EP4341161A1 - Procédé d?optimisation d?une recette de remplissage pour un récipient de médicament - Google Patents

Procédé d?optimisation d?une recette de remplissage pour un récipient de médicament

Info

Publication number
EP4341161A1
EP4341161A1 EP22731368.1A EP22731368A EP4341161A1 EP 4341161 A1 EP4341161 A1 EP 4341161A1 EP 22731368 A EP22731368 A EP 22731368A EP 4341161 A1 EP4341161 A1 EP 4341161A1
Authority
EP
European Patent Office
Prior art keywords
degrees
vial
pump
fill
setting
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22731368.1A
Other languages
German (de)
English (en)
Inventor
Devrishi GOSWAMI
Jun Zhang
Deirdre PIEDMONTE
Vikashni PADMAKUMAR
David Le
Maria Raquel SANTOS
Wei Qi
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Amgen Inc
Original Assignee
Amgen Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Amgen Inc filed Critical Amgen Inc
Publication of EP4341161A1 publication Critical patent/EP4341161A1/fr
Pending legal-status Critical Current

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
    • B65B3/00—Packaging plastic material, semiliquids, liquids or mixed solids and liquids, in individual containers or receptacles, e.g. bags, sacks, boxes, cartons, cans, or jars
    • B65B3/003—Filling medical containers such as ampoules, vials, syringes or the like
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
    • B65B3/00—Packaging plastic material, semiliquids, liquids or mixed solids and liquids, in individual containers or receptacles, e.g. bags, sacks, boxes, cartons, cans, or jars
    • B65B3/04—Methods of, or means for, filling the material into the containers or receptacles
    • B65B3/10—Methods of, or means for, filling the material into the containers or receptacles by application of pressure to material
    • B65B3/12—Methods of, or means for, filling the material into the containers or receptacles by application of pressure to material mechanically, e.g. by pistons or pumps
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
    • B65B3/00—Packaging plastic material, semiliquids, liquids or mixed solids and liquids, in individual containers or receptacles, e.g. bags, sacks, boxes, cartons, cans, or jars
    • B65B3/26—Methods or devices for controlling the quantity of the material fed or filled
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65B—MACHINES, APPARATUS OR DEVICES FOR, OR METHODS OF, PACKAGING ARTICLES OR MATERIALS; UNPACKING
    • B65B3/00—Packaging plastic material, semiliquids, liquids or mixed solids and liquids, in individual containers or receptacles, e.g. bags, sacks, boxes, cartons, cans, or jars
    • B65B3/26—Methods or devices for controlling the quantity of the material fed or filled
    • B65B3/28—Methods or devices for controlling the quantity of the material fed or filled by weighing

Definitions

  • the present disclosure generally relates to filling recipes for drug containers and, more particularly, to a universal method of optimizing a filling recipe for a drug container.
  • existing fill recipes are individually tailored to a single drug product, each of which has a unique filling process and set of operating parameters.
  • a pump in a manufacturing facility carrying out the filling recipe must be calibrated each time a new filling recipe is needed for a new drug product.
  • the time involved to calibrate the pump or related equipment in a manufacturing facility before beginning the filling process according to a particular filling recipe is often lengthy. For example, there are typically many cycles needed, such as multiple number of strokes of the pump, until the pump is able to operate according to a particular filling recipe.
  • a method of filling a vial comprises providing a pump corresponding to a vial, and setting a drip retraction parameter for the pump to any value equal to or less than 20 degrees.
  • the method further comprises setting a no adjustment limit for a fill weight of the vial to T1 , with T 1 being at or in a range of about 2% more or less than a fill weight of a target fill weight TO, and wherein a process performance index Cpk (Cpk) for the vial throughout a fill cycle exceeds a minimum value.
  • a method of filling a plurality of vials of a nested syringe and vial line comprises providing a plurality of pumps corresponding to a plurality of vials of a nested syringe and vial line, and setting a drip retraction parameter for each pump in 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 a drug product via a corresponding pump of the plurality of pumps; and wherein a Cpk for each vial of the plurality of vials exceeds a minimum value throughout a fill cycle.
  • a method of optimizing a filling recipe for a nested syringe and vial line comprises setting a drip retraction parameter for at least one pump in an offline manufacturing system corresponding to any value equal to or less than 20 degrees, and monitoring a performance of the at least one pump with the drip retraction parameter of the at least one pump set to any value equal to or less than 20 degrees.
  • the method also includes obtaining at least a minimum value for a Cpk for the at least one container throughout at least one fill cycle and for at least one drug product using the at least one pump in the offline manufacturing system; and finalizing a filling recipe for a nested syringe and vial line using data from fill cycles of the at least one drug product using the at least one pump in the offline manufacturing system.
  • a method of filling a vial may comprise providing a pump corresponding to a vial, setting a drip retraction parameter for the pump to any value equal to or less than 20 degrees, and setting a no adjustment limit for a fill weight of the vial to any value within a range of a target fill weight TO and T1 , with T 1 being at or in a range between the target fill weight TO and T2. So configured, a minimum value for a process performance index Cpk (Cpk) for the vial throughout a fill cycle is exceeded.
  • Cpk process performance index
  • setting a drip retraction parameter for the pump to any value equal to or less than 20 degrees may comprise setting the drip retraction parameter for the pump to one of 10 degrees, 20 degrees, or any value in a range of 10 degrees to 20 degrees.
  • the method may further comprise setting an end drip retraction value to 290 degrees when setting the drip retraction parameter to 20 degrees or setting an end drip retraction value to 280 degrees when setting the drip retraction parameter to 10 degrees.
  • providing a pump corresponding to a vial may comprise providing a pump corresponding to a vial of a nested syringe and vial line.
  • providing a pump corresponding to a vial may comprise providing one or more of a first fill set or a second fill set, the first fill set including a peristaltic pump filling assembly having a needle with an outer diameter of about 2.0mm, and the second fill set including a peristaltic pump filling assembly having a needle with an outer diameter of about 3.0mm.
  • a Cpk for the vial exceeds a minimum value throughout a fill cycle may comprise 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 during a temperature range throughout the fill cycle, the temperature range is one of: (1) 5 (+/-3) degrees Celsius; (2) 20 (+/-5) degrees Celsius; or (3) 10 to 19 degrees Celsius.
  • the method may further comprise filling the vial with a drug product via the pump, wherein the drug product has one or more of the following characteristics: (a) a density in a range of about 1.0-1.2 g/cm 3 ; (b) a viscosity in a range of about 1.0-10.0 cP; and (c) a surface tension in a range of about 40.0-72.7 mN/m.
