Hey all, I’ve got some thoughts here. I worked in biopharma and spent some time working on a high-cell density perfusion system with CHO cells, so I’ve got some unique insight here. Right now for biologics production, there is a ton of effort in developing medium-scale perfusion processes run in single-use bioreactors (i.e. plastic bags). None of the analyses focused on this mode of production. There are potentially massive benefits to this approach.
Single-use equipment solves the sterility issue. Single-use equipment can be pre-assembled and sterilized in place. This allows for plants that don’t maintain strict sterility, saving on capital costs and operational costs. Note that this is not standard right now; biopharma plants with single-use equipment still usually maintain high air quality. However, for food-grade applications I bet you could get away without high quality air if you relied on single-use equipment.
There are massively reduced capital costs when using single-use equipment. I’ve heard that single-use bioreactors (SUBs) can cut CAPEX by ~70% or so, although I imagine these numbers are inflated by companies advertising the sale of SUBs. Still, this puts us much closer to a reasonable cost. Of course, this is offset somewhat by the cost of the bags. However, with a sufficiently long perfusion culture (maybe say 60 days), you can cut the amount of single-use materials required. You also save on cleaning costs, as you can dispose of single-use equipment after use. There is potentially a higher labor cost here, as you will need labor to remove old equipment and install new equipment between runs. This is likely offset somewhat by less labor cost for cleaning.
Humbird suggests using ATF membranes for cell separation in perfusion, which is incredibly expensive (10% of the cost in his optimistic scenario). ATF and other membranes are the standard separation method for biopharma perfusion right now, but there are potentially better methods out there. Stuff like acoustic wave settling or Hydrocyclones could be significantly cheaper (full disclosure, I contributed in a small way to this hydrocyclone work).
Spent media could be purified to recover and recycle any micronutrients. Macronutrient recovery would be harder, but is still potentially feasible. (To be fair, you could do this with any approach, but it’s worth nothing)
The main downside is that right now SUBs are limited to ~2,000L. There are bags as large as 6000L out there, although I have no experience with them. However, in general the use of SUBs is relatively new in biopharma, so I expect there is still ample room for scale-up. In any case, this approach would likely require a larger number of smaller perfusion reactors running in parallel.
I’m generally skeptical of the assertion that this will require “Nobel Prize winning” efforts to fix this. Honestly, sterility seems like the hardest problem of the bunch to me, which is why single-use materials seems like a winner. My gut tells me that it really shouldn’t be that hard to get cheap amino acids from soy; this isn’t based on a careful analysis mind you, it just really seems like this would be solvable if scaled-up sufficiently.
Single-use technology (SUT) in biopharmaceutical manufacture offloads many risks associated with upstream cell culture farther upstream—to media suppliers etc. A producer with a full-SUT process does not even carry the risk of cleaning and maintaining their own equipment. The purported economic and environmental benefits of SUT are related to the elimination of sterilization steam (because everything is gamma-sterilized before shipping) and the elimination of cleaning chemicals (because the bags are not cleaned for reuse).
The size limit of 2,000 L arises from the mode of sterilization—the penetration depth of gamma radiation from a cobalt-60 source is about 30 cm. In a stirred-tank configuration, this means that the rigid impeller inside the bag can be no larger than ~50 cm in diameter when the bag is folded up and irradiated from two sides. Following typical bioreactor geometry rules for animal cell culture (vessel height/diameter ratio and vessel/impeller diameter ratio), a 50-cm impeller indeed limits the scale to 2,000 L. For typical microbial bioreactor guidelines (very high OUR), the SUT limit is rather closer to 1,000 L. The 6,000 L bags are meant for very low cell density processes (very low OUR), like vaccine production in Vero cells on microcarriers. An alternate SUT configuration is the wave bag; the largest out there today is also 2,000 L (looks like a queen-size water bed) with a 50% working volume.
