Small-scale mixer

Abstract

A system and method for manufacturing small-scale mixers are provided. [Solution] In some implementations, the method includes obtaining the dimensions of a large-scale mixer. The method also includes determining first dimensions of a small-scale mixer based on the respective dimensions of the large-scale mixer. The method further includes determining second dimensions of the small-scale mixer that are independent of the dimensions of the large-scale mixer. In addition, the method includes using a three-dimensional printer to generate the small-scale mixer using the first and second dimensions.

Description

Technical Field

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 062,129, filed Aug. 6, 2020; U.S. Provisional Patent Application No. 63 / 085,080, filed Sep. 29, 2020; and U.S. Provisional Patent Application No. 63 / 150,540, filed Feb. 17, 2021, the contents of each of which are hereby incorporated by reference in their entirety.

Background Art

[0002] Background Biopharmaceutical products can contain large, unstable molecules. For example, biopharmaceutical proteins can have a specific three-dimensional (“3D”) structure that is involved in their biological activity. Due to their instability, preventing degradation during manufacture is a challenge. Several external factors can cause degradation. For example, when biopharmaceutical products are mixed into an aqueous formulation, the biopharmaceuticals can degrade due to mechanical agitation, high shear forces, adsorption, and aggregation.

Summary of the Invention

[0003] Summary The following presents a simplified summary of the disclosed subject matter in order to provide a basic understanding of some aspects of the disclosed subject matter. This summary is not intended to identify key or critical elements of the disclosed subject matter or to delineate the scope of the claimed subject matter.

[0004] In some implementations, a system for manufacturing a small-scale mixer is provided. The system includes a three-dimensional printer configured to manufacture a small-scale mixer having a first dimension based on each dimension of a large-scale mixer and based on a second dimension independent of the dimensions of the large-scale mixer. The system also includes a smoothing device configured to smooth the surface of the small-scale mixer.

[0005] In several implementation embodiments, a method for manufacturing a small-scale mixer is provided. The method includes obtaining the dimensions of a large-scale mixer. The method also includes determining first dimensions of a small-scale mixer based on the respective dimensions of the large-scale mixer. The method further includes determining second dimensions of a small-scale mixer that are independent of the dimensions of the large-scale mixer. In addition, the method includes generating a small-scale mixer using the first and second dimensions. [Brief explanation of the drawing]

[0006] [Figure 1] A block diagram illustrating an example of an environment for implementing a system and method according to the aspects of this disclosure is shown. [Figure 2] An example of the physical dimensions of a mixer according to an aspect of this disclosure is shown in the cutaway side view of a mixer. [Figure 3] Figure 3A shows a top view of an example of an impeller for a large-scale mixer according to an embodiment of the present disclosure. Figure 3B shows a side view of an example of a large-scale mixer impeller according to an embodiment of the present disclosure. [Figure 4] Figure 4A shows a top view of an example of a small-scale mixer propeller according to an embodiment of the present disclosure. Figure 4B shows a side view of an example of a small-scale mixer propeller according to an embodiment of the present disclosure. [Figure 5] A flow block diagram illustrating an example of a method for manufacturing a small-scale mixer according to an aspect of this disclosure is shown. [Figure 6] A table illustrating exemplary scaling factors for small-scale mixers according to aspects of this disclosure is provided. [Figure 7] A table illustrating exemplary scaling factors for small-scale mixine propellers according to aspects of this disclosure is provided. [Figure 8] A table illustrating exemplary scaling factors for small-scale mixine propellers according to aspects of this disclosure is provided. [Figure 9] A table illustrating exemplary scaling factors for small-scale mixine propellers according to aspects of this disclosure is provided. [Figure 10]A table illustrating the ratios between exemplary dimensions of large-scale mixer propellers according to aspects of this disclosure is provided. [Figure 11] A table illustrating exemplary differences between target dimensions and actual dimensions of a small-scale mixer tank according to aspects of this disclosure is provided. [Figure 12] A table illustrating the difference between the exemplary expected dimensions and the actual dimensions of a small-scale mixer propeller produced according to aspects of this disclosure is provided. [Figure 13] A table illustrating the difference between the exemplary expected dimensions and the actual dimensions of a small-scale mixer propeller produced according to aspects of this disclosure is provided. [Figure 14] A table illustrating the difference between the exemplary target speed and the actual speed of a small-scale mixer propeller according to aspects of this disclosure is provided. [Figure 15] A chart illustrating a comparison of average surface roughness between an exemplary large-scale mixine propeller and an exemplary small-scale mixine propeller according to an aspect of this disclosure is provided. [Figure 16] A chart illustrating an exemplary comparison of tank surface roughness between an exemplary large-scale mixer tank and an exemplary small-scale mixer tank according to an aspect of this disclosure is provided. [Figure 17] An image illustrating the surface roughness of an exemplary small-scale mixine propeller according to an aspect of this disclosure is shown. [Figure 18] An exemplary verification process according to the aspects of this disclosure is illustrated below. [Figure 19] An exemplary verification process according to the aspects of this disclosure is illustrated below. [Figure 20] An exemplary verification process according to the aspects of this disclosure is illustrated below. [Figure 21] An exemplary verification process according to the aspects of this disclosure is illustrated below. [Figure 22] An exemplary verification process according to the aspects of this disclosure is illustrated below. [Figure 23] An exemplary verification process according to the aspects of this disclosure is illustrated below. [Figure 24] An exemplary verification process according to the aspects of this disclosure is illustrated below. [Figure 25] Illustrate an exemplary verification process according to an aspect of the present disclosure. [Figure 26] Illustrate an exemplary verification process according to an aspect of the present disclosure. [Figure 27] Illustrate an exemplary verification process according to an aspect of the present disclosure. **DETAILED DESCRIPTION**

[0007] Detailed Description The present disclosure generally relates to mixing devices. More specifically, the present disclosure relates to mixing devices for manufacturing pharmaceutical products. Devices and methods consistent with the present disclosure provide small-scale mixing devices. In some implementations, the small-scale mixing devices are manufactured using 3D printing.

