Development of an Experimental Dead-End Microfiltration Layout and Process Repeatability Analysis

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In this manuscript, the author described the microfiltration technology to process the control of repeatable analysis. Although it looks interesting, it requires some typical revision to improve the paper quality. My comments are below:

1, The abstract is too short, and it is hard to mention the objective and main result. Please revise the abstract section.

2, There is only a brief description in the introduction section. Please write more of the previous research, and what is the new objective of the current research.

3, The figure images in this research are really simple, please use some softwares such as origin and matlab to figure out.

4, What's the difference between Fig. 6 and Fig. 7??

5, From the data usage, what is the main result of this research??

6, Conclusion is too long, please re-write this section.

Comments on the Quality of English Language

Please check the grammatical error and revise the descriptions.

Author Response

Dear Reviewer 1

Thank you for your time and comments.

Comments

Reviewer 1

In this manuscript, the author described the microfiltration technology to process the control of repeatable analysis. Although it looks interesting, it requires some typical revision to improve the paper quality. My comments are below:

1, The abstract is too short, and it is hard to mention the objective and main result. Please revise the abstract section.

2, There is only a brief description in the introduction section. Please write more of the previous research, and what is the new objective of the current research.

3, The figure images in this research are really simple, please use some softwares such as origin and matlab to figure out.

4, What's the difference between Fig. 6 and Fig. 7??

5, From the data usage, what is the main result of this research??

6, Conclusion is too long, please re-write this section

Response

1,2         The abstract and the introduction have been modified

3             Figure 1 modified with upper and lower fluid level

          All Excell figures drawn out in Matplotlib

4             Figure 7 (now Figure 9) is a zoom in of Figure 6 (now) Figure 8 with the focus on the beginning of the plunger movement. Caption modified to »Close up of Figure 8. Focus is on the beginning of the plunger movement.”

5          new chapter 4:

“4. Discussion

The presented system was used for flow measurements and dynamic tests. The main purpose of acquired dynamic data was calculation of the stress acting on the filter [20].”

The other result is identification of parameters influencing repeatability of the process and gathering data for validation of numerical simulations.

6          The whole paper was modified and Conclusion shortened.

Reviewer 2 Report

Comments and Suggestions for Authors

Development of an experimental dead-end microfiltration layout and process repeatability analysis

This study focused on the significance of microfiltration in the pharmaceutical industry, highlighting the challenges associated with filter selection and validation, both in terms of time and cost. The research focuses on the instrumentalization and process control of a laboratory-scale dead-end microfiltration layout, designed as a downscaled model of an actual production line.

The primary objectives of the study include filter validation and the analysis of process parameters that could impact filter operation. Notably, the emphasis is placed on identifying the most influential process parameters and their effects on the repeatability of pressure oscillations resulting from valve openings.

The study involves testing several filters ranging in sizes from 3.5 cm2 to 6900 cm2. The findings aim to provide recommendations for reducing the energy intake of the filter and enhancing the repeatability of the filtration process. This research contributes valuable insights to the optimization of microfiltration processes in the pharmaceutical industry, addressing key challenges associated with filter selection, validation, and operational efficiency.

Abstract:

Micro filtration is an important process in pharmaceutical industry. Filter selection and validation is time consuming and expensive process. The article covers the instrumentalization and process control of a laboratory scale dead-end microfiltration layout. The layout is downscale model of actual production line, and the goal is filter validation and analysis of process parameters which may influence filter operation. The focus is on identification of most influential process parameters and their influence on the repeatability of pressure oscillations caused by valve opening. Several filters in sizes between 3.5 cm2 and 6900 cm2 were tested and some recommendations suggested for reduction of energy intake of the filter and to improve repeatability of the process.

Special comments:

The abstract is short and might need more data!

Introduction is short as well and need to discuss more about membranes filtration and other studies.

Why the paper is not divided into regular sections? Abstract, Intro, M&M, Results & discussions, Conclusions, etc

Statistical analysis???

 

References are not enough although there are a lot about this subject that can be used in the study

Comments on the Quality of English Language

Minor!

