Development of an Automated Continuous Clarification Bypass

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Development of an Automated Continuous Clarification Bypass System to Remove Suspended Particulate Matter Wei Wu, Matthew G Lesher, Chuntian Hu, Khrystyna Shvedova, Bayan Takizawa, Thomas F. O'Connor, Xiaochuan Yang, Sukumar Ramanujam, and Salvatore Mascia Org. Process Res. Dev., Just Accepted Manuscript • DOI: 10.1021/acs.oprd.8b00195 • Publication Date (Web): 28 Aug 2018 Downloaded from http://pubs.acs.org on August 28, 2018

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Organic Process Research & Development

Development of an Automated Continuous Clarification Bypass System to Remove Suspended Particulate Matter Wei Wu,

§,†

Matthew G. Lesher, ‡

§,†

,†

†

Chuntian Hu,* Khrystyna Shvedova, Bayan Takizawa, ‡

Thomas F. O’Connor, Xiaochuan Yang, Sukumar Ramanujam,

※

and Salvatore Mascia,*

,†

†

CONTINUUS Pharmaceuticals, 25R Olympia Ave, Woburn, MA, 01801, USA

‡

Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD, 20993, USA

※

†

USV Private Limited, Arvind Vithal Gandhi Chowk, BSD Marg, Station Road, Govandi East, Mumbai, 400080, India

1 Environment ACS Paragon Plus

Organic Process Research & Development 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

TOC Graphic


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ABSTRACT: An automated continuous clarification bypass system was developed to remove the suspended particulate matter in the pre-reaction material. Compared to commercially available duty/standby filters, the proposed clarification bypass system able to self-clean, and does not require to detachment of the filter and manually cleaning. In a stainless steel (SS) filter, effects of flow direction, ultra-sonication, viscosity (=f(temperature)) were investigated. The data showed that the filtration performance could not meet the requirement of high clarification efficiency because of the high switch frequency (high switch frequency results from short filtration time before the filter fouls, which is indicated by increasing pressure differential across the filter). The deposition of crystals on the SS filter medium, and not the suspended particulate matter (SPM), was the primary cause of the pressure build-up. Experiments with PTFE filter elements with comparable pore size and surface area to the stainless-steel filter were performed, and improved filtration performance (e.g., after the first cycle, the filtering time was 1-3 min with SS versus 30-60 min with PTFE) was observed. At the beginning of the SPM filtration process with the PTFE filter elements, three filtration mechanisms occurred (i.e., straining, impingement, and entanglement). As the filtration cake formed on the filter element surface, straining gradually dominated the filtration process, while the effects of impingement and entanglement became negligible. Keywords: Clarification Bypass, Filtration, Suspended Particulate Matter, Continuous Manufacturing 1. INTRODUCTION Continuous manufacturing processes are important for valuable products in many industry sectors, such as food, polymers, petrochemicals, fine chemicals, and pharmaceuticals1. For the continuous manufacturing of pharmaceuticals, the pre-reaction material usually contains some



extraneous suspended particulate matter (SPM) that prevents the final API from passing the appearance of solution test required by the European Pharmacopeia, and needs to be filtered before entering the reaction vessel (i.e., clarification). Filtration is a separation process that removes solids or droplets from liquids or gases by adding a filter medium that is permeable to only the fluid phase being separated.2 The term “clarification” is usually used when solids or droplets do not exceed 1.0%, and the filtrate is the primary product. The solids or droplets can be deposited on the outer surface of the filter medium, known as surface filtration,3 as well as within the filter medium’s depth, known as depth filtration.4-6 Most filtration processes are a combination of surface filtration and depth filtration, due to the wide range of the particle size distribution of solids. Usually, an initial depth filtration is followed by surface filtration; this transition starts once the void spaces of the upstream layers of the filter medium are reduced to a certain extent7. Subsequently, particles start to deposit on the surface, leading to the buildup of the cake. During surface filtration, particles do not pass through the filter medium, but are collected on the surface. In this case, the particle size should be larger than the pore size; however, in certain cases slightly smaller particles can bridge across the surface pores, preventing their passage through the filter.8 Surface filtration is also known as cake filtration9-14 if the flow of particles is directed perpendicular to the filter medium surface. The disadvantage of this process is that the filter cake builds up over time, reducing the flowrate of the filtrate. One solution to this problem is to use cross-flow filtration.3,

15-24

In this case, fluids flow parallel to the surface, and the

deposited cake is later removed by ongoing fluid flow. During depth filtration, particles penetrate the structure of the filter medium, and are captured and retained. As particles accumulate in the interstices, the cross-sectional area of the filter medium is reduced, damaging


