Hear Me Out — Cell Therapy GMP Starts With The Donor

By Jennifer Chain, Ph.D., CABP, Consultant, CSM Consulting LLC

A significant portion of the cell therapy field asserts that good manufacturing practice (GMP) begins with the isolation of cells from the starting material source, like the leukopak, bone marrow aspirate, or umbilical cord tissue.

However, there’s a growing movement, and I count myself as part of it, that believes GMP begins much earlier than that. More importantly, regulators have also joined the movement and expect cell therapy developers to climb aboard, too.

In this article, I’ll show how the current FDA regulations and guidance documents define cellular starting materials, outline the collection of starting materials using good tissue practice (GTP), and support the notion that GMP-compliant processes for manufacturing allogeneic cell therapies must start with donor qualification.

Cellular Starting Materials Are Tissues

Except for non-mobilized leukopaks, cellular starting materials used in the manufacturing of cellular therapies are classified by the FDA as human cells and tissue-based products (HCT/Ps).¹ Non-mobilized leukopaks, officially termed "source leukocytes" by the FDA, are classified as blood products.^2,3 However, if the cells from a non-mobilized leukopak are intended for use in manufacturing a CAR T cell therapy product, the leukopak is regulated in the same manner as HCT/Ps.⁴

It's worthwhile to pause here and dig a little deeper into the difference between blood-products and HCT/Ps and, in particular, how the FDA defines them.

HCT/Ps

The FDA Code of Federal Regulation, Chapter 21, Part 1271 (21 CFR 1271) creates “an electronic registration and listing system for establishments that manufacture human cells, tissues, and cellular and tissue-based products (HCT/Ps)” and establishes “donor-eligibility, current good tissue practice, and other procedures to prevent the introduction, transmission, and spread of communicable diseases by HCT/Ps.”¹

Within this CFR chapter, HCT/Ps are defined as “articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient.”¹ To register with the FDA as a tissue establishment, the facility must collect one or more of the designated HCT/Ps defined in this regulation.

Blood products

The definition of HCT/Ps in 21 CFR 1271 specifically excludes blood products by stating, “The following articles are not considered HCT/Ps: (2) Whole blood or blood components or blood derivative products subject to listing under parts 607.”¹ Blood products are defined by the FDA in 21 CFR 607 as “a drug which consists of human whole blood, plasma, or serum or any product derived from human whole blood, plasma, or serum.²

The FDA’s BER Instructions for Completing the Electronic Blood Establishment Registration and Product Listing Form include “source leukocytes” in an expanded list of blood products, defining them as “White Blood Cells intended as source material for further manufacturing use.”³ Additionally, the Compliance Program Guidance Manual Chapter 42 – Blood and Blood Components defines source leukocytes as “human leukocytes (white blood cells) prepared manually from Whole Blood or collected by apheresis and intended as source material for further manufacturing use.”⁵

Since “leukopak” is a colloquial term for source leukocytes collected by apheresis, a leukopak fits within the FDA’s definition of a blood product.

Guidance For CAR-T Developers

Most allogeneic CAR-T products are made from donor-derived leukopaks as starting material. While leukopaks collected for further manufacturing use are classified by the FDA as blood products,^1-3,5 a guidance document released in January of 2024, Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products, calls for the collection of starting material used in the manufacturing of CAR therapies (“material obtained from leukapheresis”) to be “conducted in accordance with the regulations in 21 CFR part 1271.”⁴

The guidance further states that allogeneic starting material “does require a donor eligibility determination, including screening and testing for relevant communicable disease agents and diseases (21 CFR Part 1271, Subpart C).”⁴ Identical requirements are listed for allogeneic cellular starting material the Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs) Guidance for Industry.⁶

Despite leukopaks being classified as blood products, and thus would otherwise be excluded from the definition of a tissue product by the FDA, these guidance documents instruct CAR-T developers to treat leukopaks like HCT/Ps, as defined in 21 CFR 1271, rather than as blood products defined in 21 CFR 607.^4,6

