Standardization of conventional chemoembolization for hepatocellular carcinoma.

INTRODUCTION AND OBJECTIVES: Conventional transarterial chemoembolization (cTACE) has several limitations due to the lack of standardization. The aim of this study was to evaluate the chemical and physical characteristics and behaviors over time of emulsions for cTACE and to assess intra- and inter-operator variabilities in the preparation processes. MATERIALS AND METHODS: This in vitro study involved evaluation of emulsions for cTACE prepared using two methods: water-in-oil (WiO) and chemotherapeutic-in-oil (CiO). Three emulsions were prepared with each method and obtained after 20, 50, and 100 pumping exchanges. A drop from each final mixture was analyzed via light microscopy (time 1) and after 5, 10, 15, and 20min since the end of preparation. After 20min, all preparations were re-mixed and new drops were re-evaluated. The intra- and inter-operator variabilities were analyzed. RESULTS: The mean droplet diameter decreased non-significantly when the number of pumping exchanges increased and increased significantly over time for both WiO and CiO. The droplets returned to their initial diameters after re-mixing. There were no significant differences in the intra- and inter-operator variabilities (P>0.01). CONCLUSIONS: Any interventional radiologist, regardless of their experience, may prepare these emulsions. These data may represent a set of instructions to standardize cTACE.

Physicochemical Evaluation of Compounded Oral Preparations for Respiratory Illnesses, also known as Mezclitas.

OBJECTIVE: Compounded oral solutions for respiratory illnesses such as the common cold and cough are commonly prepared and dispensed by licensed pharmacists in the United States and Puerto Rico (PR). Standard protocols for their preparation and quality assessment and for patient counseling are available for most of the prescribed compounded solutions. However, in PR there is a common prescription approach colloquially referred to as "mezclitas": mixtures of antitussives, expectorants, decongestants, and other active ingredients available in commercial solutions for which there are no science-driven compounding guidelines for local pharmacists. METHODS: This study evaluated the physicochemical stability of a commonly dispensed compounded preparation (containing guaifenesin, dextromethorphan, and dexamethasone) that is used for the treatment of respiratory illnesses in PR. The stability indicators tested included clarity, odor, pH, and viscosity. Changes in stability indicators were evaluated for different storage conditions (ambient temperature and refrigerated) over a period of 6 months. RESULTS: The samples exhibited small changes in color, odor, and viscosity. Although the observed changes were small, they may be indicative of chemical and/or physical transformations that occurred over time. A survey of local pharmacists also evidenced the absence of standardized protocols for the preparation and dispensation of the mezclitas in PR. CONCLUSION: In spite of the absence of protocols for compounding oral solutions for respiratory illnesses, our study suggests that the stability of such solutions is not heavily compromised. However further chemical and physical testing is needed and the findings of such testing used to develop standardized protocols for the compounding of oral solutions for respiratory illnesses.

In vitro toxic evaluation of two gliptins and their main impurities of synthesis.

BACKGROUND: The presence of impurities in some drugs may compromise the safety and efficacy of the patient's treatment. Therefore, establishing of the biological safety of the impurities is essential. Diabetic patients are predisposed to tissue damage due to an increased oxidative stress process; and drug impurities may contribute to these toxic effects. In this context, the aim of this work was to study the toxicity, in 3 T3 cells, of the antidiabetic agents sitagliptin, vildagliptin, and their two main impurities of synthesis (S1 and S2; V1 and V2, respectively). METHODS: MTT reduction and neutral red uptake assays were performed in cytotoxicity tests. In addition, DNA damage (measured by comet assay), intracellular free radicals (by DCF), NO production, and mitochondrial membrane potential (ΔψM) were evaluated. RESULTS: Cytotoxicity was observed for impurity V2. Free radicals generation was found at 1000 µM of sitagliptin and 10 µM of both vildagliptin impurities (V1 and V2). A decrease in NO production was observed for all vildagliptin concentrations. No alterations were observed in ΔψM or DNA damage at the tested concentrations. CONCLUSIONS: This study demonstrated that the presence of impurities might increase the cytotoxicity and oxidative stress of the pharmaceutical formulations at the concentrations studied.

Pharmaceutical excipients properties and screw feeder performance in continuous processing lines: a Quality by Design (QbD) approach.

