How to Optimize Filling Recipes for Drug Containers

Abstract

A method of filling a vial, the method including providing a pump corresponding to the vial and setting a droplet entrainment parameter of the pump to any value equal to or less than 20 degrees. The method also includes setting a no-adjust limit for the fill weight of the vial to T1, T1 being within a range of about 2% more or less than the fill weight of a target fill weight T0, where a process performance index Cpk (Cpk) for the vial throughout the fill cycle exceeds a minimum value.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the filing date of U.S. Provisional Patent Application No. 63 / 191,797, filed May 21, 2021, which is incorporated by reference in its entirety.

[0002] The present disclosure relates generally to filling recipes for drug containers, and more particularly to a universal method for optimizing filling recipes for drug containers. [Background technology]

[0003] Existing filling recipes are known for filling drug containers, such as recipes for filling mAb formulations in nested syringe and vial lines. However, many existing filling recipes create several problems, including extended fill weight optimization cycles, a large number of rejected units, and low manufacturing yields. In addition, existing filling recipes often have low process capability, as indicated by poor process capability indices, such as values ​​of Cpk<1.33.

[0004] More specifically, existing filling recipes are individually tailored to a single drug product, and each existing filling recipe has a unique filling process and set of operating parameters. As a result, every time a new filling recipe is needed for a new drug product, the pump in the manufacturing facility that executes the filling recipe must be calibrated. In addition, it often takes a very long time to calibrate the pump or related equipment in the manufacturing facility before starting the filling process according to a particular filling recipe. For example, typically many cycles, such as multiple strokes of the pump, are required before the pump can operate according to a particular filling recipe. This increases the overall time to fill a drug container, such as a syringe or vial, using a particular filling recipe for a drug product, leading to inefficiencies in the manufacturing and filling process. In addition, existing filling recipes typically deviate from the desired range of filling volumes for the container, causing problems in the manufacturing system and process. In one example, if the filling volume is outside the desired filling volume range, the unit is discarded and the pump must be re-learned how to fill the target within that range, again leading to inefficiencies in the manufacturing process. Summary of the Invention [Means for solving the problem]

[0005] According to a first aspect, a method of filling a vial includes providing a pump corresponding to the vial and setting a droplet entrainment parameter of the pump to any value equal to or less than 20 degrees. The method further includes setting an unadjusted limit for the fill weight of the vial to T1, T1 being within a range of about 2% more or less than the fill weight of the target fill weight T0, such that a process performance index Cpk (Cpk) for the vial throughout the fill cycle exceeds a minimum value.

[0006] According to a second aspect, a method of filling a plurality of vials of a nested syringe and vial line includes providing a plurality of pumps corresponding to a plurality of vials of the nested syringe and vial line, and setting a droplet draw parameter of each pump of the plurality of pumps to any value equal to or less than 20 degrees. The method also includes filling each vial of the plurality of vials with drug product via a corresponding pump of the plurality of pumps, wherein a Cpk for each vial of the plurality of vials exceeds a minimum value throughout the fill cycle.

[0007] According to yet another aspect, a method of optimizing a fill recipe for nested syringe and vial lines includes setting a droplet draw parameter of at least one pump in an offline manufacturing system corresponding to at least one container to an arbitrary value equal to or less than 20 degrees, and monitoring performance of the at least one pump with the droplet draw parameter of the at least one pump set to an arbitrary value equal to or less than 20 degrees. The method also includes obtaining at least a minimum value of Cpk for the at least one container and for the at least one drug product throughout at least one fill cycle using the at least one pump in the offline manufacturing system, and finalizing a fill recipe for the nested syringe and vial lines using data from a fill cycle of the at least one drug product using the at least one pump in the offline manufacturing system.

[0008] According to yet another aspect, a method of filling a vial may include providing a pump corresponding to the vial, setting a droplet entrainment parameter of the pump to any value equal to or less than 20 degrees, and setting an unadjusted limit for the fill weight of the vial to any value within a range of target fill weights T0 to T1, where T1 is within or within a range of target fill weights T0 to T2. So configured, a minimum value of the process performance index Cpk (Cpk) for the vial throughout the fill cycle is exceeded.

[0009] In some aspects, setting the droplet retraction parameter of the pump to any value equal to or less than 20 degrees may include setting the droplet retraction parameter of the pump to one of 10 degrees, 20 degrees, or any value in the range of 10 degrees to 20 degrees. Additionally, the method may further include setting a final droplet retraction value to 290 degrees when the droplet retraction parameter is set to 20 degrees, or setting a final droplet retraction value to 280 degrees when the droplet retraction parameter is set to 10 degrees. Additionally, providing a pump corresponding to the vial may include providing a pump corresponding to a vial of the nested syringe and vial line.

[0010] In other aspects, preparing a pump corresponding to the vial may include preparing one or more of a first filling set or a second filling set, where the first filling set includes a filling assembly for a peristaltic pump having a needle with an outer diameter of about 2.0 mm, and the second filling set includes a filling assembly for a peristaltic pump having a needle with an outer diameter of about 3.0 mm.

[0011] In yet other embodiments, the Cpk for the vial exceeding a minimum value throughout the fill cycle may include one or more of: (1) the Cpk for the vial exceeding a value of 1.33; or (2) the Cpk for the vial exceeding a minimum value while in a temperature range throughout the fill cycle, the temperature range being one of: (1) 5 (± 3) degrees Celsius; (2) 20 (± 5) degrees Celsius; or (3) 10-19 degrees Celsius.

[0012] In other embodiments, the method may further include filling the vial with a drug product via a pump, the drug product having the following characteristics: (a) about 1.0 to 1.2 g / cm 3 0-72.7 mN / m。 In one example, the drug product has one or more of: (a) a density in the range of about 1.0-1.2 g / cm; (b) a viscosity in the range of about 1.0-10.0 cP; and (c) a surface tension in the range of about 40.0-72.7 mN / m. 3In another example, the drug product comprises a biological drug (e.g., peptide, mAb, siRNA) or a small molecule drug.

[0013] In yet another aspect, the method may further include monitoring performance of a filling recipe in the nested syringe and vial line and obtaining at least a minimum value of Cpk for at least one container for each pump of the plurality of pumps in the nested syringe and vial line.

[0014] The present disclosure will be more fully understood when the following description is taken in conjunction with the accompanying drawings. Some of the drawings may be simplified by omitting selected elements to more clearly show other elements. The omission of such elements in some of the drawings does not necessarily indicate the presence or absence of the particular element in any of the example embodiments, unless expressly depicted in the corresponding written description. Additionally, none of the drawings are necessarily drawn to scale. [Brief description of the drawings]

[0015] [Figure 1] FIG. 1 is a schematic diagram of one embodiment of an offline filling system utilizing the filling recipes of the present disclosure. [Figure 2A] FIG. 2 is a perspective view of a filling device of the system of FIG. 1. [Figure 2B] 2B is a portion of the filling device of FIG. 2A. [Figure 2C] FIG. 2 is a perspective view of a filling set of the system of FIG. 1. [Figure 2D] 2 is a perspective view of another filling set of the system of FIG. 1. [Figure 2E] FIG. 2 is a perspective view of an exemplary loading object of the system of FIG. 1. [Diagram 3](FIG. 3A) is a chart showing parameters for each filling set of FIG. 1. (FIG. 3B) is a chart showing in-process control parameters for the filling sets of FIG. 1. (FIG. 3C) is a chart showing product characteristics of a drug product for use with the methods of the present disclosure. [Figure 4] 13 is a flow chart illustrating a fill recipe parameter optimization procedure for a fill recipe of the present disclosure. [Diagram 5] FIG. 5A is a perspective view of fill performance results for vials after filling at various droplet entrainment values. FIG. 5B is a chart showing an embodiment of an exemplary fill recipe used in conjunction with the fill performance results of FIG. 5A. [Figure 6] FIG. 6A shows an example filling recipe according to one embodiment of the present disclosure. FIG. 6B shows a graph illustrating filling performance results of the filling recipe of FIG. 6A. FIG. 6C shows a chart illustrating filling performance results of the graph of FIG. 6B. [Figure 7] 7A and 7B are charts illustrating needle parameters for a needle and pump parameters for at least one pump used with a filling recipe of the present disclosure. [Figure 8] FIG. 8A is a graph showing fill performance results for a fill recipe of the present disclosure over a temperature range of 10-11 degrees Celsius using a second fill set of the system of FIG. 1. FIG. 8B is a chart showing the fill performance results of the graph of FIG. 8A. [Figure 9] FIG. 9A is a graph showing fill performance results for a fill recipe of the present disclosure at a temperature of about 19 degrees Celsius using the second fill set of the system of FIG. 1. FIG. 9B is a chart showing the fill performance results of the graph of FIG. 9A. [Figure 10] FIG. 10A is a graph showing fill performance results for a fill recipe of the present disclosure at a temperature of about 10-11 degrees Celsius using the first fill set of the system of FIG. 1. FIG. 10B is a chart showing the fill performance results of the graph of FIG. 10A. [Figure 11]FIG. 11A is a graph showing fill performance results for a fill recipe of the present disclosure at a temperature of about 19 degrees Celsius using the first fill set of the system of FIG. 1. FIG. 11B is a chart showing the fill performance results of the graph of FIG. 11A. [Figure 12] FIG. 1 is a schematic diagram of a production line in a manufacturing plant using the optimized filling recipe of the present disclosure. [Figure 13A-1] FIG. 13 is a perspective view of a nested syringe and vial line of the manufacturing line of FIG. [Figure 13A-2] Same as above. [Figure 13B-1] FIG. 13B is a schematic diagram of the nested syringe and vial line of FIG. [Figure 13B-2] Same as above. [Figure 13C] FIG. 13C is a perspective view of the nested syringe of FIGS. 13A-13B and a plurality of pumps corresponding to a plurality of vials in a vial line. [Figure 14] 13 is a chart showing fill performance results of a fill recipe of the present disclosure for at least one of the nested syringe and vial lines of FIG. [Figure 15] 1 is a chart showing fill performance results of a previously used fill recipe used on a nested syringe and vial line. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] Generally, an efficient filling recipe is disclosed for filling formulations including therapeutic proteins in nested syringe and vial lines. The universal filling recipe includes droplet retraction parameter optimization within a range of predetermined values ​​that results in a significantly more efficient filling recipe compared to other existing known filling recipes. In particular, for example, the novel filling recipe of the present disclosure may be used with many different drug products, resulting in a 95% reduction in fill weight optimization cycles. This results in an improvement of 10-30% increase in fill time utilization of nested syringe and vial lines, potentially preventing a significant number of units, such as vials, from being rejected. In at least one example, the drug product referred to herein includes a therapeutic protein, such as a monoclonal antibody, as further described below.

