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QbD and Quality Systems Challenges Ahead as Cell Therapy Moves Forward

As someone who worked on CAR-T cells and cell-based vaccines in the 1990’s, it was exciting to learn while attending the recent IBC Cell Therapy Bioprocessing and Commercialization conference that some of these cell-based therapies are moving towards commercialization. Marc Better (Kite Pharma) and Bruce Levine (U. Penn.) presented stunning clinical data on the use of anti-CD19 CAR-T cells for the treatment of various forms of hematological cancers. These results are the outcome of a better understanding of T cell biology, an improved conditioning of patients, and the appropriate choice of clinical indications. Levine also indicated his colleagues are turning their attention toward solid tumors. Similarly, Bluebird Bio representatives presented impressive data on the treatment of Beta thalassemia using genetically modified CD34+ cells.

Various presenters described some of the commercialization challenges associated with cell-based therapies. These challenges included the control of starting and raw materials, comparability strategies, and appropriate potency assays. Critical starting materials, such as patient apheresis samples, need to be generated using stricter quality standards to minimize variability. Apheresis use to produce a critical raw material does not necessarily have to be GMP, nevertheless suitable controls will be required. For example, an analysis of bone marrow isolates showed a 3-log variation in number of isolated CD34+cells/Kg at the same clinic. These differences appear to arise from individual patient variations as well as subtle differences in isolation methodology.

Critical raw material quality standards for such starting materials as plasmids and cell lines used in vector manufacture and the vector itself need to be adequately controlled. Consequently, there is a need to ensure that suppliers of these materials have adequate Quality Systems in place, that the facilities are adequate to meet these standards and that there are specifications and limits in place. Similarly, controls need to be in place for all ancillary materials, e.g. growth factors, media, bags, etc. Such controls are particularly critical for cell-based products due to the potential carryover of contaminants into the product. A USP risk-based approach for this quality control process was described.

Comparability studies are particularly challenging for cell-based products because there may be no suitable animal models to correlate efficacy with perceived CQA’s. In addition, the mechanism of action of these cells is not always fully understood. In such cases, clinical data is sometimes required as well as a matrix approach to comparability in terms of risk assessments, certificates of analysis results, and process validation documentation. Comparability studies on patient specific products present a unique challenge. One common approach is to split a patient’s cells into two volumes and process these samples in parallel using the processes to be compared. Further, careful consideration needs to be given to the mode of statistical analysis employed as well as how many cell-processing replicates need to be performed. To add further complications, often a source of patient cells is unavailable and normal donor cells must be used. In an ideal situation, at least some initial experimentation would show that patient and normal donor cells are equivalent.

There were two major take-away messages from this conference. First, great strides are being made in cell-based therapies and patient outcomes are extremely encouraging. Second, companies are moving forward with commercialization plans and need to adapt QbD and Quality Systems approaches to address novel safety and efficacy issues associated with such products. Establishing a clear QbD and Quality Systems strategy as early in product development as possible is paramount to assure that cell-based therapy companies maintain momentum across the regulatory approval process.


Blog article by: David Broad