Microbial safety of cell based medicinal products – what can we learn from cellular blood components?

Abstract

Today, sterility of established parenteral drugs including biologicals, such as plasma derived products, is practically guaranteed. Bacterially contaminated products are extremely rare exceptions owing to the efficiency of the manufacturing processes in the pharmaceutical industry. In contrast, the manufacturing processes of cell based medicinal products or tissue preparations show much less defined conditions. The sterility of source materials cannot be guaranteed in many cases. As a rule, these source materials cannot be sterilised, as it holds true for the final products. Furthermore, the established methods for sterility testing are not applicable for cell preparations. Sterility of a restricted sample does not guarantee sterility of the whole preparation. Thus, small amounts of residual bacteria in the product can be overlooked and can grow up to enormous numbers during storage and shipping of cell based medicinal products. Considering these problems, there are some parallels in the warranty of microbial safety of cellular blood components. Therefore, the experiences collected in transfusion medicine in the past decade can be successfully used in the production of cell based medicinal products. Comparable to the situation regarding cellular blood components, there is a need for new principles in rapid bacteria detection.

Cell therapy products: focus on issues with manufacturing and quality control of chimeric antigen receptor T‐cell therapies

“…Levels of endotoxin, mycoplasma, superfluous ancillary components and CD3 negative impurities carried over from the apheresis must be within tightly defined conformance limits . Microbial safety is a significant concern for CAR‐T products and cellular therapeutics in general, as the manufacturing processes have much less defined conditions than conventional parenteral drugs . Ensuring the sterility of source materials can be problematic and final product sterilisation is not applicable.…”

“…43,96 Microbial safety is a significant concern for CAR-T products and cellular therapeutics in general, as the manufacturing processes have much less defined conditions than conventional parenteral drugs. 102 Ensuring the sterility of source materials can be problematic and final product sterilisation is not applicable. Conventional methods of sterility testing may be less sensitive for cell-based products; for example, sterility of a sample may not ensure sterility of the whole infusion product and standard sterility test protocols, such as microbiological growth media inoculation may not detect all potential contaminants.…”

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

“…The turbidity of the medium is used as parameter for microbial growth. Sample preparation can be performed by direct inoculation or filtration . Moreover, automated culture systems (e.g.…”

Comparison of different methods of bacterial detection in blood components

“…To harmonize future studies, Montag et al . [40] developed and characterized bacterial standards within the ISBT working party for transfusion‐transmitted infectious diseases. All bacterial standards are ready to use frozen samples containing a defined number of viable bacterial colonies.…”