Immune checkpoint inhibitors for the treatment of non-small cell lung cancer: The regulatory journey in Brazil.

BACKGROUND: Recent therapeutic advances such as immune checkpoint inhibitors (ICIs) have impact on the care of non-small cell lung cancer (NSCLC) patients, however, they bring new setbacks for regulatory agencies. OBJECTIVE: To evaluate the regulatory journey of ICIs registered for NSCLC treatment in Brazil and to establish comparisons of Brazilian regulatory agency with the US regulatory agency. METHODS AND DATA SOURCE: Information for each ICI prescribing as well as the date of regulatory approval of the therapeutic indications of interest were collected from the Anvisa and the FDA websites. The search took place on October 2022. KEY FINDINGS: There are only 20 % disagreements on regulatory approvals between Anvisa and FDA. The prioritization review at Anvisa in 2008 has made the regulatory assessment faster. CONCLUSIONS: The results of this study identified a potential improvement in Anvisa's time performance to connect the target established by the legal framework of the sector.

Advanced Therapy Products in Brazil: Regulatory Aspects.

Advanced therapy products, considered special medications, require Anvisa approval for use and commercialization in Brazil. They include advanced cellular therapy products, tissue engineering products, and gene therapy products, which due to their complexity involve innovation and risks, optimized regulatory channels for their development and life cycle monitoring. The scientific elements and the compliance with applicable regulatory aspects are fundamental pillars for the advancement of clinical trials, the positive evidence of the benefit-risk profile, and the definition of the critical quality attributes, from the perspective of making safe, efficacy, and high-quality products available to the population. The approval models of these products in Brazil adapt to the specificities and characteristics of the technology and the patient target population, with accelerated regulatory analyses, use in emergency situations by risk controls and specific monitoring mechanisms, principally those related to rare diseases without other therapeutic alternatives. The opportune access to the advance therapy product with safety, efficacy, and quality involves innovative normative elements that include the long-term follow-up of the safety and efficacy and of the adaptive pharmacovigilance requisites, as well as the traceability mechanisms for starting materials, products, and patients.

Recall of substandard medicines in Brazil during the period 2010-2018.

BACKGROUND: Even with all the care taken during the production process, the pharmaceutical industries are still subject to manufacturing medicines with quality deviations, generating commercialized products without the required quality and necessitating their subsequent recall from the market. The objective of this study was to evaluate the reasons that led to the recall of medicines in Brazil in the period evaluated. METHODS: This is a descriptive study (using document analysis), on the recall of substandard medicines registered on the website of the National Health Surveillance Agency (ANVISA), from 2010 to 2018. The variables studied were the type of medicine (reference, generic, similar, specific, biological, herbal, simplified notification, new and radiopharmaceutical), type of pharmaceutical dosage form (solid, liquid, semi-solid and parenteral preparation), and reason for recall (Good manufacturing practices, quality and quality/good manufacturing practices). RESULTS: A total of n = 3,056 recalls of substandard medicine were recorded. Similar medicines had a higher recall index (30.1%), followed by generics (21.3%), simplified notification (20.7%) and reference (12.2%). Different dosage forms had similar recalls: solids (35.2%), liquids (31.2%) and parenteral preparations (30.0%), with the exception of semi-solids (3.4%). The reasons for the highest occurrences were related to good manufacturing practices (58.4%) and quality (40.4%). CONCLUSION: The probable cause for this high number of recalls is the fact that, even with all the quality controls and processes in accordance with good manufacturing practices, errors can occur, both human and in automated processes, thus causing the release of batches that should not have been approved. In summary, it is necessary for manufacturers to implement a robust and well structured quality system in order to avoid such deviations, and it is up to ANVISA to apply greater oversight in the post marketing of these products.

