The technology transfer inhibitors solution agreed by both parties INK1197 in vivo – in addition to addressing logistic, time and financial constraints – comprised oversight of the production plant design and selection of equipment (partly produced in Brazil), supervision of the construction of the plant and its validation, as well as assistance in the selection of an adequate source of eggs and training of senior staff. The Ministry of Health, under an agreement concluded with Butantan in 2004, provided US$ 10 million to purchase the basic equipment, and the State of São Paulo Office of Health agreed to fund the construction of the plant, estimated at US$ 20 million. Significant delays

were incurred because of a legal challenge during the tender process, difficulties experienced by the construction company, and the emergence of highly pathogenic H5N1 avian influenza. The latter required Butantan to upgrade its containment facilities and to identify and implement a technical solution to process residual egg shells and chicken embryos so that they could not be used for animal feed. The cost of the

plant thus increased to US$ 35 million. Akt inhibitor As with its other non-live vaccines, Butantan intends to transfer the monovalent inactivated bulk vaccine produced in the new production plant to its central formulation and filling plants. Two filling lines – one automated and the other manual – can sterilize, fill, cap, label and control 26 000 vials per hour. To save on transport and cold-room storage, each fill-finished vial will contain 10 doses. Sanofi Pasteur fulfilled all the terms of the technology transfer agreement, including the provision of expert advice, site visits and training for key staff. Sanofi experts were also instrumental in overseeing the building of a large additional fertilized egg production farm near ADAMTS5 to Butantan. In September 2010, after final validation by sanofi pasteur, the influenza production plant was ready for production. Starting

from 2011, Butantan intends to produce 20–25 million doses of trivalent southern hemisphere seasonal vaccine per year. The development and registration of an adjuvanted formulation would allow for the production of significantly more vaccine, as reported below. This is particularly important in view of the fact that non-adjuvanted H5N1 split inactivated influenza vaccine is poorly immunogenic and requires immunization of vaccines twice with very high doses of haemagglutinin (HA) antigen (90 μg compared to 15 μg for seasonal vaccine). In order to alleviate this problem – i.e. to “spare” antigen in case of a pandemic and maximize the number of persons who can be immunized – multinational vaccine manufacturers have developed much more immunogenic H5N1 adjuvanted vaccine formulations.