[0008] Small-scale mixers according to aspects of the present disclosure may have a first dimension based on the dimensions of each large-scale mixer and a second dimension independent of each large-scale mixer. In some implementations, the first dimension is scaled from each dimension of the large-scale mixer. The second dimension can prevent the decomposition of the pharmaceutical product blended within the small-scale mixer. For example, the second dimension can limit the friction, particle generation, and shear forces imparted to the pharmaceutical product. In some implementations, the second feature includes the smoothness of the impeller blade, the thickness of the impeller blade, and the hub size of the impeller. In some implementations, the hub size of the small-scale impeller is the same or similar to the hub size of the large-scale impeller such that an impeller drive unit adapted to drive the large-scale impeller can also drive the small-scale impeller. Additionally, in some implementations, the second dimension of the small-scale impeller is adapted to withstand the substantial forces imparted by the large-scale drive unit.

[0009] Figure 1 shows a block diagram illustrating an exemplary environment 100 for implementing a system and method according to an aspect of the present disclosure. Environment 100 may include a small-scale mixer 103, a large-scale mixer 105, a 3D printer 109, and a smoothing device 113. The large-scale mixer 105 may be any type of mixing device. In some implementations, the large-scale mixer 105 may be configured for the manufacture of pharmaceutical products. For example, the large-scale mixer 105 may be able to mix pharmaceutical components from intermediates to the final drug product, and may also be able to mix for the preparation of process solutions such as buffers and media. According to an aspect of the present disclosure, the large-scale mixer 105 may have a filled volume of about 10 liters or more. In some implementations, the large-scale mixer 105 may have a filled volume of about 10 liters to about 1000 liters. It is understood that the actual capacity of the mixer may exceed its indicated capacity. For example, the actual capacity of the mixer (e.g., 110 liters) may exceed its stated capacity (e.g., 100 liters) by approximately 10%. In some implementations, the large-scale mixer 105 may include a tank, an impeller, a single-use mixing bag (e.g., a "bio-container"), and a separate, replaceable drive unit. For example, the large-scale mixer 105 may be the Mobius® Single-Use Mixing Systems by Merck KGaA of Darmstadt, Germany. In some implementations, the dimensions 117 of the large-scale mixer 105 may include the impeller clearance from the bottom of the mixer ("C2"), the impeller diameter ("D2"), the liquid level ("H2"), the rotational speed ("N2"), the tank diameter ("T2"), the blade width ("W2"), and the baffle width ("WB2").

[0010] The small-scale mixer 103 may have dimensions 121 that are proportional to the dimensions 117 of the large-scale mixer 105. In some implementations, the small-scale mixer 103 may have a filling volume of about 2 liters or less. In some implementations, the small-scale mixer 103 may have a filling volume of about 0.5 liters to about 2 liters. For example, the small-scale mixer 103 may have a filling volume of about 1 liter. It is understood that the actual capacity of the small-scale mixer may exceed its target capacity (e.g., about 10%). The dimensions 121 of the small-scale mixer 103 may include the impeller clearance from the bottom of the mixer ("C1"), the impeller diameter ("D1"), the liquid level ("H1"), the rotational speed ("N1"), the tank diameter ("T1"), the blade width ("W1"), and the baffle width ("WB1"). According to aspects of this disclosure, the dimensions 121 of the small-scale mixer 103 are proportionally the same as the dimensions of the large-scale mixer 105. In some implementations, the dimensions of the small-scale mixer 103 are related to the dimensions of the large-scale mixer 105 by equal or substantially equal scaling factors. For example, as illustrated by block 109 in Figure 1, the scaling factors are ratios C1 / C2, D1 / D2, H1 / H2, N1 / N2, T1 / T2, W1 / W2, and WB1 / WB2, where these ratios have equal or substantially equal values. In some implementations, the scaling factors may be values ​​greater than about 2.0. For example, the scaling factors may be about 2.2, about 3.7, about 4.6, about 5.8, or about 7.9.

[0011] The 3D printer 109 may be a conventional 3D printing system that can use fused deposition modeling, stereolithography, selective laser sintering, selective laser melting, electron beam melting, or other suitable 3D printing techniques. In some implementations, the 3D printer 109 can print 3D structures using PC (polycarbonate), ABS (acrylonitrile butadiene styrene), polycarbonate (PC), PLA (polylactic acid), PET (polyethylene terephthalate), nylon, metal, glass / PET, or other suitable materials.

[0012] The smoothing device 113 may be configured to deburr and smooth objects such as those produced by the 3D printer 109. The smoothing device 113 may include mechanical and chemical smoothing devices. In some implementations, the smoothing device 113 may include one or more devices having one or more friction heads configured to deburr, sand, and polish the 3D shape. In addition, the smoothing device 113 may include a bath of solvent for polishing the 3D shape formed from the material used by the 3D printer 109. For example, the bath of solvent may use acetone, dichloromethane, or other solvents to smooth, for example, ABS or polycarbonate. In some implementations, the rough small-scale mixer 103 produced by the 3D printer 109 is polished using vapors produced by the solvent. In other implementations, the rough small-scale mixer 103 is polished by direct immersion in a pool of solvent.

