Comparator product issues for biowaiver implementation: the case of Fluconazole

The aim of this work was to assess if the commercially available Fluconazole drug products (Reference, Generic and Similar) would meet the biowaiver criteria from Food and Drug Administration (FDA) and Brazilian Agency for Health Surveillance (ANVISA) agencies. All formulations were evaluated considering the dissolution profile carried out in Simulated Gastric Fluid (SGF) pH 1.2, Acetate Buffer (AB) pH 4.5 and Simulated Intestinal Fluid (SIF) pH 6.8. The results demonstrated that all formulations fulfilled the 85% of drug dissolved at 30 min criterion in SGF pH 1.2. However, in AB pH 4.5 and SIF pH 6.8, some formulations, including the comparator, did not achieve this dissolution percentage. The discrepant dissolution profiles also failed the ƒ2 similarity factor analysis, since none of the formulations showed values between 50 and 100 in the three dissolution media. Comparative dissolution profiles were not similar, considering that the main issues concerning the dissolution were evidenced for the comparator product. Hence, a revision in the regulatory norms in order to establish criteria to switch the comparator could result in an increased application of drugs based on biowaiver criteria

Requisitos de bioisenção com base no Sistema de Classificação Biofarmacêutica no Brasil e no mundo / Biowaiver requirements based on the Biopharmaceutical Classification System in Brazil and worldwide

O acesso a medicamentos pode ser facilitado por programas globais de desenvolvimento farmacêutico, mas há necessidade de que as agencias regulatórias e as indústrias farmoquímicas e farmacêuticas interajam e haja um consenso quanto as exigências para o registro de medicamentos. Este artigo examinou a legislação especifica sobre bi isenção com base no Sistema de Classificação Biofarmacêutica, comparando os cenários do Brasil e do mundo. A partir dessa análise, identificou os entraves a aplicação dos critérios internacionais na realidade regulatória nacional, identificando algumas fragilidades da legislação, como no caso de pro-fármacos. Analisaram-se os critérios de cinco organismos regulatórios (Agência Europeia de Medicamentos, Food and Drug Administration, Health Canada, Conselho Internacional para Harmonização de Requisitos Técnicos para Medicamentos de Uso Humano e Organização Mundial da Saúde) frente aos requisitos da Agência Nacional de Vigilância Sanitária, pontuando as diferenças e o que já se encontra pacificado no tocante a classe do Sistema de Classificação Biofarmacêutica aceita, a comparabilidade entre formulação teste e de referência, solubilidade, permeabilidade intestinal e perfil de dissolução in vitro. Concluiu--se que a Agência Nacional de Vigilância Sanitária deve internalizar os preceitos e critérios da bioisenção com base no Sistema de Classificação Biofarmacêutica por meio de um novo marco regulatório. Além disso, para que esse marco regulatório seja bem-sucedido e produza resultados palpáveis, em especial na área de saúde publica e vigilância sanitária, a agência brasileira deve estar aberta ao diálogo com o setor regulado e as inovações e orientações da academia, sem desviar o foco de sua missão institucional.

Access to medicines can be facilitated by global pharmaceutical development programs, but there is a need for regulatory agencies and the pharmochemical and pharmaceutical industries to interact and to have a consensus on the requirements for drug registration. This article examined the specific legislation concerning to biowaiver based on the Biopharmaceutical Classification System, comparing the scenario in Brazil and worldwide. Based on this analysis, it identified the obstacles to the application of international criteria in the national regulatory reality, identifying some weaknesses of the legislation, as in the case of prodrugs. The criteria of five regulatory bodies (European Medicines Agency, Food and Drug Administration, Health Canada, International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use and World Health Organization) were analyzed in relation to the requirements of the Brazilian Health Regulatory Agency (Anvisa), pointing out the differences and what has already been settled regarding the accepted class of the Biopharmaceutical Classification System, the comparability between test and reference formulations, solubility, intestinal permeability and in vitro dissolution profile. It was concluded that Anvisa should internalize the percepts and criteria of the biowaiver based on Biopharmaceutical Classification System, through a new regulatory framework. Moreover, for this regulatory framework to be successful and produce tangible results, especially in the area of public health and health surveillance, Anvisa must be open to dialogue with the regulated sector and to innovations and guidance from academia, without losing focus of its institutional mission.