  • the drug product has a density in a range of 1.0-1.2 g/cm3; a viscosity in a range of about 1.0-10.0 cP; and a surface tension in a range of about 40.0- 72.7 mN/m.
  • the drug product comprises a biologic drug (e.g., peptides, mAb, siRNA) or a small molecule drug.
  • the method may further comprise monitoring a performance of the filling recipe in the nested syringe and vial line and obtaining at least a minimum value for the Cpk for the at least one container for each pump in a plurality of pumps in the nested syringe and vial line.
  • FIG. 1 is a schematic representation of one embodiment of an offline filling system utilizing a filling recipe of the present disclosure
  • FIG. 2A is a perspective view of a filler of the system of FIG. 1 ;
  • FIG. 2B is a portion of the filler of FIG. 2A;
  • FIG. 2C is a perspective view of a fill set of the system of FIG. 1 ;
  • FIG. 2D is a perspective view of another fill set of the system of FIG. 1 ;
  • FIG. 2E is a perspective view of an exemplary fill target of the system of FIG. 1 ;
  • FIG. 3A is a chart depicting parameters of each of the fill sets of FIG. 1;
  • FIG. 3B is a chart depicting in process control parameters of the fill sets of FIG. 1 ;
  • FIG. 3C is a chart depicting product characteristics of drug products for use with the methods of the present disclosure.
  • FIG. 4 is a flow chart depicting a filling recipe parameter optimization strategy relative to the filling recipe of the present disclosure
  • FIG. 5A is a perspective view of fill performance results of a vial after filling at various drip retraction values
  • FIG. 5B is a chart depicting aspects of an exemplary fill recipe used with the fill performance results of FIG. 5A;
  • FIG. 6A depicts an exemplary filling recipe according to one aspect of the present disclosure
  • FIG. 6B is a graph depicting filling performance results of the filling recipe of FIG. 6A;
  • FIG. 6C is a chart depicting the filling performance results of the graph of FIG. 6B;
  • FIG. 7A is a chart depicting needle parameters of a needle used with a filling recipe of the present disclosure
  • FIG. 7B is a chart depicting pump parameters of at least one pump used with a filling recipe of the present disclosure
  • FIG. 8A is a graph depicting filling performance results of the filling recipe of the present disclosure in a temperature range of 10 - 11 degrees Celsius and using a second fill set of the system of FIG. 1;
  • FIG. 8B is a chart depicting the filling performance results of the graph of FIG. 8A;
  • FIG. 9A is a graph depicting the filling performance results of the filling recipe of the present disclosure at a temperature of about 19 degrees Celsius and using the second fill set of the system of FIG. 1;
  • FIG. 9B is a chart depicting the filling performance results of the graph of FIG. 9A;
  • FIG. 10A is a graph depicting the filling performance results of the filling recipe of the present disclosure at a temperature of about 10-11 degrees Celsius and using the first fill set of the system of FIG. 1;
  • FIG. 10B is a chart depicting the filling performance results of the graph of FIG. 10A;
  • FIG. 11A is a graph depicting the filling performance results of the filling recipe of the present disclosure at a temperature of about 19 degrees Celsius and using the first fill set of the system of FIG. 1;
  • FIG. 11 B is a chart depicting the filling performance results of the graph of FIG. 11 A;
  • FIG. 12 is a schematic representation of a manufacturing line in a manufacturing plant using the optimized filling recipe of the present disclosure
  • FIG. 13A is a perspective view of a nested syringe and vial line of the manufacturing line of FIG. 12;
  • FIG. 13B is a schematic view of the nested syringe and vial line of FIG. 13A;
  • FIG. 13C is a perspective view of a plurality of pumps corresponding to a plurality of vials of the nested syringe and vial line of FIGS. 13A-13B;
  • FIG. 14 is a chart depicting filling performance results of the filling recipe of the present disclosure in at least one of the nested syringe and vial line of FIG. 12;
  • FIG. 15 is a chart depicting filling performance results of a previously used filling recipe used in a nested syringe and vial line.
  • an efficient filling recipe for filling formulations comprising therapeutic proteins in a nested syringe and vial line is disclosed.
  • the universal filling recipe include a drip retraction parameter optimization within a specified value, which results in a significantly more efficient fill recipe compared to other existing, known filling recipes.
  • the new filling recipe of the present disclosure may be used with many different drug products and results in 95% reduction in fill weight optimization cycles. This led to an improvement of 10-30% increase utilization of a nested syringe and vial line fill time and potentially saving a significant number of units, such as vials, from rejection.
  • the drug products referred to herein comprise therapeutic proteins, such as monoclonal antibodies, as explained more below.
  • the offline manufacturing system 10 is a small scale bench set-up in a pilot facility, which made various tests related to the new filling recipe easier to assess and update based on test results for various attempted recipes, for example.
  • the offline manufacturing system 10 includes a filler 12, a first fill set 14, and a second fill set 16.
  • the first fill set 14 includes a corresponding first fill target 18, such as a vial
  • the second fill set 16 likewise includes a corresponding second fill target 20, also such as a vial.
  • the filler 12 is a Bausch+Strobel (B&S) scale-down filler in which recipe optimization, including many experiments, were conducted before arriving at the optimal, universal filling recipe of the present disclosure. While the specific B&S scale-down filler was used, it will be appreciated that various other fillers may also or alternatively be used.
  • B&S scale-down filler was used, it will be appreciated that various other fillers may also or alternatively be used.
  • each of the first and second fill targets 18, 20 are referred to as a vial in one example, it will be understood that the fill targets 18, 20 may alternatively and more generally be any other similar drug container and still fall within the scope of the present disclosure.
  • the optimal filling recipe selected from the recipe optimization from the scale-down filler 12 and first and second fill sets 12, 16 is transferable to a manufacturing line, such as a nested syringe and vial line in FIGS. 13A and 13B.
  • FIGS. 2A-2E a perspective view of each of the filler 12, first and second fill sets 14, 16 and first and second fill targets 18, 20 of FIG. 1 is depicted.
  • the filler 12 is a Bausch+Strobel Filler, a bench scale down filler, and more generally a developmental filler to support clinical and commercial manufacturing, as explained more below.
  • Exemplary containers that may be used with this filler include bulk ISO 2R, 6R, 20R, 3cc, 5cc, 10cc, 20cc vials, bulk 1mL glass and 1 mL plastic syringes, and bulk 5cc plastic cartridges.
  • the filler 12 includes a dosing vessel 21, a pump 22, such as a peristaltic pump, and a product bag 23.
  • FIG. 2B depicts a portion of the filler 12 of FIG. 2A.