[0013] Furthermore, referring to Figure 1, the illustrative diagram of environment 100 shows an example of a functional flow for manufacturing a small-scale mixer 103 based on a large-scale mixer 105 using a 3D printer 109 and a smoothing device 113. As shown by block 109, the dimensions 117 of the large-scale mixer 105 (e.g., C2, D2, H2, N2, T2, W2, and WB2) can be converted to the dimensions 121 of the small-scale mixer 103 (e.g., C1, D1, H1, N1, T1, W1, and WB1) using the same scaling factors for the individual dimensions such that C1 / C2=D1 / D2=H1 / H2, N1 / N2=T1 / T2, =W1 / W2=WB1 / WB2. In addition, a second dimension 125 of the small-scale mixer can be determined. The second dimension 125 can be determined, for example, by modeling and simulation using conventional computational fluid dynamics techniques. Using the first and second small-scale mixer dimensions 121 and 125, the 3D printer 109 can manufacture the small-scale mixer 103. In some implementations, the tank and impeller of the small-scale mixer 103 can be produced as a single part. In other implementations, the tank and impeller can be produced separately.

[0014] Furthermore, as illustrated in Figure 1, the surface of the small-scale mixer 103, including the tank and impeller, output by the 3D printer 109 may be rough due to imperfections such as burrs and rough edges. These imperfections may arise from the 3D printing process and could, for example, cause friction, particle generation, and shear forces, potentially leading to the breakdown of pharmaceutical products during mixing. The smoothing device 113 can process the rough small-scale mixer 103 to remove imperfections and smooth the surface of the small-scale mixer 103.

[0015] Figure 2 shows a cutaway side view of an example of a mixer 205 illustrating the dimensions according to an embodiment of the present disclosure. The mixer 205 and its dimensions may be the same as or similar to those discussed above. For example, the dimensions of mixer 205 may include the impeller clearance from the bottom of the mixer (C), the impeller diameter (D), the liquid level (H), the tank diameter (T), the blade width (W), and the baffle width (WB). The dimensions of mixer 205 (C, D, H, N, T, W, and WB) may correspond to the dimensions of the small-scale mixers described above (e.g., small-scale mixer 103 dimensions C1, D1, H1, N1, T1, W1, and WB1) and the large-scale mixers (e.g., large-scale mixer 105 dimensions C2, D2, H2, N2, T2, W2, and WB2).

[0016] Figure 3A shows a top view of an example of an impeller 305 for a large-scale mixer according to an embodiment of the present disclosure. Figure 3B shows a side view of an impeller 305 according to an embodiment of the present disclosure. The impeller 305 may be the same as or similar to that of the large-scale mixer (e.g., large-scale mixer 105) described above. The impeller 305 may have an impeller diameter (D2) and a blade width (W2), which may be the same as the dimensions described above. In addition, the impeller 305 may have a blade height (BH2). Furthermore, the impeller 305 may have a hub 309 having a hub diameter (HD2) and a hub height (HH2).

[0017] Figure 4A shows a top view of an example of an impeller 405 of a small-scale mixer according to an embodiment of the present disclosure. Figure 4B shows a side view of an impeller 405 according to an embodiment of the present disclosure. The impeller 405 may be the same as or similar to that of a small-scale mixer (e.g., small-scale mixer 103) described above. The impeller 405 may have an impeller diameter (D1) and blade width (W1) which may be the same as the dimensions described above. In addition, the impeller 405 may have a blade height (BH1). Furthermore, the impeller 405 may have a hub 409 having a hub diameter (HD1) and hub height (HH1). As described above, the impeller diameter (D1) and blade width (W1) of the impeller 405 may be proportional to the impeller diameter (D2) and blade width (W2) of the impeller 305, based on a common scaling factor. In some implementations, unlike the impeller diameter (D1) and blade width (W1), the hub diameter (HD1) and hub height (HH1) of hub 409 are independent of the hub diameter (HD2) and hub height (HH2) of hub 309. Rather than being based on the dimensions of the hub diameter (HD2) and hub height (HH2) of hub 309, the dimensions of the hub diameter (HD1) and hub height (HH1) of hub 409 may be configured to limit the friction, particle generation, and shear forces applied to the pharmaceutical product during mixing. In addition, in some implementations, the surface of impeller 405 may be smoother or substantially smoother than the surface of impeller 305.

[0018] Figure 5 shows a flow block diagram illustrating an example of a method 500 for manufacturing a small-scale mixer according to an aspect of the present disclosure. In block 505, the method 500 includes obtaining the dimensions (e.g., C2, D2, H2, N2, T2, W2, HD2, and HH2) of a large-scale mixer (e.g., large-scale mixer 105). The dimensions may be determined from reference materials, measured manually, or measured automatically (e.g., by optical scanning).

[0019] In block 509, method 500 may include determining first dimensions (e.g., C1, D1, H1, N1, T1, W1, HD1, and HH1) of a small-scale mixer (e.g., small-scale mixer 103) to be manufactured based on the dimensions of a large-scale mixer determined in block 505. In some implementations, all of the first dimensions of the small-scale mixer are determined using the same scaling factor. The value of the scaling factor may be the ratio between the dimensions of the large-scale mixer and each of the dimensions of the small-scale mixer. For example, as illustrated in Figure 6, the height (H2) of the large-scale mixer may be 18.533 cm and the height (H1) of the small-scale mixer may be 8.601 cm. Thus, the scaling factor may be approximately 2.2 (i.e., 18.533 / 8.601). It is understood that the same scaling factor can be used to determine the dimensions of each small-scale mixer (e.g., C1, D1, H1, N1, T1, W1, BH1, HD1, and HH1) using other dimensions (e.g., C2, D2, H2, N2, T2, W2, BH2, HD2, and HH2). In some implementations, the scaling factor can be selected to obtain a target filling volume for the small-scale mixer. For example, the scaling factor may be selected to provide a filling volume of 1 liter.