Author Response

Dear Reviewer 2

Thank you for your time and comments. According to your comments you are an expert in this field. Thank you for your statement “This research contributes valuable insights to the optimization of microfiltration processes in the pharmaceutical industry, addressing key challenges associated with filter selection, validation, and operational efficiency.” It is exactly what we were trying to achieve, but I do not dare to write this in the paper.

Commnents

Reviewer 2

Development of an experimental dead-end microfiltration layout and process repeatability analysis

This study focused on the significance of microfiltration in the pharmaceutical industry, highlighting the challenges associated with filter selection and validation, both in terms of time and cost. The research focuses on the instrumentalization and process control of a laboratory-scale dead-end microfiltration layout, designed as a downscaled model of an actual production line.

The primary objectives of the study include filter validation and the analysis of process parameters that could impact filter operation. Notably, the emphasis is placed on identifying the most influential process parameters and their effects on the repeatability of pressure oscillations resulting from valve openings.

The study involves testing several filters ranging in sizes from 3.5 cm2 to 6900 cm2. The findings aim to provide recommendations for reducing the energy intake of the filter and enhancing the repeatability of the filtration process. This research contributes valuable insights to the optimization of microfiltration processes in the pharmaceutical industry, addressing key challenges associated with filter selection, validation, and operational efficiency.

Abstract:

Micro filtration is an important process in pharmaceutical industry. Filter selection and validation is time consuming and expensive process. The article covers the instrumentalization and process control of a laboratory scale dead-end microfiltration layout. The layout is downscale model of actual production line, and the goal is filter validation and analysis of process parameters which may influence filter operation. The focus is on identification of most influential process parameters and their influence on the repeatability of pressure oscillations caused by valve opening. Several filters in sizes between 3.5 cm2 and 6900 cm2 were tested and some recommendations suggested for reduction of energy intake of the filter and to improve repeatability of the process.

Special comments:

The abstract is short and might need more data!

Introduction is short as well and need to discuss more about membranes filtration and other studies.

Why the paper is not divided into regular sections? Abstract, Intro, M&M, Results & discussions, Conclusions, etc

Statistical analysis???

 

References are not enough although there are a lot about this subject that can be used in the study

Response

1,2         The abstract and the introduction have been modified

3             The paper was reorganized into regular sections. It might be more straightforward now. I hope it is easier for the readers to follow. The original was focused on influential parameters, since we thought they will be the most interesting.

4             I am not sure about the meaning of this comment, but in a new version of the paper subchapter 2.4. Statistical analysis was added and the analysis explained.

5          references added according to the modified abstract and introduction:

1. Drioli, E., A.I. Stankiewicz, and F. Macedonio, Membrane engineering in process intensification—An overview. Journal of Membrane Science, 2011. 380(1): p. 1-8.
2. Anis, S.F., R. Hashaikeh, and N. Hilal, Microfiltration membrane processes: A review of research trends over the past decade. Journal of Water Process Engineering, 2019. 32: p. 100941.
3. Tang, C.Y., et al., Potable Water Reuse through Advanced Membrane Technology. Environmental Science & Technology, 2018. 52(18): p. 10215-10223.
4. Council, N.R., Water reuse: potential for expanding the nation's water supply through reuse of municipal wastewater. 2012: National Academies Press.
5. Pizzichetti, A.R.P., et al., Kinetic and mechanistic analysis of membrane fouling in microplastics removal from water by dead-end microfiltration. Journal of Environmental Chemical Engineering, 2023. 11(2): p. 109338.
6. Al-Tayawi, A.N., et al., Wastewater Treatment in the Dairy Industry from Classical Treatment to Promising Technologies: An Overview. Processes, 2023. 11(7): p. 2133.
7. Košir, T., et al., Bacterial Filtration Efficiency of Different Masks. 2022, 2022. 68(4): p. 8.
8. Jalundhwala, F., V. Londhe, and B. Shah, Ensuring regulatory compliance by quality by design (QbD) approach to optimize the manufacturing process of API: ferric ammonium citrate as an example. Chemical Papers, 2023. 77(3): p. 1469-1477.
9. Somma, R., Development Knowledge Can Increase Manufacturing Capability and Facilitate Quality by Design. Journal of Pharmaceutical Innovation, 2007. 2(3): p. 87-92.
10. Helgers, H., et al., Digital Twins for scFv Production in Escherichia coli. Processes, 2022. 10(5): p. 809.
11. Arden, N.S., et al., Industry 4.0 for pharmaceutical manufacturing: Preparing for the smart factories of the future. International Journal of Pharmaceutics, 2021. 602: p. 120554.
12. Enten, A.C., et al., Optimizing Flux Capacity of Dead-end Filtration Membranes by Controlling Flow with Pulse Width Modulated Periodic Backflush. Scientific Reports, 2020. 10(1): p. 896.
13. Meng, S., et al., Insights into the Fouling Propensities of Natural Derived Alginate Blocks during the Microfiltration Process. Processes, 2019. 7(11): p. 858.
14. Chen, J.P., et al., Gravity Filtration, in Physicochemical Treatment Processes, L.K. Wang, Y.-T. Hung, and N.K. Shammas, Editors. 2005, Humana Press: Totowa, NJ. p. 501-543.
15. Wang, Q., et al., Effects of Filtration Mode on the Performance of Gravity-Driven Membrane (GDM) Filtration: Cross-Flow Filtration and Dead-End Filtration. Water, 2022. 14(2): p. 190.
16. Prasad, V.S.D. and S. Subramanian, Successful filter press pump selection guide. Filtration + Separation, 2014. 51(5): p. 28-31.
17. Yu, Q., F. Li, and X. Tan, Influence Analysis and Performance Optimization of a Pneumatic Actuator Exhaust Utilization System. 2023, 2023. 69(3-4): p. 16.

Reviewer 3 Report

Comments and Suggestions for Authors

Reviewer comments:

The goal of the manuscript is filter validation and analysis of process parameters which may influence filter operation. Several filters in sizes between 3.5 cm2 and 6900 cm2 were tested. The authors' attention is focused on the pressure fluctuations that occur during the opening of the system valve, and subsequently on the energy effect on the filter.

The article is up-to-date and written at a good professional level. It is clear from the text that a large number of experiments and evaluation of the results were necessary. On the other hand, this affected the quality of the text and in some cases also its comprehensibility, it is not clear from the text whether the microfiltration itself or the entire system of the technological line is being assessed, the article is devoted to the valve when the system is turned on.

I have a big reservation about the figures, they are unreadable, especially the legend under the pictures. It was only possible to read the legend when the pdf file was enlarged to 200.

I have some comments and question:

1. What is a large and small filter? Please can you explain it because it is often repeated in the text. Describe the basic filter parameters (membrane type, membrane module, membrane material, filter diameter, pore size, max. discharge in m3/hour, etc.). In the text, the authors focused only on membrane area and pressure.

2. The experiments were carried out in a closed system under pressure, as microfiltration works under a pressure of about 1 bar. This pressure was achieved by a stream of nitrogen. Wouldn't it be better to use a pump? Also considering the removal of gas from the liquid.

3. Please explain the lift (mm) parameter, you can see it in the pictures. what does it have to do with microfiltration, with the pressure before and after the filter. What was the maximum transmembrane pressure in the case of a small or a large filter?

4. The manuscript states, I quote: “The measurement of the fluid flow was repeated, to be able to control possible changes in the filter characteristics due to fouling”. What fluid flow was used during the experiments?

5. Please explain how filter clogging can occur when distilled water is filtered? The results presented are for distilled water.

6. Why was mass flow (g/sec) observed during filtration, in general microfiltration uses filtration speed, or filter flow (in dm3/s), which expresses mass flow? What was the fluid used?

7. The mass flow was 0.178 g/s (Optiscale 25), and 452 g/s (Opticap XL10), what does that mean? What does this parameter represent? This certainly does not apply to distilled water, which substance was monitored?