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porosity and impairing permeability. Flow through the filter decreases, and higher pressure is required to maintain the flowrate, according to Darcy’s Law25-28. One solution is to remove, or partially remove, these solids with a solvent backwash. There are four well known filtration mechanisms: straining, impingement, entanglement, and attractive forces (see Figure S1 in the supporting information).29-37 Straining is the simplest, and it occurs when the solid particles are larger than the pore size, resulting in particles retained on the surface of the filter medium. During impingement, solid particles have momentum, move along the flow path, strike (impinge) the filter medium, and are retained on the filter medium. However, some particles follow the streamlines, and are not retained. During entanglement, solid particles that are smaller than the pore size become entwined (entangled) in the mass of fibers within the filter medium. Impingement may also be involved in this process, due to the presence of small particles (compared with the filter medium pore sizes). In certain cases, solid particles are retained on the filter medium as a result of attractive force from electrostatic precipitation. Usually, a filtration process combines various mechanisms; however, straining will dominate once the first solid layer forms. The purpose of filtration is to clarify liquids, recover solids, or both. In most clarification processes, especially in the field of end-to-end continuous manufacturing of pharmaceuticals,38-40 the liquid is retained, while the solids are discarded without further treatment. The accumulation of solids on the filter medium surface increases the hydraulic resistance of the filter to the fluid, which results in an increased loss of pressure across the filter. Accordingly, filtration could be effected by the application of a pressure difference that can be achieved by gravity, vacuum, centrifugal force, or pressurized fluid.2, 41-49



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Filtration is a complicated and non-steady state process, and the observed relationship between pressure drop and captured solid mass is typically nonlinear.7,

13, 50, 51

Optimally

designing the filter elements and process control to obtain high filtration efficiency and a low pressure drop can be challenging. For improved filtration performance, the selected filters should: (1) have good durability; (2) have sufficient mechanical strength; (3) be capable of delivering a clear filtrate at a suitable production rate; (4) retain the solids without clogging at the start of filtration; and (5) not absorb dissolved material. The filter medium should allow liquid to flow through freely, while preventing excessive migration of solid particles. There are many parameters (e.g., particle size and particle size distribution, particle shape and surface charge, compressibility of the solid particles, filter element materials, filter size, flowrate, aging of the suspension, viscosity and density) that can influence the filtration performance52-55. Ultra-sonication, which is widely used for cleaning, is the irradiation of a liquid sample with ultrasonic (greater than 20 kHz) waves resulting in agitation. Ultrasonic cleaners create compression waves in the appropriate solvent (e.g., water) that “tear” the solvent apart, generating millions of partial vacuum bubbles (i.e., cavitation). During the collapse and implosion of these bubbles, temperatures in excess of 5,000 °C and pressures in excess of 10,000 psi can be generated at the implosion sites of the cavitation bubbles.56 This energy effectively cleans and removes surface contaminants, but is not destructive to the system because the bubbles are so small. In the present study, an automated pilot-scale continuous clarification bypass system was developed to remove suspended particulate matter (SPM) from the pre-reaction material, allowing the final API (1-3 kg/h throughput) to pass the appearance of solution test required by the European Pharmacopeia. Compared to commercially available duty/standby filters, the


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proposed clarification bypass system has the ability to self-clean, and does not require to detachment of the filter and manual cleaning. Effects of flow direction, ultra-sonication, feed viscosity/temperature, filter elements material, filter size, pore size, and switching pressure on the filter performance were investigated, and the filtration mechanisms are discussed. 2. EXPERIMENTAL SECTION 2.1. Chemicals and instruments. Digital overhead stirrer was purchased from Chemglass Life Sciences (Vineland, NJ). VICI 3-position and 4-position valves were manufactured by Valco Instruments Co. Inc. (Brockville, ON). Stainless steel (SS) filters (SS-4TF-7, pore size R=7µm) and SS pressure transducers were purchased from Swagelok Cambridge (Billerica, MA). PTFE filters, and plastic pressure transducers (Model 4100) were purchased from United Filtration Systems, Inc. (Sterling Heights, MI), and SemiTorr Group, Inc. (Medfield, MA), respectively. Diaphragm pump (SimDos 10) and electric heat cables were obtained from KNF Neuberger, Inc. (Trenton, NJ), and McMaster-Carr (Elmhurst, IL), respectively. The rheometer (AR1500ex), FBRM (D600L) and ultrasonic cleaner (5210RDTH) were manufactured by TA Instruments (New Castle, DE), Mettler Toledo (Columbus, OH), and Branson Ultrasonics (Danbury, CT), respectively. 2.2. Experimental setup for clarification bypass system. The continuous clarification bypass system is comprised of a pair of filters (Filter A and B in Figure 1a). Figure 1b-f shows the cross section of the SS filter, a photograph of the PTFE filter, plastic pressure transducer, VICI valve, and Simdos 10 Diaphragm pump, respectively. When the pressure drop (∆P) of the operating filter (e.g., Filter A) reaches a specified maximum limit (e.g., 50 or 70 psi), the process stream is automatically diverted to the secondary filter (i.e., Filter B). Concurrently,



