Manufacturing of pharmaceutical compositions

{
  "publication_number": "US2020222319A1",
  "country": "US",
  "kind": "A1",
  "title": "Manufacturing of pharmaceutical compositions",
  "abstract": "The present disclosure discloses a process for the continuous manufacture of a liquid pharmaceutical composition, the process comprising providing a mixing unit, feeding a therapeutic agent and a liquid vehicle to the mixing unit, operating the latter thereby mixing the agent and the vehicle into a liquid pharmaceutical composition, discharging the composition into a holding unit.",
  "claims": [
    "1. A process for the continuous manufacture of a liquid pharmaceutical composition, the process comprising the steps of: providing a supply of a therapeutic agent and a supply of a liquid vehicle, dispensing the therapeutic agent and the liquid vehicle from the corresponding supplies and feeding them into a mixing unit (1), said dispensing and feeding being performed according to a predetermined, timely-steady rate, the rate of the agent and the rate of the liquid vehicle being each independently adjustable, operating the mixing unit (1) thereby obtaining a liquid composition having a therapeutic agent concentration, discharging the liquid composition from the mixing unit (1) into a holding unit (2), the holding unit (2) being configured so that the unit residence time of the liquid composition is at least sufficient to normalize the therapeutic agent concentration, discharging the liquid composition from the holding unit (2) and processing the same. 2. The process according to claim 1, wherein the pharmaceutical composition includes any one or more of a peptide, a protein and an antibody. 3. The process according to any one or more of the preceding claims, wherein the liquid composition is in the form of a solution or a suspension. 4. The process according to any one or more of the preceding claims, wherein the liquid pharmaceutical compositions contains more than about 0.05 mg/mL of a therapeutic agent per volume unit of the composition. 5. The process according to any one or more of the preceding claims, wherein the dispensing and feeding of the agent and the vehicle is made according to a steady flow. 6. The process according to any one or more of claims 1 to 4, wherein the dispensing and feeding of the agent is made according to a frequency while the dispensing and feeding of the vehicle is made according to a steady flow. 7. The process according to claim 1, including the following steps: providing a supply of a therapeutic agent and a liquid vehicle, the supplies being contained in dedicated dispensing units (3, 4), dispensing the therapeutic agent and the liquid vehicle from the corresponding supplies and feeding them into a screw mixer (1) by means of conveying elements (5, 6) fluidly connecting the corresponding dispensing units (3, 4) and the screw mixer (1), said dispensing and feeding being performed according to a predetermined, timely-steady rate, the rate of the agent and the rate of the liquid vehicle being each independently adjustable, the screw mixer (1) including a barrel and at least one screw arranged within the barrel and rotating along a central axis of the latter, at least a feeding inlet (10, 11) at a proximal end of the barrel and a discharging outlet (12) at a distal, opposite end of the barrel, operating the screw so as to mix the agent and the vehicle thereby obtaining a liquid composition while conveying the agent and the vehicle down the barrel towards the discharging outlet (12), said composition having a therapeutic agent concentration, discharging the liquid composition from the discharging outlet (12) of the barrel into a holding unit (2), the holding unit (2) being configured so that the unit residence time of the liquid composition is at least sufficient to normalize the therapeutic agent concentration, discharging the liquid composition from the holding unit (2) and processing the same. 8. The process according to any one or more of the preceding claims, wherein the dispensing of the therapeutic agent includes microdosing the same. 9. The process according to any one or more of the preceding claims, wherein the dispensing and feeding of the therapeutic agent includes in-line weighing the same. 10. The process according to claim 9, wherein in-line weighing of the therapeutic agent includes in-line taking of microwave spectra suitable to measure mass and moisture content of the dispensed therapeutic agent, outputting data representing the measured mass and water content, processing the data thereby generating a corresponding signal, and using this signal to dynamically adjust the dispensing and feeding rates of either the therapeutic agent and/or the liquid vehicle. 11. The process according to claim 9 or 10, wherein in-line weighing of the therapeutic agent includes measuring weight loss of the corresponding supply during the dispensing of the therapeutic agent. 12. The process according to any one or more of the preceding claims, further including a step of discharging the composition from the holding unit (2) and controlling the therapeutic agent's concentration in the discharged liquid pharmaceutical composition, wherein said controlling includes quantifying the agent's concentration in the composition, outputting data representing the measured concentration, processing the data thereby generating a corresponding signal and using this signal to dynamically adjust the dispensing and feeding rates of either the therapeutic agent or the liquid vehicle in order to keep the ratio between therapeutic agent and liquid vehicle fed to the mixing unit (1) stable over time. 13. The process according to any one or more of the preceding claims which is an automated process. 