---
_id: '10193'
abstract:
- lang: eng
  text: Development and optimization of biopharmaceutical production processes with
    cell cultures is cost- and time-consuming and often performed rather empirically.
    Efficient optimization of multiple objectives such as process time, viable cell
    density, number of operating steps & cultivation scales, required medium, amount
    of product as well as product quality depicts a promising approach. This contribution
    presents a workflow which couples uncertainty-based upstream simulation and Bayes
    optimization using Gaussian processes. Its application is demonstrated in a simulation
    case study for a relevant industrial task in process development, the design of
    a robust cell culture expansion process (seed train), meaning that despite uncertainties
    and variabilities concerning cell growth, low variations of viable cell density
    during the seed train are obtained. Compared to a non-optimized reference seed
    train, the optimized process showed much lower deviation rates regarding viable
    cell densities (<10% instead of 41.7%) using five or four shake flask scales and
    seed train duration could be reduced by 56 h from 576 h to 520 h. Overall, it
    is shown that applying Bayes optimization allows for optimization of a multi-objective
    optimization function with several optimizable input variables and under a considerable
    amount of constraints with a low computational effort. This approach provides
    the potential to be used in the form of a decision tool, e.g., for the choice
    of an optimal and robust seed train design or for further optimization tasks within
    process development.
author:
- first_name: Tanja
  full_name: Hernández Rodriguez, Tanja
  id: '52466'
  last_name: Hernández Rodriguez
- first_name: Anton
  full_name: Sekulic, Anton
  last_name: Sekulic
- first_name: Markus
  full_name: Lange-Hegermann, Markus
  id: '71761'
  last_name: Lange-Hegermann
- first_name: Björn
  full_name: Frahm, Björn
  id: '45666'
  last_name: Frahm
citation:
  ama: 'Hernández Rodriguez T, Sekulic A, Lange-Hegermann M, Frahm B. Designing robust
    biotechnological processes regarding variabilities using multi-objective optimization
    applied to a biopharmaceutical seed train design. In: Pörtner R, Möller J, eds.
    <i>Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing</i>.
    Vol special issue. Processes : open access journal. MDPI; 2022:21-48. doi:<a href="https://doi.org/10.3390/pr10050883">https://doi.org/10.3390/pr10050883</a>'
  apa: 'Hernández Rodriguez, T., Sekulic, A., Lange-Hegermann, M., &#38; Frahm, B.
    (2022). Designing robust biotechnological processes regarding variabilities using
    multi-objective optimization applied to a biopharmaceutical seed train design.
    In R. Pörtner &#38; J. Möller (Eds.), <i>Bioprocess Systems Engineering Applications
    in Pharmaceutical Manufacturing: Vol. special issue</i> (pp. 21–48). MDPI. <a
    href="https://doi.org/10.3390/pr10050883">https://doi.org/10.3390/pr10050883</a>'
  bjps: '<b>Hernández Rodriguez T <i>et al.</i></b> (2022) Designing Robust Biotechnological
    Processes Regarding Variabilities Using Multi-Objective Optimization Applied to
    a Biopharmaceutical Seed Train Design. In Pörtner R and Möller J (eds), <i>Bioprocess
    Systems Engineering Applications in Pharmaceutical Manufacturing</i>, vol. special
    issue. Basel: MDPI, pp. 21–48.'
  chicago: 'Hernández Rodriguez, Tanja, Anton Sekulic, Markus Lange-Hegermann, and
    Björn Frahm. “Designing Robust Biotechnological Processes Regarding Variabilities
    Using Multi-Objective Optimization Applied to a Biopharmaceutical Seed Train Design.”
    In <i>Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing</i>,
    edited by Ralf Pörtner and Johannes Möller, special issue:21–48. Processes : Open
    Access Journal. Basel: MDPI, 2022. <a href="https://doi.org/10.3390/pr10050883">https://doi.org/10.3390/pr10050883</a>.'
  chicago-de: 'Hernández Rodriguez, Tanja, Anton Sekulic, Markus Lange-Hegermann und
    Björn Frahm. 2022. Designing robust biotechnological processes regarding variabilities
    using multi-objective optimization applied to a biopharmaceutical seed train design.