  • the pump 22 is depicted cooperating with a fill target, such as the first fill target 18 or the second fill target 20.
  • the first and second fill targets 18, 20 are the same vial, but may also be any other container and still fall within the scope of the present disclosure.
  • the first filling set 14 of FIG. 1 is depicted.
  • the first filling set 14 is a peristaltic pump and includes a bag 27, tubing 28A, and a needle 29A.
  • the tubing 28A is coupled to the bag 27 at one end and the fill target 18 at the other end, such that the fluid in the bag is able to be drawn into the tubing and to the fill target 18 by way of the needle 29A, for example.
  • the outer diameter of the needle 29A is 2.0m
  • the inner diameter of the needle is 1 6mm
  • the inner diameter of the pump tubing 28A is 1.6 mm.
  • the tubing 28A branches into two tubing and converges again.
  • FIG. 2D depicts the second fill set 16 of FIG. 1.
  • the second fill set 16 is a peristaltic pump and includes the bag 27, tubing 28B, and a needle 29B, which is different from the needle 29A of the first fill set 14.
  • the tubing 28B is again coupled to the bag 27 at one end and the second fill target 20 at the other end, such that fluid in the bag is able to be drawn through the tubing and into the second fill target 20 by way of the needle 29B.
  • the tubing 28B again branches into two tubing and then converges again, but the two tubing have a different inner diameter.
  • the inner diameter of the tubing 28B is 1 6mm and 3.2 mm, respectively.
  • the outer diameter of the needle 29B is 3.0mm
  • the inner diameter of the needle is 2.6mm
  • the inner diameter of the pump tubing is 1.6 mm.
  • the exemplary fill target may include the first and second fill targets 18, 20 of FIG. 1, for example.
  • the first and second fill targets 18, 20 include a 1.3 mL fil in ISO 2R vial.
  • the target weight is 1.365 grams
  • T2+ is 0.05grams, which is 1.415 grams
  • T2- is 0.05 grams, which is 1.315 grams.
  • T1+ is 0.03 grams, which is 1.395 grams
  • T1- is 0.03 grams, which is 1.335 grams.
  • the net weight no adjustment limit + is 0.02 grams, which is 1.385 grams
  • the net weight no adjustment limit - is 0.02 grams, which is 1.345 grams.
  • the first fill set 14 is a peristaltic pump filling assembly having a needle with an outer diameter of 2.0mm and an inner diameter of 1 6mm.
  • the peristaltic pump filling assembly includes tubing (in FIG. 2C) having an inner diameter of 1 6mm.
  • the chart in FIG. 3A also includes information about the second fill set 16, which in this example also includes a peristaltic pump filling assembly having a needle with an outer diameter of 2.0mm and an inner diameter of 2.6mm.
  • the second fill set 16 also includes tubing having an inner diameter of 1 6mm, and another tubing having an inner diameter of 3.2mm, as mentioned above.
  • a no adjustment limit for a fill weight of the second fill target 20, such as the vial was set to T1 , with T 1 being at or in a range of about 2% more or 2% less than a fill weight of a target fill weight TO.
  • the target fill weight TO includes a volume of 1.3 mL and a mass of 1.365 grams.
  • the no adjustment limit was 80% of T1 , which may be +/- 0.02 grams of T1 +/- 0.03 grams.
  • the fill target mass of a vial in which no adjustment is needed is any value in the range of 1.345 grams to 1.385 grams in this example.
  • the no adjustment limit for a fill weight of the vial, such as the second fill target 20 may be set to any value within a range of a target fill weight TO and T1 , with T 1 being at or in a range between the target fill weight TO and T2 based on process performance, for example. In some examples, T 1 is set at 2%, but may be changed.
  • the filling recipe of the present disclosure includes filling a vial, such as the vials of the first and second filling targets 18, 20, with a drug product via a pump, and the drug product includes a mAb formulation.
  • the mAb formulations used are drug product 1 (DP1) and drug product 1 (DP2) As provided in the chart, at 5 degrees Celsius the density of DP1 is 1.055 g/cm 3 and the viscosity is 4.857.
  • 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 .
  • the density of DP2 is 1.054 g/cm 3 and the viscosity is 4.07 cP.
  • the density of DP2 is 1.049 g/cm 3 , the viscosity is 2.19 cP, and the surface tension is 43.716 mN/m .
  • the drug product used in the filling recipe is a mAb formulation including one or more of: (1) a density in a range of either about 1.054-1.055 g/cm 3 at 5 degrees Celsius or about 1.049-1.05 g/cm 3 at 25 degrees Celsius;
  • the method disclosed herein can be used to fill any liquid drug product, such as drug products comprising a biologic drug (e.g., peptides, mAbs, siRNAs) and a small molecule drug, provided the drug product has a specified physical parameter range.
  • the drug product may include one or more of the following characteristics: (1) a density in a range of about 1.0-1.2 g/cm 3 ; and/or (2) a viscosity in a range of about 1.0-10.0 cP; and/or (3) a surface tension in a range of about 40.0-72.7 mN/m.
  • preferred ranges for the viscosity are one or more of 1.0-8.0 cP, 1.0-6.0 cP,
  • the drug product has a density in a range of 1.0-1.2 g/cm 3 ; a viscosity in a range of about 1.0-10.0 cP; and a surface tension in a range of about 40.0-72.7 mN/m.
  • the drug product has one or more of a density in a range of 1.0-1.2 g/cm 3 and a viscosity in a range of about 1.0-10.0 cP, and any value for a surface tension.
  • the determining factors for the filling recipe are the density and the viscosity of the drug product, and the filling recipe may work with any surface tension. It will be understood that a drug product meeting any of these parameters may be used with the methods and filling recipe of the present disclosure.
  • manufacturing data suggests that a drug product with a viscosity of about 8.0 cP or more worked well with a drip retraction value of 20 degrees.
  • the preferred density of the drug product is about 1.0-1.1 g/cm 3 . It will be appreciated that many other values within the density, viscosity, and surface tension ranges provided above may be used for the drug products used with the methods and filling recipes of the present disclosure and fall within the scope of the present disclosure.
  • step 30 an initial optimization based on an existing filling recipe, which is referred to as existing filling recipe No. 1, was conducted on the second fill set 16.
  • step 32 with this initially optimized DP1 filling recipe for the second fill set 16, a range of drip retraction parameters ranging from 0 degrees to 45 degrees was tested.
  • step 34 another existing filling recipe, referred to as existing filling recipe No. 2, was started and a range of drip retraction parameters from 10 degrees to 20 degrees was tested.
