Safety Testing of Human Allogeneic Cells Expanded for Use in Cell-Based Medical Products

Description

Allogeneic cells of human origin may be expanded in culture to manufacture medical products consisting of live cells, inactivated cells, cell lysates, or other cell-based materials such as cell-derived particles. We, FDA, are providing you, sponsors of allogeneic cell-based medical products, recommendations for determining the appropriate cell safety testing to support an Investigational New Drug Application (IND) or a Biologics License Application (BLA). Cell safety testing should be based on a risk analysis that considers the expansion potential of the cells, the reagents that are used to expand the cells in culture, and the number of individuals the cell-based medical product is capable of treating.

Key Topics

Terms and concepts identified from this document

Scope & Applicability

Product Classes

8

Human Allogeneic Cells

Safety testing of human allogeneic cells expanded for use in cell-based medical products.

Immortal cancer cell lines

tested as outlined in section V of the guidance

Embryonic stem cells

expanded into MCB and WCBs for cellular therapy

Combination Product

Products combining drug, device, or biological constituents; Generally recommended for Enhanced Documentation; Requires 14971-based framework incorporating ICH Q9; A drug-device combination where the device constituent part detects ingestion.

cell-based medical product

The nature and extent of cell safety testing needed depends on the expansion potential of the cells.

continuous cell lines

Cellular products may be produced from continuous cell lines, including induced pluripotent stem cells.

induced pluripotent stem cells

Continuous cell lines include induced pluripotent stem cells.

Primary Cells

Primary cells from a single donor can be expanded in culture.

Stakeholders

1

Sponsor

Entity responsible for submitting applications under section 524B

Regulatory Context

Regulatory Activities

4

Investigational New Drug Application

IND for treatment use; Regulatory submission required for clinical trials and expanded access.

Biologics License Application

BLA for biological products

IND

Investigational New Drug submissions

BLA

Biologics License Application

Document Types

2

Electronic Common Technical Document

eCTD specifications for regulatory submissions

Certificate of Analysis

Document indicating analytical results of testing; record relied on to control L. monocytogenes in ingredients; document provided for a food prior to or upon receipt of the food; COA documentation

Attributes

2

Genomic Integrity

Factors that affect the quality of cell-based medical products.

Genomic stability

should be evaluated for continuous cell lines

Technical Details

Substances

2

drug substance

Active ingredient in the CGT product

Animal-derived reagents

contact during manufacturing may require additional safety testing

Testing Methods

10

Cytogenetic testing

Should be performed on highly expanded primary cells.; not recommended for continuous cell lines or highly expanded genetically modified cells

Endotoxin testing

Required performance data for sterility support.

Targeted sequencing

used for genome edited cells to assess off-target sites

PCR

Used for MRD measurement and chimerism testing.

Mycoplasma testing

required for cells with limited expansion potential

Sterility testing

Standard release test that may be replaced by CCIT in stability; Performed annually to ensure product safety

Tumorigenicity testing

cell lines used for manufacturing biological products shall be described with respect to tumorigenicity

G-banding analysis

Used to confirm the cells have a normal karyotype.

polymerase chain reaction

Human pathogen testing using PCR.

In vitro adventitious virus testing

Three cell lines should generally be used for in vitro testing.

Identified Hazards

Hazards

4

Adventitious Agents

Transmission of adventitious agents is a key issue in human- and animal-derived materials.; Human- and animal-derived materials increase the risk of introducing adventitious agents

Replication competent retrovirus

testing required if a retroviral vector is used

Tumorigenicity

Risk associated with intended pharmacology or off-target effects

adventitious viruses

Cell banks made from continuous cell lines should be tested for adventitious viruses.

Standards & References

External Standards

4

USP <71>

Sterility testing may be performed in accordance with USP <71>.

USP <63>

Mycoplasma testing can consist of culture-based methods per USP <63>.

9 CFR 113.53

Testing for animal viruses consistent with 9 CFR 113.53.

9 CFR 113.47

Detection of extraneous viruses by the fluorescent antibody technique.

Related CFR Sections (5)

21CFR610.18§ 610.18 Cultures.
(a) Storage and maintenance. Cultures used in the manufacture of products shall be stored in a secure and orderly manner, at a temperature and by a method that will retain the initial characteristics of the organisms and insure freedom from contamination and deterioration.Read 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 →
21CFR610.13§ 610.13 Purity.
Products shall be free of extraneous material except that which is unavoidable in the manufacturing process described in the approved biologics license application. In addition, products shall be tested as provided in paragraphs (a) and (b) of this section.Read full regulation →
21CFR610.1§ 610.1 Tests prior to release required for each lot.
No lot of any licensed product shall be released by the manufacturer prior to the completion of tests for conformity with standards applicable to such product. Each applicable test shall be made on each lot after completion of all processes of manufacture which may affect compliance with the standarRead full regulation →

Enforcement Impact

Deficiencies cited in Warning Letters referencing the same regulations

Failure to ensure that the investigation was conducted according to the investigational plan

21

Unapproved new drugs

10

Failure to submit an Investigational New Drug application (IND)

9

Unapproved new drug

7

Unlicensed biological products

6

Misbranded drug

6

Failure to obtain informed consent

5

Failure to validate aseptic processes

5

Failure to establish and maintain procedures for donor eligibility

4

Failure to establish and follow appropriate written procedures designed to prevent microbiological contamination