Recently, the FDA has published a new Draft Guidance for Industry titled “Safety Testing of Human Allogeneic Cells Expanded for Use in Cell-Based Medicinal Products”. The guidance document contains non-binding recommendations and is currently open for comments. Here is a review on the most relevant topics addressed.
Allogeneic cells of human origin may be expanded in culture to manufacture medicinal products consisting of live cells, inactivated cells, or other cell-based materials. This guideline provides sponsors of allogeneic cell-based medicinal products with recommendations for determining the appropriate cell safety testing to support Investigational New Drug Application (IND) or a Biologics License Application (BLA).
Considerations for Cell Safety Testing
For an IND, the sponsors should provide a list of all materials used in manufacturing, including the quality or grade of these materials, which assist FDA in determining if the proposed cell safety testing is adequate to assure the safety of the investigational product.
Information about the source of every reagent and its component, accompanied with a Certificate of Analysis, should be submitted within the IND. The origin of animal and human-derived reagents, and the acceptance criteria, will influence the appropriate amount and types of safety testing.
Culture methods used to expand the cells to manufacture the allogeneic cell-based medicinal product should be provided in the IND or BLA submission, with especial attention to:
- Continuous Cell Lines: Manufacturing process for a cellular product made from continuous cell lines usually includes de creating of a cell bank. These should be tested for adventitious viruses and undergo additional safety evaluation.
- Primary Cells: If allogeneic primary cells from a single donor are expanded to a cell number sufficient to be administered to many individuals, the safety testing should be performed on a cryopreserved cell bank. If primary cells have a limited expansion potation and wont be use to treat many individuals, an abbreviated test matrix is recommended.
- Cells for only a few or a single individual: It is not recommended that primary allogeneic cells that are minimally expanded in culture undergo cytogenetic analysis or adventitious virus testing.
Testing Recommendations for Highly Expanded Cells
Cell-based medicinal products may use a one-tier or two-tier cell banking system. A one-tier system consists of a master cell bank (MCB) only, while a two-tier system there is also at least one working cell bank (WCB) derived from the MCB.
Some manufacturing schemes may use multiple levels of cell banks, however, it may not be necessary to test all the cell banks. For instance, the cells used as a starting material for genetically engineered stem cells would not be considered the MCB. The cell bank of already genetically modified stem cells would be the MCB.
The guideline makes recommendations regarding safety testing for a MCB, in line with the United States Pharmacopeia (USP) for example for, sterility testing mycoplasma, adventitious virus testing, retroviral testing, among others.
Finally, the guideline presents a table with the recommended safety testing recommended and on which cells, depending on the cell description or product use:
Cell description | Cell culture and preparation | Cells that should be tested | Product use | Cell safety testing recommended |
Embryonic stem cells and allogeneic induced pluripotent cells | Cells are expanded into an MCB and WCBs. WCBs are differentiated into final cellular therapy product | MCB and WCBs | Potentially, many individuals | The MCB and WCBs should be tested as outlined in section V of this guidance |
Immortal cancer cell lines and transformed cell lines | Cells are expanded into an MCB and WCBs. Cell-based product is derived from WCBs. | MCB and WCBs | Potentially, many individuals | The MCB and WCBs should be tested as outlined in section V of this guidance |
Primary allogeneic cells capable of extensive expansion (highly expanded) | Cells are expanded to make an MCB. MCB vials are thawed and further expanded to make final product | MCB and WCBs (if one is made) | Potentially, many individuals | The MCB and WCBs (if one is made) should be tested as outlined in section V of this guidance |
Primary allogeneic cells, including some genetically engineered cells, capable of limited expansion before loss of cell quality | Cells are expanded several passages to make a small to midsized MCB or a single lot of cells that is used as the cellular therapy product | MCB or lot of expanded cells, or end of production cells | Limited number of individuals | MCB or lot of expanded cells, or end of production cells should be tested as outlined in section VI of this guidance |
Primary allogeneic cells expanded in culture to make a product for a few subjects or a single subject | Cells are expanded to make product lots of cells capable of being administered to a few subjects or a single subject. | The lot of expanded cells | A few individuals or a single individual | Sterility, mycoplasma, and endotoxin testing |
This is some of the information included in the FDA’s Guidance for Industry, if you want to consult the complete document, you can check it here! https://www.fda.gov/regulatory-information/search-fda-guidance-documents/safety-testing-human-allogeneic-cells-expanded-use-cell-based-medical-products
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