Naltrexona em baixa dose (LDN): tendência de consumo nas capitais brasileiras e Distrito Federal, 2014-2020 / Low-dose naltrexone (LDN): consumption trend in Brazilian capitals and the Federal District, 2014-2020

Resumo Estudo ecológico com objetivo de determinar o consumo de naltrexona em baixa dose (LDN) nas 26 capitais brasileiras e Distrito Federal e acompanhar a tendência entre os anos de 2014 e 2020. A coleta de dados da dispensação de naltrexona manipulada, se deu por meio do Sistema Nacional de Gerenciamento de Produtos Controlados, publicizado em 2020, considerando-se baixa dose prescrições de até 5 mg. O cálculo dos coeficientes de dispensação utilizou as estimativas populacionais do Instituto Brasileiro de Pesquisa Geografia e Estatística. Utilizou-se análise estatística descritiva e de regressão generalizada de Prais-Winsten para a série temporal. As tendências observadas foram classificadas em crescentes, estáveis ou decrescentes, com intervalo de confiança de 95% e nível de significância de 5%. Os resultados demonstraram maiores coeficientes de consumo de LDN nas regiões Centro-Oeste, Sul e Sudeste e menores nas Norte e Nordeste. Observou-se dispensação de LDN crescente em 55,6% das capitais, estacionária em 44,4% e ausência de coeficientes decrescentes. Apesar das evidências limitadas quanto à farmacoterapia de LDN e da sua prescrição off-label, os dados demonstram que a prescrição, dispensação e consumo vem crescendo no Brasil, com ênfase nas regiões centro-sul do país.

Abstract The scope of this paper is an ecological study to determine the consumption of low-dose naltrexone (LDN) in the 26 Brazilian capitals and the Federal District and monitor the trend between the years 2014 to 2020. Data collection on the dispensation of manipulated naltrexone was done through the National Management System of Controlled Products, published in 2020, considering low-dose prescriptions of up to 5 mg. The calculation of the dispensation coefficients used the population estimates of the Brazilian Institute of Geography and Statistics. Descriptive statistical analysis and generalized Prais-Winsten regression analysis were used for the time series analysis. The trends observed were classified as increasing, stable, or decreasing, with a 95% confidence interval and 5% significance level. The results showed higher LDN consumption coefficients in the Mid-West, South and Southeast regions and lower coefficients in the North and Northeast. Increasing dispensation of LDN was observed in 55.6% of the capitals, being stationary in 44.4%, with no decreasing coefficients. Despite the limited evidence regarding LDN pharmacotherapy and its off-label prescription, the data show that prescription, dispensing, and consumption have been on the increase in Brazil, with emphasis on the central-south regions of the country.

Difusão de política na prática: o caso da regulação brasileira de medicamentos / Difusión de políticas en la práctica: el caso de la regulación brasileña de medicamentos / Policy diffusion in practice: the case of Brazilian medicinal products regulation

Resumo O presente estudo busca contribuir para a melhor compreensão de processos de difusão de política com base em arenas transnacionais - mais especificamente, do processo de difusão que influenciou a regulação das Boas Práticas de Fabricação (BPF) de medicamentos no Brasil num contexto envolto por atores internacionais. Por meio de pesquisa qualitativa, analisamos o processo de adesão da Agência Nacional de Vigilância Sanitária (Anvisa) ao arranjo de cooperação Pharmaceutical Inspection Co-operation Scheme (PIC/S), iniciado em 2010 e alcançado em 2021. Foi identificado um processo influenciado por 2 constelações de difusão, motivado por interesses da agência nacional em manter sua relevância e por atores que integram o Sistema Nacional de Vigilância Sanitária, no qual o modelo de equivalência e convergência regulatória do PIC/S se mostrou fundamental para a adaptação da referência internacional em nível nacional, mantendo o sistema em funcionamento. Tal processo de difusão de política ficou mais relevante nos últimos anos por ampliar a convergência regulatória e, potencialmente, tornar mais eficiente a avaliação das BPF de medicamentos pelas diversas autoridades sanitárias.

Resumen El presente estudio pretende contribuir a una mejor comprensión de los procesos de difusión de políticas, más concretamente, del proceso de difusión que influyó en la regulación de las Buenas Prácticas de Fabricación (BPF) de medicamentos en Brasil, a partir de arenas transnacionales. A través de una investigación cualitativa, analizamos el proceso de adhesión de la Agencia Nacional de Vigilancia Sanitaria (Anvisa) al Esquema de Cooperación de Inspección Farmacéutica (PIC/S), iniciado en 2010 y alcanzado en 2021. Se identificó un proceso influenciado por dos constelaciones de difusión, motivado por el interés de la agencia nacional en mantener su relevancia y por los actores que componen el Sistema Nacional de Vigilancia Sanitaria, en el que el modelo de equivalencia y convergencia normativa del PIC/S resultó fundamental para la adaptación de la referencia internacional al ámbito nacional, manteniendo el sistema nacional en funcionamiento. Este proceso de difusión de políticas adquirió aún más relevancia en años recientes al ampliar la convergencia normativa y hacer potencialmente más eficiente la evaluación de las BPF de los medicamentos por parte de las distintas autoridades sanitarias.