Screw feeder performance is a critical aspect in continuous manufacturing processes. Pharmaceutical excipients, such as mannitol, microcrystalline cellulose, lactose monohydrate, and anhydrous dibasic calcium phosphate can present problems in ensuring a continuous stable feed rate due to their sub-optimal flow properties. In alignment with Quality by Design (QbD) goals, the aim of this work was to identify and explain critical sources of variability of some powder excipients delivery by screw feeding, in particular to continuous processing lines. Pharmaceutical excipients with a wide range of material properties were selected, and the impact of their flow and density properties on screw feeder performance was investigated. The analysis of the powder conveying by the screws was performed at different hopper fills and different screw speeds. A multivariable model involving bulk density (CBD) and parameters from FT4 dynamic downwards testing (SI) and dynamic upwards testing (SE) explained 95.7% of excipients feed rates (p < .001). The study gathers valuable information about the screw feeder performance and input materials properties that can help process understanding and QbD-based development of solid dosage forms in continuous processing lines.

Chemometrics-assisted study of the interconversion between the crystalline forms of nimodipine.

Nimodipine (NIM) is a calcium channel-blocking agent, which in the solid state exhibits two crystalline modifications, Mode I and Mode II. The first one is a racemic mixture, while the second is a conglomerate. Because the drug has poor aqueous solubility and Mode I is twice as soluble as Mode II, the former is widely preferred for the development of pharmaceutical forms. In order to study the effect of thermal stimuli on the behavior of NIM, an analytical method was developed coupling ATR-FTIR spectroscopy to Multivariate Curve Resolution with Alternating Least Squares (MCR-ALS). The method allowed to monitor the transformations of each polymorph, their respective mixtures and commercial samples, during the thermal treatment. It was observed that Mode II experienced changes during the experiments and the chemometric technique provided the abundance profile and the pure spectra of the different species involved. In this way, it was established that Mode II has two transitions, at 116.8 °C and 131.9 °C, which reflect that Mode II is first transformed into Mode I, which then melts. The liquid phase solidifies to give an amorphous (AM) vitreous solid, which does not revert to the crystalline state. The analysis of a commercial sample of NIM exhibited the similar transformations than Mode II; however, a pronounced decrease was noted in the first transition temperature (95 °C), whereas the second remained essentially unchanged (131.6 °C). This could be a result of the presence of mixtures of Mode I and Mode II (0.32:0.68) in the bulk solid, as confirmed by the analysis of a physical mixture of crystals of Modes I and II. Therefore, it was concluded that the developed ATR-FTIR/MCR-ALS method is suitable for the detailed analysis of the crystalline forms of NIM in bulk drug and enables de study of their possible thermally promoted interconversions.

Assessment of the preparation and administration of oral medications to institutionalized children.

OBJECTIVE: to evaluate the preparation and administration of oral medications to institutionalized children by nursing professionals. METHOD: quantitative study, developed from August to September 2016, in a shelter in Fortaleza, Ceará. 323 observations of preparation and administration of oral drugs were carried out. Interview and non-participant direct observation of the process of drug administration were performed, whose data were analyzed through descriptive statistics. RESULTS: Of the 29 actions of preparation and administration of the drugs, ten were considered satisfactory. Sanitizing of hands before touching the pills occurred in only 5.2% of the observations and cleansing of the bottle for liquid drugs was performed in 23.8%. The actions "check the right child"; "checking medication with the prescription", and "check the right dose" obtained percentages below 15%. CONCLUSION: measures recommended by the literature for the administration of medication were not, in their clear majority, followed, making specific training and protocols necessary.

Assessment of the preparation and administration of oral medications to institutionalized children / Evaluación del preparo y de la administración de medicinas orales a los niños institucionalizados / Avaliação do preparo e da administração de medicamentos orais às crianças institucionalizadas

ABSTRACT Objective: to evaluate the preparation and administration of oral medications to institutionalized children by nursing professionals. Method: quantitative study, developed from August to September 2016, in a shelter in Fortaleza, Ceará. 323 observations of preparation and administration of oral drugs were carried out. Interview and non-participant direct observation of the process of drug administration were performed, whose data were analyzed through descriptive statistics. Results: Of the 29 actions of preparation and administration of the drugs, ten were considered satisfactory. Sanitizing of hands before touching the pills occurred in only 5.2% of the observations and cleansing of the bottle for liquid drugs was performed in 23.8%. The actions "check the right child"; "checking medication with the prescription", and "check the right dose" obtained percentages below 15%. Conclusion: measures recommended by the literature for the administration of medication were not, in their clear majority, followed, making specific training and protocols necessary.

