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Echo Veterinary Consulting

Consultant Vétérinaire Écho

Review of Techno-Economic Assessment

of Cultivated Meat

For: Australian Sustainable Animal Protein Production

Huw P. A. Hughes, B.Sc., Ph.D.,

ISO 9001:2015 QMSA Accredited


Executive Summary:

A review of the TEA document finds the following:

A finished product fit for consumption is not defined, and so estimating a cost for
an acceptable consumer product is challenging. The TEA cost estimates for a
cell slurry (an intermediate product) may also be an underestimate, based on
current process understanding, media costs etc. An estimate is prepared with a
process architecture suited to mammalian and avian stem cell propagation,
assumptions on media requirements and overall factory costs, competitive fully
loaded FTE costs and other process requirements.

It is estimated that the cost of 1 kg of cell culture product for consumption would
be in excess of ~$8,500 to $36,000 per kg. By comparison the wholesale price of
trimmed chicken meat in the US is $3.11 (February, 2021).

These cost estimates should be revised upwards as the consumer product is

defined, including the methods for purifying, processing and packaging the raw
ingredient into a tasty product that is free from harmful contamination. R&D
costs for continuous improvements should also be included. It is advised that a
proper concept design for a factory be completed, including costs for the correct
quality standards for the long-term culture of mammalian and avian cells.
Review of Techno-Economic Assessment of Cultured Meat


Adipocyte – Fat cell

CCP – Cell cultured product ( equivalent to ‘Cultured Meat’ or ‘CM’)
CEF – Chicken embryo fibroblasts
COGs – Cost of good(s)
CIP – Clean in place
CM – Cultured meat
dO2 – Dissolved oxygen
DSP – Downstream processing
FDA – Food and Drug Administration (USA)
FGF-2 – Fibroblast growth factor 2
FSIS – Food Safety and Inspection Service (USA)
GRAS – Generally recognized as safe
HPV – Hydrogen peroxide vapour
HTP – High throughput
kLa – Efficiency of oxygen supply
MCB – Master cell bank
MTO – Make to order
Myocyte – Muscle cell
QA – Quality assurance
QC – Quality control
QS – Quality system(s)
R&D – Research and development
SCM – Stem cell medium
SMART (goals) – Specific, measurable, achievable, relevant, time-bound
SIP – Steam in place
SS – Stainless steel
SUB – Single use bioreactors
TEA – Techno-environmental assessment
TFF – Tangential flow filtration
TGF-beta – Transforming growth factor-beta
UHP – Ultra high pressure
USD – US Dollars
USDA – United States Department of Agriculture
USP – United States Pharmacopoeia
WCB – Working cell bank
WFI – Water for injection
wv – Working volume

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A document has been completed by CE Delft entitled “TEA of cultivated meat’,

which defines production costs for a large-scale production of cells that may be
used to produce palatable nourishment replacing conventional meat products, in
particular chicken and beef.

This report discusses the methods and assumptions that are made, and
concludes that further work is required.


In order to replace meat products with cell cultured products (CCP), one needs a
basic understanding of the cell types themselves and the issues surrounding their

The Good Food Institute (GFI, 2020) states that the following cell lines are used
for CCP:
• Pluripotent stem cells
• Adult stem cells
• Fibroblasts, myoblasts and fibroadipogenic progenitor cells
• Myosatellite cells

Culturing these cells, unfortunately, is not simple. Chicken embryo fibroblasts

(CEF) and animal stem cells (embryonic and adult) are used in animal and human
health large-scale pharmaceutical production for vaccines and
biopharmaceuticals. Stem cells are also used in custom products for cell therapy.
While there is less experience with other cell types in large-scale production, one
can expect similar issues to be raised during the industrial development of CCP.

Fibroblastoid cells (e.g. CEF).

While easy to cultivate over a short term, generally these are close to terminally
differentiated cells, and therefore extremely difficult to culture to high densities
over a prolonged period of time unless one has a huge supply of cells at the
onset. These cells are generated through the homogenization of embryos,
followed by a coarse filtration to get rid of any extraneous matter (feather, bone,

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beak, etc.). Cells are then washed in medium and/or saline and suspended in
culture medium.
These cells generally have limited cell differentiation capacity and only one or
two subcultures (or 4-5 cell divisions) are used before the cells start undergoing
apoptosis (or programmed cell death). Unless these cells are transformed for
example, by introducing virus genome into the cellular DNA, they are generally
incapable of culture for more than 7-10 days, and will not undergo unlimited

Stem Cells

Stem cells are extremely fastidious in their requirements for extended division
and growth. They may require a number of hormonal and growth factor
ingredients as stated in the TEA, and the basal medium for cultivation is usually a
custom item. For example, during the development of a medium for chicken
and duck cell stem cells, over 250 candidates were tested. After 2 years of
intense R&D, a serum-free medium was defined. After more years of industrial
development, this is now available for all levels of production from Millipore-
Sigma. The catalogue price is (USD) $78/L or $4,110/100 L as a bulk supply.

In an analysis of culture medium costs, Specht (2019) used DMEM/F12 medium

as a base, with a cost of $62,400 for a 20,000 L batch (or $3.12/L). However, this
appears to be the cost for powdered bulk medium (from, e.g., MP Bio), and does
not include the cost for labour, USP water, formulation, filtration and testing prior
to culture. Given the fact that up to now stem cells require custom media, the
price for base medium alone could rise to $822,000 for the same sized (20,000 L)
batch. However, it should be noted that a properly developed medium may rely
less on growth factor additives.

