Advanced aseptic blow-fill-seal (BFS) packaging technology has been around for almost 100 years, and it historically has been used for liquid filling of primary containers for solutions, suspensions, and emulsions. While the technology is popular within the ophthalmic and respiratory segments of the healthcare industry, organizations have been hesitant to use BFS for biologics and large molecule formulations due to those products’ thermal sensitivity and concerns about the heat that is naturally generated during the BFS process—but that is changing. One reason for the change is that the biopharma industry is growing, and more biomolecules are being introduced to the market. With the greater volume, organizations are looking for ways to stand out from competitors and are investigating other forms of drug delivery, such as BFS. The other contributing factor is recent advancements to BFS that have made the process a viable option for thermally sensitive drugs, including biologics.

BFS technology

Blow-fill-seal packaging technology is a method where a container is formed, filled with product, and then sealed in a sterile environment. The whole process takes seconds to complete, and what comes out is a fully sterile finished product.

Looking at the BFS process in more detail, thermoplastic polymer pellets are fed into an extruder that creates a polymer melt. The melt is continuously extruded through a die into a tubular shape called a parison. When the tube reaches the proper length, the mold closes, and the parison is cut. The bottom of the parison is pinched closed, and the top is held in place with a set of holding jaws. The mold is then transferred to a position under the filling station.

Fill nozzles lower into the parison until they form a seal with the neck of the mold. Container formation is completed by applying vacuum to the exterior of the container and by blowing filtered air into the interior. The electronic fill system then dispenses a specified, metered quantity of product into the container.¹

BFS is considered a good presentation for many drugs, including biopharmaceuticals, as sterility is critical to prevent microbial contamination. When BFS packaging is employed, the steps in the process inherently reduce microbial contamination because the controls and monitoring systems on BFS machines are sophisticated and multilayered. A sterile environment is maintained throughout the manufacturing process.

When transitioning to BFS from packaging with traditional glass vials, stoppers, crimp tops and the other closures that are involved with glass packaging are removed. That means BFS containers do not have to go through the cleaning steps that are needed with glass vials, and there are no material treatment steps (e.g. glass depyrogenation) for BFS packaging.

The BFS process also takes place completely inside the cabinet of a machine that is continually monitored for viable and non-viable particulate, and there is a constant, positive pressure shower of HEPA-filtered air that covers the filling section of the BFS machine. With those controls in place, and the automation of the BFS machine, the need for human intervention—or even operation of the machine itself—is virtually eliminated. This is a distinct advantage, as human intervention is the biggest cause of contamination.

An additional advantage of BFS technology is that it can be used to mold a container into unique delivery systems to achieve specific therapeutic solutions while attaining a superior level of filling accuracy. Any kind of form that can be imagined can be molded using BFS, and the designs can serve both market-differentiation and functional purposes.

There are also logistical advantages to consider. BFS molded containers are break-resistant/shatter-resistant, which introduces more tolerance for freezing conditions and far less risk for damage during shipment. Shipping benefits from lighter per-unit weights of BFS containers as compared to glass as well.

Scale up of manufacturing using BFS is also easier. BFS machines produce in various sizes to meet customer needs—a pilot-scale machine can produce one parison at a time for limited volume programs, while larger machines can produce 10 to 24 parisons at a time to satisfy full commercial production. The filling process is the same and the mold is exactly the same, just replicated. Paper dolls provide an appropriate analogy—as a pilot production is scaled up to full commercial production, additional cutouts are added to the strand.

While BFS is capable of manufacturing multidose dropper bottles, manufacturers expanding their product portfolio may want to move to a preservative-free formulation for their product, and single-use BFS containers present a great option. Single-use containers are convenient, don’t need to be kept track of, and don’t need re-capping. Preservative-free packaging has patient benefits too, especially in the ophthalmic area, where the presence of preservatives can cause irritation.

History of BFS packaging with biologics

As mentioned above, BFS is widely used in respiratory and ophthalmic markets, and it also is popular with topical, otic and oral healthcare products. While it is currently not the packaging option of choice for biologics and large molecules, real-world use of BFS has already proven it to be a practical solution for decades. BFS has been used to successfully package drug products to treat, cystic fibrosis, and other diseases.

What is more, BFS has also fared well in research comparing it with traditional glass vial packaging. In one study a model monoclonal antibody (mAb) product was filled into BFS containers and glass-filled vials. The mAb was put through a series of 16 analytical and biological tests to determine how mAb responds to the BFS process as compared to glass, using the drug product in a bulk solution as the baseline. Size-exclusion chromatography (SEC) analysis found that the product in both its pre- and post-fill states showed comparable percentages of high-molecular-weight using either glass or BFS packaging. Capillary isoelectric focusing (cIEF) analysis at T=0 also showed comparable charge distributions between the two packaging options. This shows us that the antibodies in the solution are not changing as they pass through the BFS process, even during bottle formation and the inherent implications associated with heat.²

In an extension of the same study, a two-year profile was completed to test the stability of the mAb formulation in BFS versus glass vials. The data from both the glass and BFS vials were virtually identical, and what was particularly encouraging was that even after the protein underwent chemical digestion, the molecular weights were still virtually identical between the two container materials. The biological activity in the mAb whether it was in glass or BFS, showed again that it was virtually identical. This gives us a high level of confidence that not only does a biologic formulation survive the initial filling process as demonstrated in the earlier study, but even at a two-year stability all the metrics are virtually identical for BFS compared to glass.³

Using BFS for thermally sensitive products

While BFS has demonstrated it is a viable option for packaging of large molecule formulations and biologics, including vaccines, proteins, monoclonal antibodies, there is still great opportunity for growth in the market. Many biomolecules are heat sensitive, and there are many proteins that can denature or degrade with heat which could lead to a loss of activity, so the biopharma industry has stayed away from BFS for the most part, preferring to package with glass, a tried-and-true option.