[0017] More specifically, referring now to FIG. 1, an offline manufacturing system 10 utilizing the filling recipes of the present disclosure is shown. In one example, the offline manufacturing system 10 is a small-scale bench setup in a pilot facility, for example, to facilitate easier evaluation and updating of various tests for new filling recipes based on test results for various trial recipes. The offline manufacturing system 10 includes a filling apparatus 12, a first filling set 14, and a second filling set 16. The first filling set 14 includes corresponding first filling objects 18, such as vials, and the second filling set 16 also includes corresponding second filling objects 20, also such as vials. In one example, the filling apparatus 12 is a Bausch+Strobel (B&S) scaled-down filling apparatus, for which recipe optimization involving many experiments was performed before arriving at an optimal universal filling recipe of the present disclosure. Although a specific B&S scaled-down filling apparatus was used, it will be appreciated that various other filling apparatuses may be used as well or alternatively. Additionally, while each of the first and second filling objects 18, 20 are referred to as vials in one example, it should be understood that the filling objects 18, 20 may alternatively and more generally be any other similar drug containers and still fall within the scope of the present disclosure. As described further below, optimal filling recipes selected from recipe optimization from the scaled-down filling apparatus 12 and the first and second filling sets 12, 16 can be transferred to a manufacturing line, such as the nested syringe and vial line in Figures 13A and 13B.

[0018] 2A-2E, there are shown perspective views of the filling apparatus 12, first and second filling sets 14, 16, and first and second filling objects 18, 20 of FIG. 1. In FIG. 2A, the filling apparatus 12 is a Bausch+Strobel filling apparatus, a bench scale-down filling apparatus, or more generally, a developmental filling apparatus to support clinical and commercial production, as described further below. Exemplary containers that may be used with the filling apparatus include ISO 2R, 6R, 20R, 3cc, 5cc, 10cc, 20cc vials, 1mL glass and 1mL plastic syringes, and 5cc plastic cartridges. The filling apparatus 12 includes a dosing container 21, a pump 22, such as a peristaltic pump, and a product bag 23. FIG. 2B shows a portion of the filling apparatus 12 of FIG. 2A. In particular, pump 22 is shown in cooperation with a filling object, such as a first filling object 18 or a second filling object 20. In this example, first and second filling objects 18, 20 are the same vial, but may be any other container and still fall within the scope of the present disclosure.

[0019] Now referring to FIG. 2C, the first filling set 14 of FIG. 1 is shown. The first filling set 14 is a peristaltic pump and includes a bag 27, a tube 28A, and a needle 29A. The tube 28A is connected at one end to the bag 27 and at the other end to the filling object 18, for example, so that the fluid in the bag can be drawn into the tube and into the filling object 18 by the needle 29A. In this example, the outer diameter of the needle 29A is 2.0 mm, the inner diameter of the needle is 1.6 mm, and the inner diameter of the pump tube 28A is 1.6 mm. In addition, the tube 28A branches into two tubes and merges again. The two tubes have the same inner diameter in this example. For example, the inner diameter of the tube 28B is 1.6 mm. Similarly, FIG. 2D shows the second filling set 16 of FIG. 1. Like the first filling set 14, the second filling set 16 is a peristaltic pump and includes a bag 27, a tube 28B, and a needle 29B, which is different from the needle 29A of the first filling set 14. Specifically, the tube 28B is again connected to the bag 27 at one end and to the second filling object 20 at the other end, so that the fluid in the bag can be drawn through the tube into the second filling object 20 by the needle 29B. In this example, the tube 28B again branches into two tubes and then merges again, but the two tubes have different inner diameters. For example, the inner diameters of the tube 28B are 1.6 mm and 3.2 mm, respectively. In addition, the outer diameter of the needle 29B is 3.0 mm, the inner diameter of the needle is 2.6 mm, and the inner diameter of the pump tube is 1.6 mm.

[0020] Now referring to FIG. 2E, an exemplary filling object is shown. In particular, the exemplary filling object may include the first and second filling objects 18, 20 of FIG. 1. In this example, the first and second filling objects 18, 20 include a 1.3 mL filling in an ISO 2R vial. For this exemplary filling object, the object weight is 1.365 grams, T2+ is 0.05 grams, the object weight is 1.415 grams, T2- is 0.05 grams, and the object weight is 1.315 grams. Also, T1+ is 0.03 grams, the object weight is 1.395 grams, T1- is 0.03 grams, and the object weight is 1.335 grams. Furthermore, the net weight no adjustment limit + is 0.02 grams, the object weight is 1.385 grams, the net weight no adjustment limit- is 0.02 grams, and the object weight is 1.345 grams.

[0021] 3A, a chart is shown illustrating exemplary parameters of the first and second filling sets 14, 16 of FIG. 1. As shown in the chart, in this example, the first filling set 14 is a peristaltic pump filling assembly having a needle with an outer diameter of 2.0 mm and an inner diameter of 1.6 mm. In addition, the peristaltic pump filling assembly includes a tube (FIG. 2C) having an inner diameter of 1.6 mm. The chart in FIG. 3A also includes information about the second filling set 16, which in this example also includes a peristaltic pump filling assembly having a needle with an outer diameter of 2.0 mm and an inner diameter of 2.6 mm. Similar to the first filling set 14, the second filling set 16 also includes a tube with an inner diameter of 1.6 mm and another tube with an inner diameter of 3.2 mm, as described above.

[0022] 3B, various in-process control parameters are initially set for the second filling set 16. In particular, a no-adjust limit for the fill weight of the second filling object 20, such as a vial, is set to T1, where T1 is within a range or range of about 2% more or less than the fill weight of the object fill weight T0. Specifically, in one example presented in the chart of FIG. 3B, the object fill weight T0 includes a volume of 1.3 mL and a mass of 1.365 grams. In this example, the no-adjust limit was 80% of T1, which may be T1±0.03 grams±0.02 grams. Thus, the amount of material to be filled in the vial that does not need to be adjusted is any value in this example in the range of 1.345 grams to 1.385 grams. In another example, the no adjustment limit for the fill weight of a vial, such as second filling target 20, may be set to any value within the range of target fill weights T0 to T1, e.g., T1 is within a range or ranges of target fill weights T0 to T2 based on process performance. In some examples, T1 is set at 2%, but may be varied.

[0023] 3C, a chart is shown listing the parameters of various drug products that are initially used in the optimization process. In particular, the filling recipe of the present disclosure includes filling a drug product via a pump into vials, such as vials of first and second filling objects 18, 20, where the drug product includes a mAb formulation. In this example, the mAb formulations used are Drug Product 1 (DP1) and Drug Product 2 (DP2). As presented in the chart, at 5 degrees Celsius, DP1 has a density of 1.055 g / cm 3 and the viscosity is 4.857. At 25 degrees Celsius, the density of DP1 is 1.05 g / cm 3 The viscosity is 2.604 cP and the surface tension is 41.63 mN / m. At 5 degrees Celsius, the density of DP2 is 1.054 g / cm 3 and the viscosity is 4.07 cP. In addition, at 25 degrees Celsius, DP2 has a density of 1.049 g / cm 3The viscosity is 2.19 cP and the surface tension is 43.716 mN / m. Therefore, in this example, the drug product used in the filling recipe has a viscosity of approximately 1.054 to 1.055 g / cm at 5 degrees Celsius. 3 Or about 1.049-1.05g / cm at 25 degrees Celsius 3 (2) a viscosity in the range of about 4.07 to 4.857 cP at 5° C. or about 2.19 to 2.604 cP at 25° C.; and (3) a surface tension in the range of about 41.00 to 43.80 mN / m at 25° C.

[0024] The methods disclosed herein can be used to fill any liquid drug product, such as drug products including biological drugs (e.g., peptides, mAbs, siRNAs) and small molecule drugs, provided that the drug product has a range of predefined physical parameters. More specifically, in one example, the drug product meets the following characteristics: (1) about 1.0-1.2 g / cm 3 and / or (2) a viscosity in the range of about 1.0-10.0 cP; and / or (3) a surface tension in the range of about 40.0-72.7 mN / m. In one example, preferred ranges of viscosity are one or more of 1.0-8.0 cP, 1.0-6.0 cP, 1.0-5.0 cP, and 1.0-4.0 cP. In another example, the drug product has a viscosity of 1.0-1.2 g / cm. 3 In another example, the drug product has a density in the range of about 1.0 to 10.0 cP, a viscosity in the range of about 1.0 to 10.0 cP, and a surface tension in the range of about 40.0 to 72.7 mN / m. 3 The drug product may have one or more of a density in the range of about 1.0 to 10.0 cP, a viscosity in the range of about 1.0 to 10.0 cP, and any value of surface tension. In other words, in one example, the determining factors of the filling recipe are the density and viscosity of the drug product, and the filling recipe can work with any surface tension. It will be understood that drug products that meet any of these parameters may be used with the methods and filling recipes of the present disclosure.

[0025] For example, in one example, manufacturing data suggests that a drug product having a viscosity of about 8.0 cP or greater performed well at a drop pull value of 20 degrees. Additionally, in another example, the preferred density of the drug product is about 1.0 to 1.1 g / cm 3 It will be appreciated that many other values ​​within the ranges of density, viscosity, and surface tension presented above may be used for drug products used with the methods and filling recipes of the present disclosure and fall within the scope of the present disclosure.

[0026] Referring now to FIG. 4, a flow chart illustrating the filling parameter optimization procedure for drug product DP1 is provided. Specifically, in step 30, an initial optimization based on an existing filling recipe, referred to as Existing Filling Recipe No. 1, was performed for the second filling set 16. Then, in step 32, this initially optimized DP1 filling recipe was used for the second filling set 16 to test a range of droplet retraction parameters ranging from 0 degrees to 45 degrees. In step 34, another existing filling recipe, referred to as Existing Filling Recipe No. 2, was started to test a range of droplet retraction parameters from 10 degrees to 20 degrees. Then, in step 36, a hybrid of Existing Filling Recipe No. 1 and Existing Filling Recipe No. 2 was developed, and various droplet retraction parameters were also tested, including 5 degrees, 10 degrees, and 20 degrees. In step 38, the hybrid recipe was finalized for the second filling set 16 with the droplet retraction parameter set to 20 degrees. Finally, in step 40, the same fill recipe was used for the first fill set 14, with the droplet draw parameters set to 10 degrees and 20 degrees. Based on the fill performance, the fill recipe for the first fill set 14 was finalized with the droplet draw parameter set to 20 degrees.

[0027] 5A, filling performance results are provided for a second filling object 20, such as a vial, of a second filling set 16 after utilizing a filling recipe having various droplet entrainment values. In particular, tests were conducted to monitor the filling performance into a vial when the droplet entrainment parameter of the filling recipe for the pump was set at 0 degrees, 10 degrees, 20 degrees, 30 degrees, 40 degrees, and 45 degrees, respectively. As noted in FIG. 5A, the void AG in the filling object 20 or vial increases with increasing droplet entrainment parameter, resulting in a gas-liquid bilayer, explaining the possible reason for the poor filling performance when a higher droplet entrainment parameter was set in the filling recipe. As noted in the chart in FIG. 5B, the droplet entrainment parameter set was different for each prepared vial, but all other parameters of the filling recipe used in this experiment were the same. Specifically, the start pump dose was set at 40 degrees, the pump dose start slope was set at 90 degrees, the pump dose stop slope was set at 210 degrees, the final pump dose was set at 260 degrees, the final drop retract was set at 310 degrees, and the distance traveled per dose was 766 degrees.