From my perspective, the SUT argument got too tortured between the small maximum size, the amount of waste generated (including daily media-prep bags, filters, and hoses), the observation that large stirred bags still need to sit in a permanent stainless-steel shell, and some discussion I found in “the trades” which said that SUT automation is suboptimal, apparently because the best single-use sensors (pH, temperature, etc) are not good enough for fully automatic operation. Combined with 100% manual unpacking, setting, connect/disconnect, and teardown of bags, the single-use idea seemed very much at odds with the fully automatic plant that many propose.
Finally, the gamma sterilization industry is extremely strained right now—the cobalt supply is tapped, or at least promised to EV-makers. New production of Co-60 is barely keeping pace with attrition at existing sterilization facilities, and the industry is already in triage mode with respect to what healthcare/biotech equipment gets to go through gamma sterilization versus what can go through an alternate sterilization, like ethylene oxide. So a significant expansion in the supply chain of SUT would be out of the question today.
(Aside: yes, ATFs are incredibly expensive today and their price could be expected to come down with market volume, but it doesn’t matter in the terms of my analysis. In my perfusion analysis, the perfusion devices contribute $10 out of $50/kg, and I assert an affordability threshold of $25.)
Given recent events, it is perhaps relevant to note that half of the nuclear facilities capable of turning Co-59 into Co-60 are in Russia. Cobalt supply issues are not easing up anytime soon.
I appreciate the response here and want to clarify my argument a bit. I totally understand that currently available SUT isn’t sufficient to make cultured meat cost-effective. I’m mostly arguing against the notion that these problems are intractable. To your point about the difficulties with gamma irradiation, it seems likely that there could be a reasonable alternative to gamma irradiation for SUT sterilization. At the moment, pharma companies get by just fine using stainless steel for processes > 2kL, so there isn’t much pressure to improve from that angle. If single-use is truly enabling for cultured meat, then that provides an impetus for more investment in improved sterilization technologies.
The purported economic and environmental benefits of SUT are related to the elimination of sterilization steam (because everything is gamma-sterilized before shipping) and the elimination of cleaning chemicals (because the bags are not cleaned for reuse).
The major cost savings I see for a cultured meat plant would be in a reduction in the requirements for air quality. A fully single use plant with completely aseptic connections can (in-theory) be run aseptically without a clean room. There would just be a small clean room for media and solution prep. Existing pharma plants using SUT tend to still need high quality air as there are some steps in the process that require manual manipulation. I’ve seen it suggested though that future biopharma processes which use fully integrated and continuous systems can be run in clean rooms with drastically lower air quality than existing plants.
Combined with 100% manual unpacking, setting, connect/disconnect, and teardown of bags, the single-use idea seemed very much at odds with the fully automatic plant that many propose.
Moving to long duration perfusion (> 30 days) reduces the need for unpacking / teardown. There have been biopharma companies which have demonstrated the ability to run stable perfusion for up to 60 days. For the most part, companies haven’t gone longer than that mostly because it’s not really necessary.
Thanks a lot for your expertise and notes here! For context, how expensive are the single-use bioreactor bags? Both right now and realistic projections 5,10,20 years out?
I’m wondering to what extent this is something where the costs would seem very cheap for biopharma applications but too expensive for a commodity.
The internet claims about $30K for a 1K L bag, do these numbers seem approximately right to you? If so, how amenable are costs to >10x decreases?
Having never purchased a SUB myself, I don’t know the exact cost, but $30k for 1000L bag seems ballpark correct for biopharma. That all said, it’s just a big ’ol plastic bag, I would bet that a food-grade version could be at least 10x cheaper.
Looking at the materials (Single-use bioreactor—Wikipedia), these are all very typical polymers that should be quite cheap (in theory at least). You could get away with food grade plastics, which should be significantly cheaper than pharma grade.
SUBs have also only become popular relatively recently. My major biopharma employer only started using SUBs in a significant fashion in the last decade. My point being, I bet there is still room for improvement in manufacturing costs since SUBs are a relatively recent innovation.