Woodstock Sterile Solutions has developed a new process for manufacturing temperature sensitive drug products that incorporates a combination of manufacturing techniques to help control the amount of heat that is imparted onto a drug product to mitigate its effects. During the typical BFS process, there is naturally quite a bit of heat involved because raw resin is being melted to make bottles. Low density polyethylene, for example, must be heated to temperatures of 170- to 180-degrees Celsius in order to form a melt. The temperature of the flash (the resin that is squeezed outside of the mold during container formation) can be as warm as 120-degrees Celsius, and the bottle itself has been measured at about 70-degrees Celsius.

Throughout this process there are opportunities to address the temperature and heat that is generated. For starters, the process tank can be kept at a refrigerated temperature – at 2- to 8-degrees Celsius. The lower the temperature of the product, the lower it will be at the end of the process. As the bottle is formed, controlling the tare weight helps to reduce the amount of thermal energy generated during the process. The more plastic there is, the more heat is retained, so tuning the tare weight, which is measured by wall thickness, helps control the amount of heat produced.

The process timing can also be manipulated, including adjusting the amount of time the formed bottle is held inside the mold. The mold itself has chilled water flowing through it to quench the plastic from its molten form in the parison to a vial that has structural integrity. The longer the formed bottle is held in the mold, the more it will quench and the more the temperature will drop. There is an optimization point that needs to be met because if the bottle is quenched too much, or the temperature is reduced too dramatically, the bottle will be compromised and difficult to seal.

There is also a relationship between the bottle and the fill volume. The larger the fill volume, the greater the heat capacity of the product. Greater heat capacity provides more resistance to temperature changes within the bottle.

Testing was conducted to determine the effectiveness of the using the BFS process for temperature-sensitive drugs, using bottles with tare weights of 1.75 grams and 1.4 grams in both ambient temperature and refrigerated temperature. Predictably, the final product temperatures were lower for bottles with lower tare weight in both ambient and refrigerated temperatures, and refrigerating the holding tank also lowered the temperature in the final product. The clearest correlation was the comparison of different fill weights. When the fill weight was increased, there was a steady decline in the temperature of the finished ambient and refrigerated bulk product.

The lowest observed temperature of the finished bulk product using the BFS process was around 22-degrees Celsius. The maximum temperature of any combination of parameter settings was approximately 40-degrees Celsius. The results from this study should alleviate any concerns that manufacturers have with using the BFS process for packaging of biologics and large molecules, and it is expected that its use will continue to expand in the near future. Before implementing BFS technology, however, there are factors to consider.

The first is the drug product’s compatibility with plastic, including concerns about adsorption or absorption. Plastic containers are permeable whereas glass is not, and it is critical to understand if that will have an impact on the product throughout its shelf life. However, permeation—whether it’s water vapor moving out or oxygen moving in—can be mitigated in order to maintain the quality of the product inside. Mitigation can be achieved through aluminum pouching, the use of nitrogen in secondary packaging, or through the inclusion of oxygen scavengers in secondary packaging.

Another consideration is the viscosity of the product. While BFS can be used to fill liquids that are as viscous as ointments, the filling process becomes more challenging the more viscous the product. Pushing high viscosity materials through piping, filling manifolds, and other parts of the system requires carefully controlling machine parameters.

The biopharma industry is working to deliver drug products to patients with the highest quality possible, and as biomolecules comprise a growing portion of the drug products available on the market, the use of BFS will continue to increase. Cutting-edge protein and genomic drug therapies introduce unexplored territory and a bigger playing field for BFS in the future. 

References

1. Wong, Waiken; Khine, Wendy, “Complex Liquid Formulations: Solutions for Scale-Up Challenges”, Pharmaceutical Technology ebook, “BFS Solutions for Inhaled and Biologic Therapies”, July 2020.
2. Shah, Dipesh, et al., “Compatibility Assessment of a Model Monoclonal Antibody Formulation in Glass and Blow-Fill-Seal Plastic Vials”, BioProcess International, 15 Oct 2015, https://bioprocessintl.com/manufacturing/formulation/compatibility-assessment-of-a-model-monoclonal-antibody-formulation-in-glass-and-blow-fill-seal-plastic-vials-2/, Accessed 31 Aug 2022.
3. Shah, Dipesh, et al., “Compatibility Assessment of a Model Monoclonal Antibody Formulation in Glass and Blow-Fill-Seal Plastic Vials”, BioProcess International, 15 Oct 2015, https://bioprocessintl.com/manufacturing/formulation/compatibility-assessment-of-a-model-monoclonal-antibody-formulation-in-glass-and-blow-fill-seal-plastic-vials-2/, Accessed 31 Aug 2022.

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Dr. Waiken Wong is Manager, Product Development Engineering at Woodstock Sterile Solutions, where he leads a team of engineers and scientists performing contract pharmaceutical development and manufacturing.