RESUMEN Objetivo: evaluar el preparo y la administración de medicinas orales por profesionales de enfermería a niños institucionalizados. Método: estudio cuantitativo desarrollado en agosto y septiembre de 2016, en un refugio de niños de Fortaleza, Ceará. Fueron realizadas 323 observaciones del preparo y de la administración de medicinas. Se realizaron encuesta y observación directa en el participante del proceso de administración de las medicinas, cuyos datos fueron evaluados por la estadística descriptiva. Resultados: de entre las 29 acciones del preparo y de la administración de las medicinas, diez fueron consideradas satisfactorias. La higienización de las manos antes de manosear las pastillas ocurrió en el 5,2% de las observaciones y la limpieza de los frascos de medicinas se dio en el 23,8%. Las acciones "verificar el niño bien"; "verificar la medicina con la prescripción" y "certificar la dosis correcta" obtuvieron porcentuales inferiores al 15%. Conclusión: medidas recomendadas por la literatura para administración de medicinas no fueron, en su gran parte, adoptadas, convirtiéndose necesarias las capacitaciones y los protocolos específicos.

RESUMO Objetivo: avaliar o preparo e a administração de medicamentos orais por profissionais de enfermagem a crianças institucionalizadas. Método: estudo quantitativo desenvolvido em agosto e setembro de 2016, em um abrigo de Fortaleza, Ceará. Foram realizadas 323 observações do preparo e da administração de medicamentos. Realizaram-se entrevista e observação direta não participante do processo de administração dos medicamentos, cujos dados foram avaliados pela estatística descritiva. Resultados: dentre as 29 ações do preparo e da administração dos medicamentos, dez foram consideradas satisfatórias. A higienização das mãos antes de tocar em comprimidos ocorreu em 5,2% das observações e a limpeza dos frascos de medicamentos deu-se em 23,8%. As ações "conferir a criança certa"; "conferir o medicamento com a prescrição" e "verificar a dose certa" obtiveram percentuais inferiores a 15%. Conclusão: medidas recomendadas pela literatura para administração de medicamentos não foram, em maioria, adotadas, tornando-se necessários treinamentos e protocolos específicos.

Biosimilars in psoriasis: Clinical practice and regulatory perspectives in Latin America.

Latin American countries view biosimilar agents as an effective approach to curtail health-care expenditures while maintaining the safety and efficacy profile of their branded innovator comparators. To understand the complexities of the regulatory landscape and key therapeutic issues for use of biosimilars to treat moderate to severe psoriasis in Latin America, the International Psoriasis Council convened dermatology experts from Argentina, Brazil, Chile, Colombia and Mexico in October 2015 to review the definition, approval, marketing and future of biosimilars in each country and develop a consensus statement. The regulatory framework for marketing approval of biosimilars in Latin America is currently a mosaic of disparate, country-specific, regulatory review processes, rules and standards, with considerable heterogeneity in clarity and specificity. Regulations in Argentina, Brazil, Chile and Mexico have undergone multiple refinements whereas Colombia is finalizing draft guidelines. Verification of the similarity in quality, safety and efficacy of biosimilars to the innovator biologic remains a key challenge for policy makers and regulatory authorities. Other key regulatory challenges include: naming of agents and traceability, pharmacovigilance, extrapolation of indications, and interchangeability and substitution. An urgent need exists for more Latin American countries to establish national psoriasis registries and to integrate their common components into a multinational psoriasis network, thereby enhancing their interpretative power and impact. A Latin American psoriasis network similar to PSONET in Europe would assist health-care providers, pharmaceutical companies, regulators and patients to fully comprehend specific products being prescribed and dispensed and to identify potential regional trends or differences in safety or outcomes.