    In: <i>Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing</i>,
    hg. von Ralf Pörtner und Johannes Möller, special issue:21–48. Processes : open
    access journal. Basel: MDPI. doi:<a href="https://doi.org/10.3390/pr10050883">https://doi.org/10.3390/pr10050883</a>,
    .'
  din1505-2-1: '<span style="font-variant:small-caps;">Hernández Rodriguez, Tanja</span>
    ; <span style="font-variant:small-caps;">Sekulic, Anton</span> ; <span style="font-variant:small-caps;">Lange-Hegermann,
    Markus</span> ; <span style="font-variant:small-caps;">Frahm, Björn</span>: Designing
    robust biotechnological processes regarding variabilities using multi-objective
    optimization applied to a biopharmaceutical seed train design. In: <span style="font-variant:small-caps;">Pörtner,
    R.</span> ; <span style="font-variant:small-caps;">Möller, J.</span> (Hrsg.):
    <i>Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing</i>,
    <i>Processes : open access journal</i>. Bd. special issue. Basel : MDPI, 2022,
    S. 21–48'
  havard: 'T. Hernández Rodriguez, A. Sekulic, M. Lange-Hegermann, B. Frahm, Designing
    robust biotechnological processes regarding variabilities using multi-objective
    optimization applied to a biopharmaceutical seed train design, in: R. Pörtner,
    J. Möller (Eds.), Bioprocess Systems Engineering Applications in Pharmaceutical
    Manufacturing, MDPI, Basel, 2022: pp. 21–48.'
  ieee: 'T. Hernández Rodriguez, A. Sekulic, M. Lange-Hegermann, and B. Frahm, “Designing
    robust biotechnological processes regarding variabilities using multi-objective
    optimization applied to a biopharmaceutical seed train design,” in <i>Bioprocess
    Systems Engineering Applications in Pharmaceutical Manufacturing</i>, vol. special
    issue, R. Pörtner and J. Möller, Eds. Basel: MDPI, 2022, pp. 21–48. doi: <a href="https://doi.org/10.3390/pr10050883">https://doi.org/10.3390/pr10050883</a>.'
  mla: Hernández Rodriguez, Tanja, et al. “Designing Robust Biotechnological Processes
    Regarding Variabilities Using Multi-Objective Optimization Applied to a Biopharmaceutical
    Seed Train Design.” <i>Bioprocess Systems Engineering Applications in Pharmaceutical
    Manufacturing</i>, edited by Ralf Pörtner and Johannes Möller, vol. special issue,
    MDPI, 2022, pp. 21–48, <a href="https://doi.org/10.3390/pr10050883">https://doi.org/10.3390/pr10050883</a>.
  short: 'T. Hernández Rodriguez, A. Sekulic, M. Lange-Hegermann, B. Frahm, in: R.
    Pörtner, J. Möller (Eds.), Bioprocess Systems Engineering Applications in Pharmaceutical
    Manufacturing, MDPI, Basel, 2022, pp. 21–48.'
  ufg: '<b>Hernández Rodriguez, Tanja u. a.</b>: Designing robust biotechnological
    processes regarding variabilities using multi-objective optimization applied to
    a biopharmaceutical seed train design, in: <i>Pörtner, Ralf/Möller, Johannes (Hgg.)</i>:
    Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing, Band
    <i>special issue</i>, Basel 2022 (Processes : open access journal),  S. 21–48.'
  van: 'Hernández Rodriguez T, Sekulic A, Lange-Hegermann M, Frahm B. Designing robust
    biotechnological processes regarding variabilities using multi-objective optimization
    applied to a biopharmaceutical seed train design. In: Pörtner R, Möller J, editors.
    Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing. Basel:
    MDPI; 2022. p. 21–48. (Processes : open access journal; vol. special issue).'
date_created: 2023-08-08T12:58:36Z
date_updated: 2023-08-16T09:24:16Z
department:
- _id: DEP4000
doi: https://doi.org/10.3390/pr10050883
editor:
- first_name: Ralf
  full_name: Pörtner, Ralf
  last_name: Pörtner
- first_name: Johannes
  full_name: Möller, Johannes
  last_name: Möller
keyword:
- Gaussian processes
- Bayes optimization
- Pareto optimization
- multi-objective
- cell culture
- seed train
language:
- iso: eng
page: 21-48
place: Basel
publication: Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing
publication_identifier:
  eisbn:
  - 978-3-0365-5209-5
  eissn:
  - 2227-9717
  isbn:
  - 978-3-0365-5210-1
publication_status: published
publisher: MDPI
quality_controlled: '1'
series_title: 'Processes : open access journal'
status: public
title: Designing robust biotechnological processes regarding variabilities using multi-objective
  optimization applied to a biopharmaceutical seed train design
type: book_chapter
user_id: '83781'
volume: special issue
year: '2022'
...