[0020] In block 513, method 500 may determine a second dimension of a small-scale mixer. In some implementations, the second dimension is independent of the dimensions of the large-scale mixer. The second dimension may be determined, for example, by modeling and simulation using computational fluid dynamics techniques to determine the physical forces acting on the impeller (e.g., impeller 405) of the small-scale mixer and the shear forces acting on the solution by the impeller over various rotational speeds, fluid densities, and temperatures.

[0021] In block 517, using the first and second small-scale mixer dimensions determined in blocks 509 and 513, method 500 may manufacture a small-scale mixer 103 using a 3D printer (e.g., 3D printer 109). As described above, the 3D printer may produce the small-scale mixer by a fused filament method using materials including ABS, PLA, PET, nylon, metal, glass / PET, or other suitable materials. It is understood that small-scale mixers may be produced using other 3D printing techniques.

[0022] In block 521, method 500 may include smoothing the small-scale mixer manufactured in block 517 using a smoothing device (e.g., smoothing device 113). Smoothing the small-scale mixer in block 525 may include mechanically abrading the surface to remove burrs and rough edges, and polishing the surface. In addition, in block 529, smoothing the small-scale mixer may include chemically polishing the surface of the small-scale mixer. For example, smoothing may include immersing the small-scale mixer in a bath of a solvent such as acetone one or more times. In some implementations, the immersion is limited to two immersions for a total of less than 15 seconds. In addition, in some implementations, the immersion is limited to two immersions for a total of less than 10 seconds. For example, the small-scale mixer may be immersed in a bath of solvent for 5 seconds, dried for about 10 minutes, and then immersed a second time for another 5 seconds.

[0023] In addition, in some implementations, Method 500 may include validating the mixing of the product by a small-scale mixer against the corresponding large-scale mixer. As will be described in more detail below with respect to Figures 18 to 27, the validation may include mixing the product for a certain period (e.g., 24 hours) using the large-scale and small-scale mixers, periodically sampling the product from the large-scale and small-scale mixers, and determining whether the quality of the product has substantial differences in any of the following, based on a comparison of the respective samples: pH, protein concentration, surfactant density, turbidity, purity, and particle density.

[0024] Figure 6 shows Table 601 illustrating an example of scaling factors for small-scale mixers according to embodiments of the present disclosure. In particular, Table 601 relates the dimensions of exemplary small-scale mixers 603A, 603B, 603C, 603D, and 603E to the respective dimensions of large-scale mixers 605A, 605B, 605C, 605D, and 605E. The dimensions include the relationships between the filled volume (L) 609, conical height 611, cylindrical filled height 613, total filled height (H) 615, tank diameter (T) 617, impeller diameter (D) 619, slant height 621, and bottom diameter 623. The respective dimensions of the small-scale mixers 603A-603E and the large-scale mixers 605A-605E may be related by the corresponding scaling factors 625. As previously described herein, the ratio of dimensions 613 to 623 between each small-scale mixer 603A to 603E and the large-scale mixers 605A to 605E can be substantially the same scaling factor 625. For example, the filling volume (L) 609, conical height 611, cylindrical filling height 613, total filling height (H) 615, tank diameter (T) 617, impeller diameter (D) 619, inclined height 621, and bottom diameter 623 of the small-scale mixer 603A and the large-scale mixer 605A can be scaled using the same scaling factor 625, such as 2.2. The dimensions 609 to 623 of the small-scale mixers 603B to 603E and the corresponding large-scale mixers 605B to 605E have scaling factors of 3.7, 4.6, 5.8, and 7.9, respectively.

[0025] Figures 7, 8, and 9 illustrate tables 701, 801, and 901 illustrating exemplary scaling factors 625 for determining the dimensions of an exemplary small-scale mixer impeller 405, such as impeller diameter 703, impeller height 705, and impeller thickness 707, based on the respective dimensions of a corresponding large-scale mixer impeller 305, according to an aspect of the present disclosure. The dimensions 703, 705, and 707 of the small-scale mixer impeller 405 and the corresponding large-scale mixer impeller 305 have scaling factors of 3.7, 4.6, 5.8, and 7.9, respectively, as described above.

[0026] Figure 10 shows Table 1001 illustrating the ratios between impeller dimensions of exemplary large-scale mixer impellers according to embodiments of the present disclosure. Table 1001 associates the large-scale mixers 1003A, 1005A, and 1007A with their respective tank filling volume (L) 609, tank height (H) 613, tank diameter (T) 617, impeller diameter (D) 619, tank aspect ratio (H / T) 627, and impeller ratio (D / T) 629. The tank filling volume 609, tank height 613, tank diameter 617, impeller diameter 619, tank aspect ratio 627, and impeller ratio 629 of the large-scale mixers 1003A, 1005A, and 1007A may be the same as or similar to those previously discussed above. In some implementations, the large-scale mixers 1003A, 1005A, and 1007A may be mixers of the same type, product, or system with different capacities (e.g., mixers from the same manufacturer). As illustrated in Figure 10, the large-scale mixers 1003A, 1005A, and 1007A may have impeller ratios of approximately 0.234, 0.191, and 0.153, respectively. In some implementations, the dimensions of the impeller of the small-scale mixer (e.g., impeller 405) are based on one of the large-scale mixers 1003A, 1005A, and 1007A having the largest impeller ratio of 629 to improve the shear stress on the impeller.