Basic procedure and technical requirements of equilibrium solubility experiments / 中国药学杂志

OBJECTIVE: To introduce the basic procedure and technical requirements of equilibrium solubility experiments and provide reference for design and conduct of equilibrium solubility experiments scheme. METHODS: The concept and influence factors of solubility, principle and determination method of solubility experiments, equilibrium solubility project of world health organization were analyzed. RESULTS: The influence factors of equilibrium solubility include composition of buffers, temperature, time of oscillation, time of sedimentation, techniques for separation of solid and liquid phases etc. CONCLUSION: To ascertain the BCS classification of drugs, the first step is to determine the equilibrium solubility of drugs under physiological pH conditions. To date, there is no accepted standard method for the determination of equilibrium solubility. This paper introduces the basic procedure and technical requirements of equilibrium solubility experiments recommended by WHO, which would provide instructive and practical assists to conduct of equilibrium solubility experiments and standardize its application in BCS classification and biowaiver.

Principles of biowaiver about consistency evaluation of generic drug products and varieties of biowaiver in countries and international organizations / 药物评价研究

Objective For bioequivalence test of the consistency evaluation of generic drug products,providing a reference of varieties of biowaiver.Methods Based on Human bioequivalence test waiver guidelines (draft),on condition that first drug of the consistency evaluation,to introduce and conclude briefly the standards of biowaiver and varieties of biowaiver in FDA,WHO and EMA.Results Contrast to FDA,there are 59 varieties applied for the waiver and 19 varieties not applied for the waiver in the 289 varietie;compared to WHO,10 drugs are exempted and 1 grug is exempted in EMA.Conclusion At present,the specific list of drugs are not published of biowaiver in our country,the pharmaceutical companies should compare and consult revelant standards and specific drugs in China and abroad,to speed up the progress of the consistency evaluation.

Bioequivalencia de medicamentos in vivo e in vitro (Bioexención) / Bioequivalence of drugs in vivo and in vitro (Biowaiver)

El desarrollo de los medicamentos químicos de los últimos 50 años ha permitido la obtención de notables mejoras en la salud humana. La calidad, seguridad y eficacia así como las Buenas Prácticas de Manufactura (BPM), y las Buenas Prácticas de Laboratorio (BPL), son exigencias implantadas en la industria farmacéutica en la mayoría de los países. La aparición y desarrollo de las especialidades farmacéuticas genéricas en los últimos 35 años ha acompañado al desarrollo de los estudios de Biodisponibilidad y Bioequivalencia in vivo e in vitro (Bioexención). Se revisa los avances en estudios de Bioequivalencia en el Perú y los requisitos de la Ley de medicamentos aprobada en 2009. Los estudios de Bioequivalencia principalmente farmacocinéticos constituyen el estándar para que los organismos regulatorios en materia farmacéutica asuman la equivalencia terapéutica. Esta a su vez es un criterio aceptado para asumir intercambiabilidad del medicamento. En este artículo se revisan las definiciones, los diferentes tipos de diseños empleados en los estudios de Bioequivalencia, sus requisitos principales así como los criterios de aceptabilidad y rechazo de los resultados de los estudios de Bioequivalencia. Se hace especial mención a la posición de la OMS, la FDA y EMEA en los últimos años. Se describe la Clasificación Biofarmacéutica (SCB), que considera cuatro grupos y su aplicación para la bioexencin, bajo los criterios de la FDA y de la OMS.

In the last 50 years the development of the chemical medicines has allowed to achieve remarkable improvements in human health care. In many countries the pharmaceutical industry regulations on quality, safety and effectiveness as well as Good Manufacturing Practices (GMP) and Good Laboratory Practices (GLP) are mandatory requirements. Generic pharmaceutical products have been developed in the last 35 years, along with studies of bioavailability, bioequivalence in vivo and in vitro (Biowaiver). In this article the progress in Bioequivalence studies in Peru will be reviewed as well as the requirements of the Medicines Act adopted in 2009. The pharmacokinetic Bioequivalence is the standard for pharmaceutical regulatory agencies; in this way they are able to establish pharmaceutical therapeutic equivalence and this is an accepted criteria for the medication interchangeability. The most important requirements of acceptability and rejection of the results of the studies of Bioequivalence are reviewed in this article, as well as the criteria and the definitions related to them and the different programs designed for these studies. In this article we review definition, different study designs used bioequivalence, their requirements and the criteria of acceptability and rejection of the results bioequivalence studies. The position of the WHO, the FDA and EMEA in the last few years has a special reference in the article. The Biopharmaceutics Classification System (BCS), that consider four groups and their application to biowaiver, under the criteria of FDA and WHO is reviewed.