  • step 36 was then developed in step 36 and various drip retraction parameters were also tested, including 5 degrees, 10 degrees and 20 degrees.
  • step 38 the hybrid recipe was finalized for the second fill set 16 with a drip retraction parameter set at 20 degrees.
  • step 40 the same filling recipe was used for the first fill set 14 and drip retraction parameters were set at 10 degrees and 20 degrees. Based on the fill performance, a filling recipe for the first fill set 14 was finalized with a drip retraction parameter set at 20 degrees.
  • fill performance results of the second fill target 20, such as the vial, of the second fill set 16 after utilizing a filling recipe with various drip retraction values is provided.
  • a test was conducted and the fill performance of the vial monitored when the drip retraction parameter of the filling recipe for the pump was set to each of 0 degrees, 10 degrees, 20 degrees, 30 degrees, 40 degrees, and 45 degrees.
  • an air gap AG in the fill target 20 or vial increased with increasing drip retraction parameter leading to an air liquid bilayer, explaining a likely reason for poor fill performance when a higher drip retraction parameter is set in the filling recipe.
  • FIG. 5A an air gap AG in the fill target 20 or vial increased with increasing drip retraction parameter leading to an air liquid bilayer, explaining a likely reason for poor fill performance when a higher drip retraction parameter is set in the filling recipe.
  • the start pump dosing was set at 40 degrees
  • the pump dosing start ramp was set at 90 degrees
  • the pump dosing stop ramp was set at 210 degrees
  • the end pump dosing was set at 260 degrees
  • the end drip retraction was set at 310 degrees
  • the distance run per dose was 766 degrees.
  • the start pump dosing was set at 40 degrees
  • the pump dosing start ramp was set at 90 degrees
  • the pump dosing stop ramp was set at 210 degrees
  • the end pump dosing was set at 260 degrees
  • the end drip retraction was set at 290 degrees
  • the distance run per dose was 766 degrees.
  • the impact of the drip retraction parameter set at 20 degrees on fill performance of DP1 in the second fill set 16 is provided.
  • the minimum filling weight was 1.348 grams and the maximum filling weight was 1.384 grams, making the average fill weight 1.366 grams, with a standard deviation of 0.006.
  • the process performance index Cpk value was 2.69, which is considerably higher than experiments using a filling recipe with the same parameters except for the drip retraction parameter of 45 degrees. Said another way, the process performance index was much higher when the drip retraction parameter was set to 20 degrees compared to higher values, such as 45 degrees, further indicating the impact of the drip retraction parameter on the fill performance.
  • the process performance index Cpk provides a value indicative of the efficiency of a particular process.
  • the process performance index value Cpk relates to how close an actual fill weight of a container, such as a vial, is to a target fill weight.
  • the process performance index value Cpk also relates to how close each subsequent fill rate of the additional containers, e.g., vials, are to each other. If there is a high number of the process performance index value Cpk, a given pump is providing an optimal performance. Likewise, a low number for the process performance index value Cpk indicates the pump is poorly performing.
  • the filling recipe 50 includes specific needle parameters, including setting a needle setting dimension to one of 134.5 mm and 39.0 mm, setting a basic needle position to 7.0 mm, and setting the start needle down to 25 degrees.
  • the needle parameters for the filling recipe 50 also include setting the needle at a dosing start of 10 mm, setting the needle down to one of 60 degrees and 23 degrees, and setting the needle up at 125 degrees.
  • the filling recipe 50 also includes setting the needle at the end of dosing to 13.0 mm and 310 degrees, setting the start needle to cut-off position of 315 degrees, setting the cut off position reached to 13.0 mm and 315 degrees, setting the start needle to a basic position of 315 degrees, and the basic needle position reached to 359 degrees.
  • the finalized filling recipe 50 of the present disclosure also includes setting several parameters for the pump.
  • the filling recipe 50 includes setting the start pump dosing to 40 degrees, setting the pump dosing start ramp to 90 degrees, setting the pump dosing stop ramp to 210 degrees, and setting the end pump dosing to 260 degrees.
  • the filling recipe includes setting the drip retraction parameter to 20 degrees, such as the pump distance run for the drip retraction to 20 degrees, the end drip retraction parameter to 290 degrees, and the distance run per dose parameter to 766 degrees.
  • the filling recipe 50 may include setting the drip retraction parameter to any value equal to or less than 20 degrees and still fall within the scope of the present disclosure.
  • the lowest value of the drip retraction parameter is 0 degrees.
  • the filling recipe 50 may include setting the drip retraction parameter for the pump to one of 10 degrees, 20 degrees, or any value in a range of 10 degrees to 20 degrees.
  • the filling recipe 50 may include setting the end drip retraction to 290 degrees when the drip retraction parameter is set to 20 degrees, or setting the end drip retraction value to 280 when setting the drip retraction parameter to 10 degrees, for example.
  • the finalized filling recipe 50 also includes setting a no adjustment limit for the fill weight of any vial to T1 , with T 1 being at or in a range of about 2% more or 2% less than a fill weight of a target fill weight TO, as explained above relative to FIG. 3B, for example.
  • the same filling recipe 50 was finalized for the exemplary drug product DP1 in the second fill set 16
  • the same filling recipe 50 may also be used for the first fill set 14 using DP1 or other drug products in the mAb formulation programs, for example.
  • the same finalized filling recipe 50 is also effectively used for a nested syringe and vial line of a manufacturing plant.
  • the method of optimizing a filling recipe for a nested syringe and vial line or other manufacturing line in a manufacturing plant includes using the first and second fill sets 14, 16 of the offline manufacturing system 1 of FIG. 1, for example.
  • FIGS. 8A and 8B the impact of temperature on fill performance of the second fill set 16 was evaluated for efficacy and the results are provided in the graph of FIG. 8A and the table of FIG. 8B.
  • the temperature was set at 10-11 degrees Celsius and the process performance parameter Cpk during this temperature range of 10-11 degrees Celsius throughout the fill cycle well exceeded a minimum value of 1.33.
  • the cycle included 103 fills, with a minimum fill weight of 1.340 g, a maximum fill weight of 1.393 g, and an average fill weight of 1.362 g with a standard deviation of 0.008 grams.
  • the process performance parameter Cpk value was 1.95, well above the target minimum value of 1.33, for example. While FIG. 8A shows that occasional filling weights were close to the T 1 limits at this temperature range, subsequent fill weights were able to return close to the target without significantly impacting the process performance index Cpk.
  • FIGS. 9A and 9B the impact of a temperature higher than 10-11 degrees Celsius (as in FIGS. 8A and 8B) on fill performance of the second fill set 16 was evaluated, and the results are provided in the graph of FIG. 9A and the table of FIG. 9B.