---
_id: '7983'
abstract:
- lang: eng
  text: For the manufacturing of complex biopharmaceuticals using bioreactors with
    cultivated mammalian cells, high product concentration is an important objective.
    The phenotype of the cells in a reactor plays an important role. Are clonal cell
    populations showing high cell-specific growth rates more favorable than cell lines
    with higher cell-specific productivities or vice versa? Five clonal Chinese hamster
    ovary cell populations were analyzed based on the data of a 3-month-stability
    study. We adapted a mechanistic cell culture model to the experimental data of
    one such clonally derived cell population. Uncertainties and prior knowledge concerning
    model parameters were considered using Bayesian parameter estimations. This model
    was used then to define an inoculum train protocol. Based on this, we subsequently
    simulated the impacts of differences in growth rates (±10%) and production rates
    (±10% and ±50%) on the overall cultivation time, including making the inoculum
    train cultures; the final production phase, the volumetric titer in that bioreactor
    and the ratio of both, defined as overall process productivity. We showed thus
    unequivocally that growth rates have a higher impact (up to three times) on overall
    process productivity and for product output per year, whereas cells with higher
    productivity can potentially generate higher product concentrations in the production
    vessel.
author:
- first_name: Tanja
  full_name: Hernández Rodriguez, Tanja
  id: '52466'
  last_name: Hernández Rodriguez
- first_name: Sophie
  full_name: Morerod, Sophie
  last_name: Morerod
- first_name: Ralf
  full_name: Pörtner, Ralf
  last_name: Pörtner
- first_name: Florian M.
  full_name: Wurm, Florian M.
  last_name: Wurm
- first_name: Björn
  full_name: Frahm, Björn
  id: '45666'
  last_name: Frahm
citation:
  ama: 'Hernández Rodriguez T, Morerod S, Pörtner R, Wurm FM, Frahm B. Considerations
    of the impacts of cell-specific growth and production rate on clone selection
    – a simulation study. In: <i>Bioprocess Systems Engineering Applications in Pharmaceutical
    Manufacturing</i>. Vol special issue. Processes : open access journal . MDPI;
    2021:49-74. doi:<a href="https://doi.org/10.3390/pr9060964">10.3390/pr9060964</a>'
  apa: 'Hernández Rodriguez, T., Morerod, S., Pörtner, R., Wurm, F. M., &#38; Frahm,
    B. (2021). Considerations of the impacts of cell-specific growth and production
    rate on clone selection – a simulation study. In <i>Bioprocess Systems Engineering
    Applications in Pharmaceutical Manufacturing: Vol. special issue</i> (pp. 49–74).
    MDPI. <a href="https://doi.org/10.3390/pr9060964">https://doi.org/10.3390/pr9060964</a>'
  bjps: '<b>Hernández Rodriguez T <i>et al.</i></b> (2021) Considerations of the Impacts
    of Cell-Specific Growth and Production Rate on Clone Selection – a Simulation
    Study. <i>Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing</i>,
    vol. special issue. Basel: MDPI, pp. 49–74.'
  chicago: 'Hernández Rodriguez, Tanja, Sophie Morerod, Ralf Pörtner, Florian M. Wurm,
    and Björn Frahm. “Considerations of the Impacts of Cell-Specific Growth and Production
    Rate on Clone Selection – a Simulation Study.” In <i>Bioprocess Systems Engineering
    Applications in Pharmaceutical Manufacturing</i>, special issue:49–74. Processes :
    Open Access Journal . Basel: MDPI, 2021. <a href="https://doi.org/10.3390/pr9060964">https://doi.org/10.3390/pr9060964</a>.'
  chicago-de: 'Hernández Rodriguez, Tanja, Sophie Morerod, Ralf Pörtner, Florian M.
