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Global Sensitivity Analysis as Good Modelling Practices tool for the identification of the most influential process parameters of the primary drying step during freeze-drying

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Abstract
Pharmaceutical batch freeze-drying is commonly used to improve the stability of biological therapeutics. The primary drying step is regulated by the dynamic settings of the adaptable process variables, shelf temperature T-s and chamber pressure P-c. Mechanistic modelling of the primary drying step leads to the optimal dynamic combination of these adaptable process variables in function of time. According to Good Modelling Practices, a Global Sensitivity Analysis (GSA) is essential for appropriate model building. In this study, both a regression based and variance-based GSA were conducted on a validated mechanistic primary drying model to estimate the impact of several model input parameters on two output variables, the product temperature at the sublimation front T-i and the sublimation rate m(sub). T-s; was identified as most influential parameter on both T-i and m(sub), followed by P-c and the dried product mass transfer resistance alpha(Rp) for 71 and m(sub), respectively. The GSA findings were experimentally validated for m(sub) via a Design of Experiments (DoE) approach. The results indicated that GSA is a very useful tool for the evaluation of the impact of different process variables on the model outcome, leading to essential process knowledge, without the need for time-consuming experiments (e.g., DoE).
Keywords
BIOMATH, Freeze-drying, Mathematical modelling, Global Sensitivity Analysis, DYNAMIC DESIGN SPACE, PHARMACEUTICAL LYOPHILIZATION, UNCERTAINTY ANALYSIS, MASS-TRANSFER, QUALITY, FORMULATIONS, PROPAGATION, RESISTANCE, PRODUCT, IMPACT

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MLA
Van Bockstal, Pieter-Jan, Séverine Mortier, Jos Corver, et al. “Global Sensitivity Analysis as Good Modelling Practices Tool for the Identification of the Most Influential Process Parameters of the Primary Drying Step During Freeze-drying.” EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS 123 (2018): 108–116. Print.
APA
Van Bockstal, P.-J., Mortier, S., Corver, J., Nopens, I., Gernaey, K. V., & De Beer, T. (2018). Global Sensitivity Analysis as Good Modelling Practices tool for the identification of the most influential process parameters of the primary drying step during freeze-drying. EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, 123, 108–116.
Chicago author-date
Van Bockstal, Pieter-Jan, Séverine Mortier, Jos Corver, Ingmar Nopens, Krist V Gernaey, and Thomas De Beer. 2018. “Global Sensitivity Analysis as Good Modelling Practices Tool for the Identification of the Most Influential Process Parameters of the Primary Drying Step During Freeze-drying.” European Journal of Pharmaceutics and Biopharmaceutics 123: 108–116.
Chicago author-date (all authors)
Van Bockstal, Pieter-Jan, Séverine Mortier, Jos Corver, Ingmar Nopens, Krist V Gernaey, and Thomas De Beer. 2018. “Global Sensitivity Analysis as Good Modelling Practices Tool for the Identification of the Most Influential Process Parameters of the Primary Drying Step During Freeze-drying.” European Journal of Pharmaceutics and Biopharmaceutics 123: 108–116.
Vancouver
1.
Van Bockstal P-J, Mortier S, Corver J, Nopens I, Gernaey KV, De Beer T. Global Sensitivity Analysis as Good Modelling Practices tool for the identification of the most influential process parameters of the primary drying step during freeze-drying. EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS. 2018;123:108–16.
IEEE
[1]
P.-J. Van Bockstal, S. Mortier, J. Corver, I. Nopens, K. V. Gernaey, and T. De Beer, “Global Sensitivity Analysis as Good Modelling Practices tool for the identification of the most influential process parameters of the primary drying step during freeze-drying,” EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS, vol. 123, pp. 108–116, 2018.
@article{8581919,
  abstract     = {Pharmaceutical batch freeze-drying is commonly used to improve the stability of biological therapeutics. The primary drying step is regulated by the dynamic settings of the adaptable process variables, shelf temperature T-s and chamber pressure P-c. Mechanistic modelling of the primary drying step leads to the optimal dynamic combination of these adaptable process variables in function of time. According to Good Modelling Practices, a Global Sensitivity Analysis (GSA) is essential for appropriate model building. In this study, both a regression based and variance-based GSA were conducted on a validated mechanistic primary drying model to estimate the impact of several model input parameters on two output variables, the product temperature at the sublimation front T-i and the sublimation rate m(sub). T-s; was identified as most influential parameter on both T-i and m(sub), followed by P-c and the dried product mass transfer resistance alpha(Rp) for 71 and m(sub), respectively. The GSA findings were experimentally validated for m(sub) via a Design of Experiments (DoE) approach. The results indicated that GSA is a very useful tool for the evaluation of the impact of different process variables on the model outcome, leading to essential process knowledge, without the need for time-consuming experiments (e.g., DoE).},
  author       = {Van Bockstal, Pieter-Jan and Mortier, Séverine and Corver, Jos and Nopens, Ingmar and Gernaey, Krist V and De Beer, Thomas},
  issn         = {0939-6411},
  journal      = {EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS},
  keywords     = {BIOMATH,Freeze-drying,Mathematical modelling,Global Sensitivity Analysis,DYNAMIC DESIGN SPACE,PHARMACEUTICAL LYOPHILIZATION,UNCERTAINTY ANALYSIS,MASS-TRANSFER,QUALITY,FORMULATIONS,PROPAGATION,RESISTANCE,PRODUCT,IMPACT},
  language     = {eng},
  pages        = {108--116},
  title        = {Global Sensitivity Analysis as Good Modelling Practices tool for the identification of the most influential process parameters of the primary drying step during freeze-drying},
  url          = {http://dx.doi.org/10.1016/j.ejpb.2017.12.006},
  volume       = {123},
  year         = {2018},
}

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