Standardized Apheresis Would Fix Cell Therapy's Variability Problem

Variation in how apheresis is performed at collection sites directly degrades the quality of cell therapy starting materials — and, by extension, the comparability work every manufacturer depends on when scaling or transferring processes. That is the central finding of a new analysis by Christina Celluzzi, PhD, of the Association for the Advancement of Blood & Biotherapies (AABB) and colleagues, published in the journal Cytotherapy.

The problem starts with biology. Donor age, disease status, treatment regimen and donation history all shift the quality of harvested cells. Developers must then convert those variable inputs into consistent products. But biology is not the only variable in the chain, and Celluzzi argues the industry underestimates how much collection practice itself contributes.

"Variability at the apheresis stage complicates comparability assessments when manufacturers change processes, transfer technology, or add capacity," Celluzzi told GEN. "It also limits how efficiently sponsors can use comparability protocols and post-approval change strategies."

What does the study actually propose?

Not blanket harmonization. Celluzzi and co-authors draw a line between what should stay flexible and what should be locked down.

"Not every area needs the same degree of standardization," she said. "For example, there will always need to be flexibility with regard to device selection and vascular access techniques."

The flip side: elements that support comparability and traceability need tight standardization. Those include:

• minimum donor eligibility data elements
• definitions of quality attributes
• product identification and labeling

One existing standard already covers part of this ground. ISBT 128 — the blood and tissue labeling terminology standard maintained by the International Council for Commonality in Blood Banking Automation — addresses terminology, labeling and chain of identity. Celluzzi calls it an ideal starting point for industry-wide standardization of collection practice.

Adoption alone is not enough, she cautions. "Adoption of such standards should be paired with implementation support, so that standardization doesn't widen capability gaps between collection sites." A rule that large academic centers can absorb easily could squeeze smaller collection operations out of qualified-site lists.

Who writes the standards — and what should FDA do?

Celluzzi's model puts stakeholders, not regulators, in the drafting seat. The technical content of best practices, she argues, is best developed through consensus efforts led by organizations such as PDA (the Parenteral Drug Association) and ASTCT (the American Society for Transplantation and Cellular Therapy). Regulators would then recognize or incorporate those standards rather than authoring them from scratch.

That does not leave FDA with no role. Celluzzi and her colleagues want the agency to clarify three specific points:

• how it distinguishes investigational from commercial starting materials
• its expectations for collections made outside the United States
• how consensus standards can support regulatory submissions

Each answer would feed directly into sponsor filing strategy and site-qualification budgets.

What would change on the plant floor?

The analysis also targets the manufacturing side of the handshake. Harmonizing material receipt procedures at production facilities — Celluzzi cites strictly defined temperature limits and cryopreservation media specifications as examples — would remove another source of lot-to-lot noise.

Documentation is the other lever. "Common templates for leukapheresis manuals, SOPs, and chain-of-custody and chain-of-identity records would be beneficial," she said.

Audit strategy would shift too. "Risk-based site qualification would let manufacturers focus audits on product-specific risks instead of repeatedly reassessing established quality systems," Celluzzi said — a change that translates directly into fewer duplicated audit days per program.

What happens next?

The analysis stakes out a stakeholder-led path: consensus bodies draft, FDA clarifies, and standards such as ISBT 128 get adopted with implementation support. Whether PDA, ASTCT and FDA pick up that division of labor will determine if cell therapy's front end gets any less variable.