  • 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 well exceeded a minimum value of 1.33.
  • the cycle included 103 fills, with a minimum fill weight of 1.348 g, a maximum fill weight of 1.384 g, and an average fill weight of 1.366 g with a standard deviation of 0.006 grams.
  • process performance parameter Cpk against T2 was 2.69, 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, in this example. This indicates an even better fill performance for the finalized filling recipe at slightly higher temperatures.
  • the impact of a temperature on fill performance of the first fill set 14 was evaluated, and the results are provided in the graph of FIG. 10A and the table of FIG. 10B.
  • the temperature was set at about a range of 10-11 degrees Celsius, and the process performance parameter Cpk during this temperature throughout the fill cycle well exceeded a minimum value, such as 1.33.
  • the cycle included 100 fills, with a minimum fill weight of 1.354 g, a maximum fill weight of 1.380 g, and an average fill weight of 1.365 g with a standard deviation of 0.005 grams.
  • the process performance parameter Cpk against T2 was 3.16, well above each of the target minimum value of 1.33, and the process performance parameter Cpk for the fill performance of the second fill set 16 at both the lower temperature of 10-11 degrees Celsius (FIGS. 8A and 8B) and the higher temperature 19 degrees Celsius (FIGS. 9A and 9B), for example.
  • these results further show the universal nature and applicability of the finalized filling recipe on different fill sets, and this filling recipe may also be successfully transferred and used with a nested syringe and vial line of a manufacturing plant, for example.
  • FIGS. 11 A and 11 B the impact of a temperature higher than 10-11 degrees Celsius (as in FIGS. 10A and 10B) on fill performance of the first fill set 14 was evaluated, and the results are provided in the graph of FIG. 11A and the table of FIG. 11 B.
  • 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 well exceeded a minimum value of 1.33.
  • the cycle included 120 fills, with a minimum fill weight of 1.352 g, a maximum fill weight of 1.373 g, and an average fill weight of 1.362 g with a standard deviation of 0.004 grams.
  • the process performance parameter Cpk against T2 was 3.61 , well above both the target minimum value of 1.33, and the process performance parameter Cpk of 3.16 for the fill performance at the lower temperature of 10-11 degrees Celsius, for example.
  • the manufacturing line 102 includes at least one nested syringe and vial line 104 in which the efficient universal filling recipe 50 of the present disclosure is effectively used.
  • 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.
  • NSVL nested syringe and vial line
  • the filling recipe 50 of the present disclosure may be utilized in a variety of other nested syringe and vial lines and still fall within the scope of the present disclosure.
  • the vial 105 may more generally be any container 105, such as a syringe, and still fall within the scope of the present disclosure.
  • the manufacturing line 102 may include a plurality of nested syringe and vial lines 106, each of which includes the at least one nested syringe and vial line 104, for example.
  • the manufacturing line 102 also includes at least one pump 110 that corresponds to and cooperates with at least one vial of the at least one nested syringe and vial line 104.
  • the nested syringe and vial line 104 is a B20 nested syringe and vial line (NSVL) that includes a semi-automated debagger 104a, an automated debagger 104b, a rapid transfer airlock 104c, a nested filler (isolator) 104d, and a capper 104e.
  • NSVL B20 nested syringe and vial line
  • Various other clinical or commercial manufacturing fillers may alternatively be used and still fall within the scope of the present disclosure.
  • FIG. 13B depicts a plurality of pumps, which may be the plurality of pumps 112 that correspond to the plurality of vials 114 of the nested syringe and vial line 104 of FIG. 12, for example.
  • the plurality of pumps 112 include five pumps 110 that cooperate with each vial 105 of the plurality of vials 114.
  • the nested syringe and vial line 104 is a clinical manufacturing filler, such a Bausch & Strobel filler.
  • the containers 105 are referred to generally as vials, it will be understood that the containers 105 may be one or more of vials, syringes or plastic cartridges and still fall within the scope of the present disclosure.
  • the containers 105 may include nested ISO 2R vials, nested 1mL glass and plastic syringes, or nested 5cc plastic cartridges.
  • the plurality of pumps include five pumps 110 in this example, it will be understood that more or fewer pumps may alternatively be used and still fall within the scope of the present disclosure.
  • the plurality of pumps may include 10 pumps or 2 pumps for different filler, or any other number of pumps within this range, for example, and still fall within the scope of the present disclosure.
  • a method of filling the plurality of vials 105 of the nested syringe and vial line 104 comprises providing one of the pump 110 or a plurality of pumps 112 corresponding to one of the vial 105 or the plurality of vials 105 of the nested syringe and vial line 104.
  • the method also includes setting the drip retraction parameter for each pump 110 to any value equal to or less than 20 degrees.
  • the method also includes setting a no adjustment limit for the fill weight of the vial 105 to T 1 , with T 1 being at or in a range of about 2% more or 2% less than the fill weight of the target fill weight TO.
  • 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 still also include exceeding a minimum value for the process performance index Cpk for each vial 105 of the plurality of vials 105 during a temperature range throughout a fill cycle, the temperature range one of: (1) 5 (+/-3) degrees Celsius; (2) 20 (+/-5) degree Celsius; or (3) 10 to 19 degrees Celsius.
  • the minimum value for the process performance index Cpk is 1.33. In other examples, such as in clinical fills, a minimum value for the process performance index Cpk is 1.0. However, in this example, and as generally understood in commercial fills, the minimum value for the process performance index Cpk is 1.33.
  • filling each vial 105 with the drug product via the corresponding pump 110 of the plurality of pumps 112 comprises filling each vial 105 with a drug product, wherein the drug product has one or more of the following characteristics: (1) a density in a range of about 1.0-1.2 g/cm3; (b) a viscosity in a range of about 1.0-10.0 cP; and (c) a surface tension in a range of about 40.0-72.7 mN/m.
  • the drug product has a density in a range of 1.0-1.2 g/cm3; a viscosity in a range of about 1.0-10.0 cP; and a surface tension in a range of about 40.0-72.7 mN/m.
  • the fill performance of the new filling recipe of the present disclosure in the nested syringe and vial line 104 is provided.
  • the total dose optimization cycle such as the number of strokes of the pump 110 (or pumps 112) needed to teach the pump 110 how to operate using the new filling recipe is minimized.
  • the total dose optimization cycle value is 4, which is significantly reduced compared to values of the total dose optimization cycle of previous filling recipes set forth in FIG. 15, for example.
  • the process performance index Cpk for each nozzle (not shown) of each pump 110 of the plurality of pumps 112 of the nested syringe and vial Iine104 exceeds the minimum value of 1.33 for the process performance index Cpk desired.