Derivation of stem cells for continuous culture is also not a trivial task. Many
attempts at obtaining the ‘right clone’ will need to be done before one has a
population of cells that will spontaneously grow without undergoing terminal
differentiation, resulting in a different cell phenotype, lack of proliferation and
ultimately apoptosis.

Once the cell clone has been identified, and appears to grow spontaneously, a
master cell bank will need to be manufactured under strict quality standards, and
then it will be required to undergo considerable testing (see below).

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Stem Cell Culture

Stem cells may be successfully cultured in bioreactors at different volumes.

However, scale-up is hindered by the fact that stem cells generally do not grow
in a single cell suspension. Instead, stem cells tend to grow in aggregates, and
the aggregates can become quite large. This is to be expected, as cell-to-cell
cooperation and communication is essential for stem cell proliferation and
survival. In larger clumps, cells in the center will become starved of oxygen and
nutrients, and will die. Therefore, when propagating stem cells in large scale
cultures, the feed rates of nutrients, oxygen tension and stirring (impeller speed)
all must be adjusted precisely to ensure that the culture remains on the knife
edge between encouraging cells to grow in aggregates and ensuring the
aggregates do not become so large that there is significant cell death. These
growth conditions will be difficult to replicate and validate in the larger volumes
(>1,000 L) where the response time to various biofeedback stimuli is by the
nature of the environment, slow.

Adipocytes (fat cells)

A lot of the flavour in meat products, particularly in meat products such as

hamburger, sausage, and chicken nuggets, comes from fat. Therefore, to be
‘authentic-tasting’ CCP must have a certain fatty component to be palatable.
While this may be introduced in cooking (e.g. by deep frying, etc.), it is generally
recognized that adipocytes would become part of the growth and production
process of a CCP (Post M.J., et al, (2020). However, simple co-culture of 2
different cell types will not result in the correct balance in the final cell yield.
Therefore, each cell must be cultured independently and somehow blended or
added to provide a tasty consumer product. Exactly how this may be achieved is
uncertain and not discussed in the TEA. As an alternative, plant oils may be
added to the product.


The TEA authors have proposed that a number of recombinant growth factors be
included in the medium. While this may be required for R&D, it is possible that
some of them may not be required once the product goes to industrial
development. This has been the case with certain stem cell cultures, but
depends heavily on the investment to define custom media for cell growth, which

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can take several years, and cost between $5 M and $10 M. The probability of
success to gain cost efficiencies will depend on (a) the cell lines/clones chosen;
(b) the R&D investment in defining new media, supplements and processes; and
(c) the ability to transfer these processes to an industrial scale.

The medium proposed may contain the following ingredients: Albumin, insulin,
transferrin, FGF-2 and TGF-beta. While some of these components are GRAS,
others may be prohibited from human food as an ‘additive’, and so would have
to be removed from the product during downstream processing (DSP).


The development and industrialization of a cell culture process is defined by the

following factors:

Demand. In general, one achieves economies of scale, so the larger the batches,
the cheaper the product. This is because most production systems these days
are automated and require few people to run each unit operation. However, the
cost of the equipment is high, and usually these costs are depreciated over a
period of 10 years. These costs in a single product factory will go directly against
the product. Thus, at year 11 after launch a CCP may become less expensive
due to the ‘paying off’ of the depreciation costs. In general, a modest decrease
or over-run in factory design and building costs do not adversely affect finished
product costs, as they are depreciated. However, retrofitting once the factory is
fully depreciated can severely erode expected margins due to increased capital

Cell growth characteristics. How easily the cells proliferate in the medium can
define how the scale-up is achieved. For bacteria, one may generally subculture
in the range of 1:10 to 1:100, depending on the bacterium. For stem cells, which
are more fastidious, the highest subculture ratio (i.e. the amount of an old culture
one uses to seed or start a new culture) is typically 1:5. This is significantly less
than the 1:200 cell ratio that is proposed in the TEA. Experience dictates that if
stem cells are sub-cultured at the ratio proposed, they will either differentiate
and stop growing, or simply will die. Likewise, for the CEF-like cell lines that
have very limited cell propagation, they will undergo their terminal differentiation
and growth or they may die. As stated above, in cells that are poorly adapted to
bulk growth as established or transformed cell lines, cell-to-cell communication is

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vital, and if cells are subcultured at a ratio encouraging high dilution, they may
simply not grow and die. Other factors that affect cell growth include essential
feeding or supplementation to overcome the build-up of toxic metabolites,
provide adequate dissolved oxygen, and other nutritional and physiological
parameters that can be controlled in bioreactors.

Process Architecture. The types of methods used (static culture, adherent cell
culture, suspension culture, etc.) and the types of vessels used for culture are vital
for successful and consistent yields. Sometimes one trades off the possibility of
inconsistent or occasional high yields for consistent, albeit lower, yields.


The process as defined in the TEA is likely inadequate for the successful scale-up
of stem cells, for the reasons stated above. In general a scale-up train such as
the one described below may be used, and will result in the following economic
and operational benefits: (1) less scrap, (2) production of intermediate product
(working cell banks – WCB) that may be used to ‘jump start’ successive cultures,
and (3) consistent cell culture dynamics. However, with this efficiency come the
disadvantages that there is more equipment required, and a larger footprint,
resulting in higher overall cost.

