Standardized guidelines for Africanized honeybee venom production needed for development of new apilic antivenom.

Africanized bees have spread across the Americas since 1956 and consequently resulted in human and animal deaths attributed to massive attacks related to exposure from Argentina to the USA. In Brazil, more than 100,000 accidents were registered in the last 5 years with a total of 303 deaths. To treat such massive attacks, Brazilian researchers developed the first specific antivenom against Africanized honey bee sting exposure. This unique product, the first of its kind in the world, has been safely tested in 20 patients during a Phase 2 clinical trial. To develop the antivenom, a standardized process was undertaken to extract primary venom antigens from the Africanized bees for immunization of serum-producing horses. This process involved extracting, purifying, fractionating, characterizing, and identifying the venom (apitoxin) employing mass spectrometry to generate standardized antigen for hyperimmunization of horses using the major toxins (melittin and its isoforms and phospholipase A2). The current guide describes standardization of the entire production chain of venom antigens in compliance with good manufacturing practices (GMP) required by regulatory agencies. Emphasis is placed upon the welfare of bees and horses during this process, as well as the development of a new biopharmaceutical to ultimately save lives.

Development of a Rapid Adeno-Associated Virus (AAV) Identity Testing Platform through Comprehensive Intact Mass Analysis of Full-Length AAV Capsid Proteins.

Adeno-associated viruses (AAVs) are commonly used as vectors for the delivery of gene therapy targets. Characterization of AAV capsid proteins (VPs) and their post-translational modifications (PTMs) have become a critical attribute monitored to evaluate product quality. Liquid chromatography-mass spectrometry (LC-MS) analysis of intact AAV VPs provides both quick and reliable serotype identification as well as proteoform information on each VP. Incorporating these analytical strategies into rapid good manufacturing practice (GMP)-compliant workflows containing robust, but simplified, data processing methods is necessary to ensure effective product quality control (QC) during production. Here, we present a GMP-compliant LC-MS workflow for the rapid identification and in-depth characterization of AAVs. Hydrophilic interaction liquid chromatography (HILIC) MS with difluoroacetic acid as a mobile phase modifier is utilized to achieve the intact separation and identification of AAV VPs and their potential proteoforms. Peptide mapping is performed to confirm PTMs identified during intact VP analysis and for in-depth PTM characterization. The intact separations platform is then incorporated into a data processing workflow developed using GMP-compliant software capable of rapid AAV serotype identification and, if desired, specific serotype PTM monitoring and characterization. Such a platform provides product QC capabilities that are easily accessible in a regulatory setting.

Mini-review: Equipment evaluation for process scalability and readiness for current Good Manufacturing Practices in cell therapy workflows.

Cell therapies present a promising treatment for a variety of diseases and are a rapidly growing market. This facilitates the need for robust biomanufacturing processes that can be implemented early during process establishment which enables scalable and reproducible manufacturing. Historically, cell therapy has used equipment originally repurposed from biologics, where the supernatant is harvested at the end of production and not the cells. Unlike biologics, cell therapy requires the preservation of cell phenotype and potency, as well as the functional recovery of the cells for the final formulation. These traditional equipment platforms have been widely adopted and, in many cases, successfully. However, given that cell therapy processes are complex, equipment specifically designed for the intended application will add immense value by producing products that are pure, potent and stable. New equipment better suited for cell therapy is being introduced to improve efficiency and product quality compared with current systems, fill key gaps that exist in current workflows or address an emerging need in new paradigms. Integration of these new instruments in laboratories using current Good Manufacturing Practices to produce cell-based drug products and drug substances requires a risk-based approach to evaluate features based on suitability and compliance with regulatory requirements. The speed at which new equipment is evaluated and implemented into new workflows is critical to match the speed of therapeutic product innovations and manufacturing capabilities. Here, we outline a framework to evaluate new equipment and de-risk implementation based on a series of features, namely, hardware, software, consumables, and workflow compatibility for the intended use. A hypothetical evaluation of three cell processing workflows is used as an example to inform equipment deployment for early process establishment and translational use for current Good Manufacturing Practices-destined workflows.

Small-scale manufacturing of neoantigen-encoding messenger RNA for early-phase clinical trials.

