Innovative Biopharma Leaders Gather to Discuss the CMC 'Risk Triangle' in Cell and Gene Therapy

"One person can run fast, but a group of people can go further."

On the afternoon of January 23, the third stop of the [No Need to Compete, Go Further] CGT Industry Upgrade Series - Park Tour, jointly organized by HIEA, Hangzhou Xingcheng Biotechnology Co., Ltd., Yeasen, LePure Introduction, Austar, VectorBuilder, Life Biosciences, Danaher Corporation, and Legend Capital, and hosted by VCBeat New Medicine, arrived at Nanjing Biopharmaceutical Valley.

This event was jointly initiated by a group of outstanding companies focusing on the CGT industry chain, and also invited representatives from pharmaceutical enterprises to discuss the key points and solutions of CMC in the CGT field. The pharmaceutical enterprises mentioned that being more stable, faster, and more cost-effective are the core demands. Supply chain enterprises believe that they can help pharmaceutical enterprises achieve these goals. However, are the demands and services between the two truly matched?

IASO Bio's Quality Director Huang Yijun, Nanjing Bioheng Biotech Co., Ltd. CEO Ren Jiangtao, Nanjing Aoluo Biotechnology Co., Ltd. General Manager Sun Shichao, Hangzhou Xingcheng Biotechnology Co., Ltd.'s Plasmid Upstream Process and Production Director Cao Chenghao, Yeasen's Key Account Director Tan Guosheng, and LePure BioService Head and Quansheng Bio CTO Yuan Jun held a discussion under the moderation of Dr. Liu Xiao to jointly explore service solutions that can help innovative companies transition smoothly, quickly, and cost-effectively from IND to BLA.

VCBeat has compiled the content of the roundtable discussion as follows:

Sun Shichao:I am Sun Shichao from Nanjing Aoluo Biotechnology Co., Ltd. Nanjing Aoluo is a company specializing in the research and development to production of mRNA vaccines, established at the end of 2020 as a joint venture between Grand Pharmaceutical and Belgian eTheRNA. As an mRNA technology-based enterprise, the most critical aspects are quality, compliance, and value—especially given the current stage of development needs, I pay particular attention to these three points.

Liu Xiao:It sounds like quality is stability, and the supply chain is also stable. Value is saving, and the requirement for speed is not that high, right?

Sun Shichao:For companies in our early development stage, speed is actually relative. Speed is certainly important—everyone wants to be among the TOP 3 or even the TOP 1. However, considering the entire product development cycle,Drug development is actually a marathon-like process. Especially for small and medium-sized biotech companies in China or companies that have emerged from traditional enterprises, they tend to prioritize stability. This "stability" refers not only to product quality but also to the stable growth of the company, aiming to be too big to fail.

Ren Jiangtao:I am Ren Jiangtao, President and Chief Scientific Officer of Bioheng Biotech. Bioheng mainly focuses on the development of universal CAR-T cells, and our goal is to reduce the production cost of cell therapy. Regarding the CAR-T cell manufacturing process, there are already some automated and closed systems for autologous cells that help reduce production risks. However, there aren’t many suitable devices for universal cell therapy, and corresponding consumables are also relatively scarce. We have collaborated with manufacturers to develop some equipment suitable for universal cell production. Of course, compared to when we started in 2018, the development of domestic equipment in China has improved, but given the relatively short development time, many needs still haven’t been met.

Moreover, as you may know, the commercialization of the cell therapy industry in China is somewhat limited. Many companies are considering expanding to overseas markets, which would involve the transfer of production and require corresponding instruments, equipment, consumables, and supply chain systems to be available abroad. This presents some challenges for domestic manufacturing companies. In terms of raw materials, if it's autologous CAR-T, production needs to occur overseas. For allogeneic cell therapies, cells from foreign donors can be collected domestically, but this comes with certain rigid requirements, such as compliance with FDA review standards, including donor health screening, regulations for laboratories and testing, and so on.