Open Phase:

Initially, a high concentration of cells will be taken from a freezer and grown at
small scale. All manipulations would be carried out in a Class A biosafety
isolation hood to avoid contaminating the culture. Experience has shown that
stem cells adapt readily to the process described below.

During these initial passages the total medium usage will be approximately 2.6 L,
and the time taken will be 12 to 15 days. The turn-around time (i.e. tear down
and reconfigure) for this unit operation will be 24 hours, when using disposable

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Cell Banking: Cells are Initial cultures will be in a The cells will be added to a
banked in the vapour small scale ‘spinner flask’. disposable culture bag that is
phase of liquid nitrogen. Medium (25 mL) and cells (1.5 used in a rocking motion
This is the Master Cell to 2 mL) are introduced into (wave) bioreactor. Initial
Bank (MCB). A vial may the flask and as the culture volumes may be 500 mL,
be thawed quickly and grows, a further 25 and then scaled up to 2.5 L. Oxygen,
used to start the culture. 50 mL of medium is added, motion and other parameters
depending on cell type. are controlled.

Closed Phase (1):

Once cells are in a wave or small benchtop bioreactor, they may be transferred
to other vessels in a ‘closed system’. In this system, plastic tubing may be
welded to sterile joints or tubing of the same diameter using plastic welding and
connection systems available on the market. This helps to reduce the chance of
contamination, while ensuring overall system compliance. Generally, transfers
may be carried out quickly at the smaller scale. In the cartoon below, a
bioreactor chain is represented that will scale up from the wave bioreactor to a
1,000 L scale. In these instances, capital costs and turn-around time may be
reduced through the use of disposable bioreactors (SUBs), although the cost-
per-run in consumables (plastic SUBs, totes, manifolds, tubing, etc. ) is estimated
as US $20,000 ±30%, depending on the system that is chosen.

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Cells are transferred Contents of the 50 L The 250 L culture is similarly

from the wave bioreactor bioreactor are aseptically scaled to another higher
to a 50 L bioreactor with transferred through plastic volume bioreactor with a wv
reduced volume (25 L), tubing (SUB) or through hard of 1,000 L. This may be the
which is replenished to pipe (SS bioreactors) to a 250 largest economically viable
full working volume (wv) L bioreactor. Some of the 50 SUB container for this
after 5 to 7 days’ culture. L culture may be kept for a process. Some cells may be
Antifoam may be added. working cell bank (WCB). kept for a WCB.

The total time taken for this phase will be ~20 days, and the total volume of fluid
will be 1,275 L. The turn-around time for this unit operation will be 24-48 hours if
using SUBs, and 5 to 7 days if using SS bioreactors.

Note that cells may be used during scale up to create working cell banks that
eliminate the need to constantly go back to the frozen MCB for future batches.

Closed Phase (2):

Following culture at the 1,000 L scale, cells may be transferred to a 5,000 L

bioreactor, or a 10,000 L bioreactor that has reduced volume. In the scenario
described below, a 5,000 L bioreactor is chosen, to mitigate any risks associated
with subculturing small volumes of cells in a large vessel. Exact calculations of
kLa and other process parameters at lower scales would have to be completed in
the R&D phases to assess the feasibility of moving from a 1,000 L to a 10,000 L
bioreactor at reduced volume. The process calls for 3 harvests of 6,000 L each.

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The contents of the 1,000 L SUB

or SS bioreactor are transferred
through a hybrid aseptic system
(such as STT Quick-connect®)
that can allow the connection of
disposable tubes to SS tubes.
The contents of the 1,000 L are
transferred to the 5,000 L tank
and from there to the 10,000 L
tank using an air pressure system
and conventional SS tubing.

The total time taken for this phase will be 10-15 days. The total volume of fluid
used in this unit operation is 33,000 L. Note that the total volume of the
bioreactors will need to be ~20 to 25% larger than the culture volume to account
for headspace in the factory.

Closed Phase (3):

Cultures from the 10,000 L bioreactor will be used to feed 4 perfusion reactors.
In this instance, the TEA authors had proposed a 10-day perfusion culture that
would use 800 L of media for each 2,000 L of product. At present this is a
hypothesis. Depending on the cell metabolism and other criteria, the volume of
media required for perfusion may be many times more than the 800 L per 2,000 L
proposed. The timing proposed for this stage also appears to be optimistic at
10 days. For such a short perfusion time, normally the process would be better
suited to a high-density fed-batch process (10-12 d). Perfusion generally is
reserved for longer-term cultures (20-35 d or more, Bausch et al., 2019).

It is therefore recommended to carry out trials comparing fed-batch to perfusion

culture, since in a 10-12 day time frame yields between the two are generally
similar, and fed-batch production is considerably less expensive in all respects
(labour, equipment, medium, factory footprint, maintenance and validation, etc.).

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UPSTREAM PROCESS SUMMARY – Myocytes (stem cells as an example)

Stage Time Volume

Open Phase 12 -15 d 2.6 L
Closed Phase 1 20 d 1,275 L
Closed Phase 2 10 -15 d 33,000 L
Closed Phase 3 10 d 11,200 L
TOTAL 52 – 60 d 49,778 L

Note that this process takes 10 to 18 days longer, and uses about 8,500 L of
media more than anticipated in the TEA document. This is largely due to the
addition of scale-up steps to make the process more capable.