Desarrollo tecnológico y estudio de estabilidad de una formulación de oxaliplatino 100 mg, solución inyectable / Technological development and stability study of a 100 mg oxaliplatinum formulation in injectable solution

Introducción: el oxaliplatino, es un análogo de los complejos derivados del platino en el cual el átomo de platino central está rodeado por un oxalato y en posición trans el 1,2‒diaminociclohexano. La cinética de enlace del oxaliplatino sobre el ADN se produce en 15 minutos como máximo y en comparación con el cisplatino presenta una cinética bifásica de 4 a 8 horas y demuestra mayor eficacia sobre ciertos tumores. Objetivo: diseñar una formulación de oxaliplatino, solución inyectable, conteniendo 100 mg del ingrediente activo por bulbo, que cumpla con los índices de calidad para esta forma farmacéutica y proporcione el efecto terapéutico deseado. Métodos: se realizaron los estudios de formulación correspondientes y se ensayaron cinco variantes tecnológicas, en las que se ajustó el pH de la formulación según las exigencias de un preparado parenteral. Se efectuó un estudio de temperatura, para lograr la disolución del principio activo, sin que se afectaran sus propiedades, dada su poca solubilidad en medio acuoso. Se estudiaron diferentes materiales de envase y temperaturas de conservación del producto, además se estandarizó una técnica analítica por Cromatografía Líquida de Alta Resolución para la estabilidad de la formulación, determinar su fecha de vencimiento y para su control de la calidad. Resultados: el desarrollo tecnológico resultó satisfactorio, en una de las variantes ensayadas, se obtuvo un producto que cumple con todas las especificaciones descritas en la monografía para el control de la calidad del preparad, mantiene sus propiedades físicas, químicas y microbiológicas inalterables por un período de 18 meses, almacenada a temperatura ambiente, con un escalado a nivel piloto, sin que se presentaran problemas tecnológicos. Conclusiones: se obtuvo la formulación de un medicamento en forma de solución inyectable, que contiene oxaliplatino como principio activo, que cumple con todas las especificaciones de calidad para este tipo de forma farmacéutica, lo que aumenta arsenal terapéutico de Cuba(AU)

Introduction: oxaliplatinum is an analogue of the platinum-derived complexes in which the central platinum atom is surrounded by an oxalate and 1,2?diaminocyclohexane in transposition. The link kinetics of oxaliplatinum on the DNA occurs in 15 minutes at most and if compared with the cysplatinum, it presents a 4-8 h biphasic kinetics and higher efficacy over certain tumors. Objective: to design an oxaliplatinum formulation, for injection solution that contains 100mg of the active ingredient per ampoule, comply with the quality parameters for this pharmaceutical form and provides the desired therapeutic effect. Methods: the corresponding formulation studies were performed together with the testing of five technological variants in which the formulation pH was adjusted according to the requirements of a parenteral product. A temperature study was also conducted to reach dissolving the active principle without any damage to its properties, given that it is poorly water-soluble. Different packing materials and storage temperatures of the product were studied in addition to standardizing an analytical technique based on high performance liquid chromatography for the stability of the formulation, estimation of the expiry date and for the quality control. Results: the technological development was satisfactory in one of the tested variants. The obtained product complied with all the described specifications in the monograph for the quality control of the product; its physical, chemical and microbiological properties remained unchanged for a period of 18 months and stored at room temperature, with pilot scale-up with no further technological problems. Conclusions: there was obtained the formulation of a drug in its injectable form that contains oxaliplatinum as active ingredient, complies with all the quality specifications for this pharmaceutical form and increases the therapeutical arsenal available in Cuba(AU)

Enfoque basado en riesgo desde la etapa de desarrollo del producto succinilcolina infantil 100 mg / Risk-based approach from the development phase of 100mg infant succinylcoline product

