As cellular drugs are distinct from traditional chemical drugs and biological drugs in terms of process technology, instruments, equipment, and personnel requirements, the CDMO service of cellular drugs is unique with vastly different process and production standards. Furthermore, laws and regulations to be complied with are constantly refined and adjusted as the technology develops.

The development and services of domestic cell therapy products requires comprehensive understanding of the current regulations and guidelines of cell therapy products in China, including Technical Guidance for the Research and Evaluation of Cell Therapy Products (for Trial Implementation) issued by National Medical Products Administration (NMPA) in 2017 and appendix on cell therapy products in Good Manufacturing Practice for Pharmaceuticals (GMP) (Exposure Draft). When it comes to the development of stem cell therapy products, it's crucial to strictly adhere to relevant regulations and industry guidelines, such as Guideline on Quality Control and Preclinical Research of Stem Cell Preparations (2015), Self-regulation for Quality Management of Stem Cell Preparations (2016), and Technical Guidance for the Pharmaceutical Research and Evaluation of Human-Derived Stem Cell Products (Exposure Draft) (2021).

Under the dual regulatory system of domestic clinical research on stem cells, the preclinical research of stem cell therapy products involves basic research, pharmaceutical research, pharmacological and toxicological research, and clinical trial protocol for both project filing (non-IND) and IND application of stem cell clinical research. The CMC (chemistry, manufacturing, controls) of stem cells runs through the whole life cycle of the development of stem cell therapy products, and the preclinical stage mainly includes the studies on production process, quality control and preliminary stability.

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The business scope of stem cell therapy product CDMO of CytoNiche is focused on the preclinical research of mesenchymal stem cells (MSCs), including cell separation, cell bank development, process development and scale-up, analytical method development and quality study, clinical sample production and release, and IND application of MSCs from different tissue sources. CDMO services include the following items:

1. Stem cell product development strategy based on the concept of Quality by Design (QbD)

Due to the biological complexity of cells, the preparation and production of stem cells based on laboratory practices cannot generate real cell therapy products (CTP), thus ultimately affecting the quality and efficacy of cell products. The manufacturer of CTP shall design the cell preparation process according to scientific, risk-oriented process principles based on product and process attributes, while taking into consideration of product quality.

CytoNiche offers the following services:

① Product development roadmap design according to cell type related cell properties, key quality parameters, clinical indications, large-scale cell production and other factors.

② Evaluation on existing process studies and non-clinical data.

③ Clarification of the action mechanism of stem cell therapy products and the basis for project approval.

2. CMC process for three-dimensional stem cell amplification, which is different from other two-dimensional cell preparation processes

Adopt CytoNiche 3D TableTrix® microcarrier tablets and 3D FloTrix® series bioreactors to evaluate the production process and stem cell quality involved in the large scale amplification of stem cells. The details of this process have been listed in Large-scale Production Process and Quality Control of 3D Microcarriers of Stem Cells (Part 1 and Part 2).

Based on the 3D FloTrix® cell technology platform, CytoNiche offers the following services:

① CMC process design for pharmaceutical research.

② Research on two-dimensional cell culture process and cell preparation.

③ Research on three-dimensional cell culture process and cell preparation.

④ Scale-up scheme of cell preparation process and cell bank development at all levels. 

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3. Establishment of cell quality analysis method and quality standards that conform to the requirements of stem cell clinical research and IND application

Stem cell therapy products shall be prepared following Good Manufacturing Practice for Pharmaceuticals (GMP) and drug production shall be conducted in accordance with IND regulations and quality requirements. Stem cell preparations shall conform to Guideline on Quality Control and Preclinical Research of Stem Cell Preparations. The scope of quality research shall cover basic biological properties analysis of stem cells, microbial safety analysis, biological safety analysis, and bioavailability analysis.

CytoNiche offers the following services:

① Determination of the cell quality control strategy combined with existing data and scale-up process.

② Establishment of quality inspection items, inspection methods, and inspection standards for cell banks at all levels.

③ Establishment of cell preparation production process system and quality standard system.

4. Third party review of stem cell quality

Currently in China, filing of stem cell clinical research projects, IND application of stem cell drugs, and stem cells prepared and produced according to the specified process shall pass third party quality review, which serves as the basis for subsequent preclinical pharmacological and toxicological studies. Depending on different approaches, National Institute for Food and Drug Control or other CNAS-accredited third party institutions can be selected to conduct quality review of stem cell preparations involved in clinical trials.

CytoNiche offers the following services:

① Document writing for third party (National Institute for Food and Drug Control or CNAS accredited third party institutions) cell quality review.

② Signing of inspection service contract for cell quality review by third party institutions.

③ Performance of three batches of stem cell preparation and quality inspections on the client side or CytoNiche 3D FloTrix® cell technology platform, with cells being submitted to third party institutions for cell quality review inspections.

Case: Stem cells prepared by the three-dimensional process of CytoNiche were reviewed and inspected by National Institute for Food and Drug Control

5. Preclinical pharmaceutical research - CMC pharmaceutical research documents

Control strategies for CMC of stem cell therapy products shall be developed before the start of clinical trials. The whole process of production shall be monitored and go through repeated optimization to establish quality control and risk management systems according to critical process parameters and quality attributes involved in cell production and preparation.

CytoNiche offers the following services:

① Monitoring of environment, facilities and equipment.