In vitro-in vivo studies of the quantitative effect of calcium, multivitamins and milk on single dose ciprofloxacin bioavailability / 药物分析学报

Ciprofloxacin, commonly used in India as an anti-microbial for prolonged use in chronic and non-specific indications, may affect the bioavailability of the drug. The drug prescribed is commonly taken with multivitamins, calcium and milk. A simple and reliable analytical methodology obtaining a correlation with in vivo urinary excretion studies using UV and HPLC and in vitro dissolution studies (IVIVC) has shown a significant increase in elimination rate of ciprofloxacin co-administered with multivitamins, calcium and milk. Appreciable IVIVC results proved that dissolution studies could serve as an alternative to in vivo bioavailability and also support bio-waivers.

Biopharmaceutics classification system: importance and inclusion in biowaiver guidance

Pharmacological therapy is essential in many diseases treatment and it is important that the medicine policy is intended to offering safe and effective treatment with affordable price to the population. One way to achieve this is through biowaiver, defined as the replacement of in vivo bioequivalence studies by in vitro studies. For biowaiver of new immediate release solid oral dosage forms, data such as intestinal permeability and solubility of the drug are required, as well as the product dissolution. The Biopharmaceutics Classification System (BCS) is a scientific scheme that divides drugs according to their solubility and permeability and has been used by various guides as a criterion for biowaiver. This paper evaluates biowaiver application, addressing the general concepts and parameters used by BCS, making a historical account of its use, the requirements pertaining to the current legislation, the benefits and risks associated with this decision. The results revealed that the use of BCS as a biowaiver criterion greatly expands the therapeutics options, contributing to greater therapy access of the general population with drug efficacy and safety guaranteed associated to low cost.

O tratamento farmacológico é essencial frente a várias patologias e é fundamental que a política de medicamentos tenha por objetivo oferecer à população tratamento seguro, eficaz e de preço acessível. Uma forma de alcançar esse objetivo é por meio da bioisenção, definida como a substituição de estudos de bioequivalência in vivo por estudos in vitro. Para bioisentar novos medicamentos sob a forma farmacêutica sólida oral de liberação imediata são utilizados dados de permeabilidade intestinal e solubilidade do fármaco, bem como sua dissolução a partir da forma farmacêutica. O Sistema de Classificação Biofarmacêutica (SCB) é um esquema científico que divide os fármacos em classes de acordo com a solubilidade e permeabilidade e vem sendo utilizado como critério para bioisenção em diversas legislações. O presente artigo faz uma avaliação da aplicação da bioisenção, abordando os conceitos gerais e parâmetros utilizados pelo SCB, fazendo um relato histórico da aplicação da bioisenção, das exigências pertinentes às legislações vigentes, dos benefícios e riscos inerentes a uma tomada de decisão sobre bioisenção baseada neste critério. Os resultados revelaram que a utilização do SCB como critério amplia enormemente as possibilidades de bioisenção, contribuindo para o maior acesso da população em geral a medicamentos com garantida eficácia, segurança e menor custo.

Estudio comparativo de la liberación in vitro de metformina, a partir de dos productos multifuente de liberación inmediata, comercializados en Colombia / Comparative study for in vitro release of metformin of two immediate-release multisource products, marketed in Colombia

El presente estudio se realizó con el objetivo de establecer mediante pruebas de disolución in vitro, si dos formas farmacéuticas multifuente de liberación inmediata, de administración peroral con metformina como principio activo, son equivalentes en relación con su producto de referencia. Los datos de porcentaje de disolución obtenidos en tres niveles de pH (1,2; 4,5 y 6,8) y en dos equipos de disolución diferentes, se analizaron mediante el método de modelo independiente para comparar los perfiles de disolución de los productos a través del cálculo de los factores de diferencia (f1) y de similitud (f2), según las recomendaciones de la Food and Drug Administration (FDA). Para evaluar la cinética de liberación del fármaco, se aplicaron tres modelos matemáticos (ecuación de orden cero, de primer orden e Higuchi); además, para la comparación de los productos se aplicó un método basado en análisis multivariado para un diseño de medidas repetidas. Los resultados mostraron que existen diferencias estadísticamente significativas entre los productos, razón por la cual en este estudio no se demostró la equivalencia de los productos B y C con relación al producto A, con base en pruebas de disolución in vitro.