Little attention in the TEA document is directed towards DSP, which is an

essential part of the production process. The end product described in the TEA
is cell slurry. Regulations will likely prohibit the presence of pharmaceutically
active compounds that are or could be medicinal (e.g. insulin, TGF-beta, etc.) as
well as any contaminating infective material (e.g. retroviral contamination). In
order to respect this guidance, all extraneous materials from the cell culture must
be replaced with an innocuous transport medium. To do this a bank of filtration
systems is proposed for each cell type.

Cells from the culture system (whether

perfusion or fed-batch) will need to be
separated from medium components
using either a column filtration system or
a plate-and-frame TFF system. In both
systems, one can expect some cell death
(see risks, below).

The filtration systems would have to be continuous, as any batch system would
not be able to carry out the filtration easily in single shifts. These systems, while
they exist, are expensive and tend to be custom-built for the unit operation. A
filtration skid would have to be downstream of each perfusion system (or fed
batch reactor), so 4 in total would be needed for myocyte culture as proposed in

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the TEA, with an additional spare in the case of any major failure event. It is
anticipated that a further 2 DSP systems would be required for adipocyte culture,
if employed (see below). The cost of any DSP does not appear to be included in
the assessment, nor is the time. Commonly, DSP is a bottleneck in any biological
production process, and scaling up to a 10,000 L total volume will not be a trivial

Another factor to consider in the DSP is that most systems are designed to
isolate proteins from cell culture systems. In this case however, the reverse is
true, and keeping cells alive and ensuring that they maintain their structure
during this process may be difficult to achieve due to the shear stresses on the
cells during processing (see risks, below). As cells come out of the reactors, they
will need to be cooled to +4ºC, and continuously processed at this temperature
prior to further processing and packaging. Filtration is preferred over continuous
centrifugation as it is easier to validate and easier to run as an aseptic or low
bioburden process.

Downstream processing of this kind will use at least 2 to 5 volumes of buffer to

do a complete exchange and concentration (i.e. ~40,000 L to 100,000 L per
batch), depending on technical feasibility, product profile and other factors.


The figure below indicates a reasonable process flow for a finished product CCP.
The TEA authors propose that their cost evaluation would be for a ‘modeled
product’ that would consist of 1 kg of cell paste or slurry, that would be made out
of myocytes or meat (muscle) cells (top left in the figure). However, as discussed
above, for additional flavour adipocytes or fat cells may need to be added to the
mixture (Post et al., 2020). This requires a separate cell culture system that would
have to be running concurrently to the muscle cell CCP, albeit at a lower overall
capacity. These cells would then need to be blended with the muscle cell slurry
prior to further processing and packaging. An alternative strategy would be to
use plant-based fats (Rubio et al., 2020), though these authors also indicate that
the culture of fat cells to produce the right flavour and texture may be a viable
method. However, they propose co-culturing the two cell types, which will only
be an option if the cells were being cultured on an edible scaffold, rather than in
a bioreactor. For the purposes of this document, it is assumed that adipocyte
culture yields the best taste and texture product.

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Once a slurry of myocytes (and in this recommendation, adipocytes) has been

prepared, it is unclear as to how this gets turned into a finished product ready for
the consumer. Most articles on the topic speak of a solid phase upon which cells
would grow, similar to the 3-D printed medical devices that are used for cell
replacement therapy (Post et al., 2020). If the slurry were the final product, there
would have to be some kind of processing and preservation added and then
shaping (nuggets, burgers, etc.) and then packaging. These steps are unclear.

Nutritional Value

A cell slurry, whether processed as a ‘nugget’ or ‘hamburger’, may have different

nutritional value compared to meat. It may have protein, cholesterol and overall
fat content similar to the authentic product, but other nutrients might be lacking.
Typically, these would include the following: Vitamins B6, B12, E, and K, Calcium,
Iron, Magnesium Phosphorus, Zinc, and other trace elements that are important
in maintaining a nutritional balance. It is unclear whether these might be or
would be added back to the product during processing, so that there is a
nutritional value similar to the authentic (animal-derived) meat.

Packaging and sterilization

If the packaging is done with a low bioburden, and the CCP is to remain at +2 to
8ºC, then bacterial inactivation may have to be carried out to ensure that the
product does not carry any harmful human pathogens (e.g. enterotoxigenic E.coli
0157:H7, Salmonella, Listeria, norovirus, etc.). The food industry may use an
ultrahigh pressure (UHP) system to sterilize meat, as this does not affect taste nor
does it introduce any extraneous chemicals (Campus, 2010). However, how a

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single cell slurry will respond to UHP is unknown, and the CCP may be destroyed.
If this were to be the case, the CCP would need to have preservative chemicals
added back to it or would need to be packaged as a sterile product, which would
greatly increase the factory design and build cost.


The finished package must be labeled appropriately. For example, the package
in the figure above has the word ‘Meat’ and a cartoon of a chicken. Correct
labeling will have to be discussed with the agencies involved so that the label
represents the product itself, and not what the product is trying to imitate, or
intending to be. The Oxford dictionary definition of meat presently is “The flesh
of an animal or a bird eaten as food”. Cells grown in a bioreactor arguably do
not fall within this definition. In the US, 12 states have already passed laws
restricting the use of the word ‘meat’ on CCP. Legislation would also require
nutritional value to be accurately represented on the label, so addition of trace
nutrients (above) may be advised.