Abstract The present study seeks to contribute to a better understanding of policy diffusion processes, more specifically, of the diffusion process from a transnational arena that influenced the regulation of Good Manufacturing Practices (GMP) for medicinal products in Brazil in a context surrounded by international authorities. By conducting qualitative research, we analyzed the process of adhesion of the Brazilian Health Regulatory Agency (Anvisa) to the Pharmaceutical Inspection Co-operation Scheme (PIC/S), initiated in 2010 and achieved in 2021. A process influenced by two constellations of diffusion was identified, motivated by the national agency's interests in maintaining its relevance and by actors that make up the National Sanitary Surveillance System, in which the PIC/S model of regulatory equivalence and convergence proved to be fundamental for the adaptation of the international reference to the national level, keeping the national system functioning. Such a policy diffusion process became even more relevant in the past years due to the expansion of regulatory convergence and potentially making the various health authorities' GMP assessment of medicinal products more efficient.

Elaboration of guideline for monitoring in relative bioavailability / pharmaceutical bioequivalence study by the sponsor / Elaboração de diretriz para monitoramento em biodisponibilidade relativa / estudo de bioequivalência farmacêutica pelo patrocinador / Elaboración de la directriz para el seguimiento en la biodisponibilidad relativa / estudio de bioequivalencia farmacéutica por parte del promotor

For registration of generic and similar drugs, it is necessary to carry out pharmaceutical equivalence (PE) tests and pharmaceutical bioequivalence (PB). To carry out these tests, duly qualified research centers are contracted, which need to be monitored by the sponsor who is legally responsible for the activities. To this end, it is the recommendation of the Document of the Americas, periodic monitoring to verify compliance with quality requirements, Standard Operating Procedures, Good Clinical Practices (GCP), Good Laboratory Practices (GLP), of the applicable regulatory framework, as well as of compliance with the study protocol. Thus, monitoring is a methodical and documented process to evaluate the degree of adhesion of the center to the planned design for the evaluation of the formulations. To this end, the implementation of a standardized and easily completed guideline is a very important tool to guarantee a consistent evaluation and maintain the organizational memory of the evaluated items by monitors designated by the sponsor, contributing to the constant improvement of the contracted centers and supporting traceability of the studies. This work provided a systemic view of the evidence process related mainly to pharmaceutical bioequivalence, with the monitoring guideline summarizing the items of greatest relevance to be verified.

Para registro de medicamentos genéricos e similares, é necessária a realização de testes de equivalência farmacêutica (EF) e bioequivalência farmacêutica (BF). Para a realização desses testes, são contratados centros de pesquisa devidamente habilitados, que precisam ser monitorados pelo patrocinador legalmente responsável pelas atividades. Há também a recomendação do Documento das Américas de realizar monitoramentos periódicos para verificar o cumprimento dos requisitos de qualidade, Procedimentos Operacionais Padrão, Boas Práticas Clínicas (BPC), Boas Práticas de Laboratório (BPL), de marco regulatório aplicável, bem como de cumprimento do protocolo do estudo. Assim, o monitoramento é um processo metódico e documentado para avaliar o grau de adesão do centro ao desenho planejado para a avaliação das formulações. Para tanto, a implantação de uma diretriz padronizada e de fácil preenchimento é uma ferramenta muito importante para garantir uma avaliação consistente e manter a memória organizacional dos itens avaliados por monitores designados pelo patrocinador, contribuindo para a melhoria constante dos centros contratados e apoiando rastreabilidade dos estudos. Este artigo forneceu uma visão sistêmica do processo de evidência relacionado principalmente à bioequivalência farmacêutica, com a diretriz de monitoramento resumindo os itens de maior relevância a serem verificados.