Just to hedge a bit, it’s a bit hard for me to give you exact numbers here in terms of how much room for improvement there truly is. I’m not a materials scientist and don’t have intimate knowledge of SUB construction. It’s entirely possible there is some super expensive step required to make those things, that just can’t feasibly be reduced.
Hey all, I’ve got some thoughts here. I worked in biopharma and spent some time working on a high-cell density perfusion system with CHO cells, so I’ve got some unique insight here. Right now for biologics production, there is a ton of effort in developing medium-scale perfusion processes run in single-use bioreactors (i.e. plastic bags). None of the analyses focused on this mode of production. There are potentially massive benefits to this approach.
Single-use equipment solves the sterility issue. Single-use equipment can be pre-assembled and sterilized in place. This allows for plants that don’t maintain strict sterility, saving on capital costs and operational costs. Note that this is not standard right now; biopharma plants with single-use equipment still usually maintain high air quality. However, for food-grade applications I bet you could get away without high quality air if you relied on single-use equipment.
There are massively reduced capital costs when using single-use equipment. I’ve heard that single-use bioreactors (SUBs) can cut CAPEX by ~70% or so, although I imagine these numbers are inflated by companies advertising the sale of SUBs. Still, this puts us much closer to a reasonable cost. Of course, this is offset somewhat by the cost of the bags. However, with a sufficiently long perfusion culture (maybe say 60 days), you can cut the amount of single-use materials required. You also save on cleaning costs, as you can dispose of single-use equipment after use. There is potentially a higher labor cost here, as you will need labor to remove old equipment and install new equipment between runs. This is likely offset somewhat by less labor cost for cleaning.
Humbird suggests using ATF membranes for cell separation in perfusion, which is incredibly expensive (10% of the cost in his optimistic scenario). ATF and other membranes are the standard separation method for biopharma perfusion right now, but there are potentially better methods out there. Stuff like acoustic wave settling or Hydrocyclones could be significantly cheaper (full disclosure, I contributed in a small way to this hydrocyclone work).
Spent media could be purified to recover and recycle any micronutrients. Macronutrient recovery would be harder, but is still potentially feasible. (To be fair, you could do this with any approach, but it’s worth nothing)
The main downside is that right now SUBs are limited to ~2,000L. There are bags as large as 6000L out there, although I have no experience with them. However, in general the use of SUBs is relatively new in biopharma, so I expect there is still ample room for scale-up. In any case, this approach would likely require a larger number of smaller perfusion reactors running in parallel.
I’m generally skeptical of the assertion that this will require “Nobel Prize winning” efforts to fix this. Honestly, sterility seems like the hardest problem of the bunch to me, which is why single-use materials seems like a winner. My gut tells me that it really shouldn’t be that hard to get cheap amino acids from soy; this isn’t based on a careful analysis mind you, it just really seems like this would be solvable if scaled-up sufficiently.
Single-use technology (SUT) in biopharmaceutical manufacture offloads many risks associated with upstream cell culture farther upstream—to media suppliers etc. A producer with a full-SUT process does not even carry the risk of cleaning and maintaining their own equipment. The purported economic and environmental benefits of SUT are related to the elimination of sterilization steam (because everything is gamma-sterilized before shipping) and the elimination of cleaning chemicals (because the bags are not cleaned for reuse).
The size limit of 2,000 L arises from the mode of sterilization—the penetration depth of gamma radiation from a cobalt-60 source is about 30 cm. In a stirred-tank configuration, this means that the rigid impeller inside the bag can be no larger than ~50 cm in diameter when the bag is folded up and irradiated from two sides. Following typical bioreactor geometry rules for animal cell culture (vessel height/diameter ratio and vessel/impeller diameter ratio), a 50-cm impeller indeed limits the scale to 2,000 L. For typical microbial bioreactor guidelines (very high OUR), the SUT limit is rather closer to 1,000 L. The 6,000 L bags are meant for very low cell density processes (very low OUR), like vaccine production in Vero cells on microcarriers. An alternate SUT configuration is the wave bag; the largest out there today is also 2,000 L (looks like a queen-size water bed) with a 50% working volume.