Introducción: en la actualidad las guías emitidas por la Agencia de Medicamentos y Alimentos, de los EU considera que los procesos fallan porque las fuentes no son debidamente identificadas, eliminadas o controladas y plantean un nuevo enfoque de Buenas Prácticas de Producción basado en riesgos. Objetivo: aplicar un enfoque basado en riesgos en el aseguramiento de la calidad desde la etapa de desarrollo del producto succinilcolina 100 mg. Métodos: se realizó una breve descripción del proceso mediante un diagrama de bloque, se empleó el Árbol de Fallas como herramienta para identificar las posibles fuentes de falla; la valoración de riesgos partiendo de la identificación de las posibles fuentes de fallos se ejecutó a través de un método matricial. Se identificó un orden de prioridad en la toma de acciones correctivas para eliminar o mitigar el riesgo de ocurrencia. Resultados: el diagrama de bloque permitió tener un conocimiento sobre el proceso, lo que contribuyó de forma decisiva a un mejor ejercicio de la gestión de riesgos. El Árbol de Fallas resultó útil al revelar de forma gráfica las diferentes combinaciones de fallos e interrelaciones entre causa y efecto que pudieran dar lugar al evento tope indeseado. El método empleado para la valoración de riesgos permitió determinar las prioridades, siendo el tiempo extensivo de llenado (fuera de 2-8 °C) el componente crítico a considerar con especial atención; si se tiene en cuenta que la estabilidad de este producto se puede afectar a temperaturas superiores a estas, por lo que disponer de un plan de acciones correctivas acorde a los riesgos identificados permitirá la eliminación o mitigación de las mismas. Conclusiones: la herramienta de gestión de riesgos permitió identificar desde la etapa de desarrollo del producto succinilcolina 100 mg, las principales fuentes de fallas relacionadas con este proceso(AU)

Introduction: the guidelines presently issued by the Food and Drug Agency of the United States considers that processes fail because the sources are not duly identified, eliminated or controlled and submit a new approach of Good Manufacture Practice based on risks. Objective: to apply a risk-based approach to the quality assurance from the development phase of the 100 mg succinylcoline product. Methods: the process was briefly described through a block diagram with Failure Tree as a tool for identification of possible sources of failures; the risk assessment based on the detection of the possible sources of failures was made with the matrix method. An order of priority was given in the implementation of corrective actions to eliminate or mitigate the risk of occurrence. Results: the block diagram allowed knowing the process, which contributed in a decisive way to a better application of risk management. The Failure Tree proved to be useful when showing in a graphical way the different failure combinations and interrelations between cause and effect that might give rise to the unwanted top event. The method for the risk assessment made it possible to determine priorities, being the long time of filling (not within 2 to 8oC) the critical component to be specially considered if one takes into account that stability of the product may be affected by higher temperatures, therefore, a plan of corrective actions according to the identified risks will allow their elimination or mitigation. Conclusions: the risk management tool allowed identifying the main process-related sources of failures from the very development phase of the 100 mg succinylcoline product.

Quality assessment of compounded 17-hydroxyprogesterone caproate.

OBJECTIVE: The purpose of this study was to evaluate the quality of compounded 17-hydroxyprogesterone caproate (17-OHPC). STUDY DESIGN: Compounded 17-OHPC that was obtained from 15 compounding pharmacies throughout the United States was analyzed for potency, impurities, sterility, and pyrogen status. RESULTS: Eighteen samples were supplied by 15 compounding pharmacies. The concentration of 17-OHPC in all samples was within the specification limits, and all tested samples passed sterility and pyrogen testing. Only 1 of 18 samples was out of specification limits for impurities. CONCLUSION: Compounded 17-OHPC that was obtained from 15 pharmacies throughout the United States did not raise safety concerns when assessed for potency, sterility, pyrogen status, or impurities.

Brazilian National System for the Monitoring and Improvement of Compounding Practices: program outcomes.

Compounding pharmacies in Brazil have to comply with a complex and strict set of drug manufacturing regulations. The authors reported in the International Journal of Pharmaceutical Compounding (November/December 2009, Volume 13, Issue 6) on the development and implementation of a National System for the Monitoring and Improvement of Compounding Practices in Brazil, a process-focused program aiming to help compounding pharmacies improve drug manufacturing processes and meet the standards set forth by the applicable legislation This article reports the results obtained in the first three editions of the National System for the Monitoring and Improvement of Compounding Practices in Brazil (2006-2010) and presents new foci explored in the 2011 cycle. The results obtained over the years demonstrate that participating in the National System for the Monitoring and Improvement of Compounding Practices in Brazil has helped pharmacies achieve legal compliance and improve the quality of their preparations, which has contributed substantially to meeting quality standards never before achieved in the compounding sector in Brazil.

[Identification and analysis of errors in the preparation of drugs in a pediatric hospital unit]. / Identificação e análise de erros no preparo de medicamentos em uma unidade pediátrica hospitalar.

