The transition from late 2024 into early 2025 represented a definitive watershed for the Mesenchymal Stem Cell (MSC) sector. On 28 December 2024, the FDA granted approval for Ryoncil (also known as remestemcel-L); this was followed swiftly on 2 January 2025 by the NMPA’s conditional approval of Amimestrocel Injection. These milestones—specifically the increasing reliance on "conditional approval" pathways—have elevated product lifecycle management and manufacturing consistency to an unprecedented strategic importance.
Whether seeking full or conditional marketing authorisation, the fundamental prerequisite remains constant: "The safety, efficacy, and controllability of the product manufactured under the current process have been demonstrated." For "living" cell products such as MSCs, the process effectively is the product. Subtle variables at every stage—from donor screening and in vitro expansion to cryopreservation and recovery—can have a direct and profound impact on cell viability, purity, and functional potency. Consequently, the manufacturing protocol established at the point of approval serves as the definitive quality baseline for the product throughout its entire commercial lifecycle. Any deviation from this baseline risks compromising the therapeutic integrity of the treatment.
In the following analysis, we focus on MSC products to explore the inherent logic, core strategies, and critical timings involved in managing process changes during the high-stakes clinical development phase.

I. Process Changes: Logic, Science, and Control

Why Do Process Changes Occur?

Process changes in pharmaceutical manufacturing are rarely arbitrary. They are typically driven by a combination of internal operational needs and external regulatory or supply-chain pressures. Broadly, such changes can be grouped into four principal categories:

• Mandatory changes arise from factors beyond the manufacturer’s control, such as updates to regulatory requirements or the discontinuation of critical raw materials or components. These changes are unavoidable and must be implemented to maintain compliance and supply continuity.
• Improvement changes are initiated proactively to strengthen the manufacturing process. These may include optimisations designed to improve process robustness, increase yield, enhance operational efficiency, or reduce manufacturing costs, without altering the product's fundamental quality attributes.
• Adaptive changes are introduced to accommodate shifts in the manufacturing environment, such as technology upgrades, equipment replacement, or manufacturing site transfers. While not driven by deficiencies, these changes are necessary to ensure consistent product performance under new operational conditions.
• Corrective changes are implemented in response to identified deficiencies or risks within the existing process. Their purpose is to address deviations, close gaps revealed through investigations or trend analyses, and restore the process to a state of control.

On What Basis Is “Change” Justified?

In pharmaceutical development, changes are never arbitrary adjustments. They are anchored in robust scientific principles that ensure product quality, patient safety, and regulatory confidence. Two core pillars underpin this approach.
First, Quality by Design (QbD) provides the conceptual framework for managing change. By defining Critical Quality Attributes (CQAs) upfront, QbD establishes clear benchmarks against which proposed modifications are assessed. Changes are therefore evaluated not in isolation, but in terms of their impact on the attributes that ultimately determine product quality, ensuring alignment with the intended clinical performance throughout the product lifecycle.
Second, comparability studies supply the empirical evidence required to support change. Through carefully designed, head-to-head assessments, these studies generate data demonstrating that the post-change product remains comparable to the pre-change reference in critical quality characteristics, as well as in safety and efficacy where relevant. This comparability evidence provides the scientific foundation for regulatory acceptance, translating a technical adjustment into a controlled, evidence-based evolution of the product.

How to Manage "Change"?

Effective change management in cell therapy manufacturing is grounded in a graded, risk-based, and scientifically driven approach. During clinical development, the primary objective is to ensure that any change does not compromise subject safety or the integrity and interpretability of clinical data, while still enabling the systematic accumulation of evidence required for future marketing applications.
Equally important is adopting a lifecycle perspective. Process change studies conducted in early development should be inherently forward-looking. Data generated at this stage should be sufficiently robust to support later confirmatory clinical trials and, ultimately, regulatory submissions. Inadequate early change management often results in downstream bottlenecks, where insufficient comparability data necessitate costly study repetition or delays in programme progression.
Against this backdrop, three representative directions of process evolution illustrate both the logic and the regulatory challenges of managing change.

Direction 1: From 2D Adherent to 3D Suspension—A Paradigm Shift in Core Technology

Conventional two-dimensional adherent culture systems are highly labour-intensive and difficult to monitor comprehensively. They are prone to capacity constraints and pronounced batch-to-batch variability, placing pressure on process robustness, commercial scalability, and cost control.
In contrast, three-dimensional suspension culture technologies—most notably those based on microcarriers—more closely mimic the in vivo cellular microenvironment. By enabling substantially higher cell expansion efficiency, they can compress manufacturing footprints from workshop-scale operations to room-scale systems, significantly reducing facility investment and operational complexity.
Despite these advantages, the transition from 2D to 3D culture represents a fundamental shift in underlying biological and engineering principles. Such changes can directly influence cell proliferation, metabolism, and secretory profiles. As a result, this transition is typically classified as a Major Change, necessitating comprehensive comparability studies to evaluate its impact on predefined Critical Quality Attributes (CQAs) and to ensure continued product consistency.

