RESUMEN
BACKGROUND: Current knowledge is limited about which manufacturers are active in the global field of biopharmaceutical product development and how many unique follow-on biologics are approved in global markets. OBJECTIVE: This study aimed to provide a cross-sectional overview of manufacturers of follow-on biologics approved in 15 large countries from different regions of the world, as well as in five major biosimilar markets with long established biosimilar frameworks. METHODS: We screened national drug databases to identify follow-on biologics and their manufacturers approved in 15 countries in Asia, Africa, Latin America and the rest of the world, as well as five major biosimilar markets: the European Union (including the UK), USA, Canada, Australia and Japan. RESULTS: This study identified a total of 304 follow-on biologics from different manufacturers for 18 active substance classes included in the analysis. Of these, 67 products are approved as biosimilars in at least one of the five major biosimilar markets. A total of 140 (46%) follow-on biologics are manufactured in India or China, of which only eight (seven from India and one from China) are approved as biosimilars in any of the five major biosimilar markets. This study found that the majority of follow-on biologics are only approved in the respective country of manufacturing. A small number of manufacturers, primarily from India and Argentina, supply their products to other regions in the world. As some countries have less stringent regulatory approaches for biosimilars, or have only recently implemented biosimilar guidance in line with World Health Organization standards, follow-on biologics could have been approved that would not be considered biosimilars according to the World Health Organization standards. CONCLUSIONS: With this study, we try to contribute to discussions on creating more transparency about global approvals of follow-on biologics and promoting access to high-quality biosimilars in countries around the world.
Asunto(s)
Biosimilares Farmacéuticos , Humanos , Biosimilares Farmacéuticos/uso terapéutico , Estudios Transversales , Comercio , IndiaRESUMEN
The first global workshop on implementation of the WHO guidelines on procedures and data requirements for changes to approved biotherapeutic products adopted by the WHO Expert Committee in 2018 was held in June 2019. The workshop participants recognized that the principles based on sound science and the potential for risk, as described in the WHO Guidelines on post-approval changes, which constitute the global standard for product life-cycle management are providing clarity and helping national regulatory authorities in establishing guidance while improving time-lines for an efficient regulation of products. Consequently, the regulatory situation for post-approval changes and guideline implementation is changing but there is a disparity between different countries. While the guidelines are gradually being implemented in some countries and also being considered in other countries, the need for regional workshops and further training on post-approval changes was a common theme reiterated by many participants. Given the complexities relating to post-approval changes in different regions/countries, there was a clear understanding among all participants that an efficient approach for product life-cycle management at a national level is needed to ensure faster availability of high standard, safe and efficacious medicines to patients as per the World Health Assembly Resolution 67.21.
Asunto(s)
Productos Biológicos/normas , Evaluación de Medicamentos/normas , Guías como Asunto , Organización Mundial de la Salud , Aprobación de Drogas , Control de Medicamentos y Narcóticos , Humanos , SeúlRESUMEN
Protein interaction networks play a key role in signal processing. Despite the progress in identifying the interactions, the quantification of their strengths lags behind. Here we present an approach to quantify the in vivo binding of proteins to their binding partners in signaling-transcriptional networks, by the pairwise genetic isolation of each interaction and by varying the concentration of the interacting components over time. The absolute quantification of the protein concentrations was performed with targeted mass spectrometry. The strengths of the interactions, as defined by the apparent dissociation constants, ranged from subnanomolar to micromolar values in the yeast galactose signaling network. The weak homodimerization of the Gal4 activator amplifies the signal elicited by glucose. Furthermore, combining the binding constants in a feedback loop correctly predicted cellular memory, a characteristic network behavior. Thus, this genetic-proteomic binding assay can be used to faithfully quantify how strongly proteins interact with proteins, DNA and metabolites.
Asunto(s)
Espectrometría de Masas/métodos , Proteómica/métodos , Proteínas de Saccharomyces cerevisiae/metabolismo , Saccharomyces cerevisiae/metabolismo , Galactoquinasa/genética , Galactoquinasa/metabolismo , Regulación Fúngica de la Expresión Génica/fisiología , Unión Proteica , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Saccharomyces cerevisiae/genética , Proteínas de Saccharomyces cerevisiae/genética , Transducción de Señal/fisiología , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
Bistability plays an important role in cellular memory and cell-fate determination. A positive feedback loop can generate bistability if it contains ultrasensitive molecular reactions. It is often difficult to detect bistability based on such molecular mechanisms due to its intricate interaction with cellular growth. We constructed transcriptional feedback loops in yeast. To eliminate growth alterations, we reduced the protein levels of the transcription factors by tuning the translation rates over two orders of magnitude with designed RNA stem loops. We modulated two ultrasensitive reactions, homodimerization and the cooperative binding of the transcription factor to the promoter. Either of them is sufficient to generate bistability on its own, and when acting together, a particularly robust bistability emerges. This bistability persists even in the presence of a negative feedback loop. Given that protein homodimerization is ubiquitous, it is likely to play a major role in the behavior of regulatory networks.
Asunto(s)
Retroalimentación Fisiológica/fisiología , Multimerización de Proteína/fisiología , Proteínas/metabolismo , Redes Reguladoras de Genes/genética , Humanos , Modelos Genéticos , Regiones Promotoras Genéticas/genética , Biosíntesis de Proteínas/genética , Multimerización de Proteína/genética , Proteínas/genética , ARN/metabolismo , Factores de Transcripción/metabolismo , Transcripción Genética/genética , Levaduras/genética , Levaduras/metabolismo , Levaduras/fisiologíaRESUMEN
Caustic regeneration procedures are often used in chromatographic purification processes of peptides and proteins to remove irreversibly bound impurities from the stationary phase. Silica-based materials are the most commonly used materials in reversed phase chromatography of peptides. Their limited chemical stability at high pH can be, however, problematic when high pH column regeneration (i.e. cleaning in place) is required. The effect of cleaning in place on the surface chemistry of the stationary phase has been investigated using the Tanaka test. It has been shown that the high pH treatment does not significantly affect the hydrophobicity of the material, but it strongly increases its silanol activity. A representative peptide purification process has been used to investigate the impact of cleaning in place on the separation performance. It has been shown that the caustic regeneration increases the peptide retention at high pH (pH 6.5), due to the interactions between the peptide and the negatively charged silanol groups. These unwanted interactions reduce the separation performances by decreasing the selectivity between the late eluting impurities and the main peptide. However, it has been shown that the effect of the silanol groups on the peptide adsorption and on the separation performance can be minimized by carrying out the purification process at low pH (pH approximately 2). In this case, the silanol groups are protonated and their electrostatic interactions with the positively charged analyte (i.e. peptides) are suppressed. In these conditions, the peptide adsorption and the impurity selectivity is not changing upon high pH column regeneration and the separation performance is not affected.