By William Schaut, B.S., M.B.A, Brian Jones, B.A., SBB(ASCP), and Robert Bowden, Ph.D. at Janssen Pharmaceuticals, Inc.
Current United States (U.S.) and European Union (E.U.) regulations identify requirements necessary to manufacture a cell therapy product, also known as an advanced therapy medicinal product (ATMP).1 As the use of chimeric antigen receptor T cell (CAR-T) therapies continues to increase, we have identified a need to better define standardized regulatory requirements applicable to the collection, cryopreservation, storage, and transportation of cellular starting material used in CAR-T production.
In our opinion, a combination approach of applying regulations would best suit the unique challenges associated with preparing CAR-T treatments, such that the process for preparing CAR-T starting material, including leukapheresis and the formulation of white blood cells to a cryopreserved state, should follow current Good Tissue Practice (cGTP) requirements, while the subsequent steps performed to manufacture the ATMP should follow both current Good Manufacturing Practice (cGMP) regulations and cGTP regulations.
To support our position, we have considered the merits of applying cGTP regulations to the collection and processing of the leukapheresis starting material required for CAR-T manufacture. First, we will summarize the steps involved in CAR-T production and then review the applicable regulations.
CAR-T Production Background
Several autologous CAR-T products are commercially available for the treatment of various hematologic malignancies. Processes in the commercial autologous CAR-T product workflow typically include the following:2
- Starting material preparation
- Testing, formulating, and cryopreserving the cells (as needed)
- Transporting/shipping the cells (i.e., starting material) to the manufacturer
- Cell selection and manufacturing of the CAR-T product
- Transporting/shipping the final CAR-T product to the treatment facility
- Infusion into the patient
Starting materials are considered an input to the manufacture of an ATMP and are generally characterized as complex biological materials (usually tissues and cells) from either autologous or allogeneic donors. CAR-T starting material consists of white blood cells collected by leukapheresis. Since leukapheresis instruments do not differentiate between white cell subsets, a collection may result in a heterogenous mixture of mononuclear cells and granulocytes. Typically, early in the CAR-T manufacturing process, the mixture of cells may undergo a selection process to isolate the targeted cell population.3 The cell selection process is a defining point between handling starting material and initiating the manufacturing process; however, this is dependent on how each manufacturer defines the starting point in biologics license application filings.
Regulatory Hallmarks and Current Regulations
Before discussing current regulations, we will first define the hallmarks of each regulatory paradigm. The US Code of Federal Regulations (CFR) Title 21 Food and Drugs is the portion of the CFR that governs food and drugs within the US for the Food and Drug Administration (FDA).4 Title 21 Food and Drugs, Chapter 1, Subchapter C (Drugs: General), Subchapter F (Biologics), and Subchapter L (Regulations Under Certain Other Acts Administered by the FDA; parts 1210-1271) outline the regulations for the manufacture of drugs.4 Title 21 CFR 1271 Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/P’s) specifically focuses on human and tissue-based products,5 and HCT/P’s are further divided into Public Health Services (PHS) 351 and 361 product classifications.
PHS 351 products are regulated as drugs, devices, and/or biological products under section 351 of the PHS Act and/or the Federal Food, Drug, and Cosmetic Act.6,7 Products regulated under PHS section 351 include finished ATMPs (i.e. CAR-T) because they undergo significant transformation steps from a starting material to a finished ATMP and therefore are categorized as “more than minimally manipulated.” PHS 351 HCT/P’s that are regulated as drugs, devices, or biological products are required to be either licensed by their manufacturers, or be covered under an active Investigational New Drug (IND) application with the FDA.8 Sections 21 CFR Part 210 cGMP in Manufacturing, Processing, Packing, or Holding of Drugs (General), 21 CFR Part 211 cGMP for Finished Pharmaceuticals, and 21 CFR Part 820 Quality System Regulation (devices) are also required regulations for PHS 351 products. Thus, cGMP requirements are mandated for HCT/P’s manufactured as PHS 351 products.5,8,9
PHS 361 products registered with the FDA are described in 21 CFR 1271.10 and include products that are collected from an autologous or allogeneic first- or second-degree related donor, minimally manipulated, not combined with any other articles, and are for homologous use only.10,11 Products meeting PHS 361 requirements are expected to comply with the requirements outlined in 21 CFR Part 1271 Subpart B (Procedures for Registration and Listing), Subpart C (Donor Eligibility), and Subpart D (cGTP).
