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Pyrogens are fever-inducing substances routinely investigated in health products through tests such as the Rabbit Pyrogen Test (RPT), the Limulus Amebocyte Lysate (LAL), and the Monocyte Activation Test (MAT). However, the applications of the MAT for medical devices and biomaterials remain limited. This work aimed to overview the studies evaluating the pyrogenicity of medical devices and biomaterials using the MAT, highlighting its successes and potential challenges. An electronic search was performed by December 2023 in PubMed, Scopus, and Web of Science, identifying 321 records which resulted in ten selected studies. Data were extracted detailing the tested materials, MAT variants, interferences, and comparisons between methods. Methodological quality was assessed using the ToxRTool, and the results were synthesized descriptively. The selected studies investigated various materials, including polymers, metals, and natural compounds, employing the different biological matrices of the MAT. Results showed the MAT's versatility, with successful detection of pyrogens in most materials tested, though variability in sensitivity was noted based on the material and testing conditions. Challenges remain in optimizing protocols for different material properties, such as determining the best methods for direct contact versus eluate testing and addressing the incubation conditions. In conclusion, the MAT demonstrates significant potential as a pyrogen detection method for medical devices and biomaterials. However, continued research is essential to address existing gaps, optimize protocols, and validate the test across a broader range of materials.

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The Bacterial Endotoxin Test (BET) is a method for exclusion of endotoxin-related pyrogen contamination in pharmaceutical products, as an alternative to the Rabbit Pyrogen Test (RPT). However, BET does not detect a broad range of biologically relevant pyrogens, and interferences can limit its practical use for different medical products. This work aimed to scope the evidence in the scientific literature for case-by-case validity assessments of BET in different uses for medical products. A search strategy was conducted in PubMed, Scopus, and Web of Science in April 2020, according to the PRISMA-ScR statement. Twenty-two references were included, evaluating medical products for endotoxin contamination through both BET and RPT according to standardized protocols. A critical appraisal was performed through ToxRTool, followed by data extraction and qualitative synthesis of outcomes and methodological issues. Four classes of products assessed by BET were identified, including nanoparticles, drugs, blood and biological products. A considerable variation was observed on the BET methods used. Collectively, the evidence indicates different factors influencing the outcome of BET, including the chemical nature of samples that may cause interference depending on the selected method. While some applications to medical products appear adequate, others, such as nanoparticles, may require the use of different in vitro pyrogen testing methods, reinforcing the need for case-by-case validation for each BET method and type of medical product.

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The need for alternatives to animal use in pyrogen testing has been driven by the Three Rs concept. This has resulted in the inclusion of the monocyte activation test (MAT) in the European Pharmacopoeia, 2010. However, some technical and regulatory obstacles must be overcome to ensure the effective implementation of the MAT by the industry, especially for the testing of biological products. The yellow fever (YF) vaccine (17DD-YFV) was chosen for evaluation in this study, in view of: a) the 2016-2018 outbreak of YF in Brazil; b) the increase in demand for 17DD-YFV doses; c) the complex production process with live attenuated virus; d) the presence of possible test interference factors, such as residual process components (e.g. ovalbumin); and e) the need for the investigation of other pyrogens that are not detectable by the methods prescribed in the YF vaccine monograph. The product-specific testing was carried out by using cryopreserved and fresh whole blood, and IL-6 and IL-1ß levels were used as the marker readouts. After assessing the applicability of the MAT on a 1:10 dilution of 17DD-YFV, endotoxin and non-endotoxin pyrogens were quantified in spiked batches, by using the lipopolysaccharide and lipoteichoic acid standards, respectively. The quantitative analysis demonstrated the correlation between the MAT and the Limulus amoebocyte lysate (LAL) assays, with respect to the limits of endotoxin recovery in spiked batches and the detection of no pyrogenic contamination in commercial batches of 17DD-YFV. The data demonstrated the applicability of the MAT for 17DD-YFV pyrogen testing, and as an alternative method that can contribute to biological quality control studies.

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ABSTRACT The use of a commercial kit for the monocyte-activation test (MAT) was evaluated for assessing pyrogenic contamination of hyperimmune sera . Three batches of sera, two pyrogen free and one pyrogenic, were tested. Endotoxin spike recover indicated that sample dilutions from 1/2 to 1/10 are suitable. Kit transport and storage conditions were also evaluated, proving that an adequate cold chain must be assured to achieve good results. Furthermore, the commercial MAT kit seemed suitable to replace the rabbit pyrogen test (RPT) for pyrogen testing of hyperimmune sera, although further tests are needed to a full validation.

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Radiopharmaceuticals play an important role in modern nuclear medicine, and 18F-FDG (2-[18F] fluoro-2-deoxy-D-glucose) is the most frequently used in imaging examinations today. The pyrogen test represents an important parameter for the quality of radiopharmaceuticals since most of them, 18F-FDG included, are injectable solutions. However, the standard test proposed by the U.S. Pharmacopeia using limulus amebocyte lysates takes too long (about 1 h). An alternative test is the Portable Test System, which takes no more than 15 min. In order to compare both tests, 10 batches of 18F-FDG produced in the Nuclear Engineering Institute, Rio de Janeiro, Brazil, were analyzed. The results showed that in 40% of the samples analyzed, different results were found. From the total analyzed, 20% showed totally diverging results, and 80% demonstrated partial similarity. These differences have a great impact in the choice of the test used for radiopharmaceutical injectable solutions and the importance of validation tests before the implementation in the daily routine.

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Introdução: A reação pirogênica é desencadeada pela presença, na corrente sanguínea, de soluções contaminadas, infundidas no paciente, contendo endotoxinas ou produtos de degradação proteica. Apesar da baixa incidência, seu foco deve ser investigado e erradicado, pois essas ocorrências podem ser deletérias e refletem a qualidade do serviço prestado, já que a causa pode ser proveniente de fatores relacionados ao exame, às soluções utilizadas ou ao processo de esterilização. Método: Estudo prospectivo avaliando pacientes submetidos a procedimentos coronários percutâneos diagnósticos ou terapêuticos que desenvolveram reação pirogênica. Essa amostra foi comparada a um grupo controle de pacientes consecutivos que não apresentaram a referida intercorrência, sendo a possível causa pesquisada por meio do uso de um protocolo tipo check list...

Background: Pyrogen reactions are triggered by intravenous injection of fluids or medications contaminated by bacterial endotoxins. Despite its low incidence, it must be investigated and eliminated, as it may be harmful to the patient and reflects the quality of the catheterization laboratory. Methods: Prospective study to evaluate patients undergoing diagnostic or therapeutic percutaneous coronary procedures who develop pyrogen reactions. This group was compared with a historical cohort of patients undergoing invasive procedures with no pyrogen reactions. The possible causes of pyrogen reactions were established based on the use of a check-list protocol...

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Los pirógenos han sido y son en la actualidad uno de los principales problemas que presentan en la Industría Farmacéutica al nivel mundial y por eso varios han sido los intentos por estandarizar un método para su análisis y numerosos los esfuerzos por eliminarlos de las soluciones contaminadas. Pero sólo el método que emplea al conejo es el que se acepta internacionalmente como oficial. Con respecto a la eliminación del pirógeno podemos decir que resulta más conveniente evitarlo que suprimirlo. Los productos de origen biológico son de los que mayor complicación presentan a la hora de su análisis y en donde menos se ha profundizado. Este trabajo tiene por objetivo dar a conocer los aspectos fundamentales estudiados hasta el presente sobre los pirógenos e introducir el aspecto del mismo en la albúmina como tema que cobra en nuestro país gran actualidad

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