Cell pastes or slurries are notoriously unstable and will deteriorate very quickly,
losing their cellular structure. Real meat on the other hand is built on a scaffold
of blood vessels, interdigitating cell structure and layers of connective tissues,
tendons etc., that helps to maintain structure. Even ground meat will maintain
some of this structure at the macro level, and is seldom if ever homogenized to a
single cell slurry. Given the large yields of CCP, a process must be devised to
ensure that the slurry maintains its structure. Further, for longer-term stability the
CCP would optimally be frozen-shipped, and sold in the freezer aisle at the
market. How to attain stability at 4 ºC or -20 ºC is not addressed. Cell slurries
may decompose relatively quickly at refrigerator temperature, and may not
survive freeze-thaw cycles as well as meat.

These and other issues concerning the stability (or shelf life) of a finished
product, how it would survive refrigeration, snap freezing, shipping, and thawing
prior to cooking appear to be neither discussed nor assigned a cost.

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The TEA does not seem to address process risks in any detail. Rather, the
authors identify costs savings through capital equipment becoming less
expensive, and include undefined process improvements, enabling a less
expensive and more efficient production process.

Equipment costs.

Large scale bioreactors (>2,000 L) will remain custom built items for the
foreseeable future, and thus will be expensive to build and install. In general, the
pharmaceutical biological industry relies on bioreactors up to 1,000 L or 2,000 L
scale for the production of biological products (vaccines and biotherapeutics).
Cost savings are initiated through process and genetic engineering to increase
yields, cell line development, etc. For CCP, genetic manipulation is likely not an
option for a multitude of regulatory and social reasons, so the production
process may only make some incremental efficiencies.

Media and supplements

As stated above, the cost basis does not include a base medium for stem cell
production that would increase cost, in this case by c. $41/L. The cost-reduction
assumptions are that (a) some growth factors and recombinant proteins may be
produced at lower cost, (b) cells will be grown to a higher density, (c) there will
be a shorter production time, and (d) a larger volume of cells. All of these are
lofty aspirations, and figures concerning cost reduction are put against them.
There is no explanation as to how any of these aspirations may be turned into
SMART goals, and all will depend on the biological characteristics of the cells
that are used to make the MCB.

As explained above, costs of recombinant chemicals and growth factors likely will
not be reduced appreciably. Focused R&D towards new synthetic media may
bear fruit (see above). However, none of these options is discussed in any detail,
most will take between 4 and 10 years to implement and validate, and will cost
several millions of dollars in R&D and more to implement at the industrial scale.

A scientific assessment needs to be completed on each of the improvements

proposed, together with a risk/benefit analysis and estimated probability of
technical and regulatory success. In addition, as all of these factors depend on

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the inherent characteristics of the MCB, the choice of cell line/clone at the start
of the programme is vital. This will be confounded by the time taken to get an
optimal production clone vs. a clonal cell population that produces the correct
texture and taste (i.e. balancing customer demands with manufacturing

Upstream Process Risks

Contamination. Contamination remains the most significant risk, especially with

the long cell culture process, estimated to be between 52 and 60 days.

Cell loss during bio-fermentation. Stem cells will tend to grow in clumps, and
attempts to grow in a single cell suspension will result in a severe reduction in
viable cell count and yields. There will be some cell loss during fermentation as
cells in the middle of clumps will be starved of oxygen and media components.
Additionally, when the bioreactors are in operation, there will be hydrodynamic
shear stresses on the cells from oxygenation and mechanical shear stress from
the impellers, both of which will also lead to some cell death. At the larger
volumes (>1,000 L), all of these issues are exacerbated by the slower response
time of the equipment to maintain temperature, pH, dO2 and any feeds during
fermentation, simply due to the volume of fluids in the reactor.

Downstream Process Risk

Cell loss during filtration and buffer exchange. Filtration is required to ensure
bioactive molecules and viral contaminants are removed from the CCP. During
this process one can expect at least 5% of cells to be destroyed as the buffer
exchange and concentration occurs. Depending on the equipment used, there
may be further loss due to the volumes being processed and processing times.

Adipocyte/myocyte blending. Should the CCM contain both cell types, then
clearly a drop in quality of either cell during culture or DSP will jeopardize the
whole batch. Unlike other biological products, it is unlikely that batches can be
held and blended due to (a) the long overall process time (52-60 d) or (b) the
shelf life of an unprocessed slurry that is likely quite short before processing.
However, the process time may be decreased by using working cell stocks at
different points during the production process.

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A certain number of packages will be rejected, which will be a part of the overall
scrap rate. If a sterile fill is required, then the scrap rate may be increased 0.25-
0.5% based on experience with bulk filling in bags. Storage and shelf life need to
be assessed; if the CCP cannot be frozen, then there is a risk of scrap unless the
production is MTO. Given the size of the factories projected, one assumes a
MTO strategy. However, the product evolution from market entry to a broader
market share and how this affects manufacturing strategy is unclear.

Scrap rate.

Scrap is not included in the TEA cost model, which therefore assumes that every
batch is satisfactory. Scrap occurs because of contamination, human error,
equipment failure, process wobble and other unforeseen instances, such as
described in the risks above. In a new factory with complex, large-scale
processes such as this, one can assume at start-up an overall 5 to 10% scrap rate,
which will fall to 3% once processes become fully validated and capable at scale.
These rates would apply to a pharmaceutical grade run factory. If operated at
food grade, the scrap rate may be much higher.