back wash solvent flows and air purges in the reverse direction through the clogged Filter A, cleaning and preparing it for the next cycle. The SPM is collected in a waste bottle, so the process can run continuously. The flow is regulated by a fully automated process control system that monitors and records the real time ∆P across the filters, in addition to providing valve control (see Figure 2). Diaphragm liquid metering pumps with a maximum operating pressure of 88 psi are used to regulate the flowrates. Figure 2a-b shows the front view and top view of the continuous bypass filtration system that has been fully assembled. An advanced automation system was developed using DAQ hardware and LabView software (National Instruments) (see Figure 2c-d). The graphic user interface (GUI) (Figure 2d) facilitates manipulation of set-point values, such as the cut-off ∆P, and also provides an easy-to-read schematic of the physical system. The software also allows the operator to toggle between manual and automated control, and view real-time measurements of pressure, feed temperature, flow, or other parameters, through an easy-to-read display.


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Figure 1. (a) Process flow diagram of the continuous bypass filtration system (PT: pressure transducer), (b) cross section of the SS filter, (c) photograph of the PTFE filter, (d) plastic pressure transducer, (e) VICI valve, and (f) SimDos 10 diaphragm pump



Figure 2. (a) Front view and (b) top view of the continuous clarification bypass system, (c) DAQ hardware and (d) local control graphical user interface (GUI) 3. RESULTS AND DISCUSSION 3.1. Particle size of the SPM. In the present study, the uniformly dispersed SPM consists of spherical solid particles at a concentration of 0.017 wt% in the pre-reaction material. To determine the chord length distribution, SPM was collected by filtering several liters of prereaction mixture, after which it was uniformly dispersed into solvent by sonication. The volumebased chord length distribution of SPM was measured using FBRM, and the chord length ranged from 3 to 320 µm and centered at 35 µm (see Figure 3).


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Figure 3. Chord length distribution of the SPM measured using FBRM 3.2. Effect of flow direction. Figure S2 in the supporting information shows the cross section of the SS filters and the feed flow direction: (a) flow through the inside, and (b) flow through the outside of the filter elements. The pre-reaction material was heated, plug-in extreme temperature heat tapes were used to heat the transfer tubing to maintain the desired temperature, and the switch pressure difference (∆P) was set at 50 psi (maximum pressure rated for the diaphragm pumps used in the present study was 88 psi). The pre-reaction material was initially processed by Filter A, and ∆P increased to 50 psi in approximately 10 min. The process stream then automatically switched to Filter B, and back wash solvent flowed through Filter A in a reverse direction, removing most of the SPM and preparing Filter A for the next cycle. After approximately 8 min, the process stream switched to Filter A again. From Figure 4, the filtering time for the first cycle was approximately 8-10 min, and it decreased to 1-3 min from the 2nd cycle onward, as switching occurred more frequently. As expected, the feed flow direction did not significantly influence filter performance (Figures 4a-b), because the working surface areas are almost the same. Clearly, the observed high frequency of switching after the first cycle did not meet the requirement of high filtration efficiency (i.e., too much wash solvent usage, and



inability to process/filter material continuously for long durations), so ultra-sonication was applied into the system.

Figure 4. Effect of flow direction on the filtration performance, (a) △P as a function of time and (b) filtering time as a function of filtration cycles 3.3. Effect of ultra-sonication. A Branson ultrasonic cleaner (42 kHz) was used to disperse particles in the liquid medium and remove particles from the solid surfaces. Filter B was placed in the ultrasonic cleaner, while Filter A was not. Figure 5 shows the effect of sonication on the filtration performance. The filtering time for the first cycle was approximately 12 min, and the time decreased to 4-7 min from the 2nd cycle for Filter B (with sonication), which was superior to the performance of Filter A (without sonication). However, even with ultra-sonication, the SS filter performance could not meet the requirement of high filtration efficiency, as the switch frequency remained high. It is important to note that ultra-sonication may disrupt the formation of the filter cake, which is usually the true medium for solid-liquid separation.56 Furthermore, ultra-sonication could complicate the process of depth filtration, as it may allow solid particles to penetrate deeper into the filter medium, making the filter harder to clean with backwash solvent.