Overall, we will consider,Whether the current equipment and consumables meet the conditions to承接 (take over) autologous or universal processes. If domestic instrument and consumable suppliers have a well-established overseas supply chain and enhance process adaptability, it would be relatively convenient during process transfer. This is also an important aspect currently considered by client enterprises when developing processes in China.

Huang Yijun:I am Huang Yijun from IASO Bio. IASO Bio is an innovative enterprise focusing on gene and cell therapy. Currently, its first product has been approved for marketing. For commercial production, the stability of the entire supply chain is the most critical requirement. Taking IASO Bio's autologous CAR-T cell infusion as an example, the process from apheresis to final reinfusion involves highly complex procedures and testing across the entire chain. Additionally, it encompasses various components, while patients’ clinical treatment demands extremely short reinfusion cycles.In this process, only stable and trouble-free production and testing processes can truly ensure product quality and timely supply to patients within the cycle for infusion.From the perspective of the supply chain, the stable supply of reagents, consumables, and some key raw materials is also something we need to consider.For example, IASO Bio started by establishing its own production end for the key raw materials used in CAR-T product manufacturing, such as plasmids and viruses, to ensure a stable supply of these critical materials.

Liu Xiao:In summary, the demand of Party A enterprises at different stages is still centered around the word "stability." This differs somewhat from what supply chain enterprises mentioned — that they can help Party A enterprises achieve greater stability, speed, and cost savings. How do supply chain enterprises view this issue?

Yuan Jun:Indeed, there are times when the three aspects of "stability," "speed," and "cost-effectiveness" form a triangle that is difficult to balance perfectly. As I mentioned earlier, I chose "speed" and "stability." In terms of R&D progress, we need to respond quickly to customer needs, maintain a fast R&D pace, and keep up with market changes. Our supply chain companies actually put in significant effort to meet customers' demands for "speed." This is because biotechnology is advancing rapidly, and breakthroughs may occur within just one or two years. For instance, the development of CGT, stem cells, and nuclear medicine has accelerated much more in the past two years compared to the previous development of antibody drugs.

However, "speed" does not conflict with the long-term road that supply chain companies need to take. The stability of supply chain enterprises is an important foundation for the smooth operation of the industrial chain.Therefore, from the perspective of "speed," I may still maintain a certain level of persistence. However, "stability" will never be compromised, as "stability" represents the ultimate core strength of an enterprise.

Tan Guosheng:"Saving" is built on the foundation of "stability." The premise of cooperation is that our product performance can meet the customer's R&D and production needs. On this basis, we can also help them save some costs. For example, the prices of some CAR-T marketed drugs are very high. How to improve drug accessibility? One way is to expand the range of indications, and the other is to reduce the cost of the drugs. Drug costs involve R&D expenses and production costs, so every step requires "saving." For instance, nucleases may not seem to have a high cost in cell therapy.But in production applications, our products can save over 50% of costs annually compared to imported products. The saved amount could even support a high-level research talent. This is the kind of help suppliers can offer to their clients.

Sun Shichao:I completely agree with Mr. Tan's opinion,The "Stable, Fast, and Cost-effective" we just discussed is like a risk triangle, where risks do not disappear into thin air but are merely transferred.Each company has a completely different development background and stage, and their considerations for risk also vary. This is why we say that enterprises, along with their supply chain ecosystems and long-term supply chain partners, are in a phase of co-development.

Huang Yijun:Customer demands vary at different stages. Currently, like our autologous CAR-T, we interact with patients very frequently. The needs of the company are essentially an extension of patient needs—patients hope for safe and effective disease treatment, quick access to medication, and if the cost could be lower, that would be even better. For companies, once a drug has other varieties launched subsequently, price competition becomes inevitable. Our company’s idea is to maintain stability while also saving costs, without compromising stability, to enhance patient accessibility.

Liu Xiao:Although it is difficult to calculate specifically to what extent is "saving," everyone has a sense — to "save." From the supply chain perspective, "saving" includes domestic substitution, using cheaper suppliers, and saving through process improvements. From the perspective of pharmaceutical companies, how should they view the concept of "saving"? How to balance "stability," "speed," and "saving"?

