2017 is considered the "first year" of CAR-T cell immunity**. This was the year that Novartis' CAR-T cell** Kymriah was the first approved CAR-T product in the world, followed by Yescarta from Gilead's subsidiary Kite Therapeutics.
The success of Kymriah made the industry boil, and at that time, the industry believed that the tumor ** had entered a new era, and a number of subsequent cell** products were also launched one after another. Such cases have profoundly changed the way cancers, especially hematological tumors, have significantly prolonged the progression-free survival of patients, and can even completely eliminate cancer cells.
However, while cell products such as CAR-T have changed the paradigm of patients, they also have the problems of complex production and manufacturing, and it is difficult to popularize commercialization. Due to the more complex and demanding production process of this type of cell** productThe corresponding high R&D investment and high production costs have led to high pricing levels, so the actual commercial development is less than expected.
According to public information, the sales of Gilead yescarta products in 2022 reached 11$600 million, but there is still a big gap between the return on investment, and Gilead also announced a 7% layoff in the CAR-T divisionGSK, for its part, announced its withdrawal from the CAR-T competition, arguing that CAR-T may not be profitable at all.
Recently, the FDA released an untitled letter sent to Novartis in August, which mentioned in the letterDuring a review of Novartis' facility in Morris Plains, New Jersey, it was discovered that there were new and significant problems with the way Kymriah was produced.
In fact, the FDA has repeatedly found problems with Kymriah's production processThe latest review results have undoubtedly exacerbated the industry's concerns about the manufacturing specifications and subsequent commercialization of CAR-T cell products.
ThisUntitled LetterThe investigation dates back to the end of November last year. From November 28 to December 9, 2022, the FDA inspected Novartis' manufacturing facility in Morris Plains, New Jersey, and issued a 483** detailing "significant" deviations in the Kymriah manufacturing process. Since then, the FDA has identified "other significant deviations" related to the Kymriah manufacturing process.
The letter states that Kymriah may have a problem with microbial contamination. "The influencing factors identified in the production process include gaps in processes related to cleaning and disinfection of production areas and equipment, equipment transportation, material handling, personnel attire, cleanroom management, handwashing and hygiene, as well as failure to comply with some of these norms. ”
*: Novartis) continues to have manufacturing problems that even those as strong as Novartis still face many problems in the production of cell products. Not only Novartis, but also a microcosm of the manufacturing problems in the entire cell field. In the middle of this month, the FDA announced the suspension of clinical trials of three cells** in the United States by CARsgen Pharmaceutical, a cell company, and said that it was mainly due to CMC-related issues, and some residual issues such as staff training needed to be improved.
In the field of cell **, there is such a saying: "."process is the product".）”。This sentence almost perfectly explains the importance of manufacturing processes and processes to products in the research and development process of cells, and also reflects the test of manufacturing. It is often extremely difficult to produce these cell products, so the manufacturing process is regarded as a major bottleneck that limits the development of the cell industry.
On the one hand, unlike traditional small molecules and antibody drugs and other single drug components, cell research and development covers basic biology, genetic engineering, pharmaceutical engineering, clinical science and other technical disciplines.
On the other hand, cell** is a "live" drug, and the production process is very different, the production process is extremely complex, and it needs to be "personalized customization". The industrialization of cells includes cell extraction and storage in the upstream, cell technology research and development in the midstream, and clinical application in the downstream. One of the biggest challenges is the development, optimization, and production of cell processes. The process flow of cell products involves multiple steps such as cell culture, activation, transduction, purification, and enrichment.
Specifically, doctors need to isolate immune T cells from cancer patients and then use genetic engineering methods for reprogramming (which may involve transfection of viral or non-viral vectors) and in vitro expansion, which takes a long time to prepare and at least billions or even tens of billions of CAR-T cells in a patient, and then re-infuse these cells into the patient.
*:National Academy of Medicine) In the production process, in vitro cultured cells are highly susceptible to contamination, so to ensure the quality of cell products and prevent contamination, high quality and strict control of cold chain transportation and storage are requiredNot only that, but strict quality control is required for aseptic handling, purity, preparation results, and more.
Due to the large number of production links, slight differences or changes in each link may eventually lead to differences in the phenotype, subtype ratio, and expansion ratio of T cells, which may affect the clinical effect of CAR-T.
The continuous occurrence of particulate matter and microbial contamination in Kymriah particulate reflects the difficulty of traditional GMP-level production due to the complex production process and high-level experimental operation procedures of cells**.
On the other hand, there are still problems such as capacity and long production cycle in the cell ** process and process. For example, BMS acknowledged that in the first half of 2022, the company experienced difficulties in increasing the production capacity of ABECMA and Breyanzi cells**;For example, in terms of production cycle, Legend Biotech's Johnson & Johnson's Carvykti takes about four weeks from cell collection to infusion. Novartis' Kymriah, as well as Bristol-Myers Squibb's Breyanzi, take about three to four weeks from white blood cell removal to infusion.
In this context, automation platforms, especially end-to-end automation technology, are seen as promising means of scaling up production and achieving large-scale and standardized production. Some industry insiders pointed outAutomated production platforms may become the key to breaking the game.
Automated preparation process is the key to solving the problems of standardization, industrialization and quality control. Traditional manual operations can have errors and make it difficult to ensure the stability and consistency of different batches of cells, which can be compensated for by automation technology. In addition, the extraction of cells is often very demanding in a laboratory environment. Liu Baochi, chief surgeon of the Shanghai Public Health Clinical Center and president of the Cell Industry and Clinical Research Branch of the National Health Industry Enterprise Management Association, said in an interview with **.
To a certain extent, automation allows for efficient integration and simplification of production processes, allowing products to be produced with little or no human intervention. This minimizes human intervention and reduces the potential for human error or contamination. At the same time, automated methods can improve the consistency of production processes, reduce turnaround times and increase throughput, ultimately reducing the cost of cell** production.
And because of this,The cell industry is actively exploring the direction of automation technology. As early as 2018, Novartis said that it would continue to improve the manufacturing process, increase efficiency, reduce the impact of operational differences on products, and pursue the automation of the car-t manufacturing processKite Therapeutics is also embracing automated car-T cell manufacturing, and the company is looking to improve production efficiency through automation;BMS is also betting on automated cell-based smart factories called Cellares, which has developed a cell-based drug manufacturing platform called "Cell Shuttle" and is trying to integrate all the technologies needed for the entire cell-based manufacturing process in a flexible, high-throughput manufacturing platform.
Shenghui noted that ALP Regenerative Medicine is the first cell company in the world to achieve closed, fully automated production. This company has developed its own productsFully automated cell robotics platform, including automated intelligent mass production platform and automated quality control platform. According to public information, this platform technology has more advantages than traditional labor in terms of standardization, implementation reporting, operation error, cost and other aspects, and now the cost of the entire production and quality control is reduced by about 80% to 90% compared with traditional labor. At the same time, the standard production of the company's closed, fully automated platform also reduces operational errors and potential contamination.
The company's fully automated industrial-grade cell robot platform has an annual output of 100,000 people, and the platform has also been selected for the national "13th Five-Year Plan" Science and Technology Innovation Achievement Exhibition. It is worth mentioning that HICM-188, a human iPSC**cardiomyocyte injection based on a fully automated cell robotics platform, has also initiated a phase IIIA clinical trial.
Disclaimer: This article aims to convey the latest information of the life sciences and medical and health industry, and does not represent the position of the platform, and does not constitute any investment advice and recommendations. This article is not a **plan recommendation, if you need to get **plan guidance, please go to a regular hospital for treatment.