Production Quality Standard (QS)

The Authors make the assumption that the QS will be food rather than
pharmaceutical grade. While this may be strictly true, the following must be

It is highly unlikely that any Regulatory Authority will allow the use of certain or
any antibiotics during cell culture, due to concerns about the increase in
antibiotic-resistant bacteria. Therefore, the complete cell culture of myocytes
(and adipocytes if required) will need to be completed under strict aseptic
procedures. Even if antibiotics were to be allowed during cell culture, the
following general principles may apply:

The cell culture and DSP zones will need to be constructed and operated
to pharmaceutical grade, which will entail the following: air handling to at

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least Grade A/B for the open phase operations, and C/D for closed phase
operations. All SS piping will need to be rotary welded, and validated for
lack of dead space. Fumigation and cleaning protocols with HPV must be
in place, as must training protocols.

Cell cultures of 52-60 days duration carry significant risk of contamination, and so
cannot be completed in a food grade environment.

In the US, it is already agreed that 2 different Regulatory Authorities will regulate
any CCP. The FDA will regulate the collection of cells, selection and growth,
while the USDA-FSIS will regulate final product quality, i.e. processing and
labeling. Thus, the factory design and operation must take into account this dual
standard/dual inspection model.

Requirements for cell banking

General requirements for cell banking are that (a) the cells are sterile – free from
bacterial, yeast or fungal contamination, (b) free from extraneous viruses that
could be harmful to the manufacturing process or the end user, (c) neither
oncogenic or tumorigenic, and (d) have a stable phenotype and genotype for the
duration of the culture. Whether FDA will permit cell banking for CCP without
passing some or all of these tests is unknown at present, though it is certain that
FDA does have jurisdiction over this part of the process. Regardless, it is advised
that the MCB be sterile, and free from extraneous agents to promote cell growth
with minimal scrap.

Quality requirements for cell processing through to concentrated slurry

Cell growth will require aseptic procedures, minimally sterile water to USP grade
(WFI not required) and CIP/SIP for all hard pipe SS installations.

The building will require air locks with increasing air handling quality, for both
materials and personnel. Typically this comprises a Class D corridor, with Class C
rooms except where open phase is carried out, which must be Class A in a Class
B environment with Class C minimal changing rooms. The TEA document does
not take into account this quality standard, nor does it take into account the
additional personnel time. For example, in an 8 hour shift, 30 to 60 minutes may
be spent in prep time for the personnel as they make their way in and out of

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production zones due to passage through the various air locks and additional
gowning procedures.

An annual shutdown should be considered to test and confirm all QS.


The Capital costs appear to only take into account the myocyte cell
manufacturing process. Further, a multiplier of tank capital costs is used to
extrapolate to the total capital, rather than drawing a concept design and
estimating surface area and cost to within a certain margin of error.

As discussed above, adipocyte cell culture may need to be added to ensure that
the CCP has the right texture, taste and ability to be cooked properly. Usually
hamburger has ~ 30% fat, though lower amounts (20-25%) may be acceptable.
This would require essentially the same cell scale up as the myocyte cells without
the perfusion/fed batch step. Given that production may be at the 10,000 L
scale, at least 2 DSP skids capable of high volume and high throughput would be

Below are listed the major requirements of a factory capable of large-scale cell
cultures. Many of these important details are omitted in the TEA:

Warehouse goods in. Storage (ambient, 4ºC, -20ºC, -80ºC) for all
ingredients, packaging and labeling supplies for the factory.

Machine room. USP water production, steam generator, clean steam

generator, centralized HPV generator. Due to volumes, the scale of the
machine room will be large, or may be in a separate building from the

Tank Farm. Gases and vacuum line/compressor for air and gas feeds to
bioreactors and other equipment.

Production freezer area. Storage of frozen cells for culture (vapour phase
liquid N2 and -80 ºC freezers).

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Media Kitchen. Normally, media components would arrive as dry powder

or granules, and would be formulated with USP water or media and
essential supplements for the bioreactors. Very large volumes would be
required, and a high throughput/high volume double bacterial filtration
system is required.

Myocyte cell fermentation. This area would comprise 4 areas: (1) small
scale/open phase, (2) scale up to 1,000 L (using SUBs), (3) scale-up to
10,000 L, and (4) perfusion or fed-batch reactors (This is included in the

Adipocyte cell fermentation. This area would comprise 3 areas: (1) small
scale/open phase, (2) scale up to 1,000 L (using SUBs), and (3) scale-up to
10,000 L.

DSP. These areas would have a total of 4 HTP skids for the Myocyte cell
culture, and 2 HTP skids for the Adipocyte cell culture. A seventh spare
should be available and ready to place on-line in case of failure or other

Packaging. A sterile packaging area would have to be installed, or, if not

sterile, then a terminal sterilization step may need to be employed.

Warehouse goods out. Areas at -4 ºC and -20 ºC (assumed), with areas

defined in each for finished goods, goods being tested in QC, and WIP.
Included loading dock with +4 ºC transition for refrigerated lorries.

Sanitary Equipment. Wastewater treatment, frontier autoclaves and other

sanitary areas/procedures

Other Requirements on site:

QC laboratory
Scale-down laboratory for trouble-shooting (may be in QC)
Offices (QA, Management, record retention)

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The following may be added for little additional cost:

BBQ area with executive chef for cooking schools and demonstrations
Executive dining and reception

The cartoon above (not to scale) indicates the functions that would be required
to make a slurry of myocytes/adipocytes that could be used to make a CCP ready
for the consumer. Note that it does not include airlocks, change rooms,
autoclaves and other ancillary spaces. Further, the larger bioreactors (10,000 L)
may need at least 2 floors of a building due to their height.

