Blow-Fill-Seal Expands in Aseptic Filling, Vaccines

“I reference PDA Technical Report 77 because most of us who are used to an isolator or RABS know that you’ll do continuous monitoring for viable and non-viable, and you can also do surface plating either at the end of beginning of the process,” he said. The BFS situation is so different that this is not possible—this is a challenge to some quality groups. It also changes how brands think about environmental monitoring for aseptic filling.

While both filling techniques can run at speeds of approximately 300 to 400 containers/min, there are some parameter differences to note. With BFS, the container is plastic instead of glass, and the relatively tiny critical zone is installed within the machine. “The critical zone or environment for a BFS machine is approximately 36 square inches of space that includes the needles. All this monitoring is outside the parison. Compare that to a medium-sized isolator or RABS which has approximately 2,304 square inches of Grade A environment. Where our needles are located in BFS is not considered grade A,” he said.

Controlling temperature

Vaccines bring temperature challenges, but they can be overcome with careful BFS design. Most vaccines are heat sensitive, and can be out of refrigeration anywhere from 10 hours up to 30 or 70 hours—depending on the product—with a typical target temperature of 2 to 8°C. 

Pauzer said BFS technology has advanced to the point where you can refrigerate or control throughout the product filling. “At the point of dosing, you're merging with a warm parison. The molds are cooled, but you do have to take that into account when you design your facility. Today, you can bring the product right to the point of dosing at a specific temperature.” 

Most vaccines require a range of 2 to 8°C, but this may depend on the product and viscosity. He said most companies try to target 4°C because it allows for variation while staying in the 2 to 8°C window.

Double walled piping for temperature control (Image: IPS)

One design he highlighted includes a double-walled piping system with cooling media circulating through it, which is a fairly new development. Cooling media will depend on the site and country as the U.S. and Europe, for example, differ on which type of glycol is accepted.  He offered the following temperature control considerations:

• Maintain the product temperature in the buffer tank. This improves dosing accuracy.
• Consider a dedicated chilling system. Any reduction in temperature variation reduces risk. “Many companies have a house glycol unit but there's quite a bit of variation in that. What we've learned is if you dedicate a very detailed, designed unit for your blow-fill-seal, it gives you the best results,” Pauzer said. He described a tiered cooling concept with multiple temperature control units, each with a consecutively tighter range to increase control as they stepped down. Three units were individual circuits on the BFS machine, one covering the product tank, one for product piping, and another for the molds.
• Determine how you will evacuate the glycol out of the piping when you need to clean in place (CIP) and steam in place (SIP).
• Consider where safety relief devices within the cooling will be placed. “This is very small tubing… and now you have a jacket on top of it or another pipe around it. We have to get safety devices in because we are now running steam through the inner pipe, radiant energy goes out to the glycol, and it expands the glycol. Again, we’re dealing with a process that was not previously done so this was a first of its kind for us working with a vendor to create this,” he said.
• Pauzer explained they ran into some challenges with piping radiuses, ultimately opting for a complex fabrication process: “Our risk assessment looked at what would happen to the product if it sat for a minute, two minutes, and then what happens to product temperature on continuous flow.”
• In the example he highlighted, valves were not cooled like the tank and long runs of the piping were. They insulated the loop as much as possible, which helps maintaining temperature.

Other challenges when making the switch

Automated inspection brings considerations, particularly because BFS containers are opaque (See sidebar below). “We have industry standards for glass vials and syringes. Even plastic vials are used in automated inspection machines. Inspection standards and criteria will be compared to vials and syringes for comparable products. It’s a different way of thinking,” he said.

The container has the benefit of being flexible, but if it is secondary packaged at a different location, then a tray and rigid container are needed for shipment. 

Companies must establish of a viral boundary. “Closed parison gives you your first level of containment for viral boundary. Now this can be discussed with the quality group, but many companies believe that it is your first level,” he explained. “Then you think about aligning the technology with existing technology—some companies will introduce this technology into a facility that already has a traditional vial and syringe filling line. And you're going to have contrasts on how the viral boundary is managed. For BSL-1 products, this is not too challenging, but as you increase in your biosafety levels you have to take this into account and understand how you're going to manage it.” Finally, most vaccines require a chemical or heat inactivation step. Both are possible because a BFS machine has an integrated CIP and SIP system within it. Pauzer noted, “Some products need a specific chemical. So rather than a cleaning step, you need a true inactivation step before opening the machine up and before going to drain with your product.”

Designing for a POD

The height of the BFS system for the highlighted project required IPS to use a double stacked POD, referred to as a “high hat” configuration. (Image: IPS)A POD is a prefabricated clean room which can be transported to a facility, using a truck, plane or ship. The room is completely built in a factory, with wall panels, doors, and even some equipment and furniture, then loaded and shipped. One critical factor not to be overlooked is the sheer weight of a BFS system. The base or foundation has to be strong to support it. “When you combine all the equipment within a POD, it's 31,000 pounds—the filler itself is 28,000 pounds. We're talking about a unit that's nominally 14 feet high, 10 feet wide, and 20 feet long,” he said. “The challenge also is that is just your filling machine. You have to include in any air handling, ductwork, lighting and structure above it.”  

The height of the BFS system for the highlighted project required IPS to use a double stacked POD, referred to as a “high hat” configuration to accommodate the two levels. (They only extended the second level where the BFS was.) The location of the BFS machine within the POD needed to be strategically chosen because it had to be moved into place.

Adding a needle

Dealing with COVID-19, the industry as a whole has been figuring out on the fly how to get mass doses out to the public. “For years, the industry has been moving away from multi-dose containers. Vaccines used to be distributed 10 doses per vial and the doctor's office would draw out one container. There has been a push to go to single-dose prefilled syringes—it reduces the doctor making that manipulation and multiple entries into one container,” he said.

Using BFS technology, the syringe barrel is a multi-chamber container that's fabricated immediately, and a company can attach the needle right then—the concept is a BFS container, a connector and a needle. “You can fill, form, and assemble in one process step. Because we're using BFS containers, it reduces the weight and if you can remove a processing step, you can get to the market quicker,” he said. With COVID-19, every week or month matters, but for any vaccine or life-saving medication, speeding output means getting to patients in need faster.

The 2021 PDA Annual Meeting is full of on-demand content on aseptic filling, flexible facilities, vaccine considerations, cell therapies, and more. Presentations and Q&A videos will be available through May 16, 2021. Register here.