8. Dynamic testing of 30+ repetitions were used during the experiments. Presented results are average values from at least 30 cycles. How long did one filter cycle last?

9. Why was mass flow (g/sec) observed during filtration, in general microfiltration uses filtration speed, or filter flow (in dm3/s), which expresses mass flow? What was the fluid used?

10. If one filter cycle would last e.g. 30 minutes, so turning on the valve only affects the entire system for 0.5-1,0 seconds? Why then is this time important to watch?

11. The manuscript states, I quote: “within the system at high flow rates, the pressure level in the N2 tank in the case of a large filter must be approx. 0.4 bar higher than the small filter to get the same filter pressure drop”, what is high flow? Can you provide a numerical value?

12. Figure 6. Comparison of different fluid pressures, can you explain term fluid? What fluid was used?

13. 12. Please explain the term 2→1.

Author Response

Dear Reviewer 3

Thank you for your time and comments. The first goal of our research was filter testing, but as additionally explained in introduction “Process repeatability is important for process stability and product quality. The results acquired during stable and repeatable process are more reliable than a single set of data. Some statistical analysis must be used when comparing the process data on laboratory and production line. It is impossible to compare data when the process repeatability is poor. Poor repeatability of first tests was the main reason for the analysis presented in this paper.”

Comments

Reviewer 3

The goal of the manuscript is filter validation and analysis of process parameters which may influence filter operation. Several filters in sizes between 3.5 cm2 and 6900 cm2 were tested. The authors' attention is focused on the pressure fluctuations that occur during the opening of the system valve, and subsequently on the energy effect on the filter.

The article is up-to-date and written at a good professional level. It is clear from the text that a large number of experiments and evaluation of the results were necessary. On the other hand, this affected the quality of the text and in some cases also its comprehensibility, it is not clear from the text whether the microfiltration itself or the entire system of the technological line is being assessed, the article is devoted to the valve when the system is turned on.

I have a big reservation about the figures, they are unreadable, especially the legend under the pictures. It was only possible to read the legend when the pdf file was enlarged to 200.

I have some comments and question:

1. What is a large and small filter? Please can you explain it because it is often repeated in the text. Describe the basic filter parameters (membrane type, membrane module, membrane material, filter diameter, pore size, max. discharge in m3/hour, etc.). In the text, the authors focused only on membrane area and pressure.
2. The experiments were carried out in a closed system under pressure, as microfiltration works under a pressure of about 1 bar. This pressure was achieved by a stream of nitrogen. Wouldn't it be better to use a pump? Also considering the removal of gas from the liquid.
3. Please explain the lift (mm) parameter, you can see it in the pictures. what does it have to do with microfiltration, with the pressure before and after the filter. What was the maximum transmembrane pressure in the case of a small or a large filter?
4. The manuscript states, I quote: “The measurement of the fluid flow was repeated, to be able to control possible changes in the filter characteristics due to fouling”. What fluid flow was used during the experiments?
5. Please explain how filter clogging can occur when distilled water is filtered? The results presented are for distilled water.
6. Why was mass flow (g/sec) observed during filtration, in general microfiltration uses filtration speed, or filter flow (in dm3/s), which expresses mass flow? What was the fluid used?
7. The mass flow was 0.178 g/s (Optiscale 25), and 452 g/s (Opticap XL10), what does that mean? What does this parameter represent? This certainly does not apply to distilled water, which substance was monitored?
8. Dynamic testing of 30+ repetitions were used during the experiments. Presented results are average values from at least 30 cycles. How long did one filter cycle last?
9. Why was mass flow (g/sec) observed during filtration, in general microfiltration uses filtration speed, or filter flow (in dm3/s), which expresses mass flow? What was the fluid used?
10. If one filter cycle would last e.g. 30 minutes, so turning on the valve only affects the entire system for 0.5-1,0 seconds? Why then is this time important to watch?
11. The manuscript states, I quote: “within the system at high flow rates, the pressure level in the N2 tank in the case of a large filter must be approx. 0.4 bar higher than the small filter to get the same filter pressure drop”, what is high flow? Can you provide a numerical value?
12. Figure 6. Comparison of different fluid pressures, can you explain term fluid? What fluid was used?
13. 12. Please explain the term 2→1.

