Regulatory Challenges in Manufacturing of Pancreatic Islets

Linetsky, Elina; Ricordi, Camillo

doi:10.1016/j.transproceed.2008.01.027

Cited by 16 publications

(8 citation statements)

References 9 publications

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“…The FDA has stated that, before allogeneic islet transplantation is approved as a treatment option for T1DM, the safety, purity, potency and efficacy of the islets must be assessed. For islets to be considered suitable for transplantation, the islet isolation and purification processes must be defined, validated, and proved to be able to generate consistently high-quality products (33). Therefore, the last step in the isolation process consists of QC tests for purity, number of islet equivalents (IEQ -one IEQ corresponds to one islet with 150 μm diameter or greater), viability, cell functionality and sterility (34).…”

Section: Isolation Of Human Pancreatic Isletsmentioning

confidence: 99%

Human pancreatic islet transplantation: an update and description of the establishment of a pancreatic islet isolation laboratory

Rheinheimer

Bauer

Silveiro

et al. 2015

Arch. Endocrinol. Metab.

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Type 1 diabetes mellitus (T1DM) is associated with chronic complications that lead to high morbidity and mortality rates in young adults of productive age. Intensive insulin therapy has been able to reduce the likelihood of the development of chronic diabetes complications. However, this treatment is still associated with an increased incidence of hypoglycemia. In patients with "brittle T1DM" , who have severe hypoglycemia without adrenergic symptoms (hypoglycemia unawareness), islet transplantation may be a therapeutic option to restore both insulin secretion and hypoglycemic perception. The Edmonton group demonstrated that most patients who received islet infusions from more than one donor and were treated with steroid-free immunosuppressive drugs displayed a considerable decline in the initial insulin independence rates at eight years following the transplantation, but showed permanent C-peptide secretion, which facilitated glycemic control and protected patients against hypoglycemic episodes. Recently, data published by the Collaborative Islet Transplant Registry (CITR) has revealed that approximately 50% of the patients who undergo islet transplantation are insulin independent after a 3-year follow-up. Therefore, islet transplantation is able to successfully decrease plasma glucose and HbA1c levels, the occurrence of severe hypoglycemia, and improve patient quality of life. The goal of this paper was to review the human islet isolation and transplantation processes, and to describe the establishment of a human islet isolation laboratory at the Endocrine Division of the Hospital de Clínicas de Porto Alegre -Rio Grande do Sul, Brazil. Arch Endocrinol Metab. 2015;59(2):161-70

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Section: Isolation Of Human Pancreatic Isletsmentioning

confidence: 99%

Human pancreatic islet transplantation: an update and description of the establishment of a pancreatic islet isolation laboratory

Rheinheimer

Bauer

Silveiro

et al. 2015

Arch. Endocrinol. Metab.

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“… 6 , 16 This is especially critical for acquiring a biologic license application for clinical islet transplantation. 29 , 30 Although, whole organ transplantation is not overseen by the FDA, pancreatic islet transplantation is strictly regulated due to the complexity of the preparation of the final product. 11 In compliance with FDA guidelines and regulations, the islet isolation process is completed without using antibiotics that may cause an allergic reaction in certain transplant recipients.…”

Section: Discussionmentioning

confidence: 99%

Prophylactically Decontaminating Human Islet Product for Safe Clinical Application