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Figure 5. Effect of sonication on the filtration performance, (a) △P as a function of time and (b) filtering time as a function of filtration cycles 3.4. Effect of feed viscosity/temperature. According to the Darcy’s Law,57 the filtration rate is inversely proportional to the viscosity of the fluid, as increases in viscosity increase the resistance of flow. The influence of temperature on the viscosity of the pre-reaction material was investigated. At 30 °C the viscosity is 0.088 Pa·s, and the value decreases to 0.012 Pa·s at 80 °C, and 0.005 Pa·s at 110 °C. The black squares and red circles in Figure 6 clearly show that temperature/viscosity is not a key factor in the switch frequency of the valves. Based on experimental observations, the working hypothesis was modified, suggesting that the deposition of crystals on the SS porous media surface (and not the SPM) was the primary cause of the frequent valve switching. More specifically, the SPM concentration in the prereaction material was determined to be too low for it to be the culprit of frequent valve switching. To confirm this hypothesis, the pre-reaction material was pre-filtered at 80 °C (this removes the SPM), and then the same experiments were performed, as shown in Figure 6. The filtering time after the first cycle was 1-3 min, which indicated no improvement. Thus, the deposition of crystals on the porous media depended mainly on the surface chemistry of the solid materials.



Consequently, PTFE filter elements were tested and results compared to those with the SS filter elements.

Figure 6. Effect of viscosity/temperature and pre-filtration on the filtration performance 3.5. Effect of filter material (SS/PTFE). To compare the filtration performance of SS and PTFE filters, a SS filter (pore size R=7 µm, surface area A=20 cm2) and a small PTFE filter (pore size R=3 µm, surface area A=30 cm2) were used. Figure 7 shows photographs of a small PTFE filter during filtration at 10, 50 and 70 psi, and during backwash. The original PTFE filter elements were white, and became darker as ∆P increased and SPM accumulated on their surfaces. During back wash, SPM was observed to fall off the element surface. The results in Figure 8 show that the PTFE filters increased the filtering time from 1-3 min (for SS elements) to approximately 30-60 min after the first cycle. The increase in surface area of the PTFE filters helps to improve the filtration performance (Darcy’s Law25-28, 57); however, the material itself (PTFE vs. SS) plays a more important role, as shown in Figure 8 (more specifically, the significant difference in filtering time between the top two lines and bottom two lines). In addition, there was a significant difference in filtering time for the first cycle between


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the two PTFE filter experiments (comparing the first points in line A and Line B). A possible explanation is that the raw material was not homogenous, so the SPM was not uniformly distributed. To clarify the distribution issue in subsequent experiments, 20 L of pre-reaction material was prepared in a large vessel and stirred vigorously to ensure the SPM is uniformly distributed. All the following experiments used this SPM-uniformly-distributed pre-reaction material.

Figure 7. Photographs of a small PTFE filter during filtration at 10, 50 and 70 psi, and during backwash

Figure 8. Effect of filter material (SS/PTFE) on the filtration performance 3.6. Effect of pore size and switching pressure. Figure 9 shows the impact of switching pressure and pore size on the filtration performance (the smaller error bars at the different 15 Environment ACS Paragon Plus


operating conditions indicate that the discrepancy observed in Figure 8 was eliminated with adequate mixing). In general, 25 µm PTFE filter elements worked better than 3 µm elements (both passed the appearance of solution test). For 25 µm PTFE filter elements, a switching pressure of 70 psi worked better than that of 50 psi for the first several cycles, but starting from cycle five, the reverse was true. This was because at the higher switching pressures, the SPM was more forcibly packed into the filter element (i.e., depth filtration), resulting in compromised performance in later runs. Finally, experiments with pre-filtered material were performed with the PTFE filters, and no reduction was observed in performance. This indicates that with PTFE filters fouling was due to the accumulation of SPM, not crystals (as was the case with the SS porous media in Figure 6).

Figure 9. Impact of switching pressure and pore size on the filtration performance 3.7. Effects of flowrate and filter size. Feed flowrate and filtration surface area are two key parameters that impact filtration performance. From Figure 10a, the filtering time for a small PTFE filter (R=3 µm, A=30 cm2) was approximately 1.3 h for the first cycle at 16 mL/min and a switching pressure of 50 psi. The time was reduced to 25 min at a flowrate of 33 mL/min and < 5 min at a flowrate of 66 mL/min, the highest flowrate in the present study (maintaining the


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switching pressure at 50 psi). However, when a larger PTFE filter (R=3 µm, A=60 cm2) was used at 66 mL/min, the filtering time increased from < 5 min to approximately 0.9 h for a switching pressure of 50 psi and approximately 1.4 h for a switching pressure of 70 psi (Figure 10b). To further increase the filtering performance, a larger PTFE filter (R=25 µm, surface area A=180 cm2) was tested, and the preliminary results showed that the pressure only increased to approximately18 psi after 23 h, and 70 psi after 52 h at 33 mL/min (the nominal flowrate in the present study). The observations are consistent with Darcy’s law,25-28,

57

as pressure drop

(resistance) is inversely proportional to the surface area of the filter medium and directly proportional to the flowrate.