[0028] 6A, for example, a fill recipe is shown that includes many of the same constant parameters in the optimization cycle partially described in FIG. 5B, but with the droplet retract parameter set to 20 degrees for the second fill set 16. In particular, the fill recipe included a start pump dose set to 40 degrees, a pump start slope set to 90 degrees, a pump stop slope set to 210 degrees, a final pump dose set to 260 degrees, a final droplet retract set to 290 degrees, and a run distance per dose of 766 degrees.

[0029] 6B and 6C, the effect of the droplet entrainment parameter set to 20 degrees on the fill performance of DP1 in the second fill set 16 is provided. Specifically, for fill number 103 in the second fill set 16 using the fill recipe described in FIG. 6A, the minimum fill weight was 1.348 grams, the maximum fill weight was 1.384 grams, resulting in an average fill weight of 1.366 grams with a standard deviation of 0.006. The process performance index Cpk value was 2.69, significantly higher than the experiment using the fill recipe with the same parameters except for the droplet entrainment parameter of 45 degrees. In other words, the process performance index was much higher when the droplet entrainment parameter was set to 20 degrees compared to a higher value such as 45 degrees, further illustrating the effect of the droplet entrainment parameter on the fill performance.

[0030] Generally, the process performance index Cpk provides a value indicative of the efficiency of a particular process. In this example, the process performance index value Cpk relates to how close the actual fill weight of a container, such as a vial, is to the target fill weight. In addition, the process performance index value Cpk also relates to how close each subsequent fill rate of additional containers, such as vials, is to each other. A high value of the process performance index value Cpk indicates that a given pump is providing optimal performance. Similarly, a low value of the process performance index value Cpk indicates that the pump is under-capacity. Since it is important to fill each container (e.g., vial) with a consistent dose of drug product during the manufacturing process, a higher process performance index value Cpk also indicates the consistency of the filling process and is a critical value for the success of efficiently and accurately filling vials.

[0031] 7A and 7B, based on the optimization cycle and experimental data described above with respect to the filling recipe for the exemplary drug product DP1 in the second filling set 16, a universal filling recipe 50 of the present disclosure was completed for each of the offline manufacturing system 10 of FIG. 1 and the manufacturing line 102 of the manufacturing plant 100 of FIG. 12, as described in more detail below. In particular, as described in FIG. 7A, the filling recipe 50 includes specific needle parameters, including setting the needle setting dimension to one of 134.5 mm and 39.0 mm, setting the basic needle position to 7.0 mm, and setting the starting needle to 25 degrees downward. In addition, the needle parameters of the filling recipe 50 also include setting the needle at the start of administration to 10 mm, setting the needle to one of 60 degrees and 23 degrees downward, and setting the needle to 125 degrees upward. Additionally, the fill recipe 50 also includes setting the needle at the end of dose at 13.0 mm and 310 degrees, setting the start needle to a shutoff position of 315 degrees, setting the shutoff position to be reached at 13.0 mm and 315 degrees, and setting the start needle to a base position of 315 degrees, with the reached base needle position being 359 degrees.

[0032] In addition, as depicted in FIG. 7B, the completed fill recipe 50 of the present disclosure also includes setting several parameters of the pump. In particular, the fill recipe 50 includes setting the start pump dose to 40 degrees, the pump dose start slope to 90 degrees, the pump dose stop slope to 210 degrees, and the final pump dose to 260 degrees. Additionally, the fill recipe includes setting the droplet draw parameter to 20 degrees, the pump travel distance for droplet draw to 20 degrees, the final droplet draw parameter to 290 degrees, the travel distance per dose parameter to 766 degrees, etc. In another example, more generally, the fill recipe 50 may include setting the droplet draw parameter to any value equal to or less than 20 degrees and still be within the scope of the present disclosure. In one example, the lowest value for the droplet draw parameter is 0 degrees. In another example, the fill recipe 50 may include setting the droplet draw parameter of the pump to one of 10 degrees, 20 degrees, or any value in the range of 10 degrees to 20 degrees. Still further, the filling recipe 50 may include, for example, setting the final droplet retraction to 290 degrees when the droplet retraction parameter is set to 20 degrees, or setting the final droplet retraction value to 280 when the droplet retraction parameter is set to 10 degrees. In other words, depending on the value selected for the droplet retraction parameter, for example, any value equal to or less than 20 degrees, the final droplet retraction parameter is adjusted and set accordingly to match the set droplet retraction parameter value. In addition, the completed filling recipe 50 may also include setting a no-adjustment limit for the fill weight of any vial to T1, for example, T1 being within a range or range of about 2% more or less than the fill weight of the target fill weight T0, as described above with respect to FIG. 3B.

[0033] Although this fill recipe 50 has been completed for the exemplary drug product DP1 in the second fill set 16, the same fill recipe 50 may also be used for the first fill set 14 using, for example, DP1 or other drug products in a mAb formulation program. Still further, as described in more detail below, the same completed fill recipe 50 may also be effectively used in nested syringe and vial lines in a manufacturing plant. More generally, a method of optimizing a fill recipe for a nested syringe and vial line or other manufacturing line in a manufacturing plant may include, for example, using the first and second fill sets 14, 16 of the offline manufacturing system 10 of FIG.

[0034] 8A-8B, the effect of temperature on the fill performance of the second fill set 16 was evaluated for effectiveness, the results of which are provided in the graph of FIG. 8A and the table of FIG. 8B. In particular, in this experimental cycle, the temperature was set at 10-11 degrees Celsius, and the process performance parameter Cpk while in this temperature range of 10-11 degrees Celsius throughout the fill cycle was well above the minimum value of 1.33. In particular, the cycle included 103 fills, with a minimum fill weight of 1.340g, a maximum fill weight of 1.393g, an average fill weight of 1.362g, and a standard deviation of 0.008 grams. Furthermore, the process performance parameter Cpk value was 1.95, for example, well above the target minimum value of 1.33. FIG. 8A shows that in this temperature range, occasional fill weights were close to reaching the T1 limit, but subsequent fill weights were able to return near the target without a significant effect on the process performance index Cpk.

[0035] 9A-9B, the effect of temperatures above 10-11 degrees Celsius (similar to FIGS. 8A and 8B) on the fill performance of the second fill set 16 was evaluated, the results of which are provided in the graph of FIG. 9A and the table of FIG. 9B. In particular, in this experimental cycle, the temperature was set at about 19 degrees Celsius, and the process performance parameter Cpk during this temperature of about 19 degrees Celsius throughout the fill cycle was well above the minimum value of 1.33. Specifically, the cycle included 103 fills, with a minimum fill weight of 1.348g, a maximum fill weight of 1.384g, an average fill weight of 1.366g, and a standard deviation of 0.006 grams. Additionally, the process performance parameter Cpk for T2 was 2.69, which in this example was well above both the target minimum value of 1.3 and the process performance parameter Cpk for the fill performance at the lower temperature of 10-11 degrees Celsius. This indicates even better fill performance for the completed fill recipe at a slightly higher temperature.

[0036] 10A-10B, the effect of temperature on the fill performance of the first fill set 14 was evaluated, the results of which are presented in the graph of FIG. 10A and the table of FIG. 10B. In particular, in this experimental cycle, the temperature was set in the range of approximately 10-11 degrees Celsius, and the process performance parameter Cpk during this temperature throughout the fill cycle was significantly above the minimum value, such as 1.33. Specifically, the cycle included 100 fills, with a minimum fill weight of 1.354g, a maximum fill weight of 1.380g, an average fill weight of 1.365g, and a standard deviation of 0.005 grams. Furthermore, the process performance parameter Cpk for T2 was 3.16, significantly exceeding each of the process performance parameter Cpk and the target minimum value of 1.33 for the fill performance of the second fill set 16 at both the low temperature of, for example, 10-11 degrees Celsius (FIGS. 8A and 8B) and the high temperature of, for example, 19 degrees Celsius (FIGS. 9A and 9B). Such results therefore demonstrate the universal nature and applicability of the completed filling recipe to different filling sets, which may also be successfully transferred and used, for example, in nested syringe and vial lines in a manufacturing plant.

[0037] 11A-11B, the effect of temperatures above 10-11 degrees Celsius (similar to FIGS. 10A and 10B) on the fill performance of the first fill set 14 was evaluated, the results of which are provided in the graph of FIG. 11A and the table of FIG. 11B. In particular, in this experimental cycle, the temperature was set at about 19 degrees Celsius, and the process performance parameter Cpk during this temperature of about 19 degrees Celsius throughout the fill cycle was well above the minimum value of 1.33. Specifically, the cycle included 120 fills, with a minimum fill weight of 1.352g, a maximum fill weight of 1.373g, an average fill weight of 1.362g, and a standard deviation of 0.004 grams. Additionally, the process performance parameter Cpk for T2 was 3.61, e.g., well above both the target minimum value of 1.33 and the process performance parameter Cpk of 3.16 for fill performance at low temperatures of 10-11 degrees Celsius.

[0038] Thus, the results show that the fill weight performance is superior for the first set 14 of Figures 10A-11B compared to the fill performance of the second fill set 16 of Figures 8A-9B, although the minimum process performance index Cpk is exceeded over the entire temperature range for both the first set 14 and the second set 16. Additionally, the temperature effect observed for the second fill set 16 is less pronounced for the first fill set 14.

[0039] 12, a schematic diagram of a manufacturing line 102 in a manufacturing plant 100 is shown. In this example, the manufacturing line 102 includes at least one nested syringe and vial line 104 in which the efficient and universal filling recipe 50 of the present disclosure is effectively used. In one example, the nested syringe and vial line 104 is a nested syringe and vial line (NSVL) having a plurality of vials 105, such as ISO 2R RTU vials. It will be understood that the filling recipe 50 of the present disclosure may be utilized with a variety of other nested syringe and vial lines and still fall within the scope of the present disclosure. It will also be understood that the vial 105 may more generally be any container 105, such as a syringe, and still fall within the scope of the present disclosure. Additionally, in other examples, manufacturing line 102 may include multiple nested syringe and vial lines 106, each of which may include, for example, at least one nested syringe and vial line 104. Manufacturing line 102 also includes at least one pump 110 that corresponds to and cooperates with at least one vial in at least one nested syringe and vial line 104. Additionally, there may be multiple pumps 112 that correspond to multiple vials 114 in nested syringe and vial line 104. In yet other examples, there may be multiple nested syringe and vial lines in which a fill recipe 50 of the present disclosure is implemented.

[0040] 13A and 13B, an exemplary nested syringe and vial line 104 of FIG. 12 is shown in FIG. 13A. The nested syringe and vial line 104 is a B20 nested syringe and vial line (NSVL) that includes a semi-automated debugger 104a, an automatic debugger 104b, a rapid transfer airlock 104c, a nested filling device (isolator) 104d, and a capper 104e. A variety of other clinical or commercial production filling devices may alternatively be used and still fall within the scope of the present disclosure.

