A Simulation Analysis of an Influenza Vaccine Production Plant in Areas of High Humanitarian Flow. A Preliminary Study for the Region of Norte de Santander (Colombia)

The production of vaccines of biological origin presents a tremendous challenge for researchers. In this context, animal cell cultures are an excellent alternative for the isolation and production of biologicals against several viruses, since they have an affinity with viruses and a great capacity f...

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Autores:
Contreras Ropero, Jefferson Eduardo
Ruiz Roa, Silvia Liliana
García-Martinez, Janet
Urbina-Suarez, Nestor Andres
López Barrera, German Luciano
Barajas Solano, andres F
ZUORRO, Antonio
Tipo de recurso:
Article of journal
Fecha de publicación:
2021
Institución:
Universidad Francisco de Paula Santander
Repositorio:
Repositorio Digital UFPS
Idioma:
eng
OAI Identifier:
oai:repositorio.ufps.edu.co:ufps/6933
Acceso en línea:
https://repositorio.ufps.edu.co/handle/ufps/6933
https://doi.org/10.3390/app12010183
Palabra clave:
modeling process
SuperPro Designer®
cell culture
public health
developing countries
Rights
openAccess
License
https://creativecommons.org/licenses/by/4.0/
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dc.title.eng.fl_str_mv A Simulation Analysis of an Influenza Vaccine Production Plant in Areas of High Humanitarian Flow. A Preliminary Study for the Region of Norte de Santander (Colombia)
title A Simulation Analysis of an Influenza Vaccine Production Plant in Areas of High Humanitarian Flow. A Preliminary Study for the Region of Norte de Santander (Colombia)
spellingShingle A Simulation Analysis of an Influenza Vaccine Production Plant in Areas of High Humanitarian Flow. A Preliminary Study for the Region of Norte de Santander (Colombia)
modeling process
SuperPro Designer®
cell culture
public health
developing countries
title_short A Simulation Analysis of an Influenza Vaccine Production Plant in Areas of High Humanitarian Flow. A Preliminary Study for the Region of Norte de Santander (Colombia)
title_full A Simulation Analysis of an Influenza Vaccine Production Plant in Areas of High Humanitarian Flow. A Preliminary Study for the Region of Norte de Santander (Colombia)
title_fullStr A Simulation Analysis of an Influenza Vaccine Production Plant in Areas of High Humanitarian Flow. A Preliminary Study for the Region of Norte de Santander (Colombia)
title_full_unstemmed A Simulation Analysis of an Influenza Vaccine Production Plant in Areas of High Humanitarian Flow. A Preliminary Study for the Region of Norte de Santander (Colombia)
title_sort A Simulation Analysis of an Influenza Vaccine Production Plant in Areas of High Humanitarian Flow. A Preliminary Study for the Region of Norte de Santander (Colombia)
dc.creator.fl_str_mv Contreras Ropero, Jefferson Eduardo
Ruiz Roa, Silvia Liliana
García-Martinez, Janet
Urbina-Suarez, Nestor Andres
López Barrera, German Luciano
Barajas Solano, andres F
ZUORRO, Antonio
dc.contributor.author.none.fl_str_mv Contreras Ropero, Jefferson Eduardo
Ruiz Roa, Silvia Liliana
García-Martinez, Janet
Urbina-Suarez, Nestor Andres
López Barrera, German Luciano
Barajas Solano, andres F
ZUORRO, Antonio
dc.subject.proposal.eng.fl_str_mv modeling process
SuperPro Designer®
cell culture
public health
developing countries
topic modeling process
SuperPro Designer®
cell culture
public health
developing countries