Although 21 CFR Part 1271 outlines cGTP requirements associated with the manufacture of CAR-T therapies, it does not define what constitutes starting material,5 and the demarcation of where cGMP requirements need to begin to be implemented in this process is unclear. Consequently, 21 CFR 1271 fails to provide clear guidance and leaves the decision about when to initiate cGMP open to interpretation at the discretion of individual manufacturers.
Defining CAR T Starting Material
Without a clear definition of starting material and its application with respect to a PHS 351 product, individuals may turn to other sources to help identify applicable regulations, which contributes to a varied approach to starting material classification.
There are several cGMP regulations that define starting materials for cGMP processes, including documents such as the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guidance for Industry, Q11 Development and Manufacture of Drug Substances (ICH Q11),12 which defines a starting material as “drug substance manufacturing process begins with one or more starting materials. The Good Manufacturing Practice (GMP) provisions described in the ICH guidance Q7 GMP Guidance for Active Pharmaceutical Ingredients (ICH Q7) apply to each branch beginning with the first use of a starting material.” ICH Q11 further refers to ICH Q5A, Q5B, Q5D, and Q10, which all support the need for starting material to be prepared under cGMP conditions.12
In addition, 21 CFR Part 606 cGMP for Blood and Blood Components outlines requirements for cell collection for blood components and blood products, and aligns with activities associated with collection of the starting material, including equipment, facilities, personnel, labeling, and testing.13 Since 21 CFR Part 606 focuses on blood and blood components that are distributed as products and have similar process steps, one could interpret that this requirement must be applied to CAR-T starting material collection and processing. However, the application of this regulation or the extension of the definition of starting material to cGMP regulations may result in the overapplication of cGMP requirements to the collection and cryopreservation of starting material. In our opinion, the starting material for CAR-T therapies does not meet the requirement of a PHS 351 product, and 21 CFR Part 606 does not apply to the starting material that will be used for further manufacture; consequently, cGMP regulations would not be applicable to the starting material.
Rationale for Applying cGTP Instead of cGMP Regulations to CAR-T Starting Material Preparation
Although 21 CFR 1271.10 Subpart C (Donor Eligibility) and Subpart D (cGTP) are applicable to both PHS 351 and 361 products, the question that needs to be addressed is whether the collection and cryopreservation of starting material constitutes a manufacturing step or whether they are considered to occur prior to a manufacturing operation.
The collection of blood cells as a starting material occurs in a clinical setting with a focus on preventing the introduction and transmission of communicable diseases. Facilities, equipment, and processes are developed to ensure that a safe collection is performed. Furthermore, the testing and requirements for the material collected are varied depending on the donor and the intended use of the collected material. While the process, and therefore the starting material, may differ from donor to donor, each of the identified control points are designed for patient and material safety.
cGMP requirements are regulated by the agencies who control the authorization and licensing of the manufacture of pharmaceutical products and are intended to provide minimum requirements that a manufacturer must apply to assure their products have consistent high quality in every batch and to prevent harm to the end user. Common US cGMP regulations cover product quality, safety, and efficacy, including: 21 CFR Part 210 cGMP in Manufacturing, Processing, Packing, or Holding of Drugs: General; 21 CFR Part 211 cGMP for Finished Pharmaceuticals; 21 CFR Part 600 Biological Products: General; and 21 CFR Part 606 cGMP for Blood and Blood Components.4 However, these regulations are specific to the manufacture of products and are not applicable to the collection of starting materials.
Expanding cGMP regulations to include the collection of the cells needed for CAR-T starting material places undue burden on the different collection facilities (e.g. hospitals, apheresis centers) and necessitates cGMP audits to meet artificially assigned requirements, which would increase complexity and negatively impact the delivery of CAR-T starting material.
By following cGTP requirements to prepare CAR-T starting material, the ATMP manufacturing process can then be initiated with the addition of cGMP expectations to the regulatory framework, leading ultimately to the manufacture of the final ATMP product. In this way, the quality of the CAR-T starting material resulting from the collections remains unaffected, while the cost of goods is kept down, and the supply and delivery of the starting material cells are not impeded, which ultimately benefits the patients who need access to this effective treatment.