The objective of the study was to determine the equivalence of two multisource drug products of metformin tablets using in vitro testing. The in vitro dissolution profiles were done in phosphate buffer (pH 6.8), acetate buffer (pH 4.5), hydrochloric acid (pH 1.2) and two dissolution apparatus were used. Multivariate analysis for repeated measures design was employed to compare the percentage dissolved of the drug products. According to Food and Drug Administration (FDA) guidance for dissolution data equivalence, model independent approach was applied. This involves the use of difference factor (f1) and similarity factor (f2). The drug release from drug products was analyzed by various mathematical models such as zero order, firs order and Higuchi. The results showed that there were significant differences between the drug products, and for this reason it was not possible to demonstrate equivalence based in vitro assays.

Estudios de bioexención (in vitro) para establecer equivalencia de medicamentos / Biowaiver studies (in vitro) to establish equivalence of drugs

En el presente trabajo se hace un análisis de los conceptos, normativas y propuestas sobre la equivalencia terapéutica de medicamentos similares con respecto a los innovadores, desde una perspectiva internacional y nacional, explicando las bases científicas de los estudios de bioexención in vitro para determinar la intercambiabilidad de aquellos medicamentos similares provenientes de diferentes fuentes que se han liberado de los estudios de bioequivalencia (in vivo). Además, se presentan algunos resultados de estudios de test de disolución para dar a conocer la metodología usada en la bioexención y se detallan los requisitos para aprobar un Centro de Bioequivalencia in vitro.

In this review, the concepts, guidelines and proposals regarding the determination of therapeutic equivalence of similar drug products are analyzed from a national and international point of view. The scientific background of the in vitro biowaiver studies that may result in the interchange ability of multisource drug product that have been waived from the demonstration of in vivo bioequivalence studies is also explained. In order to explain the methods in biowaiver studies, results of dissolution kinetics are shown as well as the requirements to approve an in vitro biopharmaceutic center.

Importancia y fundamentación del sistema de clasificación biofarmacéutico, como base de la exención de estudios de biodisponibilidad y bioequivalencia in vivo / The biopharmaceutic drug classification, the theoretical basis and its importance in the biowaiver studies

El Sistema de Clasificación Biofarmacéutica (SCB), publicado por Gordon Amidon y cols. en 1995, se basa en un sólido fundamento científico para clasificar un fármaco considerando los parámetros de solubilidad y permeabilidad, factores estrechamente relacionados con el proceso de absorción, y plantea como objetivo, la posibilidad de establecer correlaciones in vitro-in vivo que permitan sustituir los ensayos realizados en humanos por ensayos de disolución in vitro, de acuerdo con la clasificación obtenida para el fármaco. Actualmente la aplicación del SCB está enfocada a los estudios de bioequivalencia para demostrar intercambio de medicamentos, presentados en forma sólida de liberación inmediata, de administración peroral y al aseguramiento de que los cambios realizados durante el escalonamiento o en las formulaciones o procesos de éstos, una vez aprobados, no tengan incidencia en su comportamiento in vivo. La proyección de la aplicación del SCB se está dando hacia su implantación como herramienta en el desarrollo de nuevos fármacos, en el diseño y desarrollo de medicamentos y en la posibilidad de bioexenciones para los sistemas de liberación controlada.

The Biopharmaceutics Classification System (BCS), published in 1995 by Gordon Amidon and coworkers, is proposed based on recognizing the underlying process that is controlling the drug absorption rate and extent, namely, drug solubility and intestinal membrane permeability, classifying a drug according to this. Its objective is the possibility to set standards for in vitro drug dissolution testing methodology which will correlate with the in vivo process, avoiding human studies. The BCS can be used to classify drugs and set standards for scale-up and post-approval changes to show that the efficacy has not been altered, as well as standards for in vitro/in vivo correlation for bioequivalence studies, for solid oral immediate release products. About this, exists discusses for further potential applications of the BCS in the development of new drugs and drug products and in the possibility of biowaivers for controlled-release products.