Ching-Huai Ko1, Feng-Cheng Chou2 & Ling-Mei Wang3
1 President and CEO, Steminent Biotherapeutics Inc.
2 Senior manager, Business development division, Steminent Biotherapeutics Inc.
3 Chairperson and Chief Strategy Officer, Steminent Biotherapeutics Inc.

Abstract

Background: Cell therapy products are living drugs that serve as alternative therapeutic strategies for various unmet medical needs, including cancers, tissue degeneration, and immune dysregulations. To achieve global success, developers must navigate the evolving complexities of advanced therapy medicinal product (ATMP) development.

Findings: This review focuses on the lifecycle of cell product development. Key translational phases are discussed, including navigating regulatory pathways in major global markets, embedding Quality by Design (QbD) principles to establish the Quality Target Product Profile (QTPP), defining Critical Quality Attributes (CQAs), and scaling up manufacturing while maintaining strict Good Manufacturing Practice (GMP) compliance.

Conclusion: This brief review provides actionable insights into the cell therapy ecosystem, effectively bridging the gaps between early stage research and development, regional clinical development, complex regulatory strategies, and the scalability offered by specialized Contract Development and Manufacturing Organization (CDMO) partnerships.

Keywords: mesenchymal stem/stromal cell, quality by design, regulatory pathways

Introduction

Cell therapies represent “living drugs” characterized by unique mechanisms of action, biological activities, and regulatory challenges that distinguish them from traditional small molecules and biologics.

Their inherent manufacturing complexity, batch-to-batch heterogeneity, and short shelf life necessitate integrated development strategies that tightly couple manufacturing, clinical development, and regulatory planning from the earliest stages.

Mesenchymal stem/stromal cells (MSCs) are abundant adult stem cells that can be isolated and culture-expanded from bone marrow, adipose tissue, and neonatal tissues. These cells exert potent immunomodulatory effects and secrete trophic factors, which have led to their approval for treating various diseases, such as acute graft-versus-host disease (e.g., TEMCELL in Japan and Ryoncil in US), osteoarthritis (e.g., CARTISTEM in Korea), and critical limb ischemia (e.g., Stempeucel in India).

There are at least three critical factors for successful MSC product development: indication selection, route of administration, and manufacturing consistency. Indication selection is intrinsically linked to clinical trial design and regional regulatory requirements, which govern parameters such as donor eligibility criteria and preclinical safety profiles.

Furthermore, donor variation and labor-intensive, large-scale production present significant hurdles for commercialization. To mitigate these risks, developers should embed QbD principles during early product development, ensuring product quality throughout the entire lifecycle. Last but not least, for biotech companies, early engagement with global professional CDMOs can effectively de-risk manufacturing challenges and product logistics. More importantly, this allows companies to remain focused on pipeline expansion and indication development, rather than allocating excessive resources to maintaining a GMP-compliant facility. In conclusion, this article introduces the concept of the cell therapy ecosystem, advocating for a transition from isolated operations to strategic collaboration to achieve global success.

Findings

Mesenchymal stem/stromal cells (MSCs) represent a novel drug modality exhibiting multifaceted biological activities, which have been widely leveraged in clinical studies to treat a broad spectrum of conditions, including inflammatory, skeletal, neurological, cardiocerebral vascular, and respiratory diseases (1). To date, more than 1,700 clinical trials have been registered on ClinicalTrials.gov, spanning both high-prevalence conditions and rare or severe diseases. However, despite this robust pipeline, only a limited of products have successfully secured final regulatory approval and been launched into the market. To bridge this critical gap between clinical research and commercial approval, the following key considerations are essential to address.

• Strategic Product Development and Goal Definition. Developers must first establish robust core technology platforms and comprehensively characterize the therapeutic product tailored to target indications. This involves thoroughly assessing existing unmet medical needs and defining a distinct therapeutic differentiation profile for the investigational product relative to current standard-of-care therapies. Furthermore, it is highly recommended to proactively evaluate regional healthcare infrastructures and patient access capabilities, alongside country-specific reimbursement frameworks and health economic considerations, to pre-emptively mitigate market entry barriers.

• Regional Expedited Development Programs and Clinical Trial Frameworks. To accelerate patient access, various jurisdictions have established distinct regulatory pathways tailored to expedite the translation of cell and gene therapy (CGT) products. These frameworks offer strategic mechanisms—such as expedited reviews, rolling submissions, and priority designations—designed to compress clinical development timelines and fast-track market entry. The prominent global frameworks include:

• United States (FDA): Utilizes specialized pathways including Regenerative Medicine Advanced Therapy (RMAT) and Breakthrough Therapy designations, alongside Fast Track, Accelerated Approval, and Priority Review mechanisms to expedite unmet clinical needs. A prominent case is Ryoncil, which strategically leveraged the RMAT designation to accelerate its clinical development and Biologics License Application (BLA) regulatory review for pediatric steroid-refractory acute graft-versus-host disease.
• Europe (EMA): Leverages the PRIority MEdicines (PRIME) scheme and accelerated assessment procedures to optimize development timelines for innovative therapeutics. A pioneering example is Alofisel, which became the first allogeneic MSC product to receive marketing authorization through the EMA’s advanced therapy frameworks; however, due to post-marketing strategic re-evaluations, this product’s authorization has recently been withdrawn.
• Japan (PMDA): Employs the Sakigake designation system to accelerate the development and approval of regenerative therapies addressing severe and unmet medical needs. Furthermore, under Japan’s PMD Act, a dedicated conditional and time-limited approval scheme is established for regenerative medicine.
• Taiwan (TFDA): Official implementation of Regenerative Medicine Dual Acts 2026, allows conditional approval for products designed for the treatment of life-threatening or severely disabling diseases, confirmed safety and preliminary efficacy in phase II clinical trials. In addition, the Ministry of Health and Welfare has initiated a pilot program, the Taiwan Regenerative Medicine Advanced Therapy (T-RMAT) framework, which is designed to facilitate early regulatory alignment, rolling reviews and guidance, with the aim of identifying and addressing potential development risks at an early stage.