Ren Jiangtao:I think that products like CAR-T, although priced relatively high, are essentially still price-sensitive. Therefore, the process is important, and so is the price.If domestic alternatives can be achieved, everyone will tend to use domestically produced materials. However, when transferring processes abroad, some key equipment or critical steps may be affected. But if the components and raw materials are not impacted, then production substitution is highly likely to be feasible.

Returning to the production of CAR-T, if we only calculate the manufacturing cost, it is approximately 2-3 million yuan, which may meet the demand for 100 patients, with a production cost of about 30,000 yuan per person. However, this is only the production cost. Many other patents and costs need to be considered, all of which will be included in the final pricing. Therefore, it is impossible to determine the pricing based solely on simple costs. Thus, I believe that for universal CAR-T or gene therapy, this is still not a particularly mature topic. Because so far, no universal cell therapy has truly reached the final stage.

Sun Shichao:"Saving" may be an inevitable trend, but it definitely means more than just saving. The issue of pricing has just been discussed.People are relatively sensitive to prices, but the price is not entirely determined by its production cost. The difference between price and cost is profit. When considering the final market launch of the entire product, it is not only about the success rate of the entire development process and production costs, but also about the product line and business model. Because only when this product is profitable enough will people continue to develop it, forming a positive cycle.

Especially for innovative products like CAR-T, when you are among the top 3 in the industry's development, making money is really quite difficult. When you are between the 5th and 500th positions, technology prices will drop, production costs will decrease, and all pathway costs will go down, creating a large profit margin. When discussing how to save money, you need to consider the scope of your own development. On the issue of "saving," I would still like to say that risks do not disappear; they only shift.

Cao Chenghao:I really like the phrase "Begin with the end in mind" that is often mentioned by our General Manager Lijun of Hangzhou Xingcheng Biotechnology Co., Ltd. in our daily work. For us process people and CMC, beginning with the end in mind has a deeper meaning. For example, when we are in the early stages of process development or even earlier, we will consider many issues faced by customers—commitment issues, quality issues, and so on. If we look at the starting point from the perspective of the endpoint, and address potential problems while they are still small, we can prevent major issues as the CMC grows. Therefore, as a company focused on CDMO, we prefer to leverage our own process advantages to help customers achieve a balance across these three dimensions as much as possible.

Liu Xiao:CMC needs to establish a dynamic balance among the three. If speed needs to be accelerated, more money may need to be spent; if costs are to be reduced, quality may be compromised; if quality is to be improved with more testing points, speed may be sacrificed and it could lead to higher expenses. Therefore, the relationship among the three seems to be a process of pushing down one gourd and having another pop up.

We just mentioned "beginning with the end in mind." In the process of reaching the endpoint of drug development or commercialization, it is inevitable that we take detours. However, taking detours for the sake of taking detours is different from taking detours because we haven’t thought things through. Many times, we have no choice but to take a detour and then quickly return to our intended path. This is because I can stand at the endpoint, at a higher perspective, and from a god's-eye view, examine how each step is taken.

And in this process, China lacks CMC talent, and CMC doesn’t know how to avoid some pitfalls, making it difficult to ensure compliance and risk avoidance in advance.Many of these issues will involve strategic trade-offs by the client company, whose strategy is defined by CMC's focus and choices. I believe that at different stages of a company’s development or investment, the key areas of focus will vary.However, "stability, speed, and cost-effectiveness" are all indispensable. When we blindly pursue speed, stability, or cost-effectiveness alone, other problems will arise.

As Dr. Sun said again, "Troubles don't disappear out of thin air; they only shift." In the past, many pharmaceutical companies reached the later stages and realized that CMC had not been well-designed, so they had to go back and redo it. To avoid such risks, supply chain enterprises need direct dialogue with the client side to truly understand the requirements and jointly build an overall ecosystem that is stable, fast, and cost-effective.