Figure 10. Impact of filter size on filtration performance 3.8. Filtration mechanism. For SS filter elements, the deposition of reactant crystals within the filtration medium may affect the underlining mechanism of the filtration process. Therefore, only the filtration mechanisms within the PTFE filter elements are discussed. The PTFE filter elements consist of pure PTFE sintered (under pressure) into cylinders. Due to their manufacturing process, PTFE filters can have a wide range of pore size distributions. For example, 3 µm PTFE filter elements (i.e., 98% efficiency for 3 µm solid particles) may contain



pore sizes that range from 10 nm to 10 µm. As the chord length of SPM ranges from 3 to 320 µm, entanglement, and potentially impingement, can occur within the 3 or 25 µm PTFE filter elements, leading to depth filtration. These SPM particles that penetrate the filter elements were difficult to remove by a solvent back wash, leading to a reduction of filter performance after the first cycle (see Figure 8 and 9). Straining and impingement occur on the surface, as there are SPM particles that are larger than the pores of the 3 and 25 µm PTFE filter elements. Thus, at the start of the filtration process, all of these three mechanisms (i.e., straining, impingement, and entanglement) occur. However, as the filtration cake forms on the filter element surface, straining gradually dominates the filtration process, and impingement and entanglement can be neglected in cake filtration. This formed cake effectively removes more SPM than the actual filter elements during filtration. More work is necessary to determine whether attractive forces exist within and contribute to the filtration system described in the present study. Identifying the filtration mechanism is important for several reasons. First, knowledge of the filtration mechanism is essential for selecting, designing, and optimizing a filter (e.g., material, surface area, pore size). Second, knowledge of the filtration mechanism will help determine favorable operating conditions (e.g., flowrate, flow direction, presence of ultra-sonication) that will ensure high performance filtration. Third, understanding of the filtration mechanism will allow for identification of appropriate pre-reaction material that can be filtered adequately, ultimately leading to the production of high purity API and drug product.

4. CONCLUSIONS This paper presents the development of a novel technique to clarify the pre-reaction material from solid impurities. More specifically, an automated bypass filtration system


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was developed to remove the suspended particulate matter (SPM) with a chord length distribution of 3-320 µm. In SS filters, the effect of flow direction (inside-out and outside-in) was investigated, and the results indicated that direction did not significantly influence filter performance because of the similar surface area in the filters tested. The application of ultra-sonication improved filtration performance; however, high filtration efficiency was still not achieved, as the switch frequency remained high. Investigation of the effect of viscosity/temperature showed that they were not key factors in improving switch frequency. Considering these findings, the following hypothesis was proposed: the deposition of crystals on the SS filter medium surface, and not SPM, was the primary cause of pressure build-up. The hypothesis was confirmed when filtration experiments with pre-filtered material (i.e., SPM already removed) showed no improvement in switch frequency. Because the precipitation and deposition of crystals on the filter medium depends mainly on the surface chemistry of solid materials, PTFE filter elements were tested in subsequent experiments. Experiments with PTFE filter elements of comparable pore size and surface area were performed, and greatly improved filtration performance was observed. At 16 mL/min, the filtering time for the small PTFE filter was approximately 30-50 min after the first cycle, compared to 1-3 min for the SS filter. The effects of pore size and switching pressure were also investigated. In general, 25 µm PTFE filter elements were found to work better than 3 µm elements. For the 25 µm PTFE filter elements, a switching pressure of 70 psi worked best for the first several cycles than a switching pressure of 50 psi. However, the reverse was true after the 5th cycle (i.e., switching frequency was improved when the



switching pressure was 50 psi). This reversal was attributed to the SPM being more forcibly packed into filter elements when the higher switching pressure was applied. Feed flowrate and filtration surface area were identified as two key parameters that impact the filtration performance – larger filters with lower flowrates improve results. At the beginning of the SPM filtration process with the PTFE filter elements, three filtration mechanisms (i.e., straining, impingement, and entanglement) are occurring. As the filtration cake form on the filter element surface, straining gradually dominates the process. Ultimately, the effects of impingement and entanglement can be neglected during cake filtration. AUTHOR INFORMATION Corresponding Author * E-mail: [email protected] * E-mail: [email protected] Author Contributions §