[0041] In addition, FIG. 13B illustrates a plurality of pumps, which may be, for example, a plurality of pumps 112 corresponding to a plurality of vials 114 of the nested syringe and vial line 104 of FIG. 12. In this example, the plurality of pumps 112 includes five pumps 110 that cooperate with each vial 105 of the plurality of vials 114. In this example, the nested syringe and vial line 104 is a clinical production filling device, such as a Bausch & Strobel filling device. Although the containers 105 are generally referred to as vials, it will be understood that the containers 105 may be one or more of a vial, a syringe, or a plastic cartridge and still fall within the scope of the present disclosure. For example, the containers 105 may include nested ISO 2R vials, nested 1 mL glass and plastic syringes, or nested 5 cc plastic cartridges. In addition, the plurality of pumps includes five pumps 110 in this example, but it will be understood that more or less pumps may alternatively be used and still fall within the scope of the present disclosure. In one example, the multiple pumps may include, for example, ten pumps or two pumps for different filling devices, or any other number of pumps within this range and still be within the scope of the present disclosure.

[0042] The method of filling a plurality of vials 105 of a nested syringe and vial line 104 includes providing one of a pump 110 or a plurality of pumps 112 corresponding to the vial 105 or one of the plurality of vials 105 of the nested syringe and vial line 104. The method also includes setting a droplet draw parameter of each pump 110 to any value equal to or less than 20 degrees. Additionally, in one example, the method also includes setting a no-adjust limit for the fill weight of the vial 105 to T1, where T1 is within a range or range of about 2% more or less than the fill weight of the target fill weight T0. The method may still further include filling each vial 105 of the plurality of vials 105 with a drug product, such as a mAb formulation, via a corresponding pump 110 of the plurality of pumps 112. The method may further include exceeding a minimum value of a process performance index Cpk for each vial 105 of the plurality of vials 105 while in a temperature range throughout the fill cycle, the temperature range being one of: (1) 5 (±3) degrees Celsius, (2) 20 (±5) degrees Celsius, or (3) 10 to 19 degrees Celsius.

[0043] In this example, the minimum value of the process performance index Cpk is 1.33. In other examples, such as in clinical filling, the minimum value of the process performance index Cpk is 1.0. However, in this example, as is commonly understood in commercial filling, the minimum value of the process performance index Cpk is 1.33. In addition, filling each vial 105 with drug product via a corresponding pump 110 of the plurality of pumps 112 includes filling each vial 105 with drug product, the drug product meeting the following characteristics: (1) about 1.0-1.2 g / cm 3 0-72.7 mN / m。 In one example, the drug product has one or more of: (a) a density in the range of about 1.0-1.2 g / cm; (b) a viscosity in the range of about 1.0-10.0 cP; and (c) a surface tension in the range of about 40.0-72.7 mN / m. 3 , a viscosity in the range of about 1.0-10.0 cP, and a surface tension in the range of about 40.0-72.7 mN / m.

[0044] 14 and 15, the filling performance of the new filling recipe of the present disclosure in the nested syringe and vial line 104 is provided. In particular, the total dose optimization cycle, such as the number of strokes of the pump 110 (or pump 112) required to teach the pump 110 how to operate using the new filling recipe, is minimized using the new filling recipe. Specifically, the total dose optimization cycle value is 4, which is significantly reduced compared to the total dose optimization cycle value of the previous filling recipe described in FIG. 15, for example. In addition, the process performance index Cpk for each nozzle (not shown) of each pump 110 of the multiple pumps 112 of the nested syringe and vial line 104 (of FIG. 12) exceeds the desired minimum process performance index Cpk value of 1.33. In fact, the average process performance index Cpk value for all nozzles of the pump 110 is 1.4.

[0045] Referring now to FIG. 15, there is provided a chart listing the process performance index Cpk of the nozzles of the pump using the old filling recipe. Specifically, when using the old filling recipe for a wide variety of different drug products, including the mAb formulation, the average process performance index Cpk for all the nozzles of the pump was significantly below the desired process performance index Cpk value of 1.33. In other words, the process performance index Cpk values ​​were all below 1.33. In addition, the total dose optimization cycle was better for each drug product using the old filling recipe compared to the dose optimization cycle values ​​listed in FIG. 14 when using the new filling recipe 50.

[0046] In view of the foregoing, it will be appreciated that a method for optimizing a filling recipe for a container, such as a vial 105 of a nested syringe and vial line 104, has been completed using, for example, the first and second filling sets 14, 16 and corresponding first and second filling objects 18, 20 of the offline manufacturing system 10 described above and shown in FIG. 1. By completing the recipe using an offline system, such as the offline system 10, a team of scientists can perform experiments and testing that cannot be performed in a large scale manufacturing plant such that the manufacturing line in the manufacturing plant is not moved or interrupted. In addition, the offline system 10 often includes a camera and does not include the limitations of required operator equipment and other constraints of a large scale manufacturing plant. Furthermore, this same optimized filling recipe may be used for different drug products, as described above.

[0047] More specifically, the method of optimizing a fill recipe for a nested syringe and vial line 104 includes setting a droplet draw parameter of at least one pump 14, 16, 22 in an offline manufacturing system 10 corresponding to at least one container 18, 20 to any value equal to or less than 20 degrees. The method further includes monitoring performance of the at least one pump 14, 16, 20 with the droplet draw parameter of the at least one pump 14, 16, 22 set to any value equal to or less than 20 degrees. The method still further includes obtaining at least a minimum value of a process performance index (Cpk) for the at least one container 18, 20 and for the at least one drug product throughout at least one fill cycle using the at least one pump 14, 16, 22 in the offline manufacturing system 10. The method also includes finalizing a fill recipe for the nested syringe and vial line 104 using data from a fill cycle of the at least one drug product using the at least one pump 14, 16, 22 in the offline manufacturing system 10.

[0048] Thus, optimized filling recipes have been developed for drug products, such as mAb drug products, that are applicable to manufacturing lines in a manufacturing plant, thereby saving significant time associated with programming pumps corresponding to nested syringe and vial lines in the manufacturing plant (e.g., often required for different recipes for different drug products).

[0049] The above description describes various systems and methods for filling vials in a nested syringe and vial line. It should be clear that the system or method may further include the use of drugs as described below, but note that the following list should not be considered exhaustive or limiting. The drug is contained within a reservoir. In some cases, the reservoir is the primary container into which the drug is filled for treatment. The primary container may be a vial, cartridge, or syringe.

[0050] For example, drug products that may be used with the methods disclosed herein may include colony stimulating factors, such as granulocyte colony stimulating factor (G-CSF). Such G-CSF agents include, but are not limited to, Neupogen® (filgrastim) and Neulasta® (pegfilgrastim). In various other embodiments, the methods may use various pharmaceutical products, such as erythropoietin stimulating agents (ESAs), which may be in liquid or lyophilized form.ESAs include Epogen® (epoetin alfa), Aranesp® (darbepoetin alfa), Dynepo® (epoetin delta), Mircera® (methoxypolyethylene glycol epoetin beta), Hematide®, MRK-2578, INS-22, Retacrit® (epoetin zeta), Neorecormon® (epoetin beta), Silapo® (epoetin zeta), any molecule that stimulates red blood cell production, such as, for example, Binocrit® (epoetin alfa), epoetin alfa hexal, Abseamed® (epoetin alfa), Ratioepo® (epoetin theta), Eporatio® (epoetin theta), Biopoin® (epoetin theta), epoetin alfa, epoetin beta, epoetin zeta, epoetin theta, and epoetin delta, each of which is incorporated by reference in its entirety. The following patents or patent applications are incorporated herein: the following patents or patent applications: U.S. Pat. No. 4,703,008; U.S. Pat. No. 5,441,868; U.S. Pat. No. 5,547,933; U.S. Pat. No. 5,618,698; U.S. Pat. No. 5,621,080; U.S. Pat. No. 5,756,349; U.S. Pat. No. 5,767,078; U.S. Pat. No. 5,773,569; U.S. Pat. No. 5,955,422; U.S. Pat. No. 5,986,047 Nos. 6,583,272, 7,084,245, and 7,271,689, and PCT Publication Nos. WO 91 / 05867, WO 95 / 05465, WO 96 / 40772, WO 00 / 24893, WO 01 / 81405, and WO 2007 / 136752, or variants or analogs thereof.

[0051] The ESA may be an erythropoietin stimulating protein. As used herein, "erythropoietin stimulating protein" refers to any protein that directly or indirectly causes the activation of the erythropoietin receptor, for example, by binding to the receptor and causing the dimerization of the receptor. Erythropoietin stimulating proteins include erythropoietin and its variants, analogs or derivatives that bind to and activate the erythropoietin receptor; antibodies that bind to and activate the erythropoietin receptor; or peptides that bind to and activate the erythropoietin receptor. Erythropoietin stimulating proteins include, but are not limited to, epoetin alpha, epoetin beta, epoetin delta, epoetin omega, epoetin iota, epoetin zeta, and analogs thereof, PEGylated erythropoietin, carbamylated erythropoietin, mimetic peptides (including EMP1 / hematide), and mimetic antibodies. Exemplary erythropoietin stimulating proteins include erythropoietin, darbepoietin, erythropoietin agonist variants and peptides or antibodies that bind to and activate the erythropoietin receptor (as well as the compounds reported in U.S. Patent Application Publication Nos. 2003 / 0215444 and 2006 / 0040858, the entire disclosures of each of which are incorporated herein by reference), as well as the following patents or patent applications, the entire disclosures of which are incorporated herein by reference: U.S. Patent No. 4,703,008; U.S. Patent No. 5,441,868; U.S. Patent No. 5,547,93 ... US Patent No. 5,618,698, US Patent No. 5,621,080, US Patent No. 5,756,349, US Patent No. 5,767,078, US Patent No. 5,773,569, US Patent No. 5,955,422, US Patent No. 5,830,851, US Patent No. 5,856,298, US Patent No. 5,986,047, US Patent No. 6,030,086, US Patent No. 6,310,078, US Patent No. 6,391,633, US Patent No. 6,583,272, US Patent No. 6,586,398, US Patent No. 6,900,292,U.S. Patent No. 6,750,369, U.S. Patent No. 7,030,226, U.S. Patent No. 7,084,245 and U.S. Patent No. 7,217,689, U.S. Patent Application Publication No. 2002 / 0155998, U.S. Patent Application Publication No. 2003 / 0077753, U.S. Patent Application Publication No. 2003 / 0082749, U.S. Patent Application Publication No. 2003 / 0143202, U.S. Patent Application Publication No. 2004 / 0009902, U.S. Patent Application Publication No. 2004 / 0071694, U.S. Patent Application Publication No. US Patent Application Publication No. 2004 / 0091961, US Patent Application Publication No. 2004 / 0143857, US Patent Application Publication No. 2004 / 0157293, US Patent Application Publication No. 2004 / 0175379, US Patent Application Publication No. 2004 / 0175824, US Patent Application Publication No. 2004 / 0229318, US Patent Application Publication No. 2004 / 0248815, US Patent Application Publication No. 2004 / 0266690, US Patent Application Publication No. 2005 / 0019914, US Patent Application Publication No. 2005 / 0026834, U.S. Patent Application Publication No. 2005 / 0096461, U.S. Patent Application Publication No. 2005 / 0107297, U.S. Patent Application Publication No. 2005 / 0107591, U.S. Patent Application Publication No. 2005 / 0124045, U.S. Patent Application Publication No. 2005 / 0124564, U.S. Patent Application Publication No. 2005 / 0137329, U.S. Patent Application Publication No. 2005 / 0142642, U.S. Patent Application Publication No. 2005 / 0143292, U.S. Patent Application Publication No. 2005 / 01538 79, U.S. Patent Application Publication No. 2005 / 0158822, U.S. Patent Application Publication No. 2005 / 0158832, U.S. Patent Application Publication No. 2005 / 0170457, U.S. Patent Application Publication No. 2005 / 0181359, U.S. Patent Application Publication No. 2005 / 0181482, U.S. Patent Application Publication No. 2005 / 0192211, U.S. Patent Application Publication No. 2005 / 0202538, U.S. Patent Application Publication No. 2005 / 0227289, U.S. Patent Application Publication No. 2005 / 0244409,U.S. Patent Application Publication No. 2006 / 0088906 and U.S. Patent Application Publication No. 2006 / 0111279, and PCT Publication Nos. WO 91 / 05867, WO 95 / 05465, WO 99 / 66054, WO 00 / 24893, WO 01 / 81405, WO 00 / 61637, WO 01 / 36489, WO 02 / 014356, and WO 02 / 19963. , WO 02 / 20034, WO 02 / 49673, WO 02 / 085940, WO 03 / 029291, WO 2003 / 055526, WO 2003 / 084477, WO 2003 / 094858, WO 2004 / 002417, WO 2004 / 002424, WO 2004 / 009627, WO 2004 / 024 No. 761, International Publication No. 2004 / 033651, International Publication No. 2004 / 035603, International Publication No. 2004 / 043382, International Publication No. 2004 / 101600, International Publication No. 2004 / 101606, International Publication No. 2004 / 101611, International Publication No. 2004 / 106373, International Publication No. 2004 / 018667, International Publication No. 2005 / 001025, International Publication No. 2005 / 001136 brochure, International Publication No. 2005 / 021579 pamphlet, International Publication No. 2005 / 025606 pamphlet, International Publication No. 2005 / 032460 pamphlet, International Publication No. 2005 / 051327 pamphlet, International Publication No. 2005 / 063808 pamphlet, International Publication No. 2005 / 063809 pamphlet, International Publication No. 2005 / 070451 pamphlet, International Publication No. 2005 / 081687 pamphlet, International Publication No. 2005 / 084711 pamphlet, International Publication No. 2005 / 103076 pamphlet,The erythropoietin molecules disclosed in WO 2005 / 100403, WO 2005 / 092369, WO 2006 / 50959, WO 2006 / 02646 and WO 2006 / 29094, or variants or analogs thereof, are included.