Response

• The paper was reorganized, and a new subchapter is dedicated to the filters, but only to those two specifically mentioned

2.1. Filters

A wide spectrum of filter sizes were tested, from a single layer filter to stacked filters. Membrane was hydrophilic Durapore polyvinylidene fluoride (PVDF) with 0.22 μm pore size. The membrane area was between 3.5 cm² and 6900 cm². The minimum size filter was Optiscale 25 capsule with 3.5 cm² filtration area and 3.9 cm length. This filter is referenced as small. The maximum size filter (large) tested was Opticap XL10 with 6900 cm² filtration area and cartridge length 25 cm. The main limiting factor of filter size is tri-clamp fittings and filtering capacity at high pressure differences when pressure losses in hydraulic connections become significant because of increased fluid velocity.

• Some additional explanation and references added in the new subchapter 2.3. Figure 1 modified to explain siphon principle. Some pressure regulator data added to explain the benefits of chosen system.
• The lift has no direct impact on the filter. It can be used as a reference for the pressure signals to be able explain the pressure curves. The lift signal can be used to measure the time for valve opening/closing, which might be useful for process control. Please see new Figure 10 and Figure 11.

4,5,12               Transmembrane pressure is a little less than pressure drop on filter. “The pressure drop on the filter might be considered as transmembrane pressure, but since pressure sensors are placed in a T type fitting and there are some additional pressure losses in sealings, filter housing and reduction fittings the exact transmembrane pressure is a little lower than the pressure drop.” was added before Figure 8. In chapter 2.3.3 explanation “The fouling might have been caused by some algae [33] or micro-corrosion in the water tank. Fouling was noticeable in the case of the small filters, especially since significant amount of fluid had to be filtered during filling of the system and system venting.” was added. “Distilled water” is actually demineralized water. The system is open at the end when weighting occurs, and the water is reused by pumping so some kind of contamination is possible.

6,9        The fluid was weighted since it was the easiest way to measure the flow. Some kind of flowmeter might introduce additional pressure losses and make system venting even more complicated. The fluid temperature was measured so it is possible to convert to the volumetric flow.

7          The values apply to distilled (demineralized) water at 0.5 bar pressure drop on filter. Optiscale 25 is a small filter with 3.5 cm² filter area. The pressure drop on filter in both cases was 0.5 bar, but the reduction from 15.5 mm diameter to Luer Lok results in pressure losses. The value is as measured on scale and described in Figure 2.

8          For small filter one cycle (start, open, close, stop) lasted approx. 5 seconds. When some additional time for saving data and resetting of the amplifiers is added the cycyle lasted approx. 15 to 20 seconds.

10         The filter energy intake is mostly a consequence of pressure waves which occur during valve operation. Filter energy intake can result in membrane damage or some kind of bacteria deformation which can result in a bacteria penetrating the membrane (failure). The top-level goal of our project was to estimate the number of valve cycles before that happens.

11        Please see new figure 6 (old figure 4) The results are for large Opticap XL10 filter at 0.5 bar filter pressure drop. From the 0.94 bar static pressure before filter a pressure drop to 0.76 bar occurred when the valve was opened and 0.27 bar was measured after the filter. The results can be seen in new Figure 4 too.  

13           please see “According to [26] it was oriented 2→1 (movement of the plunger during valve opening in the same direction as fluid).” in 2.3.1.  and “. The plunger (valve orientation 2→1 was applied) moved mostly in the general flow direction, resulting in a negative pressure gradient at the beginning of the movement, and positive pressure gradient when the valve was at least partially open.” Below new Figure 11.

The figures in Excell were drawn out in matplotlib.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The author modified a lot and I suggest it can be accepted in this Journal.

Reviewer 2 Report

Comments and Suggestions for Authors

The authors handled my comments. All the best!