W. W. and M. L.: These two authors contributed equally to this work.

Notes The authors declare no competing financial interest. ACKNOWLEDGMENTS This work has been supported by the US Food and Drug Administration (FDA) under Board Agency Announcement Contract HHSF223201610104C. DISCLAIMER


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This publication only reflects the views of the authors (‡) and should not be construed to represent FDA’s views or policies. SUPPORTING INFORMATION The Supporting Information is available free of charge on the ACS Publications website at DOI: XXX and shows the filtration mechanisms and cross-section of the SS filter. REFERENCES 1.

McWilliams, J. C.; Allian, A. D.; Opalka, S. M.; May, S. A.; Journet, M.; Braden, T. M.,

The Evolving State of Continuous Processing in Pharmaceutical API Manufacturing: A Survey of Pharmaceutical Companies and Contract Manufacturing Organizations. Org. Process Res. Dev. 2018. DOI: 10.1021/acs.oprd.8b00160. 2.

Ripperger, S.; Gösele, W.; Alt, C.; Loewe, T., Filtration, 1. fundamentals. Ullmann's

Encyclopedia of Industrial Chemistry 2012. 3.

Holdich, R.; Cumming, I.; Smith, I., Crossflow microfiltration of oil in water dispersions

using surface filtration with imposed fluid rotation. J. Membrane Sci. 1998, 143, (1), 263-274. 4.

Cushing, R. S.; Lawler, D. F., Depth filtration: Fundamental investigation through three-

dimensional trajectory analysis. Environ. Sci. Technol. 1998, 32, (23), 3793-3801. 5.

Darby, J. L.; Lawler, D. F., Ripening in depth filtration: Effect of particle size on removal

and head loss. Environ. Sci. Technol. 1990, 24, (7), 1069-1079. 6.

Brunke, M., Colmation and depth filtration within streambeds: retention of particles in

hyporheic interstices. Int. Rev. Hydrobiol. 1999, 84, (2), 99-117. 7.

Iliev, O.; Kirsch, R.; Osterroth, S., Combined Depth and Cake Filtration Model Coupled

with Flow Simulation for Flat and Pleated Filters. Chemical Engineering & Technology.



8.

Hartman, R. L.; Naber, J. R.; Zaborenko, N.; Buchwald, S. L.; Jensen, K. F., Overcoming

the challenges of solid bridging and constriction during Pd-Catalyzed C− N bond formation in microreactors. Org. Process Res. Dev. 2010, 14, (6), 1347-1357. 9.

Tien, C.; Bai, R., An assessment of the conventional cake filtration theory. Chem. Eng.

Sci. 2003, 58, (7), 1323-1336. 10.

Ho, C.-C.; Zydney, A. L., A combined pore blockage and cake filtration model for

protein fouling during microfiltration. J. Colloid Interface Sci. 2000, 232, (2), 389-399. 11.

Lu, W.-M.; Tung, K.-L.; Hwang, K.-J., Effect of woven structure on transient

characteristics of cake filtration. Chem. Eng. Sci. 1997, 52, (11), 1743-1756. 12.

Lee, D., Filter medium clogging during cake filtration. AlChE J. 1997, 43, (1), 273-276.

13.

Civan, F., Practical model for compressive cake filtration including fine particle invasion.

AlChE J. 1998, 44, (11), 2388-2398. 14.

Willis, M. S.; Tosun, I., A rigorous cake filtration theory. Chem. Eng. Sci. 1980, 35, (12),

2427-2438. 15.

Luong, J. H.; Nguyen, A.-L.; Male, K. B., Affinity Cross–Flow Filtration for Purifying

Biomolecules. Nat. Biotechnol. 1987, 5, (6), 564-566. 16.

Lu, W. M.; Hwang, K. J., Cake formation in 2‐D cross‐flow filtration. AlChE J. 1995,

41, (6), 1443-1455. 17.

Mcdonogh, R. M.; Fane, A. G.; Fell, C. J., Charge effects in the cross-flow filtration of

colloids and particulates. J. Membrane Sci. 1989, 43, (1), 69-85. 18.

Harmant, P.; Aimar, P., Coagulation of colloids in a boundary layer during cross-flow

filtration. Colloid Surface A 1998, 138, (2), 217-230.


Page 22 of 28

Page 23 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


19.

Mackley, M.; Sherman, N., Cross-flow cake filtration mechanisms and kinetics. Chem.

