Cell therapy products are "live medicines" with diverse cell types, variations in quality control, stability in production cycles, and short shelf life, posing severe challenges with high risks throughout the entire process of cell therapy product production. In quality control for cell therapy products, the control of the quality risks of raw materials used in production is a critical aspect. It directly relates to the safety and effectiveness of cell therapy products.

On September 14, 2023, "Quality Management Standards for Raw Materials Used in the Production of Cell Therapy Products," hereinafter referred to as "The Standard," was officially released and implemented in Chengdu. This standard was proposed and consolidated by the China Medical Biotechnology Association (CMBA) and jointly drafted by research units including the Department of Orthopedics at the Chinese PLA General Hospital, China Food and Drug Testing Institute, and companies like CytoNiche, Beijing CytoNiche Biotech Co., Ltd., among others.

[Main Objective of the Standard]

The primary aim of "The Standard" is to ensure the quality and stability of raw materials used in the production process of cell therapy products. It aims to prevent the introduction and spread of pathogenic microorganisms, avoid contamination, errors, and other risks, and contribute to quality control for cell therapy products to ensure that they meet the expected biological efficacy and function.

"The Standard" provides a definition of production raw materials, basic quality requirements, guidance on the consistency and quality control of production raw materials, and material documentation to demonstrate inter-batch consistency. It further specifies the unique characteristics and quality requirements of certain specific components or types of production raw materials, such as serum and serum substitutes, recombinant proteins, tissue-extracted proteins, etc.

[Background of Standard Development]

As of now, China's Center for Drug Evaluation (CDE) has accepted over 60 applications for investigational new drug (IND) registration for stem cell medicines, with 47 products entering clinical trial stages under implied consent. Additionally, China has more than 111 registered clinical research projects related to stem cells. Therefore, with the rapid development of cell therapy products, it has become crucial to enhance risk control and quality management in their production processes.

In the context of the fast growth of the cell therapy product industry in China, ensuring the safety and effectiveness of these products becomes imperative. One significant aspect of quality control in cell therapy products is the quality risk control of raw materials used throughout the entire process of preparing cell formulations. Currently, there is no standardized regulatory standard in China for the quality management of raw materials used in the production of cell therapy products. Internationally, discussions on and the development of related management standard regulations have just begun. In light of the rapid development of the cell therapy industry in China, there is an urgent need to establish standardized quality management for auxiliary materials used in the production of cell preparations.

The publication and implementation of "The Standard," a group standard, play an essential demonstrative role in promoting the technological and industrial development of cell therapy products. It also signifies that the biopharmaceutical industry in China is taking a solid step towards standardization and legal management, laying a solid foundation for the rapid and healthy development of China's cell therapy product industry.

CytoNiche, as a backbone unit of the association, participated in the drafting of "The Standard." This participation showcases CytoNiche's important role in stimulating industry innovation and leading industry development by unleashing its standardization capabilities.

[Interpretation of the Standard]

Core Raw Materials for CytoNiche's 3D FloTrix® Billion-Cell Preparation Process:

● 3D TableTrix® Microcarriers

● 3D FloTrix® Serum-Free Culture Medium for Mesenchymal Stem Cells

CytoNiche has developed these critical raw materials and established a manufacturing process based on CytoNiche's 3D TableTrix® microcarriers, the 3D FloTrix® series of automated bioreactors, and the 3D FloTrix® vivaPREP PLUS cell harvesting system. This process is automated, continuous, and closed, and it meets all the requirements of "The Standard" for raw materials used in production. 

1. GMP Production and Relevant Qualifications for 3D TableTrix® Microcarriers:

▣  Two Chinese CDE drug adjuvant qualifications, record numbers: F20200000496, F20210000003.

▣  Three U.S. FDA qualifications, Type II: 037798 & Type IV: 035481, Type II: 29781.

▣  Sterile tablet packaging / closed loop packaging.

▣  Specific degradation technology for gentle cell harvesting.

▣  Reports on exogenous virus testing

2. Evaluation and Testing Reports for CytoNiche's 3D TableTrix® Microcarriers and Lysis Residue:

▣  China Medical Institute - Test Report (Number: QH20201861).