Omori

Mullen

et al. 2016

Transplantation Direct

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BackgroundTransplanting pancreatic islets into recipients must be safe and effective to treat type 1 diabetes. Islet quality and quantity are important; however, the final product must also be free from microbial contamination and low endotoxin levels.MethodsThis study explored a method to eliminate contamination in manufacturing islets for transplantation. A simple (single antibiotic n = 164) and refined (triple antimicrobial agents, n = 279) pancreas decontaminating methods were used to test their effects on reducing the contamination rates in the islet final product. A total of 443 pancreata were processed for islet isolations. Three samples for microbial tests (Gram stain, aerobic, and anaerobic culture) were taken at preprocess (pancreas preservation), postisolation, and postculture. Endotoxin levels were measured only for islets considered for transplantation.ResultsOf 443 pancreata used for islet isolation, 79 (17.8%) showed signs of contamination in preprocess samples; 10 (2.3%) were contaminated in both preprocess and in the final product (postisolation and postculture) samples. Contamination rates in which preprocess and final product samples were positive for contamination was significantly lower using the refined method (refined vs simple method: 5% vs 20.5%, P = 0.045). Identical microbial species were present in both preprocess and in the final product.ConclusionsThis study demonstrated that the refined method reduces the rate of contamination of the islet final product and is safe for clinical application. Moreover, it may be used as a standard method during human islet manufacturing facilitating the application of a biological license agreement from United States Food and Drug Administration.

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“…In particular, such an assay could be used among industries and/or for evaluation of recombinant enzyme product should they become commercially available. 62,63 Thus, standardization of the islet isolation protocol could be achieved so that a Biologics License Application 64,65 could be approved by the Food and Drug Administration (FDA). 66 …”

Section: Discussionmentioning

confidence: 99%

The Choice of Enzyme for Human Pancreas Digestion Is a Critical Factor for Increasing the Success of Islet Isolation

Valiente

McFadden

et al. 2015

Transplantation Direct

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Background We evaluated three commercially available enzymes for pancreatic digestion by comparing key parameters during the islet isolation process, as well as islet quality post-isolation. Methods Retrospectively compared and analyzed islet isolations from pancreata using three different enzyme groups: Liberase HI (n=63), Collagenase NB1/Neutral Protease (NP) (n=43), and Liberase Mammalian Tissue Free Collagenase/Thermolysin (MTF C/T) (n=115). A standardized islet isolation and purification method was used. Islet quality assessment was carried out using islet count, viability, in vitro glucose-stimulated insulin secretion (GSIS), glucose-stimulated oxygen consumption rate (ΔOCR), and in vivo transplantation model in mice. Results Donor characteristics were not significantly different among the three enzyme groups used in terms of age, sex, hospital stay duration, cause of death, body mass index (BMI), hemoglobin A1c (HbA1c), cold ischemia time (CIT), and pancreas weight. Digestion efficacy (percentage of digested tissue by weight) was significantly higher in the Liberase MTF C/T group (73.5 ± 1.5 %) when compared to the Liberase HI group (63.6 ± 2.3 %) (p<0.001) and the Collagenase NB1/NP group (61.7 ± 2.9%) (p<0.001). The stimulation index for GSIS was significantly higher in the Liberase MTF C/T group (5.3 ± 0.5) as compared to the Liberase HI (2.9 ± 0.2) (p<0.0001) and the Collagenase NB1/NP (3.6 ± 2.9) (p=0.012) groups. Furthermore, the Liberase MTF C/T enzymes showed the highest success rate of transplantation in diabetic NOD Scid mice (65%), which was significantly higher than the Liberase HI (42%, p=0.001) and the Collagenase NB1/NP enzymes (41%, p<0.001). Conclusions Liberase MTF C/T is superior to Liberase HI and Collagenase NB1/NP in terms of digestion efficacy and glucose-stimulated insulin secretion in vitro. Moreover, Liberase MTF C/T had a significantly higher success rate of transplantation in diabetic NOD Scid mice compared to Liberase HI and Collagenase NB1/NP enzymes.

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Regulatory Challenges in Manufacturing of Pancreatic Islets

Cited by 16 publications

References 9 publications

Human pancreatic islet transplantation: an update and description of the establishment of a pancreatic islet isolation laboratory

Human pancreatic islet transplantation: an update and description of the establishment of a pancreatic islet isolation laboratory

Prophylactically Decontaminating Human Islet Product for Safe Clinical Application

The Choice of Enzyme for Human Pancreas Digestion Is a Critical Factor for Increasing the Success of Islet Isolation

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