  • the average process performance index Cpk value for all nozzles of the pumps 110 is 1.4.
  • FIG. 15 a chart listing the process performance index Cpk of nozzles of the pumps using old filling recipes is set forth. Specifically, when using old filling recipes for a large variety of different drug products, including the mAb formulations, the average process performance index Cpk for all nozzles of the pumps was well below the desired process performance index Cpk value of 1 .33. Said another way, all of the process performance index Cpk values were less than 1.33.
  • the total dose optimization cycle was greater for each drug product using the old filling recipe compared to the dose optimization cycle value listed in FIG. 14 when using the new filling recipe 50.
  • the method of optimizing the filling recipe for the nested syringe and vial line 104 includes setting the drip retraction parameter for at least one pump 14, 16, 22 in the 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 a performance of the at least one pump 14, 16, 20 with the drip retraction 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 for the process performance index (Cpk) for the at least one container 18, 20 throughout at least one fill cycle and for at least one drug product using the at least one pump 14, 16, 22 in the offline manufacturing system 10.
  • the method also includes finalizing a filling recipe for the nested syringe and vial line 104 using data from fill cycles of the at least one drug product using the at least one pump 14, 16, 22 in the offline manufacturing system 10.
  • the above description describes various systems and methods of filling a vial of a nested syringe and vial line. It should be clear that the system or methods can further comprise use of a medicament listed below with the caveat that the following list should neither be considered to be all inclusive nor limiting.
  • the medicament will be contained in a reservoir.
  • the reservoir is a primary container that is either filled for treatment with the medicament.
  • the primary container can be a vial, a cartridge or a syringe.
  • drug products that may be used with the methods disclosed herein may include colony stimulating factors, such as granulocyte colony-stimulating factor (G-CSF).
  • G-CSF agents include, but are not limited to, Neupogen® (filgrastim) and Neulasta® (pegfilgrastim).
  • the methods may use various pharmaceutical products, such as an erythropoiesis stimulating agent (ESA), which may be in a liquid or a lyophilized form.
  • ESA erythropoiesis stimulating agent
  • An ESA is any molecule that stimulates erythropoiesis, such as Epogen® (epoetin alfa), Aranesp® (darbepoetin alfa), Dynepo® (epoetin delta), Mircera® (methyoxy polyethylene glycol-epoetin beta), Flematide®, MRK-2578, INS-22, Retacrit® (epoetin zeta), Neorecormon® (epoetin beta), Silapo® (epoetin zeta), Binocrit® (epoetin alfa), epoetin alfa Hexal, Abseamed® (epoetin alfa), Ratioepo®
  • An ESA can be an erythropoiesis stimulating protein.
  • erythropoiesis stimulating protein means any protein that directly or indirectly causes activation of the erythropoietin receptor, for example, by binding to and causing dimerization of the receptor.
  • Erythropoiesis stimulating proteins include erythropoietin and variants, analogs, or derivatives thereof that bind to and activate erythropoietin receptor; antibodies that bind to erythropoietin receptor and activate the receptor; or peptides that bind to and activate erythropoietin receptor.
  • Erythropoiesis stimulating proteins include, but are not limited to, epoetin alfa, 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 erythropoiesis stimulating proteins include erythropoietin, darbepoetin, erythropoietin agonist variants, and peptides or antibodies that bind and activate erythropoietin receptor (and include compounds reported in U.S. Publication Nos. 2003/0215444 and 2006/0040858, the disclosures of each of which is incorporated herein by reference in its entirety) as well as erythropoietin molecules or variants or analogs thereof as disclosed in the following patents or patent applications, which are each herein incorporated by reference in its entirety: U.S. Patent Nos.
  • Examples of other pharmaceutical products that may be used with the methods disclosed herein may include, but are not limited to, antibodies such as Vectibix® (panitumumab), XgevaTM (denosumab) and ProliaTM (denosamab); other biological agents such as Enbrel® (etanercept, TNF-receptor / Fc fusion protein, TNF blocker), Neulasta® (pegfilgrastim, pegylated filgastrim, 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).
  • antibodies such as Vectibix® (panitumumab), XgevaTM (denosumab) and ProliaTM (denosamab)
  • other biological agents such
  • the methods may also be used with a therapeutic antibody, a polypeptide, a protein or other chemical, such as an iron, for example, ferumoxytol, iron dextrans, ferric glyconate, and iron sucrose.
  • a therapeutic antibody for example, a polypeptide, a protein or other chemical, such as an iron, for example, ferumoxytol, iron dextrans, ferric glyconate, and iron sucrose.
  • the pharmaceutical product may be in liquid form, or reconstituted from lyophilized form.
  • proteins are the specific proteins set forth below, including fusions, fragments, analogs, variants or derivatives thereof: OPGL specific antibodies, peptibodies, and related proteins, and the like (also referred to as RANKL specific antibodies, peptibodies and the like), including fully humanized and human OPGL specific antibodies, particularly fully humanized monoclonal antibodies, including but not limited to the antibodies described in PCT Publication No.
