Cell and gene therapies (CGTs), or Advanced Therapy Medicinal Products (ATMPs), are fundamentally different from traditional medicines. Unlike conventional small molecules or biologics, these therapies are born from living systems, and with that distinction comes a host of unique manufacturing challenges. It is perhaps unsurprising, then, that regulatory authorities worldwide have been quietly reshaping the landscape—updating long-standing guidelines, adapting existing frameworks, and in some cases, building entirely new ones—to ensure that regulation keeps pace with scientific possibility. From the EMA to the FDA and beyond, a new generation of technical guidance is emerging, designed not only to safeguard patients but also to illuminate a clearer path for those developing these transformative therapies.

For example, the US Food and Drug Administration (US FDA) has issued specific guidance on cell and gene therapy facilities to address the complexities of cleanroom design and cross-contamination (Alfred Penfold, 2025). Similarly, the European Union (EU) has issued regulations specifically for cell and gene therapies in the form of EudraLex Volume 4, Part IV: "Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products (November 2017)" (Alfred Penfold, 2025). These regulations were formerly part of EudraLex Volume 4, Annex 2, Manufacture of Biological active substances and Medicinal Products for Human Use.

This global regulatory evolution is also evident in other major markets. In Japan, the Pharmaceuticals and Medical Devices Agency (PMDA) established a "time-limited conditional approval" system specifically to expedite the path for regenerative medicines (Yoon et al., 2025). Meanwhile, Australia’s Therapeutic Goods Administration (TGA) has refined its "Biologicals" framework to better categorise cell-based products based on the level of processing and intended use (Orozco-Solares et al., 2022).

Joining this global movement toward specialised oversight, China has taken a significant step forward. On 30 January 2026, the Centre for Drug Evaluation (CDE) of China's National Medical Products Administration (NMPA) officially released the "Technical Guidelines for the Study and Evaluation of Pharmaceutical Changes in Cell Therapy Products (Trial)" (“Announcement No. 13 of 2026 From the Center for Drug Evaluation of the National Medical Products Administration on Issuing the ‘Technical Guidelines for Pharmaceutical Change Research and Evaluation of Cell Therapy Drugs (Trial),’” 2026). This seminal document serves as a lighthouse for an industry previously navigating the mist of regulatory ambiguity. As the nation’s first dedicated framework for "pharmaceutical changes" in the cellular realm, it fills a long-standing void, providing a structured path for the full lifecycle management of sophisticated therapies such as CAR-T cells, stem cells, and Tumour-Infiltrating Lymphocytes (TIL).

Why "Pharmaceutical Changes" Matter

In conventional drug development, pharmaceutical changes are routine and generally manageable. In cell therapy, however, changes are often transformative.

Cell-based products are inherently sensitive to environmental and process variations. The transition from laboratory-scale development to commercial manufacturing is not linear but exponential. Scaling from millions of cells in preclinical studies to tens or even hundreds of billions of cells for commercial supply fundamentally alters equipment requirements, process parameters, and quality risks.
These changes typically arise from two broad drivers.

1.  Natural Evolution of the R&D Phase:

• From Lab to Factory: Scaling from preclinical (hundreds of millions of cells) to Phase I/II clinical (billions) and finally to commercial production (tens to hundreds of billions) represents an exponential increase in manufacturing scale. Such a progression mandates the re-evaluation and modification of equipment, process parameters, and overall procedures.
• Process Optimisation: To boost yields, drive down costs, and guarantee batch-to-batch consistency, manufacturers continuously refine the cell culture conditions and purification steps to final formulation.
• Supply Chain and Accessibility: Supplier changes, manufacturing site transfers, and the introduction of new equipment are common throughout the product lifecycle.