[0027] Figure 11 shows Table 1101 illustrating the reproducibility of exemplary small-scale mixers 1105A, 1105B, 1105C, and 1105D produced according to embodiments of this disclosure. Table 1101 correlates the measured values ​​of the respective tank diameter (T) 617 and cylindrical filling height 613 measured for the small-scale mixers 1105A to 1105D. In addition, for the tank diameter 617 and cylindrical filling height 613 of tanks 1105A to 1105D, Table 1101 illustrates the mean 1109, standard deviation 1111, expected measured value 1113, and the percentage error 1115 of the mean measured value 1109 from the expected measured value 1113. For example, for tank 1105A, Table 1101 shows that the average measured tank diameter 617 is 128.875 cm, and the standard deviation 1111 of the measured tank diameter 617 is 0.005. Furthermore, the average measured tank diameter 617 is 128.875, which is a percent error of 0.13% from the expected measurement 1113 of a tank diameter 617 of 129.048 cm.

[0028] Figure 12 shows Table 1201 illustrating the reproducibility of exemplary impellers (e.g., impeller 405) of small-scale mixers 1205A, 1205B, and 1205C according to embodiments of the present disclosure. Table 1201 correlates the measured values ​​of the impeller diameter (D) 703, blade height (BH) 705, and blade thickness (W) 707 for each impeller. In addition, for the impeller diameter (D) 703, blade height (BH) 705, and blade thickness (W) 707 of impellers 1205A to 1205C, Table 1201 illustrates the mean 1209, standard deviation 1211, expected measured value 1213, and percentage error 1215 of the mean measured value 1109 from the expected measured value 1213. For example, for tank 1205A, Table 1201 shows that the average measured impeller diameter 1209 is 30.350 mm, and the standard deviation 1111 of the measured impeller diameter 703 is 0.058. Furthermore, the average measured impeller diameter 1209 is 30.350, which is a 0.79% percent error 1215 from the expected measurement 1213 for an impeller diameter 703 of 30.590 mm.

[0029] Figure 13 shows Table 1301 illustrating, for example, the difference between the measured ratio 1305 and the expected ratio 1307 between the impeller diameter 703 and the tank diameter 617 for large-scale mixers 1105A, 1105B, and 1105C. Furthermore, for the tank diameter 617 and impeller diameter (D) 703, Table 1301 illustrates the percentage error 1309 between the measured ratio 1305 and the expected ratio 1307. For example, for the large-scale mixer 1105A, Table 1301 shows that the measured ratio 1305 is 0.235, the expected ratio is 0.234, and the error is 0.64%.

[0030] Figure 14 shows Table 1401 illustrating an exemplary difference between the set speed 1403 (rpm) and the measured speed 1405 (rpm) of a small-scale mixer propeller according to an aspect of the present disclosure.

[0031] Figure 15 shows a bar graph 1501 illustrating comparative examples of average surface roughness between a large-scale mixer insulator (e.g., the large-scale mixer insulator 305 of the large-scale mixer 105), a small-scale mixer insulator before smoothing (e.g., the small-scale mixer insulator 405 of the small-scale mixer 103), and a small-scale mixer insulator after smoothing, according to embodiments of the present disclosure. More specifically, bars 1505A, 1505B, and 1505C illustrate the average roughness of the small-scale mixer insulator before smoothing, measured at the impeller blade, the top of the impeller, and the side of the impeller, respectively. Bars 1507A, 1507B, and 1507C illustrate the average roughness of the large-scale mixer insulator measured at the impeller blade, the top of the impeller, and the side of the impeller, respectively. Rods 1509A, 1509B, and 1509C illustrate the average roughness of the smoothed small-scale mixer insulator measured at the impeller blade, impeller top, and impeller side, respectively. In some implementations, smoothing may include immersing the small-scale mixer insulator twice (2×) in a bath of solvent, as described earlier herein, or exposing it to solvent vapor. For example, smoothing may include immersing the small scale in solvent twice, followed by exposing the small-scale mixer to the solvent evaporated for 6 hours or more under a chemical fuming hood. Roughness can be measured using a contact profilometer, conformal microscope, or other suitable measuring device. As shown in the figures, by smoothing, the roughness of the small-scale mixer insulator was reduced to substantially the same roughness as that of the large-scale mixer insulator.

[0032] Figure 16 shows a bar graph 1601 illustrating comparative examples of average surface roughness of mixer tanks of a large-scale mixer (e.g., large-scale mixer 105), a small-scale mixer before smoothing (e.g., rough small-scale mixer 103), and a small-scale mixer after smoothing (e.g., smoothed small-scale mixer 103) according to embodiments of this disclosure. More specifically, bar 1605 illustrates the average roughness of the small-scale mixer tank before smoothing, bar 1607 illustrates the average roughness of the large-scale mixer tank, and bar 1609 illustrates the average roughness of the small-scale mixer tank after smoothing. In some embodiments, smoothing may include immersing the small-scale mixer tank in a bath of solvent or exposing the small-scale mixer tank to solvent vapor, as described earlier in this specification.

[0033] Figure 17 shows images 1703, 1705, 1707, and 1709 illustrating the respective impeller surface roughnesses 1713, 1715, 1717, and 1719 of exemplary small-scale mixer impellers according to aspects of the present disclosure. Image 1703 shows a large-scale impeller blade (e.g., of a large-scale impeller 305). Images 1705, 1707, and 1709 show images of a small-scale impeller blade (e.g., of a small-scale impeller 405) after immersion in dichloromethane once, twice, and three times, respectively. As illustrated, the smoothing value for the two-times case shown in image 1707 substantially matches the smoothing value of the large-scale impeller blade in image 1703.