New draft guidance released this month, Recommendations for Determining Eligibility of Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps), reinforces the requirement for donors to be qualified under 21 CFR 1271 Subpart C and incorporates updates on current recommendations to appropriately screen and test donors.⁷ The guidance provides additional clarity for how establishments should make donor eligibility determinations to meet 21 CFR 1271 Subpart C, and when finalized, will supersede previous donor eligibility determination guidance from August 2007.⁸

Good Tissue Practices Vs. Good Manufacturing Practices

cGTP

Current good tissue practice (cGTP) is the hallmark of HCT/P collection.⁹ Outlined in 21 CFR 1271 Subpart D, cGTP regulations govern the handling of HCT/Ps to “prevent the introduction, transmission, or spread of communicable disease agents, that they are not contaminated, and that they do not become contaminated during manufacturing.” Additionally, cGTP provisions specifically regulate “determinations of donor eligibility, including donor screening and testing,” which are found in 21 CFR 1271 Subpart C.¹⁰

cGTP requirements also cover facilities, environmental controls, equipment, supplies and reagents, recovery, processing, labeling controls, storage, distribution, and receipt of HCT/Ps.⁹ Therefore, it is essential to follow cGTP throughout the entire process of collecting and supplying starting material for cell therapy manufacturing — from donor qualification to product shipping.^4,6,7 This applies to facilities collecting leukopaks if they will be used in the manufacturing of drug products like CAR-T therapies.

cGMP

Current good manufacturing practice (cGMP) establishes a system to “assure proper design, monitoring, and control of manufacturing processes and facilities.”¹¹ These regulations require drug manufacturers to institute the proper controls over manufacturing operations by establishing SOPs, investigating product quality deviations, and maintaining product testing. GMP-compliant processes help prevent contamination, mix-ups, deviations, failures, and errors, as outlined in 21 CFR 210 and Current Good Manufacturing Practice for Phase 1 Investigational Drugs, Guidance for Industry.^12,13

To comply with cGMP regulations, drug manufacturers must include donor eligibility and cGTP procedures as set forth in 21 CFR 1271 Subparts C and D.¹² Therefore, to be cGMP-compliant, CAR-T therapy developers must ensure that establishments involved in donor screening, testing, processing, storage, labeling, packing, and distribution of cellular starting materials adhere to GMP regulations as early as their Phase 1 clinical trials.¹³

GTP is GMP-compliant

cGTP and cGMP regulations share the same goal: ensuring the safety of the final product.^9,12 For cGTP, the "final product" is the starting material collected from a donor or patient,⁹ while for cGMP, the "final product" is the clinical drug product used for treatment in clinical trials or commercial use.¹²

Both sets of regulations describe similar controls for starting material collection and drug product manufacturing.^1,12 Industry guidance also points to 21 CFR 1271 Subpart C for donor eligibility and testing of starting material used in the manufacturing of clinical drug products.^4,6,7

Therefore, starting material intended for drug product manufacturing must be collected under cGTP conditions, which begins with donor qualification and testing.^1,4,6,7,12

How do developers define “GMP-compliant”?

cGMP regulations were designed to be flexible, allowing drug manufacturers to implement controls that best meet their manufacturing needs.¹¹ While this adaptability enables updates to practices as new technologies and systems become available, it also leads to nonstandard practices among manufacturers of similar drug products. This is particularly true in the field of allogeneic cell therapy development, which is relatively new compared to autologous therapies and has yet to receive any FDA approvals.

Developers submitting IND applications for their therapies should propose donor qualification and collection practices in line with 21 CFR 1271;^4,6,7 however, they may also propose additional requirements that differ from other developers. Additionally, the FDA may require one developer to comply with a regulation differently than another developer working on a therapy with a novel mechanism of action or a distinct therapeutic indication.