    Wurm und Björn Frahm. 2021. Considerations of the impacts of cell-specific growth
    and production rate on clone selection – a simulation study. In: <i>Bioprocess
    Systems Engineering Applications in Pharmaceutical Manufacturing</i>, special
    issue:49–74. Processes : open access journal . Basel: MDPI. doi:<a href="https://doi.org/10.3390/pr9060964">10.3390/pr9060964</a>,
    .'
  din1505-2-1: '<span style="font-variant:small-caps;">Hernández Rodriguez, Tanja</span>
    ; <span style="font-variant:small-caps;">Morerod, Sophie</span> ; <span style="font-variant:small-caps;">Pörtner,
    Ralf</span> ; <span style="font-variant:small-caps;">Wurm, Florian M.</span> ;
    <span style="font-variant:small-caps;">Frahm, Björn</span>: Considerations of
    the impacts of cell-specific growth and production rate on clone selection – a
    simulation study. In: <i>Bioprocess Systems Engineering Applications in Pharmaceutical
    Manufacturing</i>, <i>Processes : open access journal </i>. Bd. special issue.
    Basel : MDPI, 2021, S. 49–74'
  havard: 'T. Hernández Rodriguez, S. Morerod, R. Pörtner, F.M. Wurm, B. Frahm, Considerations
    of the impacts of cell-specific growth and production rate on clone selection
    – a simulation study, in: Bioprocess Systems Engineering Applications in Pharmaceutical
    Manufacturing, MDPI, Basel, 2021: pp. 49–74.'
  ieee: 'T. Hernández Rodriguez, S. Morerod, R. Pörtner, F. M. Wurm, and B. Frahm,
    “Considerations of the impacts of cell-specific growth and production rate on
    clone selection – a simulation study,” in <i>Bioprocess Systems Engineering Applications
    in Pharmaceutical Manufacturing</i>, vol. special issue, Basel: MDPI, 2021, pp.
    49–74. doi: <a href="https://doi.org/10.3390/pr9060964">10.3390/pr9060964</a>.'
  mla: Hernández Rodriguez, Tanja, et al. “Considerations of the Impacts of Cell-Specific
    Growth and Production Rate on Clone Selection – a Simulation Study.” <i>Bioprocess
    Systems Engineering Applications in Pharmaceutical Manufacturing</i>, vol. special
    issue, MDPI, 2021, pp. 49–74, <a href="https://doi.org/10.3390/pr9060964">https://doi.org/10.3390/pr9060964</a>.
  short: 'T. Hernández Rodriguez, S. Morerod, R. Pörtner, F.M. Wurm, B. Frahm, in:
    Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing, MDPI,
    Basel, 2021, pp. 49–74.'
  ufg: '<b>Hernández Rodriguez, Tanja u. a.</b>: Considerations of the impacts of
    cell-specific growth and production rate on clone selection – a simulation study,
    in: o. Hg.: Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing,
    Band <i>special issue</i>, Basel 2021 (Processes : open access journal ),  S.
    49–74.'
  van: 'Hernández Rodriguez T, Morerod S, Pörtner R, Wurm FM, Frahm B. Considerations
    of the impacts of cell-specific growth and production rate on clone selection
    – a simulation study. In: Bioprocess Systems Engineering Applications in Pharmaceutical
    Manufacturing. Basel: MDPI; 2021. p. 49–74. (Processes : open access journal ;
    vol. special issue).'
date_created: 2022-05-05T12:55:52Z
date_updated: 2023-08-16T09:17:50Z
department:
- _id: DEP4021
doi: 10.3390/pr9060964
keyword:
- clonal cell population
- phenotypic diversity
- inoculum train
- uncertainty-based
- cell culture model
- biopharmaceutical manufacturing
language:
- iso: eng
page: 49-74
place: Basel
publication: Bioprocess Systems Engineering Applications in Pharmaceutical Manufacturing
publication_identifier:
  eisbn:
  - 978-3-0365-5209-5
  isbn:
  - 978-3-0365-5210-1
  issn:
  - '2227-9717 '
publication_status: published
publisher: MDPI
quality_controlled: '1'
series_title: 'Processes : open access journal '
status: public
title: Considerations of the impacts of cell-specific growth and production rate on
  clone selection – a simulation study
type: book_chapter
user_id: '83781'
volume: special issue
year: '2021'
...