[0034] Figures 18–27 illustrate an exemplary process for verifying a small-scale mixer produced according to an aspect of this disclosure and modeling the performance of the small-scale mixer compared to the performance of a corresponding large-scale mixer. The small-scale and large-scale mixers may be the same or similar as those described earlier in this specification (e.g., small-scale mixer 103 and large-scale mixer 105). In some implementations, the products used in the process are biopharmaceutical products. For example, the biopharmaceutical product may contain shear-sensitive molecules such as formulated drug substances ("FDS"). In some implementations, the biopharmaceutical product may also contain surfactants. In addition, in some implementations, the process determines the effect of shear stress from mixing the products using the small-scale mixer compared to the large-scale mixer. For example, the determination of the effect is based on a constant impeller tip velocity and / or power-to-volume ratio (P / V). The impeller tip velocity is the speed of the outer edge of the impeller. Since the maximum mixing shear stress occurs at the impeller tip, maintaining a constant tip velocity in the small-scale mixer relative to the large-scale mixer avoids damage to products such as biopharmaceutical proteins. The power-to-volume ratio (P / V) is the effective energy input per unit volume of fluid. P / V (W / m³ (SI units)) can be determined using the following equation, where Np is the power number, ρ is the fluid density (kg / m³), N is the impeller velocity (rpm or s⁻¹), and D is the impeller diameter (m): TIFF2026065143000002.tif11128

[0035] Furthermore, in some implementations, the size of the small-scale mixers used in the process represents a worst-case scenario. For example, among a set of small-scale mixers, each having a volume scaled from a large-scale mixer, the worst-case scenario is the small-scale mixer having the smallest size and the largest scaling factor, and therefore capable of generating the largest shear force.

[0036] Figures 18–20 illustrate an exemplary verification process according to an embodiment of the present disclosure. Figure 18 shows Table 1801 illustrating exemplary parameters for a large-scale mixer 1802 and a small-scale mixer 1803. In Table 1801, column 1805 includes the dimensions of the large-scale mixer 1802, including a volume of approximately 2 L, an impeller diameter (D) of approximately 65.9 mm, and a tank diameter (T) of approximately 278 mm. Column 1807 includes the dimensions of the corresponding small-scale mixer 1803, including a volume of approximately 0.2 L, an impeller diameter (D) of approximately 31 mm, and a tank diameter (T) of approximately 129 mm. In some implementation embodiments, the dimensions of the small-scale mixer 1803 represent a worst-case scenario in which verification of the small-scale mixer 1803 also verifies other small-scale mixers corresponding to the large-scale mixer 1802. For example, the small-scale mixer 1803 may have the largest scaling factor (e.g., 7.9) among the exemplary small-scale mixers described above with respect to Figures 7, 8, and 9.

[0037] In this example, the process illustrated in Figures 18 to 20 compares the mechanical shear caused by mixing the product using the impellers (e.g., impeller 405 and impeller 305) of a large-scale mixer 1802 and a small-scale mixer 1803 operating at constant tip speeds of 0.626 m / s and 0.621 m / s, respectively. Figures 19 and 20 show Tables 1901 and 2001 illustrating a comparison of the products mixed using the large-scale mixer 1802 and the small-scale mixer 1803. More specifically, columns 1903 and 2003 show product samples taken at different times from the start of mixing, including 0 min (T0), 30 min (T30), 60 min (T60), 90 min (T90), 150 min (T150), 240 min (T240), 300 min (T300), 480 min (T480), and 1,320 min (T1320). Corresponding to the sample times T0 to T1320 in columns 1903 and 2003, column 1905 compares the pH of products mixed using large-scale mixer 1802 and small-scale mixer 1803. Column 1907 compares the protein concentration of products mixed using large-scale mixer 1802 and small-scale mixer 1803. Column 1909 compares the surfactant density (percent w / v) of products mixed using large-scale mixer 1802 and small-scale mixer 1803. Column 1911 compares the turbidity of products mixed using large-scale mixer 1802 and small-scale mixer 1803. In Table 2001 of Figure 20, column 2005 compares the purity of products mixed using large-scale mixer 1802 and small-scale mixer 1803. Column 2007 compares the particle density (# / ml) of products mixed using large-scale mixer 1802 and small-scale mixer 1803. As shown in Tables 1901 and 2001, the modeling process verifies that there is no substantial difference in the quality of products mixed using large-scale mixer 1802 and the corresponding small-scale mixer 1803 in terms of pH, protein concentration, surfactant density, turbidity, purity, and particle density.

[0038] Figures 21–24 illustrate another exemplary verification process according to an aspect of the present disclosure. This example verifies the quality of a product (e.g., a fully human monoclonal antibody) mixed without any surfactant (e.g., PS20) using a small-scale mixer 1803 against a large-scale mixer 1802. The verification process evaluates two approaches to scaling the large scale based on different parameters. The large-scale mixer 1802A is scaled to a constant power per volume (P / V), and the large-scale mixer 1802B is scaled to mixing at a constant impeller tip speed. As shown in columns 2105, 2107, and 2109, the dimensions of the large-scale mixers 1802A, 1802B, and the small-scale mixer 1803 may be the same as or similar to those described above with respect to Figures 18–20. Furthermore, according to this example, the tip velocity of the large-scale mixer 1802B shown in column 2105, which is 0.483 m / s, may be substantially equal to the tip velocity of the small-scale mixer shown in column 2109, which is 0.481 m / s. In addition, according to this example, the 43.0 W / m of the large-scale mixer 1802B shown in column 2107 3 The power per unit volume (for example) is 43.3 W / m for the small-scale mixer 1803 shown in column 2109. 3 This can be substantially equivalent to the power per unit volume.