These differing requirements can result in varying definitions of “GMP-compliant starting material” among developers. It is crucial for developers to collaborate closely with suppliers of cellular starting material to communicate exactly how to be GMP compliant with their IND, develop contracts to allocate cGTP and donor qualification responsibilities, and perform quality audits to confirm compliance before using the material for clinical therapy manufacturing.^4,7

As more allogeneic therapies progress into clinical trial phases and data on the outcomes of these differing IND requirements become available, the FDA will have additional information to better standardize the definition of GMP-compliant starting material across the cell therapy industry.

Other Materials

Other materials used in a cGMP-compliant manufacturing process include vectors, media, media supplements, cytokines, cell culture consumables, isolation reagents, cryopreservation reagents, and final containers. Each of these items must be produced under cGMP conditions to qualify for use in the manufacturing of a clinical drug product.^4,6 Developers are responsible for ensuring that the facilities producing all materials used in their drug product manufacturing comply with cGMP regulations. This mandate clearly applies to the cellular starting material as well.^4,6,7

Conclusion

Key takeaways from this review of FDA regulations and industry guidance:

1. The FDA has historically distinguished between blood products and tissue products.^1,2 However, the rise of manufactured cell-based therapies has led industry guidance to focus developers on following HCT/P-specific regulations found in 21 CFR 1271 for all cellular starting materials.^4,6,7
2. Regulations mandate the use of cGTP when collecting and handling tissues for clinical therapy manufacturing.⁹
3. cGTP includes specific donor screening and testing requirements outlined in 21 CFR 1271 Subpart C.¹⁰
4. cGMP compliance requires developers to establish controls over all aspects of the manufacturing process and facilities.¹¹ According to 21 CFR 210, these controls must extend to the collection of cellular starting material and all other materials used in the manufacturing process.^4,6,7,12
5. Compliance with cGMP means that the collection of starting material should begin with FDA-compliant donor qualification and use cGTPs.¹²

References:

1. eCFR :: 21 CFR Part 1271 -- Human Cells, Tissues, and Cellular and Tissue-Based Products
2. eCFR :: 21 CFR Part 607 -- Establishment Registration and Product Listing for Manufacturers of Human Blood and Blood Products and Licensed Devices
3. BER Instructions for Completing the Electronic Blood Establishment Registration and Product Listing Form
4. Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products | FDA
5. Compliance_Program_Guidance_Manual_7342.002
6. Chemistry, Manufacturing, and Control Information for Human Gene Therapy Investigational New Drug Applications; Guidance for Industry
7. Recommendations for Determining Eligibility of Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps); Draft Guidance for Industry
8. Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)
9. eCFR :: 21 CFR Part 1271 Subpart D -- Current Good Tissue Practice
10. eCFR :: 21 CFR Part 1271 Subpart C -- Donor Eligibility
11. Facts About the Current Good Manufacturing Practice (CGMP) | FDA
12. CFR - Code of Federal Regulations Title 21
13. Current Good Manufacturing Practice for Phase 1 Investigational Drugs | FDA

About The Author:

Jennifer Chain, Ph.D., CABP, is a cellular therapy expert with 26 years of experience in T cell immunology, product development, blood banking, and consulting. She holds a Ph.D. in immunology and a Certified Advanced Biotherapies Professional credential from the Association for the Advancement of Blood & Biotherapies (AABB). She currently works as a consultant in the cellular starting material space, helping blood centers and cell therapy companies develop CSM collection and procurement programs and donor screening strategies. From 2016 to early 2024, she led efforts to collect RUO and GMP-compliant leukopaks and bone marrow from more than 1,000 healthy donors and developed novel blood- and cell-based culture materials for early-stage cell therapy companies. She volunteers and consults for AABB, where she engages in educational program development, strategic planning, and advocacy efforts in the field of cellular therapy. Reach her on LinkedIn or CSM Consulting’s website, www.cellsmatter.com.