Messenger RNA (mRNA) has become a promising tool in therapeutic cancer vaccine strategies. Owing to its flexible design and rapid production, mRNA is an attractive antigen delivery format for cancer vaccines targeting mutated peptides expressed in a tumor-the so-called neoantigens. These neoantigens are rarely shared between patients, and inclusion of these antigens in a vaccine requires the production of individual batches of patient-tailored mRNA. The authors have developed MIDRIXNEO, a personalized mRNA-loaded dendritic cell vaccine targeting tumor neoantigens, which is currently being evaluated in a phase 1 clinical study in lung cancer patients. To facilitate this study, the authors set up a Good Manufacturing Practice (GMP)-compliant production process for the manufacture of small batches of personalized neoantigen-encoding mRNA. In this article, the authors describe the complete mRNA production process and the extensive quality assessment to which the mRNA is subjected. Validation runs have shown that the process delivers mRNA of reproducible, high quality. This process is now successfully applied for the production of neoantigen-encoding mRNA for the clinical evaluation of MIDRIXNEO. To the authors' knowledge, this is the first time that a GMP-based production process of patient-tailored neoantigen mRNA has been described.

A comprehensive report of long-term stability data for a range ATMPs: A need to develop guidelines for safe and harmonized stability studies.

BACKGROUND AIMS: Advanced therapy medicinal products (ATMPs) are novel drugs based on genes, cells or tissues developed to treat many different diseases. Stability studies of each new ATMP need to be performed to define its shelf life and guarantee efficacy and safety upon infusion, and these are presently based on guidelines originally drafted for standard pharmaceutical drugs, which have properties and are stored in conditions quite different from cell products. The aim of this report is to provide evidence-based information for stability studies on ATMPs that will facilitate the interlaboratory harmonization of practices in this area. METHODS: We have collected and analyzed the results of stability studies on 19 different cell-based experimental ATMPs, produced by five authorized cell factories forming the Lombardy "Plagencell network" for use in 36 approved phase I/II clinical trials; most were cryopreserved and stored in liquid nitrogen vapors for 1 to 13 years. RESULTS: The cell attributes collected in stability studies included cell viability, immunophenotype and potency assays, in particular immunosuppression, cytotoxicity, cytokine release and proliferation/differentiation capacity. Microbiological attributes including sterility, endotoxin levels and mycoplasma contamination were also analyzed. All drug products (DPs), cryopreserved in various excipients containing 10% DMSO and in different primary containers, were very stable long term at <-150°C and did not show any tendency for diminished viability or efficacy for up to 13.5 years. CONCLUSIONS: Our data indicate that new guidelines for stability studies, specific for ATMPs and based on risk analyses, should be drafted to harmonize practices, significantly reduce the costs of stability studies without diminishing safety. Some specific suggestions are presented in the discussion.

Implantation of the clinical-grade human neural stem cell line, CTX0E03, rescues the behavioral and pathological deficits in the quinolinic acid-lesioned rodent model of Huntington's disease.

Huntington's disease (HD) is a devastating, autosomal-dominant neurodegenerative disease, for which there are currently no disease-modifying therapies. Clinical trials to replace the damaged striatal medium spiny neurons (MSNs) have been attempted in the past two decades but have met with only limited success. In this study, we investigated whether a clonal, conditionally immortalized neural stem cell line (CTX0E03), which has already shown safety and signals of efficacy in chronic ischemic stroke patients, could rescue deficits seen in an animal model of HD. After CTX0E03 transplantation into the quinolinic acid-lesioned rat model of HD, behavioral changes were measured using the rotarod, stepping, and staircase tests. In vivo differentiation and neuronal connections of the transplanted CTX0E03 cells were evaluated with immunohistochemical staining and retrograde tracing with Fluoro-Gold. We found that transplantation of CTX0E03 gave rise to a significant behavioral improvement compared with the sham- or fibroblast-transplanted group. Transplanted CTX0E03 formed MSNs (DARPP-32) and GABAergic neurons (GABA, GAD65/67) with BDNF expression in the striatum, while cortically transplanted cells formed Tbr1-positive neurons. Using a retrograde label, we also found stable engraftment and connection of the transplanted cells with host brain tissues. CTX0E03 transplantation also reduced glial scar formation and inflammation, as well as increasing endogenous neurogenesis and angiogenesis. Overall, our results demonstrate that CTX0E03, a clinical-grade neural stem cell line, is effective for preclinical test in HD, and, therefore, will be useful for clinical development in the treatment of HD patients.

Assessing the Performance of Food Safety Management System Using Food Safety Management System Diagnostic Tools and Microbial Assessment Scheme: A Case of Powdered Beverage Manufacturers.