[0039] Figures 22, 23, and 24 illustrate Tables 2201, 2301, and 2401 with respect to Figure 21, illustrating the comparison results between the large-scale mixers 1802A and 1802B and the small-scale mixer 1803 described above. More specifically, columns 2205, 2305, and 2405 show product samples taken at different times from the start of product mixing, including 0 hours (T0), 1 hour (T1h), 2 hours (T2h), 5 hours (T5h), 8 hours (T8h), 24 hours (T24h), and 30 hours (T30h). Corresponding to individual sample times T0h to T30h, column 2207 compares the pH of products mixed using the large-scale mixers 1802A and 1802B and the small-scale mixer 1803. Column 2209 compares the protein concentrations of products mixed using large-scale mixer 1802 and small-scale mixer 1803, illustrating no change in total protein concentration from control (or T0) to T30h. Column 2211 compares the turbidity of products mixed using large-scale mixer 1802 and small-scale mixer 1803. In Figure 23, column 2307 of Table 2301 compares the purity of products mixed using large-scale mixers 1802A, 1802B, and small-scale mixer 1803. In Figure 24, column 2407 of Table 2410 compares the particle count per volume (# / ml) of products mixed using large-scale mixers 1802A, 1802B, and small-scale mixer 1803. According to some implementations, the example illustrated in Figures 21-24 shows the worst-case tip shear value of a small-scale mixer (e.g., 9.791 s in column 2109). -1 This represents the tip shear value of a large-scale mixer (e.g., 4.555s in column 2105), as is evident from the increase in turbidity 2211. -1 and column 2107 5.857s -1 This can be expressed as being very high in relation to ). By evaluating the worst-case scenario of the small-scale mixer 1803, this evaluation determines whether the product mixed using the small-scale mixer 1803 may be affected when mixed using the large-scale mixers 1802A and 1802B.

[0040] Figures 25–27 illustrate another exemplary verification process according to an aspect of the present disclosure. The exemplary process in Figures 25–27 involves mixing a product (e.g., a fully human monoclonal antibody) that does not contain a surfactant (e.g., PS20). The verification process evaluates an example of product mixing using a substantially constant tip rate during two stages of the process. This example calculates stresses in the small-scale mixer 180 due to shear stress, cavitation (foaming, bubbles), and air / water interface stress. According to this example, the first stage (T0h–T4h) shown in Figure 25 operates for 4 hours, and the second stage (T4h–T24h) shown in Figure 26 operates for a further 20 hours. As shown in columns 2105, 2107, and 2109, the dimensions of the large-scale mixer 1802A and the small-scale mixer 1803 may be the same as or similar to those described with respect to Figures 18–20. In the first stage of this example, shown in Table 2501 of Figure 25, the large-scale mixer 1802A can mix the product at a tip velocity of 1.242 m / s and a maximum of 360 RPM, while the small-scale mixer 1802A can mix the product at a tip velocity of 1.252 m / s and a maximum of 780 RPM. In the second stage of this example, shown in Table 2601 of Figure 26, foaming reduces the tip velocity. In this example in Figure 26, the large-scale mixer 1802A can mix the product at a tip velocity of 0.863 m / s and a maximum of 250 RPM, while the small-scale mixer 1802A can mix the product at a tip velocity of 0.867 m / s and a maximum of 540 RPM. In the above example, the product may be a fully human monoclonal antibody-drug substance (DS) that may be (generally) highly sensitive to shear. Prior to each mixing test, the bulk drug substance may be diluted to the final formulated drug substance (FDS) using, for example, 10 mM sodium phosphate, 5% (w / v) sucrose, and 40 mM sodium chloride at pH 6.2, with or without PS20. The physical properties of the formulated drug substance are density: 1.02536 g / cm³, viscosity: 1.504 cP (20°C), 1.293 cP (25°C).

[0041] Figure 27 shows Table 2701 illustrating the process results comparing the large-scale mixer 1802B and the small-scale mixer 1803 described above with respect to Figures 25 and 26. More specifically, column 2705 shows samples taken at different times from the start of product mixing, including 0 min (T0), 30 min (T30), 60 min (T60), 90 min (T90), 150 min (T150), 240 min (T240), 300 min (T300), 420 min (T420), 480 min (T480), and 1440 min (T1440). Column 2707 compares the pH of the products mixed using the large-scale mixer 1802B and the small-scale mixer 1803. Column 2709 compares the protein concentration of products mixed using large-scale mixer 1802B and small-scale mixer 1803. Column 2711 compares the turbidity of products mixed using large-scale mixer 1802B and small-scale mixer 1803. Column 2713 compares the purity of products mixed using large-scale mixer 1802B and small-scale mixer 1803. Column 2715 compares the particle count per volume (# / ml) of products mixed using large-scale mixer 1802B and small-scale mixer 1803. Table 2701 shows that the samples experienced higher shear stress, and therefore higher increases in turbidity, purity, and particulate matter. Thus, small-scale mixers can be used to evaluate shear stress mixing.

[0042] This disclosure is intended to illustrate various aspects and should not be limited to the specific implementations described herein. Many modifications and variations can be made without departing from its spirit and scope, as may be apparent to those skilled in the art. In addition to those enumerated herein, functionally equivalent methods and apparatus within the scope of this disclosure will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended claims. This disclosure is limited only by the conditions of the appended claims, which are together with the entire scope of equivalents for which such claims are entitled. It should also be understood that the terminology used herein is for illustrative purposes only and is not intended to limit implementations.

[0043] With regard to the use of substantially any plural and / or singular terms herein, those skilled in the art may substitute plurals for singulars and / or singulars for plurals as appropriate to the context and / or use. Various singular / plural substitutions may be explicitly described herein for clarity.

