IN-LINE MEASUREMENT OF FILL SYSTEM

Abstract

The field of the invention relates generally to filling containers with liquid. More specifically, the invention relates to the real-time assessment of the volume filled into containers, particularly in the manufacture of medicaments such as pharmaceuticals. The invention finds specific use in the final stage of drug manufacturing known as fill/finish wherein the drug substance or active pharmaceutical intermediate is prepared as a final drug product in a formulation suitable for administration to patients in need of the same, which is then provided to patients. More particularly, the invention relates to controlling the volume in container via in-line non-destructive monitoring of the fill process.

Claims

1. A method for assessing fill volume during filling of a container comprising a) transferring formulated product from a vessel into the container while measuring hydrodynamic pressure between the vessel and the container, b) calculating the area under the measured pressure vs. time data curve, and c) assessing the fill volume based on a correlation of the calculation from step b) to a previously established standard.

2. The method of claim 1 wherein the volume in the container is not measured by destructive extractable volume testing.

3. The method of claim 1 wherein the fill weight in the container is not measured by at-line or on-line gravimetric fill weight testing.

4. The method of claim 2 wherein the fill weight in the container is not measured by at-line or on-line gravimetric fill weight testing.

5. The method of claim 4 wherein the assessment from step 1c) constitutes the required quality attribute testing for fill weight or fill volume, i.e. as an in-process control or as realtime release testing.

6. The method of claim 1 wherein the transfer is mediated by a peristaltic pump.

7. The method of claim 1 wherein the transfer is mediated by piston pump.

8. The method of claim 1 wherein the transfer is mediated by rotary piston pump.

9. The method of claim 1 wherein the transfer is mediated by timed opening of a pressurized surge vessel, also known as “time-over-pressure” filling.

10. A method for assessing tubing fidelity during filling of a container comprising a) transferring formulated product from a vessel into the container mediated by a peristaltic pump while measuring hydrodynamic pressure between the vessel and the container, and b) assessing tubing fidelity based on a correlation of measured pressure vs. time data to previously establish standards.

11. The method of claim 10 wherein tubing “break-in” is not performed, and fill volume or fill weight is otherwise verified (e.g., by gravimetric weighing) until the previously established standards are achieved.

12. The method of claim 10 wherein the process is interrupted and the tubing is replaced based on the tubing fidelity assessment.

13. The method of claim 11 wherein the process is interrupted and the tubing is replaced based on the tubing fidelity assessment.

14. A method for facilitating process understanding during filling of a container comprising a) transferring formulated product from a vessel into the container while measuring hydrodynamic pressure between the vessel and the container, b) leveraging these data to establish a process signature, drive continuous process improvements, and/or develop risk mitigation strategies.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0023] FIG. 1 shows the typical fill curve for a liquid dispense of a peristaltic pump, showing liquid motion at the nozzle. As the filling needle dives into the primary container, the pump activates in the forward direction of rotation. When the dispense has completed, the pump reverses direction so that some product may be withdrawn back into the needle.

[0024] FIG. 2 shows the Peristaltic pump and tubing set-up showing optional sensor placements. The sensor was initially placed (1) near the filling nozzle, and then moved closer to the pump (2).

[0025] FIG. 3 is a graph showing the typical pressure vs. time output of the sensor capturing a filling stroke.

[0026] FIG. 4 is a graph showing the Pressure vs. Time outputs for various delivered volumes at common pump parameters. Peak pressure is not strongly indicative of dose, rather, it is a result of system geometry and pump parameters

[0027] FIG. 5 is a graph showing the pressure output for individual filling strokes for a range of pump speeds, dispensing a common dose volume.

[0028] FIG. 6 is a graph showing the integrated area-fill weight correlation for a range of fill weights, with a line of best fit

[0029] FIGS. 7A & FIG. 7B are graphs showing the progression of the area-fill weight correlation as the pump tubing is used. After the tubing was installed in the peristaltic pump, the initial 20 dispenses were captured using the pressure sensor in set 1, after which 100 fills were performed without collecting data. This pattern was repeated for sets 2, 3, and 4.

[0030] FIG. 8 In-line pressure data from representative time-over-pressure filling.

DETAILED DESCRIPTION

[0031] Described herein are equipment, processes and methods through which in-process monitoring of fill weight accuracy of a clinical or commercial drug product fill/finish process may be carried out using in-line pressure data.

[0032] Pumps can be used according to the invention that have different mechanical properties. While peristaltic pumps are provided in the current examples, additional pump systems are contemplated within the scope of the invention.