BACKGROUND: The objective of the study is to assess the performance of the Food Safety Management System (FSMS) among powdered beverage manufacturers using Food Safety Management System Diagnostic Tools (FSMS-DI) and Microbial Assessment Scheme (MAS). METHODS: FSMS-DI was used to evaluate the context factors, core control and core assurance activities of five powdered beverage manufacturers with different types of FSMS certification. Manufacturer A is not certified with any FSMS, while manufacturers B, C, D and E are complied with MeSTI, GMP, HACCP and ISO 22000, respectively. For MAS, samples were collected from the selected critical sampling locations of two manufacturers who complied FSMS with the least (manufacturer B) and the most stringent (manufacturer E) requirements. The samples consisted of two different types of powdered beverage products were analysed for total plate count (TPC), Salmonella, Escherichia coli, Staphylococcus aureus, yeast and mould count (YMC). Results: The food safety (FS) output of powdered beverages for manufacturer E was better (overall score of 3) than manufacturer B (overall score of 2-3). Manufacturer E was able to achieve their FS objectives. The FSMS activities of manufacturer C, D and E were better (overall score of 2-3) than manufacturer A and B (overall score of 1-2). CONCLUSION: The study demonstrated that FSMS-DI and MAS can be used to differentiate the FSMS performance of powdered beverage manufacturers with different types of FSMS certification. Higher scores of FSMS activities obtained by the manufacturer who complied with stringent FSMS certifications contributed to better microbiological safety performance of powdered beverages.

Challenges of manufacturing mesenchymal stromal cell-derived extracellular vesicles in regenerative medicine.

The field of regenerative medicine has expanded greatly in the past decade, with more than 1000 current clinical trials involving mesenchymal stromal cell (MSC) treatment. Multiple recent publications have demonstrated that the beneficial effects from MSCs are not simply due to engraftment into the target organ as classically thought but rather are largely attributable to the release of paracrine factors including cytokines, growth factors and extracellular vesicles (EVs). These EVs contain miRNAs, free fatty acids and proteins that promote regeneration, proliferation and cell function and improve inflammation. Although EVs have shown promising results in animal studies, there are many obstacles to the manufacturing of EVs for clinical applications. This review discusses challenges associated with the manufacturing of clinical-grade EVs in regard to identity, purity, reproducibility, sterility, storage, potency and safety. We discuss currently employed methods and approaches for developing clinical Good Manufacturing Practices (GMP)-grade EVs and the limitations for each. We further discuss the best approaches to overcome the current hurdles in developing clinical GMP-grade EVs.

Current regulatory guidelines and resources to support research of dietary supplements in the United States.

The U.S. Dietary Supplement Health and Education Act (DSHEA) established the regulatory framework for dietary supplements as foods through the Food and Drug Administration (FDA). DSHEA outlined the legal definition, labeling requirements, and process for adverse event reporting for dietary supplements. FDA also issued formal guidance on current Good Manufacturing Practice to ensure that processes for preparation, packaging, labeling, and storage of supplements and ingredients are documented and meet specifications to ensure purity, composition, and strength. However, efficacy of dietary supplements is not required under U.S. law. Despite regulations to improve the marketplace, many challenges remain; as a result, the quality and safety of products available can be highly variable, especially for botanical and herbal products. The ability of regulators to successfully carry out their mission is hampered by the sheer number of products and manufacturing facilities and a lack of analytical methods for all ingredients and products in the marketplace, this is especially difficult for herbal and botanical dietary supplements. Safety issues continue to exist such as adulteration and contamination, especially with specific product types (i.e. body building, sexual enhancement). Thus, a need remains for continued efforts and improved techniques to assess the quality of dietary supplements, especially with regard to purity, bioavailability, and safety. This review will highlight the existing American regulatory framework for dietary supplements and will describe the remaining regulatory barriers to ensuring that safe and high-quality dietary supplements are offered in the marketplace.

A calibration disk for the correction of radial errors from chromatic aberration and rotor stretch in the Optima AUC™ analytical ultracentrifuge.