EU regulations define CAR-T products as ATMPs, with requirements for starting materials outlined in EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4, GMP, Guidelines on GMP Specific to Advanced Therapy Medicinal Products.14 Comparable to 21 CFR 1271.1,5 these EU regulations clearly state that the purpose of these directives is to prevent the transmission of communicable diseases in starting materials. In addition, the European Tissues and Cells Directive (TCD) (Directive 2004/23/EC) defines safety and quality standards for cells and tissues.15
According to the European Medicines Agency (EMA) communication entitled Questions and answers on the principles of GMP for the manufacturing of starting materials of biological origin used to transfer genetic material for the manufacturing of ATMPs, manufacturing and testing sites of ATMP starting materials do not require a cGMP certificate.16 Further requirements outlined in the EMA document state that the principles of cGMP, as applied to starting material, can be designated in different ways and that consideration should be given to manufacturing steps that are applicable to ATMP starting materials.16 EMA specifies that the donation, collection, and testing of cells for ex vivo genetically modified cells are not included in the manufacturing steps related to ATMPs that require GMP manufacturing principles.16 In addition, EMA further describes the application of GMP requirements for an autologous CAR-T cell therapy ATMP manufacture and clearly omits the donation/collection of cells from patients from the steps of the ATMP manufacturing process that require the application of full cGMP.16
As the use of CAR-T therapies continues to grow and the associated regulatory landscape evolves, the consistent application of regulations for both the preparation of starting material and the subsequent manufacture of ATMPs would better serve the patients receiving these treatments. The manufacture of an ATMP requires a complex regulatory framework designed to consider the safety of the donor and the patient, as well as to provide consistency of the final product to be administered to patients. We propose the application of cGTP (or TCD in the EU) for CAR-T starting material preparation, consisting of autologous or allogeneic cell donation/collection, followed by cGMP for the manufacture of ATMPs from the starting material, in order to more clearly define when the ATMP manufacturing process is initiated and provide the rationale to ensure that overall regulatory expectations are met.
- Iglesias-Lopez C, Agusti A, Obach M, Vallano A, Regulatory framework for advanced therapy medicinal products in Europe and United States, Front Pharmacol, 10:921 (2019).
- Panch SR, Srivastava SK, Elavia N, McManus A, Liu S, Jin P, Highfill SL, Li X, Dagur P, Kochenderfer JN, Fry TJ, Mackall CL, Lee D, Shah NN, Stroncek DF, Effect of cryopreservation on autologous chimeric antigen receptor T cell characteristics, Mol Ther, 27(7):1275 (2019).
- Guedan S, Ruella M, June CH, Emerging cellular therapies for cancer, Annu Rev Immunol, 37:145 (2019).
- United States Food and Drug Administration. Code of Federal Regulations Title 21. https://www.ecfr.gov/current/title-21. Accessed February 8, 2022.
- United States Food and Drug Administration. Title 21, Chapter 1, Subchapter L, Part 1271. Human Cells, Tissues, and Cellular and Tissue-based Products. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-L/part-1271. Accessed February 8, 2022.
- United States Food and Drug Administration. Guidance for Industry. Reference Product Exclusivity for Biological Products Filed Under Section 351(a) of the PHS Act. https://www.fda.gov/media/89049/download. Published August 2014. Accessed February 8, 2022.
- United States Food and Drug Administration. Frequently asked questions about therapeutic biological products. https://www.fda.gov/drugs/therapeutic-biologics-applications-bla/frequently-asked-questions-about-therapeutic-biological-products#:~:text=Section%20351%20of%20the%20Public,product%2C
%20or%20analogous%20product%2C%20%E2%80%A6. Published July 7, 2015. Accessed February 3, 2022.
- United States Food and Drug Administration. Guidance for Industry. Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/P’s). Small Entity Compliance Guide. https://www.fda.gov/files/vaccines%2C%20blood%20%26%20biologics/published/Regulation-of-Human-Cells--Tissues--and-Cellular-and-Tissue-Based-Products-%28HCT-Ps%29---Small-Entity-Compliance-Guide--Guidance-for-Industry.pdf. Published August 2007. Accessed February 27, 2022.