2. Mandatory Requirements of Regulatory and Quality Systems:

• Continuous Improvement: International quality standards, including ICH Q10, mandate more than just adherence to protocols; they require organisations to embed a culture of continuous improvement and proactively seek out opportunities for process optimisation.
• Risk Control: When deviations, process variability, or emerging impurity trends are identified, corrective actions are mandatory. These often require changes to manufacturing processes or controls.
• Post-Approval Changes: Even after a drug is approved, changes are still needed—to meet market demand, fix supply issues, or adopt new technology.

Adjustments to core elements such as raw materials, manufacturing processes, equipment, sites, and testing methods all fall under the umbrella of "pharmaceutical changes." Therefore, for cell therapy companies, "pharmaceutical changes" are not an option but a mandatory requirement.
However, previous guidance on pharmaceutical changes primarily targeted traditional drugs like chemical compounds and large molecule biologics, lacking specific regulations for "living drugs," i.e., cell therapies. In this vacuum, companies often found themselves in a dilemma. Avoiding changes risked outdated processes, limited capacity, and even compromised product quality. Implementing changes, however, carried the risk of regulatory non-compliance, delayed approvals, or stalled development. Given that even minor changes in cell therapy can significantly affect safety or efficacy, this uncertainty posed a serious barrier to progress.

Key Elements of the New Guideline: A Practical "Change Manual" 

This newly released guideline by the CDE precisely targets the "pain points" companies face regarding pharmaceutical changes in cell therapy. It respects the unique nature of cell therapies while ensuring consistency in product quality before and after changes:

1. Clear Definition of Scope: Not All Cell Products Apply

The guideline applies to live cell therapy products derived from human cells (autologous or allogeneic) that undergo in vitro manipulation before administration. This includes CAR-T cells, TILs, stem cells, islet cells, and chondrocytes. For combination products, the cell component falls within scope.
Excluded are blood components for transfusion, haematopoietic stem cell transplantation without ex vivo manipulation, germ cells, tissues, organs, and changes that fundamentally alter the drug design—such as switching from allogeneic to autologous products or changing the target cell population.
Furthermore, the new regulation encourages applicants/marketing authorisation holders to adopt safer raw materials, safer gene modification systems, develop more enclosed equipment, and improve quality control capabilities during process optimisation.

2. Classification of Changes: Different Paths, Different Requirements

In principle, major pharmaceutical changes should be completed before the start of confirmatory clinical trials. If major pharmaceutical changes are implemented after the completion of confirmatory clinical trials, a thorough comparability study must be conducted, and communication with the regulatory authority is encouraged.
For post-approval changes, the new guideline classifies them into three categories: Major, Moderate, and Minor. The submission pathways for each category differ significantly, directly impacting the efficiency and cost of implementing changes for companies:

• Major Changes: For instance, replacing key components of a viral vector, adding a new manufacturing site with a modified process. These changes could potentially affect product quality and require a "supplemental application" submission and approval by the CDE before implementation.
• Moderate Changes: For example, adding a new production line based on a "mirror model" (identical to the original line). This only requires "filing" with the CDE; implementation can proceed once the filing is accepted.
• Minor Changes: For instance, extending the shelf life of a plasmid (provided storage conditions remain unchanged and stability data supports it). This only requires "notification" and can proceed without waiting for approval.

3. Comparability Studies: The Cornerstone of Change Management

Regardless of change category, pharmaceutical comparability is central. Companies must demonstrate that changes do not adversely affect safety, efficacy, or quality control.
The guideline prioritises head-to-head studies, ideally using starting material from the same donor and processing it through old and new processes in parallel. Where this is not feasible, comparison against robust historical data from pre-change data is acceptable, though it introduces greater analytical complexity and risk.