  • WO 03/002713 which is incorporated herein in its entirety as to OPGL specific antibodies and antibody related proteins, particularly those having the sequences set forth therein, particularly, but not limited to, those denoted therein: 9H7; 18B2; 2D8; 2E11; 16E1; and 22B3, including the OPGL specific antibodies having either the light chain of SEQ ID NO:2 as set forth therein in Figure 2 and/or the heavy chain of SEQ ID NO:4, as set forth therein in Figure 4, each of which is individually and specifically incorporated by reference herein in its entirety fully as disclosed in the foregoing publication;
  • WO 2004/058988 which are incorporated by reference herein in their entirety particularly in parts pertinent to myostatin specific peptibodies, including but not limited to peptibodies of the mTN8-19 family, including those of SEQ ID NOS:305-351, including TN8-19-1 through TN8-19-40, TN8-19 coni and TN8-19 con2; peptibodies of 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 those of SEQ ID NOS:615-631, each of which is individually and specifically incorporated by reference herein in their entirety fully as disclosed in the foregoing publication; [0085
  • Interleukin 1-receptor 1 (“IL1-R1”) specific antibodies, peptibodies, and related proteins, and the like, including but not limited to those described in U.S. Publication No. 2004/097712, which is incorporated herein by reference in its entirety in parts pertinent to IL1-R1 specific binding proteins, monoclonal antibodies in particular, especially, without limitation, those designated therein: 15CA, 26F5, 27F2, 24E12, and 10H7, each of which is individually and specifically incorporated by reference herein in its entirety fully as disclosed in the aforementioned publication;
  • Ang2 specific antibodies, peptibodies, and related proteins, and the like including but not limited to those described in PCT Publication No. WO 03/057134 and U.S. Publication No. 2003/0229023, each of which is incorporated herein by reference in its entirety particularly in parts pertinent to Ang2 specific antibodies and peptibodies and the like, especially those of sequences described therein and including but not limited to: L1(N); L1(N) WT; L1(N) 1 K WT; 2xL1(N); 2xL1(N) WT; Con4 (N), Con4 (N) 1 K WT, 2xCon4 (N) 1 K; L1C; L1C 1 K; 2xL1C; Con4C; Con4C 1 K; 2xCon4C 1 K; Con4-L1 (N); Con4-L1C; TN-12-9 (N); C17 (N); TN8-8(N); TN8-14 (N); Con 1 (N),
  • WO 2003/030833 which is incorporated herein by reference in its entirety as to the same, particularly Ab526; Ab528; Ab531; Ab533; Ab535; Ab536; Ab537; Ab540; Ab543; Ab544; Ab545; Ab546; A551; Ab553; Ab555; Ab558; Ab559; Ab565; AbFIAbFD; AbFE; AbFJ; AbFK; AbG1D4; AbGC1E8; AbH1C12; AblA1 ; AblF; AbIK, AblP; and AblP, in their various permutations as described therein, each of which is individually and specifically incorporated by reference herein in its entirety fully as disclosed in the foregoing publication;
  • NGF specific antibodies, peptibodies, and related proteins, and the like including, in particular, but not limited to those described in U.S. Publication No. 2005/0074821 and U.S. Patent No. 6,919,426, which are incorporated herein by reference in their entirety particularly as to NGF-specific antibodies and related proteins in this regard, including in particular, but not limited to, the NGF-specific antibodies therein designated 4D4, 4G6, 6H9, 7H2, 14D10 and 14D11, each of which is individually and specifically incorporated by reference herein in its entirety fully as disclosed in the foregoing publication;
  • CD22 specific antibodies, peptibodies, and related proteins, and the like such as those described in U.S. Patent No. 5,789,554, which is incorporated herein by reference in its entirety as to CD22 specific antibodies and related proteins, particularly human CD22 specific antibodies, such as but not limited to humanized and fully human antibodies, including but not limited to humanized and fully human monoclonal antibodies, particularly including but not limited to human CD22 specific IgG antibodies, such as, for instance, a dimer of a human-mouse monoclonal hLL2 gamma-chain disulfide linked to a human-mouse monoclonal hLL2 kappa-chain, including, but limited to, for example, the human CD22 specific fully humanized antibody in Epratuzumab, CAS registry number 501423-23-0;
  • IGF-1 receptor specific antibodies such as those described in PCT Publication No. WO 06/069202, which is incorporated herein by reference in its entirety as to IGF-1 receptor specific antibodies and related proteins, including but not limited to the IGF-1 specific antibodies therein designated L1 H1, 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, L
  • anti-IGF-1 R antibodies for use in the methods and compositions of the present invention are each and all of those described in:
  • IL-15 specific antibodies, peptibodies, and related proteins, and the like such as, in particular, humanized monoclonal antibodies, particularly antibodies such as those disclosed in U.S. Publication Nos. 2003/0138421; 2003/023586; and 2004/0071702; and U.S. Patent No. 7,153,507, each of which is incorporated herein by reference in its entirety as to IL-15 specific antibodies and related proteins, including peptibodies, including particularly, for instance, but not limited to, HuMax IL-15 antibodies and related proteins, such as, for instance, 146B7;
  • IFN gamma specific antibodies peptibodies, and related proteins and the like, especially human IFN gamma specific antibodies, particularly fully human anti-IFN gamma antibodies, such as, for instance, those described in U.S. Publication No. 2005/0004353, which is incorporated herein by reference in its entirety as to IFN gamma specific antibodies, particularly, for example, the antibodies therein designated 1118; 1118*; 1119; 1121; and 1121*.
  • Specific antibodies include those having the heavy chain of SEQ ID NO:17 and the light chain of SEQ ID NO:18; those having the heavy chain variable region of SEQ ID NO:6 and the light chain variable region of SEQ ID NO:8; those having the heavy chain of SEQ ID NO:19 and the light chain of SEQ ID NO:20; those having the heavy chain variable region of SEQ ID NO:10 and the light chain variable region of SEQ ID NO:12; those having the heavy chain of SEQ ID NO:32 and the light chain of SEQ ID NO:20; those having the heavy chain variable region of SEQ ID NO:30 and the light chain variable region of SEQ ID NO:12; those having the heavy chain sequence of SEQ ID NO:21 and the light chain sequence of SEQ ID NO:22; those having the heavy chain variable region of SEQ ID NO:14 and the light chain variable region of SEQ ID NO:16; those having the heavy chain of SEQ ID NO:21 and the light chain of SEQ ID NO:33; and those having the heavy chain variable region of SEQ ID NO:14 and the
  • TALL-1 specific antibodies such as those described in U.S. Publication Nos. 2003/0195156 and 2006/0135431, each of which is incorporated herein by reference in its entirety as to TALL-1 binding proteins, particularly the molecules of Tables 4 and 5B, each of which is individually and specifically incorporated by reference herein in its entirety fully as disclosed in the foregoing publications;
  • PTH Parathyroid hormone
  • TPO-R Thrombopoietin receptor
  • TRAIL-R2 specific antibodies, peptibodies, related proteins and the like such as those described in U.S. Patent No. 7,521,048, which is herein incorporated by reference in its entirety, particularly in parts pertinent to proteins that bind TRAIL-R2;
  • Activin A specific antibodies, peptibodies, related proteins, and the like, including but not limited to those described in U.S. Publication No. 2009/0234106, which is herein incorporated by reference in its entirety, particularly in parts pertinent to proteins that bind Activin A;
  • TGF-beta specific antibodies, peptibodies, related proteins, and the like including but not limited to those described in U.S. Patent No. 6,803,453 and U.S. Publication No. 2007/0110747, each of which is herein incorporated by reference in its entirety, particularly in parts pertinent to proteins that bind TGF-beta;
  • Amyloid-beta protein specific antibodies including but not limited to those described in PCT Publication No. WO 2006/081171, which is herein incorporated by reference in its entirety, particularly in parts pertinent to proteins that bind amyloid-beta proteins.
