Prophylactically Decontaminating Human Islet Product for Safe Clinical Application: Effective and Potent Method.

Pancreatic islet transplantation is a promising approach in treating insulin-dependent diabetes.1-3 Currently, over 900 patients globally have been transplanted with islet allografts.4 Islet transplantation requires isolating islets from mass pancreatic acinar tissue, which involves extensive tissue manipulation and rigorous regulatory approvals to ensure a safe and high-quality final product for treating patients with type 1 diabetes (T1D).5-7 Studies in whole organ transplantation showed that graft failure was attributed to systemic infection due to the contamination in the organ preservation solution.8-10 The contamination issue is further exacerbated in islet isolation, which involves multiple steps, including preservation of the whole pancreas with a portion of the duodenum and/or spleen attached, trimming and decontamination of pancreas, perfusion of enzyme, digestion, collection, washing of pancreatic tissue, purification, culturing, and collection of islets.11 Although, the process of manufacturing islet final product is carried out in a current good manufacturing practice (cGMP) facility, the risk of introducing contamination at any stage of the procedure still remains.12-14 Aside from the media used in pancreas decontamination, all other solutions used throughout the pancreas preservation and islet isolation process are prepared within the cGMP facility without addition of antimicrobial agents to prevent a potential allergic reaction of the recipient. The T1D patients are more vulnerable to infection, especially after islet transplantation with the required immunosuppressive regimen to prevent allograft rejection.15 Thus, it is extremely important to take measures to prevent contamination during manufacturing the final islet product for transplantation. With the advancement of islet transplantation as a standardized treatment strategy in a clinical setting, it eventually may require a biologic license application so that a safe and effective final product would be transplanted into patients.6,16 Therefore, sterility testing of the final product to be transplanted becomes one of the critical checkpoints. Hence, it is important to understand the route and rate of contamination in this whole process to implement an effective prevention plan to ensure the safety and potency of islet preparations. A limited number of large-scale studies have been published regarding the contamination issues during the islet manufacturing process,15,17-19 and little is described regarding the effect of antiseptic agents on the outcome of the islet isolation process. In fact, the most recent article related to this topic was published 10 years ago,18 which evaluated the use of Cefazolin and Amphotericin B for decontamination in the islet isolation process. However, the current protocol from the Clinical Islet Transplantation Consortium centers only uses a single antibiotic (Cefazolin) dip to decontaminate the organ.20 We hypothesize that using multiple antimicrobial agents may further decrease or eliminate the contamination rate of the final product. Herein, we report a comprehensive review and analysis of contamination rates during islet isolation and the frequency of contamination by specific microbial species.