Performance of a Pharmaceutical Single-Use Stirred Tank Operating at Different Filling Volumes: Mixing Time, Fluid Dynamics and Power Consumption

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Nice study of a sub-optimal, with respect to mixing, commercial system.  The square design, without baffles, makes the current study necessary compared to all the studies over the last 60 plus years on cylindrical missing systems using baffles and various impeller designs. 
My only suggestion is that this summary state I just made, or something similar, is made.  The use of a square shaped mixing vessel is very unusual.  

Author Response

Reviewer 1: "Nice study of a sub-optimal, with respect to mixing, commercial system.  The square design, without baffles, makes the current study necessary compared to all the studies over the last 60 plus years on cylindrical missing systems using baffles and various impeller designs. 
My only suggestion is that this summary state I just made, or something similar, is made.  The use of a square shaped mixing vessel is very unusual."

We thank the reviewer for the appreciation of the work, we have added the following sentence in the introduction:

" In this work, one of the single use bioreactor types, the Flexel-Levmixer by Sartorius, is investigated."

Reviewer 2 Report

Comments and Suggestions for Authors

The author described a pharmaceutical technology to optimize the mixing time and fluid power consumption, however, this manuscript is too simple to find out the novelty and some key results. Therefore, I regret to say that it is not possible to be published in this Journal.

Author Response

The author described a pharmaceutical technology to optimize the mixing time and fluid power consumption,

We thank the reviewer for the evaluation of our work. This work investigated the fluid dynamics of a single-use bioreactor currently used in the pharma industry. The overall aim of this work is to relate fluid dynamics with power consumption and mixing time. Such information is critical to the end user to operate with such a system at optimal performance.

however, this manuscript is too simple to find out the novelty and some key results. Therefore, I regret to say that it is not possible to be published in this Journal.

novelty of this work: for the first time experimental results of the fluid flow dynamics of the system are presented showing the drastic changes in the flow structure and the distribution of the velocity in 3 components. Cross validated experimental techniques are presented for the mixing time, showing a technique, ERT, which has industrial application, against a more precise and with high resolution techniques suche PLIF is. Mixing time information and power consumptions results are linked to provide a summary view of the performance of the single use reactor.

key results: drastic flow pattern changes varying the filling level; power consumptions are affected by the filling level, and this is explained form the change in the flow pattern. mixing time data are presented and linked to the power consumption to show optimal process conditions for the selection of more sustainable process conditions.

Moreover, given the very generic statement of the reviewer, it is difficult to understand what is not clear or what is not considered a key result.

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript investigates the hydrodynamic performance of single-use stirred tanks across varying filling heights and impeller speeds, focusing on mixing efficiency, power consumption, and energy use. It finds that the filling height significantly affects power consumption, flow dynamics, and mixing efficiency. I consider the content of this manuscript will meet the reading interests of the readers of the journal. However, there are figure illustration issues, and the discussion and explanation should be further improved. Therefore, I suggest giving a major revision and the authors need to clarify some issues or supply more validation data to enrich the content.

1. The literature review part needs to be greatly modified, and the current version of the literature is outdated. The authors should pay attention to the latest progress in this field, and some novel literature and methods are worth understanding and supplementing. The number of references is small (30+ references are suggested), and the author should add several frontier articles.

2. In Fig.1, Can you provide more detailed schematics or photos of the experimental setup?

3. How were the injection timings and synchronization challenges addressed in the experiments?

4. Could you clarify the differences between the transient signals observed from PIV and PLIF/ERT measurements? How do these techniques complement each other in terms of accuracy and reliability for determining mixing time?

5. The presentation of experimental methods, especially the comparison between PIV, PLIF, and ERT, could be clearer. The measurement techniques should be explained in a more accessible manner, for instance for PIV methods, referencing doi.org/10.1016/j.jclepro.2022.130470, and “Dynamic mode decomposition to classify cavitating flow...”). The current explanation may be challenging for readers unfamiliar with these techniques.

6. The experimental setup mentions variations in impeller speeds and fill heights but does not elaborate on the full range of these variables or their potential impact on the results. Would varying impeller geometry provide significant improvements in the results?

7. Did you analyze the impact of different impeller speeds (e.g., 90 or 110 rpm) on the observed trends? How different types of impellers or impeller configurations impact the mixing time and power consumption?

8. While the paper uses advanced experimental methods, the theoretical analysis of the results could be further expanded. Can you make detailed discussions on the theoretical models used to predict mixing time or power consumption?

9. How do the observed results align with or deviate from expected theoretical trends?  

10. Would the results of this study hold true when scaling up the system to larger volumes or production scales?

Comments on the Quality of English Language

The English could be improved to more clearly express the research.

Author Response

Reviewer 3:

The manuscript investigates the hydrodynamic performance of single-use stirred tanks across varying filling heights and impeller speeds, focusing on mixing efficiency, power consumption, and energy use. It finds that the filling height significantly affects power consumption, flow dynamics, and mixing efficiency. I consider the content of this manuscript will meet the reading interests of the readers of the journal. However, there are figure illustration issues, and the discussion and explanation should be further improved. Therefore, I suggest giving a major revision and the authors need to clarify some issues or supply more validation data to enrich the content.