  • One antibody contemplated 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 foregoing publication;
  • c-Kit specific antibodies including but not limited to those described in U.S. Publication No. 2007/0253951, which is incorporated herein by reference in its entirety, particularly in parts pertinent to proteins that bind c-Kit and/or other stem cell factor receptors;
  • OX40L specific antibodies, peptibodies, related proteins, and the like including but not limited to those described in U.S. Publication No. 2006/0002929, which is incorporated herein by reference in its entirety, particularly in parts pertinent to proteins that bind OX40L and/or other ligands of the 0X40 receptor; and
  • Activase® (alteplase, tPA); Aranesp® (darbepoetin alfa); Epogen® (epoetin alfa, or erythropoietin); GLP-1, Avonex® (interferon beta-1a); Bexxar® (tositumomab, anti-CD22 monoclonal antibody); Betaseron® (interferon-beta); Campath® (alemtuzumab, anti-CD52 monoclonal antibody); Dynepo® (epoetin delta); Velcade® (bortezomib); MLN0002 (anti- a4b7 mAb); MLN1202 (anti-CCR2 chemokine receptor mAb); Enbrel® (etanercept, TNF-receptor /Fc fusion protein, TNF blocker); Eprex® (epoetin alfa);
  • LymphoCide® epratuzumab, anti-CD22 mAb
  • BenlystaTM lymphostat B, belimumab, anti-BlyS mAb
  • Metalyse® tenecteplase, t-PA analog
  • Mircera® methoxy polyethylene glycol-epoetin beta
  • Mylotarg® gemtuzumab ozogamicin
  • efalizumab Cimzia® (certolizumab pegol, CDP 870); SolirisTM (eculizumab); pexelizumab (anti-C5 complement); Numax® (MEDI-524); Lucentis® (ranibizumab); Panorex® (17-1 A, edrecolomab); Trabio® (lerdelimumab); TheraCim hR3 (nimotuzumab); Omnitarg (pertuzumab, 2C4); Osidem® (IDM-1); OvaRex® (B43.13); Nuvion® (visilizumab); cantuzumab mertansine (huC242- DM1); NeoRecormon® (epoetin beta); Neumega® (oprelvekin, human interleukin-11); Neulasta® (pegylated filgastrim, pegylated G-CSF, pegylated hu-Met-G
  • Tysabri® natalizumab, anti-a4integrin mAb
  • Valortim® MDX-1303, anti-B. anthracis protective antigen mAb
  • ABthraxTM Vectibix® (panitumumab); Xolair® (omalizumab); ETI211 (anti-MRSA mAb)
  • IL-1 trap the Fc portion of human lgG1 and the extracellular domains of both IL-1 receptor components (the Type I receptor and receptor accessory protein)
  • VEGF trap Ig domains of VEGFR1 fused to lgG1 Fc
  • Zenapax® diaclizumab
  • Zenapax® diaclizumab, anti-IL-2Ra mAb
  • Zevalin® ibritumomab tiuxetan
  • Zetia® ezetimibe
  • Orencia® atacicept, TACI-lg
  • sclerostin antibody such as but not limited to romosozumab, blosozumab, or BPS 804 (Novartis).
  • therapeutics such as rilotumumab, bixalomer, trebananib, ganitumab, conatumumab, motesanib diphosphate, brodalumab, vidupiprant, panitumumab, denosumab, NPLATE, PROLIA, VECTIBIX or XGEVA.
  • a monoclonal antibody that binds human Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9), e.g. U.S. Patent No. 8,030,547, U.S. Publication No.
  • talimogene laherparepvec or another oncolytic HSV for the treatment of melanoma or other cancers.
  • oncolytic HSV include, but are not limited to talimogene laherparepvec (U.S. Patent Nos. 7,223,593 and 7,537,924); OncoVEXGALV/CD (U.S. Pat. No. 7,981,669); OrienXOIO (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).
  • TIMPs are endogenous tissue inhibitors of metal loproteinases (TIMPs) and are important in many natural processes.
  • TIMP-3 is expressed by various cells or and is present in the extracellular matrix; it inhibits all the major cartilage-degrading metalloproteases, and may play a role in 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 a DNA that encodes TIMP-3 are disclosed in U.S. Patent No. 6,562,596, issued May 13, 2003, the disclosure of which is incorporated by reference herein. Description of TIMP mutations can be found in U.S. Publication No. 2014/0274874 and PCT Publication No. WO 2014/152012.
  • CGRP human calcitonin gene-related peptide
  • bispecific antibody molecule that target the CGRP receptor and other headache targets. Further information concerning these molecules can be found in PCT Application No. WO 2010/075238.
  • bispecific T cell engager (BiTE®) molecules e.g. BLINCYTO® (blinatumomab)
  • BLINCYTO® blindatumomab
  • APJ large molecule agonist e.g., apelin or analogues thereof in the device.
  • Information relating to such molecules can be found in PCT Publication No. WO 2014/099984.
  • the medicament comprises a therapeutically effective amount of an anti-thymic stromal lymphopoietin (TSLP) or TSLP receptor antibody.
  • TSLP anti-thymic stromal lymphopoietin
  • 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. Publication No. 2009/0186022.
  • anti-TSLP receptor antibodies include, but are not limited to, those described in U.S. Patent No. 8,101,182.
  • the medicament comprises a therapeutically effective amount of the anti-TSLP antibody designated as A5 within U.S. Patent No. 7,982,016.

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  • Engineering & Computer Science (AREA)
  • Mechanical Engineering (AREA)
  • Medical Preparation Storing Or Oral Administration Devices (AREA)
  • Basic Packing Technique (AREA)
  • Filling Of Jars Or Cans And Processes For Cleaning And Sealing Jars (AREA)

Abstract

La présente invention concerne un procédé de remplissage d'un flacon. Le procédé comprend la fourniture d'une pompe correspondant à un flacon et le réglage d'un paramètre de rétraction de goutte-à-goutte pour la pompe à une valeur quelconque égale ou inférieure à 20 degrés. Le procédé comprend en outre le réglage d'une limite de non-réglage pour un poids de remplissage du flacon à T1, T1 étant égal à un poids de remplissage cible T0 ou dans une plage de plus ou moins environ 2 % autour de celui-ci, un indice de performance de traitement Cpk (Cpk) pour le flacon tout au long d'un cycle de remplissage dépasse une valeur minimale.
EP22731368.1A 2021-05-21 2022-05-19 Procédé d?optimisation d?une recette de remplissage pour un récipient de médicament Pending EP4341161A1 (fr)

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WO2022246055A1 (fr) 2022-11-24
MX2023013640A (es) 2023-11-30
CL2023003444A1 (es) 2024-07-12
BR112023024278A2 (pt) 2024-01-30
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CN117320964A (zh) 2023-12-29
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