② Verification methods and validation documents of raw materials, auxiliary materials, packaging materials and containers of products in direct contact with products.

③ Validation of analytical methods.

④ Stability study documents of semi-finished products and finished products.

⑤ Manufacturing and verification records of samples for clinical trial applications.

6. Preclinical pharmacological and toxicological studies

Despite sharing common contents with the experiment design for traditional biological drugs, the pharmacodynamics experiment design for stem cell drugs shall also factor in the pharmacokinetics and pharmacodynamics of different animal species/models, including survival/colonization, differentiation/integration, distribution and safety features of cells in animals, in combination with the action mechanism of MSCs products to support the selection and design of clinical dosing protocols (dosing site, dosing frequency, dosing duration, etc.).

CytoNiche offers the following services:

① Experimental scheme design for the efficacy and safety of stem cell drugs. 

② Pharmacological and toxicological research experiments (third-party CRO services).

7. Filing and IND application of stem cell clinical research

CytoNiche offers the following services:

① Document writing for preclinical pharmaceutical research.

② Document writing for preclinical pharmacological and toxicological research.

③ Material preparation for clinical research project filing.

④ Material preparation for new drug IND application.

⑤ Process optimization, transfer and validation.

⑥ One-stop regulation related services for IND application and other regulations.

8. GMP production space design and determination, equipment and facility selection and performance confirmation

For details, see "CDMO of CytoNiche Facilitates Commercialization of Cell Therapy Products - GMP Production Environment of Cells"

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Other than the differences in terms of regulatory bodies, implementation bodies and regulatory forms, the filing of stem cell clinical research projects and IND application of stem cell drugs are basically the same in the preparation of preclinical research documents and compliance processes. For example, both include product preparation, quality validation, quality management, preclinical pharmacology and toxicology, and clinical protocol. However, this does not mean that the filing documents of stem cell clinical research projects can be directly used for IND application of stem cell drugs. The requirements of production and quality control of stem cells specified by National Medical Products Administration Center for Drug Evaluation (NMPA CDE) for compliance, safety, effectiveness and quality stability in the above mentioned aspects are difficult to be met by most of the stem cell projects filed in China.

As of July 2022, twenty-six stem cell products have been approved for clinical trials in China through Investigational New Drug (IND) registration and application. Most of these stem cell products would enter clinical trials under the 60-day implied license system.

After completing the clinical trial, whether CMC data, non-clinical pharmacological and toxicological data, human pharmacokinetic and bioavailability data, microbiological data, clinical data, safety data update report, statistical data, case report form, related patent status, samples, and packaging and labeling of stem cell therapy products can pass new drug applications (NDA) review remains uncertain.

Therefore, CTD manufacturers shall develop and design stem cell products based on the QbD concept, and ensure that the product development process meets the regulatory requirements in the preclinical research stage.

For reference:

1. Technical Guidance for the Pharmaceutical Research and Evaluation of Human-Derived Stem Cell Products (Exposure Draft)

2. Large-scale Production Process and Quality Control of 3D Microcarriers of Stem Cells (Part 1 and Part 2): CytoNiche public account/Stemceller public account

3. CDMO of CytoNiche Facilitates Commercialization of Cell Therapy Products - GMP Production Environment of Cells: CytoNiche public account/Stemceller public account

Coming up next:Cell Exosome Product Services

For more details Stay tuned for updates on CytoNiche

✦ 3D TableTrix®

 Cell microcarrier 

• Has obtained the qualification for pharmaceutical excipients from FDA (DMF) and CDE.

• Elastic porous structure with large specific surface area

• 3D biomimetic, customizable

• Specific degradation technology

• Aseptic tablet packaging, no need for pretreatment

✦ 3D FloTrix®

 Three-dimensional stem cell culture medium 

• Customized for 3D mesenchymal stem cell culture process

• GMP-grade production

• Serum-free, animal component-free

✦ 3D FloTrix®vivaSPIN

 Automated bioreactor 

• Implementation of 3D cell real-time online counting

• High precision mass flowmeter, enabling reduction in bubble generation, suitable for 3D cell dynamic culture process

• 3D TableTrix® cell microcarrier dedicated supernatant filtration system

• Audit trail function available, providing 3Q certification and complying with GMP

✦ 3D FloTrix®vivaSPIN

 Automated bioreactor 

• Implementation of 3D cell real-time online counting

• High precision mass flowmeter, enabling reduction in bubble generation, suitable for 3D cell dynamic culture process

• 3D TableTrix® cell microcarrier dedicated supernatant filtration system

• Audit trail function available, providing 3Q certification and complying with GMP

✦ 3D FloTrix®vivaEXO

Exosome harvesting device

• Capable of concentrating 10L of stock solution into less than 500mL in one single batch in 1-3 hours

• Adopting disposable fully enclosed consumable packs that are ready out of the box

• Supports setup and display of various parameters in the running process in real time.

[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.

CytoNiche's core product, 3D TableTrix® Microcarrier Tablet (Microcarrier), is an independent innovation and the first pharmaceutical excipient grade microcarrier that can be used for cell drug development. It has obtained the certificate of analysis from relevant authoritative institutions such as National Institutes for Food and Drug Control, and obtained 2 qualifications for pharmaceutical excipients from the National Medical Products Administration (CDE approval registration number: F20210000003, F20210000496). Moreover, the product has obtained the DMF qualification for pharmaceutical excipients from U.S. FDA (DMF: 35481). 

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.