[0052] Examples of other pharmaceuticals that may be used with the methods disclosed herein include, but are not limited to, antibodies such as Vectibix® (panitumumab), Xgeva™ (denosumab) and Prolia™ (denosumab); other biologics such as Enbrel® (etanercept, TNF receptor / Fc fusion protein, TNF blocker), Neulasta® (pegfilgrastim, PEGylated filgastriam, PEGylated G-CSF, PEGylated hu-Met-G-CSF), Neupogen® (filgrastim, G-CSF, hu-MetG-CSF) and Nplate® (romiplostim); small molecule drugs such as Sensipar® (cinacalcet). The methods may also be used with therapeutic antibodies, polypeptides, proteins, or other chemicals such as iron, e.g., ferumoxytol, iron dextran, ferric gluconate, and ferric oxide. The pharmaceutical agent may be in liquid form or may be reconstituted from a lyophilized form.

[0053] Among the specific exemplary proteins are the specific proteins described below, including fusions, fragments, analogs, variants, or derivatives thereof, including OPGL-specific antibodies having either the light chain of SEQ ID NO:2 as set forth in Figure 2 of PCT Publication WO 03 / 002713 and / or the heavy chain of SEQ ID NO:4 as set forth in Figure 4 of said publication, each of which is individually and specifically incorporated herein by reference in its entirety, with respect to OPGL-specific antibodies and antibody-related proteins, particularly those having the sequences set forth in said publications, specifically those set forth above (9H7, 18B2, 2D8, 2E11, 16E1, and 22B3), including but not limited to the antibodies set forth in said publications, which are incorporated herein in their entireties, OPGL-specific antibodies (also referred to as RANKL-specific antibodies, peptibodies, etc.), peptibodies, and related proteins, including fully humanized and human OPGL-specific antibodies, particularly fully humanized monoclonal antibodies.

[0054] TN8-19-1 through TN8-19-40, TN8-19 con1, and TN8-19 con2, each of which is individually and specifically incorporated herein by reference in its entirety as disclosed in U.S. Patent Application Publication No. 2004 / 0181033 and PCT Publication No. WO 2004 / 058988. peptibodies of the mTN8-19 family, including those of SEQ ID NOs: 305-351, including con2; myostatin binding proteins, peptibodies, and related proteins, including myostatin-specific peptibodies, particularly those described in the above publications, which are incorporated by reference in their entirety herein, particularly in part related to myostatin-specific peptibodies, including but not limited to the mL2 family of SEQ ID NOs: 357-383, the mL15 family of SEQ ID NOs: 384-409, the mL17 family of SEQ ID NOs: 410-438, the mL20 family of SEQ ID NOs: 439-446, the mL21 family of SEQ ID NOs: 447-452, the mL24 family of SEQ ID NOs: 453-454, and the peptibodies of SEQ ID NOs: 615-631.

[0055] L1H1, L1H2, L1H3, L1H4, L1H5, L1H6, L1H7, L1H8, L1H9, L1H10, L1H11, L2H1, L2H2, L2H3, L2H4, L2H5, L2H6, L2H7, L2H8, L2H9, L2H10, L2 ... , L2H11, L2H12, L2H13, L2H14, L3H1, L4H1, L5H1, L6H1, IL-4 receptor-specific antibodies, particularly those antibodies as described in the above publications, particularly those that inhibit activities mediated by IL-4 and / or IL-13 binding to the receptor, including, but not limited to, IL-4 receptor-specific antibodies, peptibodies, and related proteins, including those described in the above publications, particularly those that are partly related to those set forth in the above publications and are incorporated herein by reference in their entirety.

[0056] Interleukin 1-receptor 1 ("IL1-R1") specific antibodies, peptibodies, and related proteins, including, but not limited to, those set forth in U.S. Patent Application Publication No. 2004 / 097712, i.e., 15CA, 26F5, 27F2, 24E12, and 10H7, each of which is individually and specifically incorporated by reference in its entirety as disclosed in the above publications, and particularly those described in the above publications, which are incorporated by reference in their entirety, in part, with reference to IL1-R1 specific binding proteins, particularly monoclonal antibodies.

[0057] The sequences of the following publications, each of which is individually and specifically incorporated herein by reference in its entirety as disclosed in the following publications, in particular those sequences described in the following publications: L1(N), L1(N)WT, L1(N)1K WT, 2xL1(N), 2xL1(N)WT, Con4(N), Con4(N)1K WT, 2xCon4(N)1K, L1C, L1C 1K, 2xL1C, Con4C, Con4C 1K, 2xCon4C Ang2 specific antibodies and peptibodies, including, but not limited to, those described in PCT Publication No. WO 03 / 057134 and U.S. Patent Application Publication No. 2003 / 0229023, each of which is incorporated by reference in its entirety in part with particular reference to Ang2 specific antibodies and peptibodies, including, but not limited to, those described in the following publications ... and Ang2 specific antibodies, peptibodies, and related proteins, including anti-Ang2 antibodies and formulations such as those described in PCT Publication WO 2003 / 030833, which is incorporated by reference in its entirety with respect to AblP, and the like.

[0058] NGF-specific antibodies, peptibodies, and related proteins, including but not limited to, those described in U.S. Patent Application Publication No. 2005 / 0074821 and U.S. Patent No. 6,919,426, each of which is individually and specifically incorporated herein by reference in its entirety, specifically including but not limited to the NGF-specific antibodies and related proteins set forth in the above publications, 4D4, 4G6, 6H9, 7H2, 14D10, and 14D11, as disclosed in the above publications, each of which is individually and specifically incorporated herein by reference in its entirety, specifically including but not limited to the NGF-specific antibodies and related proteins set forth in the above publications, as disclosed in the above publications, each of which is individually and specifically incorporated herein by reference in its entirety,

[0059] For example, humanized and fully human monoclonal antibodies, including but not limited to, humanized and fully human antibodies, including but not limited to, particularly human CD22 specific IgG antibodies, such as, but not limited to, a dimer of human-mouse monoclonal hLL2 gamma chain disulfide linked to a human-mouse monoclonal hLL2 kappa chain, including, but not limited to, the human CD22 specific fully humanized antibody of epratuzumab (CAS Registry Number 501423-23-0), including, but not limited to, the human CD22 specific antibodies, peptibodies, and related proteins, including, but not limited to, those described in U.S. Pat. No. 5,789,554, the entirety of which is incorporated herein by reference with respect to CD22 specific antibodies and related proteins.

[0060] The IGF-1 specific antibodies shown in PCT Publication WO 06 / 069202, each of which is individually and specifically incorporated herein by reference in its entirety as disclosed therein, namely, L1H1, L2H2, L3H3, L4H4, L5H5, L6H6, L7H7, L8H8, L9H9, L10H10, L11H11, L12H12, L13H13, L14H14, L15H15, L16H16, L17H17, L18H18, L19H19, L20H20, L21H21, L22H22, L23H23, L24H24, L25H25, L26H26, L27H27, L28H28, L29H29, L30H30, L31H31, L32H32, L33H33, L34H34, L35H35, L36H36, L37H37, L38H38, L39H39, L40H30, L41H30, L42H30, L43H30, L44H30, L45H30, L46H30, L47H30, L48H30, L49 ...9H30, L49H30, L49H30, L49H30, L49H30, L49H30, L49H30, L49H30, L49H3 and IGF-1 receptor specific antibodies, peptibodies, and related proteins, such as those described in the above publications, which are incorporated by reference in their entireties with respect to IGF-1 receptor specific antibodies and related proteins, including, but not limited to, 31H31, L32H32, L33H33, L34H34, L35H35, L36H36, L37H37, L38H38, L39H39, L40H40, L41H41, L42H42, L43H43, L44H44, L45H45, L46H46, L47H47, L48H48, L49H49, L50H50, L51H51, L52H52, and IGF-1 R-binding fragments and derivatives thereof.

[0061] Also among the non-limiting examples of anti-IGF-1R antibodies for use in the methods and compositions of the invention are each of those described below.

[0062] (i) U.S. Patent Application Publication Nos. 2006 / 0040358 (published February 23, 2006), 2005 / 0008642 (published January 13, 2005), and 2004 / 0228859 (published November 18, 2004), including, but not limited to, Antibody 1A (DSMZ Deposit No. DSM ACC 2586), Antibody 8 (DSMZ Deposit No. DSM ACC 2589), Antibody 23 (DSMZ Deposit No. DSM ACC 2588), and Antibody 18 described in the above publications.