description The production of vaccines of biological origin presents a tremendous challenge for researchers. In this context, animal cell cultures are an excellent alternative for the isolation and production of biologicals against several viruses, since they have an affinity with viruses and a great capacity for their replicability. Different variables have been studied to know the system’s ideal parameters, allowing it to obtain profitable and competitive products. Consequently, this work focuses its efforts on evaluating an alternative for producing an anti-influenza biological from MDCK cells using SuperPro Designer v8.0 software. The process uses the DMEN culture medium supplemented with nutrients as raw material for cell development; the MDCK cells were obtained from a potential scale-up with a final working volume of 500 L, four days of residence time, inoculum volume of 10%, and continuous working mode with up to a total of 7400 h/Yr of work. The scheme has the necessary equipment for the vaccine’s production, infection, and manufacture with yields of up to 416,698 units/h. In addition, it was estimated to be economically viable to produce recombinant vaccines with competitive prices of up to 0.31 USD/unit.
publishDate 2021
dc.date.issued.none.fl_str_mv 2021-12-24
dc.date.accessioned.none.fl_str_mv 2024-04-16T14:08:18Z
dc.date.available.none.fl_str_mv 2024-04-16T14:08:18Z
dc.type.spa.fl_str_mv Artículo de revista
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dc.identifier.uri.none.fl_str_mv https://repositorio.ufps.edu.co/handle/ufps/6933
dc.identifier.doi.none.fl_str_mv https://doi.org/10.3390/app12010183
url https://repositorio.ufps.edu.co/handle/ufps/6933
https://doi.org/10.3390/app12010183
dc.language.iso.spa.fl_str_mv eng
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dc.relation.ispartof.none.fl_str_mv Appl. Sci. 2022, 12, 183. https://doi.org/ 10.3390/app12010183
dc.relation.citationedition.spa.fl_str_mv Vol.12 No.183 (2022)
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dc.relation.citationissue.spa.fl_str_mv 183.(2022)
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dc.relation.citationvolume.spa.fl_str_mv 12
dc.relation.cites.none.fl_str_mv Contreras-Ropero, J.E.; Ruiz-Roa, S.L.; García-Martínez, J.B.; Urbina-Suarez, N.A.; López-Barrera, G.L.; Barajas-Solano, A.F.; Zuorro, A. A Simulation Analysis of an Influenza Vaccine Production Plant in Areas of High Humanitarian Flow. A Preliminary Study for the Region of Norte de Santander (Colombia). Appl. Sci. 2022, 12, 183. https://doi.org/ 10.3390/app12010183
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dc.format.extent.spa.fl_str_mv 9 Páginas
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dc.publisher.spa.fl_str_mv Applied Sciences (Switzerland)
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spelling Contreras Ropero, Jefferson Eduardo14643edabc8451f3e53932a0a299b372600Ruiz Roa, Silvia Liliana38fb46b80826f9790354abc0b1fd8d7e600García-Martinez, Janet80edb67ba4cf51c8ef0d2bf62e0faa4d600Urbina-Suarez, Nestor Andres3e8ce1897f5d9382bb88755e9ec9cb96600López Barrera, German Luciano332ac6b52127580d0633e118d7f54cb8600Barajas Solano, andres F7237a5ca918751f9d045f15b62fd2f1f600ZUORRO, Antonio1d9ebb9bdc0d09156364b9fd1169276a6002024-04-16T14:08:18Z2024-04-16T14:08:18Z2021-12-24https://repositorio.ufps.edu.co/handle/ufps/6933https://doi.org/10.3390/app12010183The production of vaccines of biological origin presents a tremendous challenge for researchers. In this context, animal cell cultures are an excellent alternative for the isolation and production of biologicals against several viruses, since they have an affinity with viruses and a great capacity for their replicability. Different variables have been studied to know the system’s ideal parameters, allowing it to obtain profitable and competitive products. Consequently, this work focuses its efforts on evaluating an alternative for producing an anti-influenza biological from MDCK cells using SuperPro Designer v8.0 software. The process uses the DMEN culture medium supplemented with nutrients as raw material for cell development; the MDCK cells were obtained from a potential scale-up with a final working volume of 500 L, four days of residence time, inoculum volume of 10%, and continuous working mode with up to a total of 7400 h/Yr of work. The scheme has the necessary equipment for the vaccine’s production, infection, and manufacture with yields of up to 416,698 units/h. In addition, it was estimated to be economically viable to produce recombinant vaccines with competitive prices of up to 0.31 USD/unit.9 Páginasapplication/pdfengApplied Sciences (Switzerland)Appl. Sci. 2022, 12, 183. https://doi.org/ 10.3390/app12010183Vol.12 No.183 (2022)9183.