MSC manufacturing appears straightforward on paper: initiate, expand, harvest, formulate, cryopreserve. In practice, programs derail downstream when vague assumptions are allowed to persist.
Below are eleven key considerations that determine whether MSC manufacturing remains consistent and scalable.
- Source strategy and donor variability
Define controls for biological variability, especially when scaling across donors or tissue sources.
- Cell bank strategy and lifecycle
An MSC cell bank is not inventory. It is a control strategy for comparability, long-term supply, and regulatory continuity.
- 2D versus 3D expansion pathway
Two-dimensional systems are often appropriate early. At scale, automated bioreactor platforms and, in some cases, 3D microcarrier-based expansion can improve consistency, provided comparability planning begins early.
- Defined media exchange strategy
Align media changes to growth behavior using measurable signals. In-process metabolite monitoring helps detect drift before it becomes batch-limiting.
- Predictive critical quality attributes (CQAs)
Surface markers alone do not define potency. CQAs must align with mechanism of action and clinical intent.
- Harvest is a process, not a moment
Harvest and wash should be engineered unit operations with defined, controllable parameters.
- Agglomeration control
Agglomeration drives downstream risk. In-line filtration and optimized wash design improve robustness and handling.
- Automation aligned to development phase
Automate what reduces immediate risk, such as cell washing, while maintaining a roadmap for higher-throughput automation.
- Cryopreservation and formulation fundamentals
Formulation directly impacts post-thaw viability and function. This is a frequent point of GMP translation failure if not addressed early.
- DP container and fill strategy
Select phase-appropriate fill and finish early to avoid costly changes and comparability work later.
- QC testing and stability for living products
MSC programs require tailored identity, potency, sterility, and stability strategies that support shelf-life claims.
These are not optional enhancements. They are the levers that determine reproducibility, release reliability, and whether scale feels controlled or chaotic.
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