Factors affecting the turnaround time for manufacturing, testing, and release of cellular therapy products prepared at multiple sites in support of multicenter cardiovascular regenerative medicine protocols: a Cardiovascular Cell Therapy Research Network (CCTRN) study

Abstract

Background: Cellular therapy studies are often conducted at multiple clinical sites to accrue larger patient numbers. In many cases this necessitates use of localized good manufacturing practices facilities to supply the cells. To assure consistent quality, oversight by a quality assurance group is advisable. In this study we report the findings of such a group established as part of the Cardiovascular Cell Therapy Research Network (CCTRN) studies involving use of autologous bone marrow mononuclear cells (ABMMCs) to treat myocardial infarction and heart failure.

Study design and methods: Factors affecting cell manufacturing time were studied in 269 patients enrolled on three CCTRN protocols using automated cell processing system (Sepax, Biosafe SA)-separated ABMMCs. The cells were prepared at five good manufacturing practices cell processing facilities and delivered to local treatment sites or more distant satellite centers.

Results: Although the Sepax procedure takes only 90 minutes, the total time for processing was approximately 7 hours. Contributing to this were incoming testing and device preparation, release testing, patient randomization, and product delivery. The mean out-of-body time (OBT), which was to be less than 12 hours, averaged 9 hours. A detailed analysis of practices at each center revealed a variety of factors that contributed to this OBT.

Conclusion: We conclude that rapid cell enrichment procedures may give a false impression of the time actually required to prepare a cellular therapy product for release and administration. Institutional procedures also differ and can contribute to delays; however, in aggregate it is possible to achieve an overall manufacturing and testing time that is similar at multiple facilities.

Figure 1. Out of Body and Processing Times

The total out of body time for the bone marrow is shown in hours for each of the cell processing centers together with the time taken in the laboratory to perform cell processing. Bars indicate standard deviations.

Figure 2

The out of body time is broken down by component activity for each processing facility. The number of procedures performed by each facility is shown at the top of the appropriate column. At the base of the column is shown the mean processing time and total out of body time for the center. The activity descriptions are shown within the body of the columns.

Figure 3

Breakdown of the out of body time is shown for all products prepared at a single center (far left column). The center column shows the data for products administered locally at the clinical site associated with that processing center. The right hand column shows data from products collected at a distant satellite, transported to the same processing center and then returned to the satellite for administration. The overall times are similar, reflecting the request to hold products for local delivery until requested by the cardiac catheterization laboratory. This compensated for the transportation time from and to the satellite clinical center.

Figure 4

The cell processing times for Center 4 are shown from the receipt of the bone marrow to delivery of cells/placebo to the cardiac catheterization laboratory. This center was chosen since it had the median turnaround time and has processed the largest number of products There is a trend towards decreased overall processing times for the FOCUS protocol during the course of the study. Occasional delays, (shown as sharp spikes) in processing times shown are due to various technical issues.