Para el registro de medicamentos genéricos y similares, es necesario realizar pruebas de equivalencia farmacéutica (EP) y de bioequivalencia farmacéutica (PB). Para llevar a cabo estas pruebas se contratan centros de investigación debidamente cualificados, que deben ser supervisados por el promotor, que es el responsable legal de las actividades. Para ello, es la recomendación del Documento de las Américas, el monitoreo periódico para verificar el cumplimiento de los requisitos de calidad, los Procedimientos Operativos Estándar, las Buenas Prácticas Clínicas (BPC), las Buenas Prácticas de Laboratorio (BPL), del marco regulatorio aplicable, así como del cumplimiento del protocolo del estudio. Así, la monitorización es un proceso metódico y documentado para evaluar el grado de adhesión del centro al diseño previsto para la evaluación de las formulaciones. Para ello, la implantación de una pauta estandarizada y de fácil cumplimentación es una herramienta muy importante para garantizar una evaluación consistente y mantener la memoria organizativa de los elementos evaluados por parte de los monitores designados por el promotor, contribuyendo a la mejora constante de los centros contratados y apoyando la trazabilidad de los estudios. Este trabajo proporcionó una visión sistémica del proceso de evidencia relacionado principalmente con la bioequivalencia farmacéutica, con la pauta de monitoreo que resume los ítems de mayor relevancia a ser verificados.

Brazil's Regulatory Context for Using New Approach Methodologies (NAMs) on the Registration of Products.

New Approach Methodologies (NAMs) are any non-animal-based approaches that can provide information in the context of chemical hazard and safety assessment. The goal is to develop information with equivalent or better scientific quality and relevance than that provided by traditional animal models. Starting with ethical issues, these approaches are gaining regulatory relevance in different global agencies. Since 2008, with the enactment of the Arouca Law-the first Brazilian legislation dedicated to laboratory animals, NAMs are gathering pace in Brazil's regulations. Specific regulations from different sectors include the acceptance of these new methods. However, some regulation is controversial about what is needed to address specific toxicological endpoints. The resulting regulatory uncertainty induces companies to keep on adopting the traditional methods, slowing NAM's development in the country. This work brings a perspective on the regulatory acceptance of NAMs in Brazilian Legislation for the registration of pharmaceuticals, medical devices, food/supplements, and agrochemical products. This text discusses the main issues of NAM adoption for each specific regulation. Therefore, legal acceptance of NAMs results in Brazil is still a process in progress. A collective effort including regulators, industry, contract research organizations (CROs), and the academic environment is needed to build regulatory confidence in the use of NAMs.

COVID-19 and zoonoses in Brazil: Environmental scan of one health preparedness and response.

The emergence of the COVID-19 pandemic reinforced the central role of the One Health (OH) approach, as a multisectoral and multidisciplinary perspective, to tackle health threats at the human-animal-environment interface. This study assessed Brazilian preparedness and response to COVID-19 and zoonoses with a focus on the OH approach and equity dimensions. We conducted an environmental scan using a protocol developed as part of a multi-country study. The article selection process resulted in 45 documents: 79 files and 112 references on OH; 41 files and 81 references on equity. The OH and equity aspects are poorly represented in the official documents regarding the COVID-19 response, either at the federal and state levels. Brazil has a governance infrastructure that allows for the response to infectious diseases, including zoonoses, as well as the fight against antimicrobial resistance through the OH approach. However, the response to the pandemic did not fully utilize the resources of the Brazilian state, due to the lack of central coordination and articulation among the sectors involved. Brazil is considered an area of high risk for emergence of zoonoses mainly due to climate change, large-scale deforestation and urbanization, high wildlife biodiversity, wide dry frontier, and poor control of wild animals' traffic. Therefore, encouraging existing mechanisms for collaboration across sectors and disciplines, with the inclusion of vulnerable populations, is required for making a multisectoral OH approach successful in the country.

Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular Consensus on genetically modified cells. Special Article: Advanced therapy medicinal products in Brazil: regulatory panorama.

Advanced therapy medicinal products, considered special medications, requires Anvisa approval for use and commercialization in Brazil. They include the advanced cellular therapy products, tissue engineering products and gene therapy products, which due to their complexity involve innovation and risks, optimized regulatory channels for their development and life cycle monitoring. The scientific elements and the compliance with applicable regulatory aspects are fundamental pillars for the advancement of clinical trials, the positive evidence of the benefit-risk profile and the definition of the critical quality attributes, from the perspective of making safe, effective and high-quality products available to the population. The approval models of these products in Brazil adapt to the specificities and characteristics of the technology and the patient target population, with accelerated regulatory analyses, use in emergency situations by risk controls and specific monitoring mechanisms, principally those related to rare diseases without other therapeutic alternatives. The opportune access to the advance therapy product with safety, efficacy and quality involves innovative normative elements that include the long-term follow-up of the safety and efficacy and of the adaptive pharmacovigilance requisites, as well as the traceability mechanisms for the start-off materials, products and patients.