Experiments performed in the analytical ultracentrifuge (AUC) measure sedimentation and diffusion coefficients, as well as the partial concentration of colloidal mixtures of molecules in the solution phase. From this information, their abundance, size, molar mass, density and anisotropy can be determined. The accuracy with which these parameters can be determined depends in part on the accuracy of the radial position recordings and the boundary conditions used in the modeling of the AUC data. The AUC instrument can spin samples at speeds up to 60,000 rpm, generating forces approaching 300,000 g. Forces of this magnitude will stretch the titanium rotors used in the instrument, shifting the boundary conditions required to solve the flow equations used in the modeling of the AUC data. A second source of error is caused by the chromatic aberration resulting from imperfections in the UV-visible absorption optics. Both errors are larger than the optical resolution of currently available instrumentation. Here, we report software routines that correct these errors, aided by a new calibration disk which can be used in place of the counterbalance to provide a calibration reference for each experiment to verify proper operation of the AUC instrument. We describe laboratory methods and software routines in UltraScan that incorporate calibrations and corrections for the rotor stretch and chromatic aberration in order to support Good Manufacturing Practices for AUC data analysis.

Determination of antibiotic impurities in good manufacturing practices-grade cell therapy medicinal products.

Backrounds: According to the regulations of the health autorities, cell-based therapy products must be manufactured in good manufacturing production (GMP) facilities, fulfilling the required GMP standards. Products developed under the high quality control (QC) necessarity need to be approved for some QC tests. One of the main residual test is antibiotic test and this test should be validated. The aim of this study is to validate and determine the methods of detection of the antibiotic residue in the final product.Methods: Liquid Chromatography Tandem-Mass Spectrometry (LC-MS/MS) methods were used for the main steps of the production procedure, as well as the final products. Pharmaceutical Grade penicillin G and streptomycin sulfate were used as positive controls.Results: The results suggest that penicillin is broken down during cell culture and streptomycin is eliminated at the first washing step of the final product manufacture. It is shown in this study that LC-MS/MS method is one of the convenient method to test residual anibiotics and can be used to detect the antibiotic residues in cellular therapy products.Discussion: Since the antibiotic residues are eliminated in the final product and also it could be suggested that the methodology we followed is sufficiently safe and final product is pure.

[Discussion on the Application of Supercritical Carbon Dioxide Technology for Sterilization of Medical Devices].

Traditional medical device sterilization processes are mature, but there are constraints when using on medical devices by new materials. With increasing environmental concerns, using of ethylene oxide sterilization has been limited by global environmental protection administrations. Exploring new sterilization methods for medical devices is urgently needed. This paper reviews the supercritical carbon dioxide sterilization technology by arranging the exploratory work of industry researchers. In the paper, we introduce the theory of supercritical carbon dioxide sterilization technology, microbial inactivation ability, material influence research and sterilization equipment. Then we discuss the concerns and possibilities of the technology applied to the medical device industry basing on the good manufacturing practices.

Inflammation-Stimulated Mesenchymal Stromal Cell-Derived Extracellular Vesicles Attenuate Inflammation.

Extracellular vesicles (EVs) secreted by mesenchymal stromal cells (MSCs) have been proposed to be a key mechanistic link in the therapeutic efficacy of cells in response to cellular injuries through paracrine effects. We hypothesize that inflammatory stimulation of MSCs results in the release of EVs that have greater anti-inflammatory effects. The present study evaluates the immunomodulatory abilities of EVs derived from inflammation-stimulated and naive MSCs (MSCEv+ and MSCEv, respectively) isolated using a current Good Manufacturing Practice-compliant tangential flow filtration system. Detailed characterization of both EVs revealed differences in protein composition, cytokine profiles, and RNA content, despite similarities in size and expression of common surface markers. MSCEv+ further attenuated release of pro-inflammatory cytokines in vitro when compared to MSCEv, with a distinctly different pattern of EV-uptake by activated primary leukocyte subpopulations. The efficacy of EVs was partially attributed to COX2/PGE2 expression. The present study demonstrates that inflammatory stimulation of MSCs renders release of EVs that have enhanced anti-inflammatory properties partially due to COX2/PGE2 pathway alteration. Stem Cells 2018;36:79-90.

Current good manufacturing practices-compliant manufacture and measurement of biotin-labeled red blood cells.

