Page 1726 - Hematology_ Basic Principles and Practice ( PDFDrive )

1532 Part IX Cell-Based Therapies

Manufacturing
• Scale up
• Validation
• Release criteria
• CMC
Discovery; proof of Dose escalation; Dose ranging; Efficacy and safety
concept; cell product Animal studies safety and toxicity safety and studies; full product
potential; therapeutic • GLP/GMP cell studies; small trial efficacy studies; characterization;
mechanism and product size increase trial potency; scale up;
pathway; cell and • Efficacy size full GMP
disease interaction • Toxicity
IND Filing

Basic research Pre-clinical Phase Phase II Phase III
Fig. 96.1 CELL THERAPY PRODUCT DEVELOPMENT. CMC, chemistry, manufacturing and controls;
GLP, good laboratory practices; GMP, good manufacturing practices; IND, investigational new drug.

TABLE Regulation of Human Cells, Tissues, and Cellular and these five elements, developing a potency assay for cell therapy
96.1 Tissue-Based Products products is most challenging. Potency measures the product’s relevant
biological function and therefore is a critical aspect of both safety and
HCT/Ps Regulated Under 351 of HCT/Ps Regulated Under 361 of efficacy. Potency requires understanding a mechanism of action that
the PHS Act the PHS Act is relevant to the use of the product in humans. Biological products
Require IND submission and No IND required/no premarket are inherently complex, variable, and often heterogeneous, with
premarket approval; do not approval requirement complex and/or poorly defined mechanisms of action(s). Despite
meet the definition of exempt complex cell-engineering processes, the final product may contain
products described for 361 both therapeutic and nontherapeutic cells; however, it can be difficult
products; 21 CFR 1271 to ascertain if the combination of “active” and “inactive” components
More than minimally • Minimally manipulated, and contribute to biological function. Because cells and cell lines are
manipulated • For homologous use, and genetically diverse, they may behave differently during manufacturing
• Not a combination product, than they did under experimental conditions. Cell-characterization
AND either testing, particularly with respect to potency, will evolve and
• has no cellular or change significantly during pre-clinical testing and clinical product
4
systemic effect development.
or
• if it is active on a cellular Raw Materials
or systemic basis is used
in an autologous setting,
in an allogeneic setting Many types of raw materials are used in cell therapy manufacturing.
in first- or second-degree Such materials include culture media, sera, growth factors, cytokines,
blood relatives, or is for and “feeder cells,” which are used to support cell growth. They may
reproductive use be simple or complex and may remain in the final therapeutic product
as active substances, excipients, or as impurities, and, as such, their
Not intended for homologous use levels should be measured, controlled, and justified. They may also
Associated with a device or be used in the manufacturing process as ancillary products. A quali-
scaffold a fication program for raw materials that includes microbial testing
Cellular or systemic effect or (sterility, pyrogenicity [endotoxin], mycoplasma, and other adventi-
dependent of metabolic tious agents) needs to be implemented to ensure the consistency and
activity of the cells for its quality of raw materials and be designed to address identification and
primary function selection of the material, suitability of materials for use in manufac-
turing, characterization of materials, justification for use of animal-
a Cell therapies that also have a device or scaffold associated with them can be
regulated by the Center for Devices and Radiological Health (CDRH) as a derived materials (i.e., fetal bovine serum), and quality assurance
5
consultant to the Center for Biologics Evaluation and Research (CBER) or as (QA) for all materials.
the lead center if the scaffold is the primary mode of action.
Adventitious Agents

rigorous process control are therefore critical to counter the intrinsic Adventitious agents (e.g., viruses, endotoxin mycoplasma, bacteria,
heterogeneity and variability of cell therapy products. 3 parasites, fungi) may originate from the source (e.g., infected animals,
tissues), during cell culture manipulation (e.g., repeated passages and
manipulation in the laboratory), or by using contaminated biological
Characterization reagents. Unidentified diseases may exist in the use of xenogeneic
cells. The range of infectious agents that produce little or no effect
Cell therapy products are difficult to fully characterize. Critical deci- in animals may have severe consequences in humans. With xenoge-
sions need to be made in the product-development stage and the neic materials rigorous qualification of source animals and primary
establishment of a desired characterization profile should occur early cell substrates is critical. Also, complex cell engineering procedures
in the process to drive development. Successful product develop- may extend over months, and can result in increased risk of contami-
ment demonstrates that a cell therapy product can be consistently nation and other adverse effects. A risk-based assessment of the
manufactured which is safe, pure, potent, effective, and stable. Of quality control (QC) aspects of the manufacturing process is