We thank the reviewer for the comments, we hope the following answers will clarify the concerns:

1. The literature review part needs to be greatly modified, and the current version of the literature is outdated.                                                 

I regret to be in contrast with this part of the comment, given that in the introduction, I have avoided using recurring references and outdated. The oldest reference in the introduction is dated 2014 and the overall span is between 2014-2024.                                                                

The authors should pay attention to the latest progress in this field, and some novel literature and methods are worth understanding and supplementing. The number of references is small (30+ references are suggested), and the author should add several frontier articles.

 We have decided to limit the reference to a space of interest for this work, hence pharma applications or similar where PIV or other techniques investigated have been implemented.  We have added more recent references in the introduction and added references in the discussion.

2. In Fig.1,Can you provide more detailed schematics or photos of the experimental setup?           

We have added more pictures on Figure 1.

1. How were the injection timings and synchronization challenges addressed in the experiments?

The PLIF and ERT experiments were run with two people. For both techniques, the measurement was started before the injection was made, when the other operator was injecting it was annotated the number of frames at which corresponded the injection and this was defined as the time zero of each run. To ensure repeatability 3 experiments for each condition were repeated.

1. Could you clarify the differences between the transient signals observed from PIV and PLIF/ERT measurements? How do these techniques complement each other in terms of accuracy and reliability for determining mixing time?                                                                                         

 The PIV transient data corresponds to the variation of the velocity with the position of the impeller. Ensuring a sufficient number of time steps helps to reach a more reliable ensemble average velocity flow pattern.  PIV and PLIF/ERT are complementary, in fact, the mixing time is possible to determine only from PLIF/ERT. Comparing PLIF and ERT, the two techniques have different resolutions, where the first has a higher resolution compared to the second. however, the range of applicability is wider for the ERT that can be used for transparent or not transparent fluids, and it is used for industrial applications; on the contrary, PLIF is a pure research tool. Both tools are commonly used to measure mixing time. However,  ERT in the literature is mostly used with the circular sensor configuration. the difference in the transient data, as also described in the text, is due to the relative position of the impeller and the injection, the frequency of data acquisition which differs, and the areas of measurement which are different despite, they overlap. One goal of this work, in fact, was to determine the reliability of the ERT on the measurement of mixing time, given the lower resolution.

1.  The presentation of experimental methods, especially the comparison between PIV, PLIF, and ERT, could be clearer. The measurement techniques should be explained in a more accessible manner, for instance for PIV methods, referencing doi.org/10.1016/j.jclepro.2022.130470, and “Dynamic mode decomposition to classify cavitating flow...”). The current explanation may be challenging for readers unfamiliar with these techniques.                                                                   

We thank the reviewer for the comment, we have added some pictures to clarify the experimental set up. Figure 1b,c,d.

1. The experimental setup mentions variations in impeller speeds and fill heights but does not elaborate on the full range of these variables or their potential impact on the results. Would varying impeller geometry provide significant improvements in the results?                               

We have investigated the effect of impeller speed in the previous work, full characterization can be found in https://doi.org/10.1016/j.cherd.2024.02.023. The impeller geometry would affect drastically the fluid flow, however, this was not the core interest of this work which aims to understand the performance of a commercial system that has only this geometry available.

1. Did you analyze the impact of different impeller speeds (e.g., 90 or 110 rpm) on the observed trends?How different types of impellers or impeller configurations impact the mixing time and power consumption?                                                                                                                                         please refer to https://doi.org/10.1016/j.cherd.2024.02.023 for more info about effect of impeller speed. 
2. While the paper uses advanced experimental methods, the theoretical analysis of the results could be further expanded. Can you make detailed discussions on the theoretical models used to predict mixing time or power consumption?                                                       

For the power consumption, we have added the reference and this text: "Detailed information about the theoretical background of the torque measurements and standard operating procedure can be found in the previous work by Alberini et al. (2)." 

The theory behind is:

The power consumption, P, is given by:(1)P=ρPoN³D⁵where Po is the impeller power number, D is the impeller diameter and ρ is the density of the fluid. Alternatively, the power consumption can be obtained as:(2)P=2πNΓ

Substituting Eq. 1 in Eq. 2, Eq. 3 is obtained:(3)2πNΓ=ρPoN³D⁵

Finally, the equation of torque as a function of density, power number, diameter of the impeller and impeller speed is obtained as follows:(4)Γ=ρPoD⁵2πN².

For the mixing time in the literature only empirical correlations can be found like the Grenville correlation presented in this work, which are developed for different mixing systems (cylindrical tank). Again, the results generated are fundamentally important, for future CFD validations and possibly expand the theory.

1. How do the observed results align with or deviate from expected theoretical trends?                 

the main problem to compare with theoretical trends is that the Po values for such systems do not exist in the literature or they are not even available from the manufacturer. Knowing such values is critical to generate theoretical values. This is a reason why these results are important and unique. 

1. Would the results of this study hold true when scaling up the system to larger volumes or production scales?                                                                                                                         

This is an interesting question that now we don't have an answer, but we are still working on it. In fact, for these systems the manufacturer, increasing the size of the tank, keeps constant the size of the impeller to the current one; hence the ratio between the impeller and the tank size changes across scales. This makes a standard scale-up approach difficult. The reason for this choice is hidden in the power that a magnetic stirring can produce ( in the original vessel the stirring is provided with magnetic stirring due to hygienic reasons).

 

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The author revised significantly, and I suggest the current manuscript would be accepted in this Journal.

Comments on the Quality of English Language

The author should check the grammatical errors before publication.

Reviewer 3 Report

Comments and Suggestions for Authors

Basically the issues raised in comments are addressed.