Regulatory modernization for cell therapies: Bridging drug GMPs, tissue regulations, and innovation

Cell therapies in the U.S. operate within an evolving FDA regulatory playbook that is grounded in the long-standing drug GMP framework — 21 CFR Parts 210 and 211 — which define the minimum current good manufacturing practices for the manufacture, processing, packing, or holding of drugs to ensure safety, identity, strength, quality, and purity. These are paralleled by the tissue regulations — 21 CFR Parts 1270 and 1271 — which govern human cellular and tissue-based products (HCT/Ps), including donor eligibility and current good tissue practices designed to prevent communicable disease transmission.

Under the Public Health Service Act (PHSA), HCT/Ps fall into two categories:

- Section 351 Products: Regulated as biologics requiring premarket approval (IND/BLA). These apply when products fail one or more of the criteria outlined in 21 CFR 1271.10(a), such as more-than-minimal manipulation or non-homologous use.
- Section 361 Products: Minimally manipulated HCT/Ps intended for homologous use, regulated solely under Section 361 of the PHSA and 21 CFR Part 1271.  These regulations focus on preventing product contamination which could lead to communicable disease transmission.

Additionally, 21 CFR Part 610 applies to biologics, including cell therapies — establishing standards for safety, purity, potency, and lot release testing.

Quality systems and compliance imperatives

The common regulatory thread is a quality management system (QMS) that integrates flexibility, data-driven execution, and the rigor of cGMP. Organizations with long experience in blood and plasma collection and processing (e.g., transfusable blood products regulated under 21 CFR Parts 606 and 640) bring mature systems for managing the first mile (donor collection, processing, cryopreservation) and last mile (cell thaw, final dosing, hospital transport, bedside delivery).

Yet modernization is needed to accommodate:

- Risk-based manufacturing paradigms.
- Automation and robotics.
- Advanced analytics and AI.
- Integrated digital systems (MES, LIMS, ERP).

FDA’s biologics framework for blood, organ, cell, biotherapies, and gene therapy is a solid foundation to build on. However, most of the advanced cell therapies that have been approved or are in late-stage trials today, are combining requirements from different regulatory frameworks. FDA is focused on maintaining the traditional safety, quality, identity, purity, and potency (SQUIPP) paradigm without inhibiting patient access to novel therapeutics.  The question that remains is if it is enough to simply add the frameworks together?

Upstream standardization

Leukapheresis — already generally standardized in hematopoietic stem cell collection — anchors the upstream side of cell therapy manufacturing. Establishing a validated chain of identity and custody is essential for regulatory compliance and patient safety, ensuring traceability from donor to final product. Under 21 CFR 610.14, identity testing must be specific and distinguishable for each product lot, and 21 CFR 1271 Subparts C and D outline donor eligibility and current good tissue practices (cGTP) required for HCT/Ps.

Standardizing leukapheresis protocols across collection centers reduces variability in cellular starting material — one of the most significant contributors to downstream manufacturing challenges. Consistent cell yield, viability, and composition improve the predictability of expansion and differentiation processes, enhancing batch reliability and reducing the risk of costly failures. Harmonized procedures also facilitate interoperability between cellular starting material collection sites and manufacturing facilities, streamlining logistics and accelerating turnaround times.

Emerging AI-enhanced connected systems promise to convert donor variability into predictable inputs, further mitigating one of the largest drivers of batch failure and enabling scalable, reproducible production of advanced therapies.

For future allogeneic products, which will require an active donor population similar to that in the transfusable blood products industry, standardized approaches to donor recruitment, consenting, incentivization, and collection is critical. These practices should align with 21 CFR 1271, which governs donor eligibility, communicable disease screening, and cGTP.

Such standardization would allow the collection and initial processing of cellular starting materials to be common across multiple drug products using the same source material, rather than being redefined with each new Investigational New Drug (IND) submission. This can be done now through industry led standardization efforts or in collaboration with FDA resulting in formal guidance that aligns with current regulations.

One other idea for consideration — there should be an industry/regulatory discussion about creating a pathway to a shared technical file for cellular starting materials — akin to a Drug Master File (DMF) that could be submitted to the FDA and referenced across multiple applications. While not yet formalized, recent FDA guidance documents and stakeholder discussions suggest growing interest in frameworks that support modular submissions and shared data packages for common components of cell therapy manufacturing. Such a system could simplify regulatory review, reduce redundancy, and accelerate the approval process for therapies using standardized starting materials.