The basement of such a facility could be used for wastewater treatment. HVAC,
electrical supply relays etc. are also not included in the diagramme, but would be
included in a concept design pricing.

While the layout may appear overly complicated for making a food product, the
requirements to keep cells growing for over 50 days in continuous culture in an
antibiotic-free (or low concentration) environment will be the same regardless of
whether a pharmaceutical or a food grade product is being manufactured. In
general, for a factory of this complexity, the cost will be $3,000 to $6,000/m2,
depending on air handling requirements. Process equipment would normally be
added to this general cost.

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Clearly the capital costs are greater than those estimated by the authors in the
TEA, with apparently only a small fraction of the equipment and infrastructure
accounted for. It is unclear how the ‘Social Investment Criteria’ would work in
this situation, as a factory of this size and complexity will cost several hundreds of
millions of dollars to build. Due to the complexity of the manufacturing
processes, the requirement to remain as an aseptic process, commissioning and
validating the plant, even to food grade requirements, could also cost in the
millions of dollars, depending on the final product profile. Generally, these costs
would be put against the products coming from the factory over a 10-year
depreciation period.

As the capital cost depreciation will affect overall COGs, a concept design
should be completed, using standard surface area costs, and equipment
purchase, and installation costs obtained. This is especially the case as this will
be a single product factory, producing a product for which (a) there is a choice,
and (b) is a commodity rather than a specialty product.

Running Costs

Personnel costs are estimated as $100,000/annum/per FTE in the TEA, fully

loaded. This is likely an under-estimate for the operators in the aseptic areas, as
staff experienced in the operation, validation and trouble-shooting of complex
bioreactor and DSP processes would be required. This estimate could be
increased to $150,000 and even that may be on the low end depending on where
the factory is to be located. For example if in the Montreal, Boston, San
Francisco or other “Pharmaceutical corridors”, this amount may be significantly
higher for highly skilled workers and managers.

Cost Reductions

The authors claim that there will be cost or technical reductions in the following

Cost of Growth factors and recombinant proteins. As stated above, insulin costs
will likely remain as they are due to current and future manufacturing standards
and volumes. Other growth factors will only decrease if there is an incentive for

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suppliers to improve yields or make processes more efficient. The basis for this
cost reduction is unclear.

Albumin. Albumin may be replaced by commonly available protein

replacements, or through the use of an optimized defined medium (see above).
Generally, experience with these products is that there may be a reduction in
overall costs due to improved process robustness rather than decreased direct
fine chemical costs.

Capital expenditures. As stated above, the TEA has basically scratched the
surface for capital and running costs of a factory to produce a CCP. Once a final
product is defined, then this section should be re-visited This section should be
re-examined with a competent process architect and with an engineering firm to
arrive at a concept drawing, which can be costed to ±30%.

Maximum cell density and run time. Cell density may well increase as the
process becomes more familiar, and there will be incremental steps to reduce
cell death in the reactors and DSP. This may require (for example) the purchase
of additional HTP equipment that will shorten overall process time. However, to
get the degree of improvement suggested in the TEA (a consistent 4-fold
increase), there will have to be investment in new process parameters, new
media, and maybe changes to the equipment (e.g. impeller dimensions/ type,
sparging, etc.). This kind of investment, that is normal in process improvement
work, is omitted from the calculations. A similar argument can be made for run
times. As stated above, one way to decrease run time is to either retrofit or
purchase more equipment, and this also is omitted from the calculations.

Case study in cell line reduction costs

In both the human and veterinary pharmaceutical industry, the cost to produce
monoclonal antibodies has been steadily decreasing over the last 10 to 15 years.
Initial manufacturing of monoclonal antibodies produced yields that were in the
0.25 to 0.5 g/L range. This initiated the production of large SS bioreactors
(≥10,000 L) to meet market needs by some of the larger pharmaceutical
companies. However, as the technology became more mature, cell lines were
improved by genetic manipulation, new cell lines were developed and new
media and feeds were devised as a result. As well as the 10s of billions of dollars
that the pharmaceutical giants have invested in cell line and industrial

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development, adjacent industries also grew and expanded. The development of

single use technology from cell fermentation through to filling was accelerated,
and fine chemical houses were developing new media and other ingredients.
Currently, monoclonal antibodies are produced in the 3 g/L to 10 g/L range. This
is a remarkable improvement, and allows upstream bioreactor manufacturing to
be completed in SUBs.

In summary, Monoclonal antibody yields have seen a 10- to 20-fold increase in

the last 10 to 15 years, with 10s of billions of dollars of investment in R&D across
multiple industries. In the TEA example, it is proposed that costs will be
reduced, with a resulting >1000-fold decrease in costs. Given the experience
with monoclonal antibodies, this may be overly ambitious and does not take into
account the fact that every cell bank will be different – it is possible that each one
will need to be developed independently. The R&D strategy for process
improvement and a cost estimate must be defined, and included in the overall
future product cost predictions. In addition, significant changes to any
production process will trigger additional cost through regulatory review and


In the cost estimates below, the Factory cost is a ‘placeholder’ and there is no
estimate of DSP, packaging, and sterilization equipment costs, as the final
product is not defined. This should therefore be considered a low estimate of
total costs and COGs, even with the 30% contingency. A better estimate may be
made once the finished product is adequately defined through to the market,
and all the technologies from raw materials to packaging are elucidated. Note
also that some modest increase or decrease in factory capital costs do not
adversely affect overall finished goods costs due to the depreciation.