Direction 2: From Manual Open Operations to Automated Closed Systems—A Fundamental Transformation of Manufacturing Paradigm

The transition from manual, open-bench processing to integrated, fully closed automated systems represents the shift from "lab-based experimentation" to "standardised industrial production."

The Drivers for Automation

• Risk Mitigation: Consolidating steps like washing, concentration, and formulation within sealed fluid pathways reduces contamination risks by orders of magnitude.
• Enhanced Reproducibility: Minimising human intervention eliminates the primary source of batch-to-batch variability.
• Regulatory Traceability: Automated platforms provide precise, digital capture of production data, ensuring superior alignment with global GMP expectations.

Direction 3: Replacing Animal-Derived Materials with Animal-Free Alternatives—A Source-Level Revolution in Quality Control

The use of animal- or human-derived materials inherently carries the risk of introducing adventitious agents and increases both the testing burden and the complexity of quality control. In response, the adoption of chemically defined, animal-free materials has become an increasingly important strategy for meeting global GMP expectations, achieving source-level control, and improving batch-to-batch consistency.
However, animal-derived components often provide complex nutritional and signalling environments that are difficult to replicate. Substituting these materials can alter cell–material interactions, potentially affecting proliferation, metabolism, adhesion, migration, and functional potency. In three-dimensional culture systems, for example, cellular interactions with natural extracellular matrix-based microcarriers may differ significantly from those with recombinant protein-coated alternatives. Similarly, chemically defined media may not fully reproduce the metabolic and signalling support provided by complex supplements such as human platelet lysate.
For these reasons, the replacement of critical raw materials—particularly core media and matrix components—is typically regarded as a Major Change. Sponsors are expected to undertake in-depth, multidimensional comparability assessments to demonstrate consistency in CQAs, functional performance, and process robustness before and after implementation.II. Seizing the Critical Timing for Process Changes

In the lifecycle of a cell therapy product, when is often as critical as the what. Implementing a process modification is a strategic decision that must balance technical necessity with the timelines of clinical development.

While every change must be underpinned by a robust comparability study, Major Changes—such as the transition from 2D to 3D culture—carry the most rigorous data requirements. From a strategic perspective, this leads to a consistent conclusion: the earlier a significant change is introduced, the lower the overall burden tends to be. Implementing major process upgrades—such as a transition from two-dimensional to three-dimensional culture—during preclinical development or early clinical stages helps to limit downstream uncertainty and avoid disruptive process modifications during critical, value-defining phases of development.

Early clinical development represents the most favourable window for implementing Major Changes. For example, upgrading a core manufacturing process during Phase I or early Phase II allows the revised process to be used in subsequent clinical studies, where safety and preliminary efficacy can be evaluated using material representative of the intended commercial process. At this stage, the impact on programme continuity is typically manageable, and regulatory expectations for clinical comparability are proportionate to the product's developmental maturity.

In contrast, Major Changes should generally be avoided during pivotal clinical development or after marketing authorisation. Changes introduced at this stage risk undermining the interpretability of pivotal efficacy data and can lead to significant delays in approval. Where major changes are unavoidable—such as due to raw material discontinuation, supply chain constraints, or critical quality or safety concerns—early, proactive engagement with regulatory authorities is essential.

In these scenarios, sponsors are typically expected to develop a comprehensive change management strategy, which may include additional non-clinical studies, expanded comparability packages, or, in some cases, dedicated clinical bridging studies to demonstrate continuity between pre- and post-change products.
There are well-documented examples in the cell and gene therapy field of major process changes introduced during pivotal clinical development, or even later, including programmes involving CAR-T and mesenchymal stromal cell (MSC) products. Owing to the “living medicine” nature of these therapies and the inherent complexity of personalised manufacturing, process optimisation and scale-up during development are often unavoidable rather than exceptional. The following case illustrates how such changes can be successfully managed when supported by robust scientific and regulatory strategies.

Case Study 1: World's First Commercialised CAR-T Therapy

According to a Novartis press release, the product received FDA approval in August 2017, becoming the world's first commercially approved CAR-T therapy.

Application: For the treatment of relapsed/refractory diffuse large B-cell lymphoma.
Change Implementation and Timing: During Phase II clinical trials (JULIET study), the manufacturing process was transferred from academic institution facilities to the company's commercial production centre, accompanied by critical process optimisations, including:

• Replacement of certain manual operations with automated cell processing systems;
• Upgrade to a closed-system production process;
• Comprehensive optimisation of quality control testing methods.

Nature of Change: Classified as a Major Manufacturing Change, consistent with the FDA guidance on "Manufacturing Changes and Comparability for Cell and Gene Therapy Products" — specifically, a "manufacturing site transfer combined with core process step adjustments" constituting a Major Change.