- United States Food and Drug Administration. Title 21, Chapter 1, Subchapter C. Drugs: General. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-C. Accessed February 14, 2022.
- United States Food and Drug Administration. Regulatory Considerations for Human Cells, Tissues, and Cellular and Tissue-Based Products: Minimal Manipulation and Homologous Use. Guidance for Industry and Food and Drug Administration Staff. https://www.fda.gov/media/109176/download. Published July 2020. Accessed February 15, 2022.
- United States Food and Drug Administration. Title 21, Chapter 1, Subchapter L, Part 1271, Subpart A, Section 1271.10. Are my HCT/P's regulated solely under section 361 of the PHS Act and the regulations in this part, and if so what must I do? https://www.ecfr.gov/current/title-21/chapter-I/subchapter-L/part-1271/subpart-A/section-1271.10. Accessed February 8, 2022.
- International Conference on Harmonisation (ICH). Quality Guidelines. https://www.ich.org/page/quality-guidelines. Accessed February 15, 2022.
- United States Food and Drug Administration. Title 21 Chapter 1, Subchapter F, Part 606. Current Good Manufacturing Practice for Blood and Blood Components. https://www.ecfr.gov/current/title-21/chapter-I/subchapter-F/part-606. Accessed February 8, 2022.
- EudraLex. The Rules Governing Medicinal Products in the European Union, Volume 4, Good Manufacturing Practice, Guidelines on Good Manufacturing Practice Specific to Advanced Therapy Medicinal Products. https://ec.europa.eu/health/system/files/2017-11/2017_11_22_guidelines_gmp_for_atmps_0.pdf. Published November 22, 2017. Accessed February 9, 2022.
- Directive 2004/23/EC of the European Parliament and of the Council of 31 March 2004 on setting standards of quality and safety for the donation, procurement, testing, processing, preservation, storage and distribution of human tissues and cells. https://eur-lex.europa.eu/legal-content/EN/TXT/?uri=celex%3A32004L0023. Published March 31, 2004. Accessed March 17, 2022.
- European Medicines Agency. Questions and answers on the principles of GMP for the manufacturing of starting materials of biological origin used to transfer genetic material for the manufacturing of ATMPs. https://www.ema.europa.eu/en/documents/other/questions-answers-principles-gmp-manufacturing-starting-materials-biological-origin-used-transfer_en.pdf. Published February 24, 2021. Accessed February 9, 2022.
About The Authors:
Bill Schaut serves as the Senior Manager Global Cell Collection and Cryopreservation at Janssen Pharmaceuticals, Inc. In his role, Bill is responsible for interpreting and implementing the regulatory requirements for cell and gene therapy starting material. Bill has over 30 years of experience in cell therapy products, vaccines, and large molecules. Bill received both his B.S. in Microbiology and Medical Technology certification from the Pennsylvania State University and his M.B.A. from La Salle University.
Brian Jones serves as a Manager of Global Cell Collection and Cryopreservation at Janssen Pharmaceuticals, Inc. In his role, Brian is responsible for ensuring that a steady stream of regulatory-compliant, high-quality cellular starting material is supplied to the CAR T manufacturing plant. Brian has over 20 years of experience in blood donor testing, blood banking, and cellular therapies. Brian received his B.A. in Biology and Chemistry from Point Loma Nazarene University and obtained his Specialist in Blood Banking certification in 2011.
Bob Bowden is the Senior Director, CAR T Advanced Therapeutics Supply Chain at Janssen Pharmaceuticals, Inc. and leads the Global Cell Collection team which is responsible for the collection and cryopreservation of white blood cells prepared for personalized multiple myeloma therapy. Initially at Johnson & Johnson, Bob defined and conducted health outcome and social impact plans for access programs in limited resource settings. While in the US Army for over 26 years, Bob investigated and led multinational scientific teams to create life-saving vaccines and diagnostics from early preclinical stage to Phase III international trials. Bob is an inventor, a published author, and has taught as a professor and research scientist at the US Military Academy. Bob earned his B.A. in Biology from Texas A&M University-Kingsville and his Ph.D. in Immunology from Texas A&M University.