▣ Jiangsu Institute for Drug Safety Evaluation - Test Reports (Research Numbers: KY20-010-01/02/03/04/05).

3. Introduction of 3D RecomTrix™ Recombinant Collagen Microcarriers:

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2. Evaluation and Testing Reports for CytoNiche's 3D TableTrix® Microcarriers and Lysis Residue:

▣ China Medical Institute - Test Report (Number: QH20201861).

▣ Jiangsu Institute for Drug Safety Evaluation - Test Reports (Research Numbers: KY20-010-01/02/03/04/05).

3. Introduction of 3D RecomTrix™ Recombinant Collagen Microcarriers:

▣ Sourced from non-animal origins.

▣ No introduction of exogenous components, eliminating the need for exogenous virus testing, reducing quality control costs, and meeting the cell quantity and quality requirements for 3D FloTrix® billion-cell process.

4. Third-Party Quality Reassessment Reports for hUC-MSCs Prepared Using CytoNiche's 3D Microcarriers/Billion-Cell Process:

▣ China Medical Institute - Test Report (Number: SH202311161).

▣ Authoritative third-party test report (Number: Test Letter <2023> 012302052).

5. 3D FloTrix® Mesenchymal Stem Cell Serum-Free Culture Medium:

▣ Filed with the U.S. FDA - Application Number: MDF Type II-038476.

▣ Supports primary isolation and continuous passages. Eliminates the need to change this raw material during process development, simplifying the approval process.

▣ Supports 2D and 3D cell culture models, suitable for large-scale expansion of stem cells from various tissue sources.

External Virus Testing Reports

II. CytoNiche's 3D FloTrix® Cell Technology Platform:

CytoNiche can design customized three-dimensional expansion and culture processes for mesenchymal stem cells based on the growth characteristics of cells from different tissue sources. This allows meeting different cell culture requirements, achieving a breakthrough in both the "quality" and "quantity" of cell production.

The 3D FloTrix® cell technology platform, built on the foundation of billion-cell preparation processes, establishes a comprehensive GMP quality control system covering all aspects of cell production, quality control, quality assurance, plant and facilities, materials and products, confirmation and validation, product shipping and recall, self-inspection, etc. All production and quality control personnel undergo systematic training and strictly adhere to quality management system requirements for production, recording, and inspection work, ensuring traceability throughout the production process.

On this platform, CytoNiche can provide services for process changes in 3D FloTrix® billion-cell preparation, including commercial production process development, process optimization, process validation, and technology transfer (production process transfer, clean process transfer, and analytical method transfer), and more.

Industry Leadership:

CytoNiche has developed and produced a range of customized microcarriers, combined with self-developed equipment, forming a production line and establishing the 3D cell intelligent manufacturing platform. This platform eliminates complex manual operations and efficiently completes large-scale cell culture, harvesting, cleaning, concentration, and packaging using different biological reactor systems in conjunction with harvesting and distribution systems. It does so through automated, continuous, and closed production process pipelines, avoiding the various pollution risks associated with open operations.

In addition to meeting the quality and safety standards for cell therapy products for clinical applications, it can also meet the demand for cell yields during clinical application and commercialization.

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【CytoNiche】

Beijing CytoNiche Biotechnology Co., Ltd. was established by the research team of Professor Du Yanan from Tsinghua University School of Medicine, and was jointly established by Tsinghua University through equity participation. The core technologies were derived from the transformation of scientific and technological achievements of Tsinghua University. CytoNiche focuses on building an original 3D cell "smart manufacturing" platform, as well as providing overall solutions for the 3D microcarrier-based customized cell amplification process.

Products and services of CytoNiche can be widely used in the upstream process development of gene and cell therapy, extracellular vesicles, vaccines, and protein products. At the same time, it also has broad prospects for applications in the fields of regenerative medicine, organoids, and food technology (cell-cultured meat, etc.).

Our company has a R&D and transformation platform of 5,000 square meters, including a CDMO platform of more than 1,000 square meters, a GMP production platform of 4,000 square meters, and a new 1200 L microcarrier production line. The relevant technologies have obtained more than 100 patents and more than 30 articles about the technologies in international journals have been published. The core technology projects have obtained a number of national-level project support and applications.