemical engineer – I’m interested broadly in how we produce these molecules and compounds. There are two sets of tools – chemical synthesis and biological synthesis – and each has its own superpowers in terms of where it’s best applied. There are certain things chemical synthesis can do inexpensively that aren’t possible with biology and the superpower of synthetic biology is building complex structures and scaffolds that we cannot get to with chemistry. You can use synthetic biology’s superpower to build out these compounds and then use synthetic chemistry to fine-tune that molecule downstream.
Pharma is, as we mentioned, a highly regulated industry. If you make an API, it must meet the regulatory standards and it will fit into formulations directly. Synthetic biology can only take us so far in dealing with the manufacturing challenges, the rest is fitting into existing infrastructure and ensuring the bioprocesses are commercially feasible.