Bacterial safety of cellular preparations, especially haematopoietic progenitor cells (HPCs), as well as advanced therapy medicinal products (ATMPs) derived from stem cells of various origins, present a challenge for physicians, manufacturers and regulators. The article describes the background and practical issues in this area and illustrates why sterility of these products cannot currently be guaranteed. Advantages and limitations of approaches both for classical sterility testing and for microbiological control using automated culture systems are discussed. The review considers novel approaches for growth-based rapid microbiological control with high sensitivity and faster availability of results, as well as new methods for rapid bacterial detection in cellular preparations enabling meaningful information about product contamination within one to two hours. Generally, however, these direct rapid methods are less sensitive and have greater sampling error compared with the growth-based methods. Opportunities for pyrogen testing of cell therapeutics are also discussed. There is an urgent need for development of novel principles and methods applicable to bacterial safety of cellular therapeutics. We also need a major shift in approach from the traditional view of sterility evaluation (identify anything and everything) to a new thinking about how to find what is clinically relevant within the time frame available for the special clinical circumstances in which these products are used. The review concludes with recommendations for optimization of microbiological control of cellular preparations, focusing on HPCs.
Since bacterial infection of the recipient has become the most frequent infection risk in transfusion medicine, suitable methods for bacteria detection in blood components are of great interest. Platelet concentrates are currently the focus of attention, as they are stored under temperature conditions, which enable the multiplication of most bacteria species contaminating blood donations. Rapid methods for bacteria detection allow testing immediately before transfusion in a bed-side like manner. This approach would overcome the sampling error observed in early sampling combined with culturing of bacteria and would, at least, prevent the transfusion of highly contaminated blood components leading to acute septic shock or even death of the patient. Flow cytometry has been demonstrated to be a rapid and feasible approach for detection of bacteria in platelet concentrates. The general aim of the current study was to develop protocols for the application of this technique under routine conditions. The effect of improved test reagents on practicability and sensitivity of the method is evaluated. Furthermore, the implementation of fluorescent absolute count beads as an internal standard is demonstrated. A simplified pre-incubation procedure has been undertaken to diminish the detection limit in a pragmatic manner. Additionally, the application of bacteria detection by flow cytometry as a culture method is shown, i.e., transfer of samples from platelet concentrates into a satellite bag, incubation of the latter at 37 degrees C, and measuring the contaminating bacteria in a flow cytometer.
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