[0033] Peristaltic pumps are understood to include a type of positive displacement, where flexible tubes are fitted inside a circular pump casing. A rotor with lobes, rollers, shoes, or the like are attached to the external circumference of the rotor; these then compress or pinch the flexible tubing and, upon rotor rotation, these physical compressions/pinches force the fluid to flow or pump through the tubing. The compression of the tubing can either be fixed or variable, with the latter mediated by an adjustable spring within the pump head. Further, as the tube opens back to its natural uncompressed state after the passing of the cam, fluid flow is induced to the pump. The process as a whole is known as peristalsis. One of skill the art will recognize many variations of pump systems that will be compatible with the current invention. Other filling systems regularly utilized during the filling of liquid products will be compatible with the current invention, including other positive displacement pumps such as rotary piston and piston pump as well as time-over-pressure systems, which operate via the timed opening of a pressurized vessel.

[0034] Single-use pressure sensors were integrated in-line to the filling process, with the goal of assessing fill nozzle clogging due to product drying. These sensors are typically used in the laboratory as a safety device to flag over-pressurization of a fluid flow system. Through lab-scale filling experiments, several hydraulic observations were made regarding differences in pump output pressure, and the sensors became a source of lab data to track filling performance. For example, placing the sensors very near the filling nozzle provided quantitative data for drug product drying and clogging phenomena, as partially occluded nozzles dispensed material through a smaller flow orifice and saw an increase in line pressure. Eventually, a baseline understanding of pump outputs was obtained, such that pressure measurements could be taken very near the pump outlet and data rationalized to assign features to visualizations of pressure over time.

[0035] Another method of fluid transfer involves pressurizing the headspace of a stainless steel tank with an inert gas or compressed air, with an outlet manifold of flexible tubing enabling filling into the primary container. This tubing passes through a pinch valve, or pincher, which opens and closes to effectively modulate the amount of liquid driven out of the tank by the headspace pressure. The filling approach is referred to as “time-over-pressure” filling and is used throughout the drug product fill-finish industry.

Examples

[0036] The following examples, both actual and prophetic, are provided for the purpose of illustrating specific embodiments or features of the present invention and are not intended to limit its scope.

[0037] For peristaltic filling examples utilized sections of flexible platinum-cured silicone tubing fed through a peristaltic pump, dispensing deionized water from a stainless steel nozzle into a laboratory beaker. This beaker was placed on a laboratory balance and tared before peristaltic filling fill, in order to capture the fill weight of peristaltic filling pump stroke. One experimental set-up using a laboratory-scale Flexicon filling system included surge vessel connections which required 5″ of 4.8 mm I.D. tubing to connect to vessel barb. After the first sensor (barb fittings), 2″ of 4.8 mm I.D. tubing fed a reducer, which was connected to the remaining 17″ of 0.125″ I.D. surge vessel tubing before the first Y-connector. Pressure sensors were located 5″ downstream of surge vessel, 2″ downstream of second Y-connector, and 2″ upstream of nozzle. To begin peristaltic filling experiment, the following procedure was executed:

[0038] Set velocity (300 RPM) and acceleration (200, in proprietary units) and dry run for 2 minutes to break in tubing;

[0039] Set reverse (5, in proprietary units) and prime tubing;

[0040] Calibrate pump for chosen volume;

[0041] Perform 20 fills and record fill weights and pressure sensor data, varying the location of the pressure sensor across experiments;

[0042] Perform many additional fills (e.g., 100) before repeating 20 fill weight measurements.

TABLE-US-00001 TABLE 1 List of peristaltic filling set-up components Item Manufacturer Pt-cured silicone tubing, various diameters Flexicon Stainless steel nozzles Flexicon Pressure sensors Pendotech PD12L peristaltic pump Watson Marlow MC12 pump controller Watson Marlow Luer fittings various Y-connectors, 1.6 mm I.D. various

[0043] Another example with a pilot-scale time-over-pressure filling system utilized sections of silicone tubing with the in-line pressure sensor placed downstream of the pinch valve. The full length of tubing from the pressure vessel to the filling nozzle was 36″, with the pinch valve approximately 7.5″ from the vessel and the pressure sensor 14″ downstream of the pressure vessel. The silicone tubing had 2.4 mm I.D. and 7.1 mm O.D. The automated and integrated calibration and control logic on the pilot-scale time-over-pressure equipment was used, with settings approximately analogous to those used during routine manufacturing. As for the peristaltic filling experiments, 20 fills were measured via both routine fill weight checks and the in-line pressure sensor (see FIG. 8).

