Description
Chimeric antigen receptor (CAR) T cell products are human gene therapy products in which the T cell specificity is genetically modified to enable recognition of a desired target antigen for therapeutic purposes. This guidance is intended to assist sponsors, including industry and academic sponsors, developing CAR T cell products. In this guidance, we, FDA, provide CAR T cell specific recommendations regarding chemistry, manufacturing, and control (CMC), pharmacology and toxicology, and clinical study design. Recommendations specific to autologous or allogeneic CAR T cell products are noted in this guidance. This guidance also provides recommendations for analytical comparability studies for CAR T cell products. While this guidance specifically focuses on CAR T cell products, much of the information and recommendations provided will also be applicable to other genetically modified lymphocyte products, such as CAR Natural Killer (NK) cells or T cell receptor (TCR) modified T cells. These related product types can be highly specialized, and in many cases, considerations beyond those recommended in this guidance would depend on the specific product and manufacturing process. To discuss considerations specific to these related products, we recommend sponsors communicate with the Office of Tissues and Advanced Therapies (OTAT) in the Center for Biologics Evaluation and Research (CBER) before submitting an Investigational New Drug Application (IND) (e.g., by requesting a pre-IND meeting (Ref. 1)).
Scope & Applicability
Product Classes
9Guidance for Industry regarding development of these products; Considerations for the development of CAR T cell products; Considerations for the development of these products
manufactured separately for each subject
modified to reduce immunogenicity
CAR T cell products are human gene therapy products
Recommendations specific to autologous products
Recommendations specific to allogeneic products; CAR T cells derived from allogeneic sources
Information may be applicable to other genetically modified lymphocyte products
Information may be applicable to other genetically modified lymphocyte products
Considerations for the Development of Chimeric Antigen Receptor (CAR) T Cell Products; Subject of the guidance document; Considerations for the development of Chimeric Antigen Receptor T cell products
Stakeholders
3Assist sponsors in the nonclinical evaluation
Entity responsible for submitting applications under section 524B
starting material obtained by leukapheresis of patients or healthy donors
Regulatory Context
Attributes
9testing of intermediates and the final product for CQAs (Critical Quality Attributes)
Area under the concentration vs. time curve between two specific time points
time to reach peak exposure
Cmax may be more informative for safety
can differ from lot to lot
Critical Quality Attributes evaluated by RTRT
Physical, chemical, biological, or microbiological properties
CPPs (Critical Process Parameters) should be identified and used to establish in-process controls
in-process control of PPs (Process Parameters)
Identified Hazards
Hazards
6integrating vectors may increase the risk of delayed adverse events
toxicity associated with CAR T cells that can be life-threatening
human anti-mouse antibody generated from murine-derived sequences
Cytokine Release Syndrome is a particular concern of CAR T cell toxicity
Undesired targeting of healthy tissues that express the intended target antigen
Risk associated with vector integration
Related CFR Sections (13)
- 21CFR50.25§ 50.25 Elements of informed consent.
(a) Basic elements of informed consent. In seeking informed consent, the following information shall be provided to each subject:Read full regulation →
- 21CFR211.22§ 211.22 Responsibilities of quality control unit.
(a) There shall be a quality control unit that shall have the responsibility and authority to approve or reject all components, drug product containers, closures, in-process materials, packaging material, labeling, and drug products, and the authority to review production records to assure that no eRead full regulation →
- 21CFR200.10§ 200.10 Contract facilities (including consulting laboratories) utilized as extramural facilities by pharmaceutical manufacturers.
(a) Section 704(a) of the Federal Food, Drug, and Cosmetic Act specifically authorizes inspection of consulting laboratories as well as any factory, warehouse, or establishment in which prescription drugs are manufactured, processed, packed, or held.Read full regulation →
- 21CFR312.31§ 312.31 Information amendments.
(a) Requirement for information amendment. A sponsor shall report in an information amendment essential information on the IND that is not within the scope of a protocol amendment, IND safety reports, or annual report. Examples of information requiring an information amendment include:Read full regulation →
- 21CFR1271.3§ 1271.3 How does FDA define important terms in this part?
The following definitions apply only to this part:Read full regulation →
- 21CFR1271.90§ 1271.90 Are there other exceptions and what labeling requirements apply?
