Current Issue : April - June Volume : 2012 Issue Number : 2 Articles : 4 Articles
Therapeutic proteins are derived from complex expression/production systems, which can result in minor conformational\nchanges due to preferential codon usage in different organisms, post-translational modifications, etc. Subtle conformational\ndifferences are often undetectable by bioanalytical methods but can sometimes profoundly impact the safety, efficacy and\nstability of products. Numerous bioanalytical methods exist to characterize the primary structure of proteins, post\ntranslational modifications; protein-substrate/protein/protein interactions and functional bioassays are available for most\nproteins that are developed as products. There are however few analytical techniques to detect changes in the tertiary\nstructure of proteins suitable for use during drug development and quality control. For example, x-ray crystallography and\nNMR are impractical for routine use and do not capture the heterogeneity of the product. Conformation-sensitive antibodies\ncan be used to map proteins. However the development of antibodies to represent sufficient epitopes can be challenging.\nOther limitations of antibodies include limited supply, high costs, heterogeneity and batch to batch variations in titer. Here\nwe provide proof-of-principle that DNA aptamers to thrombin can be used as surrogate antibodies to characterize\nconformational changes. We show that aptamers can be used in assays using either an ELISA or a label-free platform to\ncharacterize different thrombin products. In addition we replicated a heat-treatment procedure that has previously been\nshown to not affect protein activity but can result in conformational changes that have serious adverse consequences. We\ndemonstrate that a panel of aptamers (but not an antibody) can detect changes in the proteins even when specific activity\nis unaffected. Our results indicate a novel approach to monitor even small changes in the conformation of proteins which\ncan be used in a routine drug-development and quality control setting. The technique can provide an early warning of\nstructural changes during the manufacturing process that could have consequential outcomes downstream....
Biosimilars are protein products that are suffi ciently\r\nsimilar to a biopharmaceutical already approved by a\r\nregulatory agency. Several biotechnology companies\r\nand generic drug manufacturers in Asia and Europe\r\nare developing biosimilars of tumor necrosis factor\r\ninhibitors and rituximab. A biosimilar etanercept is\r\nalready being marketed in Colombia and China. In the\r\nUS, several natural source products and recombinant\r\nproteins have been approved as generic drugs under\r\nSection 505(b)(2) of the Food, Drug, and Cosmetic\r\nAct. However, because the complexity of large\r\nbiopharmaceuticals makes it diffi cult to demonstrate\r\nthat a biosimilar is structurally identical to an already\r\napproved biopharmaceutical, this Act does not apply to\r\nbiosimilars of large biopharmaceuticals. Section 7002 of\r\nthe Patient Protection and Aff ordable Care Act of 2010,\r\nwhich is referred to as the Biologics Price Competition\r\nand Innovation Act of 2009, amends Section 351 of\r\nthe Public Health Service Act to create an abbreviated\r\npathway that permits a biosimilar to be evaluated by\r\ncomparing it with only a single reference biological\r\nproduct. This paper reviews the processes for approval\r\nof biosimilars in the US and the European Union\r\nand highlights recent changes in federal regulations\r\ngoverning the approval of biosimilars in the US....
As the first wave of biopharmaceuticals is set to expire, biosimilars or follow-on protein products (FOPPs) have emerged. The\r\nregulatory foundation for these products is more advanced and better codified in Europe than in the US. Recent approval of\r\nbiosimilar Somatropin (growth hormone) in Europe and the US prompted this paper. The scientific viability of biosimilar growth\r\nhormone is reviewed. Efficacy and safety data (growth rates, IGF-1 generation) for up to 7 years for pediatric indications measure\r\nup favorably to previously approved growth hormones as reference comparators. While the approval in the US is currently only\r\nfor treatment of growth hormone deficiency (GHD) in children and adults, the commercial use of approved biosimilar growth\r\nhormones will allow in the future for in-depth estimation of their efficacy and safety in non-GH deficient states as well....
Background: Although the World Health Organization had recommended that every child be vaccinated for\r\nHepatitis B by the early 1980s, large multinational pharmaceutical companies held monopolies on the recombinant\r\nHepatitis B vaccine. At a price as high as USD$23 a dose, most Indians families could not afford vaccination.\r\nShantha Biotechnics, a pioneering Indian biotechnology company founded in 1993, saw an unmet need\r\ndomestically, and developed novel processes for manufacturing Hepatitis B vaccine to reduce prices to less than\r\n$1/dose. Further expansion enabled low-cost mass vaccination globally through organizations such as UNICEF. In\r\n2009, Shantha sold over 120 million doses of vaccines. The company was recently acquired by Sanofi-Aventis at a\r\nvaluation of USD$784 million.\r\nMethods: The case study and grounded research method was used to illustrate how the globalization of\r\nhealthcare R&D is enabling private sector companies such as Shantha to address access to essential medicines.\r\nSources including interviews, literature analysis, and on-site observations were combined to conduct a robust\r\nexamination of Shantha�s evolution as a major provider of vaccines for global health indications.\r\nResults: Shantha�s ability to become a significant global vaccine manufacturer and achieve international valuation\r\nand market success appears to have been made possible by focusing first on the local health needs of India. How\r\nShantha achieved this balance can be understood in terms of a framework of four guiding principles. First, Shantha\r\nidentified a therapeutic area (Hepatitis B) in which cost efficiencies could be achieved for reaching the poor.\r\nSecond, Shantha persistently sought investments and partnerships from non-traditional and international sources\r\nincluding the Foreign Ministry of Oman and Pfizer. Third, Shantha focused on innovation and quality - investing in\r\ninnovation from the outset yielded the crucial process innovation that allowed Shantha to make an affordable\r\nvaccine. Fourth, Shantha constructed its own cGMP facility, which established credibility for vaccine prequalification\r\nby the World Health Organization and generated interest from large pharmaceutical companies in its contract\r\nresearch services. These two sources of revenue allowed Shantha to continue to invest in health innovation\r\nrelevant to the developing world.\r\nConclusions: The Shantha case study underscores the important role the private sector can play in global health\r\nand access to medicines. Home-grown companies in the developing world are becoming a source of low-cost,\r\nlocally relevant healthcare R&D for therapeutics such as vaccines. Such companies may be compelled by market\r\nforces to focus on products relevant to diseases endemic in their country. Sanofi-Aventis� acquisition of Shantha\r\nreveals that even large pharmaceutical companies based in the developed world have recognized the importance\r\nof meeting the health needs of the developing world. Collectively, these processes suggest an ability to tap into\r\nprivate sector investments for global health innovation, and illustrate the globalization of healthcare R&D to the\r\ndeveloping world....
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