Outcome: The product received FDA approval in August 2017, becoming the world's first commercially approved CAR-T therapy.Case Study 2: An Anti-CD19 Autologous CAR-T Cell Therapy Product

According to a regulatory submission update and clinical data presented by JW Therapeutics Co. Ltd., the company successfully implemented a post-approval manufacturing change for its autologous CD19-targeting CAR-T cell therapy used in the treatment of relapsed/refractory large B-cell lymphoma. The change involved replacing an externally sourced lentiviral vector with an in-house produced version (JWLV011). Given that lentiviral vectors are classified as critical functional components, this change was deemed high risk and required a post-marketing supplementary application to China's National Medical Products Administration (NMPA). A dedicated Phase II comparability study, including at least three months of clinical follow-up, was conducted to demonstrate product consistency following the change.
Nature of Change: This change is classified as a Major Manufacturing Change because it involves replacing a core raw material that may affect product quality and supply stability. Implementation requires approval via a supplementary application.
Outcome and Analysis: The application was officially accepted by the regulator. Interim clinical data demonstrated efficacy and safety comparable to those of the approved product, with no increase in severe CAR-T–related toxicities. This enabled the company to proceed towards implementation of the new vector while improving supply stability, reducing manufacturing costs, and strengthening process control. The case demonstrates that, for cell therapies, well-planned post-approval changes supported by robust comparability data can mitigate regulatory risk while delivering tangible operational and commercial benefits.Case Study 3: China's First Commercially Approved Stem Cell Drug

Indication: For the treatment of Graft-versus-Host Disease (GvHD).
Change Implementation and Timing: In the early research phase, a traditional 2D adherent culture was used. As development progressed, to overcome the bottlenecks of the 2D process in terms of production capacity, batch-to-batch consistency, and commercial viability, a fundamental process upgrade was implemented at a pivotal clinical study stage: transitioning from an open 2D planar culture system to a bioreactor-based 3D microcarrier suspension culture system.
Nature of the Change: This change involved a comprehensive innovation across the core logic of cell expansion, critical equipment, process parameters, and the quality control system. It was classified as a Major Pharmaceutical Change. However, the company decisively implemented this change at a critical point in a clinical study, laying a solid foundation for subsequent commercial manufacturing.
Outcome and Analysis: Based on a comprehensive and robust comparability study, the rationale for the post-change process was recognised by the CDE. The cell product manufactured using the new 3D process successfully completed the pivotal clinical studies, and the clinical data were fully accepted for the marketing authorisation application, leading to its approval as China's first marketed MSC medicine.

In the commercial stage, the cost optimisation brought by the process change has been significant, with the medicine's price reduced to 1/70th that of similar international products.
These three cases reaffirm that for living cell products with complex processes, such as MSCs and CAR-T, process optimisation and change should not be viewed as R&D "stumbling blocks," but rather as a strategic imperative to enhance product value and ensure commercial success. The key takeaway for companies is to establish a "process lifecycle management" perspective early in R&D, to plan proactively, evaluate scientifically, and, through close collaboration with regulators, convert necessary technological upgrades into a reliable engine that accelerates product approval.
In summary, the cases above collectively and clearly echo the core principles of the new CDE guidance:

• Acknowledging the Inevitability of Change:
  The transition from R&D-scale to commercial manufacturing is an essential path towards industrialisation. Major changes represent upgrades, not exceptions.
• Establishing "Comparability Studies" as the Lifeline:
  Whether through head-to-head analysis or cross-process bridging, the prerequisite for accepting any change is demonstrating consistency in the product's CQAs through robust, multi-dimensional pharmaceutical data.
• Demonstrating Regulatory Science and Flexibility:
  By recognising these cases, the CDE signals that it does not reject necessary optimisations at critical stages, but requires sufficient scientific evidence to rule out risks. This provides companies with clear regulatory confidence to "optimise scientifically."
• Highlighting the Critical Value of Pre-submission Communication:
  Reaching consensus with regulators on the plan before implementing a change is the most crucial step to control R&D risk and ensure a smooth path.

Therefore, the action guide for all cell therapy companies is clear:

• Earlier is Better:
  Strive to lock in and scale up the core process before the start of pivotal clinical trials (Phase III).
• Pursue Ultimate Scientific Rigour:
  If changes during clinical trials are unavoidable, conduct pharmaceutical comparability studies to the highest standards and actively engage with regulators.
• Embrace the Rules, Plan Proactively:
  The newly released Guideline codifies these successful practices into clear industry rules. Understanding and leveraging them effectively is, in itself, a core source of competitive advantage.Conclusion

Process changes for cell therapy products constitute a continuous scientific endeavour and strategic undertaking. Under the new regulatory framework, companies must fully understand the scientific rationale for changes, accurately assess risks, and plan timing with foresight. Only then can they transform "change" from a potential development challenge into a proactive strategy to enhance product quality and accelerate market approval, ultimately gaining a competitive edge in this race to save lives.

References

National Medical Products Administration has officially accepted the post-marketing supplemental application for Carteyva®, which uses an in-house produced lentiviral vector | JW Therapeutics. (n.d.). https://jwtherapeutics.com/en/media/press-release/20251009/
Novartis receives first ever FDA approval for a CAR-T cell therapy, Kymriah(TM) (CTL019), for children and young adults with B-cell ALL that is refractory or has relapsed at least twice. (n.d.). Novartis. https://www.novartis.com/news/media-releases/novartis-receives-first-ever-fda-approval-car-t-cell-therapy-kymriahtm-ctl019-children-and-young-adults-b-cell-all-refractory-or-has-relapsed-least-twice