Challenges and innovations

The evolving landscape of cell and gene therapy presents both formidable challenges and unprecedented opportunities. As the field advances toward personalized, high-impact treatments, it must overcome persistent hurdles — lengthy vein-to-vein timelines, labor-intensive autologous manufacturing, and batch variability driven by donor differences.

Innovation is key to addressing these barriers. Beyond AI and automation, the field is seeing momentum in modular manufacturing platforms, digital twins for process simulation, and decentralized GMP models that bring production closer to the point of care. These approaches, when combined with closed-system technologies, offer a path toward scalable, cost-effective, and more resilient manufacturing.

Innovation must also extend to regulatory thinking. The FDA’s Advanced Manufacturing Technology (AMT) designation is a promising sign that new regulatory models are being considered. For example, allowing well-characterized processes to run in controlled — but not necessarily classified — environments could significantly reduce costs without compromising safety. This shift could make advanced manufacturing more financially and logistically feasible, even with moderate levels of environmental control.

Looking ahead, platforms and processes should be selected with safety as the top priority, while also keeping efficiency and cost-effectiveness in mind. The AMT designation may be a signal of more flexible, forward-looking approaches to come.

Other exciting innovations include modular and mobile manufacturing platforms (like PODs or micro factories), digital twins for process modeling and validation, advanced analytics for donor selection and product characterization, standardized data platforms to support regulatory submissions, point-of-care manufacturing models, public-private partnerships to de-risk early adoption, and even regulatory sandboxes or pilot programs to test novel technologies.

To realize this future, industry and regulators must collaborate more intentionally. Shared frameworks, data standards, and pilot programs can accelerate the adoption of transformative technologies and reduce the friction that slows progress today.

Donor recruitment and collection regulatory nuances

While manufacturing is often regulated like drugs, the collection of cellular starting materials more closely mirrors the blood/tissue donation paradigm:

- 45 CFR 46 (Common Rule) applies if the collection is for research purposes.
- 21 CFR 56 requires IRB oversight for human subjects research.
- 21 CFR 1271 governs HCT/P donor eligibility and communicable disease testing.
- PHSA Section 361 governs minimally manipulated homologous-use collections.

Critically, cellular starting material (CSM) collection for commercial manufacturing does not meet the definition of “research” under 45 CFR 46.102(l). Donors are not exposed to investigational products, and procedures are standardized, licensed, and validated. Therefore, IRB oversight is not required, similar to transfusable blood collection.

Nevertheless, many organizations default to research frameworks (protocols, IRB review, informed consent forms), creating unnecessary administrative burdens by using systems designed for assessing the risk/benefit ratio of engaging in clinical research where the subject is being given an unproven drug product. This leads to inconsistency across institutions as each IRB approves each protocol and related consent as a singular event, instead of standardizing use and language to ensure participating donors are consistently and fully informed.

Protocol standardization and fully informed consents of donors that disclose the collection process, cellular starting material use, and any collection related risks are ethically and legally required and critical to the long-term success of collections programs. A fit-for-purpose framework should align with blood and tissue donation standards, ensuring donor safety while providing regulatory clarity.

Building an agile, rigorous regulatory ecosystem

In summary, the regulatory landscape for cell therapies reflects both the legacy of traditional drug GMPs and the evolving frameworks for human cells and tissues. The current bifurcation between 351 biologics and 361 HCT/Ps provides a risk-based foundation, but it does not fully account for the unique complexities of vein-to-vein manufacturing, donor variability, and decentralized production models.

As the industry advances from autologous therapies toward scalable allogeneic platforms, success will depend on harmonizing donor safety, manufacturing innovation, and regulatory modernization.  We need to continue to operate under some flexible frameworks based on existing regulations that allow for new workflows and models to be developed for manufacturing while the bookends of the process including cellular collection, initial processing, cryopreservation and patient infusion are ready and will benefit from standardization.

To achieve this, regulators, industry leaders, and standards-setting organizations must work together with intention to craft fit-for-purpose guidance that acknowledges the unique attributes of cell therapies while preserving the safety principles embedded in cGMP. This includes clarifying donor consent frameworks, modernizing GMP expectations, and integrating digital and automated solutions into compliance paradigms. By drawing on the mature practices of blood and tissue collection while embracing automation, AI, and connected manufacturing, stakeholders can build a regulatory ecosystem that is both agile and rigorous — one that safeguards public health, rewards innovation, and accelerates access to life-saving cellular therapies for patients worldwide.