Mapeamento dos domínios da ANVISA para o padrão ISO IDMP / Mapping of ANVISA domains to the ISO IDMP standard / Mapeo de dominios de ANVISA al estándar ISO IDMP

Objetivo: Apresentar o mapeamento entre vocabulários controlados da Agência Nacional de Vigilância Sanitária (ANVISA) para listas do European Directorate for the Quality of Medicines and Healthcare (EDQM). Método: O mapeamento obedeceu aos princípios da ABNT NBR ISO 12300. Resultados: Foram mapeadas as listas: Via de Administração, Forma Farmacêutica e Embalagem. 47% dos mapeamentos foram classificados com grau de equivalência 4, onde o conceito fonte foi mais restrito com mais significado específico que o conceito/termo alvo. Conclusão: Entende-se que este estudo fornece subsídios para a ANVISA prosseguir no trabalho de harmonização das listas locais com o padrão IDMP.

Objective: To present the mapping between controlled Brazilian Health Regulatory Agency (ANVISA) vocabularies for European Directorate for the Quality of Medicines and Healthcare (EDQM) lists. Method: The mapping followed the principles described in the ABNT NBR ISO 12300. Results: Terms of three lists were mapped: Routes of Administration, Pharmaceutical Dose Forms and Packaging. Almost half of the mappings were classified with equivalence grade 4 meaning that the source concept was more restricted with more specific meaning than the target concept / term. Conclusion: This work provides the necessary subsidies for ANVISA to proceed with the work of harmonizing local lists with the IDMP standard.

Objetivo: Presentar el mapeo entre vocabularios controlados de Agencia Nacional de Vigilancia Sanitaria (ANVISA) para listas European Directorate for the Quality of Medicines and Healthcare (EDQM). Método: El mapeo siguió los principios descritos en lo estándar ABNT NBR ISO 12300. Resultados: Se mapearon los términos de las listas: Vía de administración, Forma farmacéutica y Embalajes. La mayoría se clasificaron como grado de equivalencia 4, donde el concepto fuente era más restringido con un significado más específico que el concepto/término objetivo. Conclusión: Se entiende que este estudio proporciona subsidios para ANVISA continúe el trabajo de armonizar las listas locales con el estándar IDMP.

Avaliação das condições higiênico-sanitárias no açougue de um hipermercado em um município da Baixada Santista / Evaluation of hygienic-sanitary conditions in the butcher of a hypermarket in a municipality of Baixada Santista

As boas práticas nos serviços de alimentação são imprescindíveis para a garantia de qualidade e segurança dos alimentos. Objetivou-se nesta pesquisa avaliar as condições higiênico-sanitárias de um açougue em hipermercado no município de Guarujá-SP. O estudo de caráter observacional foi realizado in loco, e teve como ferramenta de pesquisa o check-list baseado nas portarias RDC 275/2002 e RDC 216/2004 da ANVISA, e logo após a avaliação foi coletado dez amostras dos principais pontos críticos do setor para análise microbiológica. Observou-se no estabelecimento que, mesmo atendendo uma grande porcentagem de conformidades em relação às boas práticas, foram detectadas dez amostras positivas para diversas bactérias Gram – e Gram +, o que pode representar risco eminente à segurança dos alimentos.

Good practices in food services are essential for quality assurance and food safety. The objective of this research was to evaluate the hygienic-sanitary conditions of a butcher shop in a hypermarket in Guarujá-SP. The observational study was carried out on site, and had as research tool the checklist based on ANVISA RDC 275/2002 and RDC 216/2004, and shortly after the evaluation was collected ten samples of the main critical points of the sector. for microbiological analysis. It was observed that even meeting a high percentage of compliance with good practices, the establishment presented the ten positive samples for several gram – and gram + bacteria which may represent an imminent risk to food safety.