[0063] (ii) Antibodies including, but not limited to, the antibodies 2F8, A12, and IMC-A12 described in PCT Publication Nos. WO 06 / 138729 (published December 28, 2006) and WO 05 / 016970 (published February 24, 2005), and Lu et al. (2004), J. Biol. Chem. 279:2856-2865.

[0064] (iii) PCT Publication No. WO 07 / 012614 (published on February 1, 2007), PCT Publication No. WO 07 / 000328 (published on January 4, 2007), PCT Publication No. WO 06 / 013472 (published on February 9, 2006), PCT Publication No. WO 05 / 058967 (published on June 30, 2005), and PCT Publication No. WO 03 / 059951 (published on July 24, 2003).

[0065] (iv) Antibodies described in U.S. Patent Application Publication No. 2005 / 0084906 (published April 21, 2005), including, but not limited to, antibody 7C10, chimeric antibody C7C10, antibody h7C10, antibody 7H2M, chimeric antibody *7C10, antibody GM 607, humanized antibody 7C10 version 1, humanized antibody 7C10 version 2, humanized antibody 7C10 version 3, and antibody 7H2HM.

[0066] (v) including, but not limited to, the antibodies EM164, resurfaced EM164, humanized EM164, huEM164 v1.0, huEM164 v1.1, huEM164 v1.2 and huEM164 v1.3, as described in U.S. Patent Application Publication No. 2005 / 0249728 (published November 10, 2005), U.S. Patent Application Publication No. 2005 / 0186203 (published August 25, 2005), U.S. Patent Application Publication No. 2004 / 0265307 (published December 30, 2004) and U.S. Patent Application Publication No. 2003 / 0235582 (published December 25, 2003), and Maloney et al. (2003), Cancer Res. 63:5073-5083.

[0067] (vi) U.S. Pat. No. 7,037,498, issued May 2, 2006; U.S. Patent Application Publication No. 2005 / 0244408, published November 30, 2005; and U.S. Patent Application Publication No. 2004 / 0086503, published May 6, 2004; and Cohen, et al. (2005), Clinical Cancer Res. 11:2063-2073, and each of the antibodies produced by hybridomas having ATCC Accession Nos. PTA-2792, PTA-2788, PTA-2790, PTA-2791, PTA-2789, PTA-2793, and antibodies 2.12.1, 2.13.2, 2.14.3, 3.1.1, 4.9.2, and 4.17.3, such as, but not limited to, antibody CP-751,871.

[0068] (vii) including, but not limited to, antibody 19D12, as described in U.S. Patent Application Publication No. 2005 / 0136063, published June 23, 2005, and U.S. Patent Application Publication No. 2004 / 0018191, published January 29, 2004, and an antibody comprising a heavy chain encoded by the polynucleotides of plasmid 15H12 / 19D12 HCA(γ4), deposited with the ATCC under accession number PTA-5214, and a light chain encoded by the polynucleotides of plasmid 15H12 / 19D12 LCF(κ), deposited with the ATCC under accession number PTA-5220;

[0069] (viii) With respect to the foregoing antibodies, peptibodies and related proteins specifically targeting the IGF-1 receptor, including, but not limited to, the antibodies PINT-6A1, PINT-7A2, PINT-7A4, PINT-7A5, PINT-7A6, PINT-8A1, PINT-9A2, PINT-11A1, PINT-11A2, PINT-11A3, PINT-11A4, PINT-11A5, PINT-11A7, PINT-11A12, PINT-12A1, PINT-12A2, PINT-12A3, PINT-12A4 and PINT-12A5, each of which is incorporated by reference in its entirety herein.

[0070] B-7 related protein 1 specific antibodies, peptibodies, related proteins and the like ("B7RP-1," also referred to in the literature as B7H2, ICOSL, B7h, and CD275), in particular B7RP specific fully human monoclonal IgG2 antibodies, in particular fully human IgG2 monoclonal antibodies that bind to an epitope in the first immunoglobulin-like domain of B7RP-1, in particular those that inhibit the interaction of B7RP-1 with ICOS, the natural receptor for B7RP-1, in particular on activated T cells, and in particular those that inhibit the interaction of B7RP-1 with ICOS, the natural receptor for B7RP-1, in particular on activated T cells, in all of the above respects, as disclosed in the following publications, each of which is individually and specifically incorporated herein by reference in its entirety: 16H (therein having light chain and heavy chain variable region sequences SEQ ID NO:1 and SEQ ID NO:7, respectively), 5D (therein having light chain and heavy chain variable region sequences SEQ ID NO:1 and SEQ ID NO:7, respectively), and / or and SEQ ID NO:9), 2H (having therein light chain variable region sequences SEQ ID NO:3 and SEQ ID NO:10, respectively), 43H (having therein light chain variable region sequences SEQ ID NO:6 and SEQ ID NO:14, respectively), 41H (having therein light chain variable region sequences SEQ ID NO:5 and SEQ ID NO:13, respectively), and 15H (having therein light chain variable region sequences SEQ ID NO:4 and SEQ ID NO:12, respectively) and those disclosed in U.S. Patent Publication No. 2008 / 0166352 and PCT Publication No. WO 07 / 011941, which are incorporated by reference in their entireties with respect to such antibodies and related proteins, including, but not limited to, the antibodies set forth in the following publications:

[0071] For example, IL-15 specific antibodies, peptibodies, and related proteins, particularly antibodies, particularly humanized monoclonal antibodies, such as those disclosed in U.S. Patent Application Publication Nos. 2003 / 0138421, 2003 / 023586, and 2004 / 0071702, each of which is incorporated herein by reference in its entirety for IL-15 specific antibodies and related proteins, including, inter alia, peptibodies, including, but not limited to, HuMax IL-15 antibody and related proteins, such as 146B7, and U.S. Patent Application Publication No. 7,153,507.

[0072] IFNγ-specific antibodies, peptibodies, and related proteins, etc., particularly human IFNγ-specific antibodies, in particular fully human anti-IFNγ antibodies, such as, for example, IFNγ-specific antibodies, in particular, fully human anti-IFNγ antibodies, such as those described in U.S. Patent Application Publication No. 2005 / 0004353, which is incorporated herein by reference in its entirety for the antibodies designated 1118, 1118*, 1119, 1121, and 1121* in the following patent publications: The entire sequences of the heavy and light chains of each of these antibodies, and the sequences of their heavy and light chain variable regions and complementarity determining regions, are individually and specifically incorporated herein by reference in their entirety as disclosed in the aforementioned publications and in Thakur et al. (1999), Mol. Immunol. 36:1107-1115, respectively. In addition, the descriptions of the properties of these antibodies provided in the above publications are also incorporated herein by reference in their entirety. Specific antibodies include those having a heavy chain of SEQ ID NO:17 and a light chain of SEQ ID NO:18, those having a heavy chain variable region of SEQ ID NO:6 and a light chain variable region of SEQ ID NO:8, those having a heavy chain of SEQ ID NO:19 and a light chain of SEQ ID NO:20, those having a heavy chain variable region of SEQ ID NO:10 and a light chain variable region of SEQ ID NO:12, those having a heavy chain of SEQ ID NO:32 and a light chain of SEQ ID NO:20, those having a heavy chain variable region of SEQ ID NO:30 and a light chain variable region of SEQ ID NO:12, those having a heavy chain sequence of SEQ ID NO:21 and a light chain sequence of SEQ ID NO:22, those having a heavy chain variable region of SEQ ID NO:14 and a light chain variable region of SEQ ID NO:16, those having a heavy chain of SEQ ID NO:21 and a light chain of SEQ ID NO:33, and those having a heavy chain variable region of SEQ ID NO:14 and a light chain variable region of SEQ ID NO:31, as disclosed in the aforementioned publications. A specific antibody contemplated is antibody 1119, disclosed in the aforementioned U.S. Patent Application Publication, having a complete heavy chain of SEQ ID NO: 17, disclosed in the aforementioned U.S. Patent Application Publication, and a complete light chain of SEQ ID NO: 18, disclosed in the aforementioned U.S. Patent Application Publication.

[0073] TALL-1 specific antibodies, peptibodies, and related proteins, such as those described in the following publications, each of which is individually and specifically incorporated herein by reference in its entirety as disclosed in the following publications, and in particular U.S. Patent Application Publication No. 2003 / 0195156 and U.S. Patent Application Publication No. 2006 / 0135431, each of which is incorporated herein by reference in its entirety with respect to TALL-1 binding proteins, particularly the molecules in Tables 4 and 5B, as well as other TALL specific binding proteins.

[0074] Parathyroid hormone ("PTH")-specific antibodies, peptibodies, and related proteins, such as those described in U.S. Pat. No. 6,756,480, the entirety of which is incorporated herein by reference, with particular reference in part to proteins that bind PTH.

[0075] Thrombopoietin receptor ("TPO-R")-specific antibodies, peptibodies, and related proteins, such as those described in U.S. Pat. No. 6,835,809, the entirety of which is incorporated herein by reference, with particular reference in part to proteins that bind to TPO-R.

[0076] Hepatocyte growth factor ("HGF") specific antibodies, peptibodies, and related proteins, including those that target the cMet axis (HGF / SF:c-Met), such as fully human monoclonal antibodies that neutralize hepatocyte growth factor / scatter (HGF / SF), described in U.S. Patent Application Publication No. 2005 / 0118643 and PCT Publication No. WO 2005 / 017107, huL2G7, described in U.S. Patent No. 7,220,410, and OA-5d5, described in U.S. Patent Nos. 5,686,292 and 6,468,529, and PCT Publication No. WO 96 / 38557, each of which is incorporated by reference in its entirety herein with particular reference in part to proteins that bind HGF.

[0077] TRAIL-R2 specific antibodies, peptibodies, related proteins, etc., such as those described in U.S. Pat. No. 7,521,048, which is incorporated by reference in its entirety, with particular reference in part to proteins that bind TRAIL-R2.

[0078] Activin A-specific antibodies, peptibodies, related proteins, and the like, including, but not limited to, those described in U.S. Patent Application Publication No. 2009 / 0234106, the entirety of which is incorporated herein by reference, particularly in part, with reference to proteins that bind activin A.

[0079] Particularly relevant to proteins that bind TGF-β are TGF-β specific antibodies, peptibodies, related proteins, and the like, including, but not limited to, those described in U.S. Pat. No. 6,803,453 and U.S. Patent Application Publication No. 2007 / 0110747, each of which is incorporated by reference in its entirety herein.

[0080] Amyloid β protein specific antibodies, peptibodies, related proteins, etc., including but not limited to those described in PCT Publication WO 2006 / 081171, which is incorporated herein by reference in its entirety, particularly in relation to proteins that bind to amyloid β protein. One possible antibody is an antibody having a heavy chain variable region comprising SEQ ID NO:8 and a light chain variable region having SEQ ID NO:6, as disclosed in the above publication.

[0081] c-Kit specific antibodies, peptibodies, related proteins, and the like, including but not limited to those described in U.S. Patent Application Publication No. 2007 / 0253951, which is incorporated by reference in its entirety, with particular reference in part to proteins that bind c-Kit and / or other stem cell factor receptors.