What Does This Mean for Companies? From "Extensive Development" to "Standardised Innovation"

The implementation of this new guideline represents not just a "regulatory upgrade," but also "industry empowerment," profoundly influencing the development logic for cell therapy companies:

• R&D becomes more agile: With clearer expectations, companies can plan process optimisation earlier, introduce improved technologies, and continuously enhance product quality without fear of regulatory misalignment.
• Manufacturing expansion gains a clear pathway: The recognition of the mirror model as a moderate change removes a major barrier to capacity expansion by replicating mature production lines without going through complex re-approval processes,, particularly for autologous therapies with personalised manufacturing needs.
• Global alignment improves: By referencing ICH, FDA, and EMA principles, the guideline aligns domestic development with international standards, reducing friction for future global registration.

Recommended Next Steps for Cell Therapy Developers

First, companies must establish a comprehensive study guide to synchronise departmental efforts and eliminate delays caused by regulatory misjudgments. By leading R&D, production, and quality teams in a rigorous analysis of current guiding principles, firms can map these against existing process optimisation and capacity expansion plans. This allows for a clear definition of the level of each change and its corresponding submission pathway, ensuring that "re-work" cycles stemming from misclassified technical modifications are avoided.
Second, change management must be integrated into the entire product lifecycle rather than treated as an afterthought. Companies should strive to complete all major process changes and lock in core workflows before initiating confirmatory clinical trials to minimise the risk of late-stage adjustments. For post-marketing changes, it is essential to follow established procedures strictly according to their classification, ensuring that all research data and submission documentation are meticulously retained for audit readiness.
Third, companies must prioritise proactive communication with regulatory authorities, such as the CDE, to confirm the feasibility of study plans before research begins. Engaging early for significant changes ensures that resources are deployed effectively and that strategies align with regulatory expectations. Should comparability data prove insufficient to rule out risks, seeking prompt guidance will prevent the waste of time and capital on unnecessary non-clinical or clinical studies.

Conclusion

In the entire process of pharmaceutical changes for cell therapies, three core elements take centre stage: process optimisation, quality control, and pharmaceutical comparability. Drawing on deep technical expertise in 3D large-scale cell culture and process development, CytoNiche has experience in guiding multiple clients to make the shift from 2D to 3D manufacturing processes, across different stages of drug development, including the successful pharmaceutical change during late clinical stages for China's first approved stem cell therapy, Amimestrocel. Covering the full spectrum of change nodes—from pre-clinical and Phase I/II stages to Phase III and commercial production—these capabilities enable cell therapy companies to navigate process changes with confidence while remaining fully aligned with evolving regulatory requirements. For enterprises, mastering and strategically leveraging these new regulations transforms change management from a compliance necessity into a competitive advantage. It is this forward-looking approach that empowers them to move steadily and boldly along the life-saving frontier—ultimately accelerating the delivery of high-quality cell therapies to the patients who need them most.

References

Alfred Penfold. (2025, August 18). Navigating through Advanced Therapy Medicinal Products (ATMPs) guidance and regulations. iSpeak Blog.https://ispe.org/pharmaceutical-engineering/ispeak/navigating-through-advanced-therapy-medicinal-products-atmps
Announcement No. 13 of 2026 from the Center for Drug Evaluation of the National Medical Products Administration on Issuing the “Technical Guidelines for Pharmaceutical Change Research and Evaluation of Cell Therapy Drugs (Trial).” (2026, January 30). Center for Drug Evaluation, National Medical Products Administration. https://www.cde.org.cn/main/news/viewInfoCommon/d2095373f1f57506795743870ca09c98
Orozco-Solares, T. E., León-Moreno, L. C., Rojas-Rizo, A., Manguart-Páez, K., & Caplan, A. I. (2022). Allogeneic Mesenchymal Stem Cell-Based Treatment Legislation in Latin America: The need for Standardization in a Medical Tourism context. Stem Cells and Development, 31(7–8), 143–162. https://doi.org/10.1089/scd.2022.0013
Yoon, J., Lee, S., Kim, M. J., & Kim, J. (2025). Brief summary of the regulatory frameworks of regenerative medicine therapies. Frontiers in Pharmacology, 15, 1486812. https://doi.org/10.3389/fphar.2024.1486812