From my perspective, the SUT argument got too tortured between the small maximum size, the amount of waste generated (including daily media-prep bags, filters, and hoses), the observation that large stirred bags still need to sit in a permanent stainless-steel shell, and some discussion I found in “the trades” which said that SUT automation is suboptimal, apparently because the best single-use sensors (pH, temperature, etc) are not good enough for fully automatic operation. Combined with 100% manual unpacking, setting, connect/disconnect, and teardown of bags, the single-use idea seemed very much at odds with the fully automatic plant that many propose.
Finally, the gamma sterilization industry is extremely strained right now—the cobalt supply is tapped, or at least promised to EV-makers. New production of Co-60 is barely keeping pace with attrition at existing sterilization facilities, and the industry is already in triage mode with respect to what healthcare/biotech equipment gets to go through gamma sterilization versus what can go through an alternate sterilization, like ethylene oxide. So a significant expansion in the supply chain of SUT would be out of the question today.
(Aside: yes, ATFs are incredibly expensive today and their price could be expected to come down with market volume, but it doesn’t matter in the terms of my analysis. In my perfusion analysis, the perfusion devices contribute $10 out of $50/kg, and I assert an affordability threshold of $25.)
Given recent events, it is perhaps relevant to note that half of the nuclear facilities capable of turning Co-59 into Co-60 are in Russia. Cobalt supply issues are not easing up anytime soon.
I appreciate the response here and want to clarify my argument a bit. I totally understand that currently available SUT isn’t sufficient to make cultured meat cost-effective. I’m mostly arguing against the notion that these problems are intractable. To your point about the difficulties with gamma irradiation, it seems likely that there could be a reasonable alternative to gamma irradiation for SUT sterilization. At the moment, pharma companies get by just fine using stainless steel for processes > 2kL, so there isn’t much pressure to improve from that angle. If single-use is truly enabling for cultured meat, then that provides an impetus for more investment in improved sterilization technologies.
The major cost savings I see for a cultured meat plant would be in a reduction in the requirements for air quality. A fully single use plant with completely aseptic connections can (in-theory) be run aseptically without a clean room. There would just be a small clean room for media and solution prep. Existing pharma plants using SUT tend to still need high quality air as there are some steps in the process that require manual manipulation. I’ve seen it suggested though that future biopharma processes which use fully integrated and continuous systems can be run in clean rooms with drastically lower air quality than existing plants.
Moving to long duration perfusion (> 30 days) reduces the need for unpacking / teardown. There have been biopharma companies which have demonstrated the ability to run stable perfusion for up to 60 days. For the most part, companies haven’t gone longer than that mostly because it’s not really necessary.
Thanks a lot for your expertise and notes here! For context, how expensive are the single-use bioreactor bags? Both right now and realistic projections 5,10,20 years out?
I’m wondering to what extent this is something where the costs would seem very cheap for biopharma applications but too expensive for a commodity.
The internet claims about $30K for a 1K L bag, do these numbers seem approximately right to you? If so, how amenable are costs to >10x decreases?
Having never purchased a SUB myself, I don’t know the exact cost, but $30k for 1000L bag seems ballpark correct for biopharma. That all said, it’s just a big ’ol plastic bag, I would bet that a food-grade version could be at least 10x cheaper.
Looking at the materials (Single-use bioreactor—Wikipedia), these are all very typical polymers that should be quite cheap (in theory at least). You could get away with food grade plastics, which should be significantly cheaper than pharma grade.
SUBs have also only become popular relatively recently. My major biopharma employer only started using SUBs in a significant fashion in the last decade. My point being, I bet there is still room for improvement in manufacturing costs since SUBs are a relatively recent innovation.
Just to hedge a bit, it’s a bit hard for me to give you exact numbers here in terms of how much room for improvement there truly is. I’m not a materials scientist and don’t have intimate knowledge of SUB construction. It’s entirely possible there is some super expensive step required to make those things, that just can’t feasibly be reduced.