(a) Donor-eligibility determination not required. You are not required to make a donor-eligibility determination under § 1271.50 or to perform donor screening or testing under §§ 1271.75 , 1271.80 and 1271.85 for:Read full regulation →
- 21CFR312.6§ 312.6 Labeling of an investigational new drug.
(a) The immediate package of an investigational new drug intended for human use shall bear a label with the statement “Caution: New Drug—Limited by Federal (or United States) law to investigational use.”Read full regulation →
- 21CFR610.14§ 610.14 Identity.
The contents of a final container of each filling of each lot shall be tested for identity after all labeling operations shall have been completed. The identity test shall be specific for each product in a manner that will adequately identify it as the product designated on final container and packaRead full regulation →
- 21CFR211.165§ 211.165 Testing and release for distribution.
(a) For each batch of drug product, there shall be appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release. Where sterility and/or pyrogen testing are conducted on sRead full regulation →
- 21CFR312.23§ 312.23 IND content and format.
(a) A sponsor who intends to conduct a clinical investigation subject to this part shall submit an “Investigational New Drug Application” (IND) including, in the following order:Read full regulation →
- 21CFR610.12§ 610.12 Sterility.
(a) The test. Except as provided in paragraph (h) of this section, manufacturers of biological products must perform sterility testing of each lot of each biological product's final container material or other material, as appropriate and as approved in the biologics license application or supplemenRead full regulation →
- 21CFR211.113§ 211.113 Control of microbiological contamination.
(a) Appropriate written procedures, designed to prevent objectionable microorganisms in drug products not required to be sterile, shall be established and followed.Read full regulation →
- 21CFR210.2§ 210.2 Applicability of current good manufacturing practice regulations.
(a) The regulations in this part and in parts 211 , 213 , 225 , and 226 of this chapter as they may pertain to a drug; in parts 600 through 680 of this chapter as they may pertain to a biological product for human use; and in part 1271 of this chapter as they are applicable to a human cell, tissue, Read full regulation →
Related Warning Letters (10)
- 2025-12-23
CGMP/Finished Pharmaceuticals/Adulterated
SV Labs Corporation
- 2025-12-23
CGMP/Finished Pharmaceuticals/Adulterated
Guangdong Renhe Guozhuang Biotechnology Co., Ltd.
- 2025-12-23
CGMP/Finished Pharmaceuticals/Adulterated
Medinatura New Mexico, Inc.
- 2025-12-16
CGMP/Finished Pharmaceuticals/Adulterated
Sklar Personal Care Inc.
- 2025-12-16
CGMP/Deviations/Biologics License Application (BLA)
Microvascular Tissue, Inc.
- 2025-12-16
Deviations/CFR/Regulations for Human Cells, Tissues & Cellular Products (HCT/Ps)
Green Valley Fertility Partners
- 2025-12-11
CGMP/Finished Pharmaceuticals/Adulterated
Catalent Indiana, LLC
- 2025-12-09
Unapproved New Drug/Unlicensed Biological Product/Biologics License Application (BLA)
BioXtek LLC
- 2025-12-09
CGMP/Finished Pharmaceuticals/Adulterated
DeVere Manufacturing Inc.
- 2025-12-09
CGMP/Finished Pharmaceuticals/Adulterated
CDL Services, Inc. DBA Technichem
See Also (8)
- Clinical Investigations of Devices Indicated for the Treatment of Urinary Incontinence - Guidance for Industry and FDA Staff (Status: Final)
- Process for Handling Referrals to FDA Under 21 CFR 50.54 - Additional Safeguards for Children in Clinical Investigations: Guidance for Clinical Investigators, Institutional Review Boards and Sponsors (Status: Final)
- Cellular Therapy for Cardiac Disease: Guidance for Industry (Status: Final)
- Institutional Review Board (IRB) Written Procedures: Guidance for Institutions and IRBs (Status: Final)
- Frequently Asked Questions — Developing Potential Cellular and Gene Therapy Products (Status: Draft)
- Development and Licensure of Vaccines to Prevent COVID-19: Guidance for Industry (Status: Final)
- Informed Consent: Guidance for IRBs, Clinical Investigators, and Sponsors (Status: Final)
- IND Submissions for Individualized Antisense Oligonucleotide Drug Products for Severely Debilitating or Life-Threatening Diseases: Clinical Recommendations: Draft Guidance for Industry (Status: Draft)