BACKGROUND: Red blood cells (RBCs) can be labeled with N-hydroxysuccinimidobiotin (sulfo-NHS-biotin), which binds to cell surface proteins under aqueous conditions. Biotinylated RBCs can be safely infused and detected in peripheral blood samples using flow cytometry, using a fluorochrome-conjugated streptavidin (SA) detection reagent. Biotinylated RBCs have been used to track survival of transfused RBCs, and have applications in optimizing RBC storage and in understanding donor genetic, environmental and disease factors affecting RBC products. METHODS: We have developed a closed-system, current good manufacturing practices (cGMP)-compliant procedure for biotinylation of RBCs and a quantitative flow cytometric assay to estimate the dose of cell-bound biotin delivered to the patient. Resulting products were characterized for variability, sterility, endotoxin, hemolysis, total dose of cell-bound biotin and stability. RESULTS: The density of biotin-labeling increased as a log-linear function of sulfo-NHS-biotin-labeling concentration, with greater variability at lower concentrations. The upper estimates of biotin doses in the average product (mean RBC content = 5.55 × 1011) were 9.8 and 73.0 µg for products labeled at 3 and 15 µg sulfo-NHS-biotin/mL of total reaction mixture (27 and 135 nmol/mL packed RBCs), respectively. All products were negative for bacterial and fungal growth at 14 days and were below the limit of endotoxin detection. Biotinylated RBCs were stable in vitro for up to 50 days after labeling. DISCUSSION: We have validated a closed-system procedure for biotinylating RBCs for investigational use. A standard operating procedure is presented in sufficient detail for implementation in a cGMP-compliant cell-processing facility.

Towards a common framework for defining ancillary material quality across the development spectrum.

Ancillary materials (AMs) play a critical role in the manufacture of cell and gene therapies, and best practices for their quality management are the subject of ongoing discussion. Given that the final product cannot be sterilized, AM quality becomes increasingly critical to the clinical advancement of cell and gene therapies. Despite a lack of direct legislative direction regarding AM quality, internationally harmonized guidance is available from several industry-standard bodies that describe the principles and application of a risk-based approach to AM qualification and related supply-chain risk management. According to a best-practice risk-based approach, AMs must be adequately qualified to a degree that reflects the level of risk the material presents to patient safety and the drug product's specification. This general approach can be implemented in different ways, and balancing quality with cost of goods is critical to the cost-effective manufacture of advanced therapy medicinal products. In some cases, it may be preferable or necessary to use AMs that are produced in compliance with current Good Manufacturing Practice. However, developers may be able to suppress manufacturing costs without undermining safety or regulatory compliance in the case that a material presents a lower risk profile. Despite a great deal of attention and interest in the quality of AMs in the cell and gene therapy space, there is still a need for greater harmonization to create a shared understanding of what constitutes a risk-based approach to AM production and sourcing. In this article, we propose a staged approach to AM quality that achieves a balance between the competing demands of risk mitigation and cost of goods containment at the various stages of AM quality development. Our novel, heuristic framework for communication among AM suppliers, users and regulators aims to bring down development and manufacturing costs and lessen the workload around regulatory compliance.

Microbial safety status of Serro artisanal cheese produced in Brazil.

Considering the growing consumption of artisanal foods worldwide, we aimed to evaluate the microbial safety of Serro artisanal cheese (SAC), produced in Minas Gerais State, Brazil. This cheese is produced with raw milk using 1 of 2 natural starter cultures: "pingo" and "rala." A total of 53 SAC samples (pingo = 8; rala = 45) were obtained from different farmers and subjected to conventional and molecular assays to detect and enumerate Listeria monocytogenes, Salmonella spp., coagulase-positive staphylococci (CPS), diarrheagenic Escherichia coli, Mycobacterium tuberculosis, and Brucella abortus. The SAC samples were also subjected to an ELISA to detect classical staphylococcal enterotoxins (CSE: SEA, SEB, SEC, SED, SEE) and to PCR assays to detect staphylococcal enterotoxin-related genes (sea, seb, sec, sed, see). Coagulase-positive staphylococci isolates were obtained and tested by the same assays to detect their potential in CSE production and presence of CSE-related genes. None of the SAC samples showed any of the screened food-borne pathogens and zoonotic agents, and none showed the presence of CSE by phenotypic and genotypic approaches. Despite the absence of microbial hazards, mean counts of CPS in SAC samples were 5.2 log cfu/g (pingo starter) and 4.6 log cfu/g (rala starter), indicating poor hygiene practices during production. None of the tested CPS isolates (n = 116) produced CSE or presented CSE-related genes. Despite the relative microbial safety, hygienic conditions during SAC production must be improved to meet official guidelines established in Brazil.

Regulation of Regenerative Medicine Products.