TABLE-US-00002 TABLE 2 List of set-up components for time- over-pressure filling experiments Item Manufacturer Silicone tubing, various diameters Saint-Gobain Stainless steel nozzles Groeninger Pressure sensors Pendotech Luer fittings various WDM3100 pilot-scale time-over-pressure Bausch + Ströbel filling system

Results

[0044] From fluid flow theory for flow through a pipe, system pressure drop is directly proportional to flow rate, and, in fill/finish manufacturing, fill volume is a parameter of particular interest. As fill volume is itself an artifact of the flow rate, it is likely that fill weight is also correlated to system pressure drop. However, peristaltic pump rotor motion is typically governed by a programmed speed and acceleration, such that a maximum pressure is reached for all dispenses above a certain fill volume. The pump pressure output oscillates at a certain value until the dose has been dispensed; a larger fill volume would not result in a larger pressure output for the same programmed settings. In this way, a direct correlation between fill weight and pressure drop was not clear from the maximum pressure alone. From experiment, peak pressure itself is not strongly representative of dosing volume. A comparison of several delivered volumes at common pump settings is shown in FIG. 4.

[0045] One approach towards higher pressure data resolution between dispense volumes is utilizing the differences in area under the pressure curves themselves. To perform this task, standard software packages (e.g., Microsoft Excel and Matlab from MathWorks) were used to prepare spreadsheets and scripts to analyze the pressure data, particularly applying the trapezoidal rule of calculus to integrate the area under the curve. This result, in psig-seconds per the units of measure of the in-line pressure sensor, can be plotted for typical alert and action limits for a target fill. This is of particular importance to manufacturing, where very tight statistical process control is necessary: alert limit excursions typically drive process adjustments, action limit excursions typically trigger nonconformances, and the process is monitored against process performance index (Ppk) expectations and for Nelson rule violations. may be utilized. For example, when doing so for fills of 0.3, 0.25, and 0.35 mL, distinct differences in area can be discerned, such that an area measurement from fills outside of these limits could easily be flagged as outliers.

[0046] There is a gap of approximately 0.11 psig-s between the largest 0.3 mL area and smallest 0.35 mL area, and one of approximately 0.18 psig-s between the largest 0.25 mL area and smallest 0.3 mL area. The mean area for the 0.3 mL fills (the fill target) was 1.18 psig-s, such that these gaps represent between 9 and 15 percent of the target area. By this analysis, areas representing fill weights which are outliers can be identified easily—that is to say, relevant differences in fill weight do indeed provide relevant differences in integrated areas. To be able to apply the curve area trend in to fill weights very close to one another was a surprising result.

[0047] When target fills of 0.3, 1.0, and 3.6 mL are plotted together, a linear trendline of the data passes through the origin, confirming the reasonableness of the approach. This range of fill volumes spans a valuable number of pharmaceutical parenteral products manufactured with the filling technologies for which this invention applies, indicating significant potential value for this advance. Furthermore, it stands to reason that the trendline should continue as the fill volume increases.

[0048] The time-over-pressure experiments also indicated that differences in integrated areas could be revealed between manufacturing-relevant fill weights. The in-line pressure data from the time-over-pressure filling experiments differed from the peristaltic filling data in two key regards. First, the overall pressure was lower, with a maximum pressure less than approximately 3 psig. In addition, there was significant noise in the signal at the end of the filling stroke, likely due to the nature of the time-over-pressure filling process in which the pinch valve is abruptly closed to cease flow. Despite these complexities, the mean integrated areas for 0.95 mL, 1.0 mL, and 1.05 mL target fill volume fills were 0.43 psig-s, 0.47 psig-s, and 0.49 psig-s, respectively. Note that, for this analysis, the integration was stopped at the first negative value to avoid the noise at the end of the filling stroke. Moreover, the ranges of integrated areas for each of the 20 target fill volume trials measured did not overlap; that is, the integrated areas for all 20 target 0.95 mL fills were smaller than the integrated areas for all 20 target 1.0 mL fills, which were themselves all smaller than the integrated areas for all 20 target 1.05 mL fills.

Tubing

[0049] Pump tubing used as part of the peristaltic pump manufacturing process can behave differently over prolonged use. New tubing is often specified to require a break-in period before manufacturing, in order to achieve an optimal stiffness and relaxation ability. However, no specific guideline is available as to how long this break-in period should last, nor is quantitative data available to track or suggest an optimal tubing lifespan.

[0050] Based upon the fill weight-area correlation discovered in the preceding section, it was surmised that information available in the pressure curve might provide insight into tubing break-in period, especially if the correlation were tracked over the prolonged use of a tubing set. To proceed, fills were dispensed for a target 1 mL fill and pressure data collected. Four sets of 20 samples were taken, however, 100 fills were dispensed in between data collection, such that set 2 comprised fills #121-140, and so on. Trapezoidal rule areas were computed and the correlations with fill weight calculated.

[0051] From the analysis, the behavior of the tubing can be seen to change over time, as the area/fill weight correlation (measured by r.sup.2) becomes more precise with additional fill strokes. These data document an important process discovery, namely, that tubing performance not only changes over time, but can be quantitatively tracked. It is possible that “break-in” periods might be able to be tracked in real time to an optimal use case. In this same manner, guidance as to when tubing should be discarded can be provided, as determined by a deterioration in the correlation.