• Establishing the Quality Target Product Profile and Continuous Monitoring. Cell products are highly sensitive to environmental and processing factors that can dramatically impact their biological characteristics. Every stage of the cellular manufacturing process—including cell isolation, culture media supplementation, expansion strategies, and release criteria—is critical to successful product development. Consequently, it is highly recommended to establish a QTPP as soon as the initial Target Product Profile (TPP) is drafted (2-4). Table 1 illustrates the QbD relationship matrix that links these critical parameters. As culture media evolve (from animal-derived components to chemically defined formulations) and manufacturing technologies advance (such as 3D scaffold-based cultures and automated closed systems), developers can adopt more efficient and cost-effective strategies to refine production.This QbD matrix serves as an essential framework to dissect key production variables, particularly when implementing manufacturing changes or executing technology transfers to CDMOs for commercial scale-up (5). Throughout this iterative process, it is vital to continuously re-examine the QbD matrix by addressing the following pivotal questions:
• Which product attributes directly impact efficacy and safety?
• Which raw materials and excipients critically affect product quality?
• Within which operational ranges is product quality consistently assured?
• Is the current manufacturing process robust enough to support commercial scalability?

In the cell therapy field, where “the process is the product,” a well-designed, strictly controlled manufacturing workflow is often the ultimate key to commercial and clinical success.

Table 1. Integrated QbD Matrix for Cell Therapy Development and Manufacturing

QTPP items	Critical quality attribute	Critical process parameter	Control Strategy
Identity	Morphology/ Surface markers	Population doubling level	Flow cytometry
Cell expansion	Viable cells meet commercial scale	Culture conditions, pH, pO2, glucose	Design of space, material attribute
Purity	Residual raw materials	Washing cycles	Release testing
Safety	Sterility	Closed processing	Sterility testing
Stability	Product shelf life	Storage temperature	Stability program
Potency	Functional assay	Media composition	Potency assay

Translating Strategy into Practice: Steminent Biotherapeutics’s Global Execution. Translating these complex regulatory, clinical, and manufacturing frameworks into practical execution requires seasoned expertise. With over a decade of experience in product manufacturing and clinical development, Steminent continuously upgrades its manufacturing technologies and synchronizes with evolving regulatory standards to accelerate product advancement. By engaging clinical key opinion leaders (KOLs) early on in both Taiwan and the United States, the company has successfully completed a Phase II, double-blind, placebo-controlled trial in Taiwan and is currently preparing for a Phase II trial in the US.

Furthermore, through a strategic partnership with REPROCELL in Japan, Steminent is leveraging global resources—including advanced cell culture raw materials and smart CDMO capabilities for commercial production—to pave the way for BLA approvals. This integrated global strategy serves as a successful blueprint for the translational research of MSC products, aligning with the company’s core vision: “Better ways to treat diseases, bringing innovation to promote a better life.”

Conclusion

MSC possess multifaceted biological functions that enable their allogeneic use in treating a diverse spectrum of complex medical conditions. While numerous clinical studies have consistently demonstrated their safety and therapeutic efficacy, translating this clinical promise into a viable commercial product remains exceptionally challenging. To enhance the probability of translational success, developers are required to engage clinical KOLs early to address true unmet medical needs and continuously align with regulatory agencies to leverage global expedited programs. Ultimately, integrating the QbD framework into cell therapy product development provides a robust lifecycle management strategy, ensuring strict batch-to-batch consistency in commercial manufacturing and paving the way toward global market success.

Acknowlegment

The authors would like to thank the Steminent team for their efforts in collecting and summarizing the information.

Conflict of interest

The authors declare no conflict of interest.

Reference

• Han X, Liao R, Li X, Zhang C, Huo S, Qin L, et al. Mesenchymal stem cells in treating human diseases: molecular mechanisms and clinical studies. Signal Transduct Target Ther. 2025;10(1):262.
• Lipsitz YY, Timmins NE, Zandstra PW. Quality cell therapy manufacturing by design. Nat Biotechnol. 2016;34(4):393-400.
• Campbell A, Brieva T, Raviv L, Rowley J, Niss K, Brandwein H, et al. Concise Review: Process Development Considerations for Cell Therapy. Stem Cells Transl Med. 2015;4(10):1155-63.
• Yu H, Zhang F, He YC, Zhang LS. Quality by design strategy of human mesenchymal stem/stromal cell drug products for the treatment of knee osteoarthritis. World J Stem Cells. 2025;17(5):106547.
• Yamamoto T, Arita M, Tamura T, Saito M, Katayama H, Kuroda H, et al. A Novel Approach for Determining the Critical Quality Attributes of Mesenchymal Stem Cells by Specifying Cell Population With Replication Potential. Stem Cells Transl Med. 2023;12(3):169-82.

Corresponding author:

Dr. Ling-Mei Wang is the Chairperson and Chief Strategy Officer of Steminent Biotherapeutics Inc., a pioneer in the development of mesenchymal stem cell therapies. Dr. Wang has been a driving force in advancing translational medicine and commercializing breakthrough cellular therapies for rare and incurable diseases.