This study aims to identify and analyze errors in the preparation of medicines in the pediatric unit of a hospital. This descriptive study was performed withfour professionals responsible for the preparation of medicines developed in a hospital in the interior of Minas Gerais, Brazi. They were submitted to the technique of structural observation and formulary. A descriptive analysis of the data was performed. The results highlight the lack of guidelines for the preparation of drugs, presence of interruptions during theprocess, failure in the utilization of recommended hand washing techniques and disinfection of bottles and vials. It is necessary to make professionals aware of the occurrence and consequences of the main mistakes made by the team, as a stimulus for prevention through safe and effective practices to improve the quality of care.

[Bacteriological quality of air in a ward for sterile pharmaceutical preparations]. / Calidad microbiológica del aire de una unidad de preparados farmacéuticos estériles.

BACKGROUND: An extremely clean area is required for preparation of sterile pharmaceutical compounds, in compliance with international standards, to minimize the probability of microbial contamination. AIM: To evaluate the bacteriological quality of the air in the Sterile Pharmaceutical Preparation Unit of the University of Chile's Clinical Hospital and to set up alerts and action levels of bacterial growth. METHODS: We studied eight representative sites of our Unit on a daily basis from January to February 2005 and twice a week from June 2005 to February 2006. We collected 839 samples of air by impact in the Petri dish. RESULTS: 474 (56.5%) samples were positive; 17 (3.5%) of them had an inappropriate bacterial growth (2% of total samples). The samples from sites 1 and 2 (big and small biosafety cabinets) were negative. The countertop and transfer area occasionally exceeded the bacterial growth limits. The most frequently isolated bacteria were coagulase-negative staphylococci, Micrococcus spp and Corynebacterium spp, from skin microbiota, and Bacillus spp, an environmental bacteria. CONCLUSIONS: From a microbiological perspective, the air quality in our sterile preparation unit complied with international standards. Setting institutional alerts and action levels and appropriately identifying bacteria in sensitive areas permits quantification of the microbial load and application of preventive measures.

Identificação e análise de erros no preparo de medicamentos em uma unidade pediátrica hospitalar / Identificación y análisis de errores en la preparación de las drogas en una unidade de hospital pediátrico / Identification and analysis of errors in the preparation of drugs in a pediatric hospital unit

Este estudo objetivou identificar e analisar os erros no preparo de medicamentos em unidade pediátrica de uma instituição hospitalar. Trata-se de estudo descritivo, realizado com quatro profissionais responsáveis pelo preparo dos medicamentos de um hospital do interior do Estado de Minas Gerais, que foram submetidos à técnica de observação estruturante e formulário. Utilizou-se a análise descritiva junto aos dados. Como resultados, destacam-se a inexistência de diretrizes para o preparo de medicamentos, presença de interrupções durante o processo, não utilização das técnicas de lavagem das mãos e de desinfecção de frascos e ampolas. Faz-se necessária a conscientização dos profissionais para a ocorrência e consequências dos erros cometidos pela equipe, como forma de estímulo para a prevenção dos mesmos, através de práticas seguras e efetivas, a fim de ampliar a qualidade da assistência.

Este estudio tuvo como objetivo identificar y analizar los errores en la preparación de medicamentos en la unidad de pediatría de un hospital. Este es un estudio descriptivo con 04 personas responsables de la preparación de medicamentos en una institución hospitalaria del interior de Minas Gerais, Brasil, que se sometieron a la técnica de observación estructurante y un formulario. El análisis descriptivo fue utilizado junto a los datos. Los resultados destacan la falta de directrices para la preparación de las drogas, la presencia de las interrupciones durante el proceso, no utilice las técnicas de lavado de manos y desinfección de botellas y frascos. Es necesario la toma de consciencia de los profesionales a la ocurrencia y las consecuencias de los principales errores realizados por el equipo, como un estímulo para la prevención a través de prácticas seguras y eficaces para mejorar la calidad de la atención.

This study aimed to identify and analyze errors in the preparation of medicines in the pediatric unit of a hospital. This descriptive study was performed with 04 professionals responsible for preparation of medicines developed in a hospital in the interior of Minas Gerais, Brasil, that were submitted to the technique of structural observation and formulary. A descriptive analysis of the data was performed. The results highlight the lack of guidelines for the preparation of drugs, presence of interruptions during the process failure of utilization of recommended hand washing techniques, and disinfection of bottles and vials. It is necessary to make professionals aware of the occurrence and consequences of the main mistakes made by the team, as a stimulus for prevention through safe and effective practices to improve the quality of care.