[0082] OX40L-specific antibodies, peptibodies, related proteins, and the like, including, but not limited to, those described in U.S. Patent Application Publication No. 2006 / 0002929, which is incorporated by reference in its entirety, with particular reference in part to proteins that bind OX40L and / or other ligands of the OX40 receptor;

[0083] Activase® (alteplase, tPA), Aranesp® (darbepoetin alfa), Epogen® (epoetin alfa, or erythropoietin), GLP-1, Avonex® (interferon beta-1a), Bexxar® (tositumomab, an anti-CD22 monoclonal antibody), Betaseron® (interferon-beta), Campath® (alemtuzumab, an anti-CD52 monoclonal antibody), Dynepo® (epoetin delta), Velcade® (bortezomib), MLN0002 (anti-alpha4beta7 mAb), MLN1202 (anti-CCR2 chemokine receptor mAb), Enbrel® (etanercept, TNF receptor / Fc fusion protein, TNF blocker), Eprex® (epoetin alfa), Erbitux® (cetuximab, anti-EGFR / HER1 / c-ErbB-1), Genotropin® (somatropin, human growth hormone), Herceptin® (trastuzumab, anti-HER2 / neu(erbB2) receptor mAb), Hum atrope® (somatropin, human growth hormone), Humira® (adalimumab), insulin in solution, Infergen® (interferon alfacon-1), Natrecor® (nesiritide, recombinant human B-type natriuretic peptide (hBNP), Kineret® (anakinra), Leukine® (sargamostim, rhuGM-CSF), LymphoCide® (epratuzumab, anti-CD22 mAb), Benlysta™ (lymphostat B, belimumab, anti-BlyS mAb), Metalyse® (tenecteplase, t-PA analog), Mircera® (methoxypolyethylene glycol-epoetin beta), Mylotarg® (gemtuzumab ozogamicin), Raptiva® (efalizumab), Cimzia® (certolizumab pegol, CDP870), Soliris™ (eculizumab), pexelizumab (anti-complement C5), Numax® (MEDI-524), Lucentis® (ranibizumab), Panorex® (17-1A, edrecolomab), Trabio® (lerdelimumab), TheraCim hR3 (nimotuzumab), Omnitarg (pertuzumab, 2C4), Osidem® (IDM-1), OvaRex® (B43.13), Nuvion® (vigilizumab), cantuzumab mertansine (huC242-DM1), NeoRecormon® (epoetin beta), Neumega® (oprelvekin, human interleukin-11), Neulasta® (PEGylated filgastrim, PEGylated G-CSF, PEGylated hu-Met-G-CSF), Neupogen® (filgrastim, G-CSF, hu-MetG-CSF), Orthoclone OKT3® (muromonab-CD3, anti-CD3 monoclonal antibody), Procrit® (epoetin alfa), Remicade® (infliximab, anti-TNFα monoclonal antibody), Reopro® (abciximab, anti-GP lIb / Ilia receptor monoclonal antibody), Actemra® (anti-IL6 receptor mAb), Avastin® (bevacizumab), HuMax-CD4 (zanolimumab), Rituxan® (rituximab, anti-CD20 mAb), Tarceva® (erlotinib), Roferon-A® (interferon alpha-2a), Simulect® (basiliximab), Prexige® (lumiracoxib), Synagis® (palivizumab), 146B7-CHO (anti-IL15 antibody, see U.S. Pat. No. 7,153,507), Tysabri® (natalizumab, anti-α4 integrin mAb), Valortim® (MDX-1303, anti-anthrax protective antigen mAb), ABthrax™, Vectibix® (panitumumab), Xolair® (omalizumab), ETI211 (anti-MRSAmAb), IL-1 trap (the Fc portion of human IgG1 and the extracellular domains of both IL-1 receptor components (type I receptor and receptor accessory protein)), VEGF trap (the Ig domain of VEGFR1 fused to IgG1 Fc), Zenapax® (daclizumab), Zenapax® (daclizumab, anti-IL-2Rα mAb), Zevalin® (ibritumomab tiuxetan), Zetia® (ezetimibe), Orencia® (atacicept, TACI-Ig), anti-CD80 monoclonal antibody (galiximab), anti-CD23 mAb (lumiliximab), BR2-Fc (huBR3 / huFc fusion protein, soluble BAFF antagonist), CNTO 148 (golimumab, anti-TNFα mAb), HGS-ETR1 (mapatuzumab, a human anti-TRAIL receptor-1 mAb), HuMax-CD20 (ocrelizumab, an anti-CD20 human mAb), HuMax-EGFR (zalutumumab), M200 (volociximab, an anti-α5β1 integrin mAb), MDX-010 (ipilimumab, an anti-CTLA-4 mAb, and VEGFR-1 (IMC-18F1), anti-BR3 mAb, anti-C. difficile toxin A and toxin BC mAbs MDX-066 (CDA-1) and MDX-1388), anti-CD22 dsFv-PE38 conjugate (CAT-3888 and CAT-8015), anti-CD25 mAb (HuMax-TAC), anti-CD3 mAb (NI-0401), adecatumumab, anti-CD30 mAb (MDX-060), MDX-1333 (anti-IFNAR), anti-CD38 mAb (HuMax CD38), anti-CD40L mAb, anti-Cripto mAb, anti-CTGF idiopathic pulmonary fibrosis stage 1 fibrogen (FG-3019), anti-CTLA4 mAb, anti-eotaxin 1 mAb (CAT-213), anti-FGF8 mAb, anti-ganglioside GD2 mAb, anti-ganglioside GM2 mAb, anti-GDF-8 human mAb (MYO-029), anti-GM-CSF receptor mAb (CAM-3001), anti-HepC mAb (HuMax HepC), anti-IFNα mAb (MEDI-545, MDX-1103), anti-IGF1R mAb, anti-IGF-1R mAb (HuMax-Inflam), anti-IL12mAb (ABT-874), anti-IL12 / IL23 mAb (CNTO 1275), anti-IL13 mAb (CAT-354), anti-IL2Ra mAb (HuMax-TAC), anti-IL5 receptor mAb, anti-integrin receptor mAb (MDX-018, CNTO 95), anti-IP10 ulcerative colitis mAb (MDX-1100), anti-LLY antibody, BMS-66513, anti-mannose receptor / hCGβ mAb (MDX-1307), anti-mesothelin dsFv-PE38 conjugate (CAT-5001), anti-PD1 mAb (MDX-1106(ONO-4538)), anti-PDGFRα antibody (IMC-3G3), anti-TGFβ Other exemplary proteins include mAb (GC-1008), anti-TRAIL receptor-2 human mAb (HGS-ETR2), anti-TWEAK mAb, anti-VEGFR / Flt-1 mAb, anti-ZP3 mAb (HuMax-ZP3), NVS antibody no. 1, and NVS antibody no. 2.

[0084] Sclerostin antibodies, such as, but not limited to, romosozumab, brosozumab, or BPS 804 (Novartis), may also be included. Further therapeutic agents may be included, such as rilotumumab, bixalomer, trebananib, ganitumab, conatumumab, motesanib diphosphate, brodalumab, vidupiprant, panitumumab, denosumab, NPLATE, PROLIA, VECTIBIX, or XGEVA. Additionally, the device may include a human Proprotein Convertase Subtilisin / Kexin Type I receptor antagonist. The present invention can include monoclonal antibodies (IgG) that bind to PCSK9 (prostate cancer cell type 9), and are described, for example, in U.S. Pat. No. 8,030,547, U.S. Patent Application Publication No. 2013 / 0064825, WO 2008 / 057457, WO 2008 / 057458, WO 2008 / 057459, WO 2008 / 063382, WO 2008 / 133647, WO 2009 / 100297, WO 2009 / 100318, WO 2011 / 037791, WO 2011 / 053759, WO 2011 / 053 These are Brochure No. 783, Brochure No. 2008 / 125623, Brochure No. 2011 / 072263, Brochure No. 2009 / 055783, Brochure No. 2012 / 0544438, Brochure No. 2010 / 029513, Brochure No. 2011 / 111007, Brochure No. 2010 / 077854, Brochure No. 2012 / 088313, Brochure No. 2012 / 101251, Brochure No. 2012 / 101252, Brochure No. 2012 / 101253, Brochure No. 2012 / 109530 and Brochure No. 2001 / 031007.

[0085] Also included may be talimogene laherparepvec or another oncolytic HSV for the treatment of melanoma or other cancers. Examples of oncolytic HSV include, but are not limited to, talimogene laherparepvec (U.S. Pat. Nos. 7,223,593 and 7,537,924), OncoVEXGALV / CD (U.S. Pat. No. 7,981,669), OrienX010 (Lei et al. (2013), World J. Gastroenterol., 19:5138-5143), G207, 1716, NV1020, NV12023, NV1034 and NV1042 (Vargehes et al. (2002), Cancer Gene Ther., 9(12):967-978).

[0086] Also included are TIMPs. TIMPs are endogenous tissue inhibitors of metalloproteinases (TIMPs) and are important in many natural processes. TIMP-3 is expressed by a variety of cells and / or present in the extracellular matrix, inhibits all major cartilage-degrading metalloproteases, and may play a role in many degradative diseases of connective tissue, including rheumatoid arthritis and osteoarthritis, as well as in cancer and cardiovascular conditions. The amino acid sequence of TIMP-3 and the nucleic acid sequence of DNA encoding TIMP-3 are disclosed in U.S. Patent No. 6,562,596, issued May 13, 2003, the disclosure of which is incorporated herein by reference. Descriptions of TIMP mutations can be found in U.S. Patent Application Publication No. 2014 / 0274874 and PCT Application Publication No. WO 2014 / 152012.

[0087] Also included are antagonistic antibodies of the human calcitonin gene-related peptide (CGRP) receptor and bispecific antibody molecules targeting the CGRP receptor and other headache targets. More information regarding these molecules can be found in PCT Application No. WO 2010 / 075238.

[0088] In addition, bispecific T cell targeting (BiTE®) molecules, such as BLINCYTO® (blinatumomab), can be used in the methods disclosed herein. Alternatively, an APJ macromolecule agonist, such as apelin or an analog thereof, can be included in the device. Information regarding such molecules can be found in WO 2014 / 099984.

[0089] In some embodiments, the medicament comprises a therapeutically effective amount of anti-thymic stromal lymphopoietin (TSLP) or TSLP receptor antibody. Examples of anti-TSLP antibodies that may be used in such embodiments include, but are not limited to, those described in U.S. Patent Nos. 7,982,016 and 8,232,372 and U.S. Patent Publication No. 2009 / 0186022. Examples of anti-TSLP receptor antibodies include, but are not limited to, those described in U.S. Patent No. 8,101,182. In a particularly preferred embodiment, the medicament comprises a therapeutically effective amount of the anti-TSLP antibody designated A5 in U.S. Patent No. 7,982,016.

[0090] Although the above methods and their elements have been described in terms of exemplary embodiments, they are not limited to these exemplary embodiments. The detailed description is to be construed as an example only and does not describe all possible embodiments of the invention, since describing all possible embodiments would be impractical, if not impossible. Many alternative embodiments can be implemented using either current technology or technology developed after the filing date of this patent, and still fall within the scope of the claims that define the invention.