(2022)112Contreras-Ropero, J.E.; Ruiz-Roa, S.L.; García-Martínez, J.B.; Urbina-Suarez, N.A.; López-Barrera, G.L.; Barajas-Solano, A.F.; Zuorro, A. A Simulation Analysis of an Influenza Vaccine Production Plant in Areas of High Humanitarian Flow. A Preliminary Study for the Region of Norte de Santander (Colombia). Appl. Sci. 2022, 12, 183. https://doi.org/ 10.3390/app12010183under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessAtribución 4.0 Internacional (CC BY 4.0)http://purl.org/coar/access_right/c_abf2https://www.mdpi.com/2076-3417/12/1/183A Simulation Analysis of an Influenza Vaccine Production Plant in Areas of High Humanitarian Flow. A Preliminary Study for the Region of Norte de Santander (Colombia)Artículo de revistahttp://purl.org/coar/resource_type/c_6501http://purl.org/coar/resource_type/c_2df8fbb1Textinfo:eu-repo/semantics/articlehttp://purl.org/redcol/resource_type/ARTinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/version/c_970fb48d4fbd8a85modeling processSuperPro Designer®cell culturepublic healthdeveloping countriesReed, C.; Chaves, S.S.; Kirley, P.D.; Emerson, R.; Aragon, D.; Hancock, E.B.; Butler, L.; Baumbach, J.; Hollick, G.; Bennett, N.M.; et al. Estimating Influenza Disease Burden from Population-Based Surveillance Data in the United States. PLoS ONE 2015, 10, e0118369. [CrossRef] [PubMed]Instituto Nacional de Salud. Acute Respiratory Infection Event Report, Colombia, 2019. Available online: https://www.ins.gov.co/ buscador-eventos/Informesdeevento/INFECCIÓN%20RESPIRATORIA%20AGUDA_2019.pdf (accessed on 11 September 2021).International Organization for Migration. DTM Survey—Vocation of Venezuelan Population to Stay in Colombia, Colombia, 2020. Available online: https://colombia.iom.int/sites/colombia/files/EYE/Vocacion/INFORME%20DTM%20VILLA%20DEL%20 ROSARIO.pdf (accessed on 10 December 2021).Ministerio de Salud y Protección Social de Colombia. Ten-Year Public Health Plan 2012–2021 of Colombia. 2012. Available online: https://www3.paho.org/hq/index.php?option=com_content&view=article&id=8777:2013-plan-decenal-salud-publica2012-2021-colombia&Itemid=40264&lang=es (accessed on 11 September 2021).Ministerio de Salud y Protección Social de Colombia. ABC of the Ten-Year Public Health Plan. Available online: https: //www.minsalud.gov.co/sites/rid/Lists/BibliotecaDigital/RIDE/VS/ED/PSP/IMP_4feb+ABCminsalud.pdf (accessed on 11 September 2021).Instituto Departamental de Salud de Norte de Santander. Health Situation Analysis with the Social Determinants Model Norte de Santander Department 2019, Colombia. 2019. 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[CrossRef]Tapia, F.; Vázquez-Ramírez, D.; Genzel, Y.; Reichl, U. Bioreactors for high cell density and continuous multi-stage cultivations: Options for process intensification in cell culture-based viral vaccine production. Appl. Microbiol. Biotechnol. 2016, 100, 2121–2132. [CrossRef]Xu, J.; Xu, X.; Huang, C.; Angelo, J.; Oliveira, C.L.; Xu, M.; Xu, X.; Temel, D.; Ding, J.; Ghose, S.; et al. Biomanufacturing evolution from conventional to intensified processes for productivity improvement: A case study. MAbs 2020, 12, 1770669. [CrossRef]Rubio, A.P.; Eiros, J.M. Cell culture-derived flu vaccine: Present and future. Hum. Vaccines Immunother. 2018, 14, 1874–1882. [CrossRef] [PubMed]Lee, B.Y.; Connor, D.L.; Wateska, A.R.; Norman, B.A.; Rajgopal, J.; Cakouros, B.E.; Chen, S.-I.; Claypool, E.G.; Haidari, L.A.; Karir, V.; et al. Landscaping the structures of GAVI country vaccine supply chains and testing the effects of radical redesign. Vaccine 2015, 33, 4451–4458. 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 incorporada en las Obras Colectivas.