14. An apparatus for the continuous manufacture of a liquid pharmaceutical composition, the apparatus comprising: at least two dedicated dispensing units (3, 4), containing a supply of a therapeutic agent and a liquid vehicle, respectively, each dispensing unit (3, 4) including a release actuator configured to trigger the dispense of the liquid vehicle and the agent at a predetermined, timely-steady rate, the rate of the agent and the rate of the liquid vehicle being each independently adjustable, downstream to the dispensing units (3, 4), a mixing unit (1) fluidly connected with the dispensing units (3, 4), the mixing unit (1) including a mixing chamber having proximal and distal ends, a feeding inlet at a proximal end of the chamber and a discharging outlet (12) at a distal, opposite end of the chamber, the chamber being configured to receive the therapeutic agent and the liquid vehicle through said inlet, the mixing unit being configured to obtain a liquid composition having a therapeutic agent concentration, downstream to the mixing unit (1), a holding unit (2) fluidly connected with the discharging outlet (12) of the mixing unit (1), said holding unit having an inlet (13) and an outlet (14), and said unit (2) being configured to have a residence time of the liquid composition which is at least sufficient to normalize the therapeutic agent concentration, and conveying elements (5, 6, 22) arranged to fluidly connect the dispensing units (3, 4) with the feeding inlet of the mixing unit (1) and the discharging outlet (12) of the mixing unit (1) with the inlet (13) of the holding unit (2). 15. The apparatus according to claim 14, wherein mixing device is a screw mixer. 16. The apparatus according to claim 14 or 15, wherein the conveying elements (5) connecting the agent's dispensing unit (3) and the mixing unit include an in-line weighing device (9). 17. The apparatus according to claim 16, wherein the in-line weighing device (9) is configured to in-line taking of microwave spectra of the therapeutic agent and suitable to measure mass and moisture content of the same, outputting data representing the measured mass and water content, processing the data thereby generating a corresponding signal, and using this signal to dynamically adjust the rate at which the release actuators of either the therapeutic agent and/or the liquid vehicle dispense the respective materials. 18. The apparatus according to claim 16 or 17, wherein the in-line weighing device (9) is configured to measuring weight loss of the dispensing unit (3). 19. The apparatus according to anyone or ore of the preceding claims, further including elements (23) conveying the liquid pharmaceutical composition away from the holding unit (2) towards further processing units, these conveying elements (23) including a concentration control arrangement (15) arranged to control therapeutic agent's concentration in the liquid pharmaceutical composition. 20. The apparatus according to claim 18, wherein concentration control arrangement (15) includes a device relying on UV, NIR or RAMAN spectroscopy, and is configured to quantify the therapeutic agent in the composition. 21. The apparatus according to anyone or more of the preceding claims, wherein the holding unit (2) further includes an arrangement configured to monitor the pH of the liquid pharmaceutical composition and optionally correct the same in case of divergences with respect to a predetermined target pH. 22. Use of an assembly including: a microdosing device (8), downstream to the microdosing device (8), an in-line weighing device (9), and downstream to the in-line weighing device (9), a holding unit (2), for maintaining a steady concentration of a therapeutic agent during a continuous manufacturing of a liquid pharmaceutical composition, the composition containing said agent and a liquid vehicle. 23. An assembly including: a microdosing device 8, downstream to the microdosing device 8, an in-line weighing device 9, and downstream to the in-line weighing device 9, a holding unit 2, the assembly being configured for maintaining a steady concentration of a therapeutic agent during a continuous manufacturing of a liquid pharmaceutical composition, the composition containing said agent and a liquid vehicle."
  ],
  "cpc": [
    "A61K 9/08",
    "B01F 13/1027",
    "B01F 15/0022",
    "B01F 2101/22",
    "B01F 23/024",
    "B01F 23/062",
    "B01F 27/1143",
    "B01F 27/72",
    "B01F 27/80",
    "B01F 33/80",
    "B01F 33/821",
    "B01F 33/84",
    "B01F 35/00",
    "B01F 35/20",
    "B01F 35/21111",
    "B01F 35/2117",
    "B01F 35/2132",
    "B01F 35/2135",
    "B01F 35/2144",
    "B01F 35/2203",
    "B01F 35/71",
    "B01F 35/715",
    "B01F 35/82",
    "B01F 7/00416"
  ],
  "assignees": [
    "FERRING INT CENTER SA"
  ],
  "filing_date": "2018-09-17",
  "publication_date": "2020-07-16",
  "priority_date": "2017-09-18",
  "application_number": "US-201816648372-A",
  "family_id": "59914324",
  "citations": [
    "US3034046A",
    "US3644826A",
    "US8916219B2",
    "US8960997B2"
  ]
}