[0091] It should be understood that the legal scope of the present invention is defined by the language of the claims set forth at the end of this patent. The appended claims should be interpreted broadly to include other variations and embodiments thereof that may be made by those skilled in the art without departing from the scope of the devices, systems, methods, and equivalents of their elements.

Claims

1. 1. A method of filling vials, comprising the steps of: Prepare a pump that corresponds to the vial, setting a droplet entrainment parameter of the pump to any value equal to or less than 20 degrees; setting a no-adjustment limit for the fill weight of the vial at T1, T1 being within a range of about 2% more or less than the fill weight of the target fill weight T0; Including, The process performance index Cpk (Cpk) for said vial throughout the entire filling cycle exceeds a minimum value; method.

2. 2. The method of claim 1, wherein setting the droplet drawing parameter of the pump to any value less than or equal to 20 degrees comprises setting the droplet drawing parameter of the pump to one of 10 degrees, 20 degrees, or any value in a range of 10 degrees to 20 degrees.

3. 3. The method of claim 1 or 2, further comprising setting a final droplet retraction value to 290 degrees when the droplet retraction parameter is set to 20 degrees, or setting a final droplet retraction value to 280 degrees when the droplet retraction parameter is set to 10 degrees.

4. 10. The method of claim 1, wherein providing a pump corresponding to the vial comprises providing a nested syringe and a pump corresponding to the vial of the vial line.

5. 2. The method of claim 1, wherein preparing a pump corresponding to the vial includes preparing one or more of a first filling set or a second filling set, the first filling set including a filling assembly for a peristaltic pump having a needle with an outer diameter of about 2.0 mm, and the second filling set including a filling assembly for a peristaltic pump having a needle with an outer diameter of about 3.0 mm.

6. 2. The method of claim 1, wherein the Cpk for the vial exceeds a minimum value throughout the fill cycle includes one or more of: (1) the Cpk for the vial exceeds a value of 1.33; or (2) the Cpk for the vial exceeds the minimum value while in a temperature range throughout the fill cycle, the temperature range being one of: (1) 5 (± 3) degrees Celsius; (2) 20 (± 5) degrees Celsius; or (3) 10-19 degrees Celsius.

7. and filling said vial with a drug product via said pump, said drug product having the following characteristics: (a) a viscosity of about 1.0 to 1.2 g / cm ３ 2. The method of claim 1, wherein the granular material has one or more of: (a) a density in the range of about 1.0 to 10.0 cP; (b) a viscosity in the range of about 1.0 to 10.0 cP; and (c) a surface tension in the range of about 40.0 to 72.7 mN / m.

8. The drug product has a molecular weight of about 1.0 to 1.2 g / cm ３ 8. The method of claim 7, wherein the composition has a density in the range of about 1.0 to 10.0 cP, a viscosity in the range of about 1.0 to 10.0 cP, and a surface tension in the range of about 40.0 to 72.7 mN / m.

9. The method of claim 7 or 8, wherein the drug product comprises a small molecule drug or a biological drug.

10. 1. A method for filling multiple vials in a nested syringe and vial line, comprising: providing a plurality of pumps corresponding to a plurality of vials in a nested syringe and vial line; setting a droplet entrainment parameter of each of the plurality of pumps to any value equal to or less than 20 degrees; filling each of said plurality of vials with drug product via a corresponding one of said plurality of pumps; Including, a process performance index (Cpk) for each vial of the plurality of vials throughout a fill cycle exceeds a minimum value; method.

11. 11. The method of claim 10, further comprising: setting a no-adjustment limit for the fill weight of each vial at T1, T1 being within a range of about 2% more or less than the fill weight of the target fill weight T0.

12. 12. The method of claim 10 or 11, wherein setting the droplet entrainment parameter of each pump to any value less than or equal to 20 degrees comprises setting the droplet entrainment parameter of the pump to one of 10 degrees, 20 degrees, or any value in the range of 10 degrees to 20 degrees.

13. 11. The method of claim 10, further comprising setting a final droplet retraction value to 290 degrees when the droplet retraction parameter is set to 20 degrees, or setting a final droplet retraction value to 280 degrees when the droplet retraction parameter is set to 10 degrees.

14. 11. The method of claim 10, wherein filling each vial of the plurality of vials with a drug product via a corresponding one of the plurality of pumps comprises filling each vial of the plurality of vials with a drug product that is a mAb formulation.

15. 11. The method of claim 10, wherein the Cpk for each vial of the plurality of vials exceeding a minimum value throughout the fill cycle comprises one or more of: (1) the Cpk exceeds a value of 1.33; or (2) the Cpk for each vial of the plurality of vials exceeds the minimum value while in a temperature range throughout the fill cycle, the temperature range being one of: (1) 5 (± 3) degrees Celsius; (2) 20 (± 5) degrees Celsius; or (3) 10-19 degrees Celsius.

16. Filling each vial with a drug product via a corresponding pump of the plurality of pumps includes filling each vial with a drug product via the pump, the drug product having the following characteristics: (1) about 1.0 to 1.2 g / cm ３ 11. The method of claim 10, wherein the granular material has one or more of: (1) a density in the range of about 1.0 to 10.0 cP; (2) a viscosity in the range of about 1.0 to 10.0 cP; and / or (3) a surface tension in the range of about 40.0 to 72.7 mN / m.

17. The drug product has a molecular weight of about 1.0 to 1.2 g / cm ３ 17. The method of claim 16, wherein the composition has a density in the range of about 0.1 to about 1.0 cP, a viscosity in the range of about 1.0 to 10.0 cP, and a surface tension in the range of about 40.0 to 72.7 mN / m.

18. 18. The method of claim 16 or 17, wherein the drug product comprises a biological drug or a small molecule drug.

19. 1. A method for optimizing a fill recipe for a nested syringe and vial line, comprising: setting a droplet drawing parameter of at least one pump in the offline manufacturing system corresponding to the at least one container to any value equal to or less than 20 degrees; monitoring performance of the at least one pump with the droplet entrainment parameter of the at least one pump set to any value equal to or less than 20 degrees; obtaining at least a minimum value of a process performance index (Cpk) for the at least one container and for the at least one drug product throughout at least one fill cycle using the at least one pump in the offline manufacturing system; finalizing a fill recipe for nested syringe and vial lines using data from a fill cycle of the at least one drug product using the at least one pump in the offline manufacturing system; A method comprising:

20. 20. The method of claim 19, further comprising: monitoring performance of the fill recipe in the nested syringe and vial line; and obtaining at least a minimum value of the Cpk for the at least one container for each pump of a plurality of pumps in the nested syringe and vial line.

21. 20. The method of claim 19, wherein setting a droplet drawing parameter of at least one pump in an offline manufacturing system corresponding to at least one container to any value less than 20 degrees includes setting the droplet drawing parameters of a first filling set including a pump and a second filling set including a pump, each of the first filling set and the second filling set in the offline manufacturing system, each of the first filling set and the second filling set having a corresponding filled container.

22. 20. The method of claim 19, wherein obtaining at least a minimum value of Cpk for the containers and for at least one drug product throughout at least one fill cycle comprises obtaining at least a minimum value of the Cpk of 1.33 for each container during one or more temperatures of 5 (±3) degrees Celsius, 20 (±5) degrees Celsius, or any value in the range of 10 degrees to 20 degrees throughout a fill cycle, wherein the minimum value of Cpk is 1.33 for each container.

23. Obtaining at least a minimum value of Cpk for the container and for at least one drug product throughout a fill cycle includes obtaining at least a minimum value of Cpk for the container and for the at least one drug product throughout at least one fill cycle, the at least one drug product being (1) a mAb formulation, or (2)(a) about 1.0-1.2 g / cm ３ 20. The method of claim 19, wherein the drug product comprises one or more of: (a) a density in the range of about 1.0 to 10.0 cP; (b) a viscosity in the range of about 1.0 to 10.0 cP; and (c) a surface tension in the range of about 40.0 to 72.7 mN / m.

24. and (2) (a) about 1.0-1.2 g / cm. ３ 20. The method of claim 19, comprising filling the container with a drug product comprising one or more of the drug products having one or more of: (a) a density in the range of about 1.0 to 10.0 cP; (b) a viscosity in the range of about 1.0 to 10.0 cP; and (c) a surface tension in the range of about 40.0 to 72.7 mN / m.

25. 20. The method of claim 19, further comprising setting a no-adjustment limit for the fill weight of the container to T1, T1 being within a range of about 2% more or less than the fill weight of the target fill weight T0 after setting the droplet draw parameters.

26. 20. The method of claim 19, further comprising one or more of setting a start pump dose at 40 degrees, setting a pump dose start slope at 90 degrees, setting a pump dose stop slope at 210 degrees, setting a final pump dose at 260 degrees, setting a final drop retract parameter at 290 degrees, and setting a distance traveled per dose parameter at 766 degrees.

27. 1. A method of filling vials, comprising the steps of: Prepare a pump that corresponds to the vial, setting a droplet entrainment parameter of the pump to any value equal to or less than 20 degrees; setting an unadjusted limit for the vial fill weight to any value within a range of target fill weights T0 to T1, T1 being in or within the range of target fill weights T0 to T2; Including, Exceeding the minimum value of the process performance index Cpk (Cpk) for said vial throughout the entire filling cycle; method.

28. 28. The method of claim 27, wherein setting the droplet entrainment parameter of the pump to any value less than or equal to 20 degrees comprises setting the droplet entrainment parameter of the pump to one of 10 degrees, 20 degrees, or any value in the range of 10 degrees to 20 degrees.

29. 29. The method of claim 27 or 28, further comprising setting a final droplet retraction value to 290 degrees when the droplet retraction parameter is set to 20 degrees, or setting a final droplet retraction value to 280 degrees when the droplet retraction parameter is set to 10 degrees.

30. 28. The method of claim 27, wherein providing a pump corresponding to the vial includes providing a nested syringe and a pump corresponding to the vial of the vial line.

31. 28. The method of claim 27, wherein preparing a pump corresponding to the vial includes preparing one or more of a first filling set or a second filling set, the first filling set including a filling assembly for a peristaltic pump having a needle with an outer diameter of about 2.0 mm, and the second filling set including a filling assembly for a peristaltic pump having a needle with an outer diameter of about 3.0 mm.

32. 28. The method of claim 27, wherein the Cpk for the vial exceeding a minimum value throughout the fill cycle comprises one or more of: (1) the Cpk for the vial exceeding a value of 1.33; or (2) the Cpk for the vial exceeding the minimum value while in a temperature range throughout the fill cycle, the temperature range being one of: (1) 5 (± 3) degrees Celsius; (2) 20 (± 5) degrees Celsius; or (3) 10-19 degrees Celsius.

33. and further comprising: filling the vial with a drug product via the pump, the filling of the vial with a drug product via the pump comprising: (1) about 1.0-1.2 g / cm ３ 28. The method of claim 27, comprising filling the vial with a drug product comprising one or more of: (1) a density in the range of about 0.02 to 0.5 cP; (2) a viscosity in the range of about 1.0 to 10.0 cP; and / or (3) a surface tension in the range of about 40.0 to 72.7 mN / m.

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