b.	Distribuir copias o fonogramas de las Obras, exhibirlas públicamente, ejecutarlas públicamente y/o ponerlas a disposición pública, incluyéndolas como incorporadas en Obras Colectivas, según corresponda.

c.	Distribuir copias de las Obras Derivadas que se generen, exhibirlas públicamente, ejecutarlas públicamente y/o ponerlas a disposición pública.
Los derechos mencionados anteriormente pueden ser ejercidos en todos los medios y formatos, actualmente conocidos o que se inventen en el futuro. Los derechos antes mencionados incluyen el derecho a realizar dichas modificaciones en la medida que sean técnicamente necesarias para ejercer los derechos en otro medio o formatos, pero de otra manera usted no está autorizado para realizar obras derivadas. Todos los derechos no otorgados expresamente por el Licenciante quedan por este medio reservados, incluyendo pero sin limitarse a aquellos que se mencionan en las secciones 4(d) y 4(e).

4. Restricciones.
La licencia otorgada en la anterior Sección 3 está expresamente sujeta y limitada por las siguientes restricciones:

a.	Usted puede distribuir, exhibir públicamente, ejecutar públicamente, o poner a disposición pública la Obra sólo bajo las condiciones de esta Licencia, y Usted debe incluir una copia de esta licencia o del Identificador Universal de Recursos de la misma con cada copia de la Obra que distribuya, exhiba públicamente, ejecute públicamente o ponga a disposición pública. No es posible ofrecer o imponer ninguna condición sobre la Obra que altere o limite las condiciones de esta Licencia o el ejercicio de los derechos de los destinatarios otorgados en este documento. No es posible sublicenciar la Obra. Usted debe mantener intactos todos los avisos que hagan referencia a esta Licencia y a la cláusula de limitación de garantías. Usted no puede distribuir, exhibir públicamente, ejecutar públicamente, o poner a disposición pública la Obra con alguna medida tecnológica que controle el acceso o la utilización de ella de una forma que sea inconsistente con las condiciones de esta Licencia. Lo anterior se aplica a la Obra incorporada a una Obra Colectiva, pero esto no exige que la Obra Colectiva aparte de la obra misma quede sujeta a las condiciones de esta Licencia. Si Usted crea una Obra Colectiva, previo aviso de cualquier Licenciante debe, en la medida de lo posible, eliminar de la Obra Colectiva cualquier referencia a dicho Licenciante o al Autor Original, según lo solicitado por el Licenciante y conforme lo exige la cláusula 4(c).

b.	Usted no puede ejercer ninguno de los derechos que le han sido otorgados en la Sección 3 precedente de modo que estén principalmente destinados o directamente dirigidos a conseguir un provecho comercial o una compensación monetaria privada. El intercambio de la Obra por otras obras protegidas por derechos de autor, ya sea a través de un sistema para compartir archivos digitales (digital file-sharing) o de cualquier otra manera no será considerado como estar destinado principalmente o dirigido directamente a conseguir un provecho comercial o una compensación monetaria privada, siempre que no se realice un pago mediante una compensación monetaria en relación con el intercambio de obras protegidas por el derecho de autor.

