Algal Cell Culture Media Price Considerations
Microalgae Media Implications for Biomanufacturing
(Part 2)
In part one of our algae media biomanufacturing implications series, we discussed a few common algae media and their ingredients. Part one helps demonstrate the differences between photosynthetic microalgae media and those used to grow heterotrophic biomanufacturing organisms.
Following that discussion, part two will shed some light on the cost of goods (COGs) considerations for algae media. Since media costs are affected by specific bioprocesses, species, geography, purchase agreements, and experience, we decided to focus on commercially available media materials to better replicate the cell culture media price for those looking to begin their exploration of algae biomanufacturing. As a result, this should more accurately estimate algae media costs for new users compared to our internal cell culture media costs. Importantly, the piece will also contextualize this information by comparing these algae media costs with the cost of cell culture media from more dominant cell systems.
Algae Media & COGs
While many variables go into estimating bioprocess costs across an entire biomanufacturing operation, cell culture media cost represents an essential consideration for COGs analyses. As such, there is value in considering how algae media costs compare to that of traditional biomanufacturing cell systems and chassis.
However, media development expenses, labor, automation use, existing infrastructure, clean-room/bioprocess operation, shipping costs, and other factors will vary significantly across different companies, organizational sizes, and regions. Therefore, it is difficult to make broad COGs comparisons for photosynthetic microalgae bioprocesses versus heterotrophic ones.
So, we will focus our discussion predominately on dry cell culture-grade media ingredients costs. While this is only one area impacting COGs, it still highlights unique attributes afforded to photosynthetic systems.
Why Work With Microalgae?
Cost of Dry Microalgae Media Ingredients
Approach:
For this cursory analysis, we identified major commercial sources (Sigma-Aldrich, Thermo Fisher Scientific, etc.) for cell-culture or molecular biology grade ingredients when purchased at the largest available quantities. Though supply agreements could further reduce the cost per gram of ingredients, this should help to articulate the relative price of these ingredients in the marketplace.
Results:
From our simple estimates, dry ingredients for F/2, HSM, and MLA cost (USD) approximately, $65, $695, and $44 per kL of media, respectively. The significant increase in HSM is almost entirely attributed to its high concentration of phosphates, which accounts for ~$618.5. It’s worth noting that opting for lower-grade phosphates or purchasing them in greater bulk can bring this number down substantially. In addition, ammonium chloride is a more expensive nitrogen source than sodium nitrate (~38% more per mole of nitrogen).
Comparing Heterotrophic Media
While the dry raw material costs per kL of media are helpful conceptually, these values don’t contextualize the cost difference between dry ingredients used to make traditional heterotrophic media. Rather than do cursory estimates for the much more complex ingredient mixtures of heterotrophic media (particularly chemically defined mammalian media), it’s helpful to consider commercial sources of dry media mixes. This way, we can account for the labor and margins of assembling dry commercial formulations (though shipping costs are excluded).
Approach:
We compared the cost of pre-formulated dry media ingredients from commercial providers. As before, we pulled information from major bacterial, fungal, and animal cell media providers (like Thermo Fisher Scientific, Sigma-Aldrich, Sartorius, and Cytivia). Very few commercial microalgae media providers exist today. However, we used dry media formulations from PhytoTech Labs for our comparisons. In all cases, the largest available quantities were used to calculate the cost per liter of media. Animal-origin-free and chemically-defined media formulations are emphasized where possible due to their common use in bioproduction for therapeutics, food products, and beyond.
Comparatively, purchasing Gibco™ DMEM/F12 powder (a widespread CHO cell culture medium, particularly in research settings), costs $4.5 per L. F/2 and HSM cost about 5 and 6 times less, respectively. Additionally, this particular CHO cell culture medium formulation does not include proteins, lipids, and growth factors. These materials would need to be supplemented separately or added in the form of fetal bovine serum (FBS). Both cases would add significantly to the final cost of the media, given that 10% heat-inactivated FBS could add approximately $100 per L. Chemically formulated alternatives are likely to be even more expensive, given the cost of growth factors. In 2020 the Good Food Institute estimated that chemically defined DMEM/F12 would cost $376.80 per L, even when prepared at a 20,000 L scale.
Microalgae media ingredients also appear inexpensive compared to chemically defined animal-origin-free media powders for bacterial and fungal cell systems.
