In cell and gene therapy manufacturing, human and animal-derived raw materials play a critical but carefully regulated role. These therapies often involve manipulating human cells or genetic material to treat diseases and the use of certain raw materials must adhere to strict guidelines to ensure safety. Recently, the FDA published two guidance documents containing recommendations for appropriate safety testing for biologically-derived materials including human allogenic cells and other human- and animal-derived materials that are used in the manufacture of CGT products.
Considerations for the Use of Human and Animal Derived Materials in the Manufacture of Cell and Gene Therapy and Tissue-Engineered Medical Products (April 2024) highlights key issues to consider when using human- and animal- derived materials that may come into contact with the starting materials, intermediates or final products of cell and gene therapies.
Safety Testing of Human Allogeneic Cells Expanded for Use in Cell-Based Medical Products (April 2024) highlights two major concerns. The first is amplification of low levels of adventitious agents during manufacture or as a result of the contamination of source material and the other is the genomic stability of highly manipulated or lengthy manufacturing processes used in cell and gene therapy production.
Key points of the two guidance documents include:
SAFETY
Human- and animal-derived materials must undergo rigorous screening and testing to ensure they are free from contaminants, pathogens, and other potentially harmful substances. Risk analysis is crucial to illustrate specific safety testing requirements. This process starts with proper donor screening and testing of starting material with adventitious virus testing methods that demonstrate adequate sensitivity and specificity to reliably detect low levels of viral contamination. For cellular starting material, screening and testing should be performed in accordance with the regulations in 21 CFR 1271, which requires the use of FDA-approved, licensed, or cleared donor screening kits. Testing must be performed by a laboratory that is either certified under CLIA ’88 or has met equivalent requirements as determined by Centers for Medicare and Medicaid Services (CMS). Other considerations should include the expansion potential of the cells and the number of patients the product is capable of treating, ensuring that the testing time point reflects the highest likelihood of contamination.
Safety testing may also include assessment for tumorigenicity, genotoxicity and immunogenicity given that genomic changes can result during extensive culture. Regulatory submissions should include enough detail to ensure purity and quality of both the drug substance and the drug product. This includes, at a minimum, identity testing, cytogenetic characteristics that are also assessed with respect to in vitro growth, thorough characterization of the cells and testing for viral and microbial contamination.
RISK MITIGATION
In addition to testing, risk mitigation strategies may include implementing additional monitoring, such as screening of raw materials and environmental monitoring, of manufacturing facilities to prevent contamination. Detailed documentation of adventitious virus testing protocols, results and any relevant validation studies should be maintained and included in regulatory submissions. Transparency in reporting is essential for regulatory review and assessment of product safety.
CHARACTERIZATION & QUALITY CONTROL
Establishing standardized processes and quality control measures is essential to ensure consistency, reproducibility, and scalability of manufacturing processes. This includes sourcing materials of the highest quality, implementing validated methods for screening of materials for critical quality attributes (established during characterization), and establishing acceptance criteria for each material. Material management procedures should be described in detail in your submission.