[0044] In general, it will be understood by those skilled in the art that the terms used herein, and in particular in the appended claims (e.g., the text of the appended claims), are generally intended to be “open” terms (for example, “including” should be interpreted as “including but not limited to,” “having” should be interpreted as “having at least,” and “includes” should be interpreted as “includes but is not limited to,” etc.). It will further be understood by those skilled in the art that if a particular number of descriptions of introduced claims are intended, such intention will be explicitly stated in the claims, and if there is no such statement, there is no such intention. For example, for the sake of understanding, the following appended claims may include the use of the introductory phrases “at least one” and “one or more” to introduce the descriptions of the claims. However, even if the same claim includes an introductory phrase such as "one or more" or "at least one," and an indefinite article such as "a" or "an" (for example, "a" and / or "an" should be interpreted as meaning "at least one" or "one or more"), the introduction of a claim description by the indefinite article "a" or "an" should not be interpreted as meaning that any particular claim containing such introduced claim description is limited to an implementation containing only one such description. The same applies to the use of definite articles used to introduce claim descriptions. In addition, even if a particular number in an introduced claim description is explicitly stated, a person skilled in the art will understand that such a description should be interpreted as meaning at least a number of descriptions (for example, the minimal description "two descriptions" without other modifying phrases means at least two descriptions, or two or more descriptions).Furthermore, in these examples using conventions similar to "at least one of A, B, and C, etc.," such configurations are generally intended in a sense that a person skilled in the art would understand of the convention (for example, "a system having at least one of A, B, and C" may include, but is not limited to, systems having A alone, B alone, C alone, A and B together, A and C together, B and C together, and / or A, B, and C together, etc.). It will be further understood by those skilled in the art that any de facto separate word and / or phrase for which two or more alternative terms exist should be understood as intended to include the possibility of including one of those terms, either or both of those terms, whether or not they appear in the specification, claims, or drawings. For example, the phrase “A or B” will be understood to include the possibilities of “A” or “B” or “A and B.” In addition, if a feature or aspect of the present disclosure is described in terms of the Markush group, those skilled in the art will recognize that the present disclosure is also described in terms of any individual member or subgroup member of the Markush group.

Claims

1. A system for manufacturing small-scale mixers, A three-dimensional printer configured to manufacture a small-scale mixer having a first set of dimensions based on a set of dimensions of a large-scale mixer and based on a second set of dimensions independent of the set of dimensions of the large-scale mixer, A smoothing device configured to smooth the surface of the small-scale mixer and The system comprising the above.

2. The system according to claim 1, wherein the scaling factor relates the first plurality of dimensions of the small scale mixer to the plurality of dimensions of the large scale mixer.

3. The system according to claim 1, wherein the first plurality of dimensions of the small-scale mixer and the plurality of dimensions of the large-scale mixer include impeller clearance (C) from the bottom of the mixer, impeller diameter (D), liquid level (H), rotational speed (N), tank diameter (T), blade width (W), blade height (BH), and baffle width (WB).

4. The system according to claim 1, wherein the second set of dimensions corresponds to the physical forces applied to the impeller of the small-scale mixer during the mixing of the solution.

5. The system according to claim 1, wherein the three-dimensional printer is configured to manufacture the small-scale mixer using one of the following materials: PC (polycarbonate), ABS (acrylonitrile butadiene styrene), PLA (polylactic acid), PET (polyethylene terephthalate), nylon, metal, and glass / PET.

6. The system according to claim 1, wherein the smoothing device is configured to mechanically smooth the surface of the small-scale mixer.

7. The system according to claim 1, wherein the smoothing device is configured to chemically smooth the surface of the small-scale mixer using a tank of volatile solvent.

8. The system according to claim 7, wherein the volatile solvent is acetone or dichloromethane.

9. A method for manufacturing a small-scale mixer, To obtain the dimensions of a large-scale mixer, Based on the various dimensions of the large-scale mixer, the first set of dimensions of the small-scale mixer is determined. Determining a second set of dimensions for the small-scale mixer that is independent of the multiple dimensions of the large-scale mixer, Using the first set of dimensions and the second set of dimensions, the small-scale mixer is generated. The method, including the method described above.

10. The method according to claim 9, further comprising smoothing the surface of the small-scale mixer.

11. The method according to claim 10, wherein smoothing includes mechanically abrading the surface of the small-scale mixer.

12. The method according to claim 10, wherein smoothing includes chemically polishing the surface of the small-scale mixer using a volatile solvent.

13. The method according to claim 9, wherein the first plurality of dimensions of the small-scale mixer and the dimensions of the large-scale mixer include impeller clearance (C) from the bottom of the mixer, impeller diameter (D), liquid level (H), rotational speed (N), tank diameter (T), blade width (W), blade height (BH), and baffle width (WB).

14. The method according to claim 9, wherein determining the second plurality of dimensions of the small-scale mixer includes determining the physical force acting on the impeller of the small-scale mixer during the mixing of a solution.

15. The method according to claim 9, wherein generating the small-scale mixer includes printing the small-scale mixer in three dimensions.

16. The method according to claim 15, wherein three-dimensional printing is performed to produce the small-scale mixer using one of PC (polycarbonate), ABS (acrylonitrile butadiene styrene), PLA (polylactic acid), PET (polyethylene terephthalate), nylon, metal, and glass / PET.

17. Using the aforementioned large-scale mixer, a first volume of the first product is generated, Using the aforementioned small-scale mixer, a second volume of the first product mix is ​​produced, Comparing one or more physical parameters of the first volume and the second volume The method according to claim 9, further comprising:

18. The method according to claim 17, further comprising comparing the shear stress that generates the first volume with the shear stress that generates the second volume.

19. The method according to claim 18, wherein the shear stress includes the shear stress applied to the impeller of the small-scale mixer.

20. The method according to claim 17, wherein the physical parameters include one or more of visual inspection, pH, protein concentration, turbidity, purity, and particle density.

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