Cellular therapies have moved to the forefront based upon promising results from clinical trials using both chimeric antigen receptor T lymphocytes to treat leukemia and other cell types to restore structure and function to tissues that have been damaged by disease or physical injury. The pace at which these treatments have evolved has posed a regulatory challenge to agencies, such as the Food and Drug Administration (FDA). This chapter describes how a specific regulatory strategy was developed and how it has evolved in response to the demand for these new therapies.

Evaluation of an intervention to improve the management of allergens in school food services in the city of Barcelona.

BACKGROUND: An intervention to promote the development of an allergen control plan (ACP) and preventive measures for the management of allergens in school food services was implemented in all schools of Barcelona city over a three-year period (2013-2015) by the public health services. The present study aimed to assess changes regarding the management of food allergens in school food services in Barcelona after an intervention conducted by the public health services of the city. METHODS: School meal operators of a random sample of 117 schools were assessed before and after the intervention using a structured questionnaire. The questionnaire collected general information on the students and their demand for special menus, and included 17 closed questions regarding the implementation of specific preventive measures for the management of allergens. Based on these 17 questions, a food safety score was calculated for each school. The improvement in these scores was evaluated. RESULTS: The results showed positive increments in the percentage of implementation of 12 of the 17 preventive measures assessed. The percentage of school food services with an implemented ACP increased by 49%. Schools with external and internal food supplies increased their scores by 16.5% and 19.6%, respectively. The greatest improvements were observed in smaller food services and in schools located in districts with low gross household incomes. CONCLUSIONS: The intervention was effective in improving school food services' management of allergens and in reducing the differences found among food services in the pre-intervention survey. We must also focus efforts on reducing socio-economic inequalities linked to the management of allergens.

First update of the International Xenotransplantation Association consensus statement on conditions for undertaking clinical trials of porcine islet products in type 1 diabetes--Chapter 3: Porcine islet product manufacturing and release testing criteria.

In the 2009 IXA consensus, the requirements for the quality and control of manufacturing of porcine islet products were based on the U.S. regulatory framework where the porcine islet products fall within the definition of somatic cell therapy under the statutory authority of the U.S. Food and Drug Administration (FDA). In addition, porcine islet products require pre-market approval as a biologic product under the Public Health Services Act and they meet the definition of a drug under the Federal Food, Drug, and Cosmetic Act (FD&C Act). Thus, they are subject to applicable provisions of the law and as such, control of manufacturing as well as reproducibility and consistency of porcine islet products, safety of porcine islet products, and characterization of porcine islet products must be met before proceeding to clinical trials. In terms of control of manufacturing as well as reproducibility and consistency of porcine islet products, the manufacturing facility must be in compliance with current Good Manufacturing Practices (cGMP) guidelines appropriate for the initiation of Phase 1/2 clinical trials. Sponsors intending to conduct a Phase 1/2 trial of islet xenotransplantation products must be able to demonstrate the safety of the product through the establishment of particular quality assurance and quality control procedures. All materials (including animal source and pancreas) used in the manufacturing process of the porcine islet products must be free of adventitious agents. The final porcine islet product must undergo tests for the presence of these adventitious agents including sterility, mycoplasma (if they are cultured), and endotoxin. Assessments of the final product must include the safety specifications mentioned above even if the results are not available until after release as these data would be useful for patient diagnosis and treatment if necessary. In addition, a plan of action must be in place for patient notification and treatment in case the sterility culture results are positive. In terms of the characterization of porcine islet products and product release criteria, the information on the porcine islet products should be acquired from a sample of the final product to be used for transplantation and must include the morphology of the islets, specific identity, purity, viability, and potency of the product. In addition, information on the quantity of the islet products should also be provided in a standardized fashion and this should be in terms of islet equivalents and/or cell numbers. The current consensus was created to provide guidelines that manufacturing facilities may find helpful in the manufacture of and the release criteria for porcine islet products including encapsulated islets and combined islet products. Our intent with the above recommendations is to provide a framework for individual porcine islet manufacturing facilities to ensure a high level of safety for the initiation of Phase 1/2 clinical trials on porcine islet xenotransplantation.

Virus-specific T-cell therapy in solid organ transplantation.

This article reviews the current state of T-cell therapy as therapeutic option for virus-associated diseases against the background of the most common viral complications and their standard treatment regimens after SOT. The available data of clinical T-cell trials in SOT are summarized. References to the hematopoietic stem cell transplantation are made if applicable data in SOT are not available and their content was considered likewise valid for cell therapy in SOT. Moreover, aspects of different manufacturing approaches including beneficial product characteristics and the importance of GMP compliance are addressed.