FDA drafts two guidances on safety testing for cell and gene therapy products

The US Food and Drug Administration’s (FDA) Center for Biologics Evaluation and Research (CBER) on Tuesday issued two draft guidances related to cell and gene therapy testing: one addresses safety testing products derived of human allogeneic cells expanded for use in cell-based products and the other addresses testing animal- and human-derived materials in the manufacturing of cell and gene therapy and tissue engineered medical products (TEMP).

When finalized, these documents will supplement two final guidances, Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs), which was released in January 2020, and the 2008 guidance Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs). (RELATED: FDA Finalizes 6 Gene Therapy Guidances, Unveils a New Draft, Regulatory Focus 28 January 2020)

Safety testing allogeneic cells

The draft guidance on safety testing aims to assist sponsors of allogeneic cell-based medical products develop an appropriate cell safety testing strategy to support an investigational new drug application (IND) or a biologics license application (BLAs). The guidance applies to cultured allogeneic cells, including cell banks and combination products. It does not cover cell substrates used for non-cell-based products such as viruses, gene therapy vectors, or recombinant proteins.

There is a “potential risk for all cell-based medical products, especially when the cells are cultured extensively during manufacturing. Contamination may be present in the source cells, or the cells may become contaminated with adventitious agents during manufacturing,” the guidance states. “In addition, genomic changes that result in tumorigenic cells can occur during extensive culture.”

FDA recommends that sponsors describe how they are assessing the risk of potential contamination with adventitious agents. These assessments should be aligned with the electronic Common Technical Document (eCTD) section 3.2.A.2 on “Adventitious Agents Safety Evaluation” in IND or BLA submissions.

Submissions should also include the results of donor screening and testing; and for INDs, sponsors should provide a list of all materials used in manufacturing, including the quality or grade of these materials. Such information will assist FDA in determining if the proposed cell safety testing is adequate to assure the safety of the investigational product.

For highly expanded cells, the guidance recommends that sponsors conduct bacterial and fungal sterility testing as specified in the United States Pharmacopeia’s (USP)<71> or using another appropriately qualified and validated method.

FDA also recommends sponsors conduct mycoplasma testing as specified in USP<63>. Sponsors may use alternative assays to detect mycoplasma, but assays should be shown to be as sensitive as the compendial method.

The agency warned it may place a clinical hold on INDs if the application does not contain sufficient CMC information to assess safety risks.

Testing materials for cell, gene, and tissue products

FDA’s second draft guidance addresses its expectations for safety and quality testing human- and animal-derived materials used to make cell and gene therapy products and TEMP products. The document also addresses the chemistry, manufacturing, and control (CMC) information submitted in an investigational new drug application (IND) relating to the use of human- and animal-derived materials.

The guidance covers donor screening and testing, adventitious agent testing and screening, risk assessment, and materials management for these products.

Some examples of human- and animal-derived materials include human or animal blood, antibodies produced in sera from animal hybridoma cells, and cytokines produced in insect cell lines.

The guidance states that regulatory submissions should demonstrate how the manufacturing methods for the materials can remove adventitious agents.

FDA said that “the use of human- and animal-derived materials to manufacture CGT products and TEMPs raises several key issues to consider, including transmission of adventitious agents, material lot-to-lot consistency, and material identity, as well as general material qualification considerations.”

For INDs, sponsors must provide FDA with a list of all materials used to manufacture products and a description of the quality and grade of these materials; these lists should be in a tabular format.

Submissions should also adhere to the Common Technical Document (CTD)’s section 3.2.S.2.3 on control of materials and section 3.2.P.4 on control of excipients.

The deadline to comment on both guidances is 29 July.

Guidance: Considerations for the Use of Human and Animal-Derived Materials in the Manufacture of Cellular and Gene Therapy and Tissue-Engineered Medical Products, Safety Testing of Human Allogeneic Cells Expanded for Use in Cell-Based Medical Products

FDA drafts two guidances on safety testing for cell and gene therapy products

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