CGT overall solution

In recent years, with the gradual maturity of biotechnology such as gene editing and gene modification, the development of cell and gene therapy (CGT) has advanced by leaps and bounds, bringing new hope to patients with tumors and rare diseases. Cell and Gene Therapy (CGT) is divided into two parts: cell therapy and gene therapy. By changing the genetic information in cells, and then changing gene expression and corresponding cell traits, the goal of curing diseases is finally achieved. With its incomparable advantages over traditional small molecule and macromolecular drugs in terms of therapeutic mechanism and therapeutic effect, CGT fills the gap in the treatment of refractory diseases and provides a new treatment for cancer, genetic diseases and other refractory diseases. Treatment concepts and ideas have become one of the most competitive emerging fields in the global innovative drug field.

As early as 1990, the US FDA approved the world's first human gene therapy clinical trial, but it was not until 2017 that the FDA approved Spark Therapeutics' Luxturna, as well as Novartis's Kymriah and Kite's Yescarta , which opened a new year for cell and gene therapy. As of June 2021, there are about 100 CGT clinical trials underway in China, and the global commercialization of CGT drugs continues to accelerate, with nearly 2,000 CGT clinical trial projects under development. Driven by technology, capital and policies, the global CGT industry is rapidly heating up. According to the data of ASGCT (American Society of Gene + Cell Therapy, the authoritative American Society for Cell and Gene Therapy), as of the end of the first quarter of 2022, it has reached 1986 .

With the rapid development of cell and gene therapy, the complexity and specificity of cell and gene therapy products, the complexity of the preparation process of different types of products, the biological characteristics in vivo and safety risks, and individualized applications are all different from those of existing products. There are significant differences in other drugs, which bring many challenges and uncertainties to the construction of their regulatory system. CGT is a special drug, and the most important thing as a drug is safety. Prior to this, CDE issued four guiding principles in succession, three of them ("Technical Guidelines for Pharmaceutical Research and Evaluation of Gene Modification in Vitro (Trial)", "Technical Guidelines for Pharmaceutical Research and Evaluation of In vivo Gene Therapy Products (Trial)" and "Immune Technical Guiding Principles for Pharmaceutical Research and Evaluation of Cell Therapy Products (Trial)) put forward requirements for quality control in the production process of CGT. The production process of CGT is complicated, and the quality control is difficult. Product quality control is an important part in the research and development of innovative cell and gene therapy products, and is one of the important links to determine whether the product can enter clinical research and go on the market smoothly.

01. CGT technical process route

The process route of cell and gene therapy technology mainly includes three aspects: plasmids, virus vectors and cell factories. Improve the process development technology and large-scale production capacity of these three aspects, so as to better control quality and cost. For CGT users important.

Plasmids: a key starting material for cell and gene therapy and a major source of cost for production. Plasmids are important raw materials for direct transfection of cells or assembly of viral vectors by co-transfection. Depending on the purpose of use and the virus vector selected, the production requirements of the plasmid are also different. The production cycle is generally 7-10 days.

Viruses: High production costs are a pain point in the commercialization of cell and gene therapy. Viral vectors are produced for use as genetic material delivery systems. Viral vectors commonly used in the field of cell and gene therapy include retroviruses, adeno-associated viruses, adenoviruses, and lentiviruses. The production cycle is generally 2-3 weeks.

Cell Factory: Viral vectors and culture reagents are the cost of cell therapy. Involving cell culture, activation, transduction, purification, enrichment and other steps, according to the source of cells, it can be divided into autologous therapy and allogeneic therapy. The production cycle is generally 10-15 days.

02. CGT treatment production link

There are many production links involved in cell and gene therapy, and the main processes include:

Blood collection: Whole blood is drawn from a blood donor or patient, anticoagulants are added, blood components are separated, specific components are collected or removed, and the uncollected components are then returned to the donor or patient;

Cell separation: separation and sorting of original cell stock solution materials, preparation of reserve cells;

Cell modification: using genetic engineering technology to express chimeric antigen receptors (CAR) on the cell surface through retroviral and lentiviral vectors, transposition systems or direct mRNA transduction into the acting cells (T or NK cells, etc. ) , has the function of identifying cancer cells and proliferating;

Cell expansion: complete cell culture-related operations in a sterile environment, and achieve cell number expansion with the assistance of relevant reagents;

Quality inspection: mainly based on flow cytometry;

Cryopreservation: mostly liquid nitrogen storage system.