Avaliação das condições higiênico-sanitárias no açougue de um hipermercado em um município da baixada santista / Evaluation of hygienic-sanitary conditions in the butcher of a hypermarket in a municipality of baixada santista

As boas práticas nos serviços de alimentação são imprescindíveis para a garantia de qualidade e segurança dos alimentos. Objetivou-se nesta pesquisa avaliar as condições higiênico-sanitárias de um açougue em hipermercado no município de Guarujá-SP. O estudo de caráter observacional foi realizado in loco, e teve como ferramenta de pesquisa o check-list baseado nas portarias RDC 275/2002 e RDC 216/2004 da ANVISA, e logo após a avaliação foi coletado dez amostras dos principais pontos críticos do setor para análise microbiológica. Observou-se no estabelecimento que, mesmo atendendo uma grande porcentagem de conformidades em relação às boas práticas, foram detectadas dez amostras positivas para diversas bactérias Gram ­ e Gram +, o que pode representar risco eminente à segurança dos alimentos

Good practices in food services are essential for quality assurance and food safety. The objective of this research was to evaluate the hygienic-sanitary conditions of a butcher shop in a hypermarket in Guarujá-SP. The observational study was carried out on site, and had as research tool the checklist based on ANVISA RDC 275/2002 and RDC 216/2004, and shortly after the evaluation was collected ten samples of the main critical points of the sector. for microbiological analysis. It was observed that even meeting a high percentage of compliance with good practices, the establishment presented the ten positive samples for several gram ­ and gram + bacteria which may represent an imminent risk to food safety

A Baseline Analysis of Regulatory Review Timelines for ANVISA: 2013-2016.

BACKGROUND: The Brazilian health regulatory agency (Agência Nacional de Vigilância Sanitária, ANVISA) has embarked on transformational initiatives to fulfill its mandate to provide timely access to safe, effective, and quality therapeutics. A new Brazilian law was enacted to provide the agency with greater flexibility. Optimizing Efficiencies in Regulatory Agencies (OpERA) is a regulatory-strengthening program that seeks to provide benchmarking data that can be used to define performance targets and focus performance improvement. The objective of this study was to use OpERA methodology to undertake a retrospective analysis of the timelines associated with important components of the ANVISA regulatory review process to establish a baseline against which the influence of the new law could be measured. METHODS: The OpERA tool was used to collect specific milestone data that identify time periods, review stages, and data points for products approved by ANVISA 2013-2016. RESULTS: For the 138 products approved in this cohort, the overall median approval time was 795 days. ANVISA and submitting companies will need to reduce their review and response times by approximately half in order to meet the total time goal of 365 days. CONCLUSIONS: The observations from this baseline study have identified opportunities for ANVISA and sponsor companies to collaborate to reduce regulatory assessment times while assuring the timely approval of safe and effective, quality medicines. These analyses will be repeated to determine how the provisions of the new Law will impact the activities of ANVISA and the extent of sponsors' contributions to this effort.

Innovative strategy based on mechanisms to substitute animal testing for ocular toxicity assessment of agrochemical formulations market in Brazil.

Considering the successful employment of alternative methods for eye toxicity assessment of products for regulatory purposes, and the recent advances in Brazilian legislative scenario, which adopted the UN GHS classification system for agrochemical formulations toxicity assessment, there is an emerging demand for strategies that allow the evaluation of such products. Based on this, the present study aimed to address the applicability of a mechanistic-based defined approach for eye toxicity assessment of agrochemical formulations. It was investigated the opacity/permeability, depth and location of corneal injury in bovine cornea, and vascular events in chorioallantoic membrane induced for different Brazilian agrochemicals using a Sequential Testing Strategy (STS). Cytotoxicity induced by the agrochemical formulations was evaluated by Short Time exposure (STE) (OECD TG 491) assay (step 1), corneal injury was investigated by standard Bovine Corneal Opacity and Permeability (BCOP) (OECD TG 437) followed by histopathological evaluation (step 2), and Hen Chorionic-allantoic Membrane test (HET-CAM) was used to evaluate vascular injury (step 3). The results demonstrated that the proposed defined approach enabled a classification corresponding UN GHS classification of agrochemical formulations while minimizing the use of live animals. Therefore, this approach may be useful for categorization of agrochemicals in Brazil according to the new regulatory scenario.

Compendial Methods: Suitability Verification, Challenges and Recommendations for Proteins.

