Kinetic analysis of cell decay during the filling process: Application to lot size determination in manufacturing systems for human induced pluripotent and mesenchymal stem cells

Kagihiro, Masashi; Fukumori, Kazuhiro; Aoki, Takuya; Ungkulpasvich, Umbhorn; Mizutani, Manabu; Viravaidya-Pasuwat, Kwanchanok; Kino‐oka, Masahiro

doi:10.1016/j.bej.2017.11.019

Cited by 9 publications

(9 citation statements)

References 18 publications

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“…In this study, we used the apparent specific growth rate ( μ app ) as a performance index to quantitatively assess cell quality. This index can be calculated based on conventional cell counting methods, and as such can be applied universally across different cell types and processes [8], [9].…”

Section: Discussionmentioning

confidence: 99%

Variation in the manufacturing reproducibility of autologous cell-based products depending on raw material shipment conditions

Mizutani

Samejima

Ashiba

et al. 2019

Regenerative Therapy

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To prepare an autologous cell-based product in a cell processing facility, the raw material, which is collected from a patient, must first be shipped from a medical institution to the facility. The quality of this raw material varies depending on the patient, and variations due to transport methods also occur. Because the quality must be uniform and manufacturing processes need to be adjusted to account for these variations, determining the effect of shipment conditions on raw materials is very important for estimating cell manufacturability in the process design. In this study, a group of medical institutions located in different areas requested similar cell-based products processed by the same manufacturing method to a company that is licensed under the Act on the Safety of Regenerative Medicine in Japan. Manufacturing reproducibility was analyzed based on 456 cell batches received from two clinics that were processed used the same manufacturing method. The specific growth rates that were observed in the early growth phase supposed that the proliferative potential of the primary cells in the raw material was influenced by transit time. Simultaneously, the variation of the specific growth rates in the late phase were supposed to be hardly occurred. Thus, this study evaluated shipping conditions of the raw materials for an autologous cell-based product, and a strategy for verifying the influence of transportation on quality in manufacturing was suggested.

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Section: Discussionmentioning

confidence: 99%

Variation in the manufacturing reproducibility of autologous cell-based products depending on raw material shipment conditions

Mizutani

Samejima

Ashiba

et al. 2019

Regenerative Therapy

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“…During the steps of filling, cryopreservation/thawing, and attachment, the hiPS cells are damaged, as shown by Kagihiro et al. [11]. They measured the ratio of the living and dead cells, i.e., the survival ratio, in each of the three steps at t S = {0, 1, 2, 4} h. It was observed that, in the steps of filling and attachment, the survival ratio decreased with the increasing t S , whereas in cryopreservation/thawing, there was no strong relationship between the survival ratio and t S .…”

Section: Methodsmentioning

confidence: 99%

“…The dependency of the damage on t S in each step was determined based on the characteristics reported by Kagihiro et al. [11]. The strategy in this work is to compare the types of damage defined in Eqs.…”

Section: Methodsmentioning

confidence: 99%

“…” Kagihiro et al. [11] showed that the number of living cells decreases with the filling time, because the cells are damaged, e.g., by suspension, during filling. Thus, in determining the lot size, one has to pay attention to such a change in cell quality.…”

Section: Introductionmentioning

confidence: 99%

“…The novelty of the work is in the integrated nature of the model for lot size simulation and determination, which was built on top of the experimental findings by Kagihiro et al. [11].…”

Section: Introductionmentioning

confidence: 99%

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A distribution-based approach for determining lot sizes in the filling of human-induced pluripotent stem cells

Suigyama

Shiokaramatsu

Kino‐oka

2019

Regenerative Therapy

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IntroductionToward the commercial production of human-induced pluripotent stem (hiPS) cells, the process design and operation have to be standardized. Considering the change in cell quality during filling of the hiPS cells into containers, lot sizing during filling also needs to be standardized.MethodsWe present a distribution-based approach that can be used for determining the lot sizes in the filling of hiPS cells by considering change in cell quality during filling. The approach describes the “survival capability” of the cells as a continuous probability distribution, and expresses the change in quality during filling by “trimming” the distribution.ResultsA lognormal distribution was assumed as the survival capability distribution of the cells that were to be filled. The distributions after different filling times were calculated, which were compared with the distribution of the initial filling time regarding the yield of the cells and the similarity. These conditions served as strong quality constraints in determining an economically optimal lot size.ConclusionsThe presented conceptual approach would be effective in determining the lot size considering the change in cell quality during filling. For actual application, measuring the distribution information on the survival capability of hiPS cells is encouraged.

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Apoptosis‐based method for determining lot sizes in the filling of human‐induced pluripotent stem cells

Sugiyama

Shiokaramatsu

Kagihiro

et al. 2020

J Tissue Eng Regen Med

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Standardization in process design and operation is needed in the commercial production of human-induced pluripotent stem (hiPS) cells. Lot sizing in the filling of hiPS cells into containers, a part of the preservation process, also needs to be standardized because of the temporal changes in cell quality during the process. Here, we present an apoptosis-based method that can determine lot sizes in the filling of hiPS cells considering temporal changes in cell quality. Two indicators were developed for (i) the cell quality change using reactive oxygen species (ROS) measurement and (ii) the cell survival and probability of filling success, which are parts of the lot-sizing problem. Using computational simulation, a map out of the optimal lot size was produced that minimized the expected production costs at a given cell demand and an acceptable change in cell quality. At a filling temperature of 4 C, the largest possible lot size was calculated as 6 L (corresponding to a filling time of 125 min). The results of a sensitivity analysis recommended cold filling or the addition of an antioxidant. The presented method is effective to determine the lot size considering the change in cell quality during filling. The study uniquely combines the experimental results with mathematical modeling and computational simulation techniques. The map out of the optimal lot size could guide the development of industrial filling processes of hiPS cells.

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Kinetic analysis of cell decay during the filling process: Application to lot size determination in manufacturing systems for human induced pluripotent and mesenchymal stem cells

Cited by 9 publications

References 18 publications

Variation in the manufacturing reproducibility of autologous cell-based products depending on raw material shipment conditions

Variation in the manufacturing reproducibility of autologous cell-based products depending on raw material shipment conditions

A distribution-based approach for determining lot sizes in the filling of human-induced pluripotent stem cells

Apoptosis‐based method for determining lot sizes in the filling of human‐induced pluripotent stem cells

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