03. CGT important consumables

In the field of CGT, consumables are an important part of production costs. The consumables for the production of CGT products include standardized consumables and non-standardized consumables. Control conditions, not difficult to replace later. Once a good supplier emerges, companies have sufficient incentive to find cheaper sources of consumables without making major changes to the process. For non-standardized consumables, once the replacement may cause changes in the process, the enterprise has little motivation to replace them, especially for projects that have entered the late clinical stage with IND declarations, the requirements for production stability are extremely high, and some consumables are difficult to replace, such as CGT Inevitably used cell culture medium and immunomagnetic beads etc.

1. Cell culture medium:?typical non-standardized consumables. There are currently four types of media used for cell culture, including serum-containing media, serum-free media, animal-free media, and chemically defined media. In general, CGT requires cell line culture (such as lentivirus production) and primary cell culture (such as CAR-T), the latter cells are more sensitive, and specific media need to be selected.

2. Immunomagnetic beads: Magnetic beads are important reagents in the field of CGT, almost monopolized by foreign capital. Magnetic beads are widely used in the field of CGT, and can be used in cell sorting, immune recognition, nucleic acid isolation and other processes. In the production of CAR-T, on the one hand, magnetic beads can be used for the sorting of T cells; on the other hand, magnetic beads coated with CD3/CD28 monoclonal antibodies are often used for the activation of T cells, which is comparable to interleukins that directly use monoclonal antibodies. Compared with magnetic beads, the activation is convenient, the separation after activation is easier to operate, and the activation efficiency is higher, and the product performance is stable.

Equipment and consumables constitute the main cost of CGT, and the status quo of the domestic CGT industry is that most CGT-related reagent raw materials in China have been monopolized by imported companies for a long time, with high prices and long order cycles, and are easily affected by emergencies, especially during the outbreak Obviously, it has caused the industry's "stuck neck" problem, which limits the long-term healthy development of China's CGT industry. Coupled with the introduction of the implementation plan of the "14th Five-Year Plan" in the medical field, it is imminent to accelerate the realization of domestic substitution of raw materials for cell and gene therapy industry equipment. In addition, unlike traditional biological drugs, cell therapy uses human "live" cells, which cannot be sterilized by means of filtration, or reprocessed and applied after obtaining CGT drugs, which requires the selection of CGT drugs in the production process and raw materials and excipients. Special care should be taken to ensure the safety and effectiveness of CGT drugs. In the current context, CGT therapies mostly come from academic research settings. In the preclinical phase, many of the materials used are labeled for research use only (RUO) and are often of unclear and uncontrolled composition. During the clinical phase, these materials must then be replaced with GMP grades, but at this stage it may be difficult to find alternative suppliers or certified materials with equivalent performance. When switching to GMP-grade materials, it not only prolongs the development time, but also brings higher development costs.

T&L biotechnology has been focusing on the R&D and production of upstream core reagent raw materials for cell and gene therapy (CGT) for more than ten years, with unique core competitiveness. With ISO13485 and ISO9001 quality management system certification, strictly enforced pharmaceutical standards in production, can provide CGT users with high-quality and high-activity recombinant protein/GMP-grade cytokines, immunomagnetic beads, cell culture kits, genetic modification reagents/ enzyme series And other products, covering the main production process of CGT including cell isolation and activation, cell transformation, cell expansion, and cell culture, have more obvious price advantages, can guarantee the delivery time, and the supply chain is stable and controllable. In addition, while providing products, it can also provide technical services to customers, provide overall solutions for cell and gene therapy customers, and help CGT customers accelerate the pace of domestic substitution and win market opportunities.

About T&L biotechnology

T&L biotechnology Ltd

T&L Biotechnology focuses on the R&D of upstream GMP-grade raw material reagents for cell and gene therapy (CGT), and is committed to providing reliable products and services for life sciences. The products involve eukaryotic recombinant proteins, cell isolation reagents, serum-free medium, cell culture kits, and tool enzymes. T&L Provides core raw material reagents and services for biopharmaceutical and IVD fields such as cell and gene therapy, mRNA development, antibody drug development, and cell storage.

T&L has a 10,000-class clean workshop that complies with cGMP standards, including mammalian cell expression protein engineering platform, cell culture technology development platform, and in vitro diagnostic reagent production platform.

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