Make it Clean & Make it Sterile

Edition 5, May 2024.

For the second installment in the Fill/Finish Process Series we’ll start with the preparation of the primary container. Usually made of glass, the container needs to be prepared for filling for an injectable product by cleaning and sterilizing it.? It’s worth noting Ready to Use containers (like most pre-filled syringes) arrive at the pharmaceutical factory ready to be filled, so manufacturers don’t have to complete these steps in house, rather they are completed by the container supplier.? I’ll walk you through the washing and sterilization steps you would expect for a glass vial as the example.? The process for different container materials and styles will vary.

Clean & Sterile Containers

The goal of the washing process is to remove particles and contamination from the glass surface, such as glass dust, metal, oils or lubricants.

The washing of containers starts with the unpacking of the vials and feeding them into the washer. ?At this stage the clean room can be a Grade C environment. The glass vials are usually supplied in patterned bricks or trays, the operator places them at the infeed area, unwraps or opens the tray. Depending on the packaging type and orientation, a pack rotation table is helpful to remove the outer shrink wrap packaging.? The containers are then pushed onto an infeed conveyor.? This conveyor can be flat, leading to a turntable which will singulate the container. Or if the container is unstable, or the user requires an ultra-sonic bath, the infeed conveyor will be sloped into the water bath. ?If using an ultra-sonic bath the containers are fed into a screw and singulated while in the bath, they are then lifted and rotated to remove any water inside the container.

Once the container is captured and inverted to have the opening down, they enter the cleaning area.? The container will go through multiple cycles of cleaning, rinsing, and finally drying.? Different cleaning media is used at different stages and can be designed to use what is most suitable for the required cleaning. For example, some containers may require cleaning detergents to remove oils from the glass production.? The initial wash is usually with recycled Water-for-injection (WFI).? This will wash the inside and outside of the container.? Process air may be used to remove particles and any remaining liquid. Then at the final rinse station WFI is used for the to make sure any contamination is removed.? Process air is used again to dry the inside and outside of the vial.?

After the washing phase, siliconization for the inside of the container may be needed.? This is usually the case for glass cartridges, and occasionally vials or other special situations.? This would be part of the washing machine after the air dry, liquid silicone is precisely sprayed onto the interior surface of the container.? The dry heat of the depyrogenation process is also used to cure the silicone.

After the vials are clean and dried, they enter the Depyrogenation tunnel.? It is important that the vials are dry after washing, otherwise this process can be affected.? The goal of the depyrogenation step is to breakdown any cellular remains which may be on the surface of the glass. A reduction of endotoxin levels on the vials by a factor or 1,000 – a 3 Log reduction, is required, though most processes go well beyond.? This is achieved by exposing the glass containers to a temperature of 250°C for a set period.?

The depyrogenation tunnel is a continuous process which takes vials from the washer at the infeed, passes them through the tunnel on a moving stainless steel conveyor to the filler.? The vials are in single file from the washer, and in a bulk formation in the depyrogenation tunnel.? Special handling and pressure monitoring is used to ensure the vial pack is not too dense causing glass breakage. The depyrogenation tunnel uses filtered air and heating elements to heat and recirculate the air through the system. ??The vials are exposed to a pre-heating section, then brought to full temperature, then cooled before the exit.? The vials must be brought down to a temperature suitable for the liquid product prior to being filled. ?Throughout the entire process the depyrogenation tunnel maintains an overpressure towards the room – this ensures the Grade C air does not enter the tunnel or the grade A filling environment.

This process can also be achieved in a dry heat oven in a batch process, however manually transporting sterile containers is rather difficult, as a grade A environment must be maintained between depyrogenation and filling.

Once out of the depyrogenation tunnel the vials enter the Grade A environment with laminar air flow. The vials usually enter a turntable in order to pass get them single file for the filling process.

Hopefully I haven’t bored you to tears with this super dry and sterile topic - I’ll cover the filling process next month!

In the Rearview…

April was a bit of a whirlwind. I spent a few days in Canada visiting customers with a colleague from Germany.? We visited one customer as they wrapped up the SAT for their new vial filling line from Syntegon.? ?It’s an exciting time to see a project and facility start to come together.? I spent a week in Manhattan for the Interphex show. We showcased our Microbatch Gloveless Isolated filling system at the booth, and I was able to meet with a bunch of customers and potential new ones.? I’m still buried in follow up tasks, so bear with me!?? After Interphex I spent a week in Hilton Head with the family enjoying the beach and pool in the sunshine. Then just on Tuesday I stopped by CPHI in Philadelphia.

Looking Ahead

I’ll be working hard through May on a few major projects and initiating a few new ones.? The industry seems to be gaining steam heading into the summer. I am also looking forward to being at our factory in Germany in June for an FAT of an isolated vial line.

-Mike Kerbaugh