Microbial safety of cellular therapeutics—lessons from over ten years’ experience in microbial safety of platelet concentrates

Abstract

Bacterial safety of cellular preparations, including blood products and cellular therapeutics, presents ongoing challenges for physicians, manufacturers and regulators. Although there have been many new approaches to enhance the microbial safety of cellular products during the last decade, established methods for microbiological control still need to be fully adapted to the special circumstances of cellular preparations. The experience from transfusion medicine regarding microbial safety of blood components has demonstrated the variety of problems and risk factors for the development of new strategies for microbial safety. Special attention has been given to the prevention and detection of bacterial contamination of platelet concentrates. But so far, none of the targeted strategies for rapid detection or pathogen reduction have become routinely implemented worldwide, in part at least because development and requirements of new technologies and their implementation into the routine setting are a whole different problem. But factors including the short shelf life and nontraditional lot sizes for cellular and gene therapy products are driving the need for rapid microbiological methods. In conclusion, lessons from the microbial safety of platelet concentrates enable us to understand that the detection or reduction in bacteria represents a more difficult challenge in comparison with viruses. Recent regulatory changes demonstrate that we are getting closer to the goal of a shift from the traditional view of sterility evaluation (identify and inactivate anything and everything) to a new thinking about microbiological control.

The ratio of nicotinic acid to nicotinamide as a microbial biomarker for assessing cell therapy product sterility

“…The time-point-dependent contamination experiments were performed using E. coli. Briefly, 10 5 MSCs/mL were inoculated with a high inoculum (10 4 CFUs/mL) of E. coli and incubated for 1, 2, 3, 4, 5, 6, and 24 h. Because it will take longer time to observe significant changes for low numbers of microbial contamination, additional time intervals (1,3,6,9,12,15,18,21, and 24 h) were used for low inocula (18 CFUs/mL) experiments. In addition, 10 5 MSCs/mL were also inoculated with 20 CFUs/mL of B. subtilis and 10 CFUs/mL of C. albicans and incubated for 6, 12, 18, and 24 h to investigate the detection limit of the method.…”

“…CTPs hence present a significantly high risk of possible transmission of infectious agents from cells to patients. 5 Reported rates of microbial contamination of various types of progenitor cell products or platelets range from 0.2% to 25%, 6,7 and 12% contamination was found in an analysis of 32 stem cell lines and feeder cell lines. 8 The most commonly reported contaminants are Mycoplasma spp., followed by fungal and bacterial contaminants.…”

“…16 Compared with traditional biotherapeutic products, it is harder to obtain the final results of sterility testing for CTPs within the required timeframe because they may have relatively short shelf lives and the waiting time is limited due to patient health. 6 Automated blood culture systems, such as BACTEC TM (Becton Dickinson) and BacT/ALERT Ò (bioMérieux), have been widely used as alternative testing methods. 17,18 Although they have the advantages of shorter incubation period of 7 days, the extremely short shelf lives of CTPs require approaches that provide results even sooner.…”

International haemovigilance: what have we learned and what do we need to do next?

“…It has facilitated policy changes and broad implementation of blood safety strategies by identifying the occurrence and consequences of adverse events, including those due to human error. Haemovigilance has also identified important common elements with other vigilances, such as pharmacovigilance, materiovigilance and biovigilance (New Zealand Blood Service, ; Whitaker et al, ; Störmer et al, ).…”