Compendial testing methods are not required to be fully validated, but their suitability for testing should be verified under actual conditions of use. This requirement is established in 21 CFR 211.194(a)(2) of the current Good Manufacturing Practice regulations in the United States. ANVISA (Agência Nacional de Vigilância Sanitária) also requires that compendial analytical methods shall have their suitability demonstrated for the intended use by a partial validation study. Suitability verifications or partial validation can be divided into two major categories: visual and instrumental methods. For visual methods, the color and opalescence of interferences should be checked. If the color or clarity/opalescence of the sample is outside of the range of the Pharmacopeia standards/reference solutions, the validity of the test results should be evaluated. Specificity is usually waived because the methods are not specific to products, and accuracy/precision can be addressed by comparing results from analyst to analyst. For instrument methods, specificity can also be waived for certain assays. Accuracy is addressed by implementation of instrument calibration and/or method control. Precision is required either in suitability verification or when testing the samples. Here, we present approaches for suitability verification and the scientific rationale supporting compendial methods: visible particulates, subvisible particles, pH, osmolality, color and clarity/opalescence. Current challenges and recommendations are also discussed specifically for the analysis of protein products.

Overview of Brazilian Requirements for Therapeutic Equivalence of Orally Inhaled and Nasal Drug Products.

Brazil has established a framework for provision of generic pharmaceuticals including for orally inhaled and nasal drug products (OINDP) to its populace. This includes the development of guidelines or "resolutions" and normative instructions describing the Brazilian medicines agency's (Anvisa) expectations for demonstrating OINDP therapeutic equivalence. The Anvisa regulatory framework for OINDP therapeutic equivalence, challenges, and comparisons with the US Food and Drug Administration and European Medicines Agency approaches are assessed and discussed.

Regulatory Requirements and Innovation: A Comparison of the Dermatologic Antifungal Drug Product Markets in Brazil and United States.

BACKGROUND: Development of novel dermatological topical products for the treatment of cutaneous fungal infections is a constant necessity, especially in developing countries. Through public health policies, many developing countries have facilitated in the last decades the entry of generic products, which can be superficially seen as a threat to innovation. To verify whether regulatory requirements, or the waiving of some requirements, could have an impact on innovation, we performed a detailed technical comparison of the dermatologic antifungal markets of Brazil and of the United States, taking Brazil as an example of a developing country with more lenient requirements regarding the registration of generic topical drug products. METHODS: The official databank of ANVISA (DATAVISA) and of US Food and Drug Administration (Orange Book) were assessed for valid topical dermatological antifungal drug products registered. RESULTS: The Brazilian market has a greater number of registered drug products encompassing a greater variety of drug substances than the US, but the latter comprises more products with novel technologies. In both countries, cream was the predominant dosage form and imidazoles were the major substance group. Ketoconazole was the lead active substance in Brazil and ciclopirox was the lead drug in the US. Generic products dominated both markets. CONCLUSIONS: Despite the great number of registered products, the Brazilian market lacks the latest technologies, reflecting that the ease of generics registration is not accompanied by innovation.

Brazilian clinical engineering regulations: health equipment management and conditions for professional exercise

Abstract Introduction In Brazil, professionals, scientific community, and members of regulatory bodies have not yet achieved a consensus regarding who can legally perform the professional duties of a clinical engineer. We aim at clarifying this aspect, based on a detailed analysis of the pertinent regulations. Methods We acted on three fronts: (i) reviewing the current legislation regarding the clinical engineering exercise; (ii) visiting hospitals and working as trainee to understand how this exercise is implemented on Brazil's Federal District; (iii) one of the authors participated in virtual discussion groups of clinical engineering professionals, monitoring collective understanding of regulations, checking consistency of proper knowledge, and acting as an active opinion leader in the subject among peers. Results We try to make a formal definition of clinical engineer and indicate their characteristic activities. We propose a synthesis of the regulation regarding healthcare products' integrity protection and health technology management, identifying the engineering activities necessary to achieve those legal requirements. We analyze the legal constraints and conditions to exert engineering, indicating the necessary professionals' attributions and the way to obtain them. Finally, we provide a brief analysis of the technical requirements presented by the Brazilian Consumer Protection Code and of the 15.943 Brazilian Standard (NBR). Discussion We conclude that, despite the lack of consensus about the Clinical Engineering activity, there exists in Brazil a Clinical Engineering regulation, but it is spread in complex laws and normative resolutions, defining compulsory responsibilities and attributions, as well as conditions and prerequisites for role performance.