May 17, 2023 PAO-05-23-CL-02
The concept of cultivated (or cultured or cell-based) meat has been in existence for a little over two decades. The first “tissue” was produced in 2000–2001 by a pair of different academic research groups, one funded by NASA that was looking for a way to produce muscle protein for astronauts during long-term space travel, and the other comprising “bioartists”.1
Given that meat is made of cells, the focus is on cell culture manufacturing — essentially the same processes widely implemented to manufacture monoclonal antibodies (mAbs) or stem cell therapies. Rather than express a drug substance from the cells in culture, as in mAb production, the goal is to generate the right types of cells in the right quantities, similar to what is needed for stem cell applications. The cultured meat is produced in a bioreactor using living cells taken from the relevant animal species in culture media and given appropriate feeds and supplements to encourage growth and maintenance of cell health and viability.
The challenge is to take the manufactured cells and package them to look (and taste) just like animal-based steak, hamburger, or sushi products in order to meet consumer expectations — and of course do so at a competitive price. Twenty years ago, the first cultivated meat hamburger cost about $330,000.2 By early 2022, the price has dropped to $9.80,2 a truly significant reduction that nonetheless still means that cultivated meat must be priced higher than animal-based meat (the average production cost of a hamburger worldwide is about $2).
Production of meat (beef, fish, poultry) via cell culture offers both technical and psychological advantages. There is no need to raise (and ultimately kill) large quantities of livestock in small spaces. That not only avoids mistreatment of the animals but the risk of diseases that can affect humans. Environmental impacts associated with greenhouse gases and animal waste are also reduced, and there is no need for antibiotic use. In addition, production using controlled bioprocesses results in the perfect meat — whether it is sushi or Kobe beef — every time, because exactly the same type of cells is generated throughout the manufacturing run. Furthermore, specialty meats can be obtained anywhere in the world — or beyond — rather than in limited locations where certain animals or fish are raised.
One significant challenge facing the cultivated meat industry was recently addressed to some degree when the U.S. Food and Drug Administration reported in March 2023 that it had completed a secondary pre-market consultation for a human food made from cultured animal cells by the firm GOOD Meat, which uses living cells from chickens to produce cultured animal cell food.3 The voluntary pre-market consultation was not an approval process but included evaluation of the production process, including the establishment of cell lines and cell banks, manufacturing controls, and all components and inputs.
The fact that the FDA found no issues can be viewed as a significant first step toward allowing the production and sale of cultivated food products in the United States. Currently, cultivated meat can only be sold in Singapore.
To be marketed in the United States, human food produced from cultured animal cells must meet the same stringent FDA requirements, including facility registration and applicable safety requirements, as other food. Any company producing cultivated meat products must also pass a facility inspection by the United States Department of Agriculture's Food Safety and Inspection Service (USDA-FSIS), and cultivated meat food products must receive a mark of inspection from USDA-FSIS before they can enter the U.S. market. As cultivated meat products move closer to commercialization, the FDA is working closely with USDA-FSIS to ensure that they are safe and accurately labeled.4 The two agencies jointly regulate food made from cultured cells of livestock and poultry under a formal agreement established in March 2019.5
Interest in cultivated meat has continued to rise over the last two decades, with a number of startups entering the space and slowly moving from research and development to the pilot stage. One study identified over 150 companies worldwide developing cultivated meat products.6 None have realized commercial-scale production, however, as scale-up is a tremendous challenge — even more so than the scale-up of a mAb process, which is itself an ongoing challenge. Furthermore, biopharmaceutical processes generate high-margin products that can cover the high costs associated with cell culture process development and implementation. In contrast, margins in the food industry are minimal, making it difficult to recoup the costs of producing cultured meat. Scale-up must thus be achieved in a manner that significantly reduces the cost of cell culture.
Enabling successful scale-up first requires the development of optimized processes that perform robustly and consistently through the use of effective process control measures. Ideally, optimization will enable the development of processes that behave similarly across scales.
Many of the scientists working at cultivated meat developers have come from the biopharmaceutical industry and are applying their experience and knowhow to the challenge of optimizing cell culture processes for cultivated meat production. They are using design-of-experiment (DoE) strategies to identify the relevant critical quality attributes (CQAs) and critical process parameters (CPPs).
All of that work requires access to real-time process data to ensure that the cells in the bioreactor are experiencing the optimum environment throughout the entire process. The cells need sufficient oxygen and glucose, the correct pH, and the removal of carbon dioxide. Process analytical technology (PAT) makes it possible to monitor — and ultimately control — these parameters. Sensors for tracking pH, dissolved oxygen (DO), and CO2 concentration, as well as viable cell density — a key indicator of cell health — are therefore important.
Automation of processes through the use of PAT and in-line sensors is essential for the success of cultivated meat production given the low margins associated with the food industry. In-line sensors combined with a feedback loop for automated adjustment of process conditions (e.g., DO, pH, nutrient addition) reduce personnel demands while ensuring robust and controlled processes.
Hamilton Company produces advanced in-line sensors for a variety of biotech applications. The innovative and intelligent sensors are the first that do not require an external transmitter, making them easier to install and use. They can be incorporated into automated loops and can also monitor their own performance, providing confidence in the data they generate.
In the cultivated meat industry, one of the biggest issues when scaling is unexpected accumulation of CO2 leading to reduced cell viability, which translates to less biomass and thus less cultured meat product. (In biopharma the emphasis is on DO measurements.) For these processes, therefore, in-line CO2 monitoring, for which Hamilton has effective solutions, is critically important for designing processes that can be seamlessly scaled and afford the same level of productivity in 2-liter, 100-liter, and 2,000-liter bioreactors.
In addition, the ability to monitor viable cell density in real time is of particular importance, because this measurement is typically performed off-line for biopharmaceutical applications. In the cultivated meat industry, however, it is essential to have accurate measurements of viable cell density throughout the culture process, as the cells are the product.
Hamilton’s Incyte sensor provides not only real-time viable cell density data but a range of other information about cell behavior, allowing better regulation and control of cultivated meat production processes. Specifically, the sensor measures the permittivity of the cells at many different frequencies, and these data can be correlated with texture and other attributes of cultivated meat products. Overall, it is possible to monitor the quality of the biomass, which is useful not only for ensuring optimum products but for conducting DoE experiments to identify less expensive media and feeds to help lower production costs.
As a one-stop-shop supplier of intelligent sensors for bioprocessing, Hamilton works closely with both biotech manufacturers and bioreactor vendors. Our full range of sensors are designed to support all types of cell culture/fermentation and other bioprocesses and are available for incorporation into top-quality single-use and stainless-steel bioreactors from leading equipment vendors to enable automated process control.
If scale-up (and the associated funding and cost) issues can be resolved, the potential for growth of the cultivated meat market is significant. Even if cultivated meat products account for just 10% of the entire meat production market, that would represent a completely new, multi-billion-dollar industry.
Giovanni Campolongo is a Senior Market Segment Manager at Hamilton Bonaduz AG's Process Analytics Business Unit, specializing in business development for Biotech, Pharma, and Food industries. With a strong focus on customer satisfaction, he is responsible for product development, sales coaching and customer support. As a GMP coach, Giovanni ensures process analyzers' compliance with guidelines and regulations such as GAMP 5 or CFR 21 part 11. Known for solving complex challenges, he contributes to Process Analytics effort to deliver pioneering sensor technology to solve biopharma challenges.