In the cost analyses below, the following is taken into account:

Figures from the TEA are from the High and Medium estimates. It is likely that
the low estimates are unrealistic for at least the first 10 years of operation for the
reasons stated above.

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Table 1 below indicates the base cost that was estimated in the TEA. The EVC
estimates include the new process architecture that is likely more realistic for a
product of this type, and medium costs for a stem cell medium.

TABLE 1 Medium cost/kg Medium cost /batch

Assessment Batch size kg High Medium High (TEA) Medium (TEA)
TEA 41,000 3080 $22,405 $1,691 $69,007,400 $5,208,280
EVC (52 d) 49,778 3080 $27,323 $2,062 $84,155,366 $6,351,561
EVC (60 d) 49,778 3080 $27,323 $2,062 $84,155,366 $6,351,561

Table 2 below estimates the staff for a 3-shift (24/7) operation in the factory. Due
to the addition of critical unit operations (adipocyte culture, DSP, packaging,
media prep, etc.), the number of staff is raised from 200 to 400, with an average
annual $150,000 cost per fully loaded FTE. Depreciation is based on a 10-year
term with an initial investment of $450 M.

TABLE 2 Additional cost (per batch)

Assessment Base SCM FTE Depreciation
TEA 0 0 0
EVC (52 d) $2,045,875 $10,000,000 $7,500,000
EVC (60 d) $2,045,875 $12,000,000 $9,000,000

Table 3 below gives the total cost per batch and per kg, using the TEA high- and
mid-level costs and the additional costs anticipated above.

TABLE 3 Total per batch Total per kg

Assessment High estimate Mid estimate High estimate Mid estimate
TEA $69,007,400 $5,208,280 $22,405 $1,691
EVC (52 d) $106,812,279* $26,674,360* $34,679* $8,661*
EVC (60 d) $110,417,279* $30,279,360* $35,850* $9,831*
*Includes 3% scrap rate

In this scenario planning, the ‘other costs and prices’ in the TEA are omitted as
some of these will be included in the FTE fully loaded cost of $150,000/year.

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In the most optimistic scenario, FTE and depreciation account for ~70 to 75% of
the overall cost, which for a process of this type is correct.

There are a number of omissions from this estimate such as disposable reactors
and totes, manifolds, filters, SS equipment costs, etc., so overall costs are for this
estimate at least ±30%. Also, packaging and labeling costs are not included as it
is unclear what the packaging will be, or even what the final product
specifications are.

The TEA states that the overall process may be used for poultry or beef CCP.
However, the costs of CCP production do not change for different species, as
they do for meat. Therefore, the cost estimates above are true for poultry, lamb,
pork, beef or any other species of CCP that may be considered.

The estimate for a kg of CCP using the process described above is minimally
between ~$9,000 to ~$36,000 ±30% per kg.

By contract the cost of a kg of poultry meat in February 2021 (wholesale) is

$1.808/kg. After trimming of fat and bone, this rises to a maximum of $3.11/kg
(source: USDA-NASS, Y charts).


The environmental impact of producing CCM is ill-defined. The factory itself is

expensive and energy-inefficient. Clean steam, USP water generation and use
for sterilization, wastewater treatment, and heating will all be energy intensive. In
the TEA it is proposed that renewable energy be used, and that Governments
subsidize the cost of the factory and its running costs. However, with prices of
$9,000 to $36,000/kg (±30%; see above), it may be difficult to justify the
investment given the cost of meat production. These are aspirational goals that
require more definition.

Further, in parts of the world where protein sources are desperately needed (sub-
Saharan Africa, the Indian sub-continent, poorer regions in the Americas and
Asia), it is difficult to envisage how a factory making a CCP product can then ship
with a complex refrigerated (or frozen) supply chain to the places where it is
needed the most.

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This concept therefore will remain largely a tool for investment in a product
concept that in many respects is limited to wealthy countries, and appear to
provide little if anything in terms of nutritional and cost benefit ($/kg) compared
to animal products.

The end (consumer) product needs to be better-defined, and more detail needs
to be presented on the proposed bioprocessing/biomanufacturing. This will
allow for a proper concept design for a factory to be prepared, with more
accurate cost estimates. Rational design of process and product improvements
can follow, and with that an overall evolution of the cost of the product and an
assessment to see whether there would be any advantage over animal
production can be forthcoming.

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Bausch, M. et al., (2018) Recommendations for comparison of productivity

between fed-batch and perfusion processes. Biotech Journal, 14: 1700721

Campus, M. (2010). High pressure processing of meat, meat products and

seafood. Food Engineering Reviews, 2: 256

Good Food Institute: (


MP Bio (cost of DMEM):


Post M.J., et al, (2020), Scientific, sustainability and regulatory challenges of

cultured meat. Nature Food, 1: 403

Rubio, N.R. et al., (2020) Plant-based and cell-based approach to meat

production. Nature Communications, 11: 6276

Specht, L. 2019. An analysis of culture medium costs and production volumes for
cell-based meat. Good Food Institute.

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