Eng. Sci. 1992, 47, (12), 3067-3084. 20.

Redkar, S. G.; Davis, R. H., Cross‐flow microfiltration with high‐frequency reverse

filtration. AlChE J. 1995, 41, (3), 501-508. 21.

Tarabara, V. V.; Koyuncu, I.; Wiesner, M. R., Effect of hydrodynamics and solution

ionic strength on permeate flux in cross-flow filtration: direct experimental observation of filter cake cross-sections. J. Membrane Sci. 2004, 241, (1), 65-78. 22.

Stamatakis, K.; Tien, C., A simple model of cross‐flow filtration based on particle

adhesion. AlChE J. 1993, 39, (8), 1292-1302. 23.

Chai, X.; Kobayashi, T.; Fujii, N., Ultrasound effect on cross-flow filtration of

polyacrylonitrile ultrafiltration membranes. J. Membrane Sci. 1998, 148, (1), 129-135. 24.

Fillaudeau, L.; Carrère, H., Yeast cells, beer composition and mean pore diameter

impacts on fouling and retention during cross-flow filtration of beer with ceramic membranes. J. Membrane Sci. 2002, 196, (1), 39-57. 25.

Hu, C.; Hartman, R. L., High‐throughput packed‐bed microreactors with in‐line

analytics for the discovery of asphaltene deposition mechanisms. AlChE J. 2014, 60, (10), 35343546. 26.

Hu, C.; Morris, J. E.; Hartman, R. L., Microfluidic investigation of the deposition of

asphaltenes in porous media. Lab Chip 2014, 14, (12). 27.

Hu, C.; Sabio, J. C.; Yen, A.; Joshi, N.; Hartman, R. L., Role of water on the precipitation

and deposition of asphaltenes in packed-bed microreactors. Ind. Eng. Chem. Res. 2015, 54, (16), 4103-4112.



28.

Lucia, F., Petrophysical parameters estimated from visual descriptions of carbonate

rocks: a field classification of carbonate pore space. J. Pet. Technol. 1983, 35, (03), 629-637. 29.

Tufenkji, N.; Miller, G. F.; Ryan, J. N.; Harvey, R. W.; Elimelech, M., Transport of

Cryptosporidium oocysts in porous media: Role of straining and physicochemical filtration. Environ. Sci. Technol. 2004, 38, (22), 5932-5938. 30.

Ives, K. J., Capture mechanisms in filtration. The scientific basis of filtration 1975, 2,

183-201. 31.

Jaisi, D. P.; Saleh, N. B.; Blake, R. E.; Elimelech, M., Transport of single-walled carbon

nanotubes in porous media: filtration mechanisms and reversibility. Environ. Sci. Technol. 2008, 42, (22), 8317-8323. 32.

Soo, H.; Radke, C., A filtration model for the flow of dilute, stable emulsions in porous

media—I. Theory. Chem. Eng. Sci. 1986, 41, (2), 263-272. 33.

Killilea, W. R.; Hong, G. T.; Swallow, K. C.; Thomason, T. B. Supercritical water

oxidation: microgravity solids separation; 0148-7191; SAE Technical Paper: 1988. 34.

Emmel, M.; Aneziris, C. G., Functionalization of carbon-bonded alumina filters through

the application of active oxide coatings for steel melt filtration. J. Mater. Res. 2013, 28, (17), 2234-2242. 35.

Aneziris, C. G.; Dudczig, S.; Emmel, M.; Berek, H.; Schmidt, G.; Hubalkova, J.,

Reactive filters for steel melt filtration. Adv. Eng. Mater. 2013, 15, (1‐2), 46-59. 36.

Patel, R.; Shah, D.; Prajapti, B. G.; Patel, M., Overview of industrial filtration technology

and its applications. Indian J. Sci. Technol. 2010, 3, (10), 1121-1127.


Page 24 of 28

Page 25 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


37.

Bacchin, P.; Si-Hassen, D.; Starov, V.; Clifton, M. J.; Aimar, P., A unifying model for

concentration polarization, gel-layer formation and particle deposition in cross-flow membrane filtration of colloidal suspensions. Chem. Eng. Sci. 2002, 57, (1), 77-91. 38.

Mascia, S.; Heider, P. L.; Zhang, H.; Lakerveld, R.; Benyahia, B.; Barton, P. I.; Braatz,

R. D.; Cooney, C. L.; Evans, J.; Jamison, T. F., End‐to‐end continuous manufacturing of pharmaceuticals: Integrated synthesis, purification, and final dosage formation. Angew. Chem. Int. Ed. 2013, 52, (47), 12359-12363. 39.