c.	Si usted distribuye, exhibe públicamente, ejecuta públicamente o ejecuta públicamente en forma digital la Obra o cualquier Obra Derivada u Obra Colectiva, Usted debe mantener intacta toda la información de derecho de autor de la Obra y proporcionar, de forma razonable según el medio o manera que Usted esté utilizando: (i) el nombre del Autor Original si está provisto (o seudónimo, si fuere aplicable), y/o (ii) el nombre de la parte o las partes que el Autor Original y/o el Licenciante hubieren designado para la atribución (v.g., un instituto patrocinador, editorial, publicación) en la información de los derechos de autor del Licenciante, términos de servicios o de otras formas razonables; el título de la Obra si está provisto; en la medida de lo razonablemente factible y, si está provisto, el Identificador Uniforme de Recursos (Uniform Resource Identifier) que el Licenciante especifica para ser asociado con la Obra, salvo que tal URI no se refiera a la nota sobre los derechos de autor o a la información sobre el licenciamiento de la Obra; y en el caso de una Obra Derivada, atribuir el crédito identificando el uso de la Obra en la Obra Derivada (v.g., "Traducción Francesa de la Obra del Autor Original," o "Guión Cinematográfico basado en la Obra original del Autor Original"). Tal crédito puede ser implementado de cualquier forma razonable; en el caso, sin embargo, de Obras Derivadas u Obras Colectivas, tal crédito aparecerá, como mínimo, donde aparece el crédito de cualquier otro autor comparable y de una manera, al menos, tan destacada como el crédito de otro autor comparable.

d.	Para evitar toda confusión, el Licenciante aclara que, cuando la obra es una composición musical:

i.	Regalías por interpretación y ejecución bajo licencias generales. El Licenciante se reserva el derecho exclusivo de autorizar la ejecución pública o la ejecución pública digital de la obra y de recolectar, sea individualmente o a través de una sociedad de gestión colectiva de derechos de autor y derechos conexos (por ejemplo, SAYCO), las regalías por la ejecución pública o por la ejecución pública digital de la obra (por ejemplo Webcast) licenciada bajo licencias generales, si la interpretación o ejecución de la obra está primordialmente orientada por o dirigida a la obtención de una ventaja comercial o una compensación monetaria privada.

ii.	Regalías por Fonogramas. El Licenciante se reserva el derecho exclusivo de recolectar, individualmente o a través de una sociedad de gestión colectiva de derechos de autor y derechos conexos (por ejemplo, los consagrados por la SAYCO), una agencia de derechos musicales o algún agente designado, las regalías por cualquier fonograma que Usted cree a partir de la obra (“versión cover”) y distribuya, en los términos del régimen de derechos de autor, si la creación o distribución de esa versión cover está primordialmente destinada o dirigida a obtener una ventaja comercial o una compensación monetaria privada.

e.	Gestión de Derechos de Autor sobre Interpretaciones y Ejecuciones Digitales (WebCasting). Para evitar toda confusión, el Licenciante aclara que, cuando la obra sea un fonograma, el Licenciante se reserva el derecho exclusivo de autorizar la ejecución pública digital de la obra (por ejemplo, webcast) y de recolectar, individualmente o a través de una sociedad de gestión colectiva de derechos de autor y derechos conexos (por ejemplo, ACINPRO), las regalías por la ejecución pública digital de la obra (por ejemplo, webcast), sujeta a las disposiciones aplicables del régimen de Derecho de Autor, si esta ejecución pública digital está primordialmente dirigida a obtener una ventaja comercial o una compensación monetaria privada.

5. Representaciones, Garantías y Limitaciones de Responsabilidad.
A MENOS QUE LAS PARTES LO ACORDARAN DE OTRA FORMA POR ESCRITO, EL LICENCIANTE OFRECE LA OBRA (EN EL ESTADO EN EL QUE SE ENCUENTRA) “TAL CUAL”, SIN BRINDAR GARANTÍAS DE CLASE ALGUNA RESPECTO DE LA OBRA, YA SEA EXPRESA, IMPLÍCITA, LEGAL O CUALQUIERA OTRA, INCLUYENDO, SIN LIMITARSE A ELLAS, GA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