Biopharmaceutical Manufacturing Using Blow–Fill–Seal Technology - The authors give special consideration factors affecting blow–fill–seal technology. - BioPharm International


Biopharmaceutical Manufacturing Using Blow–Fill–Seal Technology
The authors give special consideration factors affecting blow–fill–seal technology.

BioPharm International
Volume 24, Issue 7, pp. 22-29

Product temperature in a BFS process

One of the major challenges for the BFS operation compared with a conventional filling process is the high temperature involved in the plastic extrusion step. As illustrated in Figure 1, the plastic granules are melted and extruded at temperature in excess of 160 C. The hot parison will come into contact with a metal mold, be transported to the filling shroud, and be filled with drug product. Cool water circulating inside the mold helps to lower the ampul temperature. The cooling process, however, is limited by the contact time between the ampul and the mold (a total of about 10 s). In addition, the ampul cooling is restricted by the minimum temperature needed to form a hermetic seal at the end of the filling step. The ampul temperature near the neck area has to remain high enough to ensure an appropriate seal at the end of the filling process.

In the development phase of a biological drug product, when using a plastic ampul as the primary container, it is important to understand the temperature to which the product could be exposed. The folded conformations of proteins are only marginally stable, and a rise in temperature can denature the molecule leading to loss of activity. Elucidating the temperature profile during the BFS process will enable formulation scientists to develop more robust formulations.

In a BFS manufacturing process, product temperature during the filling process is not an easily controlled parameter, and it cannot be directly measured. Instead, the controllable parameters are the starting-product solution temperature in the bulk tank, plastic extrusion temperature, mold-cooling water temperature, and the cycle time for each BFS step (e.g., molding, filling, and sealing).

The authors have used a computational fluid dynamic (CFD) model (ANSYS Fluent 12) to simulate the BFS process using the Pulmozyme ampul as a model. Initial simulation results (not shown) showed that ampul-wall temperature reaches mold temperature quickly (within 1 s) during Step 2 of Figure 1. If the actual mold temperature is at cooling-water temperature (usually near room temperature of ~ 25 C), the finished ampuls at the end of BFS process should not be significantly hotter than the mold cavity. It is the authors' experience, however, that product ampuls usually feel warm right after the BFS process. This observation suggests that the actual mold temperature is much higher than the cooling-water temperature (the actual mold temperature during BFS production is not usually measured).

Figure 3: Simulation of product temperature in a blow–fill–seal process.
For the purpose of the CFD simulation, the authors adjusted the mold temperature to different settings. Figure 3 illustrates the product-temperature profile when the mold temperature was set at 60 C. The simulation assumes that it takes approximately 11 s for the entire BFS process including ~3 s for the molding step, ~3 s for filling, and ~5 s for forming a hermetic seal. The upper portion of Figure 3 shows the liquid volume in the ampul, as it is being filled (from time = 3 s). The temperature profiles of the entire ampul (including wall, solution, and air) throughout the filling and sealing step are shown in the bottom sequence of Figure 3. It should be noted that in the actual manufacturing process, the filling nozzle is retracted from the ampoule after filling is complete to allow for sealing. Since this is a nonproduct contact part the current CFD simulation simply turns off the solution flow from the inlet nozzle, instead of modeling the actual nozzle retraction.

The simulation revealed that the ampul is cooled from the initial extrusion temperature of ~160 C to 60 C (assumed actual mold temperature) in less than 2 s. Forced convection dominates heat transfer during filling (from 3 s to 6 s), thereafter natural convection becomes more prominent. By the time the filled ampul was ejected from the mold (~ 11 s), only the fluid layer near the ampul walls had been heated to within 10 C of the mold temperature. The majority of the liquid remains considerably cooler.

In the current simulation the authors assumed a worst-case scenario of liquid being filled at ~25 C. In the actual production process, the drug substance is typically maintained at 2–8 C and would be introduced in the ampoule close to these temperatures. Therefore, in a production BFS process, it is expected that the drug substance would experience temperatures that are lower than these shown in the CFD simulation results.

Based on the observation of higher actual mold temperature compared with that of the cooling water from the simulation results, it is highly recommended to monitor the actual mold temperature during the development or characterization phase of the BFS process. Monitoring could potentially be achieved by attaching thermocouples to the mold or by infrared temperature measurement of the mold surface.

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