Lakerveld, R.; Benyahia, B.; Heider, P. L.; Zhang, H.; Wolfe, A.; Testa, C. J.; Ogden, S.;

Hersey, D. R.; Mascia, S.; Evans, J. M., The application of an automated control strategy for an integrated continuous pharmaceutical pilot plant. Org. Process Res. Dev. 2014, 19, (9), 10881100. 40.

Heider, P. L.; Born, S. C.; Basak, S.; Benyahia, B.; Lakerveld, R.; Zhang, H.; Hogan, R.;

Buchbinder, L.; Wolfe, A.; Mascia, S., Development of a multi-step synthesis and workup sequence for an integrated, continuous manufacturing process of a pharmaceutical. Org. Process Res. Dev 2014, 18, (3), 402-409. 41.

Kong, B.-S.; Geng, J.; Jung, H.-T., Layer-by-layer assembly of graphene and gold

nanoparticles by vacuum filtration and spontaneous reduction of gold ions. Chem. Commun. 2009, (16), 2174-2176. 42.

Zhang, S.; Li, Y.; Pan, N., Graphene based supercapacitor fabricated by vacuum filtration

deposition. J. Power Sources 2012, 206, 476-482. 43.

Lee, J. H.; Kong, B.-S.; Baek, Y.-K.; Yang, S. B.; Jung, H.-T., Tin nanoparticle thin film

electrodes fabricated by the vacuum filtration method for enhanced battery performance. Nanotechnology 2009, 20, (23), 235203.



44.

Yim, S.-S.; Kwon, Y.-D., A unified theory on solid-liquid separation: Filtration,

expression, sedimentation, filtration by centrifugal force, and cross flow filtration. Korean J. Chem. Eng. 1997, 14, (5), 354-358. 45.

Sambuichi, M.; Nakakura, H.; Osasa, K.; Tiller, F., Theory of batchwise centrifugal

filtration. AlChE J. 1987, 33, (1), 109-120. 46.

Kiene, R. P.; Slezak, D., Low dissolved DMSP concentrations in seawater revealed by

small‐volume gravity filtration and dialysis sampling. Limnol. Oceanogr. Meth. 2006, 4, (4), 80-95. 47.

Bauer, M.; Bayley, R.; Chipps, M.; Eades, A.; Scriven, R.; Rachwal, A., Enhanced rapid

gravity filtration and dissolved air flotation for pre-treatment of river Thames reservoir water. Water Sci. Technol. 1998, 37, (2), 35-42. 48.

Zhang, J.; Jiang, D.; Peng, H.-X., A pressurized filtration technique for fabricating carbon

nanotube buckypaper: Structure, mechanical and conductive properties. Microporous Mesoporous Mater. 2014, 184, 127-133. 49.

MacLeod, C. S.; Muller, F. L., On the fracture of pharmaceutical needle-shaped crystals

during pressure filtration: case studies and mechanistic understanding. Org. Process Res. Dev. 2012, 16, (3), 425-434. 50.

Corapcioglu, M. Y.; Abboud, N. M., Cake filtration with particle penetration at the cake

surface. SPE Reserv. Eval. Eng. 1990, 5, (03), 317-326. 51.

Tien, C.; Bai, R.; Ramarao, B., Analysis of cake growth in cake filtration: Effect of fine

particle retention. AlChE J. 1997, 43, (1), 33-44. 52.

Wakeman, R., The influence of particle properties on filtration. Sep. Purif. Technol.

2007, 58, (2), 234-241.


Page 26 of 28

Page 27 of 28 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


53.

Boskovic, L.; Altman, I. S.; Agranovski, I. E.; Braddock, R. D.; Myojo, T.; Choi, M.,

Influence of particle shape on filtration processes. Aerosol Sci. Technol. 2005, 39, (12), 11841190. 54.

Connell, H.; Zhu, J.; Bassi, A., Effect of particle shape on crossflow filtration flux. J.

Membrane Sci. 1999, 153, (1), 121-139. 55.

Herzig, J.; Leclerc, D.; Goff, P. L., Flow of suspensions through porous media—

application to deep filtration. Ind. Eng. Chem. 1970, 62, (5), 8-35. 56.

Sulaiman, A. Z.; Rosli, M.; Azilah, A., Effect of Sonication for In-situ Stainless Steel

Leaf Filtration. Chemeca 2006: Knowledge and Innovation 2006, 1214. 57.

Costa, A., Permeability‐porosity relationship: A reexamination of the Kozeny‐Carman

equation based on a fractal pore‐space geometry assumption. Geophys. Res. Lett. 2006, 33, (2).




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