For example, chemically defined Bacto™ CD Supreme Fermentation Production Medium (FPM) from Thermo Fisher costs $15.65 per liter, without including the cost of glucose/glycerol, antibiotics, and other supplements. Thus, this bacterial production medium is ~17.1-fold and ~21.3-fold more expensive than commercial F/2 and HSM, respectively.
Yeast production species like Pichia pastoris or Saccharomyces cerevisiae have become commonplace in biomanufacturing efforts, including precision fermentation. Yeast Extract Peptone Dextrose (YEPD or YPD) is a traditional media choice for recombinant gene expression for growing yeast species.
Sigma-Aldrich offers a dry formulation of this nutrient-rich media for $13.25 per L. This amounts to ~14.5-fold and ~18.0-fold more expensive than F/2 and HSM, respectively.
Like with other bioproduction efforts, there’s significant use of chemically-defined synthetic media to help drive down costs, increase reproducibility, and reduce regulatory burden.
In fact, chemically defined yeast media (synthetic complete, SC) appears to have the most similar cost parity in our analysis compared to algae media. SC media used for production purposes (vs. for selection or microbiological identification) includes yeast nitrogen base (YNB), amino acid supplements, and a carbon source (IE, dextrose). Sigma Aldrich offers dry-formulated YNB at $4.79 per L and yeast synthetic drop-out supplements (amino acids) at approximately $7.19 per L (depending on the drop-out) for S. cerevisiae applications. This totals $11.98 per L (excluding the cost of carbon source and additional additives), ~13.1-fold and ~16.3-fold more than F/2 and HSM, respectively.
It is important to note that some bioproduction fungal species require more YNB input. For example, Pichia species are often grown on 2-fold more YNB, resulting in ~$16.77 per L, or ~18.3-fold and ~22.8-fold more than F/2 and HSM, respectively.
Collectively, it’s clear that heterotrophic media are significantly more expensive than algae media, driven by their need for complex biomolecule nutrients. This holds true even though the traditional cell culture media market is much more mature than the algae media market, where providers are few and far between. Over time, this may mean that the prices of pre-formulated dry media may drop further, driven by greater algae media production scales and competition.
Carbon Feedstock: The Additional Cost of Sugar
To round out our discussion on media ingredients costs, it’s worth noting that thus far, we’ve excluded the cost of carbon feedstock (predominately sugars) for heterotrophic media. Generally speaking, sugar feedstocks are considered expensive for manufacturing goods, which explains why those using sugar feedstocks tend to focus on high-value specialty chemicals.
Though cell culture grade glucose is relatively inexpensive per gram (~2.5 cents/g at a 10 Kg scale), the scale of sugar use creates a large, frequent expense (particularly for fermentation). In addition to the base cost of sugar, biomanufacturers often must also pay for shipping large quantities, which adds significant expense. In fact, this is likely a key reason why Amyris elected to build a large precision fermentation plant in Barra Bonita, Brazil. Brazil is the world’s largest sugar producer, and Barra Bonita lies in the heart of São Paulo–the Brazilian state that produces the most sugar.
Furthermore, the demand for sugars in manufacturing will continue to rise as more companies opt for biomanufactured goods. In addition, glucose is also used as a food additive; thus, the food and beverage market will also impact future costs and demand. The glucose market continues to grow quickly, reaching $48.01 billion in 2022 and an expected $51.37 billion in 2023.
Though it’s difficult to imagine glucose (or other sugars) becoming wildly expensive, it’s worth noting that we need arable land to produce it. This means that the price of glucose is sensitive to supply chain disruptions (war, pandemics, etc.) and the impact of climate change. For example, the Ukraine-Russia conflict impacted global sugar production, increasing sugar prices. It’s also not unreasonable to suspect that climate change will affect sugar farming, potentially limiting arable land or causing shifts in regional sugar production.
In short, dependence on sugar poses a considerable routine expense. Since sugar is a critical agricultural commodity, it may become increasingly expensive for large-scale biomanufacturing, posing increased cost risks in the near future.
What About Light?
While photosynthetic microalgae media offer cost advantages, it’s essential to acknowledge that photobioreactor-based bioprocesses include an additional expense not found in heterotrophic systems: light energy.
Though atmospheric CO2 is largely a “cost-free” nutrient input (excluding the cost of pump and filter operations), indoor light is not. Photobioreactors rely on artificial light (LEDs) to sustain microalgae species and supply them with energy for photosynthesis. Thus, microalgae biomanufacturers must include additional energy costs in their COGs analysis. This extra expense does increase the cost of microalgae biomanufacturing, bringing total input costs closer to heterotrophic systems despite significant media cost savings. The energy cost of light varies a lot, dependent on bioprocess, region, and energy provider. Thus it is difficult to estimate the exact cost increase associated with light compared with heterotrophic systems.
Microalgae producers can sometimes circumvent these costs using outdoor cultivation systems that instead use sunlight to power microalgae growth. That said, outdoor and raceway pond bioproduction formats are limited by the inability to control available light and weather. Thus, outdoor formats offer less bioproduction performance consistency and greater contamination risk, limiting their applications to specific regions and regulated industries.
For this reason, Provectus Algae works exclusively with our own photobioreactors. To solve the historical challenges of large-scale microalgae biomanufacturing, we need consistency and reliability in our bioproduction systems. That means lighting energy costs remain in place, increasing the bioproduction expenses.
However, there are mechanisms to bring photobioreactor light energy costs down.
Renewable Energy:
For one, biomanufacturers can save by using renewable energies instead of fossil-fuel-based sources. Already, solar and wind are some of the cheapest sources available.
In mid-2022, Bloomberg estimated that new onshore wind and large solar electricity plants cost about $46 and $45 per megawatt-hour, respectively. New coal-fired plants cost $74 per MWh and gas plants $81 per MWh. The report also indicated the war in Ukraine led to a surge in fossil fuel energy costs, further widening the cost gap between fossil fuel and renewable energies. This also helps to articulate how renewables are also more insulated from supply chain disruptions associated with socio-political events, particularly when a fossil-fuel-rich nation is involved.
As countries, corporations, and investors continue to place more and more emphasis on fostering growth in renewable energies, energy experts expect renewable costs will continue to drop over time. For example, an analysis from the ICF Climate Center of the US Inflation Reduction Act (IRA) estimated that by 2030 IRA might reduce the levelized cost of energy of wind and solar by as much as 38-49% and 20-35%, respectively.
Additional infrastructure investments, tax incentives, and technological improvements should continue to drive renewable costs down and increase access to these lower-cost energies. For these reasons, we expect the additional lighting costs of photobioreactors and artificial light to become increasingly inconsequential.
Increasing LED Efficiency:
Separate from lower cost per MWh, further technological improvements in LED efficiency can continue to lower the energy needed to grow microalgae. Between 2010 and 2022, the average LED efficacy rose by ~6-8 lumen/W every year. Though expensive, the best-available LEDs can now reach over 200 lumen/W.
While annual efficiency gains may taper off in time, there is still significant room for improvement. In addition, the most expensive LED technologies will become cheaper and cheaper with time, reducing the capital expenditures.
Improving Photosynthetic Efficiency and Cellular Productivity:
Biomanufacturers can also improve the ability of microalgae to use the light in photobioreactors. By increasing photosynthetic efficiency, either by optimizing light recipes or using synthetic biology approaches to engineer better photosystems, microalgae can use a higher percentage of the photons generated. In doing so, manufacturers can either lower total energy costs while maintaining the same cellular productivity or maintain energy costs while increasing the amount of product made. In either case, biomanufacturers can reduce their COGs.
Provectus Algae uses our Precision Photosynthesis™ technology to quickly identify optimal light recipes for microalgae growth and biomass production. In addition, we can also lower the COGs by using Precision Photosynthesis to increase the expression of target bioproducts. Interestingly, gene expression in photosynthetic organisms is highly regulated by light conditions. Thus, Precision Photosynthesis harnesses the signaling cascades of the many distinct photoreceptors found in algae species to increase target gene expression and productivity (grams or product per liter per day). Importantly, this approach works without genetic engineering of the algae species.
Interested In Precision Photosynthesis?
Final Remarks
Photosynthetic microalgae media is quite unusual in the context of traditional media used in biomanufacturing. By harnessing their autotrophic growth mode, microalgae can produce most of their critical biomolecules from light, CO2, and simplistic nutrient formulations. Although algae formulations vary, autotrophic microalgae bioproduction allows for significantly lower media costs compared to heterotrophic production.
Furthermore, microalgae bioprocesses are more insulated from supply chain disruptions. In addition to de-risking supply chains, the minimal nutrient inputs for photosynthetic bioprocesses can minimize shipping charges. By growing microalgae in photobioreactors, product developers can also minimize the distance between their ingredients and product manufacturing.
Clearly, microalgae offer unique COGs advantages in biomanufacturing